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THE FAMILY AND DISEASES OF KING DAVID

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THE FAMILY AND DISEASES
OF KING DAVID

Medical Research in Biblical Times


from the Viewpoint of Contemporary
Perspective

Liubov Ben-Nun
The research is composed of two parts: the first studies the family
system of King David, the roots of his family, the development of this
system and its subsystems, the structure and its expansion, the
dynamics of the family, and the relationships between family
members and the external world. The second part examines the
medical record of the King that is the biblical text, evaluating the
most likely diagnoses of the diseases that afflicted the King from the
viewpoint of contemporary medicine.

About the Author


Dr. Liubov Ben-Nun, the Author of dozens Books and Articles that have
been published in scientific journals worldwide.
Professor Emeritus at Ben Gurion University of the Negev, Faculty of
Health Sciences, Beer-Sheva, Israel. She has established the "LAHAV"
International Forum for research into medicine in the Bible from the viewpoint
of contemporary medicine.

NOT FOR SALE


THE FAMILY AND DISEASES
OF KING DAVID
Liubov Ben-Nun
Professor Emeritus

Ben-Gurion University of the Negev


Faculty of Health Sciences Beer-Sheva, Israel

50th Book.
Published By B.N. Publication House, Israel
First Edition (in Hebrew) 2003
Second Edition 2006
Third Edition 2009
Fourth edition 2015

Fax: +(972) 8 6883376 Mobile 050 5971592


E-Mail: L-bennun@Smile.net.il
Printed in Israel. 2015
Distributed Worldwide
Graphics and Cover: Carmela Moshe

King David.
Bolognese artist Guercino 17th century.

© All rights reserved

NOT FOR SALE


MEDICAL RESEARCH IN BIBLICAL TIMES
FROM THE VIEWPOINT
OF CONTEMPORARY PERSPECTIVE

BIBLICAL EXEGESIS
It should be noted and stressed that this research is
in no way concerned with a discussion of any
interpretations of the Bible by the great commentators
such as Rambam, the sages of the Talmud and the
Mishnah, or interpretation based on knowledge of the
ancient world found in Julius Preuss’ book. The
research is based solely on the actual words on the
verses of the Bible.
CONTENTS

MY VIEW 1
A PERSONAL ACCOUNT 2
PREFACE 2
FOREWORD 3
THE FAMILY LIFE CYCLE 9
THE ROOTS 10
OBED – THE GRANDFATHER OF KING DAVID 10
JESSE'S FAMILY 10
THE BATTLE WITH GOLIATH 10
DAVID AND KING SAUL'S FAMILY 12
KING SAUL 12
JONATHAN 15
DAVID'S FAMILY 15
DAVID, MERAB, AND MICHAL 15
A NEW FAMILY 17
THE KING OF JEHUDA 21
POLYGAMOUS FAMILY 21
THE KING OF ISRAEL 26
THE AFFAIR OF BATHSHEBA 26
UNPROTECTED SEXUAL CONTACTS 27
CONDOMS 36
FAMILY SYSTEM THEORY 39
A NEW COMPOSITION OF THE KING'S FAMILY 41
DEATH OF A NEWBORN SON 41
BIRTH ASPHYXIA 43
LOW/VERY LOW BIRTH WEIGHT 44
PREMATURITY 45
INTRAUTERINE GROWTH RETARDATION 47
PREMATURE RUPTURE OF MEMBRANES 48
CONGENITAL MALFORMATIONS 49
SEPSIS 52
MENINGITIS 53
NECROTISING ENTEROCOLITIS 54
DIARRHEA 55
NEONATAL TETANUS 56
MALARIA 58
MEASLES 59
SYPHILIS 60
RESPIRATORY DISTRESS SYNDROME 62
SUDDEN INFANT DEATH SYNDROME 64
HOME BIRTH 66
SOCIOECONOMIC STATUS 67
THE MOURNING PROCESS 69
FAMILY GROWTH 73
THE WARRIOR 74
DAVID'S SONS THE CHIEF RULERS 74
MEFIVOSHET – A NEW FAMILY MEMBER 74
AMNON 79
EATING DISORDERS 79
ANOREXIA NERVOSA 87
PARTIAL SYNDROMES OF EATING DISORDERS 88
FOOD AVOIDANCE EMOTIONAL DISORDERS 90
PRIMARY DEPRESSION 91
EATING DISORDERS NOT OTHERWISE SPECIFIED 93
CLINICAL PHENOMENON OF SELF-HARM 95
TAMAR AND AMNON 98
SEXUAL ASSAULT 99
EPIDEMIOLOGY 100
RISKY SEXUAL BEHAVIOR 108
INTIMATE PARTNER SEXUAL VIOLENCE 114
SEXUAL ABUSE IN THE WORKPLACE 118
MILITARY SEXUAL TRAUMA 122
CHARACTERISTICS OF SEXUAL ASSAULT 127
INJURIES ASSOCIATED WITH SEXUAL VIOLENCE 135
REPRODUCTIVE HEALTH AND PREGNANCY 139
SEXUALLY TRANSMITTED DISEASES 143
PSYCHOLOGICAL CONSEQUENCES 147
POSTTRAUMATIC STRESS DISORDER 152
SEXUAL ASSAULT CENTRES 155
FAMILY FUNCTIONING 158
AN ANCIENT VICTIM 159
REVENGE 160
MOURNING FOR AMNON 161
ABSALOM 164
CLASSIFICATION OF HEART INJURIES 165
ABSALOM'S REBELLION 166
PENETRATING HEART INJURIES 166
THE RELATIONSHIP BETWEEN ABSALOM AND KING DAVID 168
ABSALOM'S PERSONALITY 170
FAMILY ASSESSMENT 170
MOURNING FOR ABSALOM 171
THE FATE OF CONCUBINES 174
THE GIBEONITES 176
STRESSFUL LIFE EVENTS AND SUBSEQUENT CRISES 178
SUMMARY OF FAMILY LIFE CYCLE 180
THE DISEASES THAT AFFLICTED THE OLD KING 184
THE OLD KING 185
EYE DISEASES 185
THE BIBLICAL DESCRIPTION 187
EPIDEMIOLOGY OF BLINDNESS 188
AGE-RELATED MACULAR DEGENERATION 199
TYPES 201
EPIDEMIOLOGY 202
RISK FACTORS 207
SYMPTOMATOLOGY 209
CATARACT 210
RISK FACTORS 216
SYMPTOMATOLOGY 218
GLAUCOMA 219
TYPES 220
EPIDEMIOLOGY 220
MECHANISMS OF THE DISEASE 224
SYMPTOMATOLOGY 225
DIAGNOSIS 226
OPTIC NEUROPATHY 230
OPTIC ATROPHY 233
REFRACTIVE ERROR 239
OCULAR MANIFESTATIONS OF CANCER 245
OTHER CAUSES 258
THE DISEASE OF THE BONES 268
THE BIBLICAL DESCRIPTION 268
OSTEOPOROSIS 268
TYPES 273
MALE OSTEOPOROSIS 276
CUSHING SYNDROME 277
HYPERTHYROIDSM/HYPOTHYROIDISM 278
ACROMEGALY 281
HYPOGONADISM 285
PRIMARY HYPERPARATHYROIDISM 289
PAGET'S DISEASE 292
LACTASE DEFICIENCY 297
BILIARY CIRRHOSIS 299
WHIPPLE DISEASE 303
CHRONIC OBSTRUCTIVE LUNG DISEASE 306
RHEUMATIC DISEASES 309
RHEUMATOID ARTHRITIS 310
MALNUTRITION 313
MEDICATIONS 315
IDIOPATHIC 318
ONCOHAEMATOLOGICAL DISORDERS 320
MULTIPLE MYELOMA 321
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE 327
WALDENSTROM MACROGLOBULINEMIA 328
HEAVY CHAIN DISEASES 330
SMALL LYMPHOCYTE CELL DISORDERS 332
OSTEOMYELOFIBROSIS 335
AMYLOIDOSIS 340
PLASMACYTOMA 346
OTHER MALIGNANT DISEASES 349
LUNG CANCER 349
GASTRIC CARCINOMA 353
COLORECTAL CANCER 356
HEPATOCELLULAR CARCINOMA 359
PANCREATIC CANCER 363
GIANT CELL TUMOR 368
LEPTOMENINGEAL CARCINOMATOSIS 371
RENAL CELL CARCINOMA 372
PROSTATE CANCER 376
BLADDER CARCINOMA 380
METASTATIC BONE DISEASE 384
CLINICAL FEATURES 388
HAS THIS PATIENT CANCER? 394
THE DISEASE THAT CAUSED WEIGHT LOSS 395
INTRODUCTION 395
WEIGHT LOSS AS DESCRIBED IN THE BIBLE 396
CACHEXIA 396
WEIGHT LOSS IN THE ELDERLY 400
PHYSIOLOGICAL ANOREXIA OF AGING 403
PATHOLOGICAL CAUSES OF WEIGHT LOSS 406
THE DISEASE THAT CAUSED CHRONIC WEAKNESS 411
INTRODUCTION 411
WEAKNESS AS DESCRIBED IN THE BIBLE 411
DEFINITION 412
GENERAL WEAKNESS 412
FATIGUE IN CANCER PATIENTS 414
ANEMIA OF CHRONIC DISEASES 418
CANCER-RELATED ANEMIA 421
HYPOTHERMIA 424
INTRODUCTION 424
HYPOTHERMIA AS DESCRIBED IN THE BIBLE 425
ABNORMAL PHYSIOLOGIC MECHANISMS 425
TYPES OF HYPOTHERMIA 426
ENVIRONMENTAL HYPOTHERMIA 427
URBAN HYPOTHERMIA 429
CLINICAL STAGES 430
ADDITIONAL SIGNS 432
WAS THE KING'S TEMPERATURE TAKEN? 432
EKG CHANGES 433
HYPOTHERMIA IN THE KING 433
THERAPY 434
PRESSURE ULCERS 436
SKIN ULCERS AS DESCRIBED IN THE BIBLE 437
DEFINITION 437
MECHANISM OF DEVELOPMENT 438
EPIDEMIOLOGY 440
HOSPITAL COST 443
CLASSIFICATION 443
EUROPEAN PRESSURE ADVISORY PANNEL 443
MAKLEBUST & SIEGGREEN CLASSIFICATION SYSTEM 444
PRESSURE ULCER PAIN 444
MALODOROUS WOUNDS 446
RISK FACTORS FOR PRESSURE ULCERS 449
DIFFERENTIAL DIAGNOSIS 454
ERECTILE DYSFUNCTION 455
INTRODUCTION 455
THE BIBLICAL DESCRIPTION 456
DEFINITION 456
EPIDEMIOLOGY 457
ETIOLOGY 460
KING DAVID'S CASE 467
MENTAL DISORDER 470
INTRODUCTION 470
HISTORICAL BACKGROUND 471
PSYCHIATRIC EPIDEMIOLOGY 472
DEPRESSION 477
CRITERIA FOR MAJOR DEPESSION 483
SUBSTANCE-INDUCED MOOD DISORDER 484
GENERAL MEDICAL CONDITION 485
DYSTHYMIC DISORDER 486
MINOR DEPRESSION 488
STRATEGIES FOR DIAGNOSING DEPRESSION 490
MECHANISM OF DEPRESSION DEVELOPMENT 492
OUTCOME 497
GENERALIZED ANXIETY DISORDER 502
SUMMARY OF MEDICAL RECORD 506
ABBREVATIONS 507
PICTURES 513
1
L. Ben-Nun King David

MY VIEW

MEDICINE IN THE BIBLE AS A RESEARCH CHALLENGE

This is a voyage along the well-trodden routes of contemporary


medicine to the paths of the Bible, from the time of the first man to
the period of the People of Israel. It covers the connection between
body and soul, and the unbroken link between our earliest ancestors,
accompanied by spiritual yearning and ourselves. Through the verses
of the Bible flows a powerful stream of ideas for medical research
combined with study of our roots and the ancient texts.
It would not be too adventurous to state that if there is one book
in the world that all Jews are proud of, that is the Book of Books, the
greatest classic among all literary works, whose original language is
not Greek or Latin, but the Hebrew that I and other Israelis speak
every day, our mother's tongue, the language of Eliezer Ben Yehuda.
The Bible exists as evidence in the Book of Books, open to all
humankind. For thousands of years it has been placed before us, still
as fresh as before, the history of peoples who have disappeared and
of the Jewish people, which has survived with its Holy Text that has
been translated into hundreds of languages and dialects, and remains
our eternal taboo.
Many people ask me about the connection between the Bible and
medical science. My reply is simple: the roots of science are buried
deep in the biblical period and I am just the archeologist and medical
researcher. This scientific medical journey to the earliest roots of the
nation in the Bible has been and remains moving, exciting and
enjoyable. It has created a kind of meeting in my mind between the
present and those Ancient times, through examining events frozen in
time.
Sometimes it is important to stop, to look back a little. In real time,
it is hard to study every detail, because time is passing as they appear.
However, when we look back we can freeze the picture and examine
every detail, see many events that we missed during that fraction of a
second when they occurred.
The Book of Books, the Bible, is not just the identity card of the
Jewish, but an essential source for the whole world.
2
L. Ben-Nun King David

A PERSONAL ACCOUNT
When I arrived in Florence and saw the statue of David, I was
thrilled by the wonderful figure, and said to myself: how could a
mortal sculpt such an amazing figure, with such perfection of beauty
that seems to be alive? The sight gave me inspiration to learn more
about this giant character in the Bible, using all aspects of
contemporary medical science.
From the top of the Tower of David in Jerusalem, a symbol of the
rebirth of the Jewish people in the promised land, I set myself the
goal of diagnosing the state of health of King David, a character who
influenced the fate of the Jewish people, but solely according to the
actual text of the biblical verses, with no traditional interpretation,
from the viewpoint of contemporary medicine.

PREFACE
The purpose of this research is to analyze the medical situations and
conditions referred to in the Bible, as we are dealing with a
contemporary medical record.

These are scientific medical studies incorporating verses from the


Bible, without no interpretation or historical descriptions of places.

Fundamentally, this Research is constructed purely from an


examination of passages from the Bible, exactly as written.

The research is part of a long series of published studies on the


subject of biblical medicine from a modern medical perspective.

This is not a laboratory research. The Research is built entirely on a


secular foundation. With due to respects to people faith, this Research
takes a modern look at medical practices. Each to his own beliefs.
3
L. Ben-Nun King David

FOREWORD
Every society is age graded, and every society has a system of
social expectations regarding age of appropriate behavior. The
individual passes through a socially regulated cycle from birth to
death as inexorably as he passes through the biological cycle: a
succession of socially delineated age-statuses, each with its
recognized rights, duties and obligations. There exists a socially
prescribed timetable for the ordering of major life events: a time in
the life span when men and women are expected to marry, a time to
raise children, and a time to retire. Men and women are aware not
only of the social clocks that operate in various areas of their lives,
but also of their own timing with regard to major life events. From
this perspective, time is at least a three-dimensional phenomenon in
charting the course of the life cycles, with historical time, lifetime (or
chronological age) and social time all intricately intertwined (1).
Family is defined as any group of people related either
biologically, emotionally, or legally (2), and is a basic structure of
each society. This structure is the most important small social system
that has survived through generations. During long human history,
the family adapted to the norms of each society, and its functioning
depended on the norms of each specific society.
Man has survived in all societies by belonging to aggregates that
vary in different cultures in their level of organization and
differentiation. It is an inherent and basic human condition that man
survives in groups, and the family is the most enduring social form of
small group. Primitive cultures rely on large groupings with relatively
stable distributions of functions among subgroups. In more complex
societies requiring new survival skills, the social structures and
groupings are more widely differentiated (3).
The family had undergone changes throughout history, that
parallel changes in society and has given up or taken over many of
the functions of protecting and socializing its member's response to
society's needs. Today, many people are wondering what is
happening to the family. People are troubled about many aspects of
current family life, including the divorce rate, reports of widening
child abuse, accounts of violence between spouses, and the
abundance of couples in nontraditional living and social
arrangements – contract marriages, people living in communes, and
4
L. Ben-Nun King David

mothers who are voluntary without husbands. Urban industrial


society intruded forcefully in the family of the early 20th century,
taking over many of the functions that were previously the family's
duties. The old now live apart in housing homes, or housing
developments, or other arrangements, and economic support to
members of society is provided through social security and welfare
more often than it has been in the past (2).
As society changes, the family, which must adapt to society,
changes with it. Despite the disturbing aspects of current family life, a
number of observers believe that the family had demonstrated an
enormous capacity for innovation and endurance throughout the
ages, and the family is in the process of a transition reflecting the
changes in society, and it will survive because it is the best human
unit. The more flexibility and adaptability society requires from its
members, the more significantly the family becomes the matrix of
psychological development (2).
Through the application of systems theory, the family is more
than the sum of its parts. Interpersonal structures and processes that
enable to be both stable and adaptable over time organize the
family. Family change is the interpersonal process by which the
family adapts, alters, and becomes different (3).
Many changes occurred in the timing of the family life cycle over
the past several decades. For example, the pattern of post-WWII
family change has been generally similar in North America, Western
Europe, and even partly in Eastern Europe, suggesting that more
global rather than particular national explanations need to be sought.
The post-WWII years can be divided into two periods: 1] the period
from 1945 to 1965 that brought the unexpected marriage rush and
baby boom, and 2] the period from 1965 to the present that brought
a reversal of those trends in the form of marriage, a great increase in
no marital cohabitation, a large rise in divorce, and a sharp fall of
infertility to below the replacement level. The similarity of these
large-scale trends in North America and Western Europe is striking.
The US is most like Britain and, beyond Europe, Canada, and
Australia, suggesting the influence of the common culture of the
English-speaking Western world. Yet the US has, and probably
always has had, higher rates of fertility, marriage, and divorce than
most Western European nations. The proportion of single-parent
families is unusually high, even though some nations such as Sweden
and East German have higher proportions of births to the unmarried
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L. Ben-Nun King David

and cohabitating women. The level of cohabitation in the US,


although greatly increased, is still moderate by European standards.
Concern over the burden of government support for the elderly
already has prompted changes in the Social Security program. The
ability to support programs for children and for poor families is being
questioned, even though the level of government support for the
family is relatively low by Western standards (4).
The idea of the family life cycle is based on the notion that families,
like everything else, go through a process from birth through growth to
decline and death. A useful way of conceptualizing the family life cycle
is to look at ways that families must alter their attitudes and
relationships in order to adapt to each of six stages: the young
unattached adult; the newly married couple; the family with young
children; the family at midlife: adolescents and aging parents; the stage
of launching children and moving on; and the family in later life.
Experiences in passing through the family life cycle are affected by
social changes. Some important changes in recent times are the
lowered likelihood of experiencing the death of one’s parents or of a
child, the increased likelihood of being a grandparent, and the
increased likelihood of facing marital disruption because of divorce
rather than death, which also means a greater likelihood of
experiencing remarriage (5).
The couple with young children faces the challenge of taking on the
roles of mother and father as well as husband and wife and of enlarging
the family system to include other people. Marital satisfaction is likely
to be lower at this stage. The family at midlife faces multiple
challenges: the care of aging parents who become ill, disabled, or frail;
illness or death of one of the spouses; allowing the children to form
their own independent identities and establish a wider range of
intimate relationships; and midlife concerns with regard to the
marriage and the spouses’ careers. Adolescents are undergoing
important physical, intellectual, and social definitional changes that
lead to new expectations about responsibilities. They need increasing
autonomy and independence, which can result in conflict with the
parents. Communication, discipline problems, and financial struggles
are common. Adolescents themselves see most of their stress arising
from daily hassles with parents. The midlife couple may be further
stressed by personal concerns, including their own aging. They begin to
change the way that they view life, thinking in terms of how much time
is left and how many doors of opportunities are closed (5).
6
L. Ben-Nun King David

The aging family involves a shift of roles, with the middle generation
taking on a more central place in the family. Retirement occurs at this
stage. People may adjust well to, or even welcome, retirement when it
is voluntary. Marital problems can arise if the new roles are not worked
out satisfactorily. Couples in the sixth stage tend to be maritally rather
than parentally oriented. The marriage is likely to become more
egalitarian. The couple may continue to have an active and meaningful
sex life. Marital satisfaction is likely to be at its highest point since the
couple’s early years together. Family relationships are still important.
Contact with children tends to be frequent. Strains may result if adult
children move back into the home, however. Women are far more
likely than men to experience the death of a spouse. Both men and
women whose spouses die face a difficult period of adjustment. There
is a loss of identity and a variety of physical and emotional
consequences of bereavement. Many eventually remarry, although
widows are less likely to do so than are widowers. Companionship is
one of the most common reasons that both men and women remarry
after the death of a spouse (5).
In spite of the changes that have occurred in contemporary society,
the function of the family as a system, its pattern of interaction, the
relationships within it, the creation of subsystems within the family,
and the psychosocial problems experienced by family members have
changed little through the ages. Both highly functioning and
dysfunctional families, which have existed since the dawn of human
history, will continue to be part of each society. It is important to study
both ancient families and contemporary families in order to handle
many of the problems found in dysfunctional families.
This study assessed the association between parental style, family
functioning and adolescent well-being, contrasting intact families
with those of changed configuration. The subjects included 801 grade
10 general level teenagers in 11 high schools of a single educational
system. Results indicated that the configuration of the family was not
the key determinant of effectiveness of family functioning. Instead,
the style of parenting turned out to be the main determinant of both
family functioning and well-being of the adolescents. While both
"parents" were judged to have contributed to these outcomes, cross
gender effects were found (6).
This paper investigates how education influences marriage
behavior in the US, West Germany, and former East Germany.
Following family economics, for women a longer education decreases
7
L. Ben-Nun King David

marriage rates both during education (institutional effect) and after


the degree has been obtained (human capital effect). For men, family
economics predicts the delaying institutional effect, too, but the
human capital effect is expected to increase marriage rates. For
younger birth cohorts these sex differences should attenuate. For the
US and West Germany the observed marriage patterns confirm the
hypotheses for the most part. For East Germany, however, different
marriage patterns are observed (7).
This research deals with one family, from the high socioeconomic
stratum that lived more than 3000 years ago and was influenced by
the social norms of ancient society. The behavior of these ancient
characters resembles the behavior of people who live in
contemporary times. Many ancient life cycle events within and
outside the family system were traumatic in nature. The stresses
whether minor or major were expected or unexpected events which
led the King's family to subsequent crises. We can find examples of
love and hatred, honest and disgusting behaviors, mutual respect and
betrayal, and various psychosocial problems among these family
members. The characters described were human beings with
behaviors that can be observed in our society as well. Both ancient
and contemporary families go through the same life cycle, with
similar behavioral pattern among their members.
In 1974, Minuchin described the family developmental cycle as a
key component of any schema based on viewing the family as a
system (8). The family of King David the Great represents a system,
and in this research, the relationships within its internal subsystems
and with the external world are evaluated to assess how the system
affected the development of each family member. The disturbing
events that affected this family are investigated within the context of
a system having its own rules, above all obedience to the King, its
own patterns of interaction and varying abilities to handle problems
that arose. The family was confronted with a range of stressful events
and subsequent crises. Although the events described occurred
thousands of years ago, they are like a mirror reflecting the dynamics
of the contemporary family system.
In order to handle various problems found in contemporary
dysfunctional families, health care providers should understand and
recognize different problems, stressful life events and the
subsequent crises occurring in ancient families. The pattern of
interactions, the struggle for leadership, extramarital sexual relations,
8
L. Ben-Nun King David

sexual abuse, the structure and function of the polygamous family,


mutual affection and friendship, and extreme hatred are the
dimensions that characterize this ancient family. All these behaviors
occur equally in contemporary families. The topic is fascinating, and
gives us the tools for better management of contemporary families.
The research is composed of two parts: the first studies the family
system of King David, the roots of his family, the development of this
system and its subsystems, the structure and its expansion, the
dynamics of the family, and the relationships between family
members and the external world. The second part examines the
medical record of the King that is the biblical text, evaluating the
most likely diagnoses of the diseases that afflicted the King from the
viewpoint of contemporary medicine.

References
1. Neugarten B. Adaptation and the Life Cycle. The Counseling
Psychologist. 1976;6:1.
2. Ramsey CN, Lewis JM. Family structure and functioning. In: Robert E.
Rakel (ed.). Textbook of Family Practice. W. B. Saunders. Philadelphia,
London. Third ed. 1984, pp. 21-40.
3. McDaniel SH, Campbell TL, Seaburn DB. Basic premises of family-
oriented primary care. Family systems concepts. In: McDaniel SH, Campbell
TL, Seaburn DB (eds.). Springer-V, New York, Berlin. 1990, pp. 3-15, 33-39.
4. Cherlin A, Furstenberg Ff Jr. The changing European family: lessons for
the American reader. J Fam Issues. 1988;9:291-7.
5. Lauer RH, Lauer J. Marriage and Family. The Quest for Intimacy.
Available 15 November 2014 at highered.mheducation.com/
sites/0072487747/student _view0/ chapter15.
6. McFarlane AH, Bellissimo A, Norman GR. Family structure, family
functioning and adolescent well-being: the transcendent influence of
parental style. J Child Psychol Psychiatry. 1995;36(5):847-64.
7. Bruderl J, Diekmann A. Education, birth cohort, and marriage age: a
comparative analysis of marriage age in West Germany, East Germany, and
the United States. Z Soziol. 1994;23(1):56-73, 77.
8. Minuchin S. Families and Family Therapy. Cambridge: Harvard
University Press, 1974.
9
L. Ben-Nun King David

THE FAMILY LIFE CYCLE


10
L. Ben-Nun King David

THE ROOTS

OBED – THE GRANDFATHER OF KING DAVID. The biblical events


occurred in Beth-lehem and in Moab, 1000-1200 B.C. A family
consisting of Elimelech, his wife Naomi, and their sons, Mahlon and
Chilion, left Beth-lehem-judah because of the famine, and settled in
Moab. Eventually, Elimelech died and sometime later, his two sons
married Orpah and Ruth. Unfortunately, both couples were infertile
and the two sons died, so Naomi decided to leave Moab and return
to Beth-lehem-judah. Orpah left Naomi, but Ruth stayed with her. In
Beth-lehem-judah, Ruth met Boaz who took her to be his wife. As a
result of this marriage, a son, Obed was born, bringing happiness to
Naomi. Obed was the father of Jesse, and Jesse was the father of
King David. Thus, Obed was the grandfather of King David. In other
words, King David was a descendant of Ruth and Boaz’s family.

JESSE'S FAMILY. David, the second and greatest of Israel’s Kings,


the youngest son of Jesse, was born in Bet-lehem-judah. He grew up
in a family of eight sons. As a youth, David was ruddy and good-
looking (I Samuel 17:42). He “...tended his father’s sheep at Bet-
lehem” (17:15). He was strong, he “...slew both the lion and the
bear...” (17:36),
Three eldest sons of Jesse's were soldiers in King Saul's army "And
the three eldest sons of Jesse went and followed Saul to the battle:
and the names of his three sons were Eliab the firstborn, and the next
unto him Abinadab, and the third Shammah" (17:13).

THE BATTLE WITH GOLIATH


David the youth was sent to bring food from his father's house to
his older brothers at the Israelite camp. The Philistine giant,
meanwhile, was daring the Israelites to send out their best fighter.
After 40 days and no response, it was David who took up the
challenge. A devout believer in the power of God and an enthusiastic
patriot, David was also a cunning and pragmatic fellow. He knew of
King's Saul's promise that who conquered Goliath could take the
King's daughter as a wife and would be granted wealth for himself
11
L. Ben-Nun King David

and his family. He refused the King's proposal to don armor of heavy
metal, preferring to remain in his shepherd's garment, armed with a
mere stick, sling, and smooth stones – weapons with which he was
familiar (1).
During the battle with Goliath ".. David hastened, and ran toward
the army to meet Philistine. And David put his hand in his bag, and
took thence a stone, and slung it, and smote the Philistine in his
forehead, that the stone sunk into his forehead; and he fell upon his
face to the earth" (I Samuel 17:48,49).
Goliath, a terrifying giant from the area of Gat, was slow-moving
and ponderous (1,2-4). It is most likely that Goliath was suffering
from acromegaly. The slowness of Goliath had been attributed to
three phenomena. The first is the heavy weight. In addition to his
vast physical size, Goliath was dressed in a heavy metal suit of armor:
"And he had a helmet of brass upon his head and he was armed with
a coat of mail; and the weight of the coat was five thousand shekels,
it was of brass. And he had graves of brass upon his legs, and a target
of brass between his shoulders. And the staff of his spear was like a
weaver's beam; and his spear's head weighed six hundred shekels of
iron." (17:5-7). The second explanation is that arthropathy and
myopathy frequently appear in the late stages of acromegaly (1,5).
According to Birginer, there is no indication to suspect such
complications. The third theory claims a visual disorder. Goliath was
not blind; he saw and taunted the young boy who confronted him.
David carried a stick, yet Goliath saw "several sticks", which may be
one of the indications of his impaired vision. Thus, Goliath suffered
from visual field restriction. Bitemporal hemianopsia occur in large
pituitary microadenoma because of optic chiasm compression in the
suprasellar region (1).
Goliath did not pass away after the stone hit his forehead:
"Therefore David ran, and stood upon the Philistine, and took his
sword, and drew it out of the sheath thereof, and slew him, and cut
off his head" (17:51). After the battle with the horrifying Goliath
"David took the head of the Philistine, and brought it to Jerusalem"
(17:54).
This was a thrilling battle, in which a cunning adolescent defeated
a frightening, clumsy giant from Gat. This victory showed that the
young David was very smart and skilful.
12
L. Ben-Nun King David

References
1. Berginer VM. Neurological aspects of the David-Goliath battle:
restriction in the giant's visual field. IMAJ.2000;2:725-7.
2. Prohets, Nevi'im, Samuel 1:17. In: The Jewish Bible, Tanakh, a new
translation of the Holy Scriptures into English. Jerusalem: Jewish Publication
Society; 1985, pp. 443-7.
3. Samuel 1:17. In: Prophets, Nevi'im (with translation into Russian),
Jerusalem: Mossad Harav Kook. 1978, 93-6.
4. The works of Flavius Josehus and the life of Josehus (written by
himself and accurately translated from the original Greek). Philadelphia:
Lippincott, Crambo and Co., 1854, Vol. 1, Chapter 9, pp. 106-8.
5. Lamberts SWJ. Acromegaly. In: Grossman A (ed.). Clinical
Endocrinology. Oxford Blackwell Scientific Publications, 1992, pp. 154-68.

DAVID AND KING SAUL'S FAMILY

KING SAUL. King Saul, the first King of Israel, ruled the country
about 3007 years ago. The son of Kish, he was a tall and handsome
child “... a choice young man, and a goodly: and there was not among
the children of Israel a goodlier person than he: from his shoulders
and upward he was higher than any of the people” (I Samuel 9:2).
When Saul grew up, he was chosen to be the King since “...he was
higher than any of the people from his shoulders and upward” and
“...there is none like him among all the people. And all the people
shouted, and said God save the King” (10:23,24). When Saul became
King, he participated in endless wars “So Saul took the kingdom over
Israel, and fought against all his enemies on every side...” (14:47).
However, later in his life signs of mental distress due to manic
depressive disorder appeared (1) “...an evil spirit from the Lord
troubled him” (16:14). Consequently, Saul’s servants summoned
David to play his harp, and “ ..he (the king) loved him greatly ; and he
became his armor-bearer” (16:21). On hearing the music, the
symptoms of Saul’s mental distress disappeared: “...David took a
harp )‫ )כינור‬and played with his hand: so Saul was refreshed, and was
well, and the evil spirit departed from him” (16:23).
When David killed Goliath, a terrifying giant from the area of Gat,
and subsequently defeated the Philistines, King Saul began to hate
David. The roots of this hatred were associated with the fact that the
13
L. Ben-Nun King David

people believed that "..Saul hath slain his thousands, and David his
ten thousands (Philistines)" (18:7).
David fought the Philistines and defeated them in another battle.
This victory had a negative impact on the King's mental state "And
the evil spirit from the Lord was upon Saul.. And Saul sought to smite
David even to the wall with his javelin…; but he slipped away out of
Saul's presence, and he smote the javelin into the wall: and David
fled, and escaped that night" (19:9,1). King Saul pursued David
throughout his life in order to kill him. In the end, David had an
opportunity to kill Saul, but he did not do it. Therefore, King Saul
appointed David to succeed him as King.
Thus, we are dealing with a patient, who has suffered from a
mental disorder. His mental status was severely disturbed. The
biblical text tells us that David played with a harp. The Complete
Hebrew-English Dictionary translates the Hebrew word ‫ כינור‬as violin,
psalterium, harp, lyra, and lyra Davidis (2). On what musical
instrument did King David play?
King Saul on hearing the beautiful sounds of music calmed down
and his distressing mental symptoms disappeared. Here, we see the
positive effect of music on the soul of an individual of the highest
socioeconomic stratum. The wonderful sounds of the music had a
positive effect on the King. David's simple, therapeutic intervention
bore fruit - King Saul relaxed, calmed down and his mental status
improved. This is an example of a therapeutic intervention provided
by the music (3).

David plays the harp before Saul. Lucas van Leyden.


14
L. Ben-Nun King David

There are many ancient instruments which David could possibly


played. The psaltery of Ancient Greece (Epigonion) dates from at
least 2800 BCE, and was a harp-like instrument. The dulcimer, a
stringed musical instrument, is a version of the psaltery in which the
strings are beaten with small hammers rather than plucked. The
harp is one of the oldest musical instruments in the world, with
images discovered in rock paintings dating back to 15,000 BC in
France. Many believe that the earliest harps were based on the
sound of the hunter's bow. Over centuries, the structure of an
ancient harp has changed and from a simple bowed instrument has
developed to the concert harp, as we know it today (3).
The lyre was the favored instrument of classical Greece and Rome.
It goes back to the very beginning of human civilization and is
mentioned in Genesis 4:21 "and the name of his brother was Yuval,
he was the ancestor of all who play the kinnor, (or lyre) and ugav.
Lyres are played with one hand only and have a limited number of
strings (4). Did King David play on a psaltery, dulcimer, harp, or lyre?
David was a shepherd who tended cattle in the fields. Since the
strings on a dulcimer are beaten with small hammers, it seems
unlikely that David, who played with his hand (fingers) “...David took
a harp and played with his hand" played on dulcimer. It is obvious
that David did not play the violin, which was introduced only in the
15th century. Thus, we are left with three musical instruments:
psaltery, harp, and lyre (3).
Did David play on the simple harp? The harp was smaller in those
times, but has been improved over the years. The lyre is smaller than
the harp and more convenient for playing. Is seems therefore very
likely that King David played on lyre.
In the Hebrew biblical text, the musical instrument is called ‫כינור‬
which is translated as harp. We have insufficient data to the specific
nature of the musical instrument played by David: psaltery, harp, or
lyre. Or did he play another musical instrument, unknown to us? (3).
Whatever the case, the important fact is that this musical
instrument produced the wonderful sounds, which relieved King
Saul's mental tension and calmed his disturbed soul (5,6).

References
1. Ben-Noun L. What was the Mental Disease that Afflicted King Saul ? Clin
Case Studies (CCS) USA. 2003;2:4-7.
15
L. Ben-Nun King David

2. Alcalay R. The Complete Hebrew-English Dictionary. Israel. Massada


Publishing Co. Ramat-Gan. Jerusalem. 1963.
3. Ben-Nun L. Music Therapy in the Bible. Research in Biblical Times from
the Viewpoint of Contemporary Medicine. Israel. 2013.
4. History of harp development. Available 27 March 2013 at
www.singaporeharpist.com/history.htm.
5. Ben-Nun L. In: Ben-Nun L. (ed.). How did Biblical King Saul die? B.N.
Publication House. Israel. 2012.
6. Ben-Nun L. Mental disorder. In: Ben-Nun L. (ed.). Diseases of the Kings
of Israel. B.N. Publication House. Israel. 2006.

JONATHAN. Later, David developed a friendship with Jonathan,


King Saul’s son “..the soul of Jonathan was knit with Jonathan, and
Jonathan loved him as his own soul” (I Samuel 18:1). So, “ ...Then
Jonathan and David made a covenant, because he loved him as his
own soul” (18:3). As a sign of their friendship “...Jonathan stripped
himself of the robe that was upon him, and gave it to David, and his
garments, even his sword, and his bow, and his girdle” (18:4).
David and Jonathan remained friends all their lives. It was a true
partnership and alliance between friends. They loved each other,
without limitation. As an expression of this love, Jonathan gave
David his garments, his sword, and even his girdle. Subsequently,
when King Saul began to hate David, Jonathan did not abandon their
friendship.
Even after Jonathan's death, their friendship continued; David,
already the King found Jonathan's son, Mefivoshet, and cared for this
child as his own. This is an example of genuine friendship, which has
lasted forever. In this situation, we see the respectful and noble
characteristics of David, who was a reliable partner, paying Jonathan
back for his special unconditional love.

DAVID'S FAMILY

DAVID, MERAB, AND MICHAL. King Saul decided to give his elder
daughter Merab in marriage to David. However, when “...Merab
Saul’s daughter should have been given to David,....she was given to
Adriel the Meholathite to wife” (I Samuel 18:19). Meanwhile, the
younger daughter Michal fell in love with David. Subsequently,
16
L. Ben-Nun King David

“..Saul gave him Michal his daughter to wife” (18:27). The


personality of King Saul was unstable; he changed his mind easily, as
we see when one daughter was taken from David and given to
another man. Why was Merab given to Adriel the Meholathite? What
was behind this decision? Was Merab in love with David? Was Merab
in love with Adriel the Meholathite?
These passages do not indicate that David was in love with Merab
or with Michal. We learn that only Michal loved David. The decision
as to whom the daughters would marry was entirely in the hands of
their father, King Saul. The daughters did not express any objection
to their father's decision. It was taken for granted that only the
powerful King was responsible for the marriage and the future of his
daughters.
The family life cycle is the normal process of family development
beginning with marriage, pregnancy, launching of children,
retirement and ending with death in which specific development
tasks must be accomplished (1).
Becoming a couple is one of the most complex and difficult
transitions of the family life cycle. The positive and romanticized
view of this transition may add to its difficulty, since everyone from
the couple to the family and friends wants to see only the happiness
of the shift (2).
This paper investigates ideal ages for marriage and parenthood
among immigrants from over 160 countries origins living in 25
European countries. Ideals regarding the timing of family formation
are indicative of how individuals perceive the family life course and
provide insight into family-life aspirations and the meaning attached
to these transitions. Using data from the European Social Survey
(Round three, 2006; n=6,330) and a cross-classified multilevel
modeling approach, associations between the influences of the
dominant family formation timing patterns in countries of origin and
settlement, individual-level characteristics, and ideal ages were
investigated. Innovative use of a standard demographic measure, the
cingulated mean age of marriage to measure family formation
patterns was used. Residential context influences are associated with
the timing ideals of all migrants, but origin influences seem to be
associated with the ideals of only the most recent migrants (3).
With young David's marriage, a new family was born. The family
began its own life cycle; as a married man, David was responsible for
the well-being of his family.
17
L. Ben-Nun King David

References
1. McDaniel S, Campbell TL, Seaburn DB. Family systems concepts. In:
McDaniel S, Campbell TL, Seaburn DB (eds.). Family-Oriented Primary
Care. A Manual for Medical providers. Springer-Verlag. New York, Berlin.
1990, pp.33-39.
2. McGoldrick M. The joining of families through marriage: the new
couple. In: Carter EA, Godrick M (eds.). The Family Life Cycle: A
Framework for Family Therapy Gardner Press, New York. 1980, pp. 93-
119.
3. Holland JA, de Valk HA. Ideal ages for family formation among
immigrants in Europe. Adv Life Course Res. 2013;18(4):257-69.

A NEW FAMILY. Subsequently, David met Abigail, “..a woman of


good understanding, and of beautiful countenance..” (I Samuel 25:3).
However, her husband “...Nabal was hardhearted and evil in his
doing” (25:3). When Nabal died, David took Abigail to be his wife.
Later: “David also took Ahinoam of Jezreel...” (25:43). Now David had
three wives, but the family size was reduced when Michal was taken
from David “Saul had given Michal his daughter, David’s wife, to
Phalti the son of Laish...” (25:44).
King Saul's decision indicates an unstable and light-hearted
personality. A married woman, in this case his own daughter, was
taken from one man and given to another. Why did the King take
such an extraordinary step? What was the purpose behind this
decision? Did Phalti ask for his daughter's hand? Was Laish involved
in this decision? There was no compromise, and the new couple
were not asked for their consent. As in Merab's case, the same thing
happened to Michal. This was acceptable behavior in ancient times.
Family refers to any subdivision of this kind of social unit, which
itself possesses the same attributes of affection, loyalty and
durability of membership. So a married couple without children, a
couple with several young children, three-generation units, with a
single parent and several children, and units evolved by remarriage
from parts of previously existing units, all are families (1).
Older widowers are more likely to remarry than older widowed
women. In this study of 60 widowers, more than half spontaneously
discussed their attitudes toward, and experiences of these
relationships. However, none of the widowers had remarried and of
those who described themselves as repartnered only one was
18
L. Ben-Nun King David

cohabiting. These data in the light of Lopata's concept of 'husband


sanctification' were examined (2). Four themes were identified. First,
some widowers do sanctify their late wives. Second, wife
sanctification contributes to widowers' uncertainties about
repartnering. Third, when widowers make decisions to repartner,
wife sanctification does not appear to make an important
contribution. Finally, there is evidence to suggest that wife
sanctification influences how men refer to their new women friends.
Thus, wife sanctification influences widowers' decisions surrounding
remarriage/repartnering (3).
This study estimates the sex-specific prevalence of repartnering
after widowhood. The main objective is to examine the competing
choice between nonmarital cohabitation and remarriage as well as
repartnering differentials. The study uses data from the 2007
Canadian General Social Survey and life table methods to illustrate
gender and regional differences in the cumulative proportion of
people aged 45 and older who repartner after widowhood.
Proportional hazard models are used to examine how factors such as
socioeconomic resources, region, demographic characteristics, and
health associate with the risk of repartnering and repartnering
preferences. Most repartnering after widowhood occurs within ten
years of this event or not at all. Ten years after widowhood, about 7%
of widows and 29% of widowers have formed a new union. For both
widows and widowers, the rate of remarriage is twice as high as the
rate of cohabitation. The exception to this is the province of Quebec,
where cohabitation is a more prevalent choice of repartnering than
remarriage. There is a weak association between socioeconomic
resources and both the risk of cohabitation and remarriage. These
results confirm that constraints in marriage markets contribute to a
gender gap in the prevalence of repartnering after widowhood.
Though the widowed prefer remarriage to cohabitation as a
repartnering choice, there are important regional differences in
repartnering that reflect cultural norms in the social acceptance of
cohabitation. Socioeconomic disincentives to marriage do not appear
to push the widowed into cohabitation (4).
This study examined: 1] frequencies of remarrying or becoming
romantically involved for widows and widowers during the first two
years of widowhood; 2] attitudes toward dating and remarriage
among the recently widowed, and their evolution; 3] identifiable
factors which predict the development of new romances, such as sex,
19
L. Ben-Nun King David

age, income, and level of education; and 4] the psychological well-


being of those widows and widowers involved in romances compared
to those who were not. The San Diego Widowhood Project was a
prospective study in which 249 widows and 101 widowers who were
identified through San Diego County death certificates completed
detailed questionnaires 2, 7, 13, 19, and 25 months after their
spouses' deaths. The main outcome measures for this study were
marital and romance status, attitudes toward romance at several
time points, demographic predictors of romance status, and self-
reported measures of psychological well-being. By 25 months after
the spouse's death, 61% of men and 19% of women were either
remarried or involved in a new romance. Women expressed more
negative feelings about forming new romantic relationships. Younger
age was a predictor of becoming involved in a new romance for
women, and higher monthly income and level of education were
predictors for men. Greater psychological well-being was highly
correlated with being remarried or a new romance 25 months after
the spouse's death. It is helpful for family, friends, and therapists to
know that dating and remarriage are common and appear to be
highly adaptive behaviors among the recently bereaved (5).
Consideration and use a remarriage as a response to cope with
the death of a husband was examined in 39 women who had been
widowed and had subsequently remarried, 192 widows who had
considered remarriage but had not yet remarried, and 420 widows
who had not considered remarriage. Controlling for age, women who
had remarried reported fewer current concerns than did the other
two groups. Women who retrospectively recalled the most concerns
immediately after the death of the spouse were the ones who
eventually remarried. The remarried group believed that they were
experiencing significantly fewer concerns now than they had after
the spouse's death; the women who had not considered remarriage
believed that they were experiencing the same number of concerns
now as before; and those women who had considered remarriage
believed that they were experiencing significantly more concerns (6).
A technique was devised to estimate age specific remarriage
probabilities for newly widowed persons utilizing North Carolina
marriage certificates plus information from the 1970 US Census.
Remarriage probabilities are very high for persons widowed before
age 35 years. Remarriage probabilities decrease faster for widows
than widowers. Less than one-fourth of men widowed after age 65
20
L. Ben-Nun King David

years ever remarry. Less than 5% of women widowed after age 55


years ever remarry. Age specific intervals to remarriage were also
calculated. Men remarry more quickly than women. The median
interval to remarriage was 1.7 years for men and 3.5 years for
women (7).
Abigail was an attractive woman, and although she was a widow
David took her to be his wife. Abigail's remarriage was a coping
mechanism with the adverse life consequence - the death of her
husband.
David's family changed its composition, and now was composed
of two units - the husband, David, and his wives - Abigail, and
Ahinoam. Abigail was “..a woman of good understanding, and of
beautiful countenance..” (I Samuel 25:3). What were Abigail's
motives? Did Abigail fall in love with David? Did she seek a
companion?
We see that remarriage after the death of a spouse was an
acceptable behavior in biblical times.
After Saul’s death, David and his two wives dwelt in Hebron.

Reference
1. Terkelsen KG. Toward a theory of the family life cycle. In: Carter EA,
Goldrick M (eds.). The Family Life Cycle: A Framework for Family Therapy,
Gardner Press, New York. 1980, pp, 21-52.
2. Lopata, H. Z. Widowhood and husband sanctification. J Marriage
Family. 1981;43(2):439–50.
3. Bennett KM, Arnott L, Soulsby LK. "You're not getting married for the
moon and the stars": The uncertainties of older British widowers about the
idea of new romantic relationships. J Aging Stud. 2013;27(4):499-506.
4. Wu Z, Schimmele CM, Ouellet N. Repartnering after widowhood. . J
Gerontol B Psychol Sci Soc Sci. 2014 Jun 12. pii: gbu060. [Epub ahead of
print]
5. Schneider DS, Sledge PA, Shuchter SR, Zisook S. Dating and remarriage
over the first two years of widowhood. Ann Clin Psychiatry. 1996;8(2):51-7.
5. Gentry M, Shulman AD. Remarriage as a coping response for
widowhood. Psychol Aging. 1988;3(2):191-6.
7. Cleveland WP, Gianturco DT. Remarriage probability after
widowhood: a retrospective method. J Gerontol. 1976;31(1):99-103.
21
L. Ben-Nun King David

THE KING OF JUDAH

After dwelling in Hebron “...the men of Judah came, and there


they anointed David king over the house of Judah” (II Samuel 2:4). At
this time, David became the King, and his family entered a new phase
of its life. Now, David was the honored ruler over Judah. His social
position changed, from a simple man he became the new leader.
Undoubtedly, his social position had an effect on the dynamics of his
family system. Everybody had be obedient to the King, whether they
were within his family or outside the family system.
In Hebron, The King took four additional women to be his wives,
so his family once again expanded and included seven members: the
husband - the King and his six wives - Ahinoam, Abigail, Maacah,
Haggith, Abital, and Ithream. (3:2-5).

POLYGAMOUS FAMILY. In Hebron, six sons were born to King


David: “And his firstborn was Amnon of Ahinoam the Jezreelitess; And
his second Chileab, of Abigail..., and the third, Absalom the son of
Maacah the daughter of Talmai king of Geshur; And the fourth
Adonijah the son of Haggith, and the fifth, Shephatiah, the son of
Abital, and the sixth, Ithream, by Eglah David’s wife” (3:2-5).
Polygamy, from Late Greek πολυγαμία, polygamia, "state of
marriage to many spouses" or "frequent marriage" (1-3) is a marriage
that includes more than two partners (4). When a man is married to
more than one wife, the relationship is called polygyny; and when a
woman is married to more than one husband, it is called polyandry. If
a marriage includes multiple husbands and wives, it can be called
group or conjoint marriage (4).
King David's family can be defined as a polygamous family
consisting of 13 members: King David, the husband, his six wives, and
their six children.
Polygamous marriages engender multiple problems, for instance,
jealousy in all its forms with consequences of an explosive
confrontation, loss of self-esteem, and depression (5,6).
Many societies accord high status to senior wives: they may have
power over the other wives; enjoy special privileges within the
family; and, in some societies, arrange and consent to the husband’s
next marriage (7). A senior wife is defined as a woman who was
22
L. Ben-Nun King David

followed by another woman in the marriage while a junior wife is the


most recent wife joining the marriage (8).
The purpose of this study was to examine the psychological
symptoms, family function, marital satisfaction, life satisfaction and
the degree of agreement with the practice of polygamy among
'senior wives', the first wife in the polygamous marriage, and women
in monogamous marriages in the West Bank, Palestine. A
convenience sample of 309 women, 187 from polygamous and 122
from monogamous families, participated in this study. All women
from polygamous families were senior wives. The following
instruments were deployed: the McMaster Family Assessment Device
(FAD) (9), the ENRICH marital satisfaction questionnaire (10), the SCL-
90 mental health symptoms checklist (11), the Rosenberg self-esteem
scale (12), the Satisfaction With Life Scale (13), life and marital
satisfaction (14), and a basic socio-demographic scale, including the
degree of agreement of the practice of polygamy (15). The findings
revealed significant differences between senior wives in polygamous
marriages and wives in monogamous marriages with regard to family
functioning, marital satisfaction, self-esteem and life satisfaction.
Likewise, many of the mental health symptoms were different.
Particularly, somatization, depression, hostility psychotism and the
General Severity Index (a global index of distress). More women in
polygamous marriages agreed with the practice of polygamy in
comparison with their monogamous counterparts. Practitioners and
policy makers need to be aware of the consequences of polygamy on
first wives and on society as a whole (15).
The aim of this study was to examine the psychological, self-
esteem, family function, marital satisfaction, life satisfaction and
degree of agreement with the practice of polygamy among
polygamous women with a control group from monogamous women
in Syria. Convenience sample of 136 women, 64 of whom were wives
in polygamous marriages and 72 were wives in monogamous
marriages participated in this study. A snowball method of sampling
was used, conducted by undergraduate local female students trained
to collect data according to culturally competent methods. The
following research instruments were deployed: the symptoms
checklist-90 (11), the Rosenberg self-esteem (12), and the Life
Satisfaction, family function and marital satisfaction (14). Findings
revealed that women in polygamous marriages experienced lower
self-esteem, less life satisfaction, less marital satisfaction and more
23
L. Ben-Nun King David

mental health symptomatology than women in monogamous


marriages. Many of the mental health symptoms were different;
noteworthy were elevated somatization, depression, hostility and
psychoticism and their general severity index was higher.
Furthermore, "first wife syndrome" was examined in polygamous
families, comparing first with second and third wives in polygamous
marriages. Findings indicated that first wives reported on more
family problems, less self-esteem, more anxiety, more paranoid
ideation, and more psychoticism than second and third wives. In
conclusion, these results are best understood through consideration
of the socio-cultural and economic realities facing these women (16).
The aim of this study was to determine the different
sociodemographic variables of polygamous and monogamous wives,
and the relationship between depression and polygamous marriage.
In southern Turkey, from Kahramanmaras, 79 polygamous wives and
73 monogamous wives were interviewed. There was a statistically
significant difference between polygamous wives and monogamous
wives in terms of BDI scores. The results highlighted many
implications for clinical practice and for future research (17).
We see that first wives report on more family problems, less self-
esteem, more anxiety, more paranoid ideation, and more psychoticism
than second and third wives.
At this time, the Bible gives no further details about relationships,
between the wives, and children within David's extended family
system. We can surmise that the relationships in his family were
typical of those observed in any polygamous family.
Holmes and Rahe (18) developed their life-event scale by asking a
random sample of the population to rank how stressful they
perceived each of 43 life events to be. Many of the events on the
Holmes and Rahe scale occur within the family, and 10 of the 15 most
stressful events are family events. Several of the most stressful life
events on this scale represent major transitions in the family life
cycle. These normative life events have powerful influences on
physical and mental health that can result in symptoms that bring the
individual to the physician's office (18).
On the Holmes and Rahe scale (18), marriage is given a mean
value of 50, while the birth of child is given a mean of 39. Thus, King
David certainly was in a stressful situation when he married, and
subsequently on the birth of each child.
24
L. Ben-Nun King David

Family membership is not subject to expiration. In the life of the


family, there is nothing like being fired or laid off. Family members do
not quit or drop their membership. In clinical practice, one often sees
families in which a member is permanently cut off from the rest of
the family, and there is an occasional family that disowned or
banished a member, or in which someone has disappeared.
However, these are extreme actions indicating serious trouble.
Disregarding the extremes, there is no routine form of termination of
family membership other than death. Like all other organizations,
families place a high value on competence in instrumental role
performance. Nevertheless, unlike all others, the family places a still
higher value on attachment, caring, and personal loyalty (19).
King David's extended family included all parameters that are
described above, with family members entering the family system
through marriage or birth and ending their membership with death.
The family included six subsystems: the husband, the King, with each
wife and her child, all of them having a definite role in this system.
The King expelled no family member from the system. All judgment,
strength of will and decision making was concentrated in his hands.
This was the usual and accepted social norm of behavior in this
society. All family members were obedient to only one person, the
head of the family, King David. In order to survive, each family
member had to obey and respect the rules of this family system. This
was the way of life and survival. The internal family system operated
according to these rules. These rules were imposed on the
surrounding external environment as well. A mutual relationship
between the internal family system and the external environment
was established.

References
1."polygamy". Online Etymology Dictionary. Available 28 December 2014
at Polygamy - Wikipedia, the free encyclopedia. en.wikipedia.org/wiki/
Polygamy.
2. πολυγαμία. Henry George L, Robert S; A Greek–English Lexicon at the
Perseus Project. Available 28 December 2014 at Polygamy - Wikipedia, the
free encyclopedia. en.wikipedia.org/wiki/Polygamy.
3. Georgios B. s.v. πολυγαμία. Dictionary of Modern Greek (in Greek).
Lexicology Centre. 2002.
4. Koktvedgaard ZM. Polygamy: a cross-cultural analysis. Berg. 2008, p. 3.
ISBN 1-84520-220-1.
25
L. Ben-Nun King David

5. Achte K & Schakit T. Jealousy in various cultures in the light of


trancultural psychiatry. Psychiatria Fennica. 1980;11:33-4.
6. Camara S. Femmes africaines polygamie et authorite masculines.
Ethnopsychologie. 1987;33:43-53.
7. Altman I & Ginat J. Polygamous families in contemporary society.
Cambridge, UK: Cambridge University Press. 1996.
8. Al-Krenavi A, Graham JR, Slonim-Nevo V. Mental health aspects of
Arab-Israeli adolescents from polygamous versus monogamous families. J
Soc Psychology. 2002; 142(4):446-60.
9. Epstein NB, Baldwin LM, Bishop DS. The McMaster Family assessment
device. J Marital and Family Therapy. 1983;9(2), 171–80.
10. Blaine J. Fowers, David H. Olson. ENRICH MARITAL INVENTORY: A
discriminant validity and cross-validation assessment. J Marital and Fam
Ther. 1989;15(1):65-79.
11. Schmitz N, J Kruse, C Heckrath, et al. Diagnosing mental disorders in
primary care: the General Health Questionnaire (GHQ) and the Symptom
Check List (SCL-90-R) as screening instruments. Soc Psychiatry Psychiatr
Epidemiology. 1999;34:360-6.
12. Rosenberg M. Society and the adolescent self-image. Princeton, NJ:
Princeton University Press. 1965.
13. Diener E, Emmons RA, Larsen RJ, Griffin S. The satisfaction with life
scale. J Pers Assess. 1985;49(1):71-5.
14. Al-Krenawi A, Graham JR. A comparison of family functioning, life
and marital satisfaction, and mental health of women in polygamous and
monogamous marriages. Int J Soc Psychiatry. 2006;52(1):5-17.
15. Al-Krenawi A. A study of psychological symptoms, family function,
marital and life satisfactions of polygamous and monogamous women: the
Palestinian case. Int J Soc Psychiatry. 2012;58(1):79-86.
16. Al-Krenawi A. Mental health and polygamy: The Syrian case. World J
Psychiatry. 2013;3(1):1-7.
17. Özer A, Orhan FÖ, Ekerbiçer HÇ. Sociodemographic variables and
depression in Turkish women from polygamous versus monogamous
families. Health Care Women Int. 2013;34(11):1024-34.
18. Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J
Psychosom Res. 1967;11:213.
19. Terkelsen KG. Toward a theory of the family life cycle. In: Carter EA,
Goldrick M (eds.). The Family Life Cycle: A Framework for Family Therapy.
Gardner Press, New York. 1980, pp, 21-52.
26
L. Ben-Nun King David

THE KING OF ISRAEL

Subsequently, all the tribes of Israel came to David, to Hebron.


“...and they (the elders) anointed David king over Israel. David was
thirty years old when he began to reign and he reigned forty years. In
Hebron he reined over Judah seven years and six months; and in
Jerusalem he reigned thirty and three years over all Israel and Judah”
(II Samuel 5:3-5). As we see, David’s role expanded, and each time
his family entered a new phase in their life cycle.

THE AFFAIR OF BATHSHEBA. From the roof of his house, King


David saw a beautiful woman, Bathsheba, the wife of Uriah the
Hittite, as she was taking a bath. Therefore, the King sent
messengers, took the woman, and had sexual relations with her. As a
result, Bathsheba conceived. In order to hide this disgraceful affair,
King David orchestrated a plan for Uriah to lie with his wife and in
this way, it would appear that Bathsheba conceived by her husband.
Therefore, the King summoned Uriah and sent him home, but Uriah
did not go to his house. Therefore, the King summoned Uriah for the
second time. At this time, Uriah “...did eat and drink before him (King
David); and he made him drunk...” (II Samuel 11:13). However, again
Uriah did not go home and did not sleep with his wife. This time, the
King sent Uriah to the front in a fierce battle, where he was killed.
When Bathsheba heard that Uriah was dead, she mourned for her
husband.
For King David there were no limits to the deceit he practiced on
his own people to achieve his goal. In order to keep his good name
and reputation, the King tried to send Uriah home so he would sleep
with his wife. However, these efforts failed, so another disgraceful
act was planned to destroy Uriah. Uriah was assassinated in order to
hide the King’s disgraceful behavior (1,2).
A fundamental condition of survival was to develop skills of
adaptation to these rigid rules. When family members conflicted
with these rules, their fate was decided, as happened in the case of
Uriah. Decisions of life and death lay in the powerful King’s hands. In
David’s internal family, there was neither autonomy nor partnership
in the decision making process. Independence was not given to any
27
L. Ben-Nun King David

family member. Family members’ survival depended on obedience


to the King (1).
In this story, we also see Bathsheba's infidelity. Was she obliged
to surrender to the King’s will? Or did she fall in love with the King?

References
1. Ben-Nun L. The family life cycle of the Great King David. In: Ben–Nun L.
(ed.). Family medicine in Biblical Times. The Roots. B.N. Publication House.
Israel. 2005, pp. 165-84.
2. Ben-Nun L. The family life cycle and the medical record of King David
the Great. In Ben-Nun L. (ed.). The Kings of Israel. B.N. Publication House.
2009, pp. 31-7.

Unprotected Sexual Contacts. Although King David and


Bathsheba both were married, they had unprotected extramarital
sexual relations. Is there any danger of such sexual intercourse? This
section evaluates sexual behavior in different populations and
examines whether there are any risks with unprotected sexual
contacts.
The practice of prostitution has existed since the dawn of history.
If preventive measures are not taken, this practice is dangerous since
it is associated with the transmission of various STDs. STDs have
existed throughout human history, with the epidemiology of STDs
changing from generation to generation. Some STDs have
disappeared, others have reappeared, and some new diseases have
developed over time. For example, the first cases of AIDS were
identified in 1978, and its diverse signs and symptoms led to its
classification as a syndrome in 1980 (1). Later, the HIV was
discovered in Chennai in 1986 (2).
STIs are highly prevalent and cause a wide spectrum of diseases.
However, the majority of these infections may be unrecognized due
to lack of overt signs or symptoms of infection. Asymptomatic
infections remain significant because of the potential for long-term
sequelae, predominately in women, and the risks of complications
during pregnancy as well as mother-to-child transmission. Laboratory
diagnostics play an important role in identifying infection and in
public health efforts to reduce the prevalence of these diseases.
Serologic diagnosis is appropriate for syphilis and, in some settings,
for herpes infections. However, the organisms that cause discharge
such as C. trachomatis, N. gonorrhoeae, T. vaginalis and M.
28
L. Ben-Nun King David

genitalium are best diagnosed using molecular assays. Currently


available molecular assays are suitable for use with non-invasively
collected sample types, most notably vaginal swabs for women thus
expanding the potential reach of STI control programs to include non-
clinic based screening (3).
STIs constitute an important worldwide public health problem.
The use of sensitive and specific laboratory methods for diagnosing
this condition is crucial to reduce the transmission and sequelae of
STI. The present review describes current microbiological methods
for the diagnosis of STIs. N. gonorrhoeae and C. trachomatis are the
pathogens most frequently involved in urethral and cervical infection.
Culture continues to be the gold standard for diagnosing gonorrhea.
Nucleic acid amplification assays are considered the new gold
standard for C. trachomatis, although culture is still the most specific
technique. Genital ulcers due to T. pallidum, H. ducreyi, or HSV have
little clinical and bacteriological correlation; therefore, it is essential
to establish the microbiological diagnosis. Lesions present in the
primary or secondary period of syphilis can be diagnosed by dark
field microscopy. Serologic diagnosis for the remaining periods is
based on non-treponemal tests associated with confirmatory
treponemal tests. Cell culture is considered the gold standard for HSV
although molecular methods also have a sensitivity and specificity
near 100%. Microbiologic diagnosis of H. ducreyi and venereal
lymphogranuloma is achieved with the use of molecular methods on
samples obtained from the ulceration or lymph adenopathy. The
diagnosis of genital warts in immunocompetent patients can be
based on clinical findings because the lesions are sufficiently
characteristic. Culture is considered the reference method in T.
vaginalis infection (4).
From contemporary perspective, STDs are caused by numerous
agents which include N. gonorrhea, C. trachomatis, M. genitalium, a
new etiologic agent that causes genital infection such as non-
gonococcal urethritis (5-7), anaerobic bacteria including Peptococcus,
Peptostreptococcus species, Prevotella bivia, and other Prevotella
species (8), facultative aerobes such as E. Coli, group B streptococcus,
or G. vaginalis, T. vaginalis (9), Chandroid (H. Ducrei) (10,11), H.
influenzae (12), genital herpes (6), HPV (13-15), syphilis (6,15),
hepatitis A, hepatitis B, hepatitis C and hepatitis delta viruses (10,12-
21), molluscum contagiosum virus (10), HIV infection (22-24), and
toxoplasmosis (25). In addition, C. trachomatis, N. gonorrhea (26,27),
29
L. Ben-Nun King David

and HSV types 1 and 2 (28,29) are risk factors for subsequent or
concurrent HIV infection.
Approximately 10% of women will develop PID due to STDs during
their reproductive years, and a significant number will suffer
complications from the infections (7). PID presents a spectrum of
inflammatory disorders within the upper genital tract of women
including any combination of endometritis, salpingitis, pelvic
peritonitis, and tubo-ovarian abscess (30).
One of four women with PID experiences serious sequelae,
including tubal scarring, infertility, and ectopic pregnancy (31), or
chronic pelvic pain (32). In addition, genital papillomavirus infection
is associated with cervical dysplasia and may act as a cofactor in the
development of cervical cancer (33,34).
The STD and HIV epidemics are interdependent. Some behaviors,
such as frequent unprotected intercourse with different partners,
place people at high risk of both infections, and there is evidence that
conventional STDs increase the likelihood of HIV transmission. There
is biological evidence, too, that the presence of STDs increases
shedding of HIV, while treatment of these diseases reduces HIV
shedding. Therefore, control of the STIs has the potential to
contribute substantially to HIV prevention (35).
Among 2,982 individuals socializing at venues in seven
Madagascar towns, 78% of men and 74% of women reported new
sexual partnership or sex-trade for money, goods or services and 19%
of men and 18% of women reported symptoms suggestive STI in the
past four weeks. STI symptom levels were disproportionately high
among responders reporting either sex trade or new sexual
partnership in the past four weeks; 24% of men and 41% of women
reported condom use during the last sex act with a new partner (36).
This was an observational study of street-based sex workers
attending an inner-London genitourinary clinic between 2006 and
2007. The outreach team made contact with 120 street-based sex
workers in the borough, London. There were frequent reports of
recent recreational drug use, unprotected sex with clients and
unreliable contraception; seven were pregnant, six were HIV positive
and 12 had positive syphilis serology. A further 17 STDs were
identified. There were high frequency of HIV, syphilis, other bacterial
STDs, and unwanted pregnancies among sex workers attending this
clinic (37).
30
L. Ben-Nun King David

This study indicates that street-based sex workers are at risk for
contracting some STI.
AIDS is one of the most important diseases of our century that is
transmitted through sexual contacts. In order to deal more efficiently
with this disease we should understand its epidemiology,
characteristics, and the sexual behavior of a variety of populations.
In 2004, 71,755 new diagnoses of HIV were reported in the (WHO)
European region, which includes all European Union countries. The
number of newly diagnosed cases was lower than the peak observed
in 2001 (113,930), but was nearly twice the number in 1999 (39,602).
For different countries, reported rates reached more than 200 new
HIV diagnoses per million population in 2004; 568 in Estonia, 280 in
Portugal, and 212 in the Russian Federation (38).
Although the number of newly diagnosed cases in 2004 was lower
than in 2001, the rates of these infections are still high in European
countries.
In El Salvador, Guatemala, Honduras, Nicaragua, and Panama,
2,466 FSWs were evaluated. For FSWs, HIV seroprevalence ranged
from 0.2% in Nicaragua and Panama and 9.6% in Honduras, where
estimated HIV seroincidence was also the highest (3.2 per 100
person-years); 77% and 72% of FSWs reported using condoms
consistently with new and regular clients, respectively. The
prevalences of STDs were: 85.3% for HSV-2, 9.6% for syphilis, 20.1%
for C. trachomatis, 8.1% for N. gonorrhea, 11.0% for T. vaginalis, and
54.8% for bacterial vaginosis. HSV-2 infection was associated with
HIV infection (39).
African American women have high rates of most STIs, including
HIV. Black women (n=228) who used drugs completed a structured
questionnaire in a central Brooklyn, New-York-based research center
between 2003 and 2005. Thirty-eight (17%) women were HIV
seropositive; the prevalences of STIs included HSV-2 (79%),
trichomoniasis (37%), chlamydia (11%), and gonorrhea (2%). HIV-
infected women in comparison with uninfected women were
significantly more likely to have multiple positive screens and twice
more likely to report current sex work. Several STIs, including HIV,
seem to be endemic among black women who used drugs. Multiply
STIs infected individuals may unknowingly, but efficiently, contribute
to high STIs and HIV rates (40).
31
L. Ben-Nun King David

Women who work in sex work are at risk to be infected with STDs,
including HIV. Infected individuals may contribute unknowingly to the
high prevalence of STDs.
In Israel, despite the low sexual behavior of Israeli HIV patients,
they had a high prevalence of chronic STDs (e.g., HSV-2, HBV and
syphilis). The lower prevalence of chlamydia and gonorrhea among
HIV-immunosuppressed patients may be attributed to routine
antibiotic prophylaxis against opportunistic infections. Nevertheless,
as advocated by international health organizations, it appears
prudent to recommend the routine screening of these asymptomatic
HIV-positive patients for other STDs (41).
Syphilis, a STD, has afflicted humans since the dawn of history.
Throughout the centuries, its incidences and prevalences increased
and decreased, with recurrent epidemics spreading through the
continents. Now, we witness a recurrent upheaval of this STD
worldwide: in US (42), UK (43), France (44), Denmark (45), Germany
(46), Belgium (47), Finland (48), Russia (49), and China (50).
During 2001-2004, 7,083 cases of syphilis were diagnosed in Los
Angeles. Cases of confirmed or probable NS (n=109) occurring among
persons aged 19 to 65 years were identified during this period (1.5%).
Symptomatic NS was present in 1.2% of reported syphilis cases (86 of
7083). NS cases were inclusive of 71 (65%) men who have sex with
men. Forty-two (49%) of the symptomatic NS cases occurred during
secondary (n=28) or early latent (n=14) syphilis. Sixty-eight percent
(n=74) of the NS cases were HIV positive. The estimated incidence of
symptomatic NS among HIV-infected persons with early syphilis was
2.1% as compared with 0.6% among HIV-negative persons (51).
The aim of this research is to present syphilis among women
described as "indecent" according to the records of the Venereal
Diseases Hospital "Andreas Syggros", which is located in Athens,
during the period 1931-1935. In impoverished Greece of the Interwar
period, factors such as criminal ignorance, or lack of information on
STDs along with inadequate health controls of sex workers, resulted
in a dramatic spread of syphilis, whereas "Andreas Syggros" hospital
accommodated thousands of patients. The inflow of 1.300.000 Greek
refugees from Asia Minor, after the Greek defeat by the Turkish army
in the war of 1922, resulted in a notable change in the demographics
of the country, while the combination of miserable living conditions,
unemployment, economic crisis of the Interwar period, political
instability and dysfunction of the State led to an increased number of
32
L. Ben-Nun King David

illegal sex workers and syphilis outbreaks. Despite the introduction of


an ad hoc Act to control STDs since 1923, the State was unable to
limit the transmissibility of syphilis and to control prostitution.
Unfortunately, the value of this historical paradigm is borne out by a
contemporary example, i.e. the scandal of HIV seropositive sex
workers in, beset by economic crisis, Greece in May 2012. Ignorance,
failure to comply with the law, change in the mentality of the citizens
in an economically ruined society, and most notably dysfunction of
public services during periods of crisis are all risk factors for the
spread of serious infectious diseases (52).
The aim of this study was to determine the prevalence and
associated factors of positive syphilis serology in HIV-infected adult
patients in an outpatient setting in Thailand. A cross sectional study
was conducted among 178 HIV-infected patients. Ninety-eight
patients (55%) were male; then median (IQR) age was 43 (36-49)
years. The majority of the patients (84.3%) had a heterosexual risk.
Three patients (1.7%) had a positive RPR test (range 1:2 to 1:16), nine
(5%) patients had a positive TPPA test, and three patients (1.7%) had
positive results on both tests. On multivariate logistic regression
analysis, a pruritic papular eruption (OR 5.37, 95% CI 1.09-26.38,
p=0.038), current CD4 cell count (OR 1.22, per 50 cells/mm3, 95% CI
1.01-1.46; p=0.035), and using abacavir in the current regimen (OR
59.19, 95% CI 2.15-1,628.68, p=0.016) were associated with positive
syphilis serology. In conclusion, the prevalence of positive syphilis
serology among Thai HIV-infected patients was low. Routine
screening for syphilis in HIV-infected patients who are asymptomatic
need to be re-considered at the national level in this resource-limited
setting (53).

ASSESSMENT: the practice of prostitution has existed since the


dawn of history. If preventive measures are not taken, this practice is
dangerous since it is associated with the transmission of various
STDs. STDs have existed throughout human history, with the
epidemiology of STDs changing from generation to generation.
STDs have not disappeared and still are prevalent worldwide.
Forming new sexual partnerships is a prevalent human behavior, and
these partners are at risk for contracting some STD., including AIDS.
STIs are highly prevalent and cause a wide spectrum of diseases.
Syphilis is a prevalent disease worldwide. NS, probably due to
undiagnosed and untreated syphilis, is also prevalent, afflicting young
33
L. Ben-Nun King David

as well as old individuals. In addition, patients who are infected by


syphilis can contract HIV as well.
It is beyond the scope of this study to present all studies on this
topic. Thus, the studies discussed here are the most pertinent to the
topic analyzed in this research. In different populations, there are
different sexual behavior patterns and different prevalences of STDs.
The young and the old individuals, transmit STDs including syphilis
and HIV, especially those young adolescents who have begun their
sexual relations before the age 18 years.
King David and Bathsheba behaved immorally and both were at
risk for contracting some STD, although data did not support this
suggestion.
Contemporary women like ancient women are at risk of infection
by various STDs.

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2007;97:478-85.
50. Wong SP, Yin YP, Gao X, et al. Risk of syphilis in STI clinic patients: a
cross-sectional study of 11.5000 cases in Guangxi, China. Sex Transm Infect.
2007;83:351-6.
51. Taylor MM, Aynalem G, Olea LM, et al. A consequence of the syphilis
epidemics among men who have sex with men (MSM): neurosyphilis in Los
Angeles, 2001-2004. Sex Trans Dis. 2008;35:430-4.
52. Pagratis N, Tsiamis C, Mandyla M, et al. Medical, demographical and
social aspects of syphilis: the case of infected sex workers in Greece during
Interwar. G Ital Dermatol Venereol. 2014;149(4):461-9.
53. Kukanok S, Kiertiburanakul S. Prevalence of positive syphilis serology
among HIV-infected patients: role for routine screening in Thailand.
Southeast Asian J Trop Med Public Health. 2014;45(2):435-41.

CONDOMS. The Italian anatomist Fallopius first promoted the


prophylactic value of condoms in the 16th century (1). With the
vulcanization of rubber in the 1840s, condom production became
both practical and widespread (2). The correct and consistent use of
latex condoms is highly effective in preventing STDs, including HIV
(3). We see that in biblical times AIDS did not exist, nor were
condoms apparently available. However, the threat of contracting a
STD always remained whenever unprotected sexual relations took
place. Men are regarded as the agents who transmit STDs, not wives,
and not prostitutes (4). Is unprotected sex prevalent among
adolescents?
In the US, substantial morbidity and social problems among youth
result from unintended pregnancies and STDs, including HIV
infection. Results from the 2007 survey indicate that 47.8% of
students had ever sexual intercourse, 35% of high school students
were currently sexually active, and 38.5% of currently sexually active
high school students had not used a condom during last sexual
intercourse (5).
We see that about third of young adolescents were involved in
unprotected sex. This figure is alarming.
37
L. Ben-Nun King David

Participants included 9th-12th grade rural adolescents (n=5,745)


who completed the 2003 national Youth Risk Behavior Survey.
Smoking ≥ three days during the past 30 days was associated with
unprotected sex. Alcohol or drug use before last sexual intercourse,
having ever used marijuana, having ever used cocaine and drinking
alcohol during the past 30 days were associated with having multiple
sexual partners (6).
Among adolescents, smoking is associated with unprotected sex,
while alcohol, drug, marijuana, and cocaine usage are risk factors for
having multiple partners. The medical record, that is the biblical text,
gives no details about any of these risky behaviors in the case of
either King David or Bathsheba.
A rapid influx of Latino migrant workers came to New Orleans
after Hurricane-Katrina. Many of these men were unaccompanied by
their primary sex partner potentially placing them at high-risk for
HIV/STDs. In the last month, 68.9% engaged in sex with high-risk sex
partners, 30.0% were in potential bridge, 50.0% used condoms
inconsistently, 30.6% did not use a condom the last time they had
sex, and 21.1% were abstinent. Latino migrant workers in New
Orleans reported risky sexual behaviors and low condom use within a
potential bridge position. Although a low prevalence of C.
trachomatis and N. gonorrhea was found, there was a high percent of
self-reported HIV infection (7).
We see that in this population about half used condoms
inconsistently. This segment of population was at risk to contract
some STD, including HIV.
This study examined condom use and intimacy among Tajik male
migrants and their regular female partners in Moscow, Russia. This
study included a survey of 400 Tajik male labor migrants and
longitudinal ethnographic interviews with 30 of the surveyed male
migrants and 30 of their regular female partners. Of the surveyed
male migrants, 351 (88%) reported having a regular female partner in
Moscow. The migrants' and regular partners' intentions to use
condoms diminished with increased intimacy, yet each party
perceived intimacy differently. Migrants' intimacy with regular
partners was determined by their familiarity and the perceived sexual
cleanliness of their partner. Migrants believed that Muslim women
were cleaner than Orthodox Christian women and reported using
condoms more frequently with Orthodox Christian regular partners.
Regular partners reported determining intimacy based on the
38
L. Ben-Nun King David

perceived commitment of the male migrant. When perceived


commitment faced a crisis, intimacy declined and regular partners
renegotiated condom use. The association between intimacy and
condom use suggests that HIV-prevention programs should aim to
help male migrants and female regular partners to dissociate their
approaches to condom use from their perceptions of intimacy (8).
The objective of this study was to explore knowledge, attitudes
and barriers to condom use among FSWs and truck drivers (truckers)
operating along major transport corridors in Uganda. Structured
questionnaires were administered to explore FSWs' and truckers'
knowledge of and attitudes towards condom use among 259 FSWs
and 261 truckers. Qualitative data were collected on barriers to
condom use using focus group discussions. Condom knowledge was
high with 97% of FSWs and 95% of truckers agreeing with the
statement, "using condoms properly and consistently reduces risk of
HIV infection". Attitudes towards condom use were generally
favorable with 91% of FSWs and 82% of truckers agreeing with the
statement, "condom use is the best method of HIV prevention".
Qualitative findings show that poverty, refusal to use condoms by
male partners, alcohol use before sex and beliefs that condoms 'kill
the mood for sex' remain key barriers to consistent condom use. In
conclusion, consistent condom use among FSWs and truckers is still
hampered by economic and relationship factors (9).

ASSESSMENT: in general, these studies show that in different


countries condoms are used inconsistently.

References
1. Oakley D, Bogue E-L. Quality of condom use as reported by female
clients of a family planning clinic. Am J Public Health. 1995;85:1526-30.
2. Murphy JC. The Condom Industry in the United States. Jefferson, NC:
McFarland & Co; 1990.
3. Cates W, Stone KM. Family planning, sexually transmitted diseases and
contraceptive choice: a literature update: Part I. Fam Plann Perspect. 1992;
24:75-84.
4. Jacobson JL. The other epidemic. World Watch. 1992;5:10-7.
5. Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance –
United States, 2007. 2008;57:1-131.
6. Yan AF, Chiu YW, Stoesen CA, Wang MQ. STD-/HIV-related sexual risk
behaviors and substance use among U.S. rural adolescents. J Natl Med
Assoc. 2007;99:1386-94.
39
L. Ben-Nun King David

7. Kissinger P, Liddon N, Schmidt N, et al. HIV/STI risk behaviors among


Latin migrant workers in New Orleans pos-Hurricane Katrina disaster. Sex
Transm Dis. 2008;35:924-8.
8. Zabrocki C, Polutnik C, Jonbekov J, et al. Condom use and intimacy
among Tajik male migrants and their regular female partners in Moscow.
Cult Health Sex. 2014 Jul 18:1-17.
9. Matovu JK, Ssebadduka NB. Knowledge, attitudes & barriers to
condom use among female sex workers and truck drivers in Uganda: a
mixed-methods study. Afr Health Sci. 2013;13(4):1027-33.

TO SUM UP: the features of unprotected sex today are similar to


those in ancient times. King David and Bathsheba both behaved
immorally having unprotected sexual contacts.
If preventive measures are not taken, this practice is dangerous
since it is associated with the transmission of various STDs.
In biblical times AIDS did not exist, nor were condoms apparently
available. However, the threat of contracting a STD always remained
whenever unprotected sexual relations took place.

FAMILY SYSTEM THEORY


In the system thinking theory: 1] Families (and other social
groups) are systems having properties which are more than the sum
of the properties of their parts. 2] The operation of such systems is
governed by general rules. 3] Every system has a boundary, the
properties of which are important in understanding how the system
works. 4] The boundaries are semi-permeable; some things can pass
through them while others cannot. Moreover, certain materials can
pass one way but not the other. 5] Family systems tend to reach a
relatively, but not totally, steady state. Growth and evolution are
possible. Change can occur, or be stimulated, in various ways. 6]
Communication and feedback mechanisms between the parts of a
system are important in the functioning system. 7] Events such as
behavior of individuals in a family are examples of circular causality,
rather than a linear causality. 8] Family systems, like other open
systems, appear to have purpose. 9] Systems are made of subsystems
and themselves are parts of larger suprasystems (1).
40
L. Ben-Nun King David

Family systems theory and attachment theory have important


similarities and complementarities. Here we consider two areas in
which the theories converge: 1] in family system theorists'
description of an overly close, or "enmeshed," mother-child dyad,
which attachment theorists conceptualize as the interaction of
children's ambivalent attachment and mothers' preoccupied
attachment; 2] in family system theorists' description of the
"pursuer-distance cycle" of marital conflict, which attachment
theorists conceptualize as the interaction of preoccupied and
dismissive partners. Family systems theory evidence, and more
extensively review attachment theory evidence, pertaining to these
points of convergence are reviewed. Cross-cultural research leads to
conclude that the dynamics described in both theories reflect, in
part, Western ways of thinking and Western patterns of relatedness.
Evidence from Japan suggests that extremely close ties between
mother and child are perceived as adaptive, and are more common,
and children experience less adverse effects from such relationships
than do children in the West. In Japan, there is less emphasis on the
importance of the exclusive spousal relationship, and less need for
the mother and father to find time alone to rekindle romantic,
intimate feelings and to resolve conflicts by openly communicating
their differences. Thus, the "maladaptive" pattern frequently cited by
Western theorists of an extremely close mother-child relationship, an
unromantic, conflictual marriage characterized by little verbal
communication and a peripheral, distant father, may function
differently in other cultures. While both theories will be greatly
enriched by their integration, we caution against the application of
either theory outside the cultures in which they were developed (2).
The King's family was a special system that was governed by
special rules namely full obedience to the King. There were many
subsystems in this one family system, and the behavioral and
communication patterns of each subsystem were dependent on the
decisions of the head of the family, in this case the powerful King.
The subsystems functioned by mutual consent, and were
interconnected with open boundaries. However, all decisions flowed
only one way with full acceptance of the King's wishes, will and
choice. The family system functioned within rigid borders, and this
function was dependent on the functioning of its different
subsystems.
41
L. Ben-Nun King David

References
1. Becket JA. General system theory, psychiatry and psychotherapy. Int J
Group Psychotherapy. 1973;23:292-305.
2. Rothbaum F, Rosen K, Ujiie T, Uchida N. Family systems theory,
attachment theory, and culture. Fam Process. 2002;41(3):328-50.

A NEW COMPOSITION OF THE KING'S FAMILY

In any case, when the days of mourning were over "When the
mourning was past, David sent and fetched her (Bathsheba) to his
house; and she became his wife, and bare him a son” (II Samuel
11:27). David’s family again expanded. Two additional members
entered David’s family life cycle – Bathsheba and the newborn son.
Holmes and Rahe developed a standard list of events, the
Schedule of Readjustment Rating Scale (1). Several hundred
responders rated the amount of adaptation or "life change units"
that each event was thought to entail. According to this Scale,
marriage has a mean "life change units" value of 50, ranked seventh
out of various life events while 'gain a new family member' has a
mean value of 39. Thus, marriages and subsequent births of children
exposed the King to stressful events.

Reference
1. Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J
Psychosom Res. 1967;11:213.

DEATH OF A NEWBORN SON


The death of a newborn is a painful situation, causing great
suffering to humans. This condition can occur in both developed and
developing countries, in rich as well as poor families. Thus,
prevention of neonatal deaths is an important task of each society.
One way of dealing with this situation is to study ancient texts
concerned with the newborn death. This research deals with the
death of the newborn son of King David and Bathsheba. Causes that
could have lead to the death this newborn were examined from the
viewpoint of contemporary medicine.
42
L. Ben-Nun King David

Unfortunately, the newborn son was afflicted by incurable disease.


Numerous causes can be linked to the newborn death. These include:
birth asphyxia, LBW or ELBW, prematurity, IUGT, PROM, congenital
birth defects, sepsis, meningitis, diarrhea, NT, malaria, measles,
syphilis, RDS, SIDS, home-birth, and low socioeconomic status as well as
deprived social position (1-16).
What was the cause responsible for the death of King David's
newborn son?

References
1. Bittar Z. Rates of perinatal mortality and low birth weight among 3367
consecutive births in south of Beirut. J Med Liban. 1998;46:126-30.
2. Bang AT, Reddy HM, Bang RA, Deshmukh MD. Why do neonates die in
rural Gadchiroli, India (Part II): estimating population attributable risks and
contribution of multiple morbidities for identifying a strategy to prevent
deaths. J Perinatol. 2005;25 Suppl 1:S35-43.
3. Vaid A, Mammen A, Primrose B, Kang G. Infant mortality in an urban
slum. Ind J Pediatr. 2007;74:449–53.
4. McDermott J, Steketee R, Wirima J. Perinatal mortality in rural Malawi.
Bull World health Organ. 1996;74:165-71.
5. Jehan I, Harris H, Salat S, et al. Neonatal mortality, risk factors and
causes: a prospective population-based cohort study in urban Pakistan. Bull
World Health Org. 2009;87:130-8.
6. Chowdhury HR, Thompson S, Ali M, et al. Causes of neonatal deaths in a
rural subdistrict of Bangladesh: implications for intervention. J Health Popul
Nutr. 2010;28:375-82.
7. Boo NY, Nasri NM, Cheong SK, Sivamohan N. A 2-year study of neonatal
mortality in a large Malaysian hospital. Singapore Med J. 1991;32:142.
8. Onayade AA, Sule SS, Elusiyan JB. Determinants of neonatal mortality at
Wesley Guild Hospital, Ilesa, Nigeria. Niger J Med. 2006;15:271-6.
9. de Almeida MF, Alencar GP, Schoeps D, et al. Survival and risk factors for
neonatal mortality in a cohort of very low birth weight infants in the southern
region of São Paulo city, Brazil. Cad Saude Publica. 2011;27(6):1088-98.
10. Souza Rugolo LM, Bentlin MR, Mussi-Pinhata M, et al. Late-onset sepsis
in very low birth weight infants: a Brazilian Neonatal Research Network Study.
Trop Pediatr. J Trop Pediatr. 2014;60(6):415-21.
11. Turner C, Turner P, Hoogenboom G, et al. A three year descriptive study
of early onset neonatal sepsis in a refugee population on the Thailand
Myanmar border. BMC Infect Dis. 2013 21;13:601.
12. Hornik CP, Fort P, Clark RH, et al. Early and late onset sepsis in very-
low-birth-weight infants from a large group of neonatal intensive care units.
Early Hum Dev. 2012;88 Suppl 2:S69-74.
43
L. Ben-Nun King David

13. Manuck TA, Varner MW. Neonatal and early childhood outcomes
following early vs later preterm premature rupture of membranes. Am J
Obstet Gynecol. 2014 May 22. pii: S0002-9378(14)00498-0.
14. Gezer A, Parafit-Yalciner E, Guralp O, et al. Neonatal morbidity
mortality outcomes in pre-term premature rupture of membranes. J Obstet
Gynaecol. 2013;33(1):38-42.
15. Ben-Nun L. In: Ben-Nun L. (ed.). A Disease that Afflicted the Newborn
Son of King David. B.N. Publication House. Israel. 2011.
16. Ma Y, Guo S, Wang H, et al. Cause of death among Infants in rural
Western China: a community-based study using verbal autopsy. J Pediatr. 2014
Jun 11. pii: S0022-3476(14)00405-3.

BIRTH ASPHYXIA. Factors that place the newborn infant at high risk
for asphyxia include: 1] maternal conditions such as DM, preeclampsia,
hypertension, chronic renal disease, anemia (e.g., Hg <10 g/dl); blood
type or group alloimmunization; narcotic, barbiturate, tranquilizer, or
alcohol intoxication; history of previous perinatal loss; lupus, maternal
heart disease; maternal fever or other evidence of amnionitis; maternal
hypotension and hemorrhage, 2] labor and delivery conditions such as
forceps delivery other than low-elective or vacuum-extraction delivery;
breech or other abnormal presentation and delivery; cephalopelvic
disproportion: shoulder dystocia, prolonged second stage; Cesarian
section; prolapsed umbilical cord; cord compression, prolonged rupture
of membranes, abruption placentae, placenta previa, or other
antepartum hemorrhage, 3] fetal conditions such as premature
delivery; postmature delivery; acidosis determined by fetal scalp
capillary blood; abnormal heart rate pattern or dysrhythmia;
meconium-stained amniotic fluid; oligohydramnios; polyhydramnios;
decreased rate of growth: uterine size or fetal size determined by
ultrasonography; macrosomia; immaturity or pulmonary surfactant
system; fatal malformations determined by sonography; hydrops
fetalis; low biophysical profile; multiple births, in particular, discordant,
stuck, or monoamniotic, and abnormal umbilical artery (1).
Among the numerous fetal conditions associated with birth
asphyxia, LBW, Apgar scores, lower umbilical artery pH, and lower
neonatal Hg levels at birth, prematurity, fatal malformation, or a
combination of these conditions would be the most likely causes (2,3).
Asphyxiated infants have delayed onset of breathing, poor
movement and color, and an increased frequency of convulsions (4).
44
L. Ben-Nun King David

The biblical text does not mention any of these symptoms. However,
the lack of details does not prove the absence of birth asphyxia.
The biblical text does not tell us if Bathsheba suffered from some
maternal condition, or difficult labor, or some complication associated
with her labor. Although these details are lacking, it appears that
maternal and labor or delivery conditions were not responsible.
Were non-specific symptoms present? Did the newborn suffer from
birth asphyxia?

References
1. Phibbs RH. Delivery Room Management. In: Avery GB, Fletscher MA,
McDonald MG (eds.). Fifth ed. Lippincott, Williams & Wilkins. Philadelphia,
Baltimore. 1999, p. 23.
2. Pálsdóttir K, Thórkelsson T, Hardardóttir H, et al. Birth asphyxia, neonatal
risk factors for hypoxic ischemic encephalopathy. Laeknabladid. 2007;93:669-
73.
3. Kinoti SN. Asphyxia of the newborn in east, central and southern Africa.
East Afr Med J. 1993;70:422-33
4. Ben-Nun L. A disease that afflicted the newborn son of King David. Ben-
Nun L. (ed.). B.N. Publication House. Israel. 2011.

LOW/VERY LOW BIRTH WEIGHT. LBW/VLBW infants remain at


higher risk of mortality than infants with normal birth weight. LBW for
GA had a dose–response effect: the more growth restricted the infant
the greater the risk of mortality. The NM rate for LBW is higher than
that of FT-IUGR infants. Diarrhea and URTI occur more often in FT-IUGR
infants and premature infants than in FT-AGA infants (1-7).
In VLBW infants, a mean GA of ≤26 weeks is a risk factor for survival.
The most common neonatal complication is apnea of prematurity,
followed by RDS. The most common cause of death is sepsis, followed
by extreme prematurity and RDS. Mortality in ELBW infants includes
lower GA, Apgar scores at one minute, pulmonary hypertension, and
severe IVH (2,5,8-10). Birth weight less than 1,000 g and Apgar index <
seven were associated with increased risk (11).
Did the King's son suffer from LBW or VLBW?

References
1. McCormick MC. The contribution of low birth weight to infant mortality
and childhood morbidity. N Engl J Med. 1985;312:82-90.
45
L. Ben-Nun King David

2. Tsou KI, Tsao PN; Taiwan Infant Development Collaborative Study Group.
The morbidity and survival of very-low-birth-weight infants in Taiwan. Acta
Paediatr Taiwan. 2003;44:349-55.
3. Kilparick S, Schlueter M, Piecuch R, et al. Outcome of infants born at 24-
26 weeks gestation: I Survival and cost. Obstet Gynecol. 1997;90:803.
4. Piecuch R, Leonard C, Cooper B., et al. Outcome of infants born at 24-26
weeks gestation: II. Neurodevelopmental outcome. Obstet Gynecol. 1997:
90:809.
5. Das BK, Mishra RN, Mishra OP, et al. Comparative outcome of low birth
weight babies. Indian Pediatr. 1993;30:15-21.
6. Afjeh SA, Sabzehei MK, Fallahi M, Esmaili F. Outcome of very low birth
weight infants over 3 years report from an Iranian center. Iran J Pediatr. 2013;
23(5):579-87.
7. Sritipsukho S, Suarod T, Sritipsukho P. Survival and outcome of very low
birth weight infants born in a university hospital with level II NICU. J Med Assoc
Thai. 2007;90(7):1323-9.
8. Shankaran S, Fanaroff AA, Wright LL, et al. Risk factors for early death
among extremely low-birth-weight infants. Am J Obstet Gynecol. 2002;
186:796-802.
9. Bartels DB, Kreienbrock L, Dammann O, et al. Population based study on
the outcome of small for gestational age newborns. Arch Dis Child Fetal
Neonatol Ed. 2005;90:F53-9.
10. Committee on Fetus and Newborn. American Academy of Pediatrics.
Committee on Obstetric Practice. American College of Obstetricians and
Gynecologists Use and abuse of the Apgar score. Pediatrics. 1996;98:141–2.
11. de Almeida MF, Alencar GP, Schoeps D, et al. Survival and risk factors
for neonatal mortality in a cohort of very low birth weight infants in the
southern region of São Paulo city, Brazil. Cad Saude Publica. 2011;27(6):1088-
98.

PREMATURITY. Despite improvements in related perinatal


mortality, preterm birth remains a major obstetric and neonatal
problem with rates of preterm birth rising worldwide. Studies from the
US and Latin America suggest that much of this rise relates to increased
rates of medically indicated preterm births. By contrast, European and
Australian data indicate that increases in spontaneous preterm labor
also play a role (1).
Despite improvement in perinatal mortality, preterm birth remains a
major obstetric and neonatal problem. Prematurity is a risk factor for
NM. Very preterm infants are at risk for NM, NEC, chronic lung disease,
PROM, and PROM + hemorrhage; these infants are often twins, growth-
retarded, and malformed (2-8).
46
L. Ben-Nun King David

Premature birth interrupts normal in utero lung development, which


results in significant alterations in lung function and physiology.
Increasingly, there are reports documenting the broad range of
complications experienced by infants aged 34 to 36 weeks' GA. A
comprehensive search for studies that reported epidemiologic data and
respiratory morbidity was conducted on the PubMed, Medline, Ovid
Biosis, and Embase databases from 2000 to 2009 by using medical
subject headings "morbidity in late preterm infants," "preterm infants
and lung development," "prematurity and morbidity," and "prematurity
and lung development." Because the number of studies exclusive to
infants aged 34 to 36 weeks' GA was limited, selected studies also
included infants aged 32 to 36 weeks' GA. Of the 24 studies identified,
16 were retrospective population-based cohort studies; eight studies
were observational. Infants born at 32 to 36 weeks' GA, including
infants of 34 to 36 weeks' GA, experience substantial respiratory
morbidity compared with term infants. Levels of morbidity were, at
times, comparable to those observed in very preterm infants. The data
indicated that the immaturity of the respiratory system of infants 34 to
36 weeks' GA at birth resulted in increased morbidity in infancy and led
to deficits in lung function that may persist into adulthood (9).
Did the newborn son of King David suffer from prematurity?

References
1. Norman JE, Morris C, Chalmers J. The effect of changing patterns of
obstetric care in Scotland (1980-2004) on rates of preterm birth and its
neonatal consequences: perinatal database study. PLoS Med. 2009;6(9):
e1000153.
2. Zeitlin J, El Ayoubi M, Jarreau PH, et al. Impact of fetal growth restriction
on mortality and morbidity in a very preterm birth cohort. J Pediatr. 2010;
157(5):733-9.e1.
3. van der Heyden JL, van der Ham DP, van Kuijk S, et al. Outcome of
pregnancies with preterm prelabor rupture of membranes before 27 weeks'
gestation: a retrospective cohort study. Eur J Obstet Gynecol Reprod Biol.
2013;170(1):125-30.
4. Newman DE, Paamoni-Keren O, Press F, et al. Neonatal outcome in
preterm deliveries between 23 and 27 weeks' gestation with and without
preterm premature rupture of membranes. Arch Gynecol Obstet. 2009;
280(1):7-11.
5. Schieve LA, Handler A. Preterm delivery and perinatal death among black
and white infants in a Chicago-area perinatal registry. Obstet Gynecol. 1996;
88:356-63.
47
L. Ben-Nun King David

6. Lal MK, Manktelow BN, Draper ES, Field DJ; Population-based study.
Chronic lung disease of prematurity and intrauterine growth retardation: a
population-based study. Pediatrics. 2003;111:483-7.
7. Westby Wold SH, Sommerfelt K, Reigstad H, et al. Neonatal mortality
and morbidity in extremely preterm small for gestational age infants: a
population based study. Arch Dis Child fetal Neonatol Ed. 2009;94:F363-7.
8. Elder DE, Wong A, Zuccollo JM. Risk factors for and timing of death of
extremely preterm infants. Aust J Obstet Gynaecol. 2009;49(4):407-10.
9. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function
in preterm infants of 32 to 36 weeks' gestational age. Pediatrics. 2010;
126:115-28.

INTRAUTERINE GROWTH RETARDATION. IUGT is associated with


increased NM, NEC, RDS, and IVH (1), various deformities and
chromosomal aberrations (2). The main neonatal complications of IUGT
are related to lungs, C-V system and cerebrum (1-4). Combination of
IUGR and pre-eclampsia or HELLP syndrome ["HELLP" is an abbreviation
of the three main features of the syndrome: Hemolysis, Elevated Liver
enzymes, and Low Platelet count] (5,6) is a criterion of severity for both
the mother and the fetus (7). In infants with IUGR, pre-eclampsia
appears earlier and is more severe in women with pre-eclampsia
compared with women without (7).
Was IUGT responsible for the death of King David's newborn son?
Was IUGR combined with prematurity or other comorbidity(s)
responsible?

References
1. Bernstein IM, Horbar JD, Badger GJ, et al. Morbidity and mortality among
very-low-birth-weight neonates with intrauterine growth restriction. The
Vermont Oxford Network. Am J Obstet Gynecol. 2000;182(1 Pt 1):198-206.
2. Meyberg R, Boos R, Babajan A, et al. Intrauterine growth retardation-
perinatal mortality and postnatal morbidity in a perinatal center. J
Geburtshiefe Neonatal. 2000;204:218-23.
3. Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases
morbidity and mortality among premature neonates. Am J Obstet Gynecol.
2004;191:481-7.
4. Lee MJ, Conner EL, Charafeddine L, et al. A critical birth weight and other
determinants of survival for infants with severe intrauterine growth restriction.
Ann NY Acad Sci. 2001;943:326-39.
5. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues
and management. A review. BMC Pregnancy Childbirth. 2009;9:8.
48
L. Ben-Nun King David

6. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low


platelet count: a severe consequence of hypertension in pregnancy. Am J
Obstet Gynecol. 1982;142 (2):159-67.
7. Gey C, Clouqueur E, Lambert J, et al. Links between preeclampsia and
intrauterine growth restriction. Gynecol Obstet Fertil. 2014;42(4):229-33.

PREMATURE RUPTURE OF MEMBRANES. Despite progress in


obstetric and neonatal care over the past 20 years, perinatal outcome
in pregnancies with PROM before 23 weeks of gestation remains dismal
(1). PROM at 16 through 26 weeks of gestation complicates
approximately 1% of pregnancies in the US (2,3).
Complications include neonatal sepsis, NEC, pulmonary hypoplasia,
RSD, and severe IVH. The risk of infection is significant following
preterm PROM (1).
The perinatal survival rate based on gestational age at the onset of
PROM is poor when the fetal membrane is ruptured before 23 weeks of
gestation, however. The 100% survival rate at viable gestational age
(i.e., 24 weeks), however, is most likely due to the use of antenatal
antibiotics, corticosteroids, and improved neonatal care (4–6).
The risk of infection due solely to PROM is insignificant compared
with the risk attributable to preterm birth. Perinatal mortality and
cause-specific mortality varied inversely with GA. These rates are
insignificantly different between groups with or without PROM or with
or without associated maternal endometritis. Although the mortality
due to infection is higher in preterm compared with term groups, most
preterm deaths are attributed to other factors, particularly anoxia and
respiratory causes (7).
Recent data indicate that the presence of membrane rupture before
delivery is not associated with increased NM in any GA group. The
effects of a prolonged latency period are inconsistent across GAs (8).
A retrospective review of 228 PPROM singleton pregnancies was
followed-up between 1996 and 2005. The most common neonatal
morbidities in PPROM cases were RDS, sepsis and IVH. The route of
delivery does not affect NICU requirements, perinatal asphyxia, sepsis
and IVH rates in PPROM cases. NICU and PPV requirements, RDS, sepsis
and IVH rates increase if the Apgar score is < five. Neonatal morbidity
and mortality rates increase as the latent period lengthens. CRP on
admission, last CRP, birth weight and the five min Apgar score were
associated with NICU requirements; only the five min Apgar score was
associated with RDS; and last leukocyte count and maternal hematocrit
49
L. Ben-Nun King David

were associated with sepsis and pneumonia, independently. In PPROM


cases, CRP on admission, last CRP, birth weight, the five minutes Apgar
score, last leukocyte count and maternal hematocrit, should be
considered to predict neonatal outcomes (9).

ASSESSMENT: although PROM is related to serious complications, it


is not associated with a significant neonatal mortality. Thus, it seems
that PROM was not related to the death of King David's newborn son.

References
1. Lee C. Yang, Donald R. Taylor, Howard H. Kaufman, et al. Maternal and
Fetal Outcomes of Spontaneous Preterm Premature Rupture of Membranes. J
Am Osteopath Assoc.2004;104(12): 537-42.
2. Nourse CB, Steer PA. Perinatal outcome following conservative
management of mid-trimester pre-labor rupture of the membranes. J Paediatr
Child Health. 1997;33:125–30.
3. Fortunato SJ, Welt SI, Eggleston MK Jr, Bryant EC. Active expectant
management in very early gestations complicated by premature rupture of the
fetal membranes. J Reprod Med. 1994;39:13-6.
4. Moretti M, Sibai BM. Maternal and perinatal outcome of expectant
management of premature rupture of membranes in the midtrimester. Am J
Obstet Gynecol. 1988;159:390–6.
5. Beydoun SN, Yasin SY. Premature rupture of the membranes before 28
weeks: conservative management. Am J Obstet Gynecol. 1986;155:471 -9.
6. Taylor J, Garite TJ. Premature rupture of membranes before fetal
viability. Obstet Gynecol. 1984;64:615-20.
7. Daikoku NH, Kaltreider DF, Johnson TR Jr, et al. Premature rupture of
membranes and preterm labor: neonatal infection and perinatal mortality
risks. Obstet Gynecol. 1981;58(4):417-25.
8. Blumenfeld YJ, Lee HC, Gould JB, et al. The effect of preterm premature
rupture of membranes on neonatal mortality rates. Obstet Gynecol.
2010;116(6):1381-6.
9. Gezer A, Parafit-Yalciner E, Guralp O, et al. Neonatal morbidity mortality
outcomes in pre-term premature rupture of membranes. J Obstet Gynaecol.
2013;33(1):38-42.

CONGENITAL MALFORMATIONS. Birth defects, encountered


frequently by pediatricians, are important causes of childhood
morbidity and mortality. Birth defects can be classified according to
their severity, pathogenic mechanism, or whether they are involving a
single system or multiple systems. This hospital-based prospective
50
L. Ben-Nun King David

descriptive study highlights the prevalence of Congenital Anomalies in


one year among live born neonates delivered in Zagazig University
Hospital (Egypt). All women giving birth to viable babies were included.
Demographic details, associated risk factors and the type of congenital
anomalies in all babies were recorded. Diagnosis of congenital
anomalies was based on clinical evaluation, radiographic examination,
ultrasonography, echocardiography and chromosomal analysis of the
newborn whenever recommended. The overall incidence of congenital
anomalies among live born neonates was 2.5%, as most of the cases
were referred to Zagazig Hospital for delivery. The musculoskeletal
system (23%) was the most commonly involved followed by the CNS
(20.3%). Involvement of more than one system was observed in (28.6%)
cases. Among maternal and fetal risk factors, parental consanguinity,
maternal under nutrition and obesity, positive history of an anomaly in
the family, LBW, and prematurity were significantly associated with
higher frequency of congenital anomalies (p<0.05), with insignificant
differences for maternal age and the sex of the neonates. The current
study highlights the prevalence of congenital anomalies in one year in
Zagazig Hospital. It revealed a high prevalence of congenital anomalies
and stressed the importance of carrying out a thorough clinical
examination of all neonates at birth (1).
Congenital malformations are linked to prematurity (2,3), and are a
risk factor for increased NM, which increases if LBW/VLBW is present.
Among the very preterm, CNS and C-V defects are prevalent (4-16).
Congenital C-V anomalies include tetralogy of Fallot, pulmonary
stenosis, aortic stenosis, coarctation of aorta, complete atrioventricular
septal defect, or VSD (9). While congenital cerebral malformations
consist of heterotopia, callosal anomalies such as agenesis, posterior
fossa malformations, malformations of migration, malformations of
development, destructive lesions, cerebellar hypoplasia, cortical cleft,
polymicrogyria, porencephaly, and partial agenesis of the septi pellucid
(14-17).
Was the newborn son of the King afflicted by some congenital
anomaly? C-V? CNS?

References
1. El Koumi MA, Al Banna EA, Lebda I. Pattern of congenital anomalies in
newborn: a hospital-based study. Pediatr Rep. 2013 Feb 5;5(1):e5.
2. Rasmussen SA, Moore CA, Paulozzi LJ, Rhodenhiser EP. Risk for birth
defects among premature infants: a population-based study. J Pediatr.
2001;138:668-73.
51
L. Ben-Nun King David

3. Honein MA, Kirby RS, Meyer RE, et al. The association between major
birth defects and preterm birth. Matern Child Health J. 2009;13:164-75.
4. Cragan JD, Gilboa SM. Including prenatal diagnoses in birth defects
monitoring: Experience of the Metropolitan Atlanta Congenital Defects
Program. Birth Defects Res A Clin Mol Teratol. 2009;85:20-9.
5. Mili F, Edmonds LD, Khoury MJ, McClearn AB. Prevalence of birth defects
among low-birth-weight infants. A population study. Am J Dis Childhood. 1991;
145:1313-8.
6. Malcoe LH, Shaw GM, Lammer EJ, Herman AA. The effect of congenital
anomalies on mortality risk in white and black infants. Am J Public Health.
1999;89:887-92.
7. Druschel C, Hughes JP, Olsen C. Mortality among infants with congenital
malformations, New York State, 1983 to 1988. Public Health Rep. 1996;111:
359-65.
8. Bol KA, Rickard RS, Kirby RS. Case fatality among infants with congenital
malformations by lethality. Birth Defects Res A Clin Mol Teratol. 2004;70:580-
5.
9. Tanner K, Sabrine N, Wren C. Cardiovascular malformations among
preterm infants. Pediatrics. 2005;116:e833-8.
10. Brown WR. Association of preterm birth with brain malformations.
Pediatr Res. 2009;65:642-6.
11. Mecchia D, Casale V, Oneda R, et al. Sudden death of an infant with
cardiac, nervous system and genetic involvement - a case report. Diagn Pathol.
2013 Sep 20;8:159.
12. Laux D, Bessières B, Houyel L, et al. Early neonatal death and congenital
left coronary abnormalities: ostial atresia, stenosis and anomalous aortic
origin. Arch Cardiovasc Dis. 2013;106(4):202-8.
13. Wren C, Irving CA, Griffiths JA, et al. Mortality in infants with
cardiovascular malformations. Eur J Pediatr. 2012;171(2):281-7.
14. Simon EM, Goldstein RB, Coakley FV, et al. Fast MR imaging of fetal CNS
anomalies in utero. A J N R Am J. Neuroradiol. 2000;21:1688-98.
15. Laifer-Narin S, Budorick NE, Simpson LL, Platt LD. Fetal magnetic
resonance imaging: a review. Curr Opin Obstet Gynecol. 2007;19:151-6.
16. Levine D, Barnes PD, Madsen JR, et al. Fetal central nervous system
anomalies: MR imaging augments sonographic diagnosis. Radiology. 1997;
204:635-42.
17. Ben-Nun L. Congenital anomalies. In: A Disease that Afflicted the
Newborn Son of King David. B. N. Publication House. Israel. 2011, pp. 62-72.
52
L. Ben-Nun King David

SEPSIS. Was sepsis responsible? Neonatal sepsis is a major cause of


mortality in both developed and developing countries (1). Sepsis, either
early or late onset, is associated with high NM (2). In different
countries, different pathogens cause sepsis (3-5). Prematurity,
LBW/VLBW, abnormal WBC counts, lethargy, convulsion, inability to
feed, cyanosis, PROM, RDS, failure to feed, hypothermia, and
meconium stained liquor are risk factors for neonatal sepsis (3,6-9). A
combination of meningitis and sepsis is a prevalent condition,
associated with high mortality rate (10). Among infants surviving ≥
seven days, sepsis and severe IVH are associated with NM (11).
Sepsis is a pernicious disease that often causes infant death in a
short time. Therefore, it seems unlikely that King David's newborn son
would survive seven days without appropriate modern treatment
(including antibiotics). For this reason, the diagnosis of sepsis in this
case seems unlikely.

References
1. Kaistha N, Mehta M, Singla N, et al. Neonatal septicemia isolates and
resistance patterns in a tertiary care hospital of North India. J Infect Dev Ctries.
2009;4:55-7.
2. Souza Rugolo LM, Bentlin MR, Mussi-Pinhata M, et al. Late-onset sepsis
in very low birth weight infants: a Brazilian neonatal research network study.
Trop Pediatr. J Trop Pediatr. 2014;60(6):415-21.
3. Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD
Neonatal Research Network. Semin Perinatol. 2003;27:293-301.
4. Mokuolu AO, Jiya N, Adesiyun OO. Neonatal septicaemia in Ilorin:
bacterial pathogens and antibiotic sensitivity pattern. Afr J Med Sci. 2002;
31:127-30.
5. Aurangzeb B, Hameed A. Neonatal sepsis in hospital-born babies:
bacterial isolates and antibiotic susceptibility patterns. J Coll Physician Surg
Pak. 2003;13:629-32.
6. Hornik CP, Fort P, Clark RH, et al. Early and late onset sepsis in very-low-
birth-weight infants from a large group of neonatal intensive care units. Early
Hum Dev. 2012;88 Suppl 2:S69-74.
7. Kayange N, Kamugisha E, Mwizamholya DL, et al. Predictors of positive
blood culture and deaths among neonates with suspected neonatal sepsis in a
tertiary hospital, Mwanza- Tanzania. BMC Pediatr. 2010;10:39.
8. Shitaye D, Asrat D, Woldeamanuel Y, Worku B. Risk factors and etiology
of neonatal sepsis in Tikur Anbessa University Hospital, Ethiopia. Ethip Med J.
2010;48:11-21.
9. Iijima S, Arai H, Ozawa Y, et al. Clinical patterns in extremely preterm (22
to 24 weeks of gestation) infants in relation to survival time and prognosis. Am
J Perinatol. 2009;26:399-406.
53
L. Ben-Nun King David

10. Rodríguez Cervilla J, Fraga JM, García Riestra C, et al. Neonatal sepsis:
epidemiologic indicators and relation to birth weight and length of
hospitalization time. An Esp Pediatr. 1998;48:401-8.
11. Tiskumara R, Fakharee SH, Liu CQ, et al, and Asia-Pacific Neonatal
Infections Study. Neonatal infections in Asia. Arch Dis Child Fetal Neonatal Ed.
2009;94:F144-8.

MENINGITIS. Was meningitis responsible? NM due to meningitis is


high (1). LBW, VLBW and prematurity/extreme prematurity are risk
factors for meningitis (2-4).
In meningitis, symptoms include feed intolerance, lethargy,
temperature instability, bulging anterior fontanel that is a significant
indicator of poor prognosis, as well as and various non-specific signs
and symptoms (5-7). The combination of meningitis and sepsis is high
(8). Many patients die within 72 hours after admission to hospital (9).
In the biblical text, no symptoms of the disease that afflicted the
newborn are described. Were the disease symptoms non-specific?
The course of meningitis is pernicious, and many infants would die
in a short time. For this reason, it seems unlikely that the newborn
would survive seven days without appropriate modern treatment. For
this reason, it seems unlikely that meningitis was responsible for this
poor infant death (12).

References
1. de Louvois J. Acute bacterial meningitis in the newborn. J Antimicrob
Chemoth. 1994;34 Suppl A:61-73.
2. Ríos-Reátegui E, Ruiz-González L, Murguía-de-Sierra T. Neonatal bacterial
meningitis in a tertiary treatment center. Rev Invest Clin. 1998;50:31-6.
3. Airede KI, Adeyemi O, Ibrahim T. Neonatal bacterial meningitis and
dexamethasone adjunctive usage in Nigeria. Niger J Clin Pract. 2008;11:235-45.
4. Grupo de Hospitales Castrillo. Neonatal meningitis. Epidemiological
study of the Grupo de Hospitales Castrillo. An Esp Pediatr. 2002;56:556-63.
5. Laving AM, Musoke RN, Wasunna AO, Revathi G. Neonatal bacterial
meningitis at the newborn unit of Kenyatta National Hospital. East Afr Med J.
2003;80:456-62.
6. Airede AI. Neonatal bacterial meningitis in the middle belt of Nigeria.
Dev Med Chil Neurol. 1993;35:424-30.
7. Daoud AS, al-Sheyyab M, Abu-Ekteish F, et al. Neonatal meningitis in
northern Jordan. J Trop Pediatr. 1996;42:267-70.
54
L. Ben-Nun King David

8. Tiskumara R, Fakharee SH, Liu CQ, et al, and Asia-Pacific Neonatal


Infections Study. Neonatal infections in Asia. Arch Dis Child Fetal neonatal Ed.
2009;94:F144-8.
9. Nel E. Neonatal meningitis: mortality, cerebrospinal fluid, and
microbiological findings. J Trop Pediatr. 2000;46:237-9.

NECROTISING ENTEROCOLITIS. NEC remains one of the most


frequent G-I diseases in the NICU, with a continuing unacceptable high
mortality and morbidity rates. Up to 20% to 40% of infants with NEC
will need surgical intervention at some point. Although the exact
pathophysiology is not yet elucidated, prematurity, use of formula
feeding, and an altered intestinal microbiota are supposed to induce an
inflammatory response of the immature intestine. The clinical picture
of NEC has been well described. However, an early diagnosis and
differentiation against sepsis is challenging. Besides, it is difficult to
timely identify NEC cases that will deteriorate and need surgical
intervention. This may interfere with the most optimal treatment of
infants with NEC (1).
A retrospective analysis was performed on the clinical data of 82
neonates with NEC confirmed between January 2008 and October
2012. In the 82 cases of NEC, the cure rate decreased with the
aggravation of condition (p<0.05). The preterm infants had a
significantly higher incidence of NEC than the full-term infants at three
or more weeks after birth (p=0.004). The univariate analysis showed
that the prognosis of NEC was related to the factors such as sepsis,
CHD, scleredema, peritonitis, metabolic acidosis, hyponatremia,
leukocyte disorder, thrombocytopenia, elevated CRP, and severe
abdominal X-ray abnormalities (p<0.05), and the further logistic
regression analysis revealed that CHD, scleredema, and metabolic
acidosis were main risk factors for the clinical outcome of NEC (p<0.05).
In conclusion, the onset time of NEC is correlated with GA in neonates.
There are multiple prognostic factors in NEC; special attention should
be paid to the patients with CHD, scleredema, and metabolic acidosis
so that early intervention is performed to reduce mortality (2).
A retrospective case-control analysis of the charts of all late preterm
and term infants, who had NEC of Bell's stage ≥ II from 1995 to 2009,
along with infants of the same GA. Thirty-two late preterm infants had
NEC meeting criteria and 128 late preterm and term infants were
chosen as matched controls. The 32 NEC infants were more likely to
have the following characteristics: a culture-proven sepsis (p=0.0001),
55
L. Ben-Nun King David

be small for their GA (p=0.003), have a CHD (p=0.007), and suffer from
hypoxic-ischemic encephalopathy (p=0.04). The presence of
hypotension, metabolic acidosis, thrombocytopenia, and
pneumoperitoneum was associated with a poor prognosis. Twelve of
the 13 (92%) NEC infants who died had a surgical intervention. In this
study, late preterm and term infants who developed NEC had other
underlying clinical diagnoses and had culture-proven sepsis. Mortality
rate was high in infants who required surgical intervention, indicating
that they were gravely ill from the onset. Thrombocytopenia,
hypotension and metabolic acidosis in late preterm and term infant
with NEC were associated with poor prognosis (3).

ASSESSMENT: in general, NEC is associated with poor neonatal


outcome. The onset time of NEC is correlated with GA in neonates.
There are multiple prognostic factors in NEC; special attention should
be paid to the patients with CHD, scleredema, metabolic acidosis,
hypotension, thrombocytopenia, and pneumoperitoneum associated
with a poor prognosis
Was NEC responsible for the death of the King's newborn son?

References
1. Niemarkt HJ, de Meij TG, van de Velde ME, et al. Necrotizing
Enterocolitis: A Clinical Review on Diagnostic Biomarkers and the Role of the
Intestinal Microbiota. Inflamm Bowel Dis. 2014 Sep 29. [Epub ahead of print].
2. Yu L, Sun B, Miao P, Feng X. Risk factors for prognosis of neonatal
necrotizing enterocolitis: an analysis of 82 cases. Zhongguo Dang Dai Er Ke Za
Zhi. 2013;15(12):1082-5.
3. Al Tawil K, Sumaily H, Ahmed IA, et al. Risk factors, characteristics and
outcomes of necrotizing enterocolitis in late preterm and term infants. J
Neonatal Perinatal Med. 2013;6(2):125-30.

DIARRHEA. Acute diarrhea afflicts many children less than one year
of age (1,2). Maternal risk factors include black ethnicity, youth, single
status, low educational level, and insufficient prenatal care (1). These
factors do not seem to apply in Bathsheba's case.
Complications of diarrhea that may lead to death include
prematurity, LBW, nausea/vomiting, electrolyte disorders, shock, and
cardiac arrest (2-5). Premature birth is the main factor that can be
linked to mortality before the age of one month. The biblical text gives
no description of diarrhea or any complication associated with diarrhea
56
L. Ben-Nun King David

in the newborn. For this reason, it seems unlikely that diarrhea was
responsible for his death.

References
1. Ho MS, Glass RI, Pinsky PF, et al. Diarrheal deaths in American children.
Are they preventable? JAMA. 1988;260:3281-5.
2. Kilgore PE, Holman RC, Clarke MJ, Glass RI. Trends of diarrheal disease--
associated mortality in US children, 1968 through 1991. JAMA. 1995;274:1143-
8.
3. Aye DT, Bact D, Sack DA, et al. Neonatal diarrhea at a maternity hospital
in Rangoon. Am J Public Health 1991;81:480-1.
4. Bendib A, Dekkar N, Lamdjadani N. Factors associated with neonatal,
infant and child mortality. Results of a national survey in Algeria. Arch Fr
Pediatr. 1993;50:741-7.
5. Mehal JM, Esposito DH, Holman RC, et al. Risk factors for diarrhea-
associated infant mortality in the United States, 2005-2007. Pediatr Infect Dis
J. 2012;31(7):717-21.

NEONATAL TETANUS. Was the King's son afflicted by NT? Tetanus is


an acute, often fatal, disease caused by an exotoxin produced by C.
tetani (1). The disease was described by Hippocrates approximately 30
centuries ago (2). In 1884, Nicolaier produced tetanus in animals by
injecting them soil specimen (3). Kitasato isolated the organism, in
1889, from a human tetanus victim and reported neutralization of the
toxin by specific antibodies (4). Descombey in 1924 described a TT that
was used during the WWII (3).
Tetanus is now a rare disease in developed world. However, it
remains an important cause of death worldwide and is associated with
a high case-fatality, particularly in developing world. Tetanus is caused
by contamination of spores of C. tetani. NT results from contamination
of the umbilical stump at or following delivery of a child born to a
mother who did not possess sufficient circulatory antitoxin to protect
the infant passively by transplancental transfer (5).
Tetanus occurs in newborn infants born to mothers, who do not
have sufficient circulating antibodies to protect the infant passively, by
transplacental transfer. Prevention is possible by the vaccination of
pregnant and/or non-pregnant women with TT, and the provision of
clean delivery services. TT consists of a formaldehyde-treated toxin,
which stimulates the production of antitoxin (1).
57
L. Ben-Nun King David

LBW predicted an increased odds of death by NT. Age at onset ≤


five-seven days to diagnosis is crucial in determining survival among
neonates with tetanus (6). A week of birth is a high risk factor for
mortality (7).
Tetanus is a disease with common presenting features such as
rigidity, spasms, failure to suck, trismus, fever and seizures, vomiting,
cyanosis, flexed toes, and opisthotonus (3,8). The biblical text gives no
description of any such symptoms in the newborn.
The newborn son came from a high socioeconomic stratum, so it is
most likely that a skilful midwife assisted in Bathsheba's delivery. For
this reason, non-hygienic practices in this home delivery seem unlikely.
Moreover, the mother's vaccination against tetanus played no role in
this case (9).
Thus, we assume that this infant was not affected by tetanus.

References
1. Demicheli V, Barale A, Rivetti A. Vaccines for women to prevent neonatal
tetanus. Cochrane database Syst Rev. 2005 Oct 19;(4):CD002959.
2. Finegold SM. Tetanus. In: Collier L, Balows A, Susman M, eds. Topley and
Wilaon's Microbiology and Microbial Infections. 9th ed. London; Arnold. 1998,
pp. 693-713.
3. Bhatia R, Prabhakar S, Grover VK. Tetanus. Neurol India. 2002;50:398-
407.
4. Department of Health Science. Ministry of Health and Population.
Annual Report 2006/2007. Kathmandu: Ministry of Health and Population.
Nepal. 2008.
5. Poudel P, Budhathosi S, Manandhar S. Tetanus. Kathmandu University
Med J. 2009;7:315-22.
6. Lambo JA, Anokye EA. Prognostic factors for mortality in neonatal
tetanus: a systematic review and meta-analysis. Int J Infect Dis. 2013;17(12):
e1100-10.
7. Rai R, Singh DK. Neonatal tetanus: a continuing challenge. Indian J
Pediatr. 2012;79(12):1648-50.
8. Volpe JJ. Neurology of the Newborn. 3 rd ed. Philadelphia. WB Saunders.
1995, pp. 759-61.
9. Ben-Nun L. Neonatal tetanus. In: Ben-Nun L. (ed.). A Disease that
Afflicted the Newborn Son of King David. B.N. Publication House. Israel. 2011,
pp. 89-96.
58
L. Ben-Nun King David

MALARIA. Was the newborn afflicted by malaria? Malaria is a


serious cause of morbidity and mortality in the neonatal period and
account for a significant number of fetal wastage. Its diagnosis is
difficult because of the overlap in clinical presentation with other
infectious disease in the neonatal period (1).
Malaria transmission intensity in Africa varies, from less than one
infected bite per year to more than 1000. With very low transmission
intensity, all age groups are susceptible to severe malaria. With
increasing transmission intensities, older children and adults suffer less
severe disease while with high transmission rates the majority of severe
cases occur in infants less than one year of age. This pattern reflects the
increasingly rapid acquisition of immune responses that limit the life-
threatening effects of malaria with increasing exposure to the parasite.
The clinical spectrum of severe malaria varies with transmission: with
high transmission, severe malarial anemia dominates and cerebral
malaria is rare. With lower transmission rates, cerebral malaria
accounts for an increasingly large proportion of cases (2).
Malaria occurs in outbreak, affecting mainly young children, with
high mortality rate. Prostration, respiratory distress, and severe anemia
are the most prevalent signs. Severe anemia and inability to look for
mother's breast are independent risk factors for death in infants
younger than eight months (3).
The fact that the disease occurs in outbreaks, makes malaria an
unlikely cause of the newborn infant's death.
Was the newborn afflicted by congenital malaria? The incidence of
congenital malaria is low despite high maternal smear positivity for
malaria (4).
Maternal history of malaria/febrile illness within the two weeks
preceding the delivery is a risk factor for malaria (5). In addition,
congenital vivax malaria underlines that malaria diagnosis might need
to be included in the healthcare of neonates born in vivax-endemic
areas (6).
The biblical text gives no evidence of the presence of malaria or
febrile illness in Bathsheba. In addition, infants born to placenta-
infected mothers are more likely to develop a malaria infection
between four and six months of age (7). Since the newborn son died on
the 7th day, it seems unlikely that he acquired malaria from his mother.
59
L. Ben-Nun King David

References
1. Yilgwan CS, Hyacinth HI, Oguche S. Factors associated with decreased
survival from neonatal malaria infection in Jos, North Central Nigeria. Niger J
Med. 2011;20(3):349-54.
2. Snow RW, Marsh K. The consequences of reducing transmission of
Plasmodium falciparum in Africa. Adv Parasitol 2002;52:235-64.
3. Bassat Q, Guinovart C, Sigaúque B, et al. Malaria in rural Mozambique.
Part II: children admitted to hospital. Malar J. 2008;7:37.
4. Singh J, Soni D, Mishra D, et al. Placental and neonatal outcome in
maternal malaria. Indian Pediatr. 2014;51(4):285-8.
5. Runsewe-Abiodun YT, Ogunfowora OB, Fetuga BM. Neonatal malaria in
Nigeria - a 2 year review. BMC Pediatr. 2006;6:19.
6. Liu X, Tao ZY, Fang Q, et al. A case of congenital plasmodium vivax
malaria from a temperate region in Central China. Malar J. 2012 Jun 6;11:182.
7. Le Hesran JY, Cot M, Personne P, et al. Maternal placental infection with
Plasmodium falciparum and malaria morbidity during the first 2 years of life.
Am J Epidemiol. 1997;146:826-31.

MEASLES. Was measles responsible for the fatal disease in the


newborn son of King David? Measles, one of the ubiquitous and
persistent of human viruses, occurs regularly everywhere in the world
except very remote and isolated areas. Strains of measles virus from
different countries are indistinguishable, and serum antibodies from
diverse population have identical specificity. Yet, the epidemic pattern,
average age at infection, and mortality vary considerably from one area
to another and provide a contrasting picture between the developing
and the developed countries. In the populous areas of the world,
measles causes epidemics every two-five years, but in the rapidly
expanding urban conglomerations in the developing world, the
continuous immigration from the rural population provides a constant
influx of susceptible individuals and, in turn, a sustained occurrence of
measles and unclear epidemic curves (1)
Measles is a disease that mainly occurs in outbreaks (2-6). Maternal
antibody usually confers protection against measles to infants during
the first few months of life. Three patterns of measles transmission
occur during outbreaks: predominantly among unvaccinated pre-school
age children < five years of age, or predominantly among vaccinated
five to 17 years school age children, or predominantly among ≥ 18 years
unvaccinated and vaccinated post-school individuals. Measles,
however, can afflict children less than two years, or under one year and
even those less than nine months (2).
60
L. Ben-Nun King David

Complications of measles include acute URTI, pneumonia, and/or


diarrhea within the 30 days following onset of rash. In some cases,
measles may be fatal. Elimination of measles can be achieved by
routine administration of the first dose of measles vaccine from 12 to
15 months of age and use of a routine two-dose schedule to prevent
school and post-school outbreaks (2,6,7).
Although measles is a disease that could have afflicted the newborn,
and even could led to his death, the characteristic outbreaks of measles
occurring throughout the world eliminate this disease as the cause of
death in this weak newborn (9).

References
1. Assaad F. Measles: summary of worldwide impact. Bull World Health
Org. 1983;5:452-9.
2. Hutchins S, Markowitz L, Atkinson W, et al. Measles outbreaks in the
United States, 1987 through 1990. Am J Infect Control. 1996;15:31-8.
3. Gunnarsdottir S, Briem H, Gottfredsson M. Extent and impact of the
measles epidemics of 1846 and 1882 in Iceland. Laeknabladid. 2014;100(4):
211-6.
4. Marinova L, Muscat M, Mihneva Z, Kojouharova M. An update on an
ongoing measles outbreak in Bulgaria, April-November 2009. Euro Surveill.
2009;14(50). pii: 19442.
5. Hennessey KA, Ion-Nedelcu N, Craciun MD, et al. Measles epidemic in
Romania, 1996-1998: assessment of vaccine effectiveness by case-control and
cohort studies. Am J Epidemiol. 1999;150:1250-7.
6. Grais RF, Dubray C, Gerstl S, et al. Unacceptably high mortality related to
measles epidemics in Niger, Nigeria, and Chad. PLoS Med. 2007;4:e24.
7. Ariyasriwatana C, Kalayanarooj S. Severity of measles: a study at the
Queen Sirikit National Institute of Child Health. J Med Assoc Thai. 2004;87:581-
8.
9. Ben-Nun L. Neonatal tetanus. In: Ben-Nun L. (ed.). A Disease that
Afflicted the Newborn Son of King David. B. N. Publication House. Israel. 2011,
pp. 101-7.

SYPHILIS. Was the King's newborn son afflicted by congenital


syphilis? Syphilis remains a significant cause of preventable perinatal
death and infant mortality, with many women remaining untested and
thus untreated (1-3).
Syphilis testing in the clinic (on-site testing) is a useful strategy to
handle this disease (1). Syphilis is a major cause of adverse outcomes in
pregnancy in developing countries (2). The disease during pregnancy
61
L. Ben-Nun King David

can result in abortions, stillbirths, prematurity, neonatal deaths, and


surviving babies with features of congenital syphilis, with transplacental
infection of the fetus occurring at any stage of the pregnancy (4). Fetal
death and morbidity due to congenital syphilis are preventable if
infected mothers are identified and treated appropriately by the middle
of the second trimester. Most pregnant women with syphilis are
asymptomatic and can be identified through serological screening. Non-
treponemal test, such as the RPR test, is sensitive, simple to perform,
and inexpensive (5).
Risk factors for congenital syphilis include lack of prenatal care, low
education, having more than one partner during pregnancy, and having
the first test for syphilis at ≥28 weeks' gestation (6). Fatal outcomes
occurred in 26% of infants with congenital syphilis, including late fetal
deaths (7%), stillbirth (16%), and neonatal deaths (3%) (4).
The etiologic agent T. pallidum subsp. pallidum is transmitted to
fetus almost exclusively via placenta. Perinatal infections are less
frequent, and postnatal infections are only exceptionally. The
symptoms of congenital syphilis may be divided into prenatal
(maternal-fetal syphilis), neonatal, and rarely seen postnatal. Prenatal
symptoms causing the immaturity of fetus are recognizable from the
7th month of pregnancy and associated with miscarriages, premature
deliveries of stillborn babies or live neonates with congenital syphilis.
Neonatal and postnatal symptoms are manifested only after birth. They
may present immediately at birth, develop within first two years of life
as early congenital syphilis, or (similarly to acquired syphilis) later in life
as a late localized form, often seen many years after birth, even at
puberty - late congenital syphilis. The clinical picture depends on many
factors - primarily on the duration of the infection in mother and the
stage of pregnancy (7).
Clinical symptoms of congenital syphilis include hepatomegaly,
desquamation of palms and soles, radiological changes and abnormal
CSF (8.9).
Low education, a previous history of syphilis, and more than one
partner during the pregnancy are risk factors for syphilis (10).
The diagnosis of congenital syphilis in this case can be ruled out
since 1] the King did not suffer from syphilis, 2] Bathsheba had no other
partners during her pregnancy, 3] lack of prenatal care of Bathsheba
seems unlikely, 4] the parents came from a high socioeconomic
stratum, thus low education seems unlikely, and 5] no signs of
congenital syphilis in the newborn are given in the biblical text .
62
L. Ben-Nun King David

References
1. Myer L, Wilkinson D, Lombard C, et al. Impact of on-site testing for
maternal syphilis on treatment delays, treatment rates, and perinatal mortality
in rural South Africa: a randomised controlled trial. Sex Trans Infect. 2003;79:
208-13.
2. Chen XS, Yin YP. Syphilis: still a major cause of infant mortality. Lancet
Infect Dis. 2012;12(4):269-70; author reply 270-1.
3. Walker DG, Walker GJ. Syphilis: still a major cause of infant mortality.
Lancet Infect Dis. 2012;12(4):269; author reply 270-1.
4. Rutgers S. Syphilis in pregnancy: a medical audit in a rural district. Centr
Afr J Med. 1993;39:248-53.
5. Rosanna W. Peeling, Htun Ye. Diagnostic tools for preventing and
managing maternal and congenital syphilis: an overview. Bull World Health
Organ. 2004;82:439–46.
6. Tikhonova L, Salakhov E, Southwick K, et al. Congenital syphilis in the
Russian Federation: magnitude, determinants, and consequences. Sex Trans
Infect. 2003;79:106–10.
7. Kremenová S1, Zákoucká H, Kremen J. Issues of congenital syphilis in the
past twenty years. II. Clinical picture. Klin Mikrobiol Infekc Lek.2006;12(2):51-7.
8. Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W, et al. Outcome
of maternal syphilis at Rajavithi Hospital on offspring. J Med Assoc Thai.
2005;88:1519-25.
9. Southwick KL, Blanco S, Santander A, et al. Maternal and congenital
syphilis in Bolivia, 1996: prevalence and risk factors. Bull World Health Organ.
2001;79:33-42.
10. Ben-Nun L. Neonatal tetanus. In: Ben-Nun L. (ed.). A Disease that
Afflicted the Newborn Son of King David. B.N. Publication House. Israel. 2011,
pp. 107-13.

RESPIRATORY DISTRESS SYNDROME. RDS is a frequent acute


respiratory disorder in the newborn infants (1) and is a major
contributor to NM worldwide (2-4).
Pediatric RDS remains an important challenge for the intensive care
clinician. This syndrome can result from either direct lung injury or from
a "downstream" inflammatory process, and is manifested by profound
hypoxemia and respiratory failure (5). RDS is the most common
problem in the preterm and term infants admitted to NICU (6).
Since the original description of deficiency of the pulmonary
surfactant in premature neonates by Avery in 1959, RDS has been
attributed to developmental immaturity of surfactant production.
However, in clinical practice there was RDS in term and late-term
neonates. Many of them were recognized as transient tachypnea at the
63
L. Ben-Nun King David

beginning, as RDS until respiratory distress and the typical radiological


signs were demonstrated (1).
Acute RDS includes transient tachypnea of the newborn, meconium
aspiration syndrome, pneumonia, sepsis, pneumothorax, persistent
pulmonary hypertension (7), pulmonary hypoplasia or
bronchopulmonary dysplasia (6), diaphragmatic hernia, congenital
malformations (7), meconium aspiration, and infectious pneumonia (8).
Late preterm infants in comparison with term infants suffer more
from RDS, pneumonia and transient tachypnea of the newborn and
require more respiratory support with nasal continuous positive airway
pressure (9).
Clinical signs and symptoms of RDS are nonspecific and do not
differentiate between pneumonia and other causes of respiratory
distress (10).
Did RDS afflict the newborn son of King David? The son died on the
seventh day. Although it cannot absolutely be refuted, it seems unlikely
that an infant with this condition would survive seven days without
appropriate medical treatment. Thus, the diagnosis of RDS can be ruled
out (11).

References
1. Chen A, Shi LP, Zheng JY, Du LZ. Clinical characteristics and outcomes of
respiratory distress syndrome in term and late-preterm neonates. Honghua Er
Ke Za Zhi. 2008;46:654-7.
2. Kamath BD, Macguire ER, McClure EM, et al. Neonatal mortality from
respiratory distress syndrome: lessons for low-resource countries. Pediatrics.
2011;127(6):1139-46.
3. Marraro GA, Chen C, Piga MA, et al. Acute respiratory distress syndrome
in the pediatric age: an update on advanced treatment. Zhongguo Dang Dai Er
Ke Za Zhi. 2014;16(5):437-47.
4. Kalter HD, Khazen RR, Barghouthi M, Odeh M. Prospective community-
based cluster census and case-control study of stillbirths and neonatal deaths
in the West Bank and Gaza Strip. Paediatr Perinat Epidemiol. 2008;22(4):321-
33.
5. Anderson MR. Update on pediatric acute respiratory distress syndrome.
Respir Care. 2003;48:261-76; discussion 276-8.
6. Gnanaratnem J, Finer NN. Neonatal acute respiratory failure. Curr Opin
Pediatr. 2000;12:227-32.
7. Hermansen CL, Lorah KN. Respiratory distress in the newborn. Am Fam
Physician. 2007;76:987-94.,
8. Wood BP. The newborn chest. Radiol Clin North Am. 1993;31:667-76.
64
L. Ben-Nun King David

9. Mathur NB, Garg K, Kumar S. Respiratory distress in neonates with


special reference to pneumonia. Indian Pediatr. 2002;39:529-37.
10. Ma X, Huang C, Lou S, et al.; Provincial Collaborative Study Group for
Late-Preterm Infants. The clinical outcomes of late preterm infants: a multi-
center survey of Zhejiang, China. J Perinatol. 2009;37:695-9.
11. Ben-Nun L. Respiratory Distress Syndrome. In: Ben-Nun L. (ed.). A
Disease that Afflicted the Newborn Son of King David. B. N. Publication House.
Israel. 2011, pp. 114-20.

SUDDEN INFANT DEATH SYNDROME. Despite the decreased


incidence, SIDS remains the leading cause of death in infants mainly
between one month to one year of age of industrialized nations of the
world (1,2). Risk factors for SIDS include: male infant, prone and side
sleeping, thermal environment, bed sharing, maternal smoking,
infection, carbon dioxide rebreathing, sedative drugs, high ambient
temperature, sleeping with the face covered, high parity, youth, a
single mother, prematurity, LBW, sleeping on a soft surface, multiple
births, a previous stillbirth or infant death, non-breastfeeding, winter
preponderance, leaving school at a younger age, a greater number of
previous pregnancies, late attendance for antenatal care, heavy
wrapping, sleeping in a bassinet, unplanned pregnancy, shorter
gestation, IUGT, defects in arousal or cardiorespiratory control,
prolongation of the QT interval, magnesium deficiency, maternal
education ≤12 years, deprived social group, and childcare facility (3-
11). The constant ~50% male excess for quite different causes of
respiratory death suggests they all have a common terminal event and
that it is acute anoxic encephalopathy. This constant male excess
phenomenon must be caused by a single X-linked gene, with a recessive
condition, leading to a predisposition to succumb to acute anoxic
encephalopathy (12).
Histological neuropathological examination rarely determines the
cause of death in sudden unexpected deaths in infancy in the absence
of macroscopic abnormalities or neurological clinical history. A
macroscopically abnormal brain and the presence of a clinical history of
possible neurological disease or of inflicted injury are more likely to be
associated with histological brain abnormalities (13).
Was SIDS responsible for the death of the newborn son? Among a
variety of known factors, two can be identified in the newborn son of
King David: male gender and unplanned pregnancy. Others factors
contradict a diagnosis of SIDS: 1] SIDS occurs predominantly in infants
65
L. Ben-Nun King David

between one month to one year, while the King's newborn son died on
the seventh day, 2] the term SIDS refers to a death that occurs
suddenly, while the condition of the newborn deteriorated gradually
during the first seven days of life, 3] the newborn came from a high
socioeconomic stratum, so there were enough servants to watch the
infant day and night, 4] there is no reason to suspect other risk factors
such as the sleeping position: prone or side, bed or room sharing with
parents, maternal or/and paternal smoking, thermal environment, face
cover, multiple births, a previous stillbirth or infant death, childcare
facility, or deprived social circumstances. Although LBW, prematurity,
and IUGT as risk factors for SIDS may be suspected in this case, the
biblical text gives no specific data to support this diagnosis (14).

References
1. Otto-Buczkowska E. Sudden infant death syndrome. Pol Merkur Lekarski.
2002;13:524-5.
2. Carl E. Hunt CE, Hauck FR. Sudden infant death syndrome. CMAJ.
2006;174:1861–9.
3. Kahn A, Groswasser J, Franco P, et al. Sudden infant deaths: stress,
arousal and SIDS. Early Hum Dev. 2003;75 Suppl:S147-66.
4. Caddell JL. Magnesium deficiency promotes muscle weakness,
contributing to the risk of sudden infant death (SIDS) in infants sleeping prone.
Mag Res. 2001;14(1-2):39-50.
5. Highet AR, Berry AM, Goldwater PN. Novel hypothesis for unexplained
sudden unexpected death in infancy (SUDI). Arch Dis Child. 2009;94:841-3.
6. Fleming PJ. Understanding and preventing sudden infant death
syndrome. Curr Opin Pediatr. 1994;6:158-62.
7. Moon RY, Patel KM, Shaefer SJ. Sudden infant death syndrome in child
care settings. Pediatrics. 2000;106(2 Pt 1):295-300.
8. Fleming PJ, Blair PS, Bacon C, et al. Environment of infants during sleep
and risk of the sudden infant death syndrome: results of 1993-5 case-control
study for confidential inquiry into stillbirths and deaths in infancy. Confidential
Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers.
BMJ. 1996;313(7051):191-5.
9. Leach CE, Blair PS, Fleming PJ, et al. Epidemiology of SIDS and explained
sudden infant deaths. CESDI SUDI Research Group. Pediatrics. 1999;
104(4):e43.
10. McGarvey C, McDonnell M, Hamilton K, et al. An 8-year study of risk
factors for SIDS: bed sharing versus non-bed-sharing. Arch Dis Child. 2006;
91:318-23.
11. Task Force on Sudden Infant Death Syndrome, Moon RY. SIDS and other
sleep-related infant deaths: expansion of recommendations for a safe infant
sleeping environment. Pediatrics. 2011;128(5):e1341-67.
66
L. Ben-Nun King David

12. Mage DT, Donner EM. Is excess male infant mortality from sudden
infant death syndrome and other respiratory diseases X-linked? Acta Paediatr.
2014;103(2):188-93.
13. Pryce JW1, Paine SM, Weber MA, et al. Role of routine
neuropathological examination for determining cause of death in sudden
unexpected deaths in infancy (SUDI). J Clin Pathol. 2012;65(3):257-61.
14. Ben-Nun L. Sudden Infant Death Syndrome. In: Ben-Nun L. (ed.). A
Disease that Afflicted the Newborn Son of King David. B. N. Publication House.
Israel. 2011, pp. 120-33.

HOME-BIRTH. Was it safe for Bathsheba to give birth at home?


Home birth can be accomplished with good outcomes under the care of
qualified practitioners and within a system that facilitates transfer to
hospital care when necessary. Women with low obstetrical risk factors
can safely deliver at home (1).
However, planned home of uncomplicated singleton pregnancies
are related to increased risk of neonatal death, while for nulliparous
women also with prolonged labor and postpartum bleeding (2).
Home-births attended by certified nurse-midwives are associated
with low intrapartum and NM rates. Home-birth is a safe option for
healthy, low-risk women when emergency equipment is prepared for
immediate neonatal resuscitation and maternal emergencies (3).
Home-births in comparison with hospital-births are associated with
lower obstetric interventions, such as electronic fetal monitoring,
assisted vaginal delivery, caesarean section, instrumental delivery, and
episiotomy (4), and adverse maternal outcomes such as cervical, and
third- or fourth-degree perineal tear, postpartum hemorrhage,
prolonged labor, postpartum bleeding, retained placenta, shock, severe
anemia, less resuscitation (of infant) at birth, or oxygen therapy beyond
24 hours, and less meconium aspiration (4). Newborns in the home-
birth group are less likely than in the midwife-attended hospital-birth
group to require resuscitation at birth, or oxygen therapy beyond 24
hours (4). However, planned home-births have higher risk of
intrapartum death, death from intrapartum asphyxia, and higher NM
rate than deliveries in hospital (5).
Since Bathsheba came from a high socioeconomic stratum, it can be
assumed that a skilled midwife assisted her home-birth. Thus, many
causes that are linked to NM such as financial limitations, ignorance,
transport limitations, lack of a skilled mid-wife attendant at home, or
delivery occurring too quickly or too late at night to summon a mid-wife
67
L. Ben-Nun King David

seem unlikely. The biblical text provides no evidence of any maternal


complication in Bathsheba that can occur in the case of home delivery
such as retained placenta, excessive vaginal bleeding, or shock
requiring active resuscitation (6). For these reasons, home-birth as a
cause for death of the newborn is unlikely.

References
1. Murphy PA, Fullerton J. Outcomes of intended home births in nurse-
midwifery practice: a prospective descriptive study. Obstet Gynecol. 1998;92:
461-70.
2. Pang JW, Heffelfinger JD, Huang GJ, et al. Outcomes of planned home
births in Washington State: 1989-1996. Obstet Gynecol. 2002;100:253-9.
3. Anderson RE, Murphy PA. Outcomes of 11.788 planned home births
attended by certified nurse-midwives. A retrospective descriptive study. J Nurs
Midwifery. 1995;40:483-92.
4. Janssen PA, Saxell L, Page LA, et al. Outcomes of planned home birth
with registered midwife versus planned hospital birth with midwife or
physician. CMAJ. 2009;181:377-83.
5. Kennare RM, Keirse MJ, Tucker GR, Chan AC. Planned home and hospital
births in South Australia, 1991-2006: differences in outcomes. Med J Austr.
2010;192:76-80.
6. Ben-Nun L. Home-birth. In: Ben-Nun L. (ed.). A Disease that Afflicted the
Newborn Son of King David. B.N. Publication House. Israel. 2011, pp. 134-42.

SOCIOECONOMIC STATUS. In different countries, the proportion of


infant and children deaths less than two years is high. NM is higher in
the poorest women compared with the wealthy women. Antenatal
care and a skilled delivery rates are higher in the wealthy than the
poorest women (1).
Concentration of infant deaths among socioeconomically
disadvantaged households in the majority of low-and-middle-income
countries remains an important health and social policy concern (2).
Early neonatal, neonatal, and postneonatal mortality is higher in the
lower social classes and in more deprived communities (3). Household
socio-economic inequality and maternal education are associated with
under five-year mortality (4).
In the United Kingdom, NM of very preterm infants in the most
deprived areas is higher than in the least deprived areas (5). In Sweden,
an increased infant mortality is recorded in preterm infants born to
women with a less favorable sociodemographic profile (6). In Iran,
there was considerable socioeconomic inequality regarding infant
68
L. Ben-Nun King David

mortality in Shahroud. Mother's education is the most contributing


factor in this inequality (7).
Were socioeconomic inequalities responsible for the death of the
newborn son in Bathsheba and King David's case? NM is higher in lower
social classes and in deprived communities. This newborn came from a
wealthy socioeconomic stratum. This fact rules out that socioeconomic
status was unresponsible for his death.

References
1. Fenn B, Kirkwood BR, Popatia Z, Bradley DJ. Inequities in neonatal
survival interventions: evidence from national surveys. Arch Dis Child: Fetal &
Neonatal. 2007;92:F361–F366.
2. Hajizadeh M, Nandi A, Heymann J. Social inequality in infant mortality:
what explains variation across low and middle income countries? Soc Sci Med.
2014;101:36-46.
3. Dummer T, Parker L. Changing socioeconomic inequality in infant
mortality in Cumbria. Arch Dis Child. 2005;90:157–62.
4. Nattey C, Masanja H, Klipstein-Grobusch K. Relationship between
household socio-economic status and under-five mortality in Rufiji DSS,
Tanzania. Glob Health Action. 2013 Jan 24;6:19278.
5. Smith LK, Draper ES, Manktelow BN, Field DJ. Socioeconomic inequalities
in survival and provision of neonatal care: population based study of very
preterm infants. BMJ. 2009;339: b4702.
6. Calling S, Li X, Sundquist J, Sundquist K. Socioeconomic inequalities and
infant mortality of 46,470 preterm infants born in Sweden between 1992 and
2006. Paediatr Perinat Epidemiol. 2011;25(4):357-65.
7. Damghanian M, Shariati M, Mirzaiinajmabadi K, et al. Socioeconomic
inequality and its determinants regarding infant mortality in Iran. Iran Red
Crescent Med J. 2014;16(6):e17602.

TO SUM UP: out of 18 possible causes, 12 can be excluded due to


lack of data to prove that they caused death. These are PROM, sepsis,
meningitis, diarrhea, tetanus, malaria, measles, syphilis, RDS, SIDS,
home-birth, and low socioeconomic status. This leaves us with six
possible causes: birth asphyxia, LBW/ELBW, prematurity, IUGT, NEC,
and congenital anomaly. The biblical text gives no specific clues for any
of these causes.
Was only one condition responsible? Or a combination such as
prematurity and IUGR? Were other comorbidities involved?
The death of the newborn baby was a very traumatic experience the
King's family was faced. Multidimensional factors such as physical,
69
L. Ben-Nun King David

psychological, and social played a role in the negative experiences and


the great suffering caused by the sickness and death of the newborn
son. Very sad negative exposure such as death of newborn son was the
changing experience to which King David's family was exposed.

THE MOURNING PROCESS. Hearing this news: "David fasted, and


went in, and lay all night upon the earth" (II Samuel 12:16). The King's
pain was so severe that when: "The elders of his house arose, and went
to him, to raise him from the earth: but he would not, neither did he eat
bread with them" (12:17). Later the newborn had died: "…On the
seventh day…the child died. When David saw that his servants
whispered, David perceived that the child was dead: therefore David
said unto his servants, Is the child dead? And they said, he is dead"
(12:19). After hearing that his son had died "David arose from the
earth, and washed, and anointed himself, and changed his apparel, and
came into the house of the Lord, and worshipped: then he came to his
own house; and when he required, they set bread before him, and he
did eat" (12:20). Here his servants were astonished: "You did fast and
weep for the child while he was alive; but when the child was dead, you
did rise and eat bread" (12:21). King David responded that "While the
child was yet alive, I fasted and wept: for I said, Who can tell? God may
be gracious to me, and the child may live? But now he is dead,
wherefore should I fast? Can I bring him back again? I shall go to him,
but he shall not return to me" (12:22,23).
When a family member dies, it is a very stressful event. However,
when a newborn child died this is a real tragedy. According to the
Holmes and Rahe's Schedule of Readjustment Rating Scale (1) death
of close family member has a mean life change units value of 63,
being in the top of five various life events. Thus, the death of the
King's newborn son exposed all the family to a very negative,
traumatic experience.
When his newborn son was seriously ill, King David believed that
he could help to overcome this serious life-threatening disease and
thus he stopped eating and lay on the earth, and he mourned.
However, when the child died, nothing could change this unfortunate
fate on the earth, and therefore the King resumed his usual life:
broke his fasting, washed himself, changed his clothes and went to
worship to the house of the Lord. We see how the King accepted the
seriousness of illness and its subsequent fatal outcome. He had a
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powerful strength to cope with the very traumatic situation – the


death of his son.
The human being needs ties to grow and develop. When some of
these ties are broken, a period of great intensity arises that we call
mourning. If the loss is radical and definitive, as in the case of death,
all the person's dimensions are affected (the physical, emotional,
cognitive, behavioral, social and spiritual) to such an extent that the
person could feel unable to overcome this and/or develop a
pathological mourning that requires professional intervention for
recovery. Many factors intervene in the mourning, such as
circumstances of the death, relation to deceased, personality,
previous experience and the socio-economic context. In order to
recover following a loss, the person passes through a series of stages
and phases: 1]. Accept the reality of loss. 2]. Express emotions and
pain. 3]. Adapt to a setting from which the loved one is absent. 4].
Emotionally resituate the deceased and continue living (2).
The biblical words "The elders of his house arose, and went to him,
to raise him from the earth: but he would not, neither did he eat
bread with them" (II Samuel 12:170 indicate the physical, emotional,
cognitive, behavioral, social and spiritual dimensions of the sorrow
that afflicted the King when his newborn son suffered from a
devastating disease. However, David recovered immediately after his
son's death since he accepted the reality of this death, adapted
instantly to his loss, and returned quickly to everyday life.
Coping with grief following perinatal death is a natural process
that every individual experiences in his own personal and unique
way. Parents go thorough varying emotions in the same month
following the death of their baby; they benefit from individually
focused counseling and assistance in making their own choices with
regard to saying goodbye and the way in which they will cope with
their grief in the immediate future, as parents, within the family and
in relation to the people in their surroundings (3).
The quality of dying and death construct is multidimensional, with
seven broad domains: physical experience, psychological experience,
social experience, spiritual or existential experience, the nature of
health care, life closure and death preparation, and the
circumstances of death. The quality of dying and death is subjectively
determined with numerous factors that influence its judgment,
including culture, type and stage of disease, and social and
professional roles in the dying experience. Quality of dying and death
71
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is broader in scope than either QOL or quality of care both at the end
of life, although there is overlap among these constructs (4).
The death of the newborn baby was a traumatic exposure to a
negative stress. In King David's case, multidimensional parameters
such as physical, psychological, and social experiences and the
circumstances of the death all played a role in the negative
experiences and the great suffering caused by the sickness and death
of the newborn son.
Parents are attached to their unborn children, and loss around.
Parental grief is a normal response, and may last for many months.
Aspects of psychological management are associated with the time of
birth and is a serious trauma (5). Depression, anxiety disorder, PTSD
and somatoform disorder all have been linked to grief reactions in
response to perinatal loss (6).
In his reactions to this tragedy, King David showed a strong
character, one that was able to overcome various psychological
aspects of the grieving process. Both David and Bathsheba went
through the mourning process of the loss of their newborn son.
The purpose of this study was to understand mothers'
experiences and perspectives concerning neonatal death. Four
themes evolved: 1] Puzzlement on the brink of neonatal death:
neonatal death, as an unpredicted event, constitutes a puzzle for
mothers; they tend to seek the cause of the mishap, and in turn, fall
into a dilemma about whether to try to save the newborn. 2] Chaos
in the wake of the loss of babies: mothers' experience of physical,
mental, and behavioral changes might stymie their original positive
attitude toward the role of being the husband and wife. 3]
Adjustments in the wake of the loss: when mothers try to adjust
themselves, common approaches, such as good will with pep talk and
emotional utterance/sharing, are not ready helpful. Certain factors
also play a part, either positively or negatively, in the mental
adjustment process; they include responsibility for the household,
intentional mood-diversion, prohibiting the mother from
participating in funerals for the babies. 4] Professional guidance:
mothers expect to receive professional guidance to help them to face
the fact of death, especially in the movement of separation;
providing memorabilia and personalized follow-ups for mothers are
beneficial. In conclusion, mothers experiencing neonatal death
should be encouraged to express their grief through appropriate
emotional channels, and receive professional follow-up to rebuild
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physiologically, psychologically, and spiritually, rather that


suppressing their mourning (7).
All the parameters mentioned above can be seen in Bathsheba's
reactions to the event. The subsequent verse indicates that
Bathsheba suffered more than her husband David did: “And David
comforted Bathsheba his wife, and went in to her, and lay with her:
and she bore a son and he called his name Solomon....” (12:24). The
King calmed, reassured, and comforted her. This verse also shows
that David’s family adjusted and adapted to the death, and regained
its homeostasis.
Generally, accepted major life events include bereavement,
divorce, and job loss (8). The death of a child can be regarded and a
very stressful negative life event. The major characteristics of any
family, over its life cycle, are the changes it experiences (9,10).
We see that the structure of David’s family changes continuously,
with new family members entering and others leaving this family
system. Positive (birth of Solomon) and negative events (death of
newborn son) are some of the changing experiences to which the
family was exposed (11).

References
1. Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J
Psychosom Res. 1967;11:213.
2. Cabodevilla I. Loss and mourning. An Sist Sanit Navar. 2007;30 Suppl
3:163-76.
3. Geerinck-Vercammen CR, Duijvestinj MJ. Coping with grief following
perinatal death: a multifaceted and natural process. Ned Tijdschr Geneeskd.
2004;148:1231-4.
4. Hales S, Zimmermann C, Rodin G. The quality of dying and death. Arch
Intern Med. 2008;168:912-8.
5. Hudges P, Riches S. Psychological aspects of perinatal loss. Curr Opin
Obstet Gynecol. 2003;15:107-11.
6. Scheidtr CE, Waller N, Wangler J, et al. Mourning after perinatal death-
prevalence symptoms and treatment – a review of literature. Psychother
Psychosom Med Psychol. 2007;57:4-11.
7. Chiang CC, Lee JT, Wang CH, Tang WR. Mothers' experiences and
perspectives of neonatal death: a qualitative retrospective inquiry. Hu Li Za
Ahi. 2007;54:48-55.
8. Aldwin CM. Life events. In: Aldwin CN (ed). Stress, Coping, and
Development. An Integrative Perspective. The Guilford Press. New York,
London. 1994, pp. 57-8.
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L. Ben-Nun King David

9. Duvall EM. Marriage and family development, ed. 5. New York, JB


Lippincott, 1977.
10. Medalie JH. The family life cycle and its implications for family
practice. J Fam Pract. 1979;9:47.
11. Ben-Nun L. Deathg of the newborn son. In Ben-Nun L (ed.). The
Family Life cycle and the Medical Record of King David the Great. B.N.
Publication House. Israel. 2009, pp. 44-49.

FAMILY GROWTH
After David left Hebron “And David took him more concubines and
wives of Jerusalem.....And other children were born in Jerusalem:
Shammuah, Shobab, Nathan, Solomon, Ibhar, Elishua, Nepheg,
Japhia, Elishama, Eliada, and Eliphalet” (5:13-16). The King’s
polygamous family expanded significantly, and now included many
wives, concubines and 17 children.
Families are unique in permanence of membership and in the
primacy of affectional relationship over task performance. What are
the needs that are addressed uniquely in the family unit? There are
two fundamental orders of such needs:
1] Needs Pertinent to Survival. The family unit is uniquely
committed to the physical security of all members, hence to such
needs as food and shelter.
2] Needs to Development. Additionally, the family is committed
to the cognitive, emotional, and spiritual development of its
members, and hence is committed to creating and sustaining the
sense of being valued, the sense of being cared about, the sense of
being accepted "as it", and the sense of permanence of
affectionalties. The family unit, in this sense is a primary context for
need-attainment (1).
All these parameters can be attributable to King David who was
responsible for the survival of his polygamous family, and for the
development of his family members.

Reference
1. Terkelsen KG. Toward a theory of the family life cycle. In: Carter
EA, Goldrick M (eds.). The Family Life Cycle: A Framework for Family
Therapy, Gardner Press, New York. 1980, pp, 21-52.
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L. Ben-Nun King David

THE WARRIOR
Throughout his life, David was involved in endless wars against the
Philistines. He was a real warrior and fought bravely with the enemy.
He won many wars, and many Philistines were taken prisoners. He
also conquered Moab, Hadadezer, the son of Rehob, the King of
Zobah, and the Syrians of Damascus (8:2,3,5). “And David reigned
over all Israel; and David executed judgment and justice to all his
people” (8:15).

DAVID'S SONS THE CHIEF RULERS


King David’s family was consolidated and the sons helped their
father to rule the country “...David’s sons were chief rulers” (8:18).
We see a powerful enigmatic ruler, who conquered many countries.
His potent, authoritative and dominant character indicates a great
leader. King's special qualities helped to organize the internal family
system as well as external surrounding systems. These well-organized
systems were in mutual homeostasis, and the King's sons helped to
rule the country. The King was a perfect manager and gave the orders
to his sons, the chief rulers of the country. All these helped to build a
great empire.

MEFIVOSHET – A NEW FAMILY MEMBER


After King Saul and his three sons were killed, King David began to
seek the remaining members of Saul’s family. The son of his best
friend Jonathan, Mefivoshet, who was lame, was located and brought
to the King, who ordered that all King Saul’s property be given to
Mefivoshet. David also arranged for this boy to eat all his meals at
his table, and ordered Saul’s servant Ziba and his 15 sons, together
with 20 servants to serve Mefivoshet. Ziba agreed “As for
Mefivoshet, he shall eat at my table, as one of the king’s son” (II
Samuel 9:11). Later, however, David divided Saul’s property between
Ziba and Mefivoshet: “I have said, Thou and Ziba divide the land”
(19:30).
King David treated Mefivoshet like his own son. Finding the son of
75
L. Ben-Nun King David

his best friend was a positive stressful life event. In this way, King
David expressed great friendship towards his beloved Jonathan, and
another member joined the King’s family.
The pediatrician treating a child with a disability must focus not
only on the physical needs of the child but also on the emotional and
social issues associated with being disabled. This dual focus becomes
increasingly important as the child matures through adolescence and
transitions into adulthood. In addition, the pediatrician must
understand the complex interrelationships between the family and
their maturing, disabled child during the vital process of separation
from the family. This transition is particularly difficult for an
adolescent who is dependent on others for physical care and other
independent living skills. Many of transitional problems faced by
disabled adolescents and their parents have roots in early childhood.
With an awareness of the specific stressors on the parent caregivers
and an understanding of the influence of disability on the
developmental process, the pediatrician can play a major role in
easing the transition of a disabled adolescent into adulthood. By
guiding the parents of a young child through the important tasks of
childhood and adolescent, the pediatrician can set the stage for both
the parents and their disabled child to have independent, yet
supportive lives that are focused not on the disability but on mutual
respect and life satisfaction. It is recommended that disabled teens
and young adults be given help in independence skills; personal
counseling services should be available, and physicians should give
teen's age-appropriate information about disabilities. There are
needs for sex education, preparation for parenthood, and genetic
counseling. Other issues that should be addressed are early
vocational awareness, alternatives to work, and leisure time use. Just
because an adolescent is disabled, we cannot assume that he or she
will have self-esteem and self-concept difficulties. To adjust to being
devaluated by society, the disabled person must change societal
beliefs that strength, independence, and appearance are the
essential aspects of a QOL. The importance of being kind,
intelligence, and productive to one's capacity must become more
important (1).
The relationship between a pediatrician and a child with a
disability is important since the pediatrician accompanies such child
through childhood, and on to adolescence and adulthood. From the
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L. Ben-Nun King David

contemporary perspective, the King's family urgently needed a


pediatrician in order to cope with the disability of Mefivoshet.
Since the father of Mefivoshet, Jonathan, was killed in a fierce
battle with the Philistines (we have no further details about
Mefivoshet's other family members, for example his mother), we
suppose that Mefivoshet was left alone in the world. Fortunately, the
King adopted this disabled boy, and he can be regarded as his
stepfather, while Ziba and his 15 sons can be seen as the
stepbrothers involved in raising Mefivoshet. The King's family
received the new family member with respect and saw his needs.
Here we see the humanistic features of King David's character, who
accepted the disabled son of his friend Jonathan as his own child. In
this behavior, the King expressed his loyalty to Jonathan, even after
his death.
This study used a literature review to examine the process of
parental acceptance regarding disability in a child. The results identify
two main theoretical concepts, stages of grief and chronic sorrow,
which describe the emotional responses that parents express
following the diagnosis of a child's disability. Stages of grief involve a
long-term process through which parents struggle to accept their
child's condition, eventually leading to acceptance of their child's
disability. Alternatively, chronic sorrow describes parental life-long
sadness throughout their child's lifetime, periodically repeated at
critical times in their child's development (2).
We can assume that Mevivoshet's disability caused his nuclear
family as well as the adopted family chronic sorrow and sadness.
These reactions are a natural response to a child's disability.
Taanila et al. (3) studied how a child's physical or intellectual
disability or diabetes affected family cohesion, the parents' social life,
and leisure-time activities, and whether there was any association
between the disability and the parents' social relations and family
cohesion. The parents of 89 children aged 12-17 years returned a
questionnaire and were interviewed by a social worker. Family
cohesion increased in all the groups by an average of 27%. The effect
was smallest in the families of children with diabetes, whereas in the
families with intellectual and physical disability family cohesion
increased from six to 13 times more often compared to the families
of children with diabetes. The increased family cohesion was not
associated with the change in the parents' social relationship, work,
career or leisure-time activities; the importance of these activities did
77
L. Ben-Nun King David

not decrease even though family cohesion increased. However, a


child's chronic illness or disability affected the everyday life of the
family, for instance, 71% of the parents with diabetic children
thought that the regularity of family life increased and about a half of
the parents with physically or intellectually disabled children had to
change their hobbies because of the child.
It is most likely that the cohesion of King David's family increased
due to Mefivoshet's disability. Was their everyday life affected?
Since Saul’s servant Ziba and his 15 sons, together with 20 servants
served Mefivoshet, it seems that everyday life remained unaffected,
and family hobbies were not changed.
The parents of eight children (aged 8-10 years) with physical
and/or intellectual disability were interviewed twice, and the data
elicited in these interviews were analyzed quantatively using the
grounded theory method. Information and acceptance, good family
cooperation and social support were related to the coping strategies
most frequently used. Half of the families found successful ways of
coping, whereas another half had major problems. There were five
domains in which the high- and low-coping families differed most
from each other: 1] parents; initial experiences, 2] personal
characteristics, 3] effects of the child's disability on family life, 4]
acting in everyday life, and 5] social support (4).
King David's family seems to represent a family, which coped
successfully with the physical disability of Mefivoshet and found ways
of dealing with this problem. Among the domains that characterize
the King's family were the personal characteristics of the King as well
as of Ziba and his sons, the effect of Mefivoshet's disability on the
family's daily life and function, and social support (5).
What is the meaning of life for adolescents with disabilities?
Adolescents with physical disabilities in Korea experience meaning in
their lives when society accepts their existential problems and allows
them to live a normal live. This normality includes helping others (as
a friend or as a volunteer) and creating opportunities to achieve their
own goals in life. The main categories in the findings were
'accomplishment', 'social adaptation', improvement of the quality of
life', good deeds', 'sincerity', 'satisfaction', 'having a relationship',
'achievement of self', 'perception of one's own usefulness',
rehabilitation', and 'gain recognition by others'. Adolescent with
physical disabilities can understand the meaning of their lives when
78
L. Ben-Nun King David

meaning is framed in the context of being a social issue, and when


they are allowed to clarify their own values (6).
Which of these dimensions can be attributed to Mefivoshet?
The aim of the study was to examine whether caregiver burden,
parenting style, and sibling relationships in families raising a child
with a disability are associated with cooperative and externalizing
behaviors in typically developing sibling. This correlational study
included 189 families raising both a child with a disability and a
typically developing sibling. Multilevel modeling was used to identify
which variables were most predictive of typically developing sibling
outcomes and if there were parent gender effects. Authoritative
parenting was positively associated with cooperative behaviors.
Authoritarian parenting was positively associated with externalizing
behaviors. Multilevel modeling revealed caregiver burden was a
significant predictor of sibling behaviors in the first model. When
parenting style was added as a predictor, it was also significant.
When sibling relationships were added as predictors, they were
significant predictors for both cooperative and externalizing typically
developing sibling behaviors; however, caregiver burden was no
longer significant. Authoritarian parenting significantly predicted
externalizing behaviors, and authoritative parenting was significantly
related to cooperative behaviors. In families raising a child with a
disability, positive sibling relationships may help negate the effects of
caregiver burden and are more predictive of typically developing
sibling outcomes than some parenting practices (7).
King David regarded Mefivoshet as his son. What were
relationships between the King's children and Mefivoshet?
The aim of this study was to investigate the experiences of
parents of children with complex health needs in relation to the help
and support they receive when caring for their child. A series of in-
depth semi-structured interviews undertaken with the parents of 34
children (33 families) with a disability or a complex health need.
Families were categorized into one of three subgroups: children with
a disability, children with a life-limiting or life-threatening illness, or
children with technology dependence. In relation to parental
experience of the need for help and support, two major categories
were identified, namely 'people', and 'processes and resources', as
well as a series of subcategories. Respite care was identified as the
greatest unmet need. In conclusion, parents identified a range of
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L. Ben-Nun King David

helping behaviors among key professional staff involved in support


provision. The greatest area of unmet needs is for respite care (8).
King David's family represents an extended polygamous family.
What were relationships between the King's wives and Mefivoshet?
Did these mothers provide help and support to Mefivoshet?

References
1. Hallum A. Disability and the transition to adulthood: issues for the
disabled child, the family, and the pediatrician. Curr Prob Pediatr.
1995;25:12-50.
2. Anan A, Yamaguchi M. Process of parental acceptance of a child's
disability: literature review. J UOEH. 2007;29:73085.
3. Taanila A, Järvelin MR, Kokkonen J. Cohesion and parents; social
relations in families with a chid with disability or chronic illness. Int J Rehabil
Res. 1999;22:101-9.
4. Taanila A, Syrjälä L, Kokkonen J. Järvelin MR. Coping of parents with
physically and/or intellectually disabled children. Child Care Health Dev.
2002;28:73-86.
5. Ben-Nun L. Coping with child's disability. In: Ben-Nun (ed.) Pediatrics
from Biblical to Contemporary Times. B.N. Publication House. Israel 2012,
pp. 179-83.
6. Kim SJ, Kang KA. Meaning of life for adolescents with a physical
disability in Korea. J Adv Nurs. 2003;43:145-55.
7. Platt C, Roper SO, Mandleco B, Freeborn D. Sibling cooperative and
externalizing behaviors in families raising children with disabilities. Nurs Res.
2014;63(4):235-42.
8. Whiting M. Support requirements of parents caring for a child with
disability and complex health needs. Nurs Child Young People. 2014;26(4):
24-7.

AMNON

EATING DISORDERS. Right at the beginning of this story, Amnon


became “..so lean, from day to day?” (II Samuel 13:4). How can we
understand this verse?
Adolescents frequently engage in disordered eating behavior at an
alarming rate, with many developing partial or full-blown eating
disorders. The spectrum of eating disorders includes AN, BN, EDNOS,
and BED (1). Eating disorders are one of the "great masqueraders" of
the twenty-first century. Seemingly healthy young men and women
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L. Ben-Nun King David

with underlying eating disorders present to emergency departments


with a myriad of complaints that are not unique to patients with eating
disorders. The challenge for the Emergency Medicine physician is in
recognizing that these complaints result from an eating disorder and
then understanding the unique pathophysiologic changes inherent in
these disorders that should shape management. Anorexia and BN are
complex psychiatric disorders with significant medical complications.
Recognizing patients with eating disorders in the emergency
department is difficult, but failure to recognize these disorders, or
failure to manage their symptoms with an understanding of their
unique underlying pathophysiology and psychopathology can be
detrimental to the patient. Screening tool, such as the SCOFF
questionnaire, is available for use by the Emergency Medicine physician
(2). Once identified, the medical complications can help the emergency
medicine physician tailor management of the patient to their
underlying pathophysiology and affect a successful therapeutic
intervention (3).
Eating disorders powerfully distort psychological control irrespective
of culture. However, the degree, directionality, and form of the
displacement from normal control styles are culture dependent (4).
Eating disorders long-term evolution is good in 50% of cases, middle in
25% (recovery from eating disorders, but still psychological suffering)
and bad in 25% of cases with chronic eating disorders, anxious or
depressive comorbid disorder, having bad consequences in social
patients' life. AN has a considerably worse long-term outcome than BN
or BEDs. Purging BN is often associated with other impulsive symptoms,
such as addictions and suicide attempts. Chronic undernutrition leads
to main long-term medical complications of eating disorders: linear
growth in adolescents with AN, infertility, and osteoporosis. These
complications need a specific medical follow up, at least once a year,
added to the psychiatric and psychotherapist follow-up (5).
AN and BN are the main types of eating disorders described in the
ICD-10. The main features are eating patterns such as refusal to eat
enough food or loss of control, followed by counter-regulatory
measures. Preoccupation with body shape and weight and with food is
an important feature of eating disorders. Severe medical conditions
may occur because of starvation, malnutrition and purging. Patients
with AN are foremost underweight (BMI <17.5 kg/m2). Etiological
models are multifaceted and include predisposing and sustaining
factors as well as triggers for the onset of the disorder. The course is
81
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variable and marked by changes between remission and clinically


relevant symptoms (6).
In 1986, Morton examined a 20-year-old girl presenting with
complaints of marasmus and amenorrhea (7). He stated that her
problem was related to “sadness and anxious cares”. For centuries, AN
with its high mortality rate, and its irascible and manipulative patients
has continued to plague concerned physicians (8).
The most common presentations of eating disorder patients, the
pathophysiologic changes, and the appropriate management of each
patient are examined. Patients with AN and BN present with eating
disorders with a multitude and vague complaints. It is crucial for eating
disorders physicians to recognize that such complaints stem from an
underlying eating disorder to understand the pathophysiology behind
such complaints. This in turn will lead to appropriate management of
patient symptoms, which can often be complex for the provider and
stressful for the patient (9).
AN is a life-threatening mental disorder. One of every 250 girls
between the ages of 12 and 18 years may develop AN. The high
incidence of this disorder among adolescent girls suggests that
developmental sexual pressure inherent in adolescence may be
associated with the onset of the disease. The symptoms of AN appear
with the onset of puberty and the development of the secondary sex
characteristics. Symptom formation is related to the following
developmental issues: physiological changes (menstruation and breast
development) and psychological changes (body image and sexual
identity) (10).
In a longitudinal cohort study over three years, a high-risk sample of
236 college-age women were randomized to the control group of a
prevention trial for eating disorders. Potential risk factors and
interactions between risk factors were assessed using the methods
developed previously. Main outcome measures were time to onset of
subthreshold or full eating disorders. At the three-year follow-up,
11.2% of participants had developed full or partial eating disorders.
Seven of 88 potential risk factors could be classified as independent risk
factors, seven as proxies, and two as overlapping factors. Critical
comments about eating from teacher/coach/siblings and a history of
depression were the most potent risk factors. The incidence for
participants with either or both of these risk factors was 34.8% (16/46)
compared to 4.2% (6/144) for participants without risk factors, with a
sensitivity of 0.75 and a specificity of 0.82. targeting preventive
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interventions at women with high weight and shape concerns, a history


of critical comments about eating weight and shape, and a history of
depression may reduce the risk for eating disorders (11).
Family, twin, and adoption studies of AN, BN, BED, and the proposed
purging disorder presentation have demonstrated that genetic factors
contribute to the variance in liability to eating disorders.
Endophenotypes and component phenotypes of eating disorders have
been evaluated and provide further insight regarding genetic factors
influencing eating disorders and eating disorder diagnostic criteria (12).
Although AN is usually considered a disorder of young women and
girls, 5% to 10% of cases occur in men and boys (13).
AN is thought to appear predominantly in girls and young women.
Twenty years ago the incidence of AN was considered as one boy to 10-
15 girls. Recent data suggest that the girls to boys' rate is 4:1. The most
frequently AN in boys begin during puberty. Boys and young men
reluctantly apply for help to medical professionals trying to hide their
symptoms. The diagnosis of AN is established and the treatment is
performed only when they suffer from a marked loss of weight or a
severe depression with suicidal thoughts. Seven male patients with AN
are reported and there are the differences in a course of this disease
between male and female patients (14).
The objective of this study was to determine the distribution of age
of onset of eating disorders in males as well as the relationship
between age of onset and various clinical and demographic
characteristics. The medical records of 70 males consecutively admitted
to an inpatient eating disorders unit, 1992-2002, were retrospectively
reviewed. Age of onset differ insignificantly by admission diagnosis and
appeared to have a single peak at about age 14 years. Patients with
older ages of onset reported lower percentage of weight and longer
duration of illness than inpatients with younger ages of onset (15).
Forty-one patients with AN, admitted to the Maudsley Hospital,
between 1959 and 1966, were followed up after a mean of 20 years. An
assessment of general outcome (based on the Morgan-Russell scales)
yielded three outcome categories: 'good' (n=12), 'intermediate' (n=13)
and 'poor' (n=15). Six patients (15%) had died from causes related to
AN; at least 15% had developed BN. There was a general consistency
between the follow-up at 20 years and that previously conducted five
years after admission, although with a few individual patients there
were serious prognostic errors at the earlier follow-up. A poorer
outcome was associated with a later age of onset, a history of neurotic
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and personality disturbances, disturbed relationships in the family and


a longer duration of illness (16).
The current study investigated the background and outcome of AN
in young men. All (n=61) men, born in 1968-1977, with hospital care in
Sweden between 1987 and 1992 due to AN, were compared with the
general population. Information about socioeconomic background,
health-related outcome (hospital care for AN, other psychiatric
diagnoses, abuse of alcohol/drugs and/or suicide attempt), and social
outcome (major income from sick leave/sick pension or ≥ six months
social welfare, living with birth parents, and living with child and
partner; education level) was taken from national registers. On a group
level, the findings suggested some differences between male patients
with AN and the male population without AN concerning social
background, capacity to support oneself, and living with partner and
child. Mental ill-health outcome was almost the same for men with AN
as for the general population. In conclusion, male gender in AN on a
group level suggests a good psychiatric prognosis (17).
In Romania, the prevalence of AN was 0.6% in the female population
while clinical cases of AN were not found in the Hungarian female
sample. The prevalence of subclinical AN reached 1.9% in the Romanian
females and 0.4% in the Hungarian female sample (18).
In Tuscany, North-Central Italy, 2004-2006, the prevalence of
thinness increased with age in girls (4.9% at nine years, and 14.1% at 15
years), while boys presented a similar low prevalence at eight and 15
years (3.3% and 3.1%) (19).
In the city of Reus, Spain, diagnostic criteria of AN were found in
0.9% (95% CI: 0.4-2.4) of adolescent girls (n=551) between the ages of
12 and 21 years (20). In an additional study, a community sample of
1,115 participants, and a risk sample of 93 participants, aged between
10.9 and 17.3 years old, from the city of Barcelona, Spain, were
involved in the study. AN (of the total sample) reached 1.28-2.31% of
girls and 0.17% of boys. Symptoms of AN and BN were higher among
girls than in boys. Preoccupation with maintained low weight, body
image and shape, and taking excessive exercise in order to lose weight
are increasing among Spanish adolescents (21).
In the US Military, 1998-2006, the percentage per year of SM with
eating disorders diagnosis was 0.30%. Females were diagnosed
significantly more than males (p<0.001). The majority of AN cases
(66%) were in Marines. Females, specifically White females, have
higher incidence of eating disorders (22).
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Eating disorders can arise from a combination of biological and


psychological factors. The aim of this study was to examine the
association between cognition measurements (cognitive performance
and academic achievement) and the risk of developing eating disorders
in adolescents considering their weight status. The sample consisted of
3,307 adolescents (1,756 girls), aged 13-18.5 years, who participated in
the AVENA (n = 1,430, 783 girls) and AFINOS (n = 1,877, 973 girls)
studies. Cognitive performance was measured by the TEA test (Test of
Everyday Attention) in the AVENA study, and academic achievement
was self-reported in the AFINOS study. Eating disorders risk was
evaluated in both studies by using the SCOFF questionnaire. BMI was
calculated to classify adolescents as non-overweight or overweight
(including obesity). Overweight adolescents showed a higher risk of
developing eating disorders than non-overweight ones in both studies.
In the AVENA study, overweight boys with low performance in
reasoning ability showed increased risk of eating disorders (p = 0.05). In
the AFINOS study, overweight boys with low academic performance in
physical education and non-overweight girls with low academic
achievement in all the areas analyzed showed higher risk of eating
disorders than their peers (all p < 0.05). In conclusion: association
between cognitive performance and eating disorders risk was not
found in adolescents, while academic achievement was associated with
eating disorders risk, especially in non-overweight girls. The non-
cognitive traits that accompany academic achievement could influence
the likelihood of developing eating disorders in these girls (23).
This study was designed to compare the risk of having an eating
disorder among immigrant and native adolescents living in Madrid and
to determine the possible influence of length of residence on the risk of
the immigrants. A cross-sectional survey was conducted from
November 2007 to February 2008 in a representative sample of
adolescents aged 13 to 17 years (n=2,077, 1,052 girls) living in the
Madrid region. Data were collected using the Spanish version of the
SCOFF Eating Disorders Questionnaire. Further factors considered were
country of birth, length of residence and several biological,
sociodemographic, lifestyle and health-related variables. According to
the three logistic regression models constructed, female immigrant
adolescents on the whole showed a greater eating disorder risk (OR
1.95, 95% CI 1.29-2.95, p=0.001) than native adolescents. The likelihood
of eating disorder was higher among female immigrants living in Spain
for < six years than for Spanish native females (OR 2.44, 95% CI 1.42-
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4.18, p=0.001), while insignificant differences were found when female


natives were compared with female immigrants living in this country
for ≥ six years. Similarly, no differences were observed in the eating
disorder risk recorded for male native and immigrant adolescents, both
as a whole and by length of residence in Spain. In conclusion, the
immigrant status and the length of Spanish residence are relevant
factors concerning the eating disorders risk in adolescents living in
Madrid (24).
This paper presents three cases involving young Orthodox Jewish
males, each of whom lost 15-25 pounds over a course of time ranging
between a few months and up to two years, as the result of decreased
food intake because of misinterpretation of a religious concept learned
in their Judaic studies. Although each had a BMI between 15.8 and
16.1, they did not display the body image concerns necessary for the
diagnosis of AN. The discussion covers the distinction between AN and
the newly described diagnosis in these young men, i.e., weight loss due
to religious zeal, along with a brief history of fasting for religious
reasons as described in previous centuries (25).
This study was conducted between September 21001 and May 2002
in 238 high school students, in 7th and 12th grade, living in the Misgav
region in northern Israel. Of 360 students approached, 283 (78%)
completed the self-report EAT-26. One in every five females and one in
every 20 males had an abnormal eating attitude. In this population, a
relatively high rate of abnormal eating attitudes was observed (26).

ASSESSMENT: there are widespread prevalence rates of eating


disorders in different countries.

References
1. Sigel E. Eating disorders. Adolesc Med State Art Rev. 2008;19(3): 547-72,
xi.
2. John F Morgan, Fiona Reid, Lacey JH. The SCOFF questionnaire:
assessment of a new screening tool for eating disorders. BMJ 1999;319:1467.
3. Trent SA, Moreira ME, Colwell CB, Mehler PS. ED management of
patients with eating disorders. Am J Emerg Med. 2013;31(5):859-65.
4. Soh N, Surgenor LJ, Touyz S, Walter G. Eating disorders across two
cultures: does the expression of psychological control vary? Aust N Z
Psychiatry. 2007;41:351-8.
5. Nicolas I. Long-term evolution and complications of eating disorders. Rev
Prat. 2008;58(2):151-5.
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6. Legenbauer T, Herpertz S. Eating disorders – diagnosis and treatment.


Dtsch Med Wochenschr. 2008;133:961-5.
7. Morton R. Phthisiologia: or treatise of consumptions. Smith and Walford
(English translation). London, 1694.
8. Silverman J. Anorexia nervosa: clinical observations in a successful
treatment plan. J Pediatr. 1974;84:68-3.
9. Mascolo M, Trent S, Colwell C, Mehler PS. What the emergency
department needs to know when caring for your patients with eating
disorders. Int J Eat Disord. 2012;45(8):977-81.
10. Romeo FF. Adolescence, sexual conflict, and anorexia nervosa.
Adolescence. 1984;19(75):551-5.
11. Jacobi C, Fittig E, Bryson SW, et al. Who is really at risk? Identifying risk
factors for subthreshold and full syndrome eating disorders in a high-risk
sample. Psychol Med. 2011;41(9):1939-49.
12. Thornton LM, Mazzeo SE, Bulik CM. The heritability of eating disorders:
methods and current findings. Curr Top Behav Neurosci. 2011;6: 141-56.
13. Barry A, Lippmann S. Anorexia nervosa in males. Postgrad Med.
1990;98:161-5, 168.
14. Ziora K, Oświecimska J, Szalecki M, et al. Anorexia nervosa in boys and
men. Wiad Lek. 2006;59(5-6):352-8.
15. Forman-Hoffman VL, Watson VL, Andersen AE. Eating disorder age of
onset in males: distribution and associated characteristics. Eat Weight Disord.
2008;13:e28-31.
16. Ratnasuriya RH, Eisler I, Szmukler GI, Russell GF. Anorexia nervosa:
outcome and prognostic factors after 20 years. Br J Psychiatry. 1991;158:495-
502.
17. Lindblad F, Lindberg L, Hjern A. Anorexia nervosa in young men: A
cohort study. Int J Eat Disord. 2006;39(8):662-6.
18. Kovács T. Prevalence of eating disorders in the cultural context of the
Romanian majority and the Hungarian minority in Romania. Psychiatr Hung.
2007;22:390-6.
19. Lazzeri G, Rossi S, Pammolli A, et al. Underweight and overweight
among children and adolescents in Tuscany (Italy). Prevalence and short-term
trends. J Prev Med Hyg. 2008;49:13-21.
20. Olesti Baiges M, Piñol Moreso JL, Martin Vergara N, et al. Prevalence of
anorexia nervosa, bulimia nervosa and other eating disorders in adolescent
girls in Reus (Spain). An Pediatr (Barc). 2008;68:18-23.
21. Muro-Sans P, Amador-Campos JA. Prevalence of eating disorders in a
Spanish community adolescent sample. Eat Weight Disord. 2007;12:e1-6.
22. Antczak AJ, Brininger TL. Diagnosed eating disorders in the U.S. Military:
a nine year review. Eat Disord. 2008;16:363-77.
23. Veses AM, Gómez-Martínez S, de Heredia FP, et al. Cognition and the
risk of eating disorders in Spanish adolescents: the AVENA and AFINOS studies.
Eur J Pediatr. 2014 Jul 31. [Epub ahead of print].
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24. Esteban-Gonzalo L, Veiga OL2, Gómez-Martínez S, et al. Length of


residence and risk of eating disorders in immigrant adolescents living in
Madrid. The AFINOS study. Nutr Hosp. 2014;29(5):1047-53.
25. Fisher M. Weight loss as a result of religious zeal in young Orthodox
Jewish males. Int J Adolesc Med Health. 2013;25(2):181-3.
26. Roguin Maor N, Sayag S, Dahan R, Herm0oni D. Eating attitudes among
adolescents. IMAJ. 2006; 8:627-9.

ANOREXIA NERVOSA
Did Amnon suffer from AN? The essential features of AN are that
the individual refuses to maintain a minimally normal body weight for
his or her age and height (Criterion A), is intensely afraid of gaining
weight (Criterion B), and exhibits significant disturbance in the
perception of the shape or size of his or her body (Criterion C) (1). AN is
related to cultural, physical, and psychological pressures on vulnerable
adolescents or young adults (2). Of these criteria only one (Criterion A)
(1) can be attributed to Amnon. According to this definition, there are
insufficient criteria for a diagnosis of AN (3).
There are individuals, however, who do not strictly fulfill the DSM-IV
criteria (4). In 1995, The Society for Adolescent Medicine issued a
position paper on adolescent eating disorders, which identified a broad
spectrum of eating disorders among young people that could lead to
moderate or severe disturbance (5), while some believe that AN is
more of a dieting disorder than an eating disorder (6). Subsequently,
cases of eating disorders were classified as AN, bulimia, and partial
syndromes (3).

ASSESSMENT: according to these definitions, it seems that Amnon


suffered from partial eating disorder.

References
1. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,
Washington, DC, American Psychiatric Association, 1994.
2. Romeo F. Adolescent boys and anorexia nervosa. Adolescence.
1994;29:643-7.
3. Ben-Nun L. In: Ben-Nun L. (ed.). The Medical Record of Amnon the King
David's Son. Israel. 2014.
4. Morandé G, Celada J, Casas JJ. Prevalence of eating disorders in a Spanish
school-age population. J Adolesc Health. 1999;24:212-9.
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5. The Society for Adolescent Medicine. Eating disorders in adolescents: A


position paper. J Adolesc Health. 1995;16(6):476-9.
6. Beumont PJ, Russel JD, Touyz SW. Treatment of anorexia nervosa.
Lancet. 1993;341:1635-40.

PARTIAL SYNDROMES OF EATING DISORDERS. This review focuses


on the definition, epidemiology and clinical aspects of partial eating
disorders. Search on Medline & PsycINFO, review of websites,
screening of bibliographies of articles and book chapters were
conducted. There is still no consensus on the definition of these
disorders, which cover a wide range of severity. Affected adolescents
often suffer from physical and psychological problems owing to co-
morbidity or because of their eating patterns: chronic constipation,
dyspeptic symptoms, nausea, abdominal pain, fatigue, headaches,
hypotension, menstrual dysfunction as well as dysthymia, depressive
and anxiety disorders, or substance misuse and abuse. In comparison
with those who are unaffected, adolescents with partial eating
disorders are at higher risk of evolving into full eating disorder.
However, most of them evolve into spontaneous remission.
Adolescents with partial eating disorders engaged, over a period of
several months, in potentially unhealthy weight-control practices,
suffering from intense fear of gaining weight and a disturbed body
weight/image should be offered therapeutic support (1).
The main objective of this study was to identify prospective
predictors of eating disorders in a population-based sample of 14-year-
old boys and girls, using previously collected antenatal, biomedical,
familial, demographic, and psychosocial data. Participants (n=1,597)
were drawn from the Western Australian Pregnancy Cohort (Raine)
Study. Data were collected during pregnancy, at birth, and when
children were aged 1, 2, 5, 8, 10, and 14 years. An adapted version of
the Eating Disorder Examination Questionnaire was used to assess
eating disorder symptoms at age 14 years. At age 14 years, 6% of the
sample met full or partial criteria for a DSM-IV eating disorder. Being
female and being perceived as overweight by one's parent were the
strongest predictors of eating disorder caseness in the final multivariate
models, relative to both control groups. Maternal BMI, social problems,
low social-related self-efficacy, and neurocognitive difficulties were also
predictive of eating disorder caseness relative to the general control
group only. The results suggest that parent's perceptions of their child's
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weight are more powerful than objective child body weight in


predicting the development of eating disorders. Parent-perceived child
overweight was also a specific risk factor for eating disorders, whereas
elevated maternal weight and childhood psychosocial difficulties seem
to be associated with increased risk for psychiatric disturbance more
generally. These results have implications for the prevention of eating
disorders, particularly in light of recent increases in the prevalence of
childhood obesity (2).
The main aim of this study was to document the health and social
adjustment in young female adulthood assessed as having a partial
syndrome of eating disorder in adolescence. A community sample of
1,943 participants was tracked over 10 years in an eight-wave cohort
study. A partial syndrome was defined as the fulfillment of at least two
DSM-IV criteria for either anorexia or BN at one assessment or more
between the ages of 15 years and 17 years. Partial syndromes were in
9.4% of 15- to 17-year-old female participants and 1.4% in males. There
were few instances of progression of partial syndromes to fully-fledged
anorexia and BN. However, among those with partial syndromes
depressive and anxiety symptoms were two to three times higher in
young adulthood, substance misuse was common, and a majority of
those with a partial syndrome of AN were still underweight in their mid-
20s. In conclusion, given the level of subsequent psychopathology and
social role impairment, there may be justification for initiating trials of
preventive and early clinical intervention strategies for adolescent
partial syndromes (3).

ASSESSMENT: adolescents affected by partial syndrome eating


disorder often suffer from physical and psychological problems due to
co-morbidity or because of their eating patterns: chronic constipation,
dyspeptic symptoms, nausea, abdominal pain, fatigue, headaches,
hypotension, menstrual dysfunction as well as dysthymia, depressive
and anxiety disorders, or substance misuse and abuse.
Being female and being perceived as overweight by one's parent,
maternal BMI, social problems, low social-related self-efficacy, and
neurocognitive difficulties predict partial syndrome eating disorder.
Among individuals with partial syndromes, depressive and anxiety
symptoms, and substance misuse are prevalent.
Did Amnon suffer from partial syndrome eating disorder? Amnon's
medical record does not tell us that he suffered from any physical
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problem. All his all thoughts were concerned his half-sister Tamar, how
to invite her to his room, and how to sexually abuse her.

References
1. Chamay-Weber C, Narring F, Michaud PA. Partial eating disorders
among adolescents: a review. J Adolesc Health. 2005;37(5):417-27.
2. Allen KL, Byrne SM, Forbes D, Oddy WH. Risk factors for full- and partial-
syndrome early adolescent eating disorders: a population-based pregnancy
cohort study. J Am Acad Child Adolesc Psychiatry. 2009;48(8):800-9.
3. Striegel-Moore RH, Seeley JR, Lewinsohn PM. Psychosocial adjustment
in young adulthood of women who experienced an eating disorder during
adolescence. J Am Acad Child Adolesc Psychiatry. 2003;42(5):587-93.

FOOD AVOIDANCE EMOTIONAL DISORDERS. There are patients


who have been identified as having food avoidance emotional
disorders. These patients do not meet the criteria for AN, and they
seem to have an intermediate disorder, somewhere between AN and
food avoidance (1).
The clinical importance of a specific eating disorder in 3 to 10-year-
old children was underlined, when the majority of the works about the
prepubertal eating disorders focus either on the period just preceding
adolescence (often between 10 and 13 years), or on the second half of
the first year of the baby. Within the eating disorders described in the
literature, the clinical presentation of most of 3 to 10- year-old children
with the food avoidance emotional disorder during adolescence were
compared. The problems of eating behavior (various selective eating
with or without provoked vomiting) were ignored for a long time in
these young children because of quite a satisfactory growth, but these
children were often seen in emergency rooms because of a brutally
complete eating refusal. Therapeutic consultations allowed these
children to express their fears about diseases, poisoning and death, for
themselves or for their close relations, in particular the mother,
without endangering their body. The early recognition and care of
difficulties of conciliation between the body and the thoughts impose a
narrow collaboration between pediatric and psychiatric staffs (2).
The aim of this study was to analyze the prevalence of atypical
eating problems and their associations with anxious or oppositional
behaviors in young children. One thousand and ninety children (544
boys) were examined in the school enrolment test in a defined
geographical region. The parents completed a 25-item questionnaire
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regarding their child's eating behavior and anxious or oppositional


behaviors. Half of the parents reported that their child avoids certain
foods (53%); 23% showed selective eating, and 26% an aversion against
new foods. Children with underweight avoided more types of food and
ate smaller amounts than children with normal or overweight eat.
Three groups could be differentiated. Sixty-one percent of the children
were 'normal eaters' with avoidance of certain foods, normal weight
status and low anxious or oppositional behavior. Thirty-four percent
showed selective and/or restrictive eating, and 5% worried about their
weight. Children with selective eating and with weight concerns were
more often affected by anxious and oppositional behaviors. In
conclusion, atypical eating problems are common in young children.
Without accompanying weight loss, behavioral or emotional problems,
selective eating should be seen as a normal feature in young eating
behavior. Parents of young children with selective, restrictive eating or
with weight worrying and psychological problems should be offered
advice/treatment (3).

ASSESSMENT: there are children who have been identified as having


food avoidance emotional disorders. Children with underweight avoid
some types of food and eat smaller amounts than children with normal
weight or overweight. Children with selective eating and with weight
concerns are often affected by anxious and oppositional behaviors.
Was Amnon afflicted by a food avoidance emotional disorder?
Perhaps Amnon attempted to resolve the conflict with his sister Tamar
by focusing on food and control of food intake.

References
1. Higgins JF, Gooddyer IM, Birch J. Anorexia nervosa and food avoidance
emotional disorder. Arch Dis Childhood. 1989;64:346-51.
2. Goëb JL, Azcona B, Troussier F, et al. Food avoidance emotional disorder
in 3 to 10-year-old children: a clinical reality. Arch Pediatr. 2005;12(9):1419-23.
3. Equit M, Pälmke M, Becker N, et al. Eating problems in young children -a
population-based study. Acta Paediatr. 2013;102(2):149-55.

PRIMARY DEPRESSION. Primary depression can present with


reduced food intake and weight control (1). To investigate the
relationship between weight deficit and depressive symptoms, 48
adolescent patients (41 females, seven males) fulfilling DSM III R criteria
for AN were assessed for DSM III diagnosis of MDD. Patients who met
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diagnostic criteria for MDD had a significantly lower body weight than
those without a current episode of MDD. In turn, patients with high
weight loss had higher mean depression scores (The Hamilton Rating
scale for Depression, HAMD, SDS) than patients with less weight deficit.
With increase of body weight, a highly significant decrease of
depressive symptoms was found. The DSM III criteria for MDD may not
specifically distinguish between starvation-related psychopathology in
AN and primary affective disorder (2).
Obesity has been linked to both MDD and BED in clinical and
epidemiological studies. The present study compared weight loss
among patients with and without MDD and BED who participated in a
hospital-based weight loss program modeled after the Diabetes
Prevention Program. Of 131 obese patients who enrolled in treatment,
17% were diagnosed with MDD only, 13% were diagnosed with BED
only, 17% were diagnosed with both MDD and BED, and 53% lacked
either diagnosis in a pretreatment clinical interview. After treatment,
patients with MDD only attained 63% of the weight loss that non-
depressed patients attained. Patients with BED only attained 55% of
the weight loss that non-binge eaters attained. The effect of MDD on
weight loss was not accounted for by the presence of BED or vice versa.
Only 27% of patients with both MDD and BED achieved clinically
significant weight loss compared with 67% of patients who had neither
disorder. Results were insignificantly altered when gender, age, and
diabetes status were adjusted. In conclusion, both MDD and BED were
prevalent among this obese clinical population, and each disorder was
independently associated with worse outcomes (3).

ASSESSMENT: depression can present with reduced food intake and


weight loss. Was Amnon affected by depression? An evaluation of
Amnon's medical record, that is the biblical text, does not provide
evidence of any depressive disorder.

References
1. Fosson A, Knibbs J, Bryant-Waugh, Lask B. Early onset anorexia nervosa.
Arch Dis Childhood. 1987;62:114-8.
2. Herpertz-Dahlmann B, Remschmidt H. Anorexia nervosa and depression.
On the relation of body weight and depressive symptoms. Nervenarzt.
1989;60(8):490-5.
3. Pagoto S, Bodenlos JS, Kantor L, et al. Association of major depression
and binge eating disorder with weight loss in a clinical setting. Obesity (Silver
Spring). 2007;15(11):2557-9.
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L. Ben-Nun King David

EATING DISORDERS NOT OTHERWISE SPECIFIED. EDNOS are the


most common category of eating disorders encountered in routine
clinical practice. Their prevalence fluctuates from 2.4% to 12.6% among
female adolescents and up to 60% of cases in treatment centers. BED is
the most differentiated subtype. Peripuberal period, DM type I, intense
and increased physical activity, demographic and psychosociocultural
aspects, physical and psychopathological diseases are risk factors.
Clinical features, course, outcome and therapeutic approaches are
similar to those of full syndromes. From an etiological point of view,
there is a continuum from altered eating behaviors and concerns about
body shape and weight to typical anorectic and/or bulimic disorders.
Others classify them as subcategories of full or mixed disorders. These
conditions are heterogeneous syndromes that need to be reconsidered
from both nosological and conceptual perspectives. They also demand
an early recognition and treatment and further research about these
disorders is required (1).
Eating disorders are a common mental disorder during adolescence
and young adulthood. While prevalence rates of eating disorders
dramatically increased during the second half of the last century, these
rates have remained relatively stable over the last 20 years. According
to ICD-10, eating disorders are diagnostically categorized as AN, BN and
atypical eating disorders or EDNOS. Concerning the etiology, genetic
factors are involved, especially in AN, as well as psychological and
sociocultural factors. Evidence-based recommendations are available
for the treatment of BN and BED and in this context, cognitive
behavioral therapy is the first choice. By contrast, the state of
knowledge concerning the treatment of AN is still limited, especially
concerning effective treatments for adults. Recent data only provide
evidence for the effectiveness of family therapy for adolescents (2).
The main objective of this study was to characterize a large number
of adult outpatients diagnosed with EDNOS. The sample consisted of
1,449 patients who were classified as AN, BN, or assigned to one of six
EDNOS categories. Eating disorder groups were compared on
demographic features, symptom frequencies, and psychological
functioning. Forty percent of the sample was categorized as EDNOS. A
subgroup of purging only patients closely resembled the BN purging
subtype. Although EDNOS subthreshold BN patients reported less
psychopathology than full syndrome BN, they nevertheless, displayed
clinical levels of disturbances. Patients who binge eat once a week
demonstrate a profile of psychological functioning similarly to those
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who binge eat twice a week. In conclusion, consistent with previous


research, in this sample there were subgroups embedded in the EDNOS
category that both share similarities with and differ from full syndrome
of BN (3).
EDNOS is the most prevalent eating disorder diagnosis. In this meta-
analysis, the authors aimed to inform DSM revisions by comparing the
psychopathology of EDNOS with that of the officially recognized eating
disorders: AN, BN, and BED. A comprehensive literature search
identified 125 eligible studies (published and unpublished) appearing in
the literature from 1987 to 2007. Random effects analyses indicated
that whereas EDNOS differ insignificantly from AN and BED on eating
pathology or general psychopathology, BN exhibited greater eating and
general psychopathology than EDNOS. Moderator analyses indicated
that EDNOS groups who met all diagnostic criteria for AN except for
amenorrhea differ insignificantly from full syndrome cases. Similarly,
EDNOS groups, who met all criteria for BN or BED except for binge
frequency, differ insignificantly from full syndrome cases. Results
suggest that EDNOS represents a set of disorders associated with
substantial psychological and physiological morbidity. Although certain
EDNOS subtypes could be incorporated into existing DSM 4th ed. (4),
categories, others - such as purging disorder and non-fat-phobic AN -
may be best conceptualized as distinct syndromes (5).

ASSESSMENT: EDNOS are the most common category of eating


disorders encountered in routine clinical practice. Clinical features,
course, outcome and therapeutic approaches are similar to those of full
syndromes. From an etiological point of view, there is a continuum
from altered eating behaviors and concerns about body shape and
weight to typical anorectic and/or bulimic disorders.
Did Amnon suffer from EDNOS?

References
1. Behar A R. Eating disorders not otherwise specified, partial syndromes
and subclinical disorders: a warning in primary care. Rev Med Chil. 2008;
136(12):1589-98.
2. Voderholzer U, Cuntz U, Schlegl S. Eating disorders: state of the art
research and future challenges. Nervenarzt. 2012;83(11):1458-67.
3. Rockert W, Kaplan AS, Olmsted MP. Eating disorder not otherwise
specified: the view from a tertiary care treatment center. Int J Eat Disord.
2007;40 Suppl:S99-S103.
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4. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,


Washington, DC, American Psychiatric Association, 1994.
5. Thomas JJ, Vartanian LR, Brownell KD. The relationship between eating
disorder not otherwise specified (EDNOS) and officially recognized eating
disorders: meta-analysis and implications for DSM. Psychol Bull. 2009;
135(3):407-33.

CLINICAL PHENOMENON OF SELF-HARM. The aim with this article is


to provide an introduction to self-harm as a clinical phenomenon, with
phenomenological descriptions and definitions, and by presenting risk
factors, epidemiological data and functions of self-harm. The basis for
the article is a non-systematic literature search of the electronic
databases Medline, PsychInfo and EMBASE (1985-2008), and the
authors own archive of literature on self-harm. There is some evidence
for an increase in the prevalence of self-harm. Among possible risk
factors are childhood abuse, abandonment, neglect, trauma and
separation, and the affective quality of the attachment bonds in
childhood. A common factor is self-harm as a bodily practice for affect
regulation, and as such, it can be understood as a dysfunctional
competence (1).
Empirical studies confirm a strong association between self-harm
and eating disorders. Reported prevalence of self-harm among patients
with eating disorders varies between 13-68%. A higher prevalence has
been reported for patients with BN and AN binge-type than among
patients with AN restrictive type. Possible common factors are
impulsivity, obsessive-compulsive traits, dissociation, negative self-
evaluation, trauma, high conflict level in the family environment and
sensitivity for cultural trends. Thus, self-harm and eating disorder
represent disturbed regulation of affects, and both practices can be
interpreted as attempts of active coping (2).
Self-injurious behavior is common among adolescents, and is
associated with eating disorders. This study examines the prevalence of
self-injurious behavior and self-injurious behavior screening in
adolescents with eating disorders, and associations with binge eating,
purging, and diagnosis. Charts of 1,432 adolescents diagnosed with
eating disorders, aged 10–21 years, at an academic center between
January 1997 and April 2008, were reviewed. Of patients screened,
40.8% reported to be engaging in self-injurious behavior. Patients with
a record of self-injurious behavior were more likely to be female, have
BN, or have a history of binge eating, purging, co-morbid mood
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disorder, substance use, or abuse. Patients who engaged in both binge


eating and purging were more likely to report self-injurious behavior
than those engaged in restrictive behavior or either behavior alone.
Providers documented screening for self-injurious behavior in fewer
than half of the patients. They were more likely to screen patients who
fit a profile of a self-injurer: older patients who binge, purge, or had a
history of substance use. In conclusion, self-injurious behavior was
common in this population, and supports extant literature on
associations with BN, mood disorders, BED, purging, abuse, and
substance use (3).
The literature on the association between self-injurious behaviors
and eating disorders from the psychological-behavioral perspective was
reviewed. The main aim of this study was to investigate the extent and
possible reasons for the association. A literature search was conducted
using the following electronic databases (1989-2005): Medline,
PsychInfo and EMBASE. References in identified articles were also
screened. The reported occurrence of self-injurious behaviors in eating
disorder patients ranged between 25.4-55.2%. The figures for
occurrence of eating disorders in self-injurious behaviors patients
ranged at 54-61%. These figures indicate that there is a strong
association between these disorders. Impulsivity, obsessive-compulsive
characteristics, affect dysregulation, dissociation, self-criticizing
cognitive style and need for control were identified as potential factors
involved in the association. Early trauma such as childhood sexual
abuse and possibly certain characteristics of early family environment
might contribute to the development of these factors. A hypothetical
model includes these factors and argues that the co-existence of eating
disorders and self-injurious behaviors in patients results from several
factors. Self-injurious behaviors and eating disorder symptoms may
provide a means whereby patients can deal with each factor
simultaneously (4).
Previous research has suggested that emotion dysregulation, body-
related concerns, and depressive symptoms are associated with NSSI
and disordered eating separately and in combination. However, it has
been difficult to ascertain to what extent these constructs contribute to
NSSI and disordered eating given the relatively small number of studies
examining their co-occurrence, particularly among nonclinical samples.
Based on responses to self-report questionnaires, college-aged women
who completed the study were divided into three groups: NSSI only;
disordered eating only; and NSSI + disordered eating based on clinical
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cutoff criteria. Results support hypotheses that emotion dysregulation


is a shared vulnerability and body-related concerns and depression
exhibit unique patterns of association across the three groups. It
appears that NSSI is best understood as a response to negative
affective states relative to disordered eating, which is best understood
as a set of behaviors motivated by body image concerns. The presence
of both NSSI and disordered eating is primarily influenced by emotion
dysregulation and the dominant difficulties linked to each behavior;
depression and body dissatisfaction. These findings suggest that
treatment and prevention efforts should emphasize emotion regulation
skills and differentially target body concerns or depressive symptoms
according to the primary behavioral dysfunction (5).

ASSESSMENT: self-harm is prevalent among the patients with eating


disorders. Patients with a record of self-injurious behavior are more
likely to be female, have BN, or have a history of binge eating, purging,
co-morbid mood disorder, substance use, or abuse.
The prevalence of eating disorders in self-injurious behaviors
patients is estimated at 54-61%.
Impulsivity, obsessive-compulsive characteristics, affect
dysregulation, dissociation, self-criticizing cognitive style and need for
control, childhood abuse, abandonment, neglect, trauma and
separation, and the affective quality of the attachment bonds in
childhood are potential factors involved in the association.
NSSI is a response to negative affective states relative to disordered
eating, which is a set of behaviors motivated by body image concerns.
The presence of both NSSI and disordered eating is primarily influenced
by emotion dysregulation and the dominant difficulties linked to each
behavior; depression and body dissatisfaction.
In Amnon's case, impulsivity, obsessive-compulsive trait and an
affective attachment to Tamar are identified.

References
1. Sommerfeldt B, Skårderud F. What is self-harm? Tidsskr Nor Laegeforen.
2009;129(8):754-8.
2. Skårderud F, Sommerfeldt B. Self-harm and eating disorders. Tidsskr Nor
Laegeforen. 2009;129(9):877-81.
3. Peebles R, Wilson JL, Lock JD, M.D. Self-Injury in Adolescents With Eating
Disorders: Correlates and Provider Bias. J Adolesc Health. 2011;48(3):310-3.
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4. Svirko E, Hawton K. Self-injurious behavior and eating disorders: the


extent and nature of the association. Suicide Life Threat Behav. 2007;
37(4):409-21.
5. Muehlenkamp JJ, Peat CM, Claes L, Smits D. Self-injury and disordered
eating: expressing emotion dysregulation through the body. Suicide Life Threat
Behav. 2012;42(4):416-25.

TAMAR AND AMNON


Absalom, the son of David had a beautiful sister, Tamar. Another
son of David, Amnon, loved Tamar “And Amnon was so distressed
that he fell sick for his sister Tamar; for she was a virgin; and Amnon
found it hard to contrive any thing with regard to her” (II Samuel
13:2). Jonadab, Amnon’s friend, asked him “Why art thou, being the
king’s son, so lean, from day to day?” (13:4). Amnon told him that he
loved Tamar. Following Jonadab’s plan, Amnon pretended he was
sick. When the King, his father came to visit him, Amnon asked his
permission “...let Tamar my sister come, and make me a couple of
cakes in my sight, that I may eat at her hand” (13:6). With their
father’s agreement, Tamar was summoned to Amnon. So she
prepared cakes and brought them to Amnon. Meanwhile, Amnon
dismissed all the men from his room and demanded “Come lie with
me, my sister” (13:11). Tamar refused “..No, my brother do not force
me; for no such thing ought to be done in Israel: do not do this
shameful deed” (13:12). However, Amnon “...being stronger than
she, forced her, and lay with her” (13:14). After these sexual
relations, Amnon’s world turned around and he developed feeling of
hatred towards Tamar. Therefore, he called his servant who threw
her out of his room. Tamar suffered greatly: she “..put ashes on her
head, and tore her sleeved garments that was on her, and laid her
hand on her head, crying aloud as she went” (13:19). In spite of
Amnon’s disgraceful sexual behavior, Absalom advised her..”...keep
silence, my sister...So, Tamar remained desolate in her brother
Absalom’s house. But when king David heard of all these things, he
was very angry” (13:20,21). Following this disgusting sexual assault,
relations between Absalom and Amnon were destroyed, and they did
not speak with each other. An internal family system was disrupted.
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SEXUAL ASSAULT. Sexual assault is a problem that permeates all


socioeconomic classes and affects hundreds of thousands in the US and
millions worldwide. Most victims do not report the assault; those that
do often present to an emergency department. Care must encompass
the patients' physical and emotional needs. Providers must be
cognizant regarding handling of evidence and possible legal
ramifications. Special circumstances include IPV, male examinations,
pediatric examinations, suspect examinations, and drug-facilitated
assaults (1).
Acute sexual assault includes a broad spectrum of nonconsensual
sexual activity. Care of victims of acute sexual assault can be
challenging, especially given the significant potential psychological and
legal ramifications of the event and subsequent medical care and
forensic evidence collection. Utilization of sexual assault response
teams and sexual assault nurse examiners has demonstrated that a
systematic approach to these patients improves care. However, given
that victims of acute sexual assault are likely to present for care in
emergency departments where such teams do not exist, it is critical for
the emergency medicine physician, pediatrician, and family physician
acknowledging of aspects of history taking, the physical examination,
evidence collection, and medical record documentation (2).
Forcible sex offences are described as any sexual act directed
against another person, forcibly and/or against that person's will; or
not forcibly or against the person's will where the victim is incapable of
giving consent because of his/her temporary or permanent mental or
physical incapacity. Forcing rape (except "statutory rape") is described
as the carnal knowledge of a person, forcibly and/or against that
person's will; or not forcibly or against the person's will where the
victim is incapable of giving consent because of his/her temporary or
permanent mental or physical incapacity. If force was used or
threatened, the crime should be classified as forcible rape regardless of
the age of the victim. If no force was used or threatened and the victim
is under the statutory age of consent, the crime should be classified as
statutory rape (3).
Most definitions of sexual assaults contain three components: the
use of threat, duress, physical force, intimidation, or deception; sexual
contact; and non-consent of the victim (4). It is a crime of violence that
puts the victims at risk of physical injury, emotional disturbance,
pregnancy, and STDs (5). Women can be victims of unwanted touching,
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grabbing, oral sex, anal sex, sexual penetration with an object, and/or
sexual intercourse.
The words: Amnon “...being stronger than she, forced her, and lay
with her (Tamar)” II Samuel 13:14) indicate that sexual relations were
performed against Tamar's will. These sexual relations can be defined
as rape with Tamar as a victim (6).

References
1. DeVore HK, Sachs CJ. Sexual assault. Emerg Med Clin North Am. 2011;
29(3):605-20
2. Mollen CJ, Goyal MK, Frioux SM. Acute sexual assault: a review.
Pediatr Emerg Care. 2012;28(6):584-90; quiz 591-3.
3. Snyder HN. Sexual assault of young children as reported to law
enforcement: victim, incident and offender characteristics. U.S. Department
of Justice. Office of Justice Programs. 2000; NCJ 182990.
4. Reynolds MW, Peipert JF, Collins B. Epidemiologic issues of sexually
transmitted diseases in sexual assault victims. Obstet Gynecol Surv. 2000;
55:51-7.
5. Glasser JB, Hammerschlag MR, McCormack WM. Epidemiology of
sexually transmitted diseases in rape victims. Rev Infect Dis. 1989;11:246-54.
6. Ben-Nun L. Psychological consequences of sexual abuse. In: Ben-Nun
L. (ed.). Psychiatry in Biblical Times. B.N. Publication House. 2007, pp. 121-8.

EPIDEMIOLOGY. In a stratified sample of the general population,


adult sexual assault is reported among 941 participants by 22% of
women and 3.8% of men. Risk factors for adult sexual assault include a
younger age, being female, having been divorced, sexual abuse in
childhood, and physical assault in adulthood (1).
The lifetime prevalence of sexual assault is 38% among women and
6% among men among the veteran population (2). Among a sample of
college students, roughly 30% of the women and 12% of the men
reported having been the victim of a sexual assault sometime in their
lives (3). In secondary analysis, which included a representative
population-based sample of 8,080 students, 14 years and older at 87
New York City public high schools, lifetime history of sexual assault was
reported by 9.6% of females and 5.4% of males (4).
Sexual abuse rates in the general female population range between
15% and 25%, and sexual abuse has a long-term impact on a woman's
health (5).
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In Mexico, an estimated prevalence of sexual abuse in women


reached 17.3%, half of them in youngsters less than 15 years old (6).
The current report examined data for 872 female adolescents
obtained during the initial and follow-up interviews of the National
Survey of Adolescents, a nationally representative sample, US. Lifetime
prevalence of violence exposure reported was 12% and 13% for sexual
assault, 19% and 10% for physical assault/punishment, and 33% and
26% for witnessing violence at Waves I and II, respectively.
Racial/ethnic status, PTSD, childhood sexual abuse, and family drug
problems emerged as significant predictors of new rape. Each of the
PTSD symptom clusters significantly predicted new rape and analyses
supported the mediational role of PTSD between childhood sexual
abuse and new rape. African American or other racial identity was
associated with lower risk (7).
Dating violence is an important public health concern in adolescents.
A nationally representative sample of adolescents (n=3,614), the US,
completed a telephone-based interview that assessed serious forms of
dating violence (i.e., sexual assault, physical assault, and/or
drug/alcohol-facilitated rape perpetrated by a girlfriend, boyfriend, or
other dating partner). Prevalence of dating violence was 1.6% (2.7% for
girls, and 0.6% for boys), equating to approximately 400,000
adolescents in the US population. Risk factors included older age,
female sex, experience of other potentially traumatic events, and
experience of recent life stressors. Dating violence was associated with
PTSD and major depressive episode after controlling for demographic
variables, other traumatic stressors, and stressful events (8).
The main objective of this study was to identify determinants of
assaults using emergency department data to inform development of
programs delivered in acute Trusts for reducing assault-related injuries
in the community. Data were collected from a large North London
acute Trust on assault-related injuries reporting to Accident and
Emergency Attendances by English Local Authority area over 18 months
(July 2010-February 2012). Information was recorded on patient
demographics and assaults (place of assault, type of assault, and
relation to assailant) through questionnaires administered by
emergency department reception staff. Of 1,210 assaults recorded
between July 2010 and February 2012, 18% of assaults were severe
(strangling, stabbings, and sexual assaults), 75% of assault victims were
men, 37% were young adults (20-30 years) and 15% were teenagers. A
higher proportion of victims lived in more deprived areas. Apart from
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public streets (48%), the main location of assaults was at home (20%).
Female compared with male victims were significantly more likely to be
assaulted at home (OR 6.13, 95% CI 4.41-8.54) and by a known assailant
(family member, friend, partner/ex-partner; OR 8.20, 95% CI 5.85-
11.48). In conclusion, the results highlight the notable contribution of
domestic violence to assaults presenting to hospital emergency
department. Such findings can be used to plan interventions such as
screening hospital patients for domestic violence. Emergency
department data have the potential to inform hospital-based initiatives
to address issues such as assaults in the local population (9).
The objective of this study was to analyze demographic and event
characteristics of patients presenting to the emergency department for
evaluation after sexual assault, using a Sexual Assault Nurse Examiner
standardized database. Data were collected on 1,172 patients; 92%
were women, with a mean age of 27 years. The sample was 59.1%
black, 38.6% white, and 2.3% "other". Survivors of sexual assault were
overwhelmingly female, relatively young, who often knew the
perpetrator of the event, and were likely to be threatened and showed
signs of physical trauma (10).
Sexual behavior was examined in 17-year-old girls, Sweden. Data
were collected by anonymous self-administered 2,583 questionnaires.
Response rates from students were 92%, and for school non-attenders
44%. STDs and pregnancy were reported by 15% of early starters and
pregnancy by 14%, p<0.001 and 0.002, respectively, when compared
with later starters. Sexual abuse was reported by 20% of the early and
11% of later starters, p=0.002. A majority of 83% of the girls had
experienced voluntary intercourse, and 49% were early starters. Five
girls were mothers. STD was reported by 19% and induced abortion by
14% (11).
This study examined the prevalence of sexual aggression and
victimization in a large convenience sample (n = 2,149) of first-year
college students from different universities in Germany. Participants
were asked about both victimization by, and perpetration of, sexual
aggression since the age of 14. Both same-sex and heterosexual victim-
perpetrator constellations were examined. Prevalence rates were
established for different victim-perpetrator relationships (partners,
acquaintances, and strangers) and for incidents involving alcohol
consumption by one or both partners. The overall perpetration rate
was 13.2%, for men and 7.6% for women. The overall victimization rate
was 35.9% for women and 19.4% for men. A disparity between
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victimization and perpetration reports was found for both men and
women. Perpetration and victimization rates were highest among
participants who had sexual contacts with both opposite-sex and same-
sex partners. Sexual aggression and victimization rates were higher
between current or former partners and acquaintances than between
strangers. Alcohol consumption by one or both partners was involved in
almost 75% of all victimization and almost 70% of all perpetration
incidents. The findings portray a comprehensive picture of the scale of
sexual aggression and victimization in college students with different
sexual lifestyles (12).
This study covers information from 890 cases submitted to the
forensic science laboratory, the Republic of Ireland, in the time
between January 2004 to December 2005. The most common age
category of victims was 16-30 years, the most likely time of occurrence
was Saturday or night/Sunday morning during the summer months of
June, July or August. The victim most likely knew the assailant even if
only recently met. Loss of memory, mainly associated with the
consumption of alcohol, was a significant factor in many cases (13).
A retrospective study of emergency department visits for adult
female sexual assault in all Rhode Island emergency department, 1995-
2001, was conducted. Of the 780 patients, 78.2% sustained
anal/vaginal penetration, 5.0% genital touching only, and 3.7% oral sex
only, and 13.1% did not know what happened to them. Of those
women who were assaulted anal/vaginally, 83.8% were offered
chlamydia/gonorrhea testing, 69.4% syphilis testing, 82.9% pregnancy
testing, 77.0% chlamydia/gonorrhea prophylaxis, 47.6% emergency
contraception, and 19.2% HIV prophylaxis (14).
The main objective of this study was to carry out the
epidemiological and clinical characteristics of supposed victims of
sexual abuse and to evaluate case management. A prospective study
was conducted about cases of presumed sexual abuse received at the
gynecological and obstetrical clinic department of Aristide-le-Dantec
hospital, Sénégal from January 2003 to May 2005. Of 55 cases reported,
0.4% represented admissions in the clinic during the period of study.
Twenty percent of them (20%) were referred on judicial requisition. The
mean time between sexual abuse and consultation was 15 days.
Victims were 14 years old in average, nullipare in 96.5% of cases and
living in the suburban area of Dakar. The presumed "violenter" was a
man of 32 years, belonging to the environment of the victim in 70% of
cases (spiritual guide, joint-tenant, or friend of the family). The type of
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sexual assault was an unprotected genito-genital intercourse in 67.3%


of cases. On the clinical plan, 70.9% of patients suffered recent genital
traumatism, 54.5% genital examination showed hymeneal lesions. The
HIV test was positive in two cases. During the follow-up of the patients,
three pregnancies occurred and for only 9.1%, a psychological
assistance was proposed. In conclusion, sexual abuses represent a
current sociocultural issue. Prevention requires large information
campaign. Early management is necessary to prevent the STDs and
psychological side effects (15).
This was a retrospective study whose objective was to describe the
epidemiological and clinical aspects of the management of sexual
violence in Black Africa. The study included 373 cases of alleged female
victims of sexual assault registered in the Department of Obstetrics and
Gynecology of the University Teaching Hospital, Tokoin, Lomé from
2007 to 2009. Sexual assault accounted for 4.37% of reasons for
consultation and vaginal penetration (62.2%) was the predominant
mode. The victim was often a small girl of an average age of 12 years.
The mean reporting delay, which was about 13 days, has considerably
limited some aspects of the management. Signs of genital trauma were
found in 14.5% of cases, nine cases showed HIV serological conversions
(2.4%), and eight induced pregnancies. Sexual assault among female
victims in Lomé affected the young and vulnerable population (16).
The main objective of this study was to study the prevalence and
spectrum of sexual abuse among adolescents in Kerala, South India. A
self-report survey was conducted among adolescents in the 15-19 year
age group, studying in the plus one and plus two classes in selected
schools. Of the 1,614 respondents (688 boys and 926 girls), 36% of
boys and 35% of girls had experienced sexual abuse at some point
during their lifetime. Most instances were sexual advances while using
public transport. Feelings of insecurity and isolation at home, of being
disliked by parents and of being depressed were significantly more in
adolescents who had experienced sexual abuse, compared to those
who had not. In conclusion, sexual abuse is widely prevalent and both
boys and girls are equally susceptible. There is a need to evolve
strategies to protect children from sexual abuse and the programs
should address both boys and girls (17).
Since the year 2000, the number of rapes in Costa Rica has increased
at a rate of 42 cases per year. In 2011, 1,786 rape cases were reported
to the prosecution offices throughout the country, but only 1,081
reports continued through the investigation process by the Judicial
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Investigation Agency. A randomly collected sample of 272 reports


received by Judicial Investigation Agency, between July 2012 and June
2013, were prospectively studied. The analysis was limited to cases
reported within 30 days following the rape. Results indicate that most
of the provinces in the country show an incidence of about 38
cases/100,000 inhabitants. Ninety-six percent of the victims were
women, 50% of which were between 10 and 19 years old. More than
99.5% of violators were men. The rape was perpetrated by a single
aggressor in 85% of the cases. Of the victims, 48% were within the first
11 days of their menstrual cycle at the time of the attack. In 29%, rapes
occurred in "high rape-risk" circumstances-e.g., victims attacked by
strangers in public outdoors or indoors. In 25%, rapes occurred in
"moderate rape-risk" circumstances - e.g., victims attacked indoors at
public locations or at the home other than the victim's by relatives,
sentimental partners or acquaintances. In 15%, rapes occurred in "low
rape-risk" circumstances - e.g., victims attacked in their homes by
relatives or sentimental partners. In 67% of the cases, the perpetrator
was an acquaintance of the victim. In 11%, the cases corresponded to
rapes in which the perpetrator was a partner or ex-partner of the
victim. Fourteen percent and 25% of rapes could be classified as
"proactive drug-facilitated rapes" or "opportunistic drug-facilitated
rapes", respectively. Semen in the vaginal fluid of victims and the
genetic profile of the alleged perpetrator were detected in 55% and
33% of the cases, respectively (18).
This study determined the burden, periodicity, presentation and
management of sexual assault in Ile-Ife, Nigeria. Retrospective analysis
of the hospital records of 76 sexual assault survivors was managed over
a five-year period (2007-2011) in Obafemi Awolowo University
Teaching Hospitals complex, Ile-Ife. Sexual assault accounted for 0.69%
females and 5.2% of all gynecological emergencies. The survivors' ages
ranged from four to 50 years (mean = 17.7 ± 8.8 years) and adolescents
made up for 48%. The peak prevalence of sexual assault was in
February and December and among adults and under-16-year-old
survivors, respectively. Daytime and weekday sexual assaults were
significantly more common among the under-16-year-old survivors
(p=0.008). Majority of the survivors (62%) knew their assailant(s).
Neighbors were the commonest perpetrators identified (28.2%) and
the assailants' house was the commonest location (39.4%). Weapons
were involved in 29.6% of cases and various injuries were identified in
28.2% of the survivors. Hospital presentation was within 24 hours in
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majority (76.1%) of the survivors, but rape kit examinations were not
performed as the kits were not available. Although appropriate medical
management was routinely commenced, only 12.7% of survivors
returned for follow-up. In conclusion, seasonal and diurnal patterns
exist in the prevalence of sexual assault in Ile-Ife and most survivors
reported in the hospital presented early. Rape kit examinations were,
however, not executed, due to non-availability. Personnel training,
protocol development, provision of rape kits and free treatment of
sexual assault survivors are, therefore, recommended. Public
enlightenment on preventive strategies based on the observed
periodicity and age patterns is also suggested (19).
An anonymous survey with questions on gender-based violence,
demographic and socioeconomic characteristics and childhood
experiences with violence was administered to students at a major
public university in Santiago. Ninety percent of subjects reported that
the most severe form of undesired sexual contact they had experienced
since 14 years was rape; 6% indicated attempted rape and 16% another
form of sexual victimization; 17% of subjects reported having
experienced some form of undesired sexual contacts in the past 12
months alone. Factors associated with increased odds of victimization
included low parental education, childhood sexual abuse, and the
association between witnessing domestic violence and victimization. A
substantial proportion of young women experienced rape, attempted
rape or other forms of forced sexual contact, indicating a need for
further attention to this public health problem in Chile (20).
The assault records and forensic examination findings of 153
consecutive women who attended a sexual assault service in
Newcastle, Australia, between 1997 and 1999, were reviewed. All the
women were examined within 72 hours of the assault. Of the women,
111 (73.4%) were aged under 30 years and only 4% were over 50 years.
Penile-vaginal penetration was the most common type of sexual assault
(86%). Non-genital injuries were found in 46% of the women (mostly
minor) and genital injury in 22%. Genital injuries in the absence of non-
genital injury were rare (3%). Independent risk factors for the
detection of non-genital injury were reported threats of violence. Risk
factors for genital injury were the presence of non-genital injury,
threats of violence and being over the age of 40 years. If the woman
knew the alleged assailant, this was protective for both non-genital and
genital injury (21).
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In New Zealand's 21-year-olds, 41% experienced physical or sexual


assault in the previous 12 months (22).

ASSESSMENT: there are widespread prevalence rates and patterns


of sexual assaults in different countries.

References
1. Elliott DM, Mok DS, Briere J. Adult sexual assault: prevalence,
symptomatology, and sex difference in the general population. J Trauma
Stress. 2004;17:203-11.
2. Zinzow HM, Grubaugh AL, Frueh BC, Magruder KM. Sexual assault,
mental health, and service use among male and female veterans seen in
Veterans Affairs primary care clinics: a multi-site study. Psychiatry Res.
2008;159(1-2):226-36.
3. Ellis L, Widmayer A, Palmer CT. Perpetrators of sexual assault continuing
to have sex with their victims following the initial assault: evidence for evolved
reproductive strategies. Int J Offender Ther Comp Criminol. 2008 Apr 2.
4. Olshen E, McVeigh KH, Wunch-Hitzig RA, Ricket VI. Dating violence,
sexual assault, and suicide attempts among urban teenagers. Arch Pediatr
Adolesc Med. 2007;161:539-45.
5. Cichowski SB, Dunivan GC, Komesu YM, Rogers RG. Sexual abuse history
and pelvic floor disorders in women. South Med J. 2013;106(12): 675-8.
6. Sam Soto S, Gayón Vera E, Garcia Pioa CA. Gynecological clinical study in
girls and adolescent victims of sexual abuse. Ginecol Obstet Mex. 2008;76:404-
16.
7. Elwood LS, Smith DW, Resnick HS, et al. Predictors of rape: findings from
the National Survey of Adolescents. J Trauma Stress. 2011;24(2):166-73.
8. Wolitzky-Taylor KB, Ruggiero KJ, Danielson CK, et al. Prevalence and
correlates of dating violence in a national sample of adolescents. J Am Acad
Child Adolesc Psychiatry. 2008;47:755-62.
9. Ramsay SE, Bartley A, Rodger AJ. Determinants of assault-related
violence in the community: potential for public health interventions in
hospitals. Emerg Med J. 2013 Aug 16.
10. Avegno J, Mills TJ, Mills LD. Sexual assault victims in the emergency
department: analysis by demographic and event characteristics. J Emerg Med.
J Emerg Med. 2009;37(3):328-34.
11. Edgardh K. Sexual behaviour and early coitarche in a national sample of
17 year old Swedish girls. Sex Trans Infect. 2000;76:98-102.
12. Krahé B, Berger A. Men and women as perpetrators and victims of
sexual aggression in heterosexual and same-sex encounters: a study of first-
year college students in Germany. Aggress Behav. 2013;39(5):391-404.
13. McDermott SD, McBride BM, Lee-Gorman M. Sexual assault statistics
from the Republic of Ireland for 2004-2005. Med Sci Law. 2008; 48:142-50.
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14. Merchant RC, Phillips BZ, Delong AK, et al. Disparities in the provision of
sexually transmitted disease and pregnancy testing and prophylaxis for
sexually assaulted women in Rhode Island emergency departments. J Womens
Health (Larchmt). 2008;17:619-29.
15. Faye Dieme ME, Traore AL, Gueye SM, et al. Sexual abuse:
epidemiological, clinical aspects and management at gynaecological and
obstetrical department of Dakar University Hospital. J Gynecol Obstet Biol
Reprod (Paris). 2008;37(4):358-64.
16. Adama-Hondégla AB, Aboubakari AS, Fiagnon K, et al. Epidemiological
and clinical aspects of the management of sexual aggression among female
victims in Lomé. Afr J Reprod Health. 2013;17(1):67-72.
17. Krishnakumar P, Satheesan K, Geeta MG, Sureshkumar K. Prevalence
and Spectrum of Sexual Abuse Among Adolescents in Kerala, South India.
Indian J Pediatr. 2013 Oct 25.
18. Cerdas L, Arroyo C, Gómez A, et al. Epidemiology of rapes in Costa
Rica: Characterization of victims, perpetrators and circumstances surrounding
forced intercourse. Forensic Sci Int. 2014;242C:204-209.
19. Badejoko OO, Anyabolu HC, Badejoko BO, et al. Sexual assault in Ile-Ife,
Nigeria. Niger Med J. 2014;55(3):254-9.
20. Lehrer JA, Lehrer VL, Lehrer EL, Oyarzún PB. Prevalence of and risk
factors for sexual victimization in college women in Chile. Int Fam Plan
Perspect. 2007;33:168-75.
21. Palmer CM, Mcnulty AM, D'Este C, Dnovan B. Genital injuries in women
reporting sexual assault. Sex Health. 2004;1:55-9.
22. Feehan M, Nada-Raja S, Martin JA, Langley JD. The prevalence and
correlates of psychological distress following physical and sexual assault in a
young adult cohort. Violence Vict. 2001;16:49-61.

RISKY SEXUAL BEHAVIOR. A fifth or more of a nationally


representative sample of school-attending adolescents report engaging
in problem behaviors such as skipping school, using alcohol, fighting,
shoplifting, and stealing. A smaller but significant number of
adolescents report engaging in risky sexual behaviors. These behaviors
have potentially serious consequences for adolescents, their family and
friends, their school, and society (1).
The consequences of risky sexual behavior are of public concern.
Adolescents contribute disproportionately to negative consequences of
risky sexual behavior. The aim of the present study was to examine this
question. Twenty sexually active adolescents performed an impulse
control task during a functional MRI scan and risky sexual behaviors
were assessed through self-report. Sexual riskiness ratings were
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negatively associated with activation in the prefrontal cortex during


response inhibition. These results suggest that diminished engagement
of impulse control circuitry may contribute to sexual riskiness in
adolescents (2).
The aim of this study was to assess the prevalence of different
health risk behaviors among Romanian young people. The
interrelationship between different health risk behaviors as well as age
and gender differences with respect to health risk behaviors were
examined. Self-administered questionnaires were completed by a
sample of 1,598 junior high school students, senior high school
students and university students from urban and rural areas of two
counties of Romania. The results showed that 31% of junior high school
students, 59.7% of senior high school students and 64.8% of university
students reported more than one risk behavior. Many of the risk
behaviors were correlated with each other and the strongest
correlation was found between smoking, alcohol-related behavior and
precocious sexual intercourse. Factor analysis revealed that among
junior high school students all health risk behaviors were loaded on one
factor. In senior high school students and university students, the risk
behaviors split into two factors, based probably on their frequency and
severity. Factor one comprised smoking, alcohol-related behaviors as
well as precocious sexual intercourse, while factor two included less
common behaviors: violence, delinquency and illicit drug use. No
gender differences were observed regarding the relationship between
health risk behaviors (3).
The purpose of this study was to explain how intrinsic and extrinsic
religiosity as well as acculturation predict risky sexual behavior using
Structural Equation Modeling of a nationally representative sample of
self-identified Latinas (n=1,168) from the National Longitudinal Survey
of Adolescent Health. Results indicated that intrinsic religiosity and
acculturation assert protective effects while extrinsic religiosity
increases risk (4).
The identification of early risk factors among undergraduate
students that affect health, both mental and physical is a primary focus
of this survey. This is more so since people suffering from an illness may
not be currently engaging in any health risk behaviors but might have
engaged in such behaviors before they developed the illness condition.
Therefore, the identification of health risk behaviors among this group
of people would permit a better understanding of localized patterns of
health risk behaviors as well as help to target intervention activities
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towards this particular group of people. This study is based upon data
obtained from a cross-sectional survey of students in a tertiary
institution in South Western Nigeria. Participants voluntarily and
anonymously completed a baseline semistructured questionnaire which
elicited information on demographic information, sexual behaviors' and
substance use among others. Of the 368 respondents, the majority 225
(60.9%) was in the age group of 20-24 years. A total of 152 participants
(41.3%) were either currently or had previously indulged in heavy
drinking of alcohol and a significant association was between the use of
alcohol and having multiple sexual partners and use of commercial sex
workers (p<0.05). Ninety-four (25.5%) and 52 (14.1%) were currently
smokers or smoked cigarette and marijuana before; while 56 (15.2%)
were currently using or have before used narcotic drugs. The
relationship between hard drug use and non-use of condom was
significant (p<0.05). Ninety-two (25.0%) have more than one sexual
partners at the same given period; the male respondents indulged
more in having multiple partners than the female (p<0.05). As many as
155 (47.8%) of the sexually active respondents had never used condom
during sexual intercourse. Of this group of the respondents, 88 (27.1%)
have had sexual relationship with commercial sex workers at one time
or the other. Condom use was low among the sexually active
respondents. Only 29.3% of the respondents always use condom when
having any sexual relationship. This study indicates that students
indulge in health risk behaviors such as "unsafe sexual practices",
alcohol, cigarette smoking and other substance use. The males are
more involved in having multiplicity of sexual partners than their
female counterpart. A significant association is found between the use
of alcohol and having multiple sexual partners. Comprehensive health
education and intervention programs are needed to influence positive
behavioral change among this group of students working in partnership
with schools authorities and other local community groups (5).
STIs remain a public health problem of major significance in most of
the world. Adolescents make up about 20% of the world population, of
whom 85% live in developing countries. They are at a greater risk of
STIs because they frequently have unprotected intercourse, biologically
may be more susceptible to infection, often are engaged in multiple
monogamous relationships of limited duration, and face multiple
obstacles in accessing confidential health care services. Young people
who begin to have sexual intercourse in early or middle adolescence
are more likely to develop a STI than those who postpone intercourse
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until later adolescence or adulthood. The most common STIs among


adolescents are chlamydia, gonorrhea, HPV infection, and
trichomoniasis. Unfortunately, the incidence of HIV/AIDS and syphilis
among adolescents is growing. Comprehensive sex education programs
in schools can increase STI knowledge and prevent risky sexual
behaviors. Health care providers can promote STI prevention methods,
including counseling about safe sex (6).
The objective of this study is to investigate factors that predict
young people's practicing risky sexual behavior in the era of HIV/AIDS.
Data used in this study were obtained from a nationally representative
sample of 5,810 young people aged 15 to 29 years who had completed
an individual questionnaire of the 2,008 Botswana AIDS Impact Survey
III. Elevated OR values were obtained from a linear model analysis,
showing significant predictors of risky sexual behavior among young
people who have experienced coerced sex (OR 2.2), substance use (OR
1.8), having had sex before the age of 15 (OR 1.9), being older (OR 1.1)
and lack of sexual self-efficacy (OR 1.6). Therefore, risk reduction
strategies aimed at addressing these potential problems should target
young people before they enter adolescence and should develop
gender-specific strategies (7).
This study tested the hypothesis that individual and family factors
associated with adolescent risky sexual behavior operate differently in
their relationship to risky sexual behavior among girls who have
experienced forced sexual intercourse, as compared to those who have
not. Data were collected from 3,863 eighth-grade girls from a larger
statewide sample. Different subgroups of participants received
different sets of questions, so 655 to 2,548 students were included in
each analysis. Forced sexual intercourse was examined as a predictor of
risky sexual behavior and as a moderator of the relationship between
individual and family variables and sexual risk. Social negotiation skills
were associated with lower risky sexual behavior for all girls, but had a
stronger relationship to risky sexual behavior among girls who had
experienced forced sexual intercourse. Depression and sensation-
seeking tendencies had small positive relationships with risky sexual
behavior for all girls. For girls without a history of forced sexual
intercourse, parental monitoring was associated with lower sexual risk
behavior. Among girls who had experienced forced sexual intercourse,
parental monitoring was insignificantly related to risky sexual behavior,
but sibling deviance was associated with lower risky sexual behavior. In
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conclusion, social negotiation skills and parental monitoring may


warrant further attention in research and intervention (8).
IPV is a significant public health problem with a demonstrated link to
increased STI/HIV-related risk and vulnerability. While IPV is an
important issue in Central America, the link to STI/HIV risk has not been
explored in this region. In this study, the relationship between
emotional and physical/sexual IPV and the STI/HIV-related risk
behaviors of sex worker patronage and infidelity is assessed among
male IPV perpetrators using data from a national survey conducted in
2009 in Guatemala (n=4,773 married/partnered men). Bivariate
associations between background characteristics and emotional and
physical IPV perpetration were explored. Perpetration of emotional and
physical/sexual IPV was more common among married/partnered men
who were older than 24 years, had more education, lived in urban
areas, or were in common law vs. married unions. Reports of past-year
emotional IPV perpetration increased as wealth quintile increased.
After adjusting for demographics and other characteristics,
physical/sexual IPV perpetration was associated with past-year
infidelity (AOR 1.9, 95% CI 1.1-3.6). Lifetime emotional IPV (AOR 1.4,
95% CI 1.1-1.7) and physical/sexual IPV 1.6 (95% CI 1.2-2.0) were
positively associated with a history of sex worker patronage.
Endorsement of traditional gender role norms showed a marginally
positive association with past-year infidelity in the adjusted model (AOR
1.3, 95% CI 1.0-1.8). The study findings from Guatemala reinforce the
growing evidence globally that male IPV perpetrators are more likely to
engage in risky sexual behavior, including sex worker patronage and
main partner infidelity. The concurrency of violence and increased
STI/HIV risk may compound the health risks for female victims of IPV
who also face injury and psychological trauma. Integration of
prevention and screening of IPV and STI/HIV prevention services should
be adopted in Guatemala and other similar contexts (9).
Research has demonstrated a consistent relationship between early
sexual experience and subsequent sexual risk-taking behaviors. This
relationship is supposed to be due to a general predisposition toward
behavioral disinhibition, and relationships among behavioral
disinhibition, early sex and subsequent risky sexual behavior may be
influenced by common genetic influences for males and common
environmental influences for females. A prospective sample of 1,512
same-sex adolescent twins (50.2% female) was used. Adolescent
behavioral disinhibition was measured by clinical symptom counts of
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conduct disorder, oppositional defiant disorder, and self-reported


delinquent behavior (age 14). Age of sexual initiation was defined as
first age of consensual oral or penetrative sex (mean age ~17). Adult
risky sexual behavior was defined by sexual behaviors under the
influence of drugs and alcohol and number of casual sexual partners in
the past year (age two years). Multivariate analyses showed evidence
for substantial common genetic variance among age 14 behavioral
disinhibition, age at sexual initiation, and adult risky sexual behavior for
males, but not females. There was insignificant difference in the degree
of common environmental influence on these variables for females
compared to males. Notably, age of sexual initiation was insignificantly
correlated with age 24 risky sexual behavior for females. In conclusion,
the relationship between early sex and later risky sex can be better
understood through a general liability toward behavioral disinhibition,
which is influenced primarily by genetic factors for males. The
association between age 14 years of behavioral disinhibition and age of
sexual initiation was influenced through a combination of genetic and
environmental factors for females; however, age of sexual initiation
does not appear to be a salient predictor of adult women’s sexual risk-
taking behavior. Findings suggest that prevention programs aimed at
reducing sexual risk behavior might target youth exhibiting behavioral
disinhibition by age 14 years, particularly males (10).

ASSESSMENT: risky sexual behaviors have potentially serious


consequences for adolescents, their family and friends, their school,
and society. Adolescents are at a greater risk of STIs because they
frequently have unprotected intercourse, biologically may be more
susceptible to infection, often are engaged in multiple monogamous
relationships of limited duration, and face multiple obstacles in
accessing confidential health care services.
The most common STIs are chlamydia, gonorrhea, HPV infection,
trichomoniasis, HIV/AIDS and syphilis.
Males are more involved in having multiplicity of sexual partners
than their female counterpart. There is an association between the use
of alcohol and having multiple sexual partners.
Social negotiation skills are associated with lower risky sexual
behavior for all girls, but have a stronger relationship with risky sexual
behavior among girls who have experienced forced sexual intercourse.
Depression and sensation-seeking tendencies have small positive
relationships with risky sexual behavior for all girls.
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The association between age 14 years of behavioral disinhibition


and age of sexual initiation is influenced through a combination of
genetic and environmental factors for females; however, age of sexual
initiation does not appear to be a salient predictor of adult women’s
sexual risk-taking behavior.
Thus, Amnon was involved in risky sexual behavior with all the
consequences of such behavior.

References
1. Bartlett R, Holditch-Davis D, Belyea M. Problem behaviors in adolescents.
Pediatr Nurs. 2007;33(1):13-8.
2. Goldenberg D, Telzer EH, Lieberman MD, et al. Neural mechanisms of
impulse control in sexually risky adolescents. Dev Cogn Neurosci. 2013;6:23-9.
3. Lotrean LM, Laza V, Ionut C, de Vries H. Assessment of health risk
behaviours and their interrelationships among young people from two
counties of Romania. Z Gesundh Wiss. 2010;18(4):403-11.
4. Smith SJ. Risky sexual behavior among young adult Latinas: are
acculturation and religiosity protective? J Sex Res. J Sex Res. 2015;52(1):43-54.
5. Bamidele JO, Asekun-Olarinmoye EO, Odu OO, et al. Afr J Med Med Sci.
2007;36(2):129-36.
6. Ljubojevid S, Lipozenčid J. Sexually transmitted infections and
adolescence. Acta Dermatovenerol Croat. 2010;18(4):305-10.
7. Letamo G, Mokgatlhe LL. Predictors of risky sexual behaviour among
young people in the era of HIV/AIDS: evidence from the 2008 Botswana AIDS
Impact Survey III. Afr J Reprod Health. 2013;17(3):169-81.
8. Marchand E, Smolkowski K. Forced Intercourse, Individual and Family
Context, and Risky Sexual Behavior among Adolescent Girls. J Adolesc Health.
2013;52(1):89-95.
9. Hembling J, Andrinopoulos K. Evidence of increased STI/HIV-related risk
behavior among male perpetrators of intimate partner violence in Guatemala:
results from a national survey. AIDS Care. 2014;26(11):1411-8.
10. Samek DR, Iacono WG, Keyes MA, et al. The developmental progression
of age 14 behavioral disinhibition, early age of sexual initiation, and
subsequent sexual risk-taking behavior. J Child Psychol Psychiatry. 2014;
55(7):784-92.

INTIMATE PARTNER SEXUAL VIOLENCE. No compilation of women's


health care is complete without confronting domestic violence and
sexual assault. Long recognized as a health care and physician issue, IPV
continues to be one of the most frequent causes for injury and death
for women in the US and worldwide. According to the Commonwealth
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Fund survey in 1998, 31% of women reported either physical or sexual


abuse by a husband or boyfriend. One in five American women is raped
during their lifetime. Careful assessment and universal screening are
important tools for the primary care physician (1).
The main aim of this study was to describe and analyze nine Swedish
women's retrospective stories about IPV with a focus on power and
coping strategies as intimate partners, particularly regarding
experiences of sex, contraception, and becoming pregnant. Nine
qualitative interviews were carried out with women who had been
subjected to very severe violence in their intimate relationships and
during at least one pregnancy. The stories were analyzed using
'Narrative method' with the emphasis on the women's lived
experiences. Despite the violence and many contradictory and
ambivalent feelings, two of the women described having sex as
desirable, reciprocal and as a respite from the rest of the relationship.
The other seven women gave a negative and very different picture, and
they viewed sex either as obligatory or as a necessity to prevent or
soothe aggression or referred to it as rape and as something that was
physically forced upon them. The women's descriptions of their
pregnancies ranged from being carefully planned and mostly wanted to
completely unwelcome and including flawed contraceptive efforts with
subsequent abortions. In conclusion, women subjected to IPV have
diverse and complex experiences that have effects on all parts of the
relationship. Intimacy might for some turn into force and rape, but for
others sex does not necessarily exclude pleasure and desire and can be
a haven of rest from an otherwise violent relationship. Women may tell
stories that differ from the ones expected as 'the typical abuse story',
and this complexity needs to be recognized and dealt with when
women seek healthcare, especially concerning contraceptives,
abortions, and pregnancies (2).
The main objective of his study was to investigate whether sexual
assaults are more likely to co-occur with some types of abuse rather
than others in violent intimate relationships. In this cross-sectional
study, a self-administered questionnaire was sent to all Norwegian
women's shelters. The study population included women seeking
refuge at Norwegian women's shelters in 2002 and 2003. Sexual
assault and experiences of IPV were measured using the SVAWS (3) and
psychological violence was measured using the PMWI (4,5). Sexual
violence correlated significantly with the other eight categories in
SVAWS, and with violence directed at the pregnant woman's abdomen
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and psychological violence in PMWI. When all categories for each other
by linear regression analysis were adjusted, sexual IPV was significantly
associated with hair pulling, arm-twisting, spanking or biting,
dominance and isolation abuse and violence directed at the pregnant
woman's abdomen. In conclusion, sexual assaults are more likely to co-
occur with some types of physical and psychological violence than with
others. This knowledge is important for improving our understanding of
sexual violence in intimate partner relationships and in the efforts to
detect IPV. Bruises, loss of hair and bite marks suggest that sexual acts
were committed against the victim's will (6).
This study explores the cumulative effect of sexual assault and
physical abuse by a current or former intimate partner on help seeking.
Using a dataset of 1,072 IPV victims from eight states, women who had
experienced sexual assault in addition to physical abuse (44%) used
more help, but were more likely to say that they did not seek help
when they needed it. Among those who were aware of services, fear
was the greatest obstacle to reaching out for help. Implications include
the need for information on best practices in addressing the sequelae
of both physical and sexual assault in victim service agencies (7).
IPV against women is a serious problem throughout the world. Each
year a substantial number of women experience psychological,
physical, and sexual aggression from an intimate partner, with many
women experiencing serious mental and physical health outcomes
because of their victimization. A number of services are available to
women who sustain IPV (e.g., shelters, advocacy, and legal protection),
and the combination of these services has been termed a CCR to IPV.
The purpose of this manuscript is to review the individual components
of CCRs for IPV victims, examine the extant literature on a number of
the individual CCR components, and suggest directions for future
research on CCRs for IPV victims. There is a significant lack of research
on various CCR components, that research on the integration of CCR
services is limited, and theoretical guidance for CCR programs is almost
non-existent (8).
The aim of this study was to evaluate if disclosure of abuse among
female university students and among women at an emergency
department varied based on three different types of data collection
method used; and to explore women's development of symptoms of
PTSD and the outcome on health. Cross-sectional research design was
used (n=306 women). The women who experienced IPV in their current
relationship, and had symptoms of PTSD, reported significantly lower
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physical and mental health. In addition, the women who experienced


three types of abuse (physical, mental, and sexual) reported
significantly more symptoms of PTSD. Detecting IPV and screening for
PTSD in clinical settings might benefit women who suffer from violence
in their intimate relationships (9).

Assessment: IPV continues to be one of the most frequent causes


for injury and death to women in the world. According to the
Commonwealth Fund survey in 1998, 31% of women reported either
physical or sexual abuse from a husband or boyfriend.
Women subjected to IPV have diverse and complex experiences that
have effects on all parts of the relationship. Intimacy for some turn into
force and rape, but for others sex does not necessarily exclude pleasure
and desire and can be a haven of rest from an otherwise violent
relationship.
Sexual IPV is associated with hair pulling, arm-twisting, spanking or
biting, dominance and isolation abuse and violence directed at the
pregnant woman's abdomen. Sexual assaults are more likely to co-
occur with some types of physical and psychological violence than with
others. Bruises, loss of hair and bite marks suggest that sexual acts are
committed against the victim's will.
Women, who experience IPV in their current relationship, suffer
from PTSD and lower physical and mental health. Women who
experienced three types of abuse (physical, mental, and sexual) report
more symptoms of PTSD.
Did IPV take place in Tamar's case? If so, what type of violence?

References
1. Toohey JS. Domestic violence and rape. Med Clin North Am.
2008;92(5): 1239-52, xii.
2. Edin K, Nilsson B. Between desire and rape - narratives about being
intimate partners and becoming pregnant in a violent relationship. Glob
Health Action. 2013;6:20984.
3. Marshall LL. Development of the severity of violence against women
scales. J Fam Violence. 1992;7:103-121.
4. Tolman RM. The development of a measure of psychological
maltreatment of women by their male partners. Violence Vict. 1989;
4(3):159-177.
5. Tolman RM. The validation of the psychological maltreatment of
women inventory. Violence Vict. 1999;14(1): 25-35.
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6. Alsaker K, Morken T, Baste V, et al. Sexual assault and other types of


violence in intimate partner relationships. Acta Obstet Gynecol Scand. 2012;
91(3):301-7.
7. Cattaneo LB, DeLoveh HL, Zweig JM. Sexual assault within intimate
partner violence: impact on helpseeking in a national sample. J Prev Interv
Community. 2008;36(1-2):137-53.
8. Shorey RC, Tirone V, Stuart GL. Coordinated Community Response
Components for Victims of Intimate Partner Violence: A Review of the
Literature. Aggress Violent Behav. 2014;19(4):363-371.
9. Svavarsdóttir EK, Orlygsdottir B, Gudmundsdottir B. Reaching out to
women who are victims of intimate partner violence. Perspect Psychiatr
Care. 2014 Aug 4.

SEXUAL ABUSE IN THE WORKPLACE. Women are sexually assaulted


at an alarming rate, and the workplace is a frequent arena for assault.
However, in recent decades, attention has been given to improving
responses to sexual assault. Sexual assault is a frequent cause of injury
and death for women in the US. One in five American women admits
they have experienced a completed rape during their lifetime. These
estimates are conservative because sexual assault and sexual violence
are both underreported and underprosecuted. Fear of job loss and
discrimination are frequent reasons women do not report sexual
assault in the workplace. Women are entering the workplace in greater
numbers due in part to more single parent families and the depressed
economy. Women are entering work environments that have
traditionally been the domain of male workers: corporate
headquarters, semi trucks, health care providers' offices, rural farms,
and rural factories. Employers must have a plan to protect female
employees and effectively address incidents of sexual assault or
violence. Occupational health nurses and nurse practitioners can assist
both employees and employers to prevent sexual assault and resolve
the aftermath of sexual assault. To accomplish this goal, occupational
health nurses and nurse practitioners must be trained in sexual assault
and violence response as well as preventive interventions (1).
The purpose of this study was to determine if dental hygienists in
the Commonwealth of Virginia experienced sexual harassment while
employed in oral health care settings. Other interests were to
determine if dental hygienists experienced sexual harassment, to what
extent they felt professionally prepared to respond to unwanted sexual
behaviors, and did they perceive sexual harassment as a problem in the
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oral health care environment; and was attrition from their employment
associated with sexual harassment. A questionnaire, Sexual Harassment
in the Dental Hygiene Profession, designed by the author, was used. A
list of currently licensed and registered dental hygienists was obtained
from the Virginia Board of Dental Examiners and the questionnaire was
sent to 540 randomly selected registered Virginia dental hygienists.
Two weeks after the initial mailing, a second questionnaire was sent to
non-respondents. The survey elicited data on experience, management,
and personal opinions relative to sexual harassment, as well as
demographic information. Of returned and useable 285 surveys (53%),
54% of dental hygienists experienced sexual harassment. The
perpetrators of the harassment were either male dentists (73%) or
male clients (45%). Less than 10% reported being harassed by women.
While 70% of the sexually harassed respondents indicated that filing
formal complaints was an effective strategy for managing sexual
harassment, less than 1% actually did so. Of all dental hygienists
(harassed or not), 90% did not receive training in their dental education
to manage sexual harassment, and 85% would like the American Dental
Hygienists' Association to develop model guidelines and policies.
Demographic characteristics were typical of practicing dental hygienists
in Virginia; 99% female, 96% Caucasian, and 86% married with a mean
age of 40 years. In conclusion, information about managing sexual
harassment needs to be incorporated into the dental hygiene curricula.
This curriculum addition should include information on identifying
sexual harassment incidents, strategies for controlling unacceptable
behavior, the legal rights of employees, and the process of filing a
formal complaint. Dental hygienists need to identify sexual harassment
behaviors and receive prevention training though continuing education
courses (2).
Nurses sexually harassed at work face frustration and emotional and
economic consequences. Historically before the 1970s, nurses had little
legal recourse and tolerated sexual harassment as a necessary "evil"
associated with working. The Civil Rights Act of 1964 created the option
for legal remedies for sexual harassment/discrimination cases.
Successful court cases established the legal criteria for sexual
harassment. Prevention requires coordinated activities of employers,
individual employees, and the healthcare profession. Sexual
harassment at work increases anxiety and undermines the nurse's
ability to focus on the delivery of safe and competent care (3).
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The main purpose of this descriptive study was to identify the


prevalence and sources of sexual harassment against nurses in Turkey,
its consequences, and factors affecting harassment experiences.
Participants (n=622) were selected from nurses working in eight
Ministry of Health hospitals in Turkey. Participants were surveyed with
a Sexual Harassment Questionnaire, consisting of the
sociodemographic characteristics, types of sexual harassment, sources,
feelings, ramifications, and ways to cope with sexual harassment
behaviors. The results showed that 37.1% of participants had been
harassed sexually. Physicians were identified as the primary instigators
of sexual harassment. The most common reactions against harassers
were anger and fear; frequently reported negative effects of sexual
harassment were disturbed mental health function, decline in job
performance, and headache. "Did nothing" was the coping method
used most commonly by the nurses. About 80% of sexually harassed
nurses did not report the incident of sexual harassment. In conclusion,
the lower working status and power of nurses in the workplace, poor
working conditions in healthcare settings, and insufficient
administrative mechanisms, including the present law and regulations
against sexual harassers, were important factors in the work
environment in Turkey (4).
Students in a small, suburban high school for girls completed a
paper and pencil survey during class. A modified version of the Sexual
Experiences Questionnaire (5) was used to identify sexually harassed
working teenagers. Work attitudes, assessments of physical health and
mental health, and school-related outcomes were measured using
standardized scales. The percentage of harassed girls was significantly
higher than the figures reported in most studies of working women.
Girls who were sexually harassed were less satisfied with their jobs and
supervisors, had higher levels of academic withdrawal, and were more
apt to miss school than their non-harassed peers. In conclusion, sexual
harassment significantly affects employed high school girls' connections
to work and school. It not only taints their attitudes toward work but it
also threatens to undermine their commitment to school. Educators,
practitioners and community leaders should be aware of the negative
impact this work experience may have on adolescents and explore
these issues carefully with students who are employed outside of
school. Practice implications: teenage students, stressed by sexual
harassment experienced at work may find their career development or
career potential impeded or threatened due to school absence and
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poor academic performance. The physical safety of working students


may be at risk, creating a need for teenagers to receive training to deal
with sexual assault and other types of workplace violence. Educators,
practitioners, and community leaders should be aware of the negative
impact this work experience may have on adolescents and their overall
school experience and explore the issue of sexual harassment carefully
with students who are employed outside of school (6).

ASSESSMENT: sexual harassment is a prevalent human behavior.


Women are sexually assaulted at an alarming rate, and the workplace is
a frequent arena for sexual assault.
Dental hygienists in the Commonwealth of Virginia experience
sexual harassment while employed in oral health care settings.
Physicians are the primary instigators of nurses' sexual harassment.
The most common reactions against harassers are anger and fear; while
negative effects of sexual harassment are disturbed mental health
function, decline in job performance, and headache.
The lower working status and power of nurses in the workplace,
poor working conditions in healthcare settings, and insufficient
administrative mechanisms, including the present law and regulations
against sexual harassers, are important factors in the work
environment.
Fear of job loss and discrimination are frequent reasons women do
not report sexual assault in the workplace.

References
1. Garrett LH. Sexual assault in the workplace. AAOHN J. 2011; 59(1):15-
22.
2. Pennington A, Darby M, Bauman D, et al. Sexual harassment in
dentistry: experiences of Virginia dental hygienists. J Dent Hyg. 2000;4(4):
288-95.
3. Valente SM, Bullough V. Sexual harassment of nurses in the
workplace. Nurses who are J Nurs Care Qual. 2004;19(3):234-41.
4. Celik Y, Celik SS. Sexual harassment against nurses in Turkey. J Nurs
Scholarsh. 2007;39(2):200-6.
5. Fitzgerald LF, Shullman SL, Nancy Bailey, et al. The incidence and
dimensions of sexual harassment in academia and the workplace. J Vocat
Behav 1988;32(2): 152-175.
6. Fineran S, Gruber JE. Youth at work: adolescent employment and
sexual harassment. Child Abuse Negl. 2009;33(8):550-9.
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MILITARY SEXUAL TRAUMA. MST is defined as sexual harassment


and or sexual assault experienced by a military service member. It is
much more widespread and common than reported. It is associated
with pre-combat traumatic experiences and pathologic sequelae
including mental and medical illness. An electronic search of the major
behavioral science databases was conducted to retrieve studies
detailing the social, epidemiological and clinical characteristics of MST
and its relationship to psychiatric and medical illness. Studies indicate
that MST is related to an increase in psychiatric pathology, including
PTSD, substance abuse and dependence, depression, anxiety, eating
disorders and suicidal behavior. MST is also related to an increase in
medical illness, primarily pain-related symptoms involving multiple
organ systems, including G-I, neurological, genitourinary and
musculoskeletal. In conclusion, MST is associated with an increased
prevalence of mental and physical illness. Although there are some
gender differences in the reported rates of MST and there may be some
variables, such as prior traumatic experiences, that may make an
individual more vulnerable to the psychiatric and medical sequelae of
MST. MST is a major healthcare issue that affects both sexes and
warrants further attention and an increase in clinical resources devoted
to it. Some preventive measures for decreasing the prevalence of MST
include increasing education and legal prosecution of perpetrators in
the military and increasing access to mental health services for
individuals who have suffered from MST (1).
Sexual abuse among female veterans reportedly occurs in significant
numbers in the US military and has been recognized to cause PTSD.
PTSD, which stems from sexual abuse, called MST, has only recently
been recognized by the Department of Defense. Consequently, there
has been scant research on the prevalence, impact, and treatment of
MST (2).
This article compares the theoretical antecedents and consequences
of sexual assault by workplace personnel and other types of sexual
harassment among 22,372 women employed in the US military. Path
analysis revealed that low sociocultural and organizational power is
associated with an increased likelihood of both types of victimization.
Organizational climate and job gender context are directly associated
with sexual harassment but are only indirectly associated with sexual
assault by workplace personnel. Both types of victimization are
associated with a variety of negative outcomes, but the pattern of
negative consequences differs (3).
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This article examines an age-old sexual assault problem through the


lens of its occurrence within the military culture. Specific cases as well
as US Department of Defense responses to better handle these issues
are offered to educate psychiatric-mental health nurses of the potential
differences in symptomatology and presentation of MST. This appears
to be an increasing problem with the predicted cohort of returning
veterans appearing both in the US Department of Veterans Affairs
system as well as in civilian locations, hospitals, community centers,
and especially the workplace. It will be critical to develop training
materials and pursue further research to identify this silent syndrome
of MST to better meet the needs of returning veterans (4).
This study assessed military environmental factors associated with
rape occurring during military service, while controlling for pre-military
trauma experiences. A national cross-sectional survey of 558 women
veterans serving in Vietnam or in subsequent eras was obtained
through structured telephone interviews. Rape was reported by 30%
(n=151) of participants, with consistent rates found across eras
[corrected]. Military environmental factors were associated with
increased likelihood of rape, including sexual harassment allowed by
officers (p<0.0001), unwanted sexual advances on-duty (p<0.0001), and
in sleeping quarters (p<0.0001). In conclusion, violence towards military
women has identifiable risk factors. Work and living environments
where unwanted sexual behaviors occurred were associated with
increased odds of rape. Officer leadership played an important role in
the military environment and safety of women. Assailant alcohol
and/or drug abuse at time of rape was notable (5).
The 1991 Gulf War was the first major military deployment where
female troops were integrated into almost every military unit, except
for combat ground units. The impact of reported sexual trauma during
this deployment on the risk of PTSD after the war was evaluated. A
nested case-control analysis was conducted using the data collected in
a population-based health survey of 30,000 Gulf War era veterans. A
total of 1,381 Gulf War veterans with current PTSD were compared
with 10,060 Gulf veteran controls without PTSD for self-reported in-
theater experiences of sexual harassment/assault and combat
exposure. The AOR for PTSD associated with a report of sexual assault
was 5.41 (95% CI 3.19-9.17) in female veterans and 6.21 (95% CI 2.26-
17.04) in male veterans. The AOR for PTSD associated with "high"
combat exposure was statistically significant (AOR 4.03, 95% CI 1.97-
8.23 for females; AOR 4.45, 95% CI 3.54-5.60 for males). In conclusion,
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notwithstanding a possibility of recall bias of combat and sexual


trauma, for both men and women, sexual trauma and combat exposure
appear to be strong risk factors for PTSD (6).
The purpose of this study was to explore the relationship between
MSA and PTSD and other symptoms associated with trauma, referred
to as DESNOS or complex PTSD within a Veterans Affairs Medical Center
outpatient mental health treatment-seeking sample. The present
results focus on female Veterans only because of the low rates of
endorsement of MSA among male Veterans resulting in a sample too
small to use in analyses. Compared with those who did not endorse
MSA, those who did reported greater frequency of other potentially
traumatic events; PTSD symptoms; and symptoms characteristic of
DESNOS, such as difficulties with interpersonal relationships, emotion
regulation, dissociation, somatization, and self-perception. When
childhood and other adulthood interpersonal trauma were both taken
into account, MSA continued to contribute unique variance in
predicting PTSD and DESNOS symptoms. Veterans Affairs patients
reporting MSA may represent notably heterogeneous groups that
include more complex posttraumatic reactions. Treatment
interventions focused on complex PTSD may be warranted for a subset
of female veterans who endorse MSA (7).
In this study, associations between childhood trauma, MST, combat
exposure, and military-related PTSS in the Women Veterans Cohort
Study, a community-based sample of veterans who served in the recent
conflicts in Iraq and Afghanistan, were examined. From July 2008 to
December 2011, 365 female veterans completed a survey that assessed
combat exposure, MST, military-related PTSS (assessed using the PTSD
Checklist-Military Version), demographic, life history, and other
psychopathology variables. High rates of childhood trauma (59.7%) and
MST (sexual assault = 14.7%; sexual harassment = 34.8%) were
observed in this sample. A hierarchical regression revealed that active
duty status, childhood trauma, combat exposure, and MST were
independently associated with increased severity of military-related
PTSS (p<0.05). A significant interaction emerged between MST and
combat exposure in predicting military-related PTSS (p=0.03),
suggesting that the relationship between combat exposure and PTSS
was altered by MST status. Specifically, under conditions of high
combat exposure, female veterans with MST had significantly higher
PTSS compared to female veterans without MST. In conclusion, taken
together, results suggest that exposure to multiple traumas during
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military service may have synergistic effects on PTSS in female


veterans. These findings highlight the importance of prevention efforts
to protect female veterans from the detrimental effects of MST,
particularly those who are exposed to high levels of combat (8).
The purpose of this case study is to raise awareness about MST and
PTSD, and the physical and psychological comorbidities associated with
MST. Data sources included Health Science Data Sources-PubMed and
authors' experiences. In conclusion, Women veterans are the fastest
growing segment of the veteran population. Approximately 200,000 of
the 2.6 million veterans who have deployed in support of Operation
Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn
were women. Many were seeking care in both the Veteran
Administration and the civilian sector. Upwards of 26,000 women have
experienced some form of sexual assault in the military. MST can lead
to multiple deleterious physical and psychological comorbidities. It is
imperative that nurse practitioners ask women about military service
and utilize the Military Health History Pocket Card for Clinicians to
ascertain service-connected health risks, primarily MST and PTSD.
Prompt identification and intervention is key to reducing physical and
psychological comorbidities. This case study emphasizes the need for
nurse practitioners to ask all women about military service and
potential exposure to sexual trauma. It provides guidance on how to
incorporate the Military Health History Pocket Card for Clinicians into
practice (9).
This study examined the impact of various traumas across the life
span on screening positive for current PTSD and depression among
heterosexual and sexual minority women veterans. Women veterans
were recruited over the Internet (n=706, 37% lesbian or bisexual) to
participate in an anonymous, online survey. Childhood trauma; adult
sexual assault and adult physical victimization before, during, and after
the military; combat exposure; perceived sexist discrimination during
military service; sexual minority military stressors; past-year existing
events; and whether participants screened positive for PTSD or
depression. Lesbian and bisexual women reported higher rates of
trauma across the life span, although in some instances (e.g., sexual
assault during and after military service, and combat exposure), they
did not differ from their heterosexual counterparts. Childhood trauma
and traumas that occurred during military service added the most
variance to both PTSD and depression models. Sexual assault during
military service appeared to be especially harmful with respect to
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screening positive for PTSD for both sexual orientation groups. Results
revealed a number of other predictors of mental health status for
women veterans, some of which differed by sexual orientation.
Findings indicate a significant burden of interpersonal trauma for both
heterosexual and lesbian/bisexual women veterans and provide
information on the distinct association of various traumas with current
PTSD and depression by sexual orientation (10).

ASSESSMENT: MST is defined as sexual harassment and or sexual


assault experienced by a military service member. Sexual abuse among
female veterans occurs in significant numbers in the US military. It is
associated with pre-combat traumatic experiences and pathologic
sequelae including mental and medical illness. Military environmental
factors are related to increased likelihood of rape, including sexual
harassment allowed by officers, unwanted sexual advances on-duty
and in sleeping quarters.
MST is related to an increased psychiatric pathology, including PTSD,
substance abuse and dependence, depression, anxiety, eating
disorders, and suicidal behavior. MST is also related to an increased
medical illness, primarily pain-related symptoms involving multiple
organ systems, including G-I, neurological, genitourinary and
musculoskeletal.
Among women employed in the US military, low sociocultural and
organizational factors are associated with an increased likelihood of
both types of victimization.

References
1. O'Brien BS, Sher L. Military sexual trauma as a determinant in the
development of mental and physical illness in male and female veterans. Int J
Adolesc Med Health. 2013;25(3):269-74.
2. Williams I, Bernstein K. Military sexual trauma among U.S. female
veterans. Arch Psychiatr Nurs. 2011;25(2):138-47.
3. Harned MS, Ormerod AJ, Palmieri PA, et al. Sexual assault and other
types of sexual harassment by workplace personnel: a comparison of
antecedents and consequences. J Occup Health Psychol. 2002;7(2):174-88.
4. Burgess AW, Slattery DM, Herlihy PA. Military sexual trauma: a silent
syndrome. J Psychosoc Nurs Ment Health Serv. 2013;51(2):20-6.
5. Sadler AG, Booth BM, Cook BL, Doebbeling BN. Factors associated with
women's risk of rape in the military environment. Am J Ind Med. 2003;43(3):
262-73. Erratum in: Am J Ind Med. 2003;44(1):110.
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6. Kang H, Dalager N, Mahan C, Ishii E. The role of sexual assault on the risk
of PTSD among Gulf War veterans. Ann Epidemiol. 2005;15(3):191-5.
7. Luterek JA, Bittinger JN, Simpson TL. Posttraumatic sequelae associated
with military sexual trauma in female veterans enrolled in VA outpatient
mental health clinics. J Trauma Dissociation. 2011;12(3):261-74.
8. Cobb Scott J, Pietrzak RH, Southwick SM, et al. Military sexual trauma
interacts with combat exposure to increase risk for posttraumatic stress
symptomatology in female Iraq and Afghanistan veterans. J Clin Psychiatry.
2014;75(6):637-43.
9. Rossiter AG, Smith S. The invisible wounds of war: caring for women
veterans who have experienced military sexual trauma. J Am Assoc Nurse
Pract. 2014;26(7):364-9
10. Lehavot K, Simpson TL. Trauma, posttraumatic stress disorder, and
depression among sexual minority and heterosexual women veterans. J Couns
Psychol. 2014;61(3):392-403.

CHARACTERISTICS OF SEXUAL ASSAUL. The aim of this study was to


describe victim, assailant, and assault characteristics for sexual assault
victims according to the time between the last sexual assault and the
examination, and to provide descriptive data on medico-legal findings.
The study was based on 418 examined victims of sexual assault during
the year 1998, France. Victims were referred from investigating police
authorities. All examinations were performed with the use of
colposcopy by physicians with special training in forensic medicine. Two
groups of victims were defined: a first group of victims examined in
emergency within 72 hours after the last sexual assault; a second group
of victims examined after 72 hours. About 86% of the cases were
female victims. The mean age of the cases of the first group was 22.4
years. Conversely, 76% of the victims examined after 72 hours and
were under the age of 15 years. Vulnerability was present in 31% of the
cases examined in emergency, including disabled and pregnant victims.
Sexual assault happened once in 87% of the cases of the first group and
in 64% of the cases of the second group. The victim's home was the
most frequent place of sexual assault, 35% of the cases were in the first
group and 56% of the cases in the second group. The assailant was a
stranger in 51% of the cases in the first group. In the second group of
the victims, the assailant was a family member in 58% of the cases (the
father in 30% of the cases). There was a single assailant in the majority
of the cases for the two groups. Threats were used by the assailant in
66% of the victims examined in emergency and in 33% of the cases of
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the second group. The type of sexual assault was penetration in the
majority of the cases for the two groups. Vaginal, oral and anal
penetration was respectively involved in 55%, 23% and 13% of the
cases in the first group. General body trauma was found in 39.1% of the
cases and in 6.3% of the cases of the second group. Genital trauma
occurred in 35.7% of the cases in the first group and in 19.5% of the
cases in the second group. Hymenal, vulvo-vaginal and anal lesions
were in 11%, 20% and 7%, respectively, of the cases examined.
Toxicological analysis was performed in 14.3% of the cases examined. In
47% of the tested cases, drug was detected. Cytology was performed in
61.5% of the cases. Detection of spermatozoa was in 30.3% of these
cases. This study has shown that sexual assault victims had different
characteristics according to the time between the sexual assault and
the examination. Public health campaigns against sexual abuse and
rape as well as medical management of the sexually assaulted victims
should adapt to the needs and the characteristics of these two different
populations of victims (1).
The main aim of this study was to describe the medico-legal findings
in a population of sexual assault cases assessed in an urban French
referral centre, to analyze the subsequent legal dispositions in each
case and to determine whether the characteristics of the assault and
the medico-legal findings were associated with conviction of the
assailant. A retrospective study of medicolegal reports in all the sexual
assault cases was reported in Tours (France) during a seven-year
period. Two groups of victims were defined: children under 15 years old
and victims aged 15 years or more. Legal outcomes were obtained from
courtroom proceedings. A total of 756 cases during the study period
were enrolled. The mean age of the study population was 16.5 years
and 68.3% of the cases involved children less than 15 years old. In 57%
of these cases, the assailant was a family member; 31.7% of all the
victims were aged 15 years or more. The assailant was an acquaintance
of the victim in 62.2% of the cases. Drug-facilitated assault was
suspected in 2.9% of the cases. In 46.2% of the cases, formal criminal
charges were not filed due to insufficient evidence; 36.3% of the
assailants were convicted. Examination at the request of the police
authorities and previous acquaintance of the assailant by the victim
were associated with conviction. Allegations of penetration, the
presence of general body trauma and the presence of genital trauma
were not necessarily associated with conviction. Medical examiners
need to be circumspect when they record non-medical variables.
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Physical evidence of trauma was neither predictive nor essential for


conviction. Successful prosecution depends on the quality of the
testimony provided by the victim (2).
The purpose of this study was to describe victim, assailant, assault,
and treatment characteristics for sexual assault victims and to provide
descriptive data on the evidentiary examination. Prospective data were
collected on all sexual assault victims presenting to an urban Level I
trauma center from January 1992 to December 1995 for treatment and
evidentiary examination. Data from crime laboratory records were
retrospectively reviewed. Of 1,112 patients presented after a sexual
assault, 1,076 (97%) patients consented to the medical and evidentiary
examination. Age ranged from one to 85 years (mean, 25 years;
median, 23 years), with 96% (1,036/1,076) female and 4% (41/1,076)
male victims. The number of assailants was greater than one in 20%
(208/1,044) of cases, and the assailant was a stranger only 39%
(409/1,094) of the time. Force was used in 80% (817/1,027) of reported
assaults, and in 27% (275/1,014) of cases, a weapon was present.
Vaginal intercourse was involved in 83% (851/1,023) of female victims.
Oral assault was involved in 25% (271/1,053) of all cases, and anal
penetration was involved in 17% (178/1,058) of all cases. Overall,
general body trauma was seen 67% (621/927) of the time, and genital
trauma occurred in 53% (388/736) of cases. Of patients, 20%
(147/1,712) had no trauma noted on examination. Sperm were noted
on the emergency department wet mount in only 13% (93/716) of the
victims, and of the 612 cases with both emergency department sperm
data and crime laboratory semen data available, evidence of sperm and
semen were found 48% (296/612) of the time by either. In conclusion,
health care professionals should be aware that general body trauma is
common, the assailant is often someone known to the victim, and
evidence of semen is commonly found by the crime laboratory even
when it is not found in the emergency department analysis of a wet
mount (3).
The purpose of this descriptive study was to: 1] compare the
demographics of maltreated youth initially labeled as sexually abused
by the Department of Child and Family Services with maltreated youth
classified as sexually abused using current and past case records, 2]
identify differences in sexual abuse experiences and types of
perpetrators between boys and girls, and 3] provide a detailed
description of the sexual abuse experiences for boys and girls.
Participants were youth ages 9-12 years old with a recent maltreatment
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allegation. The Maltreatment Case Record Abstraction Instrument was


used to code child welfare records of 303 maltreated youth of whom 60
experienced sexual abuse. Perpetrators were classified by gender into
four categories (biological parent, parental figure, relative, and
unrelated) and type of abuse was classified into three categories
(penetrative, contact without penetration, and non-contact). Only 23
(38.3%) of the 60 sexually abused youth were labeled as sexually
abused in the most recent the Department of Child and Family Services
report when they entered the study. About three-quarters of the
sexually abused youth experienced non-penetrative physical contact,
40% experienced penetration, and 15% were sexually abused without
physical contact. Most youth (91.7%) were victimized by a male, and
21.7% were abused by a female. Youth experienced a large range of
sexual abuse experiences, the details of which are important for
exploration of consequences of childhood sexual abuse (4).
Women (n=319), aged 18-30 years, who represented a community
sample, were interviewed regarding their most recent unwanted sexual
experience. Four contexts in which adolescents were sexually
victimized emerged: Within Intimate Relationships, At Parties/Social
Gatherings, Abuse by Authority Figures, and While Alone with a Friend.
Thematic analysis revealed that inexperience with sex and dating, lack
of guardianship, substance use, social and relationship concerns, and
powerlessness contributed to adolescent vulnerability within these
contexts (5).
In this study, differences in the extent of violence and physical injury
in sexual assaults committed by intimate partners compared with
assaults by strangers and acquaintances were explored. Medical and
forensic records of 690 consecutive women attending a sexual assault
center in Stockholm, Sweden were reviewed. The final sample included
in the analysis consisted of 503 patients. The results showed that
women sexually assaulted by their intimate partners more frequently
reported physical violence (OR 4.1) than women assaulted by strangers
(OR 2.0) and acquaintances (OR 1.0). Genital injuries were unrelated to
the victim-assailant relationship. Extragenital injuries showed a
tendency toward being more frequently found after intimate partner
assaults compared with stranger and acquaintance assaults; however,
this was insignificant in adjusted analyses. Previous history of sexual
assault was more common, and seeking medical care within 72 hours as
well as being under the influence of alcohol during the assault was less
frequent among intimate partner victims. These results support the
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conclusion that sexual assaults committed by intimate partners,


contradictory to earlier studies, are likely to involve more physical
violence and result in injuries just as often as assaults committed by
strangers (6).
Retrospectively, examinations performed in Berne (Switzerland)
between 2006 and 2008 in cases with and without report to the police
were analyzed. Altogether, 207 examinations were carried out during
that period (65.2% reported to the police, 34.8% without report to the
police); 20% of the incidents were reported to the police after the
examination. One third of the victims in both groups claimed that the
perpetrator was unknown. More than 40% of the women in both
groups had been under the influence of alcohol at the time of the
incident; 73% of the victims (reporting the crime) and 61% of those not
filing a crime report described penile-vaginal contacts. Blackouts were
claimed in 14% of the cases reported to the police and 33% of those not
reported. Genital lesions were in about one third and extragenital
injuries in more than 50% of cases in both groups. No condom had been
used in a large percentage of cases or its use was uncertain.
Unprotected vaginal ejaculation was reported by about one third of the
victims in both groups and could not be reliably excluded in 28% of
cases. In 43.8% (reported to police) and 47.1% (not reported), no
contraceptive method had been applied by the women. The results
show similar distributions in both groups for numerous factors (factual
circumstances and injury pattern). However, in the group not filing a
complaint with the police blackouts were reported more often, which
may have induced the victims not to report the incident to the police at
first. The fact that in about 20% of these cases, the women went to the
police later underlines the importance of offering documentation
usable as evidence in court and preserving evidence independent of
whether the incident has already been reported to the police or not.
Reasons why victims present for examination may also be fear of
pregnancy or STDs (7).
Sexual revictimization is frequent among victims of child sexual
abuse. Several variables, such as sexual experience, substance abuse,
and sexual assertiveness, have been proposed to explain the link
between child sexual abuse and adolescent and adult sexual
victimization, although they have typically been tested separately. The
main objective of this study was to analyze which of these variables
better explains the revictimization phenomenon using a multiple
mediation analysis. This study also tested the frequency of sexual
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victimization experiences in a Spanish sample of college women. Of 402


women interviewed, 30.4% were engaged in undesired sexual contact
while almost 4% were victims of rape. The most frequent perpetrators
were partners or ex-partners, acquaintances, or dating partners, but
not strangers. The relationship between child sexual abuse and
adolescent and adult sexual victimization was mediated by number of
consensual sexual partners and sexual assertiveness (8).
Despite the signing of international peace agreements, a deadly war
continues in the DRC and sexual violence is a prominent modus
operandi of many military groups operating in the region. This
retrospective cohort study included women who presented to Panzi
Hospital in 2006 requesting post-sexual violence care. A total of 1,021
medical records were reviewed. A majority of attacks occurred in
individual homes (56.5%), with the fields (18.4%), and the forest
(14.3%) being frequent locations of attack. In total, 58.9% of all attacks
occurred at night. Of the four primary types of sexual violence, gang
rape predominated (59.3%) and rape Not Otherwise Specified was
common (21.5%). Sexual slavery was described by 4.9% of the survivors
and a combination of gang rape and sexual slavery was described by
11.7%. The mean number of assailants per attack was 2.5 with a range
of one to >15. There were several demographic predictors for sexual
slavery. Controlling for age, education level and occupation, a marital
status of "single" increased the risk of sexual slavery (OR 2.97, 95% CI
1.12-7.85). Similarly, after controlling for other variables, age was a
significant predictor of sexual slavery with older women being at a
slightly reduced risk (OR 0.96, 95% CI 0.92-0.99). Women who
experienced sexual slavery were 37 times more likely to have a
resultant pregnancy in comparison to those who reported other types
of sexual violence (OR 37.50, 95% CI 14.57-99.33). In conclusion, among
sexual violence survivors presenting to Panzi Hospital in 2006, the
majority of attacks occurred in women's own homes, often at night.
This represents a pattern of violence that differs from other conflict
settings. Sexual violence in South Kivu was marked with a gang rape,
thus increasing the risk of serious injury as well as the likelihood of an
individual woman contracting a STI. Sexual slavery was more common
among young, single women who had a high rate of resultant
pregnancy (9).
This study included all 123 female cases of alleged sexual assault
that presented for medical examination at the office of the surgeon
medico-legal Punjab at Lahore during 2002. Around 64% of the victims
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were between 10-19 years of age, 76% presented for medical


examination after a delay of more than 72 hours. The victim in 57%
cases knew the assailant. Two or more assailants were involved in 30%
cases. The victims had changed clothes and washed their bodies before
the medical examination in 83% cases. Physical evidence of violence on
the body was present in 15% of the victims and evidence of recent
injury to the genital tract was present in 18% individuals. A positive
semen analysis was reported in 98.4% of the samples. In conclusion,
sexual assault was more common in younger females. Late
presentation for examination was due to the embarrassment of being
exposed. A positive semen analysis was the definite factor for
confirmation of the assault (10).
Sexual assault affects two out of every five women, and it is a
substantial public health and human rights problem in developing
countries including Ethiopia. The objective of this study was to assess
the pattern of sexual assault and related complications in cases which
were treated at Jimma University Specialized Hospital from November
1, 2011 - October 31, 2012. A hospital based cross-sectional descriptive
study was conducted with the aim of assessing sexual assault patterns
and related complications on 99 sexual assault cases which were
managed at the Gynecology Out-patient Department of the Hospital.
Data on circumstances of sexual assault, survivor specific demographic
characteristics and information on complications and interventions
were collected by trained third year residents in obstetrics and
gynecology using pretested questionnaire after respondent consent
was taken. The mean (±SD) of the survivors' age was 14 (±5) years;
57.5% of the survivors were children and 68.7% were from rural areas.
Of the clients, 3% visited the Gynecology Outpatient Department for
sexual assault where rape accounted for 78.8%. The survivors knew the
majority (76.8%) of the assailants, 91% were assaulted by one assailant
and 5.1% of the rape cases were gang rape. The mean time of
presentation after sexual assault to the hospital was 15 days. Survivors
had pregnancy test, HIV test and screening for STI in 76.8%, 99%, 93%,
respectively, of which 17.1%, 5.1%, 14.1% tested positive for
pregnancy, HIV, and some STI, respectively. All HIV positive survivors
were children under 15 years of age. Forty percent of the survivors
were provided with emergency contraception, and 60.5%, 63%, and
91.9% of them were provided with PEP for HIV, and STI and were given
counseling respectively. In conclusion, sexual assault is a major problem
of women and children less than 15 years. There were gaps in providing
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and receiving packages of care and justice system to protect survivors


indicating the needs for community intervention and providing quality
of care by health care staff (11).

ASSESSMENT: youth experience a large range of sexual abuse


experiences. The victim's home is the most frequent place of sexual
assault. The assailant is often someone known to the victim, is a
stranger, or a family member. The sexual assault victim tended to be a
young single woman who is attacked by a familiar assailant in the
evening or at night.
General body trauma is common, and semen is commonly found by
the crime laboratory even when it is not found in the emergency
department analysis.
The type of sexual assault is penetration such as vaginal, oral and
anal. General body trauma includes hymenal, vulvo-vaginal and anal
lesions.
Despite the signing international peace agreements, a deadly war
continues in the DRC and sexual violence is prominent of many military
groups operating in the region. A majority of attacks occurs in individual
homes, in the fields, and the forest, often at night. Gang rape
predominates and rape Not Otherwise Specified is common, increasing
the risk of serious injury as well as the likelihood of an individual
woman contracting a STI. Sexual slavery is more common among
young, single women and has a high rate of a resultant pregnancy.
Four contexts in which adolescents are sexually victimized emerged:
Within Intimate Relationships, At Parties/Social Gatherings, Abuse by
Authority Figures, and While Alone with a Friend. Thematic analysis
reveals that inexperience with sex and dating, lack of guardianship,
substance use, social and relationship concerns, and powerlessness
contribute to adolescent vulnerability within these contexts.
Sexual assaults committed by intimate partners are likely to involve
more physical violence and result in injuries just as often as assaults
committed by strangers.
Tamar was a young single woman, attacked in her home by the
family member (Amnon). In her case the most important factor (among
the four described) was: While Alone with a Friend. Other important
factors in the thematic analysis were: inexperience with sex and dating,
lack of guardianship, and powerlessness.
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Was physical violence used in Tamar's case? Similarly to many


contemporary victims, Tamar was a young white female attacked at her
home who knew the perpetrator. Was she threatened?

References
1. Grossin C, Sibille I, Lorin de la Grandmaison G, et al. Analysis of 418 cases
of sexual assault. Forensic Sci Int. 2003;131(2-3):125-30.
2. Saint-Martin P, Bouyssy M, O'Byrne P. Analysis of 756 cases of sexual
assault in Tours (France): medico-legal findings and judicial outcomes. Med Sci
Law. 2007;47(4):315-24.
3. Riggs N, Houry D, Long G, et al. Analysis of 1,076 cases of sexual assault.
Ann Emerg Med. 2000;35(4):358-62.
4. Negriff S, Schneiderman JU, Smith C, et al. Characterizing the sexual
abuse experiences of young adolescents. Child Abuse Negl. 2013 Oct 3. pii:
S0145-2134(13)00252-4.
5. Livingston JA, Hequembourg A, Testa M, Vanzile-Temsa C. Unique
aspects of adolescent sexual victimization experiences. Psychol Women Q.
2007;31:331-43.
6. Möller AS, Bäckström T, Söndergaard HP, Helström L. Patterns of injury
and reported violence depending on relationship to assailant in female
Swedish sexual assault victims. J Interpers Violence. 2012; 27(16):3131-48.
7. Germerott T, Bode-Jänisch S, Thali MJ. Physical and gynecological
examinations in female victims of sexual violence with special emphasis on
crime-reporting behaviour. Arch Kriminol. 2012;230(3-4):88-98.
8. Santos-Iglesias P, Sierra JC. Sexual victimization among Spanish college
women and risk factors for sexual revictimization. J Interpers Violence. 2012;
27(17):3468-85.
9. Bartels SA, Scott JA, Mukwege D, et al. Patterns of sexual violence in
Eastern Democratic Republic of Congo: reports from survivors presenting to
Panzi Hospital in 2006. Confl Health. 2010;4:9.
10. Hassan Q, Bashir MZ, Mujahid M, et al. Medico-legal assessment of
sexual assault victims in Lahore. J Pak Med Assoc. 2007;57(11):539-42.
11. Amenu D, Hiko D. Sexual assault: pattern and related complications
among cases managed in Jimma University Specialized Hospital. Ethiop J
Health Sci. 2014;24(1):3-14.

INJURIES ASSOCIATED WITH SEXUAL VIOLENCE. The accurate


description and interpretation of non-genital injuries may be crucial in
cases of alleged sexual assault, and may be important in corroborating
a victim's statement of events. In many cases of sexual assault, non-
genital injuries may be either absent or trivial; nevertheless, even minor
injuries may be of significance and need to be recorded. Injuries may be
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result from attempts to restrain the victim, whereas others (e.g. bite
marks) may have a sexual motive or be part of a sado-masochistic
ritual. A standard nomenclature for injuries (i.e. using the terms
'bruises', 'abrasions', 'lacerations', 'incisions and 'stab wounds') should
avoid ambiguity between medical examiners (1).
The objective of this study was to establish inter-rater reliability for
genital injury detection among experienced forensic sexual assault
examiners. Cross-sectional observational study testing inter-rater
agreement of injury assessment among eight experienced sexual
assault examiners who each viewed two-four digital images from 50
cases. Each case was rated by four examiners and included images
before and after toluidine blue dye application. Overall agreement and
kappa (κ) were calculated. Examiners had perfect agreement in 60
cases; in 24 cases three examiners agreed; in five cases two agreed and
one was unsure; and in nine cases there were two "yes" and two "no"
ratings or one "yes," one "no," and two "unsure" ratings. Overall
agreement was 82% (κ, 0.57) when yes/unsure and no/unsure
combinations equaled disagreement and 86% (κ, 0.66) when only
yes/no dyads equaled disagreement. Neither the number of images nor
any single examiner fundamentally influenced results. Highly
experienced examiners tended to agree with each other (86%) slightly
more often than moderate examiners agreed with each other (75%). In
conclusion, the set of experienced forensic examiners achieved
moderate inter-rater agreement in assessment of the presence of
female genital injury on selected digital images obtained during sexual
assault examination (2).
All females who were 15 years or older, presenting after sexual
assault to an urban emergency department Seattle, US, underwent
standardized evaluation. Of 8,199 women, 52% had general body
injury, 20% had genital-anal trauma, and 41% were without injury.
General body trauma was associated with being hit or kicked,
attempted strangulation, and stranger assault. Genital-anal injury was
more frequent in victims younger than 20 and older than 49 years,
virgins and those examined within 24 hours and after anal assault.
General body injury was primarily associated with situational factors,
whereas genital-anal injury was less frequent and was related to victim
age, virginal status, and the time of examination (3).
A retrospective chart review of new urogynecological patients seen
at the University of New Mexico Hospital was conducted. All women
underwent a standardized history and physical examination and
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completed symptom severity and QOL measures. Of 1,899 patients


with complete information identified from January 2007 and October
2011, 1,260 (66%) were asked about a history of sexual abuse. The
prevalence of sexual abuse was 213/1260 (17%). In the multivariable
analysis, only chronic pelvic pain remained significantly associated with
a history of sexual abuse. In conclusion, a history of sexual abuse is
common among women with pelvic floor disorders, and these women
are more likely to have chronic pelvic pain (4).
The main objective of this study was to investigate the effect of rape
on sexual problems and on pelvic floor problems, as well as the
mediating role of pelvic floor problems on sexual problems, in a
homogenous group of victims of adolescence rape without a history of
childhood sexual, physical, and/or emotional abuse. Sexual functioning
and pelvic floor functioning were assessed using self-report
questionnaires. In this cross-sectional study, a group of 89 young
women aged 18-25 years who were victimized by rape in adolescence
was compared with a group of 114 non-victimized controls. The rape
victims were treated for PTSD three years prior to participation in the
study. Three years posttreatment, rape victims were 2.4 times more
likely to have a sexual dysfunction (lubrication problems and pain) and
2.7 times more likely to have pelvic floor dysfunction (symptoms of
provoked vulvodynia, general stress, lower urinary tract, and IBS) than
non-victimized controls. The relationship between rape and sexual
problems was partially mediated by the presence of pelvic floor
problems. Rape victims and controls did not differ with regard to sexual
activities. In conclusion, rape victims suffer significantly more from
sexual dysfunction and pelvic floor dysfunction when compared with
non-traumatized controls, despite the provision of treatment for PTSD.
Possibly, physical manifestations of PTSD have been left unaddressed in
treatment. Future treatment protocols should consider incorporating
(physical or psychological) treatment strategies for sexual dysfunction
and/or pelvic floor dysfunction into trauma exposure treatments (5).
Forty-five girls less than 21 years of age, at Arkansas Children's
Hospital, who required surgical repair of genital injuries between June
1986 and April 2007, were identified. Although most injuries were due
to straddle and impalement mechanisms, sexual abuse or assault was
identified in 25% of the girls. Straddle/impalement injuries involved
only the external genitalia, vestibule, perineum, or posterior fourchette
in 21 of the 28 girls (76%). The injuries in nine of the 11 (82%) sexually
abused/assaulted girls involved the hymen, vagina, anus, or rectum (6).
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The purpose of this study was to examine the frequency of cervical


injuries in women following sexual assault, the types of injuries, the
mechanisms related to the injuries, and the types of injuries related to
each mechanism. A retrospective chart review was conducted. A total
of 538 charts were examined, with a final sample size of 114. Within
this sample, 87.8% (n=100) presented with no injury to the cervix, and
12.3% (n=14) had documented injury. All statistical analyses were
insignificant (7).
Understanding differences in genital injuries after non-consensual
and consensual intercourse is an important element of prosecuting
sexual assault cases. In order to determine if the injury patterns and
total surface area of genital injuries can differentiate between the types
of intercourse (consensual or non-consensual), 80 women were
examined after non-consensual (retrospective chart review, n=40) and
consensual (recruited, n=40) intercourse within 48 hours using
colposcopy, toluidine blue dye, and digital photography to document
genital injuries. Differences between types of injuries found in the non-
consensual and consensual groups, based on the univariate analysis,
were in the number of sites with ecchymosis (p<0.01) and number of
sites with redness (p<0.01). Based on the logistic hierarchical regression
model, 85% of the nonconsensual group and 90% of the consensual
group were classified correctly by using the number of sites with tears,
ecchymosis, abrasions, redness and sexual assault of injury when
controlling for time from intercourse to examination. The number of
sites with redness (p=0.017), number of sites with ecchymosis, and
sexual assault of injury (p=0.039) were individually predictive. The
number of sites with ecchymosis was a significant finding when
addressed as an individual block (p<0.001). In this small sample,
exploratory study, while controlling for time, the injury patterns and
total sexual assault of genital injuries were able to correctly classify the
non-consensual group 85% of the time (8).

ASSESSMENT: sexual abuse is associated with genital, anal, and


extragenital injuries.
In the case of Amnon and Tamar, the victim was an adolescent
female woman. Amnon used force to sexually abuse his half-sister.
What type of force was used? What type of penetration occurred? Was
Tamar's body injured? What kind of lesions experienced Tamar? Were
her genital organs injured?
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References
1. Crane J. Interpretation of non-genital injuries in sexual assault. Best
Pract Res Clin Obstet Gynaecol. 2013;27(1):103-11.
2. Sachs CJ, Benson A, Schriger DL, Wheeler M. Reliability of female genital
injury detection after sexual assault. J Forensic Nurs. 2011;7(4):190-4.
3. Sugar NF, Fine DN, Eckert LO. Physical injury after sexual assault: findings
of a large case series. Am J Obstet Gynecol. 2004;190:71-6.
4. Cichowski SB, Dunivan GC, Komesu YM, Rogers RG. Sexual abuse history
and pelvic floor disorders in women. South Med J. 2013;106(12): 675-8.
5. Postma R, Bicanic I, van der Vaart H, Laan E. Pelvic floor muscle
problems mediate sexual problems in young adult rape victims. J Sex Med.
2013;10(8):1978-87.
6. Jones JG, Worthington T. Genital and anal injuries requiring surgical
repair in females less than 21 years of age. J Pediatr Adolesc Gynecol. 2008;
21:207-11.
7. Keller P, Lechner M. Injuries to the cervix in sexual assault victims. J
Forensic Nurs. 2010;6(4):196-202.
8. Anderson SL, Parker BJ, Bourguignon CM. Predictors of genital injury
after nonconsensual intercourse. Adv Emerg Nurs J. 2009;31(3):236-47.

REPRODUCTIVE HEALTH AND PREGNANCY. Using the nationally


representative Colombian Demographic and Health Survey (2005), the
association of sexual violence with unintended pregnancy, current
modern contraceptive use, and unmet need for contraception were
examined. Of female youth who have been pregnant in the past five
years, 13% experienced sexual violence during their lifetimes, with 6%
reporting sexual violence perpetrated by a spouse or partner and 8% by
someone else. Among female youth at risk of unintended pregnancy,
sexual violence was reported by 11%. About 5% of these female, youth
reported sexual violence from a spouse or partner, and 7% being forced
to have sex with someone else. In cross-tabulations, female youth who
have experienced sexual violence reported significantly higher levels of
unintended pregnancy and unmet need for contraception and lower
levels of current modern contraceptive use compared to those who
have not experienced sexual violence. In multivariate logistic regression
models, sexual violence was associated with increased risk for
unintended pregnancy (AOR 1.4, 95% CI 1.1-1.8), unmet need for
contraception (AOR 1.5, 95% CI 1.1-2.0), and decreased likelihood of
current contraceptive use (AOR 0.8, 95% CI 0.6-1.0). This analysis
indicates that sexual violence is pervasive in Colombia and is
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consistently linked to increased risk of unintended pregnancy among


female youth. Because youth is particularly vulnerable to sexual
violence and may have difficulty accessing services, preventive efforts
and clinical responses should be specifically crafted to curb violence
against young women as well as reduce the longitudinal impact of
experiencing sexual violence (1).
The main objective of this study was to study whether female
youths from communities with higher sexual violence were at greater
risk of negative reproductive health outcomes. Data from a 2003
nationally representative household survey of youths aged 15-24 years
in South Africa were used. The key independent variable was whether a
woman had ever been threatened or forced to have sex. Youths from
communities with greater sexual violence were significantly more likely
to have experienced an adolescent pregnancy or to be HIV-positive
than were youths from communities experiencing lower sexual
violence. Youths from communities with greater community-level
violence were less likely to have used a condom at their last sexual
encounter. Individual-level violence was only associated with condom
nonuse. In conclusion, programs to reduce adolescent pregnancies and
HIV risk in South Africa and elsewhere in sub-Saharan Africa must
address sexual violence as part of effective prevention strategies (2).
The sexual violence committed in the DRC, in the scale and
consequences on women, is real public problem, representing politico-
legal and socio-economical challenges. More than a million of women
have been victims of sexual violence on a period of less than 15 years.
Different groups involved in the Congolese war used systematic rapes
of women as war weapon. Sexual violence against women has affected
public health by spreading STDs including HIV/AIDS, causing unwanted
pregnancies, leading to the gynecological complications of rape-related
injuries, and inflicting psychological trauma on the victims. Despite high
level of unwanted pregnancies observed, the Congolese law is very
restrictive and interdict induced abortion. There are three arguments
which plead in favor of legalizing abortion in DRC: 1] a restrictive law on
abortion forces women to use unsafe abortion and increased incidence
of injuries and maternal mortality; 2] DRC has ratified the Universal
Declaration of Human Rights, the African Union Charter that has to
promote equality between sexes, including women's reproductive
rights; 3] an unwanted birth is an additional financial charge for a
woman, a factor increasing poverty and psychologically unacceptable in
case of rape. From the politico-legal point of view, ending rape
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impunity and decriminalizing abortion are recommended.


Decriminalizing abortion gives women choice and save victims and
pregnant women from risks related to the pregnancy, childbirth, or an
eventual unsafe abortion. These risks increase the maternal mortality
already high in DRC (between 950 and 3,000 for 100,000 live births) (3).
A number of countries adopt abortion laws, recognizing rape as a
legal ground for access to safe abortion service. As rape is a crime,
these abortion laws carry with them criminal and health care elements
that in turn result in the involvement of legal and medical expertise.
The most common objective of the laws should be providing safe
abortion services to women survivors of rape. Depending on purposes
of a given abortion law, the laws usually require women to undergo a
medical examination to qualify for a legal abortion. Some abortion laws
are so vague as to result in uncertainties regarding the steps health
personnel must follow in conducting medical examination. Another
group of abortion laws does not leave room for regulation and remain
too rigid to respond to changing socio-economic circumstances. Still
others require medical examination as a prerequisite for abortion. As a
result, a number of abortion laws remain on the books (4).
The main objective of this study was to investigate the association
between common mental disorders and IPV during pregnancy. A cross
sectional study was carried out with 1,120 pregnant women aged 18-49
years old, who were registered in the Family Health Program in the city
of Recife, Northeastern Brazil, between 2005 and 2006. Common
mental disorders were assessed using the SRQ-20. IPV was defined as
psychologically, physically and sexually abusive acts committed against
women by their partners. The most common form of partner violence
was psychological. The prevalence of common mental disorders was
71.0% among women who reported all form of violence in pregnancy
and 33.8% among those who did not report IPV. Common mental
disorders were associated with psychological violence (OR 2.49, 95% CI
1.8-3.5), even without physical or sexual violence. When psychological
violence was combined with physical or sexual violence, the risk of
common mental disorders was even higher (OR 3.45; 95% CI 2.3-5.2). In
conclusion, assaulted by someone with whom a woman is emotionally
involved can trigger feelings of helplessness, low self-esteem and
depression. The pregnancy probably increased women`s vulnerability
to common mental disorders (5).
This study aims to measure the association between individual and
community exposure to different forms of violence against women
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(physical/sexual violence by the partner, sexual abuse by any person, or


controlling behavior by the partner) and unintended pregnancies. Data
from the 2006/2007 Nicaraguan Demographic and Health Survey were
used. For the current study, 5,347 women who reported a live birth
prior to the survey and who were married or cohabitating at the time of
the data collection were selected. Women's exposure to controlling
behaviors by their partners was measured using six questions from the
WHO Multi-Country Study on Women's Health and Domestic Violence
against Women. Area-level variables were constructed by aggregating
the individual level exposures to violence into an exposure
measurement of the municipality as a whole (n=142), which is the basic
political division in Nicaragua. Multilevel logistic regression was used to
analyze the data. In total, 37.1% of the pregnancies were reported as
unintended. After adjusting for all variables included in the model,
individual exposure to controlling behavior by a partner (AOR 1.28, 95%
CrI 1.13-1.44), ever exposure to sexual abuse (AOR 1.31, 95% CrI 1.03-
1.62), and ever exposure to physical/sexual IPV (AOR 1.44, 95% CrI
1.24-1.66) were significantly associated with unintended pregnancies.
Women who lived in municipalities in the highest tertile of controlling
behavior by a partner had 1.25 times higher odds of reporting an
unintended pregnancy than women living in municipalities in the
lowest tertile (AOR 1.25, 95% CrI 1.03-1.48). In conclusion, Nicaraguan
women often experience unintended pregnancies, and the occurrence
of unintended pregnancies is associated with exposure to different
forms of violence against women at both the individual and the
municipality level. National policies aiming to facilitate women's ability
to exercise their reproductive rights must include actions aimed at
reducing women's exposures to violence against women (6).

ASSESSMENT: despite an increased use of contraceptive methods by


women, unintended pregnancies represent one of the most evident
violations of women's sexual and reproductive rights around the world.
Sexual violence is associated with increased risk for unintended
pregnancy, unmet need for contraception, and decreased likelihood of
current contraceptive use.
A number of countries adopted abortion laws, recognizing rape as a
legal ground for access to safe abortion service.
Being assaulted by someone with whom a woman is emotionally
involved can trigger feelings of helplessness, low self-esteem and
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depression. The pregnancy probably increased women`s vulnerability


to common mental disorders.

References
1. Gomez AM. Sexual violence as a predictor of unintended pregnancy,
contraceptive use, and unmet need among female youth in Colombia. J
Womens Health (Larchmt). 2011;20(9):1349-56.
2. Speizer IS, Pettifor A, Cummings S, et al. Sexual violence and
reproductive health outcomes among South African female youths: a
contextual analysis. Am J Public Health. 2009;99 Suppl 2:S425-31.
3. Kalonda JC. Sexual violence in Congo-Kinshasa: necessity of
decriminalizing abortion. Rev Med Brux. 2012;33(5):482-6.
4. Teklehaimanot KI, Smith CH. Rape as a legal indication for abortion:
implications and consequences of the medical examination requirement. Med
Law. 2004;23(1):91-102.
5. Ludermir AB, Valongueiro S, Araújo TV. Common mental disorders and
intimate partner violence in pregnancy. Rev Saude Publica. 2014;48(1):29-35.
6. Salazar M, San Sebastian M. Violence against women and unintended
pregnancies in Nicaragua: a population-based multilevel study. BMC Womens
Health. 2014 Feb 12;14:26.

SEXUALLY TRANSMITTED DISEASES. STDs are among the first 10


causes of unpleasant diseases in young adult males in developing
countries and the second major cause of unpleasant diseases in young
adult women. Adolescents and young adults (15-24 years old) make up
only 25% of the sexually active population, but represent almost 50% of
all new acquired STDs. In general, STDs are epidemics and present an
enormous health and economic consequences. An adequate screening
for STDs should be done on a routine basis in every part of the world.
Many STDs are asymptomatic and therefore can difficult to control. The
purpose of reporting of STDs is to ensure that persons who are infected
will be quickly diagnosed and appropriately treated to control the
spread of infection and also so that partners are notified, tested and
appropriately treated. It is estimated that reported cases of STDs
represent only 50%-80% of reportable STD infections in the United
States, reflecting limited screening and low disease reporting. High-risk
sexual behavior is a highly contributive factor of this process as it often
leads to teenage pregnancies and HIV/AIDS. One possible explanation
for this behavior is that people do not have enough information about
the transmission of STDs or ignore the precautions required for safe
sex. Approximately 60% of new HIV infections worldwide occur in
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young people. The frequency of high-risk behaviors among youths may


also be influenced by opportunity to engage in them, particularly the
amount of time that they are unsupervised by adults. However, in
diagnosing and treating these patients, we can effectively prevent the
spread of HIV/AIDS. Individuals infected with STDs are 5-10 times more
likely than uninfected individuals to acquire or transmit HIV through
sexual contact. The breaking of the genital tract lining or skin creates a
portal of entry for HIV and, hence, HIV-infected individuals with other
STDs are more likely to shed HIV in their genital secretions. To date, the
condom is the most effective method available for males for protection
against STDs. It is important to control STDs, and prevention can be the
key of this process. Prevention can be achieved through education of
the population, identification of symptomatic and asymptomatic
people, and effective diagnosis and treatment of these patients and
their partners (1).
Sexual assault and HIV are coexisting public health problems. Sexual
assault may increase HIV transmission risk through diverse
mechanisms, such as infliction of anal, oral, and genital injuries by
penile, digital, or object penetration, extragenital trauma, concurrent
STIs, condom use, and whether the perpetrator was circumcised (2).
The objective of this study was to describe the prevalence of STIs
and BBV, and prophylactic treatment offered to female postpubertal
patients attending a Norwegian Sexual Assault Centre. Whether STIs
diagnosed at the initial visit could have been assault-transmitted, and
whether background and assault characteristics were associated with
diagnosed STI/BBV were explored. Postpubertal females ≥12 years of
age attending this centre within one week of the assault were included.
Data were collected from records. A retrospective, descriptive study
was conducted. Among 412 patients with a median age of 21 years, 35
patients had an STI (8.5%), two of which probably were assault-
transmitted. C. trachomatis was the dominating agent, detected in 25
patients (6.4%). At serology screening, 3.7% tested positive for hepatitis
C and/or hepatitis B core antibody. Patient age 16-19 years was
associated with STI, while BBV positives were older. Non-Western
assailant was associated with STI, while substance abuse was
associated with STI and BBV. In order to prevent potential transmission
of STI not identified at the initial visit, 91% accepted prophylaxis against
bacterial STI, while antiviral prophylaxis was offered to less than one-
fifth of the patients. In conclusion, the C. trachomatis prevalence
among the sexual assault patients was lower than in a comparable
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clinical population. The STI was suspected to be assault-transmitted in


only two cases (3).
STDs, with special emphasis to HIV infection, involve legal and
ethical issues regarding informed consent to submit to a diagnostic,
observance of professional secrecy concerning partner(s) and
community; legal troubles of particular difficulties are related to STD
involving minors; lastly, physicians must be able to recognize the state
of so-called medical necessity. Knowledge and awareness of these
related obligations are crucial to STD in medical practice; it is also
important to allow for proper protection of victims of suspected sexual
abuse under observation of healthcare. Violence against women and
minors is a worldwide problem that has not yet been sufficiently
acknowledged. Italian legislation (Law n. 96/1996) against rapes finally
gave significant relevance to sex crimes. When sexual abusers have to
be evaluated, obstacles may arise for lack of appropriate
interdisciplinary approach, with insurance of the collection of biological
samples, related to STD diagnosis and alerts of legal authorities.
Personal preconceptions may interfere with investigation if the
biological evidences in children are few. In this regard, rules of
document "Carta di Noto" drafted in 1996 and reviewed in July 2002
include some specific indications aiming to grant the reliability of the
results of technical investigations and authenticity of the statements of
the alleged victims (4).
The current study investigated factors related to risks for STIs,
including HIV, among South African women with a history of sexual
assault. An anonymous street intercept survey of women (n=272) living
in an African township in the Western Cape, South Africa assessed
demographic characteristics, history of sexual assault, HIV risk
behaviors, substance use and non-sexual relationship abuse. Surveys
were completed by 90% of women approached. Of all women, 44%
(n=119) reported a history of sexual assault. Women who had been
sexually assaulted were significantly more likely to have shared
injection drug equipment, exchanged sex to meet survival needs, and
used alcohol compared to women who had not been sexually
assaulted. Women with a history of sexual assault were significantly
more likely to have multiple male sex partners, greater rates of
unprotected vaginal intercourse, lower rates of condom protected anal
intercourse, more sexual contacts involving blood, more STIs, and
genital ulcers. Women who had been sexually assaulted were more
likely to have been non-sexually abused by relationship partners and
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were more likely to fear asking partners to use condoms. There is a


close connection between sexual assault and women's risks for STIs and
HIV. Structural and behavioral interventions are needed to
simultaneously reduce the prevalence of sexual assault against women
and prevent the transmission of HIV (5).
This study aimed to determine the prevalence of HIV infection
among survivors of sexual assault attending a large peri-urban health
facility in KwaZulu-Natal, a province of South Africa. Data from the
medical records of the available 534 sexual assault cases that attended
the facility between 2005 and 2009 were reviewed: 19.7% tested HIV
positive and HIV prevalence among the survivors over the five years
increased from 15% in 2005 to 19% in 2009. Screening sexual assault
survivors for HIV provides a good opportunity to identify those who will
benefit from HIV prophylaxis and HIV-infected persons who need HIV
care and treatment (6).
Co-infection of HIV and other STDs is common. CDC recommends
routine yearly screening for STDs in HIV carriers. There is only scarce
data on the prevalence of STD in HIV positive individuals in Israel and
no current recommendations on this issue are available. The objective
of this study was to evaluate the prevalence of STDs, in HIV positive
females attending the HIV Clinic at the Soroka University Medical
Center in Beer Sheva and to compare prevalence and risk factors for
STDs between HIV female carriers of Ethiopian and non-Ethiopian
origin. Eighty-five HIV-positive women were enrolled in the study.
Demographic data and sexual behavior were obtained and medical
records were reviewed. Cervical swabs for N. gonorrhea, HSV 1 and 2,
Ureaplasma urealyticum and M. hominis and serum samples for
hepatitis B, hepatitis C and syphilis were obtained. Of 32 of the study
participants, 37.6% had at least one STD and in 11 cases (12.9%) two or
more STDs were found. Ureaplasma urealyticum was the most frequent
pathogen (29.4%). Prevalence for M. hominis, HSV1 and 2, N.
gonorrhea, syphilis and hepatitis B virus was low. Despite significant
differences in sexual behavior between women of Ethiopian and non-
Ethiopian origin there were no differences in the prevalence of STDs in
the two groups. HCV was significantly more prevalent in women of non-
Ethiopian origin, due to high use of IV drugs in this group. There was no
correlation between CD4 levels and the prevalence of STDs in both
groups. In conclusion, a relatively low prevalence of STDs among female
HIV carriers was found, despite low condom use. The exclusion of males
in this study may have contributed to this. The most frequent pathogen
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was asymptomatic Ureaplasma urealyticum (29.4%). As this pathogen


may cause premature delivery and fetal death, it seems important to
routinely screen HIV-positive fertile women for its presence (7).

ASSESSMENT: there is a relationship between sexual assault and


women's risks for STIs including HIV. Sexual assault increases a HIV
transmission risk through diverse mechanisms, such as infliction of anal,
oral, and genital injuries by penile, digital, or object penetration,
extragenital trauma, concurrent STIs, condom use, and whether the
perpetrator was circumcised.
Women with a history of sexual assault more likely have multiple
male sex partners, greater rates of unprotected vaginal intercourse,
lower rates of condom protected anal intercourse, more sexual
contacts, more STIs, and genital ulcers.

References
1. Da Ros CT, Schmitt Cda S. Global epidemiology of sexually transmitted
diseases. Asian J Androl. 2008 Jan;10(1):110-4.
2. Draughon JE. Sexual assault injuries and increased risk of HIV
transmission. Adv Emerg Nurs J. 2012;34(1):82-7.
3. Hagemann CT, Nordbø SA, Myhre AK, et al. Sexually transmitted
infections among women attending a Norwegian Sexual Assault Centre. Sex
Transm Infect. 2014;90(4):283-9.
4. Argo A, Zerbo S, Triolo V, et al. Legal aspects of sexually transmitted
diseases: abuse, partner notification and prosecution. G Ital Dermatol
Venereol. 2012;147(4):357-71.
5. Kalichman SC, Simbayi LC. Sexual assault history and risks for sexually
transmitted infections among women in an African township in Cape Town,
South Africa. AIDS Care. 2004;16(6):681-9.
6. Adefolalu AO. Prevalence of HIV infection among survivors of sexual
assault at presentation in hospital. Trop Doct. 2013;43(3):106-7.
7. Banani S, Schlaeffer F, Leibenson L, et al. Prevalence of sexually
transmitted diseases (STD) in HIV positive women in southern Israel].
Harefuah. 2013;152(4):204-6, 248.

PSYCHOLOGICAL CONSEQUENCES. Survivors of sexual assault


display psychological sequelae including elevated rates of suicide.
Prevalence of mental health problems of 121 forensic cases between
June and August 2004 was established. Of females aged over 13 years,
8% had learning difficulties, 21% gave a history of deliberate self-harm,
and 20% had psychiatric history. In conclusion, vulnerable people are at
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increased risk for mental health problems and deliberate self-harm


following sexual violence (1).
This was a retrospective analysis of the psychological and psychiatric
history of adult patients who attended the Lancashire Sexual Assault
and Forensic Examination Centre between April 1st 2010 and March
31st 2011 for forensic examination. During this time, 269 adults
attended for forensic examination; the records of these patients were
audited for evidence of psychological or psychiatric ill health. Affective
disorders were disclosed in 48.7% of cases (depression, anxiety,
depression and anxiety, and bipolar affective disorder) and 3.0%
declared having been diagnosed with a psychotic illness (schizophrenia,
psychotic illness, and psychotic behavior). Deliberate self-harm was
disclosed by 29.4% of complainants and 22.3% of attendees had
attempted suicide at least once in their lifetime. This study highlights
increased prevalence of mental illness in sexual assault complainants
which contributes to increased states of vulnerability. This and further
similar research efforts have a role to influence prevention schemes,
management strategies and healthcare planning for those individuals
who are sexually assaulted (2).
Survivors (n=47) of sexual abuse suffered symptoms serious enough
to require therapy (3). These include PTSD, low self-esteem and low
self-worth, distrust of others, anxiety and fear, depression, anger, self-
mutilation, interpersonal problems, sexual difficulties, substance abuse,
alcohol and drug abuse, suicidal ideation or gestures, prostitution,
promiscuity, eating disorders, personality disorder or dysfunctional
personality, significant increase in somatization scores, and multiple
sick days (3-5).
Adult victims of sexual assault do not generally report the abuse
because of fear of retribution by the perpetrator, the stigma attached
to being a victim of a sexual crime, fear of being blamed for the assault,
history of negative outcomes following past disclosures, and fear of the
psychological consequence of disclosure such as increased anxiety and
depression (6).
A nationally representative sample of 3,015 girls in grades five
through 12 from 265 public, private, and parochial schools (with an
oversampling of urban schools) completed an anonymous survey
conducted by the Commonwealth Fund Adolescent Health Survey.
Among the responders, 246 (8%) reported a history of physical abuse,
140 (6%), sexual abuse, and 160 (5%), both. Those who reported both
types of abuse compared with those who did not report any were
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significantly more likely to experience moderate to severe depressive


symptoms, moderate to high level of life stress, regular alcohol
consumption, use of other illicit drugs in the past 30 days, and fair to
poor health status. Girls who reported both types of abuse were 2.1
more likely to report moderate to high depressive symptoms compared
with those reporting only sexual abuse (7).
This study aimed to investigate the moderating roles of gender and
age on emotional abuse within intimate relationships. The study
included 250 participants with an average age of 27 years. Participants
completed the Emotional Abuse Questionnaire, which four subscales
are isolation, degradation, sexual abuse, and property damage (8).
Multigroup analysis with two groups, female (n=141) and male (n=109),
was used to test the moderation effect. Younger men reported
experiencing higher levels of emotional abuse, which declined with age.
Older females reported experiencing less emotional abuse than older
males. Overall, emotional abuse was more common in younger
participants. Younger women experienced higher rates of isolation, and
women's overall experience of property damage was higher than that
of men and increased with age (9).
In this review, the most recent literature on adolescent sexual
assault is examined, and new findings regarding prevalence, risk
factors, sequelae, cultural factors, genital injury, legal issues and
practice implications are summarized. Child and adolescent sexual-
assault victims are at risk for a range of negative outcomes, including
comorbid PTSD and major depressive episode, comorbid PTSD and
substance abuse, eating disorders, delinquency, and revictimization.
Cultural factors and severity levels of trauma may serve as risk factors
to such outcomes in adolescent sexual-assault victims. Compared with
adults, adolescent sexual-assault victims have a greater frequency of
rape-related anogenital injuries, but data on healing of injuries in this
population are lacking. Factors related to a child sexual-assault victim's
demeanor and intelligence can influence the perceived credibility of the
child as a witness to the abuse. Recent studies investigating prevalence,
risk factors, and sequelae of child and adolescent sexual assault
highlight the need for educational programs and primary prevention
interventions to educate pre-pubescent children and adolescents about
sexuality, including sexual assault. Although most adolescent sexual
assault victims do not seek acute post-rape medical care, forensic nurse
examiners are often the first clinicians to encounter the adolescent
sexual assault victim. Nursing protocols that standardize evidence
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collection as well as psychological support are important in the


comprehensive care of these traumatized teens (10).
The role of sleep in psychiatric illness in general, and depression and
suicidality in particular, is poorly understood and has not been well
researched despite the pervasiveness of sleep complaints in these
conditions. As an exploratory, hypothesis-generating study, female
sexual assault survivors with PTSD (n=153) who had enrolled in a
nightmare-treatment program were assessed for subjectively
determined sleep breathing and sleep movement disorders. Diagnoses
of potential disorders were based on clinical practice parameters and
research algorithms from the field of sleep disorders medicine.
Potential sleep breathing and sleep movement disorders were present
in 80% of the participants (n=123) and included three subgroups: sleep-
disordered breathing only (n=23); sleep movement disorder only
(n=45); and both sleep disorders (n=55). Based on the Hamilton
Depression Rating Scale and Suicide subscale, participants with
potential sleep disorders suffered more from depression (p<0.01) and
suicidality (p<0.05) in comparison to participants without potential
sleep disorders. The group with both sleep disorders suffered from the
most severe depression and suicidality (11).
Depression symptomatology four to six weeks post-rape in South
Africa was explored and examined whether this differs according to the
circumstances of the rape. From public hospital services, 140
participants were recruited in the Eastern and Western Cape provinces
and were interviewed within two weeks after completing the PEP
medication. A structured questionnaire was used to collect data on
socio-demographic and sexual assault characteristics including
perpetrator. Depressive symptomatology was measured using the
Centre for Epidemiological Studies Depression Scale. Of all women,
84.3% (95% CI 78.1-90.3) had high levels of depressive symptoms, but
lower levels were among women raped in circumstances in which there
was a lesser likelihood of blame such as those raped by strangers rather
than intimate partners (OR 0.28, 95% CI 0.11-0.69) while higher levels
were associated with experiencing four or more side effects related to
PEP medication (OR 3.79, 5% CI 1.03-13.94). Receiving support and
severe sexual assaults (involving weapons and multiple perpetrators)
were not associated with depression. In conclusion, this study does not
support the general assumption that violent rape causes more
psychological harm. These results have important implications for
individual treatment because it is generally assumed that multiple
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perpetrator rapes, stranger rapes and those with weapons would result
in more psychological trauma and thus more enduring symptoms. The
findings point to the importance of understanding the socio-cultural
dimensions, including dynamics of blame and stigma of rape on mental
health sequelae (12).
This study investigated the relationship between changes in PTSD,
depression, and anxiety symptoms in the first 12 weeks following
sexual assault. Participants were 126 women who had been sexually
assaulted in the previous four weeks. Lower level mediation analyses
revealed that changes in PTSD symptoms had a greater impact on
changes in depression and anxiety than vice versa. In conclusion, the
finding highlights the role of PTSD symptoms in influencing subsequent
change in other psychological symptoms (13).

ASSESSMENT: survivors of sexual assault display psychological


sequelae including learning difficulties, deliberate self-harm, PTSD, low
self-esteem and low self-worth, distrust of others, anxiety and fear,
depression, anger, self-mutilation, interpersonal problems, sexual
difficulties, substance abuse, alcohol and drug abuse, isolation, suicidal
ideation or gestures, prostitution, eating disorders, personality disorder
or dysfunctional personality, significant increase in somatization scores,
and multiple sick days.
Child and adolescent sexual-assault victims are at risk for a range of
negative outcomes, including PTSD and major depressive episode, PTSD
and substance abuse, eating disorders, delinquency, and
revictimization.
In this research, humiliated Tamar suffered from various
psychological outcomes of the assault, including PTSD, and/or low self-
esteem, and/or anxiety, depression, anger, isolation, fear of reporting
the sexual abuse because of the stigma attached to being victim, fear of
being blamed, and fear of negative outcomes following disclosure.
Tamar in spite of suffering from a disgraceful sexual abuse was advised
to keep silent.
Contemporary assault victims similarly to ancient victims suffer from
various psychological problems and these victims need urgent
psychiatric treatment.

References
1. Campbell L, Keegan A, Cybulska B, Forster G. Prevalence of mental
health problems and deliberate self-harm in complainants of sexual violence. J
Forensic Led Med. 2007;14:75-8.
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2. Creighton CD, Jones AC. Psychological profiles of adult sexual assault


victims. J Forensic Leg Med. 2012;19(1):35-9.
3. Briere J, Zaidi LY. Sexual abuse histories and sequelae in female
psychiatric emergency room patients. Am J Psychiatry. 1989;146:1602-8.
4. Stein MB, Lang AJ, Laffaye C, et al. Relations of sexual assault history to
somatic symptoms and health anxiety in women. Gen Hosp Psychiatry.
2004;26:178-83.
5. Hegarty K, Gunn J, Chondros P, Small R. Association between depression
and abuse by partners of women attending general practice: descriptive, cross
sectional survey. BMJ. 2004;328:621-4.
6. Courtois C. Healing the incest wound: adult survivors in therapy. New
York: W.W. Norton & Company. 1988.
7. Diaz A, Simantov E, Rickert VI. Efect of abuse on health: results of a
national survey. Arch Pediatr Adolesc Med. 2002;156:811-7.
8. Jacobson N, Gottman J. When Men Batter Women: New Insights into
EndingAbusive Relationships. New York: Simon & Schuster; 1998.
9. Karakurt G, Silver KE. Emotional abuse in intimate relationships: the role
of gender and age. Violence Vict. 2013;28(5):804-21.
10. Danielson CK, Holmes MM. Adolescent sexual assault: an update of the
literature. Curr Opin Obstet Gynecol. 2004;16(5):383-8.
11. Krakow B, Artar A, Warner TD, et al. Sleep disorder, depression, and
suicidality in female sexual assault survivors. Crisis. 2000;21(4):163-70.
12. Abrahams N, Jewkes R, Mathews S. Depressive symptoms after a sexual
assault among women: understanding victim-perpetrator relationships and the
role of social perceptions. Afr J Psychiatry (Johannesbg). 2013; 16(4):288-93.
13. Nickerson A, Steenkamp M, Aerka IM, et al. Prospective investigation of
mental health following sexual assault. Depress Anxiety. 2013;30(5):444-50.

POSTTRAUMATIC STRESS DISORDER. The main objective of this


study was to evaluate PTSD, depression, and hopelessness in women
one and six months after they experienced sexual violence. This
prospective study, in which the clinician-administered PTSD scale, the
BDI and the Beck hopelessness scale included 67 women at one month
and 52 women at six months after they experienced sexual violence.
Overall, 77.6% of the women were ≤24 years of age, and 52% were
adolescents; 15% had a history of drug abuse, and 13.5% had a history
of previous sexual violence. The aggressor was unknown in 76% of
cases, and there was more than one aggressor in 9% of cases. In the
first month, 43% of the women had moderate or very severe PTSD;
52.2% had moderate or severe depression; and 22.4% had moderate or
severe hopelessness, which decreased to 21%, 20% and 10%,
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respectively, at six months. In the first month, severity of PTSD was


associated with moderate or severe depression and at six months,
severity of PTSD was associated with multiple aggressors and previous
psychiatric disorders. All scores decreased in the six month. In
conclusion, severe mental health disorders were still present six
months after women had experienced sexual violence (1).
This study investigated the relationship between changes in PTSD,
depression, and anxiety symptoms in the first 12 weeks following
sexual assault. Participants were 126 women who had been sexually
assaulted in the previous four weeks. Lower level mediation analyses
revealed that changes in PTSD symptoms had a greater impact on
changes in depression and anxiety than vice versa. In conclusion, the
findings highlight the role of PTSD symptoms in influencing subsequent
change in other psychological symptoms (2).
The main objective of this study was to examine the effects of
counselor-delivered prolonged exposure therapy compared with
supportive counseling for adolescents with PTSD. A single blind, RCT of
61 adolescent girls with PTSD used a permuted block design.
Counselors previously naive to prolonged exposure therapy provided
the treatments in a community mental health clinic. Data collection
lasted from February 2006 through March 2012. Participants received
fourteen 60- to 90-minute sessions of prolonged exposure therapy
(n = 31) or supportive counseling (n = 30). All outcomes were assessed
before treatment, at mid-treatment, and after treatment and at 3-, 6-,
and 12-month follow-up. The primary outcome, and PTSD symptom
severity were assessed by the Child PTSD Symptom Scale-Interview
(range, 0-51, higher scores indicate greater severity). Secondary
outcomes were presence or absence of PTSD diagnosis assessed by the
DSM-IV Schedule for Affective Disorders and Schizophrenia for School-
Age Children and functioning assessed by the Children's Global
Assessment Scale [range 1-100, higher scores indicate better
functioning]. Additional secondary measures, PTSD severity assessed
by the Child PTSD Symptom Scale-Self-Report [range 0-51, higher scores
indicate greater severity] and depression severity assessed by the
Children's Depression Inventory [range 0-54, higher scores indicate
greater severity] were evaluated weekly during treatment. Participants,
receiving prolonged exposure, demonstrated greater improvement on
the PTSD symptom severity scale: difference between treatments in
improvement 7.5, 95% CI 2.5-12.5, p <0.001, and on all secondary
outcomes - loss of PTSD diagnosis: difference 29.3%, 95% CI 20.2-
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41.2%, p =0 .01; self-reported PTSD severity: difference 6.2, 95% CI 1.2-


11.2, p =0 .02; depression: difference 4.9, 95% CI 1.6-8.2, p =0 .008;
global functioning: difference 10.1, 95% CI 3.4-16.8, p=0 .008. These
treatment differences were maintained through the 12-month follow-
up: for interviewer-assessed PTSD: difference 6.0, 95% CI 1.6-10.4,
p =0 .02; loss of PTSD diagnosis: difference 31.1, 95% CI 14.7-34.8,
p =0 .01; self-reported PTSD: difference 9.3, 95% CI 1.2-16.5, p =0 .02;
depression: difference 7.2, 95% CI 1.4-13.0, p =0 .02; and global
functioning: difference 11.2, 95% CI 4.5-17.9, p =0 .01. In conclusion,
adolescent girls with sexual abuse-related PTSD experience greater
benefit from prolonged exposure therapy than from supportive
counseling even when delivered by counselors who provide supportive
counseling (3).
This prospective study examined risk factors for PTSD severity in 148
female help-seeking victims of sexual assault. Approximately 70% of the
victims experienced significant levels of traumatization, with 45%
reporting symptoms consistent with a probable PTSD diagnosis.
Regression analyses showed that relationship with the assailant,
number of assailants, the nature of the assault, perceived positive
social support, support satisfaction, feeling let down by others, and
prior exposure to sexual trauma insignificantly predicted PTSD severity
at the final level of analysis. In accordance with previous suggestions
(4), this is partly caused by a very high degree of traumatization in the
sample. Instead, previous nonsexual traumatic experiences and
negative affectivity accounted for 30% of the variance in PTSD severity.
These findings suggest that although sexual assault is associated with a
high degree of PTSD severity, prior nonsexual victimization and high
levels of negative affectivity appear to further increase the vulnerability
toward developing symptoms of assault-related PTSD (5).
This study examined the relationship between PTSD and dissociative
experiences in a sample of 158 recent female assault victims (74 rape,
and 84 nonsexual assault) and 46 comparison subjects who had not
been assaulted within the last year. Results indicated that victims had
elevated scores on DES as compared to the comparison subjects, but
this elevation was not as high as for other traumatized samples. The
level of dissociation reported by assault victims declined significantly
over the three-month course of the study. DES scores were related to
PTSD diagnosis and symptom severity, but only among nonsexual
assault victims. In rape victims, there was no correlation between
dissociation and PTSD. Recent victims with a history of childhood sexual
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abuse were significantly more dissociative than those who did not
report such a history (6).

ASSESSMENT: in women with the history of sexual violence, severity


of PTSD is associated with moderate or severe depression in the first
month, and at six months severity of PTSD is associated with multiple
aggressors and previous psychiatric disorders.
Changes in PTSD symptoms have a greater effect on changes in
depression and anxiety.
Although sexual assault is associated with a high degree of PTSD
severity, prior nonsexual victimization and high levels of negative
affectivity increase the vulnerability toward developing symptoms of
assault-related PTSD.
Adolescents' girls with sexual abuse-related PTSD experience greater
benefit from prolonged exposure therapy than from supportive
counseling.
This research deals with one sexual abuse as described in the Bible.
Amnon, King's David's son, sexually abused his sister Tamar.
Subsequently, Tamar suffered from various psychological outcomes of
the abuse, including PTSD.

References
1. Machado CL, de Azevedo RC, Facuri CO, et al. Posttraumatic stress
disorder, depression, and hopelessness in women who are victims of sexual
violence. Int J Gynaecol Obstet. 2011;113(1):58-62.
2. Nickerson A, Steenkamp M, Aerka IM, et al. Prospective investigation of
mental health following sexual assault. Depress Anxiety. 2013;30(5):444-50.
3. Foa EB, McLean CP, Capaldi S, Rosenfield D. Prolonged exposure vs.
supportive counseling for sexual abuse-related PTSD in adolescent girls: a
randomized clinical trial. JAMA. 2013;310(24):2650-7.
4. Dancu CV, Riggs DS, Hearst-Ikeda D, et al. Dissociative experiences and
posttraumatic stress disorder among female victims of criminal assault and
rape. J Trauma Stress. 1996;9(2):253-67.
5. Elklit A, Christiansen DM. Risk factors for posttraumatic stress disorder in
female help-seeking victims of sexual assault. Violence Vict. 2013;28(3): 552-
68.

SEXUAL ASSAULT CENTERS. Prior research endorsed the


establishment of sexual assault centers in the Netherlands because of
the potential benefit for victims' mental recovery. In 2012, the first
Dutch sexual assault centre was founded at the Utrecht University
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Medical Center. The aim of the centre is to provide coordinated and


integrated services (i.e., medical, forensic, and psychological) in one
location. The purpose of the present study was to describe
demographic, background, and assault characteristics of victims seen at
the centre within one week post-assault, and their use of post-assault
services in order to improve current services. From January 2012 to
September 2013, prospective data of 108 patients were collected. To
describe the population included, frequency counts and proportions
were generated for categorical variables. The mean age was 21.3 years
(SD=9.8). Most victims were female (91.7%). A large proportion of
victims reported background characteristics known to increase the risk
for PTSD and revictimisation such as prior sexual abuse (32.4%), pre-
existing use of mental health services (45.4%), and not living with both
biological parents (61.7%). Most patients (88.9%) consulted the centre
within 72 hours post-assault. The uptake of services was high: 82.4%
received emergency medical care, 61.7% underwent a forensic-medical
examination, 34% reported to the police, and 82.4% utilized
psychological services. In conclusion, to prevent revictimisation and
PTSD, current psychological services could be improved with immediate
trauma-focused treatments. Current forensic services may be improved
with the use of standard top to toe forensic-medical examinations for
both children and adults (1).
This study explores the gap between assaults actually occurring and
those seen at sexual assault center, Oslo, Norway; and the
characteristics of cases presented in time/too late for forensic medical
examination (early and late cohorts). In this retrograde descriptive
study, a two-year series from a self-referral sexual assault center,
characteristics of victims, assaults, and use of services were evaluated.
Attendance rates for females were 0.12% (14-55 years); an estimated 4-
7% of sexually assaulted females in the catchment area. Of all victims,
278 arrived in time for forensic medical examination, 76 later, 6% were
males. Strangers more often performed assaults in the early cohort. Of
238 victims who underwent forensic medical examination, 55%
complied with follow-up, and 55% reported to the police. The late
cohort contained more adolescent victims, more acquainted/partner
perpetrators, and more verbal coercion; 45% medically examined, 80%
follow-up compliance; 34% reported to police. Further referrals
occurred equally often in both cohorts; 12% to somatic and 39% to
psychiatric services. Among victims, 5% died within seven years of
consultation. In conclusion, cases at Sexual Assault Centre are strongly
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selected. The late cohort seems more representative of the commonly


occurring assaults; young victims, and known assailants. Even late
presenters are in need of a multidisciplinary approach (2).
The objectives of this study were to describe the characteristics of
sexual assault victims, their assailants, the assault and the treatment,
and provide descriptive data on the evidentiary examination. A
retrospective analysis of the charts of all sexual assault victims
presenting to the Regional Center for Care of Sexual Assault Victims
was conducted between October 2000 and July 2010. The center, the
first in Israel, provides comprehensive care to victims of sexual
assault in one location 24 hours a day using a multidisciplinary
approach. The study group comprised 1,992 subjects; 91.5% of the
victims were females and 8.5% were males, and the age ranged from
1 to 88 years (mean age 22.3 years). Of the 1,992 victims, 1,635 were
single (82.2%), 195 were divorced (9.8%), 141 were married (7.1%),
18 were widowed (0.9%) and three were unspecified. The assailant
was a stranger in 794 (39.8%) of the cases, someone familiar to the
victim in 786 cases (39.0%), a partner in 127 cases (6.4%), a family
member in 117 cases (5.9%), someone met via the internet in 53
cases (2.7%), an authority figure in 39 cases (2.0%), and unspecified
in 76 (3.9%). In the majority of cases, the attack occurred either in
the evening or at night (71.7%). In conclusion, several risk factors for
sexual assault identified in this study can be used in prevention
programs. The sexual assault victim tended to be a young single
woman who was attacked by a familiar assailant in the evening or at
night. This center provides comprehensive care to victims 24 hours a
day at one location and includes a team of forensic, psychological,
physical and legal specialists (3).

ASSESSMENT: sexual assault centers aim assisting victims and to


provide forensic medical examination.
The management of sexual assault victims comprises complex
medical, psychological, social and judicial care. Sexual assault centers
deliver comprehensive care to victims of sexual assault at one
location.
Just like Tamar, the adolescent victim from antiquity, any
contemporary adolescent victim of traumatic sexual aggression
deserves appropriate assessment and treatment at the sexual assault
center.
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References
1. Bicanic I, Snetselaar H, De Jongh A, Van de Putte E. Victims' use of
professional services in a Dutch sexual assault centre. Eur J Psychotraumatol.
2014 Jun 18;5.
2. Nesvold H, Friis S, Ormstad K. Sexual assault centers: attendance rates,
and differences between early and late presenting cases. Acta Obstet Gynecol
Scand. 2008;87(7):707-15.
3. Golan A, Dishi-Galitzky M, Barda J, Lurie S. The care of sexual assault
victims: the first regional center in Israel - 10 years experience. Isr Med Assoc J.
2012;14(11):658-61.

FAMILY FUNCTIONING
Fleck (1) suggested five parameters of family functioning. These are:
1. Leadership: this is a result of the parents' personalities, the
characteristics of the marital coalition, the complementary of the
parental roles, and the parents' use of power – that is, their methods of
discipline.
2. Family boundaries: this covers ego boundaries, generation
boundaries, and family-community boundaries.
3. Affectivity: important in this parameter is interpersonal intimacy,
the equivalence of family triads, family members' tolerance of each
other's feelings, and unit emotionality.
4. Communication: relevant here are responsiveness of family
members to each other, the extent to which verbal and no-verbal
communications are consistent, the ways in which family members
express themselves, the clarity of the syntax of their talk, and the
nature of members' abstract and metaphorical thinking.
5. Task/goal performance: this covers the nurturance given to
members by the family, the ways in which the children master the
process of separation from the family, behavior control and guidance,
the nature of family members' peer relationships and the guidance they
are given in the leisure activities, how the family copes with crises, and
the adjustment of members after they leave the family of origin.
Leadership in David's family was concentrated in the King's hands,
and only he could give permission to Tamar to visit her "sick" brother,
Amnon. The visit was well organized and carried out within the family
boundary. At this time, Amnon, Tamar, Absalom and the King were
strongly connected emotionally with each other. The communication
pattern was positive, and their relationships were based on trust. The
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whole process went as planned: the father permitted Tamar to visit


Amnon, Tamar prepared cakes and took them to her "sick" brother,
while Absalom kept his eyes on this visit. However, communication in
this case between family members was obstructed; Tamar had no
telephone or other means to inform others of what was happening
behind the closed doors. Unfortunately, the door was closed therefore
there was no way to escape. Absalom did not expect that his "half"
brother had organized the invitation in order to sexually abuse his
"half" sister (2).

References
1. Fleck S. Family functioning and family pathology. Psychiatric Ann.
1980;10:46-54.
2. Ben-Nun L. Tamar and Amnon. In: Ben-Nun L. (ed.). The Family Life Cycle
and the Medical Record of King David the Great. Research in Biblical Times
from the Viewpoint of Contemporary Medicine. B.N. Publishing House. Israel.
2009, pp. 56-77.

AN ANCIENT VICTIM. This biblical story indicates that Tamar was


indeed a victim of sexual abuse perpetrated by her half-brother.
Firstly, Amnon fell in love with his beautiful sister and consequently
suffered from an eating disorder. He dreamed about his sister but
could not have sexual relations with her. Therefore, with the help of
his friend a plan was prepared. Pretended to be sick, Amnon got
permission from his father, the King, for Tamar to visit her “sick”
brother. During this visit, Tamar was forced to have sexual relations
with him. Since the sexual relations were carried out against Tamar’s
will, we can classify them as sexual abuse. This abuse occurred
within the family system, with a brother as perpetrator.
The consequences of the biblical sexual assault were devastating.
After achieving his desire, Amnon began to hate his humiliated sister,
and threw her out of his room. In addition, the words - Tamar
remained desolate in her brother Absalom’s house indicate that
Tamar suffered from PTSD, and/or low self-esteem, and/or anxiety,
fear, depression and anger. Because of Amnon’s disgusting behavior,
hatred developed between two brothers and the family atmosphere
was poisoned. No compromise could be found in the triangle:
Amnon - Absalom - Tamar.
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REVENGE. Absalom did not forget that Amnon had defiled their
sister, and he was eager for revenge. There was no way to achieve a
peaceful reconciliation between the two brothers. The painful
triangle - Tamar, Absalom, and Amnon - could never achieve a
peaceful coexistence. Resources were not used to solve this family
crisis. Even the King did not intervene or make any efforts to
reconcile this triangle.
After two years, at the first opportunity, Absalom commanded his
men to kill Amnon and the mission was performed "..Smite Amnon;
then kill him, fear nor.. be courageous, and be valiant.." (II Samuel
13:28). With the aid of external forces, Amnon paid with his life for
his disgusting behavior. Amnon's death affected profoundly David's
family: "..the king's sons came, and lifted their voices and wept: and
the king also and all his servants wept very sore" (13:36). Later,
"Absalom fled, and went to Talmai, the son of Ammihud, king of
Geshur. And David mourned for his son every day" (13:37).
Eventually Amnon was assassinated for his disgraceful behavior.
Here we are dealing with a violent death (1).
In healthy families, the ambience is nurturing, and the
relationships are filled with love, caring, affection, and loyalty. In
dysfunctional families, the relationships take on qualities like hate,
guilt and retribution; the ambience is disjunctive. However, in both
healthy and dysfunctional families, the attachments are intense and
their vicissitudes pervade the whole life of the family. Secondly,
these interactions continue over whole lifetimes. Thirdly, the
outcome of these interactions is physical survival and personal
development for all members. The purpose of the family is to evoke
between members sequences of affectional interactions sustained
over lifetimes, thereby producing survival and development for all
family members (2).
Family change is the interpersonal process by which the family
adapts, alters, or becomes different. The family is more than the
sum of its parts. Interpersonal structures and processes that enable it
to be both stable and adaptable over time organize the family (3).
Amnon's reckless behavior led the King's family into a severe
crisis. The attachment between Absalom, Amnon and Tamar was
broken, and the stable family homeostasis was disrupted. The
relationships between the siblings reached such a level of hatred that
only the death of Amnon could calm the situation. Absalom never
accepted and never forgave Amnon for defiling his beautiful sister.
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The family became unstable, it could not adjust to the consequences


of Tamar's humiliation. Because of Amnon's behavior, the attitude
towards him changed: Amnon had to pay a price for his dreadful
action. After this unforgivable event, the King's family internal system
changed forever (1).

References
1. Ben-Nun L. In: Ben-Nun L. (ed.). The Medical Record of Amnon the
King David's Son. Israel. 2014.
2. Terkelsen KG. Toward a theory of the family life cycle. In: Carter EA,
Goldrick M (eds.). The Family Life Cycle: A Framework for Family Therapy,
Gardner Press, New York. 1980, pp, 21-52.
3. McDaniel S, Campbell TL, Seaburn DB. Family system concepts. Tools
for assessing the family in primary care. In: McDaniel S, Campbell TL,
Seaburn DB (eds.). Family-Oriented Primary Care. A Manual for Medical
Providers. Springe-Verlag. New York, Berlin. 1990, pp. 33-39.

MOURNING FOR AMNON. King David was aware of Amnon's


outrageous behavior, ” But when King David heard of all these things,
he was very angry” (II Samuel 13:20). The biblical text provides no
details about any punishment or even dialogue between the father
and his son, Amnon, concerning this disgraceful action. The internal
family system was disrupted, and a peaceful coexistence was broken.
There was no room for any compromise; the behavior of Amnon
had reached such extremely negative point that now it was only a
question of when and where Amnon would pay the price. The
internal tension and hatred between Absalom, Amnon and beautiful
Tamar led to Amnon's assassination. In spite of Amnon's dreadful
behavior that led to his death, the King mourned for his son. Here we
see a very special characteristic of the King's character – he loved his
son and was ready to forgive him for his disgusting behavior.
According to the Smilkstein's Apgar Questionnaire, at this time the
family can be defined as a severely dysfunctional (1).
Grieving a loss is a profound and universal human experience (2).
Grief is not a mental disorder; it is a painful and unexpected process
in response to the death of a family member or loved one
(bereavement), or a significant loss. Despite the fact that grief is not
a mental disorder, consultations about grief are frequent in clinical
practice, which is why clinicians must be trained for these situations.
It is important to bear in mind that not every process of grief follows
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a normal development and reaches a satisfactory solution, and this is


where health care professionals must be qualified to recognize when
grief is becoming a pathological disease; they must be more alert to
these cases and intervene in an appropriate way. It is also important
to stress that grief is not a synonym for depression, but many grief-
stricken people may enter a depressive state, and they therefore
require early treatment in order to avoid complications that might
arise from the unsuitable treatment of a depressive episode, such as
suicide. Finally, the relationship between grief and psychological
disorder has been demonstrated. Grief that is insufficiently
elaborated, or which follows an abnormal development, may give
rise to a psychopathological disorder, generally a major depressive
episode, just as an established mental disorder may hinder the
elaboration of a process of working through grief (3).
The process of grieving itself takes place in time in several ways:
the extent to which the death is sudden, expected, and timely; the
passage from the beginning of anticipatory grieving itself before the
actual death through the diminishing effects of the loss over an
extended period; and the age and stage in life of the grieving
persons. During the grieving process, the survivors often develop
physical and health problems, face psychological and emotional
distress, encounter difficulties with social relationships, and must
cope with numerous practical issues. The subsequent adjustment of
widows and widowers appears to be related to the extent to which
there had been the opportunity for open communication (4).
Bereavement responses were assessed in 45 parents whose
children died six months to four years earlier. Parents of boys or
children who died suddenly experienced more despair, anger, guilt,
and depersonalization. Social support and stress since the child's
death and fate-blame vs. self-blame were also related to parental
responses on specific the Grief Experiences Inventory scales (5).
In contrast to dominant Western conceptions of bereavement in
largely intrapsychic terms, the authors argue that grief or mourning is
not primarily an interior process, but rather one that is intricately
social, as the bereaved commonly seek meaning in this unsought
transition in not only personal and familial, but also broader
community and even cultural spheres. A social constructionist model
of grieving in which the narrative processes by which meanings are
found, appropriated, or assembled occur at least as fully between
people as within them. In this view, mourning is a situated
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interpretive and communicative activity charged with establishing


the meaning of the deceased's life and death, as well as the
postdeath status of the bereaved within the broader community
concerned with the loss. They describe this multilevel phenomenon
drawing first on psychological research on individual self-narratives
that organize life experience into plot structures that display some
level of consistency over time, whose viability is then negotiated in
the intimate interpersonal domain of family and close associates.
Second, they explore public communication, including eulogies, grief
accounts in popular literature, and elegies. All of these discourses
construct the identity of the deceased as he or she was, and as she or
he is now in the individual and communal continuing bonds with the
deceased. Finally, they consider different cultural contexts to see
how expressions of grief are policed to ensure their coherence with
the prevailing social and political order. That is, the meanings people
find through the situated interpretive and communicative activity
that is grieving must either be congruent with the meanings that
undergird the larger context or represent an active form of resistance
against them (6).
On the Holmes-Rahe scale (7), the death of a close family member
receives a score of 63 and is a negative non-normative stressful life
event. Thus, in the case of Amnon, the King experienced a negative,
very stressful event.

ASSESSMENT: grieving a loss is a profound and universal human


experience. Grief is not a mental disorder; it is a painful and
unexpected process in response to the death of a family member or
loved one (bereavement), or a significant loss.
Amnon was not supposed to die. Following his behavior, Amnon's
relationships with his half-brother Absalom and his sister Tamar were
broken, and reached a point from where there was no way to return
to the previous level of normative affectionate relations.
Amnon's sudden death profoundly affected King David and other
family members. All were involved in the mourning process. The
biblical words " the King's sons came: and the King also and all his
servants wept very sore" (II Samuel 13:36), and "And David mourned
for his son every day" (13:37) indicate the severe emotional distress
that afflicted the King, other family members, and even his servants.
These words also indicate despair, anger, and guilt. We see the very
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humane reaction of the father, the King who suffered a great deal
after losing his son forever.

References
1. Smilkstein G. The Family Apgar: a proposal for a family function test
and its use by physicians. J Fam Pract. 1978;6:1231-9.
2. Pilkington FB. Grieving a loss: the lived experience for elders residing
in an institution. Nurs Sci Q. 2005;18:233-42.
3. Flórez. Grief. An Sist Sanit Navar. 2002;25 Suppl 3:77-85.
4. Kalish RA. Death and survivorship: the final transition. Ann Am Acad
Pol Soc Sci. 1982;464:163-73.
5. Hazzard A, Weston J, Gutterres C. After a child's death: factors related
to parental bereavement. J Dev Behav Pediatr. 1992;13:24-30.
6. Neimeyer RA, Klass D, Dennis MR. A social constructionist account of
grief: loss and the narration of meaning. Death Stud. 2014;38(8):485-98.
7. Holmes TH, Rahe RH. The social readjustment rating scale. J
Psychosom Res. 1967;11:213.

ABSALOM
Two years after Amnon's assassination, Absalom fled. Here, Joab
"..went to Geshur, and brought Absalom to Jerusalem. So Absalom
dwelt two full years in Jerusalem, and saw not the King's face" (II
Samuel 14:23,28). After Absalom's servants set fire to Joab's field
(14:30), he (Absalom) came to the king, and prostrated himself before
the king; and the king kissed Absalom" (14:33). After this meeting with
his father, the King, "… Absalom prepared him chariots, and horses, and
fifty men to run before him" (15:1). So Absalom decided that " ..every
man came nigh to him to do him obeisance , he put forth his hand, and
took him, and kissed him" (15:5). Here Absalom behaved like a king,
thus ignoring his father.
Absalom prepared to fight with King David's army. In spite of this "So
the king commanded Joab and Abishai and Ittai, saying, Deal gently for
my sake with the young man, even with Absalom. Beware that none
touch the young man Absalom" (18:5,12). Meanwhile "And Absalom
rode on a mule, and the mule went under the thick boughs of a great
oak, and his head caught fast in the oak…. And the mule that was under
him went away" (18:9). So "..Absalom hanged in an oak" (18:10).
Subsequently "And he (Joab) took three spears in his hand, and thrust
them through the heart of Absalom, who was still alive in the midst of
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the oak. And then ten young men that bore Joab's armour came round
in a circle and smote Absalom, and slew him " (18:14,15). Absalom was
buried like a traitor "And they took Absalom, and cast him into a great
pit in the wood, and laid a very great heap of stones upon him (18:17).
So "…it is called unto this day, Absalom's place" (18:18).

Absalom' death. Julius von Karosfeld. I860.

In spite of Absalom's unacceptable behavior, the King ordered that


Absalom be kept alive "Deal gently for my sake with the young man,
Beware that none touch the young man Absalom". However, some men
close to the King were outraged and killed Absalom. This was not
difficult since Absalom was caught in an oak tree.
A spear is a sharp weapon consisting of s long pole with a sharp
point (1). Three spears were thrown into Absalom's chest, penetrating
his heart and causing severe life-threatening injury. He did not die
instantly from this injury, so ten young men encircled Absalom and
killed him. Ten young men vs. one. Absalom had no possibility of
escaping or fighting for his life. Thus, we are dealing with traumatic
heart injury.

Reference
1. Collins Cobuild. Essential English Dictionary. Collins. London,
Glasgow. 1988.

CLASSIFICATION OF HEART INJUIES. Heart injuries are be classified


as penetrating and non-penetrating (blunt) (1,2), or sharp and blunt (3).
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References
1. Velinovid M, Vranes M, Obrenovid-Kirdanski B, et al. Penetrating wound
of the heart manifested with peripheral embolism - case report. Vojnosanit
Pregl. 2012;69(9):803-5.
2. Olsovsky MR, Wechsler AS, Topaz O. Cardiac trauma. Diagnosis,
management, and current therapy. Angiology. 1997;48(5):423-32.
3. Miyoshi Y, Ohara K. Traumatic cardiac injury. Kyobu Geka. 2004;57(8
Suppl):742-50.

ABSALOM'S REBELLION. Absalom rebelled against his father, King


David. This rebellion led to a permanently corrosive state of
disequilibrium and the additional disruption of David’s family
homeostasis. The confrontation between Absalom and David was
inevitable. Fighting followed between the camps of Absalom and
King David. In spite of his son’s opposition to his leadership, David
did not want his son to be hurt. Therefore, he asked Joab, Abishai,
and Ittai to “..Deal gently for my sake with the young man, with
Absalom” (II Samuel 18:5). In this battle, Joab killed Absalom.

PENETRATING HEART INJURIES. Individuals suffer from


penetrating traumatic heart injury in all countries, whether
developed or developing, although different prevalence rates are
observed. Penetrating heart injury is a common health problem,
which warrants attention of health care workers, policy makers and
researches, having a negative effect on the patient and society (1).
In general, the victims of stab wounds are young adults. The
literature reports that the patients were brought to the emergency
department and their life was saved by appropriate treatment.
There is a variety of sharp objects used as the weapons for stab
injuries including knives, screwdrivers, ice picks, chopsticks, nails, a
barb from a stingray, copper wire fragments, an arrow¸ needles, a
steel splinter, a bodkin, a pellet, and a broken piece of a plastic
cannula. In addition, in butchers, perforating heart injury was
observed when they made a vertical cut (1).
Similarly to many contemporary victims, Absalom was a young
adult who suffered traumatic heart injury from the spears that were
thrown at his heart. He did not die instantly, and if appropriate
measures were taken he would have had a chance of surviving. In the
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case of Absalom, three sharp spears were thrust into his heart
causing life-threatening complications (1).
In large series, gunshot wounds are the predominant cause of
cardiac penetrating trauma (2-5). Penetrating cardiac injury carries
high mortality rates. It has been commonly associated with stabbing,
but increased urban violence has led to growing numbers of gunshot
heart wounds. The latter has higher mortality rates among
penetrating cardiac injuries and may affect multiple heart chambers,
with mortality rates even higher (6).
Penetrating war injuries of heart and great vessels are among the
most serious injuries in war. The mortality rate is 58% (7).
The cause of injury is shrapnel, bullets, cluster bomb particles,
and others (blast etc). The most frequent localization of the injuries is
the right and left ventricles, left atrium, superior caval vein, inferior
caval vein, and isolated pericardial injury. Immediately after injury,
patients suffer from shock, pericardial tamponade, and bleeding (8).
Although bullets penetrating the heart are fatal, retained cardiac
bullets can sometimes have a silent course without causing any C-V
complication (9).
Penetrating cardiac injuries are a dramatic and lethal form of
trauma. Most of these patients reach the hospital already dead or in
severe shock. The prognosis is determined by early diagnosis and
operation (10).
Life-threatening sequelae (hemorrhage and cardiac tamponade)
result from the external injury rather than the intracardiac
component. Intracardiac damage is manifested as the delayed
recognition of a cardiac murmur and some degree of CHF, and when
these appear one must suspect intracardiac trauma (11).
It is obvious that in Absalom's case, the penetrating heart injury
was not treated and his injury was fatal (1).

References
1. Ben-Nun L. Predictors of survival. In Ben-Nun L. (ed.) How did Absalom
the Son of King David Die? B.N. Publication House. Israel. 2014, pp. 73-86.
2. Asensio JA, Berne JD, Demetriades D, et al. One hundred five
penetrating cardiac injuries: a 2-year prospective evaluation. J Trauma.
1998;44:1073-82.
3. Molina EJ, Gaughan JP, Kulp H, et al. Outcomes after emergency
department thoracotomy for penetrating cardiac injuries: a new
perspective. Interact Cardiovasc Thorac Surg. 2008;845-8.
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L. Ben-Nun King David

4. Baker JM, Battistella FD, Kraut E, et al. Use of cardiopulmonary bypass


to salvage patients with multiple-chamber heart wounds. Arch Surg.
1998;133: 855-60.
5. Seamon MJ, Shiroff AM, Franco M, et al. Emergency department
thoracotomy for penetrating injuries of the heart and great vessels: an
appraisal of 283 consecutive cases from two urban trauma centers. J
Trauma. 2009;67:1250-7.
6. Karigyo CJ, Fan OG, Rodrigues RJ, Tarasiewich MJ. Transfixing gunshot
wound to the heart: case report. Rev Bras Cir Cardiovasc. 2011;26(2):298-
300.
7. Delibegovid Dedid S, Bazardzanovid M, Budalica M. Penetrating injuries
of heart and great vessels in patients wounded during the 1992-1994 war in
Bosnia and Herzegovina. Croat Med J. 1999;40(1):85-7.
8. Biocina B, Sutlid Z, Husedzinovid I, et al. Penetrating cardiothoracic
war wounds. Eur J Cardiothorac Surg. 1997;11(3):399-405.
9. Burgazli KM, Cetin SM, Atmaca N, et al. An unusual case of retained
bullet in the heart since World War II: a case report. Eur Rev Med Pharmacol
Sci. 2013;17(3):420-1.
10. Göz M, Cakir O, Eren MN. Penetrating cardiac injuries: analysis of the
mortality predictors. Ulus Travma Acil Cerrahi Derg. 2009;15(4):362-6.
11. Rustad DG, Hopeman AR, Murr PC, Van Way CW 3rd. Aortocardiac
fistula with aortic valve injury from penetrating trauma. J Trauma. 1986;
26(3):266-70.

THE RELATIONSHIP BETWEEN ABSALOM AND KING DAVID.


Medical record of Absalom, that is the biblical text, describes no
disturbed relationships between the King and Absalom before
Amnon's sexual assault on Tamar. After Amnon's assassination,
Absalom fled his house; he set fire to Joab's fields, began to behave
like a king, and subsequently built his own army in order to obtain a
crown. In spite of this fact, Absalom's father ordered that his life be
saved "So the king commanded Joab and Abishai and Ittai, saying,
Deal gently for my sake with the young man, even with Absalom" (II
Samuel 18:5) and "Beware that none touch the young man Absalom"
(18:12). However, Joab and his close friends assassinated Absalom
son for his nasty betrayal.
Here we see a rigid system in which everybody must obey the
rules. Punishment was imposed on disobedient individuals, and even
the King's son was not exempt.
Humans have the cognitive abilities to implement the revenge and
forgiveness systems hypothesized by McCullough et al. (1), but the
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evidence suggests that simpler processes may underlie most revenge


cases in humans and other animals. The mediating role of emotions
can be at the basis of the flexibility needed in the hypothesized
systems and the associated assessment of social relationships (2).
Minimizing the costs that others impose upon oneself and upon
those in whom one has a fitness stake, such as kin and allies, is a key
adaptive problem for many organisms. Our ancestors regularly faced
such adaptive problems (including homicide, bodily harm, theft, mate
poaching, cuckoldry, reputational damage, sexual aggression, and the
infliction of these costs on one’s offspring, mates, coalition partners,
or friends). One solution to this problem is to impose retaliatory costs
on an aggressor so that the aggressor and other observers will lower
their estimates of the net benefits to be gained from exploiting the
retaliator in the future. Humans have an evolved cognitive system
that implements this strategy – deterrence, which was
conceptualized as a revenge system. The revenge system produces a
second adaptive problem: losing downstream gains from the
individual on whom retaliatory costs have been imposed. A
subsidiary computational system designed to restore particular
relationships after cost-imposing interactions by inhibiting revenge
and motivating behaviors that signal benevolence for the harm doer.
The operation of systems depends on estimating the risk of future
exploitation by the harm doer and the expected future value of the
relationship with the harm doer (1).
In the case of Absalom, revenge played a decisive role in
eliminating the enemy, this time David's own son. Three spears were
thrust into Absalom's chest, causing a life-threatening injury.
However, Absalom did not die instantly of this injury, so eventually
ten men who encircled him killed him. There was no way of escaping
or fighting back in this lost battle.
His body was cast into a pit, with no formal burial ceremony of
burial. Here we see absolute neglect and negative attitude towards
Absalom.

References
1. McCullough ME, Kurzban R, Tabak BA. Cognitive systems for revenge
and forgiveness. Behav Brain Sci. 2013;36(1):1-15.
2. Aureli F, Schaffner CM. Why so complex? Emotional mediation of
revenge, forgiveness, and reconciliation. Behav Brain Sci. 2013;36(1):15-6.
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ABSALOM'S PERSONALITY. What were the characteristic of


Absalom's personality? The medical record, that is the biblical text,
tells us of an ambitious, prestigious, self-confident and proud young
man, seeking justice and revenge for a crime, a careful planner and
good organizer.

TO SUM UP: this section deals with penetrating heart injury.


Absalom, the son of King David, was assassinated for his rebellious
and unacceptable behavior. Absalom, similarly to the contemporary
victims was a young adult who suffered traumatic heart injury from
the three spears that were thrown at his heart. He did not die
instantly, and if appropriate measures were taken he would have had
a chance to survive. It is obvious that in Absalom's case, the
penetrating heart injury was not treated and his injury was fatal.
Even in contemporary times, penetrating heart injury is a common
condition with a high morbidity and mortality worldwide. In spite of
more sophisticated contemporary weapons, simple ancient weapons
such as spears are a powerful tool for killing humans.

FAMILY ASSESSMENT. Among the several theories of family


function that have been used to study the King's family system, the
Circumflex Model of Marital and Family System was chosen. Olson,
Sprenkle, and Russell (1) described what they called a circumflex
model for the assessment of families, and later published a
theoretical update of it. From an extensive review of the literature
they identified two aspects of family behavior, cohesion and
adaptability, which they believe are of fundamental importance (2).
Cohesion is a measure of the emotional bonding that family
members have toward one another. Family adaptability is a measure
of how the family permits change and how far it is characterized by
stability. The satisfactory functioning of a marital dyad, or a larger
family group, requires both an element of stability and the capacity
to change, and the two characteristics are balanced. Cohesion, also,
should fall somewhere in the middle ground, being neither too great
nor too little. These two dimensions are hypothesized to be related
curvilinearly to family health, that is, the extremes of cohesion –
termed enmeshment and disengagement – are theorized to be
unhealthy, while the middle range is thought to be healthy. The same
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is hypothesized for adaptability, with the extremes of the continuum,


being labeled as rigid and chaotic. The circumflex model posits 16
types of family functioning based on cohesion and adaptability
continua, and there are three levels of family functioning: balanced,
midrange, and extreme dysfunction, the latter being labeled as
chaotically disengaged or chaotically enmeshed, and rigidly
disengaged or rigidly enmeshed (2).
The King's family is described at a time when the family
boundaries were shifting to accommodate a new situation, the son,
Absalom, hated his father and rebelled against his leadership. This
extreme hatred disrupted emotional bonding and a peaceful
coexistence between the father and the son. In spite of these
extreme tension and stress, neither familial nor extrafamilial nor
other environmental resources were used to resolve the problems
between the King and his son, Absalom. All this led to disequilibrium.
The son hated his father extremely and decided to destroy him; this
shows that an abnormal defense mechanism was used to resolve a
severe crisis. At that time the family entered either a phase of
chaotically disengaged or chaotically enmeshed, or a phase of rigidly
disengaged or rigidly enmeshed. According to the circumflex model,
the family can be labeled as an extremely dysfunctional. David’s
family system failed to resolve a stressful situation, because of the
hatred that the King’s son Absalom developed towards his father.
Absalom opposed his father’s supremacy, and two alienated camps
developed, disrupting the homeostasis of this family. The family
found itself in crisis, without the resources to resolve it. Absalom
paid for his life in the struggle for leadership.

References
1. Olson, DH, Sprenkle DH, Russel C. Circumflex model of marital and
family systems: I. Cohesion and adaptability dimensions, family types and
clinical applications. Family Process. 1979;18:3-28.
2. Olson DH, Russel C, Sprenkle DH. Circumflex model of marital and
family systems: VI. Theoretical update. Family Process. 1983;22:69-83.

MOURNING FOR ABSALOM. Following his son’s death, King David


was very upset and wept bitterly “And the King was much moved,
and wept up to the chamber over the gate, and wept: ...O my son
Absalom, my son, my son Absalom! would I had died instead of
thee....And it was told to Joab, Behold the king weeps and mourns for
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Absalom. And the victory that day turned into mourning for all the
people...” (II Samuel 19:1-3).
These biblical verses indicate the great suffering of a human being
who has lost his son forever. In spite of Absalom's rebellion, the King
was attached to his beloved son. The grief was so painful that the
King wished to die instead of his beloved son.
Mourning characterized the grief of a person who has lost a loved
one forever. Mourning is not a disease; it is one of the most painful
facts of life. In fact, the more we are attached to someone, the more
we will suffer his or her losses. This is unavoidable. The grief
expressing our attachment is accompanied by immediate and intense
regression with repeated need for consolation. For some people, it
can be the means of coming to terms with their own mortality (1).
There are several stages of mourning: the living person's
ambivalence toward the deceased, the recollection corresponding to
the progressive acceptance of the loss, which represents the first
phase of the mourning process. During the healing phase, the
mourner is gradually capable of recalling the good times during the
life of the deceased and then progressively of evacuating the
souvenirs and starts living and opening to others again (1).
The biblical text gives no details about the stages of mourning that
King David and his family went through although it is likely that the
whole family passed through all these stages.
Stress is an environmental event, a process, and an outcome. One
approach defines stress in terms of life events, that is, as "stimulus".
Circumstances or events that require the person to adapt produce
feelings of tension. These "stressors" may be major catastrophic
events (a flood or earthquake), major life events (the death of a loved
one), or chronic hassles (managing a chronic medical condition) (2).
The death of beloved son acted as a severe negative stressor,
leading subsequently to a negative outcome. This negative stressor
caused the King negative feelings of despair, anxiety, and depressive
reaction.
The purpose of this study was to describe fathers' grief and the
changes the death of a child has brought to fathers' lives.
Participants included eight fathers who lost their child. The grief of
the father manifested itself individually and dynamically in various
anticipatory feelings and in physical, social, and behavioral reactions.
The death of the child brought both positive and negative changes to
the father's life (3).
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We see that the death of a beloved son led to physical, social and
behavioral reactions in the King. Did the death of his beloved son
bring changes to the King's life?
The human being needs ties to grow and develop. When some of
these ties are broken, a period of great intensity arises that we call
mourning. If the loss is radical and definitive, as in the case of death,
all of the person's dimensions are affected (the physical, emotional,
cognitive, behavioral, social, and spiritual) to such an extent that the
person can feel unable to overcome that and/or develops a
pathological mourning that requires intervention for recovery. Many
factors intervene in the type of mourning such as circumstances of
the death, relation to the deceased, personality, previous experience
and the socio-family context. For there to be complete recovery
following a loss, the person affected passes through a series of stages
or phases and must carry out basic tasks: 1]. Accept the reality of
loss. 2]. Express emotions and pain. 3]. Adapt to a setting from which
the loved one is absent. 4]. Emotionally resituate the deceased and
continue living (4).
All these parameters can be ascribed to King David who lost his
beloved son, Absalom, forever.
Absalom's sudden death was an unpleasant experience that the
King went through. Parents of boys or children who died suddenly
experienced despair, anger, guilt, and depersonalization (5). The
sudden, unexpected death of Absalom caused his father despair,
anger, guilt, and probably depersonalization. From a contemporary
view, David required professional psychiatric intervention.
Major stressful life events, particularly those that have chronic
hardships, create a crisis for families that often leads to disruption
the family's style of functioning (6). The death of two young
unmarried sons, Amnon and subsequently Absalom were stressful
negative life events causing the King's family severe hardships and
affecting the family functioning.

TO SUM UP: King David was exposed three times to the mourning
process. First, when his newborn son died, secondly, when Amnon,
his son was killed and the third time when his rebellious son,
Absalom, was killed. In the case of the newborn child, the King
mourned for the child who suffered from an incurable disease, but
recovered quickly after the child died. In the case of his two sons -
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Amnon, who paid with his life for a disgraceful affair with his half-
sister Tamar, and of Absalom, a rebellious son who decided to fight
against his father, similar grief reactions were observed.

References
1. Barbier D. Mourning. Presse Med. 2001;30:1668-71.
2. Ahmed SA, Lemkau JP. Psychosocial influences on health. In: Rakel RE
(ed.). Textbook of Family Practice. Sixth ed. Saunders, Philadelphia, London.
2002, pp. 43-51.
3. Aho AL, Tarkka MT, Astedt-Kurki P, Kaunonen M. Fathers' grief after
the death of a child. Issues Ment Health Nurs. 2006;27:647-63.
4. Carbodevilla I. Loss and mourning. An Sist Sanit Navar. 2007;30 Suppl
3:163-76.
5. Hazzard A, Weston J, Gutterres C. After a child's death: factors related
to parental bereavement. J Dev Behav Pediatr. 1992;13:24-30.
6. Patterson JM, Garwick W. Levels of meaning in family stress theory.
Family Process. 1994;33:287-394.

THE FATE OF CONCUBINES

The fate of concubines indicates a subsequent verse: “And David


came to his house at Jerusalem; and the king took the ten women his
concubines, whom he had left to keep the house, and put them under
guard and fed them, but went not in unto them. So they were shut up
to the day of their death, widows of a living husband” (II Samuel 20:
3).
A family is a small social system made up of individuals related to
each other because of strong reciprocal affections and loyalties, and
compromising a permanent household (or clusters of households)
that persists over years and decades. Members enter through birth,
adoption, or marriage, and leave only by death (1).
The King chose these ten women because of their affection, but
they lived enclosed in the same household until they died, so they
belonged to the same family system. The miserable women had only
one husband, the King, and they had no right to leave this system.
There are open and closed family systems. Closed systems are
those in which there is no interaction with the surrounding
environment, as in chemical or physical reaction in a closed
container. Such systems obey rules different from those obeyed by
open system. Closed systems, for instance show entropy, the
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tendency to reach the simplest, least ordered possible state from


whatever may be starting situation. Thus, if two gases, which do not
react chemically with each other, are introduced into a closed
container, the result will be diffuse complete mixing of the two. Once
this process is completed the system is in a state of equilibrium (2).
Open systems such as families, by contrast, do not show entropy.
Instead, there is a steady inflow and outflow of relevant material
across the boundary of the system. If the characteristics of the
boundary remain the same and the outside environment is
unchanged, a steady state is reached. The environment of most open
systems is, however, liable to change. There may also be alterations
in the characteristics of the boundary. These properties of open
systems make the change and evolution possible (2).
In addition, a family system is a set of individuals with
relationships between them. This system consists of a number of
subsystems, such as the parental coalition, the parent-child, or the
sibling relationships, which may be in the forms of dyads, triads, and
so on. In addition, a membrane, or boundary that may be open,
semi-permeable, or relatively closed and impermeable surrounds the
family, like any system (3).
King David’s family system consisted of a number of subsystems.
One of these subsystems included ten concubines belonging to the
King. This particular subsystem was surrounded by an impermeable
membrane or closed boundary, isolating it from the outside world.
The concubines lived in an isolated environment, depending entirely
on the King. It was the King, the ruler, the decision-making authority,
who was responsible for their fate. There was no right of dispute,
disagreement or contradiction to the King’s decision or other
arrangements for these women. Ten concubines obeyed the rules
coming from the ruler, the great King. The rules were permanent and
their fate was determined.
The King’s family created its own rules that governed the family as
a whole and the individual subsystems within the family. A decision-
making process, concentrated entirely in the King’s hands,
establishing the rules of behavior. The rules were very clear and
strict, with the King as the sole authority to administer the rules. The
interaction patterns within internal family system and its interactions
with the outside world depended on these defined rules. Nobody
had a voice to decide or participate in any decision making process.
The family system was rigid and inflexible.
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References
1. Berman EM. Adult Developmental stages and marital interaction.
Audio-Digest (Psychiatry). 1978;7:5.
2. Baker P. Some Basic theoretical concepts. In: Philip Barker Basic
Family Therapy. Second ed. Blackwell Scientific Publications. Oxford
London Edinburg. 1981, pp. 33-54.
3. Medalie JH, Kitson GC, Zyzanski SJ. A family epidemiological
model: a practice and research concept for family medicine. J Fam
Practice. 1981;12:78-87.

THE GIBEONITES
A subsequent story indicates a source of stress. There was a
famine in the days of David. King Saul was blamed for this famine
because he killed the Gibeonites, so King David asked the Gibeonites
to end this famine. The Gibeonites demanded that the King hand
over seven men to be hanged as vengeance for their killed people.
Because of his oath and friendship with Jonathan, King David spared
Jonathan’s son Mephibosheth. The King’s decision fell on two sons of
Saul’s concubine Rizpah, Armoni and Mephibosheth, and five sons of
Saul’s daughter Michal, the wife of Adriel, and son of Barzillai the
Meholathite. These seven men were taken to the Gibeonites and
were hanged (II Samuel 21:7-9).
Model of stress includes three conceptual domains: sources of
stress, mediators of stress, and outcomes of stress (1). The sources of
stress are conceptualized as physical or psychological demands on a
system (e.g., the body), which upset its normal steady state of
functioning. The mediators are primarily resources (physical,
psychological, or social) and coping behaviors that influence whether
or not stress is experienced, how it is managed; how long it lasts, and
whether or not it prevents or reduces the outcome. The outcomes
focus on changes in functioning of some level of the system, from the
organ to the family (2,3).
According to this model the famine following King Saul’s murder
of the Gibeonites, was the source of stress. The famine had a
negative impact on the people, making their physical and
psychological demands on them. The mediators included physical,
psychological, and social resources used by King David to end the
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famine. In order to resolve this stress, seven members of King Saul’s


family had to be sacrificed. David respected King Saul all his life in
spite of Saul’s wish to destroy him. Now was the moment of truth,
the moment for revenge. David decided to sacrifice two sons of one
of Saul’s concubines, and five sons of Michal, his former wife, who
was later given in marriage to Phalti. His vengeance overtook the
dead King Saul even in the grave. The act of revenge encompasses
physical, psychological and social aspects of human existence. The
results were obvious - revenge was achieved.
With regard to this story, there are some inconsistencies in the
Bible. Firstly, it is stated that “..Saul gave him (to David) Michal his
daughter to wife” (I Samuel 18: 27). Later, Michal, David’s wife, was
given to Phalti the son of Laish...” (25:44), while Michal’s sister Merab
was given in marriage to Adriel the Meholathite (18:19). We learn
that “And Michal the daughter of Saul had no child to the day of her
death” (II Saul 6:23). However, a subsequent verse states “… the king
took ...the five sons of Michal the daughter of Saul, whom she
brought up for Adriel the son of Barzillai the Meholathite” (21:8). In
spite of these inconsistencies, the story indicates that King David
sacrificed members of King Saul’s family in order to save the life of
others.

References
1. Patterson J. Families experiencing stress. I The Family adjustment
and adaptation response model. II Applying the FAAR Model to health-
related issues for intervention and research. Fam Systems Med.
1988;6:202-35.
2. Seley H. The stress of life. New York: McGraw-Hill, 1956.
3. Hill R. Generic features of families under stress. Social Casework.
1958;49:139-50.
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STRESSFUL LIFE EVENTS AND


SUBSEQUENT CRISES
This research deals with an evaluation of King David’s family life
cycle. This family was continuously exposed to stressful life events
and subsequent crises. Crises occurring in a family are normative or
non-normative. Normative crises are expected events within the
normal life of the family, while non-normative crises are unexpected
life events. These crises are be divided into four categories: 1]
additions, e.g., birth or marriage (normative) or unexplained
pregnancy (non-normative); 2] abandonment, e.g., death of elderly
member of family, minor illness (normative), or family member being
involved in war, or divorce or the sudden death of a family member
(non-normative); 3] demoralization, e.g., rebellion against social
norms (normative) or alcoholism, delinquency, or jail (non-
normative); 4] status change, e.g., moving to another community,
starting a new stage in life, change in role (normative) or physical or
emotional handicap, loss of freedom, or loss of income (non-
normative) (1). Holmes and Rahe (2) calculated the social
readjustment value for each life event. For, example, the
readjustment value for death of a spouse receives a score of 100,
divorce - 73, marital separation - 63.
David’s victory over Goliath was the first normative crisis. This
victory made him very popular among his people. A subsequent
crisis occurred when King Saul promised David his daughter Merab in
marriage and then broke his promise by giving Merab to Adriel the
Meholathite. Here, David was exposed to a non-normative crisis.
Later, a normative crisis followed when David married Michal. On
the Holmes-Rahe scale, marriage receives a score of 50 and can be
regarded as a positive normative stressful life event. An expansion of
the family, with a birth of a new child receives a score of 39. Thus,
each time a child was born, the King experienced a positive stressful
event.
A normative crisis also followed when David’s status was changed
and he was anointed as King over the house of Judah, and then again
when he was crowned King over Israel. From this time onwards, King
David belonged to a high socioeconomic stratum. David, the great
King of Israel, ruled all the country. The fate of his country and his
family was legally placed in his hands.
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His sexual relations with Batsbeva, however, created a severe


non-normative crisis. As David exploited his royal status with
deception and lies, culminating in the plot to destroy Uriah.
Jonathan’s death can be considered a negative stressful life event.
Since David and Jonathan were such close friends, the loss of
Jonathan should receive the maximum points - 100, on the scale
described above (2). Similarly, the discovery and adoption of
Mefivoshet, Jonathan’s son, can be regarded as a positive stressful
life event. The entry of a new family member, receives a score of 39.
The incurable illness of a newborn son was a significant source of
stress, although the King recovered and returned to everyday life
quickly. The death of Amnon and later of Absalom caused the King
significant suffering.
The story of the Gibeonites reveals an additional negative source
of non-normative stress. The King sacrificed seven men, in order to
end a dreadful famine. His decision fell on these innocent men as a
means of saving the lives of the many others.
The King was the sole leader of his society, both within his internal
family system, as well as in the external world. As the King and the
head of his family, he had the power to decide all intrafamilial and
extrafamilial problems. In this rigid system, there was no place for
confrontation or objections to the King’s will. His decisions had to be
accepted without hesitation and his family had to adjust to such
norms of life in order to survive.
Once again, David’s family was exposed to another stressful event
“Then Adonijah the son of Haggith exalted himself, saying, I will be
king: and he prepared him chariots and horsemen, and fifty men to
run before them” (I Kings 1:5). However, King David said nothing to
his son, Adonijah. Then Bathsheba, Solomon’s mother, intervened
reminding the King that he had promised that Solomon would reign
after him. So King David anointed Solomon to be the King after him
“...Solomon thy son shall reign after me, and he shall sit upon my
throne in my stead;...I have appointed him to be ruler over Israel and
over Judah” (1:30,35).
We see that two brothers struggled for the position of King. The
appointment of Solomon imposed stressful life events on the two
brothers and a poisonous atmosphere developed between them.
Eventually, Adonijah lost the crown.
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References
1. Smilkstein G. The family in crisis. In: Taylor R (ed.). Family
Medicine-Principles and Practices. Springer Verlag. New York. 1978, pp.
235-324.
2. Holmes TH, Rahe RH. The social readjustment rating scale. J
Psychosom Res. 1967;11:213.

SUMMARY OF FAMILY LIFE CYCLE


David was the second and greatest of Israel’s Kings, a true warrior
as well as a husband and father. King David's father was Jesse, who
was the son of Obed, the son of Ruth and Boaz. It follows, that King
David was a descendant of Ruth and Boaz' family.
David was born in Bet-lehem-judah, grew up in a family of eight
sons, and was the youngest son of Jesse. As a youth, David was
ruddy, good-looking, and strong. Jesse's three eldest sons were
soldiers in King Saul's army. David joined Saul's army, killed Goliath, a
terrifying giant from the area of Gat, and subsequently defeated the
Philistines. After this battle, King Saul began to hate David. The roots
of this hatred were associated with the fact that the people believed
that "..Saul hath slain his thousands, and David his ten thousands
(Philistines)". (I Samuel 18:7).
King Saul decided to give his elder daughter Merab in marriage to
David. However, Merab was given to Adriel the Meholathite.
Meanwhile, the younger daughter Michal fell in love with David.
Subsequently, “..Saul gave him Michal his daughter to wife” (18:17).
With this marriage a new family was born.
David fought the Philistines and defeated them in another battle.
This victory had a negative impact on the King's mental state. King
Saul pursued David throughout his life in order to kill him. In the end,
David had an opportunity to kill Saul, but he did not do it. Therefore,
King Saul appointed David to succeed him as King.
Subsequently, David met a beautiful woman, Abigail whose
husband, Nabal, was a very wicked and sinful man. When Nabal died,
David took Abigail to be his wife. Later: “David also took Ahinoam of
Jezreel...”. (I Samuel 25:43). Now David had three wives, but the
family size was reduced when King Saul took Michal and gave her to
Phalti.
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After Saul’s death, David and his two wives dwelt in Hebron.
David’s family entered a new phase of its life cycle when David was
anointed as King over Judah and subsequently over Israel. At this
time, David became King, and his family started a new cycle of life.
The King also had ten concubines, locked in his house in
Jerusalem, until they died. The concubines lived in an isolated
environment, depending entirely on the King. It was the King, the
ruler, the decision-making authority, who was responsible for their
fate. There was no right of dispute, disagreement or contradiction to
the King’s decision or other arrangements for these women.
Throughout his life, David was involved in endless wars against the
Philistines. He was a real warrior and fought bravely with the enemy.
He won many wars, and many Philistines were taken prisoners. He
also conquered Moab, Hadadezer, the son of Rehob, the King of
Zobah, and the Syrians of Damascus. King David’s family was
consolidated and the sons helped their father to rule the country.
David’s polygamous family, consisting of many wives and children,
changed constantly. Feelings of tension, admiration, love and hatred
characterized the internal family system. A special friendship
developed between David and Jonathan, the son of King Saul. When
Saul and his three sons, among them Jonathan, were killed, King
David found Mefivoshet, Jonathan’s son, and treated him as his own
son.
David behaved disgracefully in his sexual relations with Bathsheba
that led to her pregnancy. In order to hide his reckless action, King
David prepared a plan to destroy Uriah, Bathsheba's husband. Uriah,
a brave soldier, was sent to a fierce battle where he was killed. Uriah
was assassinated in order to hide the King’s disgraceful behavior.
When Bathsheba heard that Uriah was dead, she mourned for her
husband. In this story, we also see Bathsheba's infidelity. King David
and Bathsheba behaved immorally and both were at risk of
contracting some STD.
When the days of mourning were over King David married
beautiful Bathsheba. David’s family again expanded. Two additional
members entered David’s family life cycle: Bathsheba and a newborn
son. Unfortunately, an incurable disease afflicted the newborn son.
The King was severely distressed; he did not sleep and did not eat.
On the seventh day, his newborn son died. After hearing this sad
news, the King washed, changed his clothes, and ate. The King
believed that if his son died, he the great King could not change the
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rules of this world, he could not bring his child to life, so he had lost
his child forever.
In other story, right at the beginning, it is written that Amnon,
King David’s son, became “..so lean, from day to day” An extensive
evaluation of the medical situation that caused Amnon to be lean
showed that there are insufficient data for a diagnosis of anorexia
nervosa. It most likely that Amnon suffered from a partial eating
disorder syndrome.
Later, Amnon sexually abused his sister Tamar. Tamar suffered
from PTSD, and/or low self-esteem, and/or anxiety, fear, depression
and anger. Because of Amnon’s disgusting behavior, hatred
developed between two brothers - Amnon and Absalom, and the
family atmosphere was poisoned. No compromise could be found in
the triangle: Amnon - Absalom - Tamar.
Absalom, Amnon’s brother, did not forgive his brother for this sin.
At the first opportunity, Absalom commanded his men to kill Amnon
and the mission was performed. The King mourned for his son
Amnon.
Absalom rebelled against his father, King David. By this behavior,
Absalom showed his extreme hatred towards his father. Fighting
broke out between the camps of Absalom and King David, and
Absalom was killed. Absalom death affected the King profoundly and
he mourned for his son.
There was a famine in the days of David. King Saul was blamed for
this famine because he killed the Gibeonites, so King David asked the
Gibeonites to end this famine. The Gibeonites demanded that the
King hand over seven men to be hanged as vengeance for their killed
people. The King’s decision fell on two sons of Saul’s concubine
Rizpah, Armoni and Mephibosheth, and five sons of Saul’s daughter
Michal, the wife of Adriel, and son of Barzillai the Meholathite. These
seven men were taken to the Gibeonites, and were hanged.
The famine following King Saul’s murder of the Gibeonites was the
source of stress. The famine had a negative impact on the people,
making their physical and psychological demands on them. The
mediators included physical, psychological, and social resources used
by King David to end the famine. In order to resolve this stress, seven
members of King Saul’s family had to be sacrificed. David respected
King Saul all his life in spite of Saul’s wish to destroy him. Now was
the decisive moment, the moment for revenge. His vengeance
overtook the dead King Saul even in the grave. The act of revenge
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L. Ben-Nun King David

encompasses physical, psychological and social aspects of human


existence.
Hatred once again developed between two of the King’s sons,
Adonijah and Solomon, since King David anointed Solomon to
succeed him as King.
In the end, King David was an old, sick man suffering from multiple
diseases and affected by various psychosocial problems. King David
died in old age, and was buried in the city of David.
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L. Ben-Nun King David

THE DISEASES THAT AFFLICTED KING


DAVID
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THE OLD KING


Eventually the King grew old “Now king David was old, advanced
in years..” (I Kings 1:1), afflicted by various diseases and suffering
from various psychosocial problems (1,2).
In the end King David was sick suffering from multiple diseases:
"Now King David was old and stricken in years" (I Kings 1:1) and
“Now the days of David drew near that he should die., And the days
that David reigned over Israel were forty years: seven years he
reigned in Hebron, and thirty three years he reigned in Jerusalem”
(2:1,11). So “..he died in a good old age, full of days, riches, and
honor: and Solomon his son reigned in his stead” (I Chronicles 29:28).
In the end, “So David slept with his fathers and was buried in the city
of David” (I Kings 2:10).

References
1. Ben-Noun L. In: Ben-Noun L. (ed.). The Diseases and Psychosocial
Problems that Affected King David. (In Hebrew). Israel. 2003.
2. Ben-Nun L. In: Ben-Nun L (ed.). The Family Life Cycle and the Medical
Record of King David the Great. B.N. Publication House. Israel. 2009.

EYE DISEASES
The impact of visual loss has profound implications for the person
affected and society as a whole (1) with self-reported VI as an
independent factor associated with mortality (2).
The majority of blind people live in developing countries, and
generally, their blindness could have been avoided or cured. Given
the current predictions that the number of blind people worldwide
will roughly double by the year 2020, there is no room for
complacency. As the world's population increases and a greater
proportion survives into late adulthood, the number of people with
visual loss will inexorably rise. As the longevity of the world's
population increases, the visual requirements at the workplace are
also changing. People with low vision may be at a disadvantage in
many common activities, and may face unemployment – particularly
in technological societies (1).
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L. Ben-Nun King David

Efforts should be made to recognize and treat those affected at an


early stage, for the benefit of the individual and society (1).
Physicians must be aware of the physical limitations and social issues
associated with vision loss to optimize health and independent living
for the visually impaired patient (3).
Global blindness exacts an enormous financial and social cost on
developing countries. Reducing the prevalence of blindness globally
requires a set of strategies that are different from those typically
used in developed countries. This was the subject of the 2013 Knapp
symposium at the American Ophthalmological Society Annual
Meeting. This article explores a range of successful strategies from
the multinational Vision 2020 Initiative to disease-specific schemes in
cataract, trachoma control, infectious corneal ulceration, CMV
retinitis, and retinopathy of prematurity. In each example, the
importance of an attitudinal change set toward public health
becomes clear. There is reason for optimism in the struggle against
global blindness in large measure because of innovative programs
such as those described here (4).
VI and blindness either unilateral or bilateral are prevalent
conditions worldwide. In the elderly, the most common causes of
vision loss are AMD, cataract, glaucoma, optic atrophy, diabetic
retinopathy, and RE (5-9). The prevalence of these conditions
increases with age and vary in different populations.
My previous research indicates that vision problems in the elderly
have existed for thousands of years. Isaac (the second of the three
biblical Patriarchs of the Jewish people), Jacob (the third of the
Patriarchs later called Israel), and Eli (the priest who judged Israel for
forty years) all suffered from a gradual VI (10).
Today’s elderly patients, like ancient patients, may suffer from VI
and blindness. It is a challenge for present-day physicians to properly
diagnose and provide appropriate treatment for these patients. In
order to widen the horizon of our knowledge, it is important that
contemporary physicians be familiar with the available literature on
various visual disorders. Studying the causes of VI and blindness
among the elderly in ancient texts may help them to handle these
painful situations more efficiently.
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L. Ben-Nun King David

References
1. West S, Sommer A. Prevention of blindness and priorities for the
future. Bull World Health Organ. 2001;79:244-8.
2. Berdaux G, Brézin AP, Fagnani F, et al. Self-reported visual impairment
and mortality: a French nationwide perspective. Ophthalmic Epidemiol.
2007;14:80-7.
3. Rosenberg EA, Sperazza LC. The visually impaired patient. Am Fam
Physician. 2008;77:1431-6.
4. Sommer A, Taylor HR, Ravilla TD, et al. Challenges of ophthalmic care
in the developing world. JAMA Ophthalmol. 2014;132(5):640-4.
5. Rohrschneider K, Greim S. Epidemiology of blindness in Baden,
Germany. Klin Monatsbl Augenheilkd. 2004;221:116-21.
6. Hiratsuka Y, Ono K, Kanai A. The present state of blindness in the
world. Nippon Ganka Zasshi. 2001;105:369-73.
7. Evans JR, Fletcher AE, Wormald RPL. Causes of visual impairment in
people aged 75 years and older in Britain: an add-on study to the MRC trial
of assessment and management of older people in the community. Br J
Ophthalmology. 2004;88:365-11.
8. Quillen DA. Common causes of vision loss in elderly patients. Am Fam
Physician. 1999;60:99-108.
9. Causes and prevalence of visual impairment among adults in the
United States. The eye diseases prevalence research group. Arch
Ophtalmol. 2004;122:477-85.
10. Ben-Noun L. What was the disease of the legs that afflicted King Asa?
Gerontology. 2001;47:96-9.

THE BIBLICAL DESCRIPTION. King David, the second and greatest


of Israel’s Kings who ruled the country more than 3537 years ago,
was about 70 years old at the end of his reign. When the King
reached old age he suffered from some type of visual disorder as
indicated by the subsequent passages “My eye is consumed…” (Psalm
6:8; 31:10) and “As for the light of my eyes, it is also gone from me”
(38:11). Severe VI is categorized as blindness or poor vision (1).
Since the King could not see even light, it follows that he was blind.
What was the cause(s) of the blindness that afflicted the old King
David, a member of the highest socioeconomic stratum? This
research aims to answer these questions by evaluating this patient’s
medical record, which is the biblical text.
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L. Ben-Nun King David

Reference
1. Fotouhi A, Hashemi H, Mohammad K, Jalali KH; Tehran Eye Study. The
prevalence and causes of visual impairment in Tehran: the Tehran eye study.
Brit J Ophthalmology. 2004;88:740-5.

EPIDEMIOLOGY OF BLINDNESS
There are over 300 million people living in the world today who
are visually impaired and a further 45 million who are blind. The large
majority (90%) of these people lives in developing countries, and up
to 75% of blindness are avoidable. With cataracts being the major
cause of blindness and VI, many ophthalmic aid programs are aimed
at alleviating the enormous burden caused by this readily treatable
disease. Having said that, caution should be exercised that short
surgical visits to remote rural areas that are not coordinated with
local national eye care managers should be discouraged because they
do little for the development of sustainable eye care programs. With
this in view, it has become imperative to design blindness prevention
and ophthalmic support programs that are workable, comprehensive,
economical and sustainable (1).
Of the 38 million people who are blind worldwide, 22 million are
over the age of 60 years (WHO Estimate) (2). Poor vision and
blindness increase significantly with age for all races and ethnicities
(3-5). These data, combined with life expectancy that is on the
increase (6), indicate that it is essential to provide effective
ophthalmologic care for the elderly.
From the most recent data, the magnitude of VI and its causes in
2010 have been estimated, globally and by WHO region. The
definitions of VI are the current definitions of presenting vision in the
ICD version 10. A systematic review was conducted of published and
unpublished surveys from 2000 to the present. For countries without
data on VI, estimates were based on newly developed imputation
methods that took into account country economic status as proxy.
Surveys from 39 countries satisfied the inclusion criteria for this
study. Globally, the number of people of all ages visually impaired is
estimated at 285 million, of whom 39 million are blind, with
uncertainties of 10-20%. People 50 years and older represent 65%
and 82% of visually impaired and blind, respectively. The major
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L. Ben-Nun King David

causes of VI are UREs (43%) followed by cataract (33%); the first


cause of blindness is cataract (51%). In conclusion, VI in 2010 was a
major health issue that is unequally distributed among the WHO
regions; the preventable causes are as high as 80% of the total global
burden (7).
VI is a leading and largely preventable cause of disability
worldwide. This systematic review estimated the prevalence of VI
and its changes worldwide for the past 20 years. A systematic review
included published and unpublished population-based data on VI and
blindness from 1980 through 2012. Hierarchical models were fitted
to estimate the prevalence of MSVI, defined as presenting VA <6/18
but ≥3/60) and the prevalence of blindness (PVA <3/60) by age,
country, and year. Main outcome measures included trends in the
prevalence of MSVI and blindness for the period 1990 through 2010.
Globally, 32.4 million people (95% CI 29.4-36.5 million people; 60%
women) were blind in 2010, and 191 million people (95% CI 174-230
million people; 57% women) had MSVI. The age-standardized
prevalence of blindness in older adults (≥50 years) was more than 4%
in Western Sub-Saharan Africa (6.0%, 95% CI 4.6%-7.1%), Eastern
Sub-Saharan Africa (5.7%, 95% CI 4.4%-6.9%), South Asia (4.4%, 95%
CI 3.5%-5.1%), and North Africa and the Middle East (4.6%, 95% CI
3.5%-5.8%), in contrast to high-income regions with blindness
prevalences of ≤0.4% or less. The MSVI prevalence in older adults
was highest in South Asia (23.6%, 95% CI 19.4%-29.4%), Oceania
(18.9%, 95% CI 11.8%-23.7%), and Eastern and Western Sub-Saharan
Africa and North Africa and the Middle East (95% CI 15.9%-16.8%).
The MSVI prevalence was less than 5% in all four high-income
regions. The global age-standardized prevalence of blindness and
MSVI for older adults decreased from 3.0% (95% CI 2.7%-3.4%)
worldwide in 1990 to 1.9% (95% CI 1.7%-2.2%) in 2010 and from
14.3% (95% CI 12.1%-16.2%) worldwide to 10.4% (95% CI 9.5%-
12.3%), respectively. When controlling for age, women's prevalence
of blindness was greater than men's in all world regions. Because the
global population has increased and aged between 1990 and 2010,
the number of blind has increased by 0.6 million people (95% CI-5.2-
5.3 million people). The number with MSVI may have increased by 19
million people (95% CI -8-72 million people) from 172 million people
(95% CI 142-198 million people) in 1990. In conclusion, the age-
standardized prevalence of blindness and MSVI has decreased in the
past 20 years. However, because of population growth and the
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L. Ben-Nun King David

relative increase in older adults, the blind population has been stable
and the population with MSVI may have increased (8).
Cataract remains the major cause of blindness, especially in the
less developed countries, while AMD in developed countries.
Substantial improvements have been achieved in the control of
blinding diseases, mainly in respect of onchocerciasis and
xerophthalmia. The WHO alliance for the eradicating of trachoma by
the year 2020 has been set up (9). The age-related eye diseases will
rapidly become the most common causes of blindness and visual loss
and, with the exception of cataract, are the more difficult to identify,
diagnose, and treat (10).
The objective of this study was to estimate the economic burden
of vision loss and eye disorders in the US population younger than 40
years in 2012. Participants included the US population younger than
40 years in 2012. Costs based on consensus guidelines were
categorized. Medical costs attributable to diagnosed eye-related
disorders, undiagnosed vision loss, and medical vision aids using
Medical Expenditure Panel Survey and MarketScan data were
estimated. The prevalence of VI and blindness were estimated using
National Health and Nutrition Examination Survey data. Costs from
lost productivity using Survey of Income and Program Participation
were estimated. Costs of informal care, low vision aids, special
education, school screening, government spending, and transfer
payments based on published estimates and federal budgets were
estimated. QALYs lost based on published utility values were
estimated. Man outcome measures included costs and QALYs lost in
2012. The economic burden of vision loss and eye disorders among
the US population younger than 40 years was $27.5 billion in 2012
(95% CI $21.5-$37.2 billion), including $5.9 billion for children and
$21.6 billion for adults 18 to 39 years of age. Direct costs were $14.5
billion, including $7.3 billion in medical costs for diagnosed disorders,
$4.9 billion in refraction correction, $0.5 billion in medical costs for
undiagnosed vision loss, and $1.8 billion in other direct costs. Indirect
costs were $13 billion, primarily because of $12.2 billion in
productivity losses. In addition, vision loss cost society 215,000
QALYs. In conclusion, a substantial burden resulted from vision loss
and eye disorders in the US population younger than 40 years, a
population excluded from previous studies. Monetizing QOL losses at
$50,000 per QALY would add $10.8 billion in additional costs,
indicating a total economic burden of $38.2 billion. Relative to
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previously reported estimates for the population 40 years of age and


older, more than one third of the total cost of vision loss and eye
disorders may be incurred by persons younger than 40 years (11).
In Canada, VI in the elderly is common and is associated with
increased odds of institutionalization, frequent falls, difficulty with
everyday practices, and poor health (12).
Diabetic retinopathy screening aims to detect people at risk of
visual loss due to proliferative diabetic retinopathy, but also refers
cases of suspected macular edema (maculopathy). At the
introduction of screening, ophthalmology was concerned that
referral rates would be unmanageable. Referable disease by referral
reason for the first five years of the program in the Scottish National
Diabetic Retinopathy Screening Program Is reported. Screening
results from a nationwide clinical diabetes database were extracted
to calculate annual referral rates to ophthalmic clinics. A total of
182,397 people underwent ≥1 successful retinal screening between
2006 and 2010. The yield of referable eye disease was highest in the
first two years of screening (7.0% and 6.0%) before stabilizing at
∼4.3%. The majority of referrals were due to maculopathy with 73%
of referrals in 2010 based on a finding of maculopathy. In conclusion,
the commonest cause for referral is for suspected macular edema
(maculopathy). Referral rates for retinopathy have stabilized, as
predicted, at relatively low rates. However, ophthalmology workload
continues to rise as new treatment options (i.e., monthly intraocular
injections) have unexpectedly increased the impact on
ophthalmology. A review of the screening referral path for
maculopathy may be timely (13).
The main aim of this study was to assess prevalence and causes of
blindness and VI in high-income regions and in Central/Eastern
Europe in 1990 and 2010. Based on a systematic review of medical
literature (MSVI; PVA <6/18 but ≥3/60 in the better eye) and
blindness (PVA <3/60) was estimated for 1990 and 2010. Age-
standardized prevalence of blindness and MSVI decreased from 0.2%
to 0.1% (3.314 million to 2.736 million people) and from 1.6% to 1.0%
(25.362 million to 22.176 million), respectively. Women were
generally more affected than men. Cataract was the most frequent
cause of blindness in all subregions in 1990, but macular
degeneration and URE became the most frequent causes of blindness
in 2010 in all high-income countries, except for Eastern/Central
Europe, where cataract remained the leading cause. Glaucoma and
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diabetic retinopathy were fourth and fifth most common causes for
blindness for all regions at both times. URE, followed by cataract,
macular degeneration, glaucoma and diabetic retinopathy were the
most common cause for MSVI in 1990 and 2010. In conclusion, in
highly developed countries, prevalence of blindness and MSVI has
been reduced by 50% and 38%, respectively, and the number of blind
people and people with MSVI decreased by 17.4% and 12.6%,
respectively, even with the increasing number of older people in the
population. In high-income countries, macular degeneration has
become the most important cause of blindness, but UREs continue to
be the leading cause of MSVI (14).
The main aim of this study was to determine the prevalence,
causes, and risk factors for blindness and VI in the elderly population
of Lebanese nursing homes, to encourage the development of an
effective campaign against blindness. Transversal study was
conducted in all nursing homes in two Lebanese regions (298
residents). All respondents (89.6%) underwent a complete ocular
examination. Personal and medical data were gathered for each
participant. The prevalence of blindness (VA ≤20/200 in both eyes)
was 22.4% (20.3% in residents aged between 80 and 89 years old,
42.9% in patients 90 years or older). The prevalence of VI (VA ≤20/40
and>20/200 in the best eye) was 36%. The rate of blindness in
underprivileged residents was found to be double than that of the
well-off residents (27% and 15%, respectively). Cataract was the
leading cause of blindness, followed by AMD and OAG. At least 55%
of the causes of blindness and 58% of the causes of VI were
potentially curable or avoidable. In conclusion, blindness and VI were
high among Lebanese nursing home residents. This is an observation
given that the leading ocular diseases are treatable and that good
vision is essential to these residents' QOL (15).
The main aim of this study was to estimate the magnitude,
temporal trends and subregional variation in the prevalence of
blindness, and MSVI in sub-Saharan Africa. A systematic review was
conducted of published and unpublished population-based surveys as
part of the Global Burden of Disease, Risk Factors and Injuries Study
2010. The prevalence of blindness and VI by country and subregion
was estimated. In sub-Saharan Africa, 52 studies satisfied the
inclusion criteria. The estimated age-standardized prevalence of
blindness decreased by 32% from 1.9% (95% CI 1.5%-2.2%) in 1990 to
1.3% (95% CI 1.1%-1.5%) in 2010 and MSVI by 25% from 5.3% (95% CI
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0.2%-0.3%) to 4.0% (95% CI 0.2%-0.3%) over that time. However,


there was a 16% increase in the absolute numbers with blindness and
a 28% increase in those with MSVI. The major causes of blindness in
2010 were: cataract 35%, other/unidentified causes 33.1%, RE 13.2%,
macular degeneration 6.3%, trachoma 5.2%, glaucoma 4.4% and
diabetic retinopathy 2.8%. In 2010, age-standardized prevalence of
MSVI in Africa was 3.8% (95% CI 3.1% to 4.7%) for men and 4.2%
(95% CI 3.6%-5.3%) for women, with subregional variations from
4.1% (95% CI 3.3%-5.4%) in West Africa to 2.0% (95% CI 1.5%-3.3%) in
southern Africa for men; and 4.7% (95% CI 3.9%-6.0%) in West Africa
to 2.3% (95% CI 1.7%-3.8%) in southern Africa for women. In
conclusion, the age-standardized prevalence of blindness and MSVI
decreased substantially from 1990 to 2010, although there was a
moderate increase in the absolute numbers with blindness or MSVI.
Significant subregional and gender disparities exist (16).
The main aim of this study was to describe the prevalence and
causes of VI and blindness in North Africa and the Middle East in
1990 and 2010. Based on a systematic review of medical literature,
prevalence and causes of MSVI; PVA <6/18 and ≥3/60) and blindness
(PVA <3/60) were examined. The age-standardized prevalence of
blindness decreased from 2.1% to 1.1% and MSVI from 7.1% to 4.5%.
In 2010, 3.119 million people were blind, and 13.700 million had
MSVI. Women were generally more often affected than men. Main
causes of blindness were cataract, URE, macular degeneration and
glaucoma. Main causes of MSVI were cataract and UREs. Proportions
of blindness and MSVI from trachoma significantly decreased. In
conclusion, although the absolute numbers of people with blindness
and MSVI increased from 1990 to 2010, the overall age-standardized
prevalence of blindness and MSVI among all ages and among those
aged 50 years and older decreased significantly (p<0.05). Cataract
and URE were the major causes of blindness and MSVI (17).
The aim of this study was to examine the prevalence, patterns and
trends of VI and its causes from 1990 to 2010 in Central and South
Asia. Based on the Global Burden of Diseases Study 2010 and ongoing
literature searches, prevalence and causes of MSVI were examined;
PVA <6/18, ≥3/60) and blindness (PVA <3/60). In Central Asia, the
estimated age-standardized prevalence of blindness decreased from
0.4% (95% CI 0.3%-0.6%) to 0.2% (95% CI 0.2%-0.3%) and of MSVI
from 3.0% (95% CI 1.9%-4.7%) to 1.9% (95% CI 1.2%-3.2%); in South
Asia blindness decreased from 1.7% (95% CI 1.4%-2.1%) to 1.1% (95%
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CI 0.9%-1.3%) and MSVI from 8.9% (95% CI 6.9%-10.9%) to 6.4% (95%


CI 5.2%-8.2%). In 2010, 135,000 (95% CI 99,000-194,000) people
were blind in Central Asia and 10,600,000 (95% CI 8,397,000-
12,500,000) people in South Asia. MSVI was present in 1,178,000
(95% CI 772,000-2,243,000) people in the Central Asia, and in
71,600,000 (95% CI 57,600,000-92,600,000) people in South Asia.
Women were generally more affected than men. The leading causes
of blindness (cataract) and MSVI (URE) did not change from 1990 to
2010. In conclusion, the prevalence of blindness and MSVI in South
Asia is still three times higher than in Central Asia and globally, with
women generally more often affected than men. In both regions,
cataract and URE were major causes of blindness and MSVI (18).
The objective of this study was to assess prevalence and causes of
VI in Southeast Asia and Oceania in 1990 and 2010. Based on a
systematic review of medical literature, prevalence of MSVI; PVA
<6/18 but ≥3/60 in the better eye and blindness - PVA <3/60) was
estimated for 1990 and 2010. In Oceania, the age-standardized
prevalence of blindness and MSVI decreased insignificantly (1.3% to
0.8% and 6.6% to 5.1%) respectively, but in Southeast Asia, blindness
decreased significantly from 1.4% to 0.8%, a 43% decrease. There
were significantly more women blind (2.18 million) compared with
men (1.28 million) in the Southeast Asian population in 2010, but
insignificant gender differences in MSVI in either subregion. Cataract
was the most frequent cause of blindness in Southeast Asia and
Oceania in 1990 and 2010. URE, followed by cataract, macular
degeneration, glaucoma and diabetic retinopathy were the most
common causes for MSVI in 1990 and 2010. With the increasing size
of the older population, there have been relatively small increases in
the number of blind (2%), and with MSVI (14%) in Southeast Asia,
whereas increases have been greater in Oceania of 14% for blindness
and of 31% for MSVI. In conclusion, the prevalence of blindness has
reduced significantly from 1990 to 2010, with moderate but non-
significant lowering of MSVI. Cataract and URE are the main causes of
VI and blindness; cataract continues as the main cause of blindness,
but at lower proportions (19).
Asians from the Indian Subcontinent form the largest ethnic
minority in the United Kingdom. Data on the prevalence of visually-
impairing eye conditions in this population are vital for planning eye
health care services. This survey was based in the two London boroughs
with the largest Asian populations. Subjects originating from the Indian
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Subcontinent were identified from GP practice records. All subjects


were asked about demographic details and were given a full
ophthalmological examination. The severity of cataract, glaucoma,
diabetic retinopathy, and AMD was recorded. Blindness was defined as
logMAR visual acuity of 0.99 (Snellen equivalence 20/200 in the better
eye) or worse, 'low vision' was defined as Snellen equivalence of 20/63
or worse (logMAR 0.5 or higher), and VI was defined as VA worse than
20/40. The median age was 56 years; 284 subjects did not attend for
eye examination. Of the 922 examined, 128 subjects (13.9%) were
'visually impaired,' 39 (4.2%) had 'low vision,' and 6 (0.7%) were
bilaterally blind. The overall prevalence of cataract, OAG, AMD, and
diabetic retinopathy were 77%, 1.0%, 8.7%, and 8.8%, respectively. In
conclusion, VI rates amongst Asians seem to be similar to Caucasian
populations in the UK. The prevalence of cataract and diabetic
retinopathy is higher. In view of the high cataract prevalence, a more
detailed assessment of the visual profile and factors limiting healthcare
accessibility in this community are needed (20).
In Brazil, Säo Paulo, (802 individuals, 60 years and older) the
prevalence of presented and BCVA worse than 20/400 in both eyes
was 1.38% (95% CI 0.69-2.45) and 1.25% (95% CI 0.60-2.29). Cataract
was the main cause of blindness - 30.0%, while VI - 54.9% (21).
The objective of this study was to assess the prevalence of blindness
and VI, their associated causes and underlying risk factors in three tribal
areas of Andhra Pradesh, India and compare this data in conjunction
with data from other countries with low and middle-income settings.
Using a validated Rapid Assessment of Avoidable Blindness
methodology, a two stage sampling survey was performed in these
areas involving probability proportionate to size sampling and compact
segment sampling methods. Blindness, VI and SVI were defined as per
the WHO guidelines and Indian definitions. Based on a prior
enumeration, 7,281 (97.1%) subjects were enrolled (mean age, 61.0+/-
7.9 years). Based on the PVA, the prevalences of VI, SVI and blindness
were 16.9% (95% CI 15.7-18.1), 2.9% (95% CI 2.5-3.4), and 2.3% (95% CI
1.9-2.7), respectively. When based on the PCVA, the prevalences were
lower in VI (6.2%, 95% CI 5.4-6.9), SVI (1.5%, 95% CI 1.2-1.9), and
blindness (2.1%, 95% CI 1.7-2.5). RE was the major cause of VI (71.4%),
whereas, cataract was the major cause of SVI and blindness (70.3%).
Based on the PVA, the OR of blindness increased in the individuals aged
60-69 years (OR = 3.8, 95% CI 2.8-5.1), 70-79 years (OR = 10.6, 95% CI
7.2-15.5) and ≥80 years (OR = 30.7, 95% CI 19.2-49). The ORs were
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relatively higher in females (OR = 1.3, 95% CI 1.0-1.6) and illiterate


subjects (OR   4.3, 95% CI 2.2-8.5), but lower in those wearing glasses
(OR   0.2, 95% CI 0.1-0.4). In conclusion, this study assessed the
prevalence of blindness and VI in tribal regions and the majority of the
causes of blindness and SVI were avoidable (88.5%) (22).
In Malay, Australia, in the population-weighted (n=3,280) the
prevalence of bilateral blindness was 0.3% and 4.4% of bilateral low
vision. Cataract was the main cause of unilateral (38.9%) and bilateral
(65.2%) blindness, whereas URE was the main cause of unilateral
(68.5%) and bilateral (52.2%) low vision. Diabetic retinopathy, AMD,
and glaucoma were the other leading causes of blindness and low
vision (23).
In Pakistan, a nationally representative sample of 16.507 adults aged
≥30 years (95.3% responsive rate) was studied. Blindness was
associated with poverty; lower access to eye care services was one
contributory factor (24). Cataract still accounts for over half of the
cases of blindness followed by corneal opacity, uncorrected aphakia
and glaucoma (25).
The purpose of this study was to determined the causes and five-
year incidence of blindness and VI in an adult, urban Chinese
population. Participants underwent a comprehensive eye examination
at baseline in 2003 and then five years later. The WHO and US
definitions were used to define incident blindness (WHO VA <20/400 in
the better-seeing eye, US VA ≤20/200) and incident VI (WHO VA
<20/60-20/400, US VA < 20/40->20/200). Among 1,405 baseline
participants, 924 (75%) of 1,232 survivors (87.7%) participated in the
five-year follow-up. The incidences of VI and blindness were 5.4% (95%
CI 3.99-7.07%) and 0.3% (95% CI 0.07-0.95%), respectively, based on
the WHO definition, and 9.85% (95% CI 7.96-12.0%) and 1.4% (95% CI
0.76-2.41%), respectively, based on the US definition. Incidence of
blindness and VI (WHO definition) increased significantly with older age
(p<0.001) and poorer baseline presenting VA in the worse seeing eye
(p<0.001). The leading cause of best-corrected VI (WHO definition) was
cataract (64.6%), whereas the main causes of presenting VI were RE
error (40.4%) and cataract (38.4%). In conclusion, the incidence of VI in
urban Southern China is high. The major causes were unoperated
cataract and URE, reflecting the need for better surgical and refractive
care, in this urban setting (26).
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ASSESSMENT: in different countries, there are widespread


prevalence rates of blindness and SVI. The main causes include
cataract, AMD, glaucoma, and URE.

References
1. Muecke J, Sia DI, Newland H, Casson RJ, Selva D. Perspective on
ophthalmic support in countries of the developing world. Clin Experiment
Ophthalmol. 2013;41(3):263-71.
2. Thylefors B, Negrel AD, Parajasegaram R, Dadzie KY. Global data on
blindness. Bull World Health Organ. 1995; 73:115-21.
3. Rysculova A, Turczyn K, Makuc DM, et al. Self-reported age-related
eye diseases and visual impairment in the United States: results of the 2002
national health interview survey. Am J Public Health. 2008;98:454-61.
4. Foster A. Patterns of blindness. In: Tasman W, Jaeger EA (eds.).
Duane's Clinical Ophtalmology. Philadelphia, Lippincott. 1991, Vol. 5, Chapt.
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5. Kollarits CR. The aging eye. In: Calkins E, Davis PJ, Ford AB (eds.). The
Practice of Geriatics. Philadelphia, Saunders. 1986, pp. 248-58.
6. Manton KG, Stallard E. Cross-sectional estimates of active life
expectancy for the U.S. elderly and oldest-old populations. J Gerontol. 1991;
46:S170-82.
7. Pascolini D Mariotti SP. Global estimates of visual impairment: 2010.
Br J Ophthalmol. 2012;96(5):614-8.
8. Stevens GA, White RA, Flaxman SR, et al. Global prevalence of vision
impairment and blindness: magnitude and temporal trends, 1990-2010.
Ophthalmology. 2013;120(12):2377-84.
9. Thylefors B, Resnikoff S. Progress in the control of world blindness
and future perspectives. Sante. 1998;8:140-3.
10. West SK. Looking forward to 20/20: a focus on the epidemiology of
eye diseases. Epidemiol Rev. 2000;22:64-70.
11. Wittenborn JS, Zhang X, Feagan CW, et al. The economic burden of
vision loss and eye disorders among the United States population younger
than 40 years. Ophthalmology. 2013;120(9):1728-35.
12. Jin YP, Wong DT. Self-reported visual impairment in elderly
Canadians and its impact on healthy living. Can J Ophthalmol. 2008;43:407-
13.
13. Looker HC, Nyangoma SO, Cromie DT, et al. Rates of referable eye
disease in the Scottish National Diabetic Retinopathy Screening Programme.
Br J Ophthalmol. 2014;98(6):790-5.
14. Bourne RR, Jonas JB, Flaxman SR, et al. Prevalence and causes of
vision loss in high-income countries and in Eastern and Central Europe:
1990-2010. Br J Ophthalmol. 2014;98(5):629-38.
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15. Waked N, Saad A, Mehanna C, et al. Prevalence, causes, and risk


factors for blindness and visual impairment among nursing home residents
in Lebanon. J Fr Ophtalmol. 2007;30(5):497-502.
16. Naidoo K, Gichuhi S, Basáñez MG, et al. Prevalence and causes of
vision loss in sub-Saharan Africa: 1990-2010. Br J Ophthalmol. 2014;
98(5):612-8.
17. Khairallah M, Kahloun R, Flaxman SR, et al. Prevalence and causes of
vision loss in North Africa and the Middle East: 1990-2010. Br J Ophthalmol.
2014;98(5):605-11.
18. Jonas JB, George R, Asokan R, et al. Prevalence and causes of vision
loss in Central and South Asia:1990-2010.Br J Ophthalmol. 2014;98(5):592-8.
19. Keeffe J, Taylor HR, Fotis K, et al. Prevalence and causes of vision loss
in Southeast Asia and Oceania: 1990-2010. Br J Ophthalmol. 2014;98(5):586-
91.
20. Rauf A, Malik R, Bunce C, Wormald R. The British Asian community
eye study: outline of results on the prevalence of eye disease in British
Asians with origins from the Indian subcontinent. Indian J Ophthalmol.
2013;61(2):53-8.
21. Araújo Filho A, Salomáo SR, Berezovsky A, et al. Prevalence of visual
impairment, blindness, ocular disorders and cataract surgery outcomes in
low-outcome elderly from a metropolitan region of Säo Paulo – Brazil. Arq
Bras Oftalmol. 2008;71:246-53.
22. Singh N, Eeda SS, Gudapati BK, et al. Prevalence and causes of
blindness and visual impairment and their associated risk factors, in three
tribal areas of andhra pradesh, India. PLoS One. 2014;9(7):e100644.
23. Wong TY, Chong EW, Wong WL, et al. Prevalence and causes of low
vision and blindness in an urban Malay population: the Singapore Malay Eye
Study. Arch Ophthalmol. 2008;126:1091-9.
24. Gilbert CE, Shah SP, Jadoon MZ, et al. Poverty and blindness in
Pakistan: results from the Pakistan national blindness and visual impairment
survey. BMJ. 2008;336(7634):29-32.
25. Dineen B, Bourne RR, Jadoon Z, et al. Causes of blindness and visual
impairment in Pakistan. The Pakistan national blindness and visual
impairment survey. Br J Ophtalmol. 2007;91:1005-10.
26. Wang L, Huang W, He M, et al. Causes and five-year incidence of
blindness and visual impairment in urban Southern China: the Liwan Eye
Study. Invest Ophthalmol Vis Sci. 2013;54(6):4117-21.
199
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AGE-RELATED MACULAR DEGENERATION


AMD is a degenerative disorder of the retinal macula that results
in loss of central vision needed for tasks such as reading, watching
TV, driving, and recognizing faces, with some people feeling suicidal
(1-3). AMD is the most common cause of severe vision loss in people
over 50 years of age in the western world (4). AMD threatens
independence, especially when comorbidity exacerbates functional
limitations (3). NVAMD is especially associated with decreased
functional abilities and QOL, which result in an increase in healthcare
resource utilization (5).
In AMD, both genetic and non-genetic (environmental) factors
play major roles in etiology, and multiple gene variants and lifestyle
factors such as smoking have been associated with the disease. While
dissecting the basic etiology of the disease remains a major
challenge, current genetic knowledge has provided opportunities for
improved risk assessment, molecular diagnosis and clinical testing of
genetic variants in AMD treatment and management (6).

Normal optical coherence tomography

Optical coherence tomography. Age-related macular degeneration.

The findings from 80 studies published since 2003 on the


association between diet and supplements in AMD were reviewed.
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Antioxidants and other nutrients with an effect on AMD susceptibility


include carotenoids (lutein and zeaxanthin, β-carotene), vitamins
(vitamin A, E, C, D, B), mineral supplements (zinc, copper, and
selenium), dietary fatty acids (monounsaturated fatty acids, PUFA -
both omega-3 PUFA and omega-6 PUFA, saturated fatty acids and
cholesterol), and dietary carbohydrates. Many of these antioxidants
and nutrients exert a protective role by functioning synergistically.
Specifically, the use of dietary supplements with targeted actions can
provide minimal benefits on the onset or progression of AMD;
however, this does not appear to be particularly beneficial in healthy
people. Furthermore, some supplements or nutrients have
demonstrated discordant effects on AMD in some studies. Since
intake of dietary supplements, as well as exposure to damaging
environmental factors, is largely dependent on population habits
(including dietary practices) and geographical localization, an overall
healthy diet appears to be the best strategy in reducing the risk of
developing AMD. As of now, the precise mechanism of action of
certain nutrients in AMD prevention remains unclear. Thus, future
studies are required to examine the effects that nutrients have on
AMD and to determine which factors are correlated with reducing
the risk of AMD or preventing its progression (7).
Ageing disorders can be defined as the progressive and
cumulative outcome of several defective cellular mechanisms as well
as metabolic pathways, consequently resulting in degeneration.
Environment plays an important role in its pathogenesis. By contrast,
developmental disorders arise from inherited mutations and usually
the role of environmental factors in the development of a disease is
minimal. AMD is one such retinal degenerative disorder which starts
with the progression of age. Metabolism plays an important role in
initiation of such diseases of ageing. Cholesterol metabolism and
their oxidized products like 7-ketocholesterol adversely affect RPE
cells. These molecules can initiate mitochondrial apoptotic processes
and influence the complements factors and expression of angiogenic
proteins like vascular endothelial growth factor precursor etc. (8).
AMD is characterized by the presence of lipoproteinaceous
deposits (drusen) in the inner layers of the retina.
Immunohistochemistry studies identified deposition of complement
proteins in the drusen as well as in the choroid. In the last decade,
genetic studies have linked common and rare variants in genes of the
complement system to increased risk of development of AMD (9).
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References
1. Harvey P. Common eye diseases of elderly people: identifying and
treating causes of vision loss. Gerontology. 2003;49:1-11.
2. Gohdes DM, Balanurugan A, Larsen BA, Mayalahn C. Age-related
diseases: an emerging challenge for public health professionals. Prev
Chronic Dis. 2005;2(3):A17.
3. Mitchell J, Bradley C. Quality of life in age-related macular
degeneration: a review of the literature. Health Qual. Life Outcomes. 2006;
Dec 21;4:97.
4. Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration.
Surv Ophtalmol. 1988;32:3375-413.
5. Pauleikhoff D, Scheider A, Wiedmann P, et al. Neovascular age-related
macular degeneration in Germany: Encroachment on the quality of life and
the functional implications. Ophthalmologe. 2009;106:242-51.
6. Ratnapriya R, Chew EY. Age-related macular degeneration-clinical
review and genetics update. Clin Genet. 2013;84(2):160-6.
7. Zampatti S, Ricci F, Cusumano A, et al. Review of nutrient actions on
age-related macular degeneration. Nutr Res. 2014;34(2):95-105.
8. Sharma K, Sharma NK, Anand A. Why AMD is a disease of ageing and
not of development: mechanisms and insights. Front Aging Neurosci. 2014
Jul 10;6:151.
9. Schramm EC, Clark SJ, Triebwasser MP et al. Genetic variants in the
complement system predisposing to age-related macular degeneration: A
review. Mol Immunol. 2014 Jul 15. pii: S0161-5890(14)00163-1.

TYPES. AMD is classified into two types: non-NV (non-exudative or


atrophic AMD) and NVAMD (exudative or serous AMD) (1). Non-
NVAMD accounts for approximately 80% of all AMD and is associated
with the formation of drusen (2). NVAMD accounts for only about
20% of all AMD, but is responsible for 90% of cases of severe,
irreversible central vision loss. Progression from non-NVAMD to
NVAMD occurs in approximately 10-20% of people with AMD (2).

References
1. Harvey P. Common eye diseases of elderly people: and treating causes
of vision loss. Gerontology elderly people: identifying. 2003;49:1-11.
2. Hyman L. Epidemiology of AMD. In: Hampton GR, Nelsen PT (eds.).
Age Related Macular Degeneration: Principles and Practice. New York:
Raven Press. 1992, pp.1-35.
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EPIDEMIOLOGY. Numerous population-based studies of AMD


have been reported around the world, with the results of some
studies suggesting racial or ethnic differences in disease prevalence.
Integrating these resources to provide summarized data to establish
worldwide prevalence and to project the number of people with
AMD from 2020 to 2040 would be a useful guide for global strategies.
A systematic literature review was conducted to identify all
population-based studies of AMD published before May, 2013. Only
studies using retinal photographs and standardized grading
classifications (the Wisconsin age-related maculopathy grading
system, the international classification for AMD, or the Rotterdam
staging system) were included. Hierarchical Bayesian approaches
were used to estimate the pooled prevalence, the 95% CrI, and to
examine the difference in prevalence by ethnicity (European, African,
Hispanic, and Asian) and region (Africa, Asia, Europe, Latin America
and the Caribbean, North America, and Oceania). UN World
Population Prospects were used to project the number of people
affected in 2014 and 2040. Bayes factor was calculated as a measure
of statistical evidence, with a score above three indicating substantial
evidence. Analysis of 129,664 individuals (aged 30-97 years), with
12,727 cases from 39 studies, showed the pooled prevalence
(mapped to an age range of 45-85 years) of early, late, and any AMD
to be 8.01% (95% CrI 3.98-15.49), 0.37% (95% CrI 0.18-0.77), and
8.69% (95% CrI 4.26-17.40), respectively. A higher prevalence of early
and any AMD in Europeans than in Asians (early: 11.2% vs 6.8%,
Bayes factor 3.9; any: 12.3% vs. 7.4%, Bayes factor 4.3) was found,
and early, late, and any AMD to be more prevalent in Europeans than
in Africans (early: 11.2% vs. 7.1%, Bayes factor 12.2; late: 0.5% vs.
0.3%, 3.7; any: 12.3% vs. 7.5%, 31.3). There was no difference in
prevalence between Asians and Africans (all Bayes factors <1).
Europeans had a higher prevalence of geographic atrophy subtype
(1.11%, 95% CrI 0.53-2.08) than Africans (0.14%, 95% CrI 0.04-0.45),
Asians (0.21%, 95% CrI 0.04-0.87), and Hispanics (0.16%, 95% CrI
0.05-0.46). Between geographical regions, cases of early and any
AMD were less prevalent in Asia than in Europe and North America
(early: 6.3% vs. 14.3% and 12.8% [Bayes factor 2.3 and 7.6]; any: 6.9%
vs. 18.3% and 14.3% [3.0 and 3.8]). Insignificant gender effect was
noted in prevalence (Bayes factor <1.0). The projected number of
people with AMD in 2020 is 196 million (95% CrI 140-261), increasing
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to 288 million in 2040 (205-399). These estimates indicate the


substantial global burden of AMD (1).
The objective of this study was to estimate the prevalence and
distribution of AMD in the US by age, race/ethnicity, and gender.
Summary prevalence estimates of drusen 125 microm or larger,
NVAMD, and geographic atrophy were prepared separately for black
and white persons in five-year age intervals starting at 40 years. The
estimated rates were based on a meta-analysis of recent population-
based studies in the US, Australia, and Europe. These rates were
applied to 2000 US Census data and to projected US population
figures for 2020 to estimate the number of the US population with
drusen and AMD. The overall prevalence of NVAMD and/or
geographic atrophy in the US population 40 years and older is
estimated at 1.47% (95% CI 1.38%-1.55%), with 1.75 million citizens
having AMD. The prevalence of AMD increased dramatically with age,
with more than 15% of the white women older than 80 years having
NVAMD and/or geographic atrophy. More than seven million
individuals had drusen measuring 125 microm or larger and were,
therefore, at substantial risk of developing AMD. Owing to the rapidly
aging population, the number of persons having AMD will increase by
50% to 2.95 million in 2020. AMD was far more prevalent among
white than among black persons. In conclusion, AMD affects more
than 1.75 million individuals in the US. Owing to the rapid aging of
the US population, this number will increase to almost three million
by 2020 (2).
The objective of this study was to obtain prevalence estimates of
AMD; late, geographic atrophy, NV by age and gender amongst
populations of European ancestry taking into account study design
and time trends. Systematic review of population-based studies
published by September 2010 with quantitative estimates of
geographic atrophy, NV, and late AMD prevalence was conducted.
Studies were identified by a literature search of MEDLINE (from
1950), EMBASE (from 1980), and Web of Science (from 1980)
databases. Data from 25 published studies (57,173 subjects: 455 with
GA, 464 with NVAMD, and 1571 with late AMD) were included.
There was considerable heterogeneity in prevalence rates between
studies; for late AMD, 20% of the variability in prevalence rates was
explained by differences in age and 50% by study characteristics. The
prevalence of AMD increased exponentially with age (OR, 4.2 per
decade; 95% CrI 3.8-4.6), which did not differ by gender. There was
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some evidence to suggest higher risk of NVAMD in women compared


with men (OR 1.2, 95% CrI 1.0-1.5). Compared with studies using
fundus imaging and international classification systems, studies using
fundus imaging with alternative classifications were more likely (OR
2.7, 95% CrI 1.1-2.8), and studies using alternative classifications
without fundus imaging most likely to diagnose late AMD (OR 2.9,
95% CrI 1.3-7.8). There was no good evidence of trends in AMD
prevalence over time. Estimated prevalence of late AMD is 1.4% (95%
CrI 1.0%-2.0%) at 70 years of age, rising to 5.6% (95% CrI 3.9%-7.7%)
at age 80 and 20% (95% CrI 14%-27%) at age 90. In conclusion,
studies using recognized classifications systems with fundus
photography reported the lowest prevalences of AMD taking account
of age and gender, and were stable over time, with a potentially
higher risk of NVAMD (3).
The aim of this study was to estimate prevalence, number and
incidence of AMD by type in the UK population aged ≥50 years. Age-
specific prevalence rates of AMD obtained from a Bayesian meta-
analysis of AMD prevalence were applied to UK 2007-2009
population data. Incidence was estimated from modeled age-specific
prevalence. Overall prevalence of late AMD was 2.4% (95% CrI 1.7% -
3.3%), equivalent to 513,000 cases (95% CrI 363,000-699,000);
estimated to increase to 679,000 cases by 2020. Prevalences were
4.8% in those aged ≥65 years, and 12.2% aged ≥80 years.
Geographical atrophy prevalence rates were 1.3% (95% CrI 0.9%-
1.9%), 2.6% (95% CrI 1.8%-3.7%) and 6.7% (95% CrI 4.6%-9.6%);
NVAMD 1.2% (95% CrI 0.9%-1.7%), 2.5% (95% CrI 1.8%-3.4%) and
6.3% (95% CrI 4.5%- 8.6%), respectively. The estimated number of
prevalent cases of late AMD were 60% higher in women vs. men
(314,000 cases in women, 192,000 men). Annual incidence of late
AMD, geographical atrophy and NVAMD per 1,000 women was 4.1
(95% CrI 2.4%-6.8%), 2.4 (95% CrI 1.5%-3.9%) and 2.3 (95% CrI 1.4%-
4.0%); in men 2.6 (95% CrI 1.5%-4.4%), 1.7 (95% CrI 1.0%-2.8%) and
1.4 (95% CrI 0.8%-2.4%), respectively; 71, 000, new cases of late AMD
were estimated per year. In conclusion, these estimates will guide
health and social service provision for those with late AMD and
enable estimation of the cost of introducing new treatments (4).
In Caucasians, drusen 63-125 μm as the predominant phenotype
were in 34.9% (95% CI, 33.1-36.8), drusen >125 μm in 24.1% (95% CI
22.5-25.8), geographic atrophy in 1.0% (95% CI 0.6-1.4), and NVAMD
in 2.5% (95% CI 1.9-3.1); bilateral involvement of late AMD was
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L. Ben-Nun King David

present in 1.1%; eyes with late AMD had a significantly lower RE


(spherical equivalent 0.078 vs. 0.99 diopters, p<0.0001), and 42.5% of
eyes had Snellen VA ≤0.32; Late AMD was present in 10.9% of
subjects aged 80 years or more (5).
In Asians Malay population, the prevalence of early AMD in Malay
persons aged 40 to 80 years was estimated at 3.5% (95% CI, 2.9%-
4.1%) and that of late AMD was 0.34% (95% CI 0.20%-0.49%). Early
AMD was more prevalent in men than in women (6.1% vs. 3.8%); this
was significant despite adjusting for age and smoking (OR 1.56, 95%
CI 1.11-2.20). Late AMD also was more prevalent in men than in
women (1.0% vs. 0.4%), although this was statistically insignificant
after adjusting for age and smoking (OR, 1.39; 95% CI, 0.52-3.68) (6).
After age-standardization to the Blue Mountains Eye Study
population, the prevalence of distinct soft drusen was significantly
higher in Singaporeans compared to Australians (23.9%, 95% CI 22.9-
25.0 vs. 6.2%, 95% CI 5.3-7.0), with an AOR of 4.6 (95% CI 3.4-6.0). By
contrast, the prevalence of indistinct soft or reticular drusen was
significantly lower in Singaporeans compared to Australians (6.5%,
95% CI 5.9-7.1 vs. 8.3%, 95% CI 7.4-9.3, with insignificant adjusted OR
of 1.2, 95% CI 0.8-1.7). Soft drusen of any type were present
frequently at the inner and outer macula (within a zone ≥500 to
<3000 μm radius from the foveal center) among Singaporeans, while
among Australians soft drusen were present more frequently at the
central macula (<500 μm radius). Singaporean Asians had a milder
spectrum of early AMD lesions and lesion characteristics
(predominantly distinct soft drusen and noncentral location)
compared to white Australians (7)
AMD is responsible for 54% of legal blindness in Iceland (8); 23.1%
in Baden, Germany (9); 2.6% in Osun State, Nigeria (n=3,204) (10); in
Malay persons aged 40 to 80 years the prevalence is estimated at
3.5% (95% CI 2.9%-4.1%) of early AMD and 0.34% (95% CI 0.20%-
0.49%) of late AMD (11); 2.0%/7.7% of low vision/blindness (n=8,816
eyes of 4,409 subjects) is recorded in Beijing, China (12); 1.95 per 100
(95% CI 1.55-2.34) of the population (n=6497) in Tehran (13), and
20.1% in Israel (n=21.585) (14).

ASSESSMENT: there are widespread rates of AMD prevalence in


different countries.
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References
1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular
degeneration and disease burden projection for 2020 and 2040: a
systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-
16.
2. Friedman DS, O'Colmain BJ, Muñoz B, et al. Prevalence of age-related
macular degeneration in the United States. Arch Ophthalmol.
2004;122(4):564-72. Erratum in Arch Ophthalmol. 2011;129(9):1188.
3. Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in
age-related macular degeneration prevalence in populations of European
ancestry: a meta-analysis. Ophthalmology. 2012;119(3):571-80.
4. Owen CG, Jarrar Z, Wormald R, et al. The estimated prevalence and
incidence of late stage age related macular degeneration in the UK. Br J
Ophthalmol. 2012;96(5):752-6.
5. Erke MG, Bertelsen G, Peto T, et al. Prevalence of age-related macular
degeneration in elderly Caucasians: the Tromsø Eye Study. Ophthalmology.
2012;119(9):1737-43.
6. Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related
macular degeneration in Asians: a systematic review and meta-analysis.
Ophthalmology. 2010;117(5):921-7.
7. Joachim N, Mitchell P, Younan C, et al. Ethnic variation in early age-
related macular degeneration lesions between white Australians and
Singaporean Asians. Invest Ophthalmol Vis Sci. 2014;55(7):4421-9.
8. Helgadóttir G, Jónasson F, Sigurdsson H, et al. Age related macular
degeneration. Laeknabladid. 2006;92:685-96.
9. Rohrshneider K, Greim S. Epidemiology of blindness in Baden,
Germany. Klin Monatsbl Augesheilkd. 2004;221:116-21.
10. Adeoti CO. Prevalence and causes of blindness in a tropical African
population. West Afr J Med. 2004;23:249-52.
6. Kawasaki R, Wang JJ, Aung T, et al. Prevalence of age-related macular
degeneration in a Malay population: the Singapore Malay Eye Study.
Ophthalmology. 2008;115(10):1735-41.
12. Xu L, Wang Y, Li Y, et al. Causes of blindness and visual impairment
in urban and rural areas in Beijing: the Beijing Eye Study. Ophthalmology.
2006;113:1134.e1-11.
13. Hatef E, Fotoufi A, Hashemi H, et al. Prevalence of retinal diseases
and their pattern in Tehran: The Tehran Eye Study. Retina. 2008;28:755-762.
14. Avisar R, Friling R, Cnir M, et al. Estimation of prevalence and
incidence rates and causes of blindness in Israel, 1998-2003. Isr Med Assoc J.
2006;8:880-1.
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L. Ben-Nun King David

RISK FACTORS. AMD pathogenesis is multifactorial, involving a


complex of interactions of various factors such as metabolic,
functional, genetic and environmental (1,2).
Advanced AMD is more likely to be present in whites than blacks,
despite the similar prevalence of soft drusen in both groups. NVAMD
is more frequent than geographic atrophy in most population-based
studies in whites in America, Australia, and the Netherlands than in
similar population-based studies in Iceland and Norway. The
relationship of smoking, hypertension, and cataract surgery to
advanced AMD has been consistent (3). Genetic factors such as
complement factor H are strongly associated with AMD (4).
Abu Asleh et al. (5) suggested that AMD is less common in Arabs
than in Jews in the city of Jerusalem. The number of patients eligible
for certification of blindness and the number of patients who
underwent photodynamic therapy for NVAMD were compared,
providing additional evidence that ethnic background plays an
important role as a risk factor for advanced AMD.
Different ethnic groups can have significantly different genetic
patterns and can vary considerably in their lifestyles in terms of diet,
cigarette smoking, alcohol consumption, etc. All these may explain, in
part, the differences in the prevalence of AMD between Jews and
Arabs in Jerusalem (6).
Arterial sclerosis in the retina is associated with two-fold
increased risk (OR=1.96) of exudative AMD. No association was
found between iris color, use of sunglasses, work conditions and
AMD. The coexistence of arterial sclerosis in the retina suggests that
vascular disorders take part in pathogenesis of exudative type of
AMD (7).
Eyes with AMD are more likely to have cataract and nuclear
sclerosis. The concomitance of cataract (especially nuclear sclerosis)
and AMD supports the theory of common pathogenesis in both
pathologies. There is increased risk of exudative type of AMD in eyes
after cataract surgery (8).
In addition, middle-aged persons who have a 3% or greater
reduction in waist-hip-ratio overtime were less likely to have AMD,
particularly among those who are initially obese (9).
AMD is the most common cause of irreversible VI among people
over 50 years of age, accounting for up to 50% of all cases of legal
blindness in Western countries. Although the aging represents the
main determinant of AMD, it must be considered a multifaceted
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L. Ben-Nun King David

disease caused by interactions among environmental risk factors and


genetic backgrounds. Mounting evidence and/or arguments
document the crucial role of inflammation and immune-mediated
processes in the pathogenesis of AMD. Proinflammatory effects
secondary to chronic inflammation (e.g., alternative complement
activation) and heterogeneous types of oxidative stress (e.g.,
impaired cholesterol homeostasis) can result in degenerative
damages at the level of crucial macular structures, that is
photoreceptors, RPE, and Bruch's membrane. In the most recent
years, the association of AMD with genes, directly or indirectly,
involved in immunoinflammatory pathways is increasingly becoming
an essential core for AMD knowledge. Starting from the key basic-
research notions detectable at the root of AMD pathogenesis, the
present up-to-date paper reviews the best known and/or the most
attractive genetic findings linked to the mechanisms of inflammation
of this complex disease (10).
AMD is a multifactorial disease that represents the most common
cause of irreversible VI among people over the age of 50 in Europe,
the US, and Australia, accounting for up to 50% of all cases of central
blindness. Risk factors of AMD are heterogeneous, mainly including
increasing age and different genetic predispositions, together with
several environmental/epigenetic factors, that is, cigarette smoking,
dietary habits, and phototoxic exposure. In the aging retina, free
radicals and oxidized lipoproteins are considered to be major causes
of tissue stress resulting in local triggers for parainflammation, a
chronic status which contributes to initiation and/or progression of
many human neurodegenerative diseases such as AMD. Experimental
and clinical evidences strongly indicate the pathogenetic role of
immunologic processes in AMD occurrence, consisting of production
of inflammatory related molecules, recruitment of macrophages,
complement activation, microglial activation and accumulation
within those structures that compose an essential area of the retina
known as macula lutea (11).

References
1. Soubrane G, Haddad WM, Coscas G. Age-related macular
degeneration. Presse Med. 2002;31:1282-7.
2. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis
and therapy. Pharmacol Rep. 2006;58:353-63.
3. Klein R, Peto T, Bird A, Vannewkirk MR. The epidemiology of age-
related degeneration. Am J Ophtalmol. 2004;137:486-95.
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L. Ben-Nun King David

4. Klein R. Overview of progress in the epidemiology of age-related


macular degeneration. Ophthalmic Epidemiol. 2007;14:14:184-7.
5. Abu Asleh S, Chowers I. Ethnic background as a risk factor for
advanced age-related macular degeneration in Israel. IMAJ. 2007;9:656-8.
6. Waisbourd M, Loewenstein A. About genetics, lifestyle and age-
related macular degeneration. IMAJ. 2007;9:674-5.
7. Drobek-Stowik M, Karczewicz D, Safranow K. Eye's risk factors in age-
related macular degeneration (AMD). Part II. Klin Oczna. 2008;110:44-9.
9. Peeters A, Magliano DJ, Stevens J, et al. Changes in abdominal obesity
and age-related macular degeneration: the atherosclerosis risk in
communities study. Arch Ophthalmol. 2008;126:1154-60.
10. Parmeggiani F, Sorrentino FS, Romano MR, et al. Mechanism of
inflammation in age-related macular degeneration: an up-to-date on genetic
landmarks. Mediators Inflamm. 2013;2013:435607.
11. Parmeggiani F, Romano MR, Costagliola C, et al. Mechanism of
inflammation in age-related macular degeneration. Mediators Inflamm.
2012;2012:546786.

SYMPTOMATOLOGY. Non-NVAMD is characterized by blurred or


distorted vision, central scotoma and slow decline or no change in
VA, while the NV type is recognized by central scotoma, image
distortion, increased glare sensitivity, decreased color perception,
photopsias, formed hallucinations, blindness, and rapid, steady
decrease in VA (1). Examination of the fundus shows: drusen (located
deposits of lipids and lipoproteins) and alterations in RPE (hypo- or
hyperpigmentation). Two forms of complications are atrophic (or
"dry") and exudative (or "wet"). The atrophic form is characterized by
the presence of degeneration in the central RPE, choriocapillaris and
photoreceptors, resulting from the enlargement and/or coalescence
of small areas of peri-foveal atrophy (or "geographic" atrophy). The
exudative form, responsible for the majority of cases of blindness due
to AMD, is characterized by the appearance of choroidal new vessels,
identifiable on fluorescein angiography and responsible for serous
retinal detachment, edema and hemorrhage, leading to the
destruction of the macular photoreceptors. RPE progressively
degenerates, which results in an irreversible degeneration of
photoreceptors (2).

ASSESSMENT: diagnosis of AMD requires an ophthalmoscopic


examination. Although data for such an evaluation are unavailable in
King David's case, the presence of blindness seems to hint at NVAMD.
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There is also a possibility that non-NVAMD progressed to NVAMD in


the King's case.

References
1. Harvey P. Common eye diseases of elderly people: identifying and
treating causes of vision loss. Gerontology. 2003;49:1-11.
2. Soubrane G, Hadda WM, Coscas G. Age-related macular degeneration.
Prese Med. 2002;31:1282-7.

CATARACT
Cataract is the leading cause of blindness, accounting for 50% of
blindness worldwide. Although significant progress has been made
toward identifying risk factors for cataract, there is no proven
primary prevention or medical treatment (1). Age-related cataracts
are by far the most common type of cataracts (2). Most cataracts are
bilateral (2) although cataract may occur in only one eye and may
mature more rapidly in one eye than in the other (2,3).
Cataract, namely subscapular, in elderly subjects is associated
with an increased mortality risk (4). Cataract, which is a lens opacity
that interferes with visual function, is the leading cause of blindness
in the world today (5), and accounts for approximately 16 million
cases of blindness (VA <20/400, Snelen equivalent) worldwide (WHO
1997 estimate) (6).
The objective of this study was to determine the prevalence of
cataract and pseudophakia/aphakia in the US and to project the
expected change in these prevalence figures by 2020. Summary
prevalence estimates of cataract and of pseudophakia/aphakia were
prepared separately for black, white, and Hispanic persons (for whom
only cataract surgery data were available) in five-year age intervals
starting at 40 years for women and men. The estimates were based
on a standardized definition of various types of cataract: cortical,
greater than 25% of the lens involved; posterior subcapsular, present
according to the grading system used in each study; and nuclear,
greater than or equal to the penultimate grade in the system used.
Data were collected from major population-based studies in the US,
and, where appropriate, Australia, Barbados, and Western Europe.
The age-, gender-, and race/ethnicity-specific rates were applied to
2000 US Census data, and projected population figures for 2020, to
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L. Ben-Nun King David

obtain overall estimates. An estimated 20.5 million (17.2%)


Americans older than 40 years have cataract, and 6.1 million (5.1%)
have pseudophakia/aphakia. Women have a significantly (OR 1.37,
95% CI 1.26-1.50) higher age-adjusted prevalence of cataract than
men in the US. The total number of persons who have cataract is
estimated to rise to 30.1 million by 2020; and for those who are
expected to have pseudophakia/aphakia to 9.5 million. In conclusion,
the number of Americans affected by cataract and undergoing
cataract surgery will dramatically increase over the next 20 years as
the US population ages (7).
The purpose of this population-based longitudinal study was to
estimate the four-year incidence and progression of lens opacities. A
total of 4,658 adult Latinos from Los Angeles County were examined
at baseline and four-year follow-up. Examination included
assessment of lens opacities using the LOCS II. Incidences of cortical,
nuclear, and posterior subcapsular opacities (with LOCS II scores ≥
two) were defined as opacity development in persons without that
opacity at baseline. Single and mixed opacities were defined in
persons without any opacity at baseline. Incidence of all lens changes
included development of at least one opacity or cataract surgery
among those without any opacity at baseline. Four-year progressions
were defined as increase of ≥ two in LOCS II score. The four-year
incidence of all lens opacities was 14.2%. Four-year incidence of
cataract surgery was 1.48%. The incidences were 4.1% for cortical-
only, 5.8% for nuclear-only, 0.5% for PSC-only and 2.5% for mixed.
The incidences for any opacities were 7.5% for cortical, 10.2% for
nuclear, and 2.5% for PSC. Incidence increased with age (p<0.0001
for all). The progressions were 8.5% for cortical, 3.7% for nuclear and
2.9% for PSC opacities. In conclusion, this Latino population had a
higher incidence of nuclear than cortical opacities, but a greater
progression of cortical than nuclear opacities. Incidence and
progression of PSC was low. Additional understanding of the natural
history and progression of various lens opacities will give us a better
understanding of the pathogenesis and management of lens
opacities (8).
The incidence of age-related cataract over a 15-year interval in
the Beaver Dam Eye Study reached 29.7% for nuclear cataract, 22.9%
for cortical cataract, and 17.7% for cataract surgery (9).
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L. Ben-Nun King David

In Lódź, the mean age of patients operated for cataract, 1997–


2004, increased and there was a tendency of performing operations
in cases with better VA (10).

Normal eye Eye with cataract

In Pakistan, 2002-2003, 16,402 adults were included to investigate


the prevalence and evaluate risk factors for lens opacity. Almost a
fifth of the adult population had lens opacity. Significant positive
associations were age, smoking status, hypertension, DM, and
increased deprivation level (11).
The aim of this study was to develop a methodology for case-mix
adjustment of surgical outcomes for individual cataract surgeons
using electronically collected multi-centre data conforming to the
cataract national data set. Routinely collected anonymised data were
remotely extracted from electronic patient record systems in 12
participating NHS Trusts undertaking cataract surgery. Following data
checks and cleaning, analyses were carried out to risk adjust
outcomes for posterior capsule rupture rates for individual surgeons,
with stratification by surgical grade. A total of 406 surgeons from 12
NHS Trusts submitted data on 55,567 cataract operations between
November 2001 and July 2006 (86% from January 2004). In all, 283
surgeons contributed data on >25 cases, providing 54,319 operations
suitable for detailed analysis. Case-mix adjusted results of individual
surgeons are presented as funnel plots for all surgeons together and
separately for three different grades of surgeon. Plots include 95% CI
and 99.8% CI around the case-mix adjusted outcomes for detection
of surgical outliers. In conclusion, routinely collected electronic data
conforming to the cataract national data provides sufficient detail for
case-mix adjustment of cataract surgical outcomes. The validation of
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L. Ben-Nun King David

these risk indicators should be carried out using fresh data to confirm
the validity of the risk model. Once validated this model should
provide an equitable approach for peer-to-peer comparisons in the
context of revalidation (12).
The purpose of this study was to assess the prevalence and causes
of avoidable blindness in Atsinanana Region, Madagascar, with the
RAAB survey. The hospital records to supplement the findings for
public health care planning were analyzed. Only villages within a
two-hour walk from a road, about half of the population of
Atsinanana, were included. Seventy-two villages were selected by
population-proportional-to-size sampling. In each village, compact
segment sampling was used to select 50 people over age 50 for eye
examination using standard RAAB methods. Records at the two
hospitals providing cataract surgery in the region were analyzed for
information on patients who underwent cataract surgery in 2010.
Cataract incidence rate and target cataract surgery rate was modeled
from age-specific prevalence of cataract. The participation rate was
87% and the sample prevalence of blindness was 1.96%. Cataract was
responsible for 64% and 85.7% of blindness and severe VI,
respectively. VI was due to cataract (69.4%) and RE (14.1%). There
was a strong positive correlation between cataract surgical rate by
district and the proportion of people living within two hours of a
road. There were marked differences in the profiles of the cataract
patients at the two facilities. The estimated incidence of cataract at
the 6/18 level was 2.4 eyes per 100 people over age 50 per year. In
conclusion, although the survey included only people with
reasonable access, the main cause of VI was still cataract. The
incidence of cataract is such that it ought to be possible to eliminate
it as a cause of VI, but changes in service delivery at hospitals and
strategies to improve access will be necessary for this change (13).
The purpose of this cross-sectional population-based survey was
to determine the extent and causes of blindness and VI in the
Varamin district, Iran, in 2009. A total of 3,000 noninstitutional
inhabitants aged ≥50 years were involved in this study from February
to August 2009. A standard protocol was used according to the RAAB
method after an initial four-day workshop. The clusters were selected
through probability-proportionate-to-size sampling. In each cluster,
people were selected by a "cluster compact sampling" method. VA
was measured using a standard tumbling "E" chart without and with
pinhole. Ophthalmologists examined participants with VA <6/18 in
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L. Ben-Nun King David

either eye. Blindness was verified by the WHO definition (best-


corrected VA in the better eye <3/60). SVI was defined as VA ≥3/60
and <6/60 and VI was defined as VA ≥6/60 and <6/18 at presentation.
The primary cause of VI was defined according to the cause in the
participant's better eye. Main outcome measures included
prevalence of blindness, SVI, and VI, and their avoidable causes.
Among 3,000 persons, 2,819 (94% response rate), including 1,289
men (45.1%) and 1,530 women (54.9%), were examined. The
standardized prevalence rates of blindness, SVI, and VI were 1.33
(95% CI 0.91-1.75), 1.39 (95% CI 0.81-1.97), and 6.91 (95% CI 5.96-
7.86), respectively, and the prevalence rates of avoidable causes
(cataract, surgical complication, RE, and corneal scar) of blindness,
SVI, and VI were 56.1%, 65.0%, and 85.6%, respectively. The principal
cause of blindness and SVI was cataract, and the principal cause of VI
was RE. In conclusion, most blindness, SVI, and VI is due to avoidable
causes. Cataract and REs were the leading causes in this context (14).
The objective of this population-based, cross-sectional survey was
to define the prevalence of blindness and VI in people in rural Hainan
using the RAAB and to report the outcomes of cataract surgery
among the residents. Participants included 6,482 rural residents of
the Hainan province. A total of 136 clusters, each of which consisted
of 50 people aged ≥50 years, were selected through probability-
proportionate-to-size sampling. Door-to-door visits were performed
by two outreach teams. VA was measured on site and those with VA
<6/18 in either eye were examined by an ophthalmologist. Causes of
blindness and VI were determined. The causes of poor visual
outcome after cataract surgery were evaluated. Information
regarding barriers to receiving surgery was collected by trained
interviewers. Prevalence and causes of blindness (VA <3/60), severe
VI (SVI) (VA <6/60 but ≥3/60), and VI (VA <6/18 but ≥6/60) based on
PVA were assessed. Outcomes of cataract surgery performed in
public and private hospitals and charitable organizations were
compared. Of 6,482 subjects were examined (response rate, 95.3%),
the prevalence of blindness was 4.4% (95% CI 2.0-6.8). The
prevalence of SVI and VI was 1.9% (95% CI 0-4.3) and 9.9% (95% CI
7.6-12.2), respectively. Age and sex were associated with increased
prevalence of blindness, SVI, and VI. Overall, cataract accounted for
approximately 60% of blindness and SVI. Of the 524 eyes that had
received cataract surgery, 87.2% had intraocular lenses implanted,
21% had a poor visual outcome (PVA <6 /60), and 20% had a
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borderline visual outcome (PVA <6/18 but ≥6/60). Eyes that received
surgery in charitable organizations had a higher rate of intraocular
lens implantation and good visual outcome (VA ≥6/18) compared
with eyes that were operated on elsewhere. In conclusion, the
prevalence of blindness, SVI, and VI was high among rural residents in
Hainan. Cataract remained the leading cause of avoidable blindness.
Outcomes of cataract surgery performed in public hospitals were
suboptimal. Quality-control initiatives should be introduced to
improve cataract surgery outcomes (15).

References
1. Javitt JC, Wang F, West SK. Blindness due to cataract: epidemiology
and prevention. Annu Rev Public Health. 1996;17:159-77.
2. Sperbuto RD, Seigel D. Senile lens and senile macular changes in a
population-based sample. Am J Ophthalmology. 1980;90:86-91.
3. Newell FW. The lens. Acquired cataracts. In: Newell FW (ed.).
Ophthalmology. Principles and Concepts, ed. 6. St Louis , Moshby. 1986, pp.
364-77.
4. Xu L, Cui TT, Wang YX, Jonas JB. Cataract and mortality. The Beijing
eye study. Graefes Arch Clin Exp Ophthalmol. 2008;246:615-7.
5. Thylefors B, Negrel AD, Parajasegaram R, Dadzie KY. Global data on
blindness. Bull World Health Organ. 1995; 73:115-21.
6. Harvey P. Common eye diseases of elderly people: and treating causes
of vision loss. Gerontology elderly people: identifying. 2003;49:1-11.
7. Congdon N, Vingerling JR, Klein BE, et al. Prevalence of cataract and
pseudophakia/aphakia among adults in the United States. Arch Ophthalmol.
2004;122(4):487-94.
8. Varma R, Richter GM, Torres M, et al. Four-year incidence and
progression of lens opacities: the Los Angeles Latino Eye Study. Am J
Ophthalmol. 2010;149(5):728-34.e1-2.
9. Klein BE, Klein R, Lee KE, Gangnon RE. Incidence of age-related
cataract over a 15-year interval the Beaver Dam Eye Study. Ophthalmology.
2008;115:477-82.
10. Bilioska E, Moll A, Kowalszyk G, Omulecki W. Epidemiology of
cataract in clinical material of Department of Ophthalmology, Medical
University of Lódź. Klin Oczna. 2004;106(3 Supl):450-2.
11. Shah SP, Dineen B, Jadoon Z, et al. Lens opacities in adults in
Pakistan: prevalence and risk factors. Ophtalmic Epidemiol. 2007;14:381-9.
12. Sparrow JM, Taylor H, Qureshi K, et al. The cataract national data set
electronic multi-centre audit of 55,567 operations: case-mix adjusted
surgeon's outcomes for posterior capsule rupture. Eye (Lond).
2011;25(8):1010-5.
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13. Randrianaivo JB, Anholt RM, Tendrisoa DL, et al. Blindness and
cataract surgical services in Atsinanana region, Madagascar. Middle East Afr
J Ophthalmol. 2014;21(2):153-7.
14. Rajavi Z, Katibeh M, Ziaei H, et al. Rapid assessment of avoidable
blindness in Iran. Ophthalmology. 2011;118(9):1812-8.
15. Li EY, Liu Y, Zhan X, et al. Prevalence of blindness and outcomes of
cataract surgery in Hainan Province in South China. Ophthalmology. 2013;
120(11):2176-83.

RISK FACTORS. Cataract is the leading cause of blindness


worldwide. Smoking, diabetes, and exposure to UVB light [solar UV
radiation reaching the earth is a combination of UVB (290-320 nm)
and UVA (320-400 nm) wavelengths] consistently have been
identified as risk factors for cataract development (1).
Cataract may be also associated with inflammation, trauma, DM,
and metabolic or nutritional disorders (2,3).
The purpose of this population-based, cross-sectional study was
to identify sociodemographic and biological risk factors associated
with having cortical, nuclear, PSC, and mixed lens opacities. A total of
5,945 Latinos aged ≥40 years from six census tracts in Los Angeles,
California, underwent an interview and detailed eye examination,
including BCVA and slit-lamp assessment of lens opacities using the
LOCS II. Of the 5,945 participants with gradable lenses, 468 had
cortical only lens opacities, 217 had nuclear only lens opacities, 27
had PSC only opacities, and 364 had mixed lens opacities. Older age,
higher hemoglobin A(1c), and history of DM were independent risk
factors for cortical only lens opacities. Older age, smoking, and
myopic RE were independent risk factors for nuclear only lens
opacities. Higher systolic BP and history of DM were independent risk
factors for PSC lens opacities. Older age, myopic RE, history of DM,
higher systolic BP, female gender, and presence of large drusen were
independent risk factors for mixed lens opacities. In conclusion, the
modifiable and non-modifiable risk factors provide insight into the
mechanisms related to the development of lens opacification.
Improved glycemic control, smoking cessation and prevention, and
BP control may help to reduce the risk of having lens opacities and
their associated vision (4).
The aim of this study was to assess the socio-demographic and
health-related risk factors associated with cataract subtypes in Korea.
A total of 11,591 participants (aged ≥40 years) were selected from
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the Korean National Health and Nutrition Examination Survey


between 2008 and 2010. The Korean Ophthalmologic Society
conducted detailed ophthalmologic examinations on these
participants based on the LOCSIII. Risk factors for developing any
type of cataract, and its subtypes (nuclear, cortical, PSC and mixed),
were identified from univariate and multivariate logistic regression
analysis. The prevalence of cataracts was 40.1% (95% CI 37.8-42.3%)
in participants over 40 years old. Older age, lower monthly household
income, lower education, hypercholesterolemia, hypertension, and
DM were independent risk factors for development of any cataract.
Older age, lower monthly household income, lower education,
hypercholesterolemia, and DM were independent risk factors for
development of pure cortical cataracts. Older age, lower education,
metabolic syndrome, and DM were independent risk factors for
development of pure nuclear cataracts. Older age and DM were
independent risk factors for development of pure PSC cataracts.
Older age, lower monthly household income, lower education, and
DM were independent risk factors for development of mixed
cataracts. In conclusion, although socioeconomic disparities are
related to cataract development, this study identified several
"modifiable" risk factors that may help to lower the incidence of
cataracts and associated vision loss. Improved control of BP, blood
glucose, and cholesterol may help to reduce the incidence of
cataracts in the general Korean population (5).

ASSESSMENT: since the King was elderly, it is very likely that he


was afflicted by mature cataract responsible for a slow and painless
deterioration in the King’s visual function, progressing subsequently
to blindness.
Since King David suffered from anorexia, fasting, extreme weight
loss, and subsequent cachexia (6), he suffered from malnutrition,
which is an identifiable risk factor for cataract in this particular
geriatric patient. There is no reason to suspect DM when evaluating
King David’s medical record (the biblical text).
In summary, it is very likely that the King suffered from cataract
that led to blindness, with malnutrition as a risk factor for cataract
development.
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L. Ben-Nun King David

References
1. Abraham AG, Condon NG, West Gower E. The new epidemiology of
cataract. Ophthalmol Clin North Am. 2006;19(4):415-25.
2. Cohen DL, Neil HA, Sparrow J, et al. Lens opacity and mortality in
diabetes. Diab Med. 1990;7:615-7.
3. Jacques PF, Chylack LT, McGandy RB, at el. Antioxidant status in
persons with and without senile cataract. Arch Ophtalmol. 1988;106:337-
340.
4. Richter GM, Torres M, Choudhury F, et al. Risk factors for cortical,
nuclear, posterior subcapsular, and mixed lens opacities: the Los Angeles
Latino Eye Study Ophthalmology. 2012;119(3):547-54.
5. Rim TH, Kim MH, Kim WC, et al. Cataract subtype risk factors identified
from the Korea National Health and Nutrition Examination survey 2008-
2010. BMC Ophthalmol. 2014 Jan 10;14:4.
6. Ben-Noun L. The disease that caused weight loss in King David the
great. J Gerontol Med Sci. 2003;59A:M143-5.

SYMPTOMATOLOGY
The chief symptom of acquired cataract is a gradual decrease of
vision that is not associated with pain or inflammation of the eye.
Double vision in one eye (monocular diplopia) is caused by the lens
opacity splitting light bundles, but this disappears with further
decrease in vision. In the early stages, lights may be surrounded by a
collar halo (1).
Dilatation of the pupil that occurs in dim illumination improves
vision. Glare and constriction of the pupil in bright illumination
reduce vision, particularly in patients with PSC that obstruct the
visual axis. Patients may complain of spots in the visual field that,
unlike those caused by vitreous floaters remain fixed. In nuclear
cataracts, there is often an increase in the refractive power of the
lens so that patients are able to read without glasses (1).
Paradoxically, in the incipient stage of cataract distant vision is
blurred, but near vision may improve slightly, so the patient will read
better without glasses ("second sight"). This artificial myopia is due to
the greater refractive index of the lens in the incipient stage. The
gradual decrease of vision is not associated with pain or
inflammation of the eye (2). Opacity of the lens can vary from a small
local opacity to a diffuse general loss of transparency (3).
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L. Ben-Nun King David

Cataracts may be located in the nuclear, posterior polar, posterior


cortical, PSC, coronary, lamellar, anterior subscapular or anterior
pyramidal area (4).

ASSESSMENT: where was the cataract located in King’s case?


Since there are no data from an ophthalmoscopic examination, this
question remains open.

References
1. Newell FW. The Lens. In: Klein EA (ed.). Newell FW Ophthalmology.
Principles and Concepts. Mosby. Sixth ed. St Louis, Toronto. 1986, pp. 364-
377.
2. Shock JP, Harper RA. Lens. Age related cataract (senile cataract). In:
Vaughan D, Asbury T, Riordan-Eva (eds.). A Lange Medical Book. General
Ophthalmology, ed. 14. Norwalk, Appleton-Lange. 1995, pp. 165-7.
3. Harvey P. Common eye diseases of elderly people: and treating causes
of vision loss. Gerontology elderly people: identifying. 2003;49:1-11.
4. Newell FW. The lens. Acquired cataracts. In: Newell FW (ed).
Ophthalmology. Principles and Concepts, ed. 6. St Louis , Moshby. 1986, pp.
364-77.

GLAUCOMA
Glaucoma is a worldwide leading cause of irreversible vision loss.
Because it may be asymptomatic until a relatively late stage,
diagnosis is frequently delayed (1). The glaucomas are a range of
disorders with a characteristic type of optic nerve damage. These
diseases are the second commonest cause of blindness in the world,
and the commonest cause of irreversible blindness (2). The
glaucomas are associated with an increased rate of mortality,
particularly CAG, in elderly subjects (3).
A general understanding of the disease pathophysiology,
diagnosis, and treatment may assist primary care physicians in
referring high-risk patients for comprehensive ophthalmologic
examination and in more actively participating in the care of patients
affected by this condition. The objective of this study was to describe
current evidence regarding the pathophysiology and treatment of
OAG and CAG. A literature search was conducted using MEDLINE, the
Cochrane Library, and manuscript references for studies published in
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English between January 2000 and September 2013 on the topics


OAG and CAG. From the 4,334 abstracts screened, 210 articles were
selected that contained information on pathophysiology and
treatment with relevance to primary care physicians. The glaucomas
are a group of progressive optic neuropathies characterized by
degeneration of RGC and resulting changes in the ONH. Loss of
ganglion cells is related to the level of IOP, but other factors may also
play a role. Reduction of IOP is the only proven method to treat the
disease. Although treatment is usually initiated with ocular
hypotensive drops, laser trabeculoplasty and surgery may also be
used to slow disease progression. Primary care physicians can play an
important role in the diagnosis of glaucoma by referring patients with
positive family history or with suspicious ONH findings for complete
ophthalmologic examination. They can improve treatment outcomes
by reinforcing the importance of medication adherence and
persistence and by recognizing adverse reactions from glaucoma
medications and surgeries (1).

Reference
1. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and
treatment of glaucoma: a review. JAMA. 2014;311(18):1901-11.
2. Khaw PT, Shah, Elkigton AR. Glaucoma – 1: Diagnosis. BMJ.
2004;328:97-99.
3. Xu L, Wang YX, Jonas JB. Glaucoma and mortality in the Beijing Eye
Study. Eye. 2008;22:434-8.

TYPES. There are two main types of glaucoma: OAG and CAG. If
the cause is evident, glaucoma is designated as secondary, but if the
cause is unknown, as primary (1).

Reference
1. Newell FW. The Glaucomas. In: Newell FW Ophthalmology. Principles
and Concepts. Klein EA ed. Mosby. Sixth ed. St Louis, Toronto. 1986, pp. 378-
98.

EPIDEMIOLOGY. Approximately 6.4 million people worldwide are


affected by blindness due to glaucoma (WHO 1997 estimate) (1). Of
those people who are legally blind (VA of 20/200 or worse in the
better-seeing eye) because of glaucoma, 75% are older than 65 years
of age (2).
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L. Ben-Nun King David

The prevalence of glaucoma in the US is estimated at 2.0%


(n=31,044) (3); OAG in adult Latinos (n=6,142) at 4.7% (4); among
Eskimos, PACG is at 2-8%, and among Caucasians 0.1% (5); in
Northern Italy, the overall PACG is at 0.6% (n=4,287) (6); in Chennai,
India, the prevalence of PACG is 0.88% (n=3,850) and 2.75% have
primary CAG (7); in Tajimi, Japan, (n=3,870) primary OAG is estimated
at 0.6%, secondary glaucoma 0.5%, and 5.0% of all glaucomas in
subjects over 40 years (8); in China, an estimated 9.4 million people
aged 40 years and older have glaucomatous optic neuropathy.
Approximately 5.2 million people (55%) would be blind at least in one
eye, and around 1.7 million (18.1%) would be blind in two eyes (9).
The self-reported prevalence of early exhaustion of glaucoma eye
drops prior to a scheduled refill, and associated risk factors were
examined. In this cross-sectional survey, glaucoma patients at the
University of Washington, who experienced eye drop application and
were on a steady regimen of self-administered glaucoma drops in
both eyes, took a survey at the time of clinic examination. The main
outcome measure was self-reported early eye drop bottle
exhaustion. Of 236 patients who were eligible and chose to
participate, patients included were relatively healthy (mean 2.3
comorbid medical conditions). Sixty patients (25.4%) reported any
problem with early exhaustion of eye drop bottles, and this was
associated with VA ≤20/70 in the better eye (p=0.049). Twelve
patients (5.1%) reported that they "often" (5-7 times per year),
"usually" (8-11 times per year) or "always" ran out of eye drops prior
to a scheduled refill. Patients affected by this higher level (≥ 5 times
yearly) of eye drop bottle exhaustion were more likely to have poor
VA in their worse eye ≤20/70 (p=0.015) and had significantly lower
worse-eye logMAR (p=0.043). In conclusion, self-reported early
glaucoma bottle exhaustion regularly affected 5% of patients in this
population and 25% reported early exhaustion at least once; the
main risk factor was poor vision in at least one eye. These results may
not be generalizable to a broad patient population, or to those
unexperienced with eye drop self-administration. However, this pilot
study compels further evaluation and consideration of early eye drop
bottle exhaustion in glaucoma patients (10).
All primary reports of population-based studies that reported the
prevalence of PACG in adult Asian populations were identified. PACG
case definition was compatible with the ISGEO (International Society
of Geographical and Epidemiological Ophthalmology) definition.
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L. Ben-Nun King David

Twenty-nine population-based studies were included. The overall


pooled prevalence estimates were calculated using a random effect
model, and ethnicity-, age- and gender-specific pooled prevalence
estimates were calculated. The overall pooled prevalence of PACG in
those of adult Asians was 0.75% (95% CI 0.58-0.96). Ethnicity-specific
pooled prevalence estimates were 0.97% (95% CI 0.22-4.27) in
Middle East group, 0.66% (95% CI 0.23-1.86) in South East Asia group,
0.46% (95% CI 0.32-0.64) in India group, 1.10% (95% CI 0.85-1.44) in
China group, and 1.19% (95% CI 0.35-3.98) in Japan group,
respectively. Age-specific prevalence was 0.21% (95% CI 0.12-0.37)
for those 40-49 years, 0.54% (95% CI 0.34-0.85) for 50-59 years,
1.26% (95% CI 0.93-1.71) for 60-69 years, and 2.32% (95% CI 1.74-
3.08) for 70 years or above. The overall female to male ratio of the
PACG prevalence was 1.51∶1 (95% CI 1.01- 2.28). In conclusion, PACG
affects approximately 0.75% adult Asians, increasing double per
decade, and 60% of cases being female. The prevalence rates vary
greatly by ethnic region (11).
The objective of this study was to estimate the prevalence of
primary glaucoma in mainland China and to quantify its association
with age, sex, and region. Population-based studies that reported
the prevalence of primary POAG or/and PACG among adult
populations in mainland China were identified through systematic
searches. Fourteen articles providing 12 population-based studies
were included. The overall pooled prevalence estimates were
calculated using a random-effects model. A logistic metaregression
was used to model the associations between the OR and 95% CI of
primary glaucoma and age, sex, and region. The overall pooled
prevalence of POAG was 0.7% (95% CI 0.4-1.2), and PACG was 1.4%
(95% CI 1.0%-1.7%). The OR per decade increase in age was 1.68
(95% CI 1.12-2.52) for POAG, and 2.11 (95% CI 1.72-2.60) for PACG.
The OR of POAG prevalence was 0.65 (95% CI 0.26-1.62) between
men and women. Chinese women were 1.75 (95% CI 1.20-2.56) times
more likely than men to have PACG. The OR between western China
and east China were 0.37 (95% CI 0.10-1.35) for POAG, and 1.06 (95%
CI 0.63-1.76) for PACG. The OR between urban China and rural China
were 3.92 (95% CI 1.55-9.92) for POAG, and 1.07 (95% CI 0.55-2.10)
for PCAG. In conclusion, the prevalence of PACG was approximately
double that of POAG in adult Chinese. The rate of change of PACG
prevalence with age increased more rapidly than that of POAG. The
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L. Ben-Nun King David

prevalence of POAG in urban was higher than that in rural. PCAG was
more common in women than in men (12).
In Israel, more than 10% of the screened population had ocular
hypertension, pre-perimetric glaucoma, or glaucoma (13).

ASSESSMENT: primary OAG and CAG are prevalent diseases in


different countries, although different prevalence rates are observed.

References
1. Harvey P. Common eye diseases of elderly people: identifying and
treating causes of vision loss. Gerontology. 2003;49:1-11.
2. Pizzarello LD. The dimensions of the problem of the eye disease
among the elderly. Ophtalmology. 1987;94:1191-5.
3. Rysculova A, Turczyn K, Makuc DM, et al. Self-reported age-related
eye diseases and visual impairment in the United States: results of the 2002
national health interview survey. Am J Public Health. 2008;98:454-61.
4. Varma R, Ying-Lai M, Francis BA, et al. Prevalence of open-angle
glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye
Study. Ophthalmology. 2004;111:1439-048.
5. Congdon N, Wang F, Tielsch JM. Issues in the epidemiology and
population-based screening of primary angle-closure glaucoma. Surv
Ophthalmol. 1992;36:411-23.
6. Bonomi L, Marchini G, Marraffa M, et al. Epidemiology of angle-
closure glaucoma: prevalence, clinical types, and association with peripheral
anterior chamber depth in the egna-Neumarket Glaucoma Study.
Ophthalmology. 2001;107:998-1003.
7. Vijaya L, George R, Arvind H, et al. Prevalence of primary-closure
disease in an urban south Indian population and comparison with a rural
population. The Chennai Glaucoma Study. Ophthalmology. 2008;115: 655-
60.
8. Yamamoto T, Iwase A, Araie M, et al. The Tajimi Study report 2:
prevalence of primary angle closure and secondary glaucoma in a Japanese
population. Ophthalmology. 2005;112:1661-9.
9. Foster PJ. The epidemiology of primary closure and associated
glaucomatous optic neuropathy. Semin Ophthalmol. 2002;17:50-8.
10. Moore DB, Walton C, Moeller KL, et al. Prevalence of self-reported
early glaucoma eye drop bottle exhaustion and associated risk factors: a
patient survey. BMC Ophthalmol. 2014 Jun 13;14:79.
11. Cheng JW, Zong Y, Zeng YY, Wei RL. The prevalence of primary angle
closure glaucoma in adult Asians: a systematic review and meta-analysis.
PLoS One. 2014 24;9(7):e103222.
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L. Ben-Nun King David

12. Cheng JW, Cheng SW, Ma XY, et al. The prevalence of primary
glaucoma in mainland China: a systematic review and meta-analysis. J
Glaucoma. 2013;22(4):301-6.
13. Nesher R, on behalf of the Israel Glaucoma Screening Group.
Prevalence of increased intraocular pressure and optic disk cupping:
multicenter glaucoma screening in Israel during the 2009 and 1010 World
glaucoma weeks. IMAJ. 2014;16:483-6.

MECHANISMS OF THE DISEASE. In OAG, the resistance to outflow


through the trabecular meshwork gradually increases for reasons not
fully understood, and the pressure in the eye slowly increases. There
are other damage mechanisms, particularly ischemia of the optic
nerve (1).
In primary CAG, relative pupillary block is the mechanism of angle
closure. This means that there is relative resistance to fluid flow of
aqueous humor between the posterior iris surface and lens due to
their close approximation at the pupil. This relative papillary block
increases the IOP of aqueous in the posterior chamber, forcing the
peripheral iris forward over the trabecular meshwork (2).
The degree of increased IOP that causes organic change is not the
same in every eye, and some individuals may tolerate for long
periods a pressure that would rapidly blind another. There are two
major factors involved in the visual loss of glaucoma: 1] the IOP,
which depends on the rate of reduction of aqueous humor and its
rate of exit through the trabecular meshwork, and 2] the resistance
of the intraocular portion of the optic nerve to the development of
optic atrophy (3). Glaucoma-caused blindness is associated with an
advanced stage of glaucoma at diagnosis, fluctuation of IOP during
treatment, the presence of exfoliation syndrome, and poor patient
compliance (4).
Recently, the association between thyroid problems and
glaucoma was evaluated in a population-based cross-sectional
sample with 12,376 participants from the 2002 National Health
Interview Survey. OR and 95% CI were used to quantify the
association between a self-reported diagnosis of glaucoma and a self-
reported history of thyroid problems, controlling for demographic
characteristics and smoking status. The overall prevalence of
glaucoma was 4.6%; 11.9% reported a history of thyroid problems.
The prevalence of glaucoma among those who did not report thyroid
problems was 6.5% and 4.4%, respectively (p=0.0003). Following
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adjustment for differences in age, gender, race and smoking status,


the association between glaucoma and thyroid problems remained
(OR 1.38, 95% CI 1.08-1.76). The results of this study indicate that
thyroid disorders may increase the risk of glaucoma (5).

References
1. Khan HA, Leibowitz HM, Ganley JP, et al. The Framingham eye study.
Outline and major prevalence study. Am J Epidemiol. 1977;106:17-32.
2. Epstein D, Pavan-Langston D. Glaucoma. In: Pavan–Langston D (ed.).
Manual of Ocular Diagnosis and Therapy. Little, Brown and Company. 1982,
pp. 195-222.
3. Newell FW. The Glaucomas. In: Newell FW Ophthalmology. Principles
and Concepts. Klein EA ed. Mosby. Sixth ed. St Louis, Toronto. 1986, pp. 378-
98.
4. Forsman E, Kivelä T, Vesti E. Lifetime visual disability in open-angle
glaucoma and ocular hypertension. J Glaucoma. 2007;16:313-9.
5. Cross JM, Girkin CA, Owsley C, McGwin G Jr. The association between
thyroid problems and glaucoma. Br J Ophthalmol. 2008;92: 1503-5.

SYMPTOMATOLOGY. OAG is usually asymptomatic. It is a silent,


surreptitious process leading to a gradual loss of vision (1). Halos
around lights and blurring of vision do not occur unless there has
been a sudden increase in IOP and many patients never have visual
difficulties. Because the visual loss is gradual, patients do not usually
present until damage has occurred. The disease can be detected by
screening high-risk groups for the signs of glaucoma. At present time,
optometrist at routine examinations detects most patients with
PACG (2).
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The symptoms of PACG are mainly related to a sudden increase in


IOP. There may be repeated attacks of ocular pain and blurred vision
occurring after a prolonged time in darkness, after emotional upset,
or after similar situations that cause papillary dilation. The rapid
increase in IOP causes an epithelial edema of the cornea that results
in blurred vision and halos surrounding streetlights. The eye
becomes red and painful, and patients may be systemically unwell
with nausea, vomiting, and severe pain or headache. Vision is
blurred, and patients notice haloes around light. They may have a
history of similar attacks that were aborted by going asleep. During
sleep, the pupil constricts and may pull peripheral iris out of the
angle (2). Severe prostrating pain, usually unilateral, may be
confused with migraine, impending rupture of a carotid aneurism,
and similar causes of hemicrania (3).

References
1. Khaw PT, Shah, Elkigton AR. Glaucoma – 1: Diagnosis. BMJ.
2004;328:97-99.
2. Epstein D, Pavan-Langston D. Glaucoma. In: Pavan–Langston D (ed).
Manual of Ocular Diagnosis and Therapy. Little, Brown and Company. 1982,
pp. 195-222.
3. Newell FW. The Glaucomas. In: Newell FW Ophthalmology. Principles
and Concepts. Klein EA ed. Mosby. Sixth ed. St Louis, Toronto. 1986, pp. 378-
398.

DIAGNOSIS. The main diagnostic tools for characterizing a


glaucoma patient typically include optic nerve evaluation, detection
of visual field loss and elevated IOP. Modern glaucoma management
has shown that a substantial proportion of patients have normal-low
intraocular tension; therefore, high IOP in no longer required for
glaucoma diagnosis. The optic nerve may be damaged as a
glaucomatous optic neuropathy pattern much earlier than visual field
defects appear (1). The diagnosis of GON prior to the appearance of
visual field defects has been termed pre-perimetric glaucoma. Thus,
visual field damage is not a requirement for a definite glaucoma
diagnosis. However, GON has a pathognomonic pattern that enables
the diagnosis of glaucoma based solely on optic nerve evaluation (2).
Advanced ocular imaging technologies facilitate objective and
reproducible quantification of change in glaucoma but at the same
time impose new challenges on scientists and clinicians for
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L. Ben-Nun King David

separating true structural change from imaging noise. The new


technologies include time-domain and spectral-domain OCT, confocal
scanning laser ophthalmoscopy and scanning laser polarimetry.
Objective assessment of RNFL, ganglion cell complex and ONH
topography may improve glaucoma monitoring when used as a
complementary tool in conjunction with the clinical judgment of an
expert (3).
Because glaucomatous damage is irreversible, early detection of
structural changes in the ONH and RNFL is imperative for timely
diagnosis of glaucoma and monitoring of its progression. Significant
improvements in ocular imaging have been made in recent years.
Imaging techniques such as OCT, scanning laser polarimetry and
confocal scanning laser ophthalmoscopy rely on different properties
of light to provide objective structural assessment of the ONH, RNFL
and macula. The capabilities of these imaging modalities are
pertinent for diagnosis of glaucoma and to detect progressive
glaucomatous damage (4).
The purpose of this perspective study was to provide an update
on the role of optic nerve and peripapillary RNFL imaging in glaucoma
clinical practice and clinical trials. Imaging technologies such as
confocal scanning laser ophthalmoscopy, scanning laser polarimetry,
and OCT provide objective and quantitative measurements that are
highly reproducible and show good agreement with clinical estimates
of ONH structure and visual function. Structural assessments
provided by imaging complement optic disk photography in clinical
care and have the potential to identify relevant structural efficacy
endpoints in glaucoma randomized clinical trials. As with other
technologies, imaging may produce false identification of glaucoma
and its progression; thus, clinicians should not make management
decisions based solely on the results of one single test or technology.
In conclusion, although optic disk stereophotography represents the
standard for documentation of glaucomatous structural damage in
practice and research trials, advances in computerized imaging
technology provide useful measures that assist the clinician in
glaucoma diagnosis and monitoring and offer considerable
opportunity for use as efficacy endpoints in clinical trials (5).
The purpose of this retrospective, cross-sectional study was to
compare optic disk and RNFL imaging methods to discriminate eyes
with early glaucoma from normal eyes. In a tertiary care academic
glaucoma center, 92 eyes of 92 subjects (46 with early perimetric
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OAG and 46 controls) were studied. Diagnostic performance of OCT


(StratusOCT; Carl Zeiss Meditec, Dublin, California, USA), scanning
laser polarimetry (GDx VCC; Laser Diagnostic Technologies, San
Diego, California, USA), confocal laser ophthalmoscopy (Heidelberg
Retinal Tomograph [HRT] III; Heidelberg Engineering GmbH,
Heidelberg, Germany), and qualitative assessment of stereoscopic
optic disk photographs were compared. Outcome measures were
aROCs and sensitivities at fixed specificities. Classification and
regression tree analysis was used to evaluate combinations of
quantitative parameters. The average (+/- SD) visual field mean
deviation for glaucomatous eyes was -4.0 +/- 2.5 dB (decibels).
Parameters with largest aROCs (+/- standard error) were: average
RNFL thickness for StratusOCT (0.96 +/- 0.02), nerve fiber indicator
for GDx VCC (0.92 +/- 0.03), Frederick S. Mikelberg (FSM)
discriminant function for HRT III (0.91 +/- 0.03), and 0.97 +/- 0.02 for
disk photograph evaluation. At 95% specificity, sensitivity of disk
photograph evaluation (90%) was greater than GDx VCC (p=0.05) and
HRT III (p=0.002) results, but insignificantly different than those of
StratusOCT. The combination of StratusOCT average RNFL thickness
and HRT III cup-to-disk area with classification and regression tree
produced a sensitivity of 91% and specificity of 96%. In conclusion,
StratusOCT, GDx VCC, and HRT III performed as well as, but not
better than, qualitative evaluation of optic disk stereophotographs
for detection of early perimetric glaucoma. The combination of
StratusOCT average RNFL thickness and HRT III cup-to-disk area ratio
provided a high diagnostic precision (6).
The aim of this study was to compare the ability of subjective
assessment of ONH and RNFL by general ophthalmologists and by a
glaucoma expert with objective measurements by optical coherence
tomography (Stratus OCT, Carl Zeiss Meditec Inc), confocal scanning
laser ophthalmoscope (HRT III; Heidelberg Engineering, Heidelberg,
Germany), and scanning laser polarimetry (GDx enhanced corneal
compensation; Carl Zeiss Meditec Inc, Dublin, CA) in discriminating
glaucomatous and normal eyes. Sixty-one glaucomatous and 57
normal eyes of 118 subjects were included in the study. Three
independent general ophthalmologists and one glaucoma expert
evaluated ONH stereophotographs. ROCs were constructed for each
imaging technique and sensitivity at fixed specificity was estimated.
Comparisons of areas under these curves (aROCs) and agreement (k)
were determined between stereophoto grading and best parameter
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L. Ben-Nun King David

from each technique. Best parameter from each technique showed


larger aROC (Stratus OCT RNFL=0.92; Stratus OCT ONH vertical
integrated area=0.86; Stratus OCT macular thickness=0.82; GDx
enhanced corneal compensation=0.91; HRT3 global cup-to-disc area
ratio=0.83; HRT3 glaucoma probability score numeric score=0.83)
compared with stereophotograph grading by general
ophthalmologists (0.80) in separating glaucomatous and normal eyes.
Glaucoma expert stereophoto grading provided equal or larger aROC
(0.92) than best parameter of each computerized imaging device.
Stereophoto evaluated by a glaucoma expert showed better
agreement with best parameter of each quantitative imaging
technique in classifying eyes either as glaucomatous or normal
compared with stereophoto grading by general ophthalmologists.
The combination of subjective assessment of the optic disc by
general ophthalmologists with RNFL objective parameters improved
identification of glaucoma patients in a larger proportion than the
combination of these objective parameters with subjective
assessment of the optic disc by a glaucoma expert (29.5% vs. 19.7%,
respectively). In conclusion, diagnostic ability of all imaging
techniques showed better performance than subjective assessment
of the ONH by general ophthalmologists, but not by a glaucoma
expert. Objective RNFL measurements may provide improvement in
glaucoma detection when combined with subjective assessment of
the optic disc (7).

ASSESSMENT: advanced ocular imaging technologies facilitate


objective and reproducible quantification of change in glaucoma but
at the same time impose new challenges on scientists and clinicians
for separating true structural change from imaging noise. Diagnostic
ability of imaging techniques showed better performance than
subjective assessment of ONH.
Was King David afflicted by glaucoma? It seems likely that OAG
with its asymptomatic, slowly deteriorating course leading to damage
of his optic nerve and eventual blindness.
It is understandable that in this ancient patient, modern
investigating technologies were not used.
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References
1. Kerrigan-Baumrind LA, Quigley HA, Pease ME, et al. Number of
ganglion cells in glaucoma eyes compared with threshold visual fields tests
in the same persons. Invest Ophtalmol Vis Sci. 2000;41:741-8.
2. Gaton D. Screening fo glaucoma. IMAJ. 2014;16:509-10.
3. Sehi M, Iverson SM. Glaucoma Diagnosis and Monitoring Using
Advanced Imaging Technologies. US Ophthalmic Rev. 2013;6(1):15-25.
4. Kotowski J, Wollstein G, Ishikawa H, Schuman JS. Imaging of the optic
nerve and retinal nerve fiber layer: an essential part of glaucoma diagnosis
and monitoring. Surv Ophthalmol. 2014;59(4):458-67.
5. Greenfield DS, Weinreb RN. Role of optic nerve imaging in glaucoma
clinical practice and clinical trials. Am J Ophthalmol. 2008;145(4):598-603.
6. Badalà F, Nouri-Mahdavi K, Raoof DA, et al. Optic disk and nerve fiber
layer imaging to detect glaucoma. Am J Ophthalmol. 2007;144(5):724-32.
7. Vessani RM, Moritz R, Batis L, et al. Comparison of quantitative
imaging devices and subjective optic nerve head assessment by general
ophthalmologists to differentiate normal from glaucomatous eyes. J
Glaucoma. 2009;18(3):253-61.

OPTIC NEUROPATHY
AION is the most common cause of acute optic neuropathy after
age 50, but may also occur in younger patients. The diagnosis is
clinical and includes painless visual loss associated with a relative
afferent pupillary defect and disc edema. In almost all cases, there is
an underlying crowded optic nerve with a small cup-to-disc ratio. The
visual prognosis is usually poor, although up to 43% of patients may
improve over time. The fellow eye is involved in up to 15% of patients
within five years, but the risk of recurrence in the same eye is less
than 5%. There is no treatment for acute NAION but it is essential to
evaluate these patients for underlying treatable atheromatous
vascular risk factors. A coagulation workup should also be considered
in younger patients. It is essential to rule out giant cell arteritis in all
patients over the age of 50 with IONs. Posterior ischemic neuropathy
(in which the optic nerve is normal acutely) is rare and should be
considered a diagnosis of exclusion (1).
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Ischemic optic neuropathy due Flourescein fundus angiograms


to giant cell arteritis of 4 eyes with nonarteritic AIOP

ION can be related to atherosclerosis or giant cell arteritis (2).


Giant cell arteritis can produce an ophthalmic catastrophe and occurs
exclusively in the elderly. It most commonly produces ischemic optic
neuritis (75% of ocular events) due to arteritis of the posterior ciliary
artery (3).
There have been many reports in recent literature concerning the
use of scanning laser polarimetry, Heidelberg retinal tomography and
OCT in assessing the optic nerve and peripapillary nerve fibre layer. It
is important to assess the validity of new equipment and see whether
this has improved our understanding of the disease. There are
reports about possible association of NAION with cataract surgery
and PDE-5i. Scanning laser polarimetry, Heidelberg retinal
tomography and OCT have been helpful in quantifying optic nerve
and peripapillary RNFL defects, with different efficacy and limitations.
Although these confirm the damage to RNFL beyond what is detected
by standard visual field examination, the effect of cataract surgery
and PDE-5i remains to be further studied on a larger scale. The few
experimental treatments for NAION need further confirmatory
studies. More studies are required to evaluate the benefits of new
imaging methods. The availability of a primate model may provide
clues to assessing experimental treatments for NAION (4).
Similarly to AION, NAION is the most common acute optic
neuropathy in patients over the age of 50 and is the second most
common cause of permanent optic nerve-related visual loss in adults
after glaucoma. Patients typically present with acute, painless,
unilateral loss of vision associated with a variable visual field defect, a
relative afferent pupillary defect, a swollen, hyperaemic optic disc,
and one or more flame-shaped peripapillary retinal haemorrhages.
The pathogenesis of this condition is unknown, but it occurs primarily
in patients with structurally small optic discs that have little or no cup
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L. Ben-Nun King David

and a variety of underlying vascular disorders that may or may not be


known at the time of visual loss. There is no consistently beneficial
medical or surgical treatment for the condition, but there are now
animal models that allow testing of various potential therapies.
About 40% of patients experience spontaneous improvement in VA.
Patients in whom NAION occurs in one eye have a 15-19% risk of
developing a similar event in the opposite eye over the subsequent
five years (4).
Incidence estimates for postoperative vision loss after nonocular
surgery range from 0.013% for all surgeries up to 0.2% following
spine surgery. The most common neuro-ophthalmologic causes of
postoperative vision loss are the IONs, either anterior or posterior.
This complication of case reports suggests that a combination of
prolonged surgery in the prone position, decreased ocular perfusion
pressure, blood loss and anemia/hemodilution, and infusion of large
quantities of IV fluids are some of the potential factors involved in
the etiology of postoperative ION. The specific pathogenesis and risk
factors underlying these neuro-ophthalmic complications remain
unknown, and physicians should be alert to the potential for loss of
vision in the postoperative period. The cases of ION after carotid
body tumor resection are reported (5).

ASSESSMENT: AION is the most common cause of acute optic


neuropathy after age 50, but may also occur in younger patients. The
diagnosis is clinical and includes painless visual loss associated with a
relative afferent pupillary defect and disc edema. Posterior ischemic
neuropathy (in which the optic nerve is normal acutely) is rare and
should be considered a diagnosis of exclusion.
ION can be related to atherosclerosis or giant cell arteritis. Giant
cell arteritis can produce an ophthalmic catastrophe and occurs
exclusively in the elderly. It most commonly produces ischemic optic
neuritis due to arteritis of the posterior ciliary artery.
NAION is the most common acute optic neuropathy in patients
over the age of 50 and is the second most common cause of
permanent optic nerve-related visual loss in adults after glaucoma.
Patients typically present with acute, painless, unilateral loss of vision
associated with a variable visual field defect, a relative afferent
pupillary defect, a swollen, hyperaemic optic disc, and one or more
flame-shaped peripapillary retinal haemorrhages. Patients in whom
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L. Ben-Nun King David

NAION occurs in one eye have a 15-19% risk of developing a similar


event in the opposite eye over the subsequent five years.
Was the King afflicted by ION related to atherosclerosis or giant
cell arteritis?
It is understandable that ION related to surgery or carotid body
tumor resection can be excluded in the King's case.
Was the King afflicted by NAION? The King medical record, that is
the biblical text, tell us that "As the light of my eyes, it is also gone
from me" (Psalm: 38:11). This verse indicates that the patient
suffered from bilateral vision loss. Although visual loss may develop
in the opposite eye over the subsequent years, NAION typically is
presented with unilateral vision loss. Thus, NAION seems unlikely.
Hereditary causes of progressive optic nerve or retinal
degeneration can be excluded, since the loss of vision occurred at an
advanced King's age.

References
1. Luneau K, Newman NJ, Biousse V. Ischemic optic neuropathies.
Neurologist. 2008;14(6):341-54.
2. Kollaritis CR. The aging eye. In: Calkin E, Davis PJ. Ford AB (eds.). The
Practice of Geriatrics. Philadelphia, Saunders. 1986, pp. 248-58.
3. Cohen MM, Lessel S. The neuro-opthalmology of aging. In: Albert M
(ed). Clinical Neurology of Aging. New York, Oxford University Press. 1984,
pp. 313-44.
4. Ho SF, Dhar-Munshi S. Nonarteritic anterior ischaemic optic
neuropathy. Curr Opin Ophthalmol. 2008;19(6):461-7.
5. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis
and management of nonarteritic anterior ischaemic optic neuropathy. Eye
(Lond). 2014 Jul 4. doi: 10.1038/eye.2014.144. [Epub ahead of print]
6. Özkiriş M, Akin I, Özkiriş A, et al. Ischemic optic neuropathy after
carotid body tumor resection. J Craniofac Surg. 2014;25(1):e58-61.

OPTIC ATROPHY
The optic nerve is a bundle of nerve fibers that carry images from
retina to the brain. Each fiber carries a part of the visual information
to the brain. If these nerve fibers become damaged, the brain does
not receive all of this vision information and sight becomes blurred.
Optic atrophy means the loss of some or most of the nerve fibers in
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the optic nerve. The effects range from visual change to severe visual
loss (1).
Optic atrophy is the result of diseases or injuries to RGC or their
axons that produces degeneration of axons anterior to the lateral
geniculate body. The chief symptom of optic atrophy is loss of central
and peripheral vision. Etiological classification of optic atrophy
includes glaucoma, DM, brain tumor, RGC or nerve fiber disease
(pigmentary degeneration of retina, chorioretinal degeneration,
inflammation, and atrophy), inflammation (demyelinating disease,
meningitis, encephalitis, and abscess), tabes dorsalis, metastatic
septicemia, optic neuropathy, papiledema, toxicity (arsenic, lead,
methanol, ethanol, quinine, cigarette smoking, tobacco, chloroquine,
ethambutol, and chlorphenicol), vitamin B deficiency (beriberi,
pellagra, and pernicious anemia), sarcoidosis, glioma, hereditary and
trauma (2-5).
DOA is a neuro-ophthalmic condition characterized by a bilateral
degeneration of the optic nerves, causing insidious visual loss,
typically starting during the first decade of life. The disease affects
primary the RGC and their axons forming the optic nerve, which
transfer the visual information from the photoreceptors to the lateral
geniculus in the brain. The prevalence of the disease varies from
1/10000 in Denmark due to a founder effect to 1/30000 in the rest of
the world. DOA patients usually suffer of moderate visual loss,
associated with central or paracentral visual field deficits and color
vision defects. The severity of the disease is highly variable, the VA
ranging from normal to legal blindness. The ophthalmic examination
discloses on fundoscopy isolated optic disc pallor or atrophy, related
to the RGC death. About 20% of DOA patients harbour extraocular
multi-systemic features, including neurosensory hearing loss, or less
commonly chronic progressive external ophthalmoplegia, myopathy,
peripheral neuropathy, multiple sclerosis-like illness, spastic
paraplegia or cataracts. Two genes (OPA1, OPA3) encoding inner
mitochondrial membrane proteins and three loci (OPA4, OPA5,
OPA8) are currently known for DOA. Additional loci and genes (OPA2,
OPA6 and OPA7) are responsible for X-linked or recessive optic
atrophy. All OPA genes yet identified encode mitochondrial proteins
embedded in the inner membrane and ubiquitously expressed, as are
the proteins mutated in the LHON. OPA1 mutations affect
mitochondrial fusion, energy metabolism, control of apoptosis,
calcium clearance and maintenance of mitochondrial genome
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L. Ben-Nun King David

integrity. OPA3 mutations only affect the energy metabolism and the
control of apoptosis. Patients are usually diagnosed during their early
childhood, because of bilateral, mild, otherwise unexplained visual
loss related to optic discs pallor or atrophy, and typically occurring in
the context of a family history of DOA. OCT further discloses non-
specific thinning of RNFL, but a normal morphology of the
photoreceptors layers. Abnormal visual evoked potentials and the
pattern ERG may also reflect the dysfunction of the RGCs and their
axons. Molecular diagnosis is provided by the identification of a
mutation in the OPA1 gene (75% of DOA patients) or in the OPA3
gene (1% of patients). Visual loss in DOA may progress during
puberty until adulthood, with very slow subsequent chronic
progression in most of the cases. In DOA patients with associated
extra-ocular features, the visual loss may be more severe over time.
To date, there is no preventative or curative treatment in DOA;
severely visually impaired patients may benefit from low vision aids.
Genetic counseling is commonly offered and patients are advised to
avoid alcohol and tobacco consumption, as well as the use of
medications that may interfere with mitochondrial metabolism. Gene
and pharmacological therapies for DOA are currently under
investigation (6).
Autosomal DOA is a major cause of VI in young adults that is
characterized by selective RGC loss. To define the prevalence and
natural history of this optic nerve disorder, a population-based
epidemiologic and molecular study of presumed DOA cases in the
north of England was performed. This case series included 76
affected probands with a clinical diagnosis of DOA identified from the
neuro-ophthalmology and neurogenetics database. OPA1 genetic
testing was performed using a PCR-based sequencing strategy. OPA1-
negative cases were then screened for large-scale OPA1
rearrangements and OPA3 mutations. Additional affected family
members identified through contact tracing were examined, and
longitudinal visual data were analyzed. The prevalence and
molecular characteristics of DOA in the north of England and visual
function and disease progression among patients with OPA1-positive
mutations were evaluated. The detection rate of OPA1 mutations
was 57.6% among probands with a positive family history of optic
atrophy (19/33) and 14.0% among singleton cases (6/43).
Approximately two thirds of families with DOA harbored OPA1
mutations (14/22, 63.6%), and five novel OPA1 mutations were
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L. Ben-Nun King David

identified. Only one family carried a large-scale OPA1 rearrangement,


and no OPA3 mutations were found in this optic atrophy cohort. The
minimum point prevalence of DOA in the north of England was 2.87
per 100,000 (95% CI 2.54-3.20), or 2.09 per 100,000 (95% CI 1.95-
2.23) when only OPA1-positive cases were considered. Snellen VA
varied markedly between OPA1-positive cases with a mean of 20/173
(range 20/20 to hand movements), and visual function worsened in
67.4% of patients during follow-up. The mean rate of visual loss was
0.032 logarithm of the minimum angle of resolution per year, but
some patients experienced faster visual decline (range = 0-0.171
logarithm of the minimum angle of resolution/year). OPA1 missense
mutations were associated with a significantly worse visual outcome
compared with other mutational subtypes (p=0.0001). In conclusion,
dominant optic atrophy causes significant visual morbidity and
affects at least one in 35,000 of the general population (7).
Hereditary optic neuropathies are a group of heterogeneous
conditions affecting both optic nerves, with an autosomal dominant,
autosomal recessive, X-related or mitochondrial transmission. The
two most common non-syndromic hereditary optic neuropathies
(LHON and autosomal dominant optic atrophy) are very different in
their clinical presentation and their genetic transmission, leading
however to a common, non-specific optic nerve atrophy. Beyond the
optic atrophy-related visual loss, which is the clinical hallmark of this
group of diseases, other associated neurological signs are
increasingly recognized (8).
Hereditary optic neuropathies, resulting from RGC degeneration,
are a heterogeneous group of diseases ranging from asymptomatic
forms to legal blindness. Two most frequent phenotypes are Kjer's
disease, an autosomal DOA caused by OPA1 gene mutations, and
Leber's disease due to maternally inherited mitochondrial DNA
mutations. Both optic neuropathies usually isolated are sometimes
associated with extraocular symptoms, especially neurological
symptoms, thus justifying a systematic neurological evaluation and
brain imaging (9).
LHON is a maternally inherited disease characterized by subacute
severe visual loss in both eyes, which usually manifests in young
adulthood and is due to mitochondrial DNA mutation. The final
diagnosis is genetic. There is still no proven treatment, but there is
significant progress in developments on the genetics of the disease to
reach gene therapy (10).
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L. Ben-Nun King David

The purpose of this study was to study mutations associated with


LHON in patients suspected of having this mitochondrial disorder in a
Latvian population. Additional aims were to determine the
heteroplasmy status of all non-synonymous polymorphisms
identified in the current study and to identify the mitochondrial
haplogroups of the studied participants because these factors may
contribute to the manifestation of LHON. Twelve patients, including
patients in two families, were enrolled in the current study. LHON
was suspected based on the findings of ophthalmologic
examinations. In clinically affected individuals, the presence of all
previously reported LHON-associated mutations was assessed with
sequencing analysis. Additionally, the SURVEYOR endonuclease assay
was used to detect heteroplasmy. The mitochondrial haplogroups
were identified with restriction analysis and the sequencing of
hypervariable segment one. In one family (mother and son), there
was one primary LHON-associated mutation, G11778A. In addition,
one rare previously reported LHON-associated polymorphism,
A13637G, was detected in two unrelated patients. A non-
synonymous polymorphism at T6253C was found in one individual.
This mutation was reported in the background of the 3,460 mutation
among LHON patients in a Chinese population. No non-synonymous
point mutations in mitochondrial DNA were found in five of the study
participants. In conclusion, molecular analysis of 12 patients with
suspected LHON confirmed the diagnosis in four patients and allowed
the use of appropriate prophylactic measures and treatment. Further
investigations and additional studies of different populations are
necessary to confirm the role of the non-synonymous polymorphisms
A13637G and T6253C in the manifestation of LHON and the
associations of these polymorphisms with mitochondrial haplogroups
and heteroplasmy (11).
LHON is regarded as the most common mitochondrial disease.
Comprehensive population-based epidemiological data on common
mitochondrial DNA (mtDNA) mutations including m.3243A>G,
m.8344A>G and large-scale mtDNA deletions in Northern Finland
were reported previosly. The aim of this study was to investigate the
prevalence of primary LHON mutations and mutations in the four
mtDNA genes considered hot spots for LHON in the same population.
The study population consisted of 42 adult patients with an
etiologically undefined bilateral optic atrophy. The major LHON
mutations m.3460G>A, m.11778G>A and m.14484T>C were analyzed
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by restriction fragment length polymorphism, and MTND1, MTND6


and MTATP6 genes were sequenced. MTND5 gene was analysed by
conformation-sensitive gel electrophoresis. No major LHON
mutations were found in the population of the province of Northern
Ostrobothnia giving the prevalence of these mutations 0-1.36:100
000 (95% CI). However, two main mutations were found elsewhere in
Northern Finland, homoplasmic m.11778G>A from Kainuu and
heteroplasmic m.3460G>A from Central Ostrobothnia. Tobacco-
alcohol amblyopia was diagnosed in five patients in the study
population and one of them had m.11778G>A. In conclusion, the
prevalence of the three major LHON mutations is lower in Northern
Finland than elsewhere in Finland or in Western Europe. As LHON
and tobacco-alcohol amblyopia have a similar phenotype, analyzing
the known LHON-associated mutations before setting tobacco-
alcohol amblyopia diagnosis is recommended (12).

ASSESSMENT: of the factors listed above, OAG can be identified as


the probable cause of optic nerve atrophy in the King’s case. Was the
King afflicted by nutritional optic atrophy?
Hereditary causes of nerve atrophy can be excluded, since the loss
of vision occurred at his advanced age.

References
1. Brodie SE. Aging and disorders of the eye. In: Brocklehurst JC, Tallis RC,
Fillit HM (eds.). Textbook of Geriatric Medicine and Gerontology ed. 4.
Churchill Livingstone. 1992, pp. 472-9.
2. Lindsey B. De Lott. What is Optic Atrophy? Available 10 December
2014 www.kellogg.umich.edu › Patient Care›.
3. Epstein DL, Pavan-Langston D. Glaucoma. In: Pavan-Langston D (ed.).
Manual of Ocular Diagnosis and Treatment. Boston, Little, Brown. 1982, pp.
195-222.
4. Newell FW. The optic nerve. Optic atrophy. In: Newell FW (ed.).
Ophthalmology. Principles and Concepts, ed. 6. St Louis, Mosby. 1986, pp.
361-2.
5. Spoor TCC. Optic atrophy. In: Spoor TCC (ed.). Atlas of Optic Nerve
Disorders. New York, Raven Press. 1992, pp. 57-67.
6. Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy.
Orphanet J Rare Dis. 2012 Jul 9;7:46.
7. Yu-Wai-Man P, Griffiths PG, Burke A, et al. The prevalence and natural
history of dominant optic atrophy due to OPA1 mutations. Ophthalmology.
2010;117(8):1538-46, 1546.e1.
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L. Ben-Nun King David

8. Milea D, Verny C. Hereditary optic neuropathies. Rev Neurol (Paris).


2012;168(10):706-9.
9. Scherer C, Procaccio V, Ferre M, et al. Hereditary optic atrophies. Rev
Neurol (Paris). 2010;166(12):959-65.
10. Hilo W, Jabaly-Habib H, Modi N, Briscoe D. Leber's hereditary optic
neuropathy. Harefuah. 2013;152(8):486-9, 497,498.
11. Aitullina A, Baumane K, Zalite S, et al. Point mutations associated
with Leber hereditary optic neuropathy in a Latvian population. Mol Vis.
2013;19:2343-51. eCollection 2013.
12. Korkiamäki P, Kervinen M, Karjalainen K, et al. Prevalence of the
primary LHON mutations in Northern Finland associated with bilateral optic
atrophy and tobacco-alcohol amblyopia. Acta Ophthalmol. 2013;91(7):630-
4.

REFRACTIVE ERROR
RE is prevalent among the causes of VI among the elderly (1). It is
defined as a state in which the optical system of the non-
accommodating eye fails to bring parallel rays of light into focus
anterior or posterior to the fovea, respectively, resulting in blurred
vision (1).
The objective of this population-based cohort study was to study the
frequency and causes of VI in relation to RE. A total of 6,597
participants from Rotterdam Study I (baseline and four follow-up
examinations) and 2,579 participants from Rotterdam Study II (baseline
and two follow-up examinations), all 55 years or older, were included.
Participants underwent an extensive ophthalmic examination, including
BCVA and objective refraction, fundus photography, visual field
perimetry, and OCT imaging of macula and optic disc. Cumulative risks
and ORs of VI for various RE categories were calculated and were
determined causes by using all screening information as well as medical
records. Main outcome measures included unilateral and bilateral low
vision (WHO criteria, VA <0.3 and VA ≥0.05; US criteria, VA <0.5 and VA
≥0.1) and blindness (WHO criteria, VA <0.05; US criteria, VA<0.1).
Cumulative risks of VI ranged from virtually 0 in all RE categories at 55
years of age to 9.5% standard error, 0.01) for emmetropia and 15.3%
(SE, 0.06) for high hyperopia to 33.7% (standard error, 0.08) for high
myopia at 85 years of age. The major causes of VI in highly hyperopic
persons were AMD, cataract, and combined causes (each 25%); in
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L. Ben-Nun King David

highly myopic persons, the major cause was myopic macular


degeneration (38.9%). The major causes of VI for the other RE
categories were AMD and cataract. Compared with those with
emmetropia, those with high myopia had a significantly increased
lifetime risk of VI; those with -six D or less and -10 D or more had an OR
risk of 3.4 (95% CI 1.4-8.2) of VI; those with less than -10 D had an OR of
22.0 (95% CI 9.2-52.6). In conclusion, of all REs, high myopia has the
most severe visual consequences. Irreversible macular pathologic
features are the most common cause of VI in this group (2).
The aim of this study was to investigate the prevalence of, and
demographic associations with, URE in an older British population.
Data from 4,428 participants, aged 48-89 years, who attended an eye
examination in the third health check of the European Prospective
Investigation into Cancer-Norfolk study and had undergone an
ophthalmic examination were assessed. URE was defined as ≥ one
line improvement of PCVA in the better eye in participants with
LogMar PVA <0.3 (PVA <6/12). RE was measured using an
autorefractor without cycloplegia. Myopia was defined as spherical
equivalent ≤-0.5 D., and hypermetropia ≥0.5 D. Adjusted to the 2010
midyear British population, the prevalence of URE in this Norfolk
population was 1.9% (95% CI 0.6% to 3.1%). Lower self-rated distance
vision was correlated with higher prevalence of URE (p(trend)<0.001).
In a multivariate logistic regression model adjusting for age, gender,
retirement status, educational level and social class, independent
significant associations with UER were increasing age
(p(trend)<0.001) and having hypermetropic or myopic RE. Wearing
distance spectacles was inversely associated with URE (OR 0.34, 95%
CI 0.21 to 0.55, p<0.001). There were 3,063 people (69.2%) who wore
spectacles/contact lenses for distance vision. Spectacle wear differed
according to type of RE (p<0.001), and use rose with increasing
severity of RE (p(trend)<0.001). In conclusion, although RE is
common, the prevalence of URE was low in this population reflecting
a low prevalence of PVA<0.3 (3).
The aim of this study was to review published data on URE as a
cause of blindness and VI in adults aged ≥40 years in sub-Saharan
Africa. Data were extracted from population-based prevalence
surveys measuring PVA. Results from 11 surveys performed in 10
countries in sub-Saharan Africa, encompassed 39,458 people aged
≥40 years and older. The prevalence of blindness (PVA<3/60 in
better eye) ranged from 1.1% in an urban district of Cameroon to
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L. Ben-Nun King David

7.9% in a rural district in Ethiopia. More than half of studies (6/11)


reported no blindness due to URE. The proportion of moderate VI
(PVA ≤6/60 and >6/18) due to URE ranged from 12.3% to 57.1%.
Excluding two studies that included uncorrected aphakia as part of
URE, the highest proportion of blindness and severe VI due to
uncorrected aphakia was in Gambia (15.2%) and Nigeria (15.8%),
respectively. Although URE is a leading cause of VI, it does not
represent a major cause of blindness in sub-Saharan Africa (4).
The WHO definitions of blindness and VI are widely based on
BCVA excluding URE as a VI cause. Recently, URE was included as a
cause of VI, thus emphasizing the burden of VI due to RE worldwide is
substantially higher. The purpose of the present study is to
determine the reversal of VI and blindness in the population
correcting RE and possible associations between RE and individual
characteristics. A cross-sectional study was conducted in nibe
counties of the western region of state of São Paulo, using systematic
and random sampling of households between March 2004 and July
2005. Individuals aged more than one year old were included and
were evaluated for demographic data, eye complaints, history, and
eye examination, including no corrected VA, BCVA, automatic and
manual refractive examination. The definition adopted for URE was
applied to individuals with NCVA > 0.15 logMAR and BCVA ≤ 0.15
logMAR after refractive correction and unmet RE individuals who had
VI or blindness (NCVA > 0.5 logMAR) and BCVA ≤ 0.5 logMAR after
optical correction. A total of 70.2% of subjects had normal no
corrected VA. URE was detected in 13.8%. Prevalence of 4.6% of
optically reversible low vision and 1.8% of blindness reversible by
optical correction were found. Unmet RE was detected in 6.5% of
individuals, more frequently observed in women over the age of 50
and in higher RE carriers. VI related to eye diseases is not reversible
with spectacles. Using multivariate analysis, associations between
URE and unmet RE with regard to sex, age and RE was observed. In
conclusion, RE is an important cause of reversible blindness and low
vision in the Brazilian population (5).
The purpose of this study was to describe the prevalence and the
risk factors of URE in an adult urban Malay population. This
population-based, cross-sectional study was conducted in Singapore
in 3,280 Malay adults, aged 40 to 80 years. All individuals were
examined at a centralized clinic and underwent standardized
interviews and assessment of REs and presenting and BCVAs.
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L. Ben-Nun King David

Distance presenting VA was monocularly measured by using a


logarithm of the minimum angle of resolution (logMAR) number
chart at a distance of four meters, with the participants wearing their
"walk-in" optical corrections (spectacles or contact lenses), if any.
Refraction was determined by subjective refraction by trained,
certified study optometrists. BCVA was monocularly assessed and
recorded in logMAR scores using the same test protocol as was used
for presenting VA. URE was defined as an improvement of at least 0.2
logMAR (two lines equivalent) in the BCVA compared with the PVA in
the better eye. The mean age of the subjects included in this study
was 58 +/- 11 years, and 52% of the subjects were women. The
prevalence rate of URE among Singaporean Malay adults in this study
(n=3,115) was 20.4% (age-standardized prevalence rate, 18.3%).
More of the women had URE than the men (21.8% vs. 18.8%,
p=0.04). URE was also more common in subjects older than 50 years
than in subjects aged 40 to 49 years (22.6% vs. 14.3%, p<0.001). Non-
spectacle wearers were more likely to have UREs than were spectacle
wearers (24.4% vs. 14.4%, p<0.001). Persons with primary school
education or less were 1.89 times (p=0.03) more likely to have UREs
than those with post-secondary school education or higher. By
contrast, persons with a history of eye disease were 0.74 times
(p=0.003) less likely to have UREs. The proportion of URE among the
Singaporean Malay adults with REs was higher than that of the
Singaporean Chinese adults with REs. In conclusion, URE is a
significant cause of correctable VI among Singaporean Malay adults,
affecting one in five persons (6).
The purpose of this study was to describe the ethnic variations in
the prevalence and risk factors for URE and its impact on vision-
specific functioning in a multiethnic Asian population. A total of
3,353 Chinese, 3,400 Indians, and 3280 Malays in Singapore
participated in this population-based cross-sectional study. Distance
VA was measured using a logarithm of the minimum angle of
resolution number chart. BCVA was assessed using the same test
protocol as presenting VA. URE was defined as an improvement of at
least 0.2 logarithm of the minimum angle of resolution (two lines
equivalent) in the BCVA compared with the presenting VA in the
better eye when presenting VA was less than 20/40 in the better eye.
The VF-11 questionnaire measured participants' vision-specific
functioning. Multivariate linear regression was performed to assess
the impact of URE on the overall vision-specific functioning score.
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L. Ben-Nun King David

Regardless of ethnicity, participants with URE had a reduction in


vision-specific functioning score compared to those with normal
vision in both eyes. The overall prevalence of URE was highest in
Indians (25.1%), followed by Malays (22.2%) and Chinese (19.7%).
URE was less common in spectacles or contact lenses wearers than in
non-spectacle wearers or non-contact lenses wearers. Adults with
mild to moderate REs were most likely to have URE (p<0.001). In
multivariate analysis, increasing age (p<0.001), Indian race (p<0.001),
lower education level (p<0.001) or poorer housing (p<0.001), having
REs (p<0.001), and not wearing optical corrections (p<0.001) were
significantly associated with increasing URE. In conclusion, in
Singapore, URE is most prevalent in Indians and least prevalent in
Chinese. The impact of URE on vision-specific functioning was
consistent across all three ethnicities. There may be higher barriers
to visual correction among Malays or Indians compared with Chinese
in Singapore (7).
The purpose of this study was to determine the prevalence and
risk factors for REs in middle-aged to elderly Singaporeans of Indian
ethnicity. A population-based, cross-sectional study of Indians aged
over 40 years of age residing in Southwestern Singapore was
conducted. An age-stratified (10-year age group) random sampling
procedure was performed to select participants. Refraction was
determined by autorefraction followed by subjective refraction.
Myopia was defined as spherical equivalent < -0.50 D., high myopia
as spherical equivalent < -5.00 D., astigmatism as cylinder < -0.50 D,
hyperopia as SE > 0.50 D., and anisometropia as spherical equivalent
difference > 1.00 D. Prevalence was adjusted to the 2000 Singapore
census. Of the 4,497 persons eligible to participate, 3,400 (75.6%)
were examined. Complete data were available for 2,805 adults with
right eye RE and no prior cataract surgery. The age-adjusted
prevalence was 28.0% (95% CI, 25.8-30.2) for myopia and 4.1% (95%
CI, 3.3-5.0) for high myopia. There was a U-shaped relationship
between myopia and increasing age. The age-adjusted prevalence
was 54.9% (95% CI 52.0-57.9) for astigmatism, 35.9% (95% CI 33.7-
38.3) for hyperopia, and 9.8% (95% CI 8.6-11.1) for anisometropia. In
a multiple logistic regression model, adults who were female,
younger, taller, spent more time reading and writing per day, or had
astigmatism were more likely to be myopic. Adults who were older or
had myopia or DM had higher risk for astigmatism. In conclusion, in
Singapore, the prevalence of myopia in Indian adults is similar to
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L. Ben-Nun King David

those in Malays, but lower than those in Chinese. Risk factors for
myopia were similar across the three ethnic groups in Singapore (8).
The purpose of this cross-sectional survey of all adults aged 40
and over within a desert and coastal community study was to assess
the contribution of trachoma, cataract and RE to visual morbidity
among Indigenous adults living in two remote communities of the
Northern Territory, Australia. Main outcome measures included VA,
clinical signs of trachoma using the simplified WHO grading system
and assessment of cataract through a non-dilated pupil. Two
hundred and sixty individuals over the age of 40 years participated in
the study. The prevalence of VI (<6/12) was 17%. The prevalence of
blindness (<3/60) was 2%, 40-fold higher than seen in an urban
Australian population when adjusted for age. In total, 78% of adults
who grew up in a desert community had trachomatous scarring
compared with 26% of those who grew up in a coastal community
(p≤0.001). In the desert community, the prevalence of trachomatous
trichiasis was 10% and corneal opacity reached 6%. No trachomatous
trichiasis or corneal opacity was seen in the coastal community. In
conclusion, trachoma, cataract and URE remain significant
contributors to visual morbidity in at least two remote indigenous
communities (9).

ASSESSMENT: UREs are important contributors to visual


morbidity. The prevalence of URE ranges widely worldwide. Since
both blindness and VI are associated with URE, a question that arises
is whether King David suffered from RE?

References
1. The prevalence of refractive errors among adults in the United States,
Western Europe, and Australia. The eye diseases prevalence research
group. Arch Ophtalmol. 2004; 122:495-505.
2. Verhoeven VJ, Wong KT, Buitendijk GH, et al. Visual Consequences of
Refractive Errors in the General Population. Ophthalmology. 2014 Sep 7. pii:
S0161-6420(14)00641-1.
3. Sherwin JC, Khawaja AP, Broadway D, et al. Uncorrected refractive
error in older British adults: the EPIC-Norfolk Eye Study. Br J Ophthalmol.
2012;96(7):991-6.
4. Sherwin JC, Lewallen S, Courtright P. Blindness and visual impairment
due to uncorrected refractive error in sub-Saharan Africa: review of recent
population-based studies. Br J Ophthalmol. 2012;96(7):927-30.
245
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5. Ferraz FH, Corrente JE, Opromolla P, Schellini SA. Influence of


uncorrected refractive error and unmet refractive error on visual
impairment in a Brazilian population. BMC Ophthalmol. 2014 Jun 25;14:84.
6. Rosman M, Wong TY, Tay WT, et al. Prevalence and risk factors of
undercorrected refractive errors among Singaporean Malay adults: the
Singapore Malay Eye Study. Invest Ophthalmol Vis Sci. 2009;50(8):3621-8.
7. Pan CW, Chiang PP, Wong TY, et al. Ethnic differences in
undercorrected refractive error in Asians. Optom Vis Sci. 2014;91(2):212-20.
8. Pan CW, Wong TY, Lavanya R, et al. Prevalence and risk factors for
refractive errors in Indians: the Singapore Indian Eye Study (SINDI). Invest
Ophthalmol Vis Sci. 2011;52(6):3166-73.
9. Wright HR, Keeffe JE, Taylor HR. Trachoma, cataracts and uncorrected
refractive error are still important contributors to visual morbidity in two
remote indigenous communities of the Northern Territory, Australia. Clin
Experiment Ophthalmol. 2009;37(6):550-7.

OCULAR MANIFESTATIONS OF CANCER


Ocular manifestations of systemic malignancy are important for
both the ophthalmologist and the internist to recognize because they
may precede the diagnosis of cancer (1). Cancer may affect the eye
and orbit as a direct result of metastatic neoplastic infiltration,
compression, or circulating antibodies involving paraneoplastic
retinal degeneration. A metastatic tumor to the uvea is the most
common form of an intraocular metastatic process. The choroid is
the most common site for uveal metastasis; metastases to the ciliary
body, iris, retina, optic disc, and vitreous are rare. Approximately
one-third of patients have no history of primary cancer at the time of
ocular diagnosis. Breast and lung carcinomas for women and lung
and G-I carcinomas for men most commonly metastasize to the eye
and orbit. The visual paraneoplastic syndromes encompass several
distinct clinical and pathological entities including CAR, melanoma-
associated retinopathy and bilateral diffuse melanocytic uveal
proliferation (2).
The CAR is a paraneoplastic retinopathy in which an antigen-
antibody reaction, due to retinal antigens, also expressed in tumors,
leads to degeneration of retinal photoreceptor cells. The CAR is most
frequently associated with SCLC and ovarian carcinomas. Clinical
symptoms (phosphenes, and progressive loss of eyesight) sometimes
occur before the diagnosis of primary cancer (3).
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L. Ben-Nun King David

The term "Masquerade Syndrome" was first used in


ophthalmology in 1967 by Theodore to describe a case of
conjunctival carcinoma that manifested as chronic conjunctivitis. The
Uveitis Masquerade Syndromes are a group of ocular diseases that
mimic chronic intraocular inflammation. Most common malignant
conditions, which may be considered masquerades, include primary
intraocular lymphoma, leukemias, uveal melanoma, retinoblastoma,
metastatic lesions, and paraneoplastic syndromes (4).
Choroidal metastasis as an initial presenting feature of metastatic
lung cancer is exceedingly rare. EBRT is an effective and widely
accepted therapeutic modality. A patient with choroidal metastases
secondary to lung cancer is presented. A 25-year-old male presented
with deterioration of vision. His evaluation revealed bilateral
choroidal metastasis secondary to adenocarcinoma of the lung.
Unfortunately, his vision continued to deteriorate despite treatment
with EBRT and chemotherapy. Choroidal metastasis as an initial
presentation of metastatic lung cancer is exceedingly rare, as 30
cases have been reported. EBRT and systemic chemotherapy are
effective therapeutic modalities. This case report could prove helpful
to clinicians faced with a similar exceedingly rare scenario (5).
Symptomatic choroidal metastasis is a rare presenting
manifestation of lung cancer. Three patients with non-squamous
NSCLC were presented with choroidal metastasis. A systematic
literature review of the previously reported patients with choroidal
metastasis from lung cancer in the English-language literature was
conducted. Case series lacking individual patient data were excluded.
Of 75 patients identified, choroidal metastasis in 23 was not the
presenting manifestation of lung cancer. Therefore, 55 patients
(three index and 52 previously reported) were included in the
analysis. The majority of patients were male (67.3%) and were
current or ex-smokers (78.3%); the mean age was 55.1 (SD 11.2)
years. Adenocarcinoma (n=23) was the most common histologic type
followed by squamous (n=11) and small cell (n=8). Left eye (n=32)
involvement was more common than right eye (n=19) or bilateral
(n=4). Among patients for whom the location of primary lesion was
specified, the left upper lobe (n=13) was the most common site. The
most common diagnostic modalities were bronchoscopic lung biopsy
(n=15) and enucleation (n=13), while the liver (30.9%) was the most
common extraocular metastatic site identified. Systemic
chemotherapy was given in 56.4% of cases, and disease progression
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L. Ben-Nun King David

was the most common outcome among evaluable patients. Ocular


treatment modalities included radiation (n=23), enucleation (n=14),
and systemic steroids (n=8). Regression of choroidal metastases with
treatment was observed in 66.7% of patients who did not undergo
enucleation as the primary treatment modality. Of the three index
patients, two each received pemetrexed-cisplatin (as first-line
therapy), gefitinib or erlotinib (as second- or third-line therapy), and
intravitreal bevacizumab; and one patient received systemic
bevacizumab. Two patients had partial response radiologically with
systemic treatment, and all three patients had regression of
choroidal metastases with ocular treatment (6).
Choroidal metastasis is the most common intraocular neoplasm
and is associated with significant morbidity. In a small percentage of
patients, ocular manifestation is the initial presentation of a systemic
malignancy and can be diagnostically difficult to distinguish from
ocular primary malignancies. A case of a never-smoker whose ocular
pathology was integral to the diagnosis and management of a lung
adenocarcinoma harboring a rare oncogene. Through this case,
important diagnostic and therapeutic considerations of pulmonary
metastases to the choroid were explored (7).
Choroidal metastasis from prostate adenocarcinoma is
exceedingly rare. A 62-year-old male patient with metastatic prostate
cancer was found to have a choroidal metastasis after complaining of
decreased vision in his left eye. Following treatment with EBRT,
complete response in the choroidal metastasis was demonstrated.
Choroidal metastasis secondary to adenocarcinoma of the prostate is
exceedingly rare, as only eight cases have been reported so far. EBRT
is an effective therapeutic modality (8).
Intraocular choroidal metastasis is a very rare cause of blindness.
Carcinoma of breast is the most common primary malignancy the
accounts for choroidal metastasis in females. Other primary
neoplasms which can uncommonly metastasize to the choroid are G-I
tract, thyroid, pancreas, prostate and testis. Metastatic neoplasm to
the eye outnumbers the primary tumors such as retinoblastoma and
malignant melanoma. A case of sudden loss of vision due to breast
cancer metastasis to the eyeball is presented. The interval between
the diagnosis of the primary tumor and the choroidal metastasis was
four years (9).
Cancerous cells metastasize to different ocular structures. This
happens especially to the choroid in males with lung cancer and
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L. Ben-Nun King David

females with breast cancer. However, two cases of cancerous


metastasis to the optic canal region are observed. Both cases showed
only a progressive decrease in vision without any other remarkable
ophthalmological symptoms or abnormalities in the affected eye.
Two females, a 60-year-old and a 73-year-old, came to the hospital
because of progressive loss of vision. These patients showed no
remarkable symptoms or signs in their eyes except VA loss. Several
ophthalmoscopic examinations, such as slit lamp microscopy and
fundoscopy, showed no abnormal changes in their affected eye but
MRI indicated a massive legion around the optic nerve. In conclusion,
it is possible for cancer to metastasize to the optic canal region and
the existence of primary tumors should be considered (10).
A 47-year-old man with a history of lung adenocarcinoma
presented a red and painful right eye with loss of VA after the fifth
course of chemotherapy. The ophthalmologic examination showed
VA at 3/1 and diffuse iris nodular lesions in the same eye. The ocular
scan demonstrated iris tumors without choroidal metastasis (11).
A case of SCC of the lung with metastasis to the iris during a stage
of complete remission obtained with chemotherapy and radiation
therapy is reported (12).
Reddish/orange color is a commonly observed feature of the
uveal metastasis of thyroid carcinoma. Although ocular and skin
metastases from thyroid carcinoma are rare, this possibility should be
considered in the differential diagnosis of reddish-colored iris and
choroidal masses (13).
A 47-year-old healthy man sought treatment for a three-week
history of a progressively enlarging red spot on the left iris. Iris biopsy
revealed the lesion represented metastasis, and a systemic
evaluation revealed the primary source of esophageal
adenocarcinoma (14).
Of 227 patients with carcinoma metastatic to the eye or orbit, 26
metastases to the anterior uveal tract was the predominant feature.
There was a definite propensity for the tumor to involve the
horizontal meridian of the iris or ciliary body, rather than the upper
or lower portion. The site of the primary tumor in the 26 patients was
as follows: lung, 14; breast, nine; kidney, two; and rectum, one.
Ocular symptoms and signs produced by the metastatic tumor at
onset or during the course of the disease included a decreased vision
(80%), a visible mass (72%), redness of the eye (56%), pain (56%),
glaucoma (56%), iridocyclitis (44%), and hyphema (24%). The median
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L. Ben-Nun King David

survival of the 26 patients with metastasis to the anterior segment of


the eye was only 5.4 months from the time of ocular surgery. This is
poorer than the median survival (7.2 months) of the patients with
metastasis confined to the posterior segment, and much worse than
the median survival (15.6 months) of the patients with orbital
involvement (15).
A case of orbital metastasis in a previously diagnosed metastatic
breast cancer in a 46-year old woman was presented with diplopia
and proptosis of her left eye bulb. An orbital CT and a MRI both
revealed an intra-orbital extra-bulbar mass of 1.5 × 3 cm in size, in
the left orbit. The patient had been diagnosed with stage IV breast
cancer four years before. She had received chemotherapy with
docetaxel and was on hormone therapy at the time of presentation
of her eye symptoms. Current treatment included systemic
combination therapy with docetaxel and capecitabine as well as local
irradiation with stereotactic radiosurgery (cyberknife). There was a
gradual improvement of local symptoms and signs. The metastatic
involvement of the orbit in malignant tumors is a rarely diagnosed
condition. Breast cancer accounts for the majority of these cases. The
appearance of eye symptoms in patients with a history of cancer
should always be investigated with a consideration of ocular
metastatic disease (16).
A case of orbital metastasis from HCC is reported. The clinical,
histopathological, and immunohistochemical characteristics of HCC
metastatic to the orbit are described. Results from histopathological
examination and histochemical findings of the orbital mass
established the diagnosis. A review of 10 cases of metastatic HCC to
the eye and orbit disclosed painful proptosis as the most common
clinical sign of HCC metastatic to the orbit. In five (56%) of the nine
cases that had orbital metastasis (including the present case), the
diagnosis was made after the patient first was examined with
symptoms from the orbital mass. Metastatic HCC should be
considered as a rare cause of painful proptosis. While patients usually
are seen with signs and symptoms of widespread metastatic
carcinoma, patients with HCC with orbital involvement may be first
examined by the ophthalmologist because of the clinical
manifestations of the disease, proptosis and pain (17).
An unusual orbital metastatic lesion as the only finding in a case of
HCC is reported. A 57-year-old man presented with a six-month
history of orbital painful right orbital mass, associated with proptosis.
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L. Ben-Nun King David

CT of the orbits showed an orbital soft tissue mass leading to bone


erosion and intracranial invasion. CT of the abdomen showed a focal
perfusion abnormality in the left lobe of the liver. Incisional biopsy
was performed and the histopathologic examination of the specimen
confirmed the diagnosis. The patient died 15 months after the initial
presentation. This is a rare case of orbital metastasis of HCC. There
was no another metastatic lesion and the patient reported only
ophthalmological symptoms (18).
A 45-year-old healthy male patient presented with proptosis due
to an orbital mass. Histopathologic examination indicated that the
tumor was a secondary from a HCC, and further investigations
revealed the primary tumor in the liver. HCC is a rare source of
metastasis to the orbit, and 14 histopathologically proven cases have
been reported. Proptosis was the most common presenting feature
in the reviewed reports. A majority of patients had occult primary
tumors at presentation and the diagnosis of the orbital mass was
based on histopathologic features (19).
HCC rarely metastasizes to the extra ocular muscles. A case of
bilateral metastasis of HCC to the extra ocular muscles is presented.
Orbital MRI revealed nodular enlargement of bilateral multiple extra
ocular muscles with isointensity on T1-weighted images and
heterogeneous, intermediate-to-high signal intensity on T2-weighted
images, and showed mild-to-significant heterogeneous contrast
enhancement with gadolinium. Physicians should be aware of this
rare cause, understand the radiologic characteristics of extra ocular
muscles metastasis, and make appropriate treatment strategy (20).
Renal cancers metastasize to the eye and the orbit. As these
tumors can be confused with other amelanotic or vascular tumors, a
high index of suspicion is required for early detection and
management of the primary tumor (21).
Prostate carcinoma, when metastatic, typically involves bones and
produces both osteoblastic and osteolytic changes. Orbital
involvement is uncommon and extraocular muscle enlargement is a
rare presentation of metastatic adenocarcinoma (22). Prostate
cancer may metastasize to an extraocular muscle many years after
treatment of the primary tumor and may not be accompanied by
elevated serum PSA (23). Clinicians should be aware that, although
rare, prostate cancer could involve the extraocular muscles (22).
A 70-year-old man without known systemic disease developed an
iris mass in his left eye. Iridocyclectomy was performed to remove
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L. Ben-Nun King David

the iris mass. Histopathologically, the iris mass was consistent with
metastatic RCC. Further evaluation disclosed a mass of the left
kidney. The patient underwent a left nephrectomy and was found to
have RCC, with focal penetration into the renal capsule. One month
after the nephrectomy, he developed a highly vascular nodule of the
left bulbar conjunctiva. An excisional biopsy was performed, and
histopathology disclosed an additional focus of RCC. In conclusion,
iris and conjunctival involvement may be a clinical manifestation of
RCC. RCC should be considered in the differential diagnosis of a
fleshy, vascular iris and a conjunctival nodule (24).
Three cases of RCC metastatic to the eye and orbit are reported.
The case reports of a 67-year-old man, a 58-year-old man, and a 23-
year-old woman with metastatic RCC are described. The iris mass
occurred in a 67-year-old man, a known case of RCC. Whereas the
orbital metastasis in the 58-year-old man was the initial presenting
sign in a hitherto undiagnosed patient, the orbital metastasis in the
23-year-old female patient was detected following nephrectomy for
RCC. RCC metastasizing to the eye and orbit are very rare, with only
68 cases reported previously. In patients presenting with atypical
orbital or ocular masses, the possibility of RCC metastasis should be
considered, especially if there is a history of previous renal disorder.
Incisional biopsy with histopathological evaluation is important to
diagnose this condition and facilitate appropriate therapy (25).
A 60-year-old woman presented with proptosis of the left eye.
Imaging showed a well-circumscribed tumor in the region of the
medial rectus muscle. Excision biopsy revealed a diagnosis of
metastatic RCC that was confirmed on abdominal imaging. RCC can
rarely present as a well-circumscribed orbital mass and should be
included in the differential diagnosis of such lesions (26).
A case of lung cancer in which symptoms due to orbital metastasis
were recognized. A 55-year-old man presented with a chief complaint
of double vision. Orbital MRI demonstrated a right intraorbital mass
with bone destruction, which resulted in oculomotor nerve palsy and
optic nerve disturbance. Chest CT scan showed a four cm mass in the
right S6, which was diagnosed on biopsy as a poorly differentiated
adenocarcinoma. A whole-body scintigram revealed multiple bone
metastases: the right orbital wall, the lower cervical spine, the left knee
joint, and so on. Based on the clinical findings, the orbital tumor was a
metastasis from the lung. Systemic chemotherapy and irradiation of the
right orbital tumor and the left knee joint were performed. Though a
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L. Ben-Nun King David

favorable response was achieved in ocular movement, the patient died


three months after initial treatment because of progression of the
primary lesion (27).
Two cases of SCLC first presented with orbital metastasis. Orbital
metastasis from solid tumors is a rare entity. The predominating
primaries in Western countries are breast and lung tumors;
hepatocellular and gastric malignancies lead in Japanese series. Clinical
symptoms and findings reflect the mass effect and the degree of extra-
ocular muscle invasion. Treatment is guided by the cancer type and the
tumor histology. The prognosis is grim, and with the exception of rare
cases secondary to hormone-responsive tumors, the majority of
patients succumb to their disease within a year of diagnosis (28).
An 88-year-old woman was referred to an eye clinic in mid-May
2000 because of limitation of ocular movement. A right orbital tumor
was recognized on orbital CT scans and she was referred to the
hospital. A chest X-ray film showed an abnormal mass in the right
middle lung field, so she was admitted for further investigations.
Adenocarcinoma was diagnosed by transbronchial lung biopsy. The
right orbital tumor was thought to be a metastasis from the lung
cancer. She received radiation therapy for the metastatic orbital tumor.
However, two months after the onset of symptoms, she died due to
progressive systemic metastasis. In summary, an elderly lung cancer
patient whose initial symptoms were related to orbital metastasis is
reported (29).
MM is a plasma cell malignancy that destroys skeletal, renal, and
neurological function. Orbital involvement is rare, but has been
considered an initial presentation for the malignancy. Furthermore,
an association between the subtype of MM and the likelihood of
orbital infiltration has been suggested. A case of an orbital mass was
a recurrence of MM. A literature search was performed to evaluate
the presentation characteristics of orbital MM, plasmacytoma and
primary (or solitary) extramedullary plasmacytoma. Past reports were
analyzed for age, sex, symptoms at presentation, time from symptom
onset to presentation, prior diagnosis before presentation for orbital
symptoms, radiological characteristics, immunoglobulin subtype, and
survival times. Less than half of published cases had orbital MM as
the primary presentation. Proptosis is the major presenting sign of
orbital MM, and radiological evaluation shows that the majority of
masses originate in the superotemporal quadrant. The dominant
immunoglobulin subtype was IgG (30).
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L. Ben-Nun King David

Ophthalmic manifestations of MM may appear at the initial


presentation of the disease or occur late in the disease process (31).
Ocular findings include: proptosis, diplopia, lid ecchymosis,
xanthomatosis, conjunctival and corneal crystalline and non-
crystalline deposits, scleritis, episcleritis, secondary glaucoma, ciliary
body cysts, ciliochoroidal effusion, uveal plasmacytoma,
hyperviscosity retinopathy, and retinal vasculitis, detachment of
sensory retina and RPE, and neuro-ophtalmic manifestations (32).
MM is the most common plasma cell tumor; however, ocular
plasmacytomas are rare and can appear in almost any structure of
the eye. Three cases, including two with unique ophthalmic
ultrasound images of ocular plasmacytoma are presented. Three
patients with ocular manifestations of MM are described. All were
noted to have known synchronous systemic disease. In this study,
patients presented with epibulbar (n=2), iridociliary (n=1), and orbital
plasmacytomas (n=2). Presenting signs included clinically visible
tumor (n=2), blurred vision (n=2), diplopia (n=2), and glaucoma (n=1).
The iridociliary plasmacytoma was defined by high-frequency 35-MHz
ultrasonography that revealed 360° of anterior chamber
involvement, secondary angle-closure, and extent of iridociliary
invasion. In another case, low-frequency B-scan ultrasonography
found MM of the orbit. In conclusion, ocular manifestations of
plasma cell neoplasms are rare. In MM, plasmacytomas can present
as a solitary tumor, as an initial sign of systemic disease, or as
recurrence. This study presents three cases in which epibulbar,
orbital, and iridociliary plasmacytoma with secondary glaucoma were
presenting signs of uncontrolled MM (33).
A case of a 62-year-old female with history of MM presented with
complains of swelling and pain in her right eye. On examination, she
has proptosis, chemosis, and diplopia along with decreased vision.
Initial workup and treatment did not yield significant results;
eventually she was found to have myelomatous changes in her right
orbit on MRI and was diagnosed with myeloma of the orbit which
resolved solely with radiation. This case tends to highlight the
importance of considering MM of the orbit as an important and early
differential diagnosis in a patient with a history of MM presenting
with a swollen and painful eye (34).
Plasma cell neoplasms, including plasma cell myeloma or MM,
MGUS, or as variants of plasma cell myeloma such as indolent
myeloma, smoldering myeloma, osteosclerotic myeloma, plasma cell
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L. Ben-Nun King David

leukaemia and non-secretory myeloma, represent autonomous


proliferations of plasma cells and can manifest as diffuse myeloma
with systemic involvement; localized neoplastic proliferation of
plasma cells presents as solitary plasmacytoma of bone or
extramedullary plasmacytoma. Involvement of orbit can occur as a
solitary plasmacytoma, or as part of systemic involvement in MM,
the clinical outcome being significantly worse in the latter setting.
Orbital involvement in MM is very rare with less than 50 cases
reported in the literature. Early cytological diagnosis of such lesions is
vital for timely institution of appropriate therapy. A 37-year-old male
presented with low-grade fever showing evening rise, headache,
diplopia and swelling in the right periorbital and temporal region.
Imaging studies revealed destructive lesion of sphenoid, frontal bone
and zygomatic arch with soft tissue component extending to
infratemporal fossa and orbit. A fine needle aspirate from the
temporal region swelling showed features of a plasmacytoma, and
subsequent workup confirmed the presence of systemic disease. A
final diagnosis of MM with orbital involvement at presentation was
made. In conclusion, present case describes the extremely rare
presentation of MM with orbital involvement and highlights the
utility of cytology in such lesions. Fine needle aspiration diagnosis of
plasmacytoma at extramedullary sites offers an opportunity for non-
invasive verification of systemic involvement, and thus plays a major
role in early diagnosis and management of these patients (35).
A case of orbital plasmacytoma in a 48-year-old man with known
MM is reported. He presented with proptosis, diplopia, and
decreased vision of the left eye for several weeks. He had been
previously treated for IgA lambda MM with chemotherapy, radiation,
and ASCT. After a left orbitotomy, flow cytometry revealed a tumor
rich in plasma cells expressing CD138 with equivocal lambda light
chain expression. The patient underwent orbital radiation, with
improvement of vision and disc edema. The patient is currently
undergoing salvage chemotherapy for relapse of MM (36).
Plasmacytomas of the ocular and adnexal tissue are rare. The
clinical features and laboratory data of five cases of plasmacytoma
involving the eye and orbit are reviewed. Plasmacytomas involved
the conjunctiva in one case, the orbit in three cases, and the iris in
one case. Plasmacytoma was the solitary plasma cell neoplasm in a
patient with a conjunctival lesion and another patient with an orbital
lesion. Two other patients who developed plasmacytomas of the
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orbit and iris, respectively, had a known history of MM. An orbital


plasmacytoma preceded the onset of systemic plasma cell neoplasia
in the final patient (37).
A case of plasmacytoma of the orbit involved lacrimal gland with
secondary transformation into MM in a 42-year-old woman. The
lesion was surgically removed. Histopathological examination with
immunostaining revealed that it was positive for Ig G and Kappa
chains, demonstrating monoclonality. However, no abnormality was
observed on serum electrophoresis, skeletal survey and bone marrow
aspiration. The tumor was diagnosed solitary plasmacytoma of bone.
The patient was treated with EBRT and has remained disease free for
five years and six months until 2007, when she presented a
pathological fracture due to MM. Extensive medical work-up to rule
out MM or other malignant lymphoproliferative conditions involving
orbit or ocular adnexa is needed when the diagnosis of solitary
plasmacytoma of bone is suspected because treatment and prognosis
are different (38).

ASSESSMENT: a wide range of tumors metastasizes into the eye/s.


Symptoms of ocular metastasis include include: proptosis, pain,
diplopia, lid ecchymosis, xanthomatosis, conjunctival and corneal
crystalline and non-crystalline deposits, scleritis, episcleritis,
secondary glaucoma, ciliary body cysts, ciliochoroidal effusion, uveal
plasmocytoma, hyperviscosity retinopathy, and retinal vasculitis,
detachment of sensory retina and RPE, and neuro-ophtalmic
manifestations, blurred vision, progressive or sudden loss of vision, a
visible mass, redness of the eye, glaucoma, iridocyclitis, hyphema,
and glaucoma. Intraocular choroidal metastasis is a very rare cause of
blindness.
Can these symptoms be related to the metastatic ocular disease in
the King?
As we see, various types of cancers may affect eyes. As previously
shown (39,40), it is most likely that the King had suffered from some
malignant disease. Among these neoplastic diseases, it is most likely
that the King was afflicted either by MM, or RCC, or prostate cancer
(41), or gastric carcinoma, or CRC, see the sections below. Did one of
these diseases spread to the eye/eyes? The passages “My eye is
consumed…” (Psalm 6:8; 31:10) and “As for the light of my eyes, it is
also gone from me” (38:11) indicate blindness.
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L. Ben-Nun King David

Although the diagnosis of metastatic ocular diseases cannot be


absolutely ignored, in the absence of ophthalmological examination
this diagnosis is unlikely in King David's case.

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malignancies. Curr Opin Opthalmol. 1999;10:447-51.
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cancer. J Fr Optalmol. 2002;25:194-202.
3. Matus G, Dicato M, Focan C. Cancer associated retinopathy (CAR). Two
clinical cases and review of the literature. Rev Med Liege. 2007;62:166-9.
4. Kubicka-Trzaska A, Romanowska-Dixon B. Malignant uveitis masquerade
syndromes. Klin Oczna. 2008;110:199-202.
5. Salah S, Khader J, Yousef Y, et al. Choroidal metastasis as the sole initial
presentation of metastatic lung cancer. Hematol Oncol Stem Cell Ther.
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presenting manifestation of lung cancer: a report of 3 cases and systematic
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7. Jiang K, Brownstein S, Sekhon HS, et al. Ocular metastasis of lung
adenocarcinoma with ELM4-ALK translocation: A case report with a review of
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9. Antosz ZS, Walocha J, Poręba R, et al. Sudden loss of vision due to breast
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10. Tamai H, Ishida K, Murakami K, et al. Compression neuropathy caused by
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11. Benhaddou R, Sayouti A, Khoumiri R, et al. Iris metastasis from lung
cancer. J F Ophtalmol. 2008;31:427-9.
12. Furuichi S, Omori C, Nakayama T, et al. Relapse of small cell carcinoma of
the lung with metastases to iris. Nihon Kokyuk Gakkai Zasshi. 2000;38:417-20.
13. Arat YO, Boniuk M. Red lesions of the iris, choroid, and skin secondary to
metastatic carcinoma of the thyroid: a review. Surv Ophtalmol. 2007;52:523-8.
14. Lee WB, Sy HM, Filip DJ, Grossniklaus HE. Metastatic esophageal
adenocarcinoma presenting in the iris. Am J Ophthalmol. 2007;144:477-9.
15. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit II. A
clinicopathological study of 26 patients with carcinoma metastatic to the
anterior segment of the eye. Arch Ophtalmol. 1975;93:472-82.
16. Lachostergios PJ, Voutsadakis IA, Papandreou CN. Orbital metastasis of
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17. Font RL, Maturi RK, Small RG, Garcia-Rojas M. Hepatocellular carcinoma
metastatic to the orbit. Arch Ophthalmol. 1998;116(7):942-5.
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18. Fonseca Júnior NL, Frizon L, Paves L, et al. An unusual orbital metastatic
lesion: the only finding in a case of hepatocellular carcinoma: case report. Arq
Bras Oftalmol. 2008;71(6):865-7.
19. Gupta R, Honavar SG, Vemuganti GK. Orbital metastasis from
hepatocellular carcinoma. Surv Ophthalmol. 2005;50(5):485-9.
20. Jiang H, Wang Z, Xian J, Ai L. Bilateral multiple extraocular muscle
metastasis from hepatocellular carcinoma. Acta Radiol Short Rep. 2012 Jan
12;1(1).
21. Kurli M, Finger PT. The kidney, cancer, and the eye: current concepts.
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22. Alsuhaibani AH, Carter KD, Nerad JA, Lee AG. Prostate carcinoma
metastasis to extraocular muscles. Ophtal Plast Reconstr Surg. 2008;24:233-5.
23. Scott IU, Tanenbaum M, Kay MD, Gould E. Extraocular muscle metastasis
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2001;32:479-80.
24. Ware GT, Haik BG, Morris WR. Renal cell carcinoma with involvement of
iris and conjunctiva. Am J Ophthalmol. 1999;127(4):460-1.
25. Shome D, Honavar SG, Gupta P, et al. Metastasis to the eye and orbit
from renal cell carcinoma - a report of three cases and review of literature. Surv
Ophthalmol. 2007;52(2):213-23.
26. Mudiyanselage SY, Prabhakaran VC, Davis GJ, Selva D. Metastatic renal
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initial symptoms due to orbital metastases. Nihon Kokyuki Gakkai Zasshi.
2003;41(1):19-24.
28. Henning M, Hu Q, Siegelmann-Danieli N. Orbital metastasis as the
presenting symptom of extensive stage small cell lung cancer. Eur J Intern Med.
2008;19(1):65-6.
29. Kikawada M, Shimizu S, Uno M, et al. An elderly case of lung cancer
presenting with symptoms of orbital metastasis. Nihon Ronen Igakkai Zasshi.
2001;38(4):560-3.
30. Burkat CN, Van Buren JJ, Lucarelli MJ. Characteristics of orbital multiple
myeloma: a case report and literature review. Surv Ophthalmol. 2009;54(6):697-
704.
31. Fung S, Selva D, Leibovitch I, et al. Ophthalmic manifestations of multiple
myeloma. Opthalmologica. 2006;219:43-8.
32. Omoti AE, Omoti CE. Ophthalmic manifestations of multiple myeloma.
West Afr J Med. 2007;26:265-8.
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myeloma: three cases and a review of the literature. Optometry.
2011;82(4):224-30.
34. Hassan M, Alirhayim Z, Sroujieh L, Hassan S. Multiple myeloma of the
orbit. Case Rep Ophthalmol Med. 2012;2012:252310.
35. Sharma A, Kaushal M, Chaturvedi NK, Yadav R. Cytodiagnosis of multiple
myeloma presenting as orbital involvement: a case report. Cytojournal. 2006
Aug 10;3:19.
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36. Hsu VJ, Agarwal MR, Chen CS, Rossi C. IgA orbital plasmacytoma in
multiple myeloma. Ophthal Plast Reconstr Surg. 2010;26(2):126-7.
37. Adkins JW, Shields JA, Shields CL, et al. Plasmacytoma of the eye and
orbit. Int Ophthalmol. 1996-1997;20(6):339-43.
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involving lacrimal gland with secondary transformation into multiple myeloma:
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39. Ben-Noun L. The disease that caused weight loss in King David the Great.
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40. Ben-Noun L. What was the disease of the bones that affected King
David? J Gerontol Med Sci. 2002;57:M152-4.
41. Ben-Noun L. In: Ben-Noun L. (ed.). The Family Life Cycle and the Medical
Record of King David the Great. B.N. Publication House. 2009. Israel.

OTHER CAUSES
Other causes of vision loss include trachoma, leprosy,
onchocerciasis, xerophthalmia, HSV keratitis, retinal detachment, and
inherited retinal degenerative disorders (1).
Trachoma is the commonest infectious cause of blindness
worldwide. Recurrent infection of the ocular surface by C.
trachomatis, the causative agent, leads to inturning of the eyelashes
(trichiasis) and blinding corneal opacification. Trachoma is endemic in
more than 50 countries. It is currently estimated that there are about
1.3 million people blind from the disease and a further 8.2 million
have trichiasis. Several estimates for the burden of disease from
trachoma have been made, giving quite variable results. The variation
is partly because different prevalence data have been used and partly
because different sequelae have been included. The most recent
estimate from the WHO placed it at around 1.3 million DALYs. A key
issue in producing a reliable estimate of the global burden of
trachoma is the limited amount of reliable survey data from endemic
regions (2,3).
Trachoma is correlated with poverty, limited access to healthcare
services and water. In 2003, the WHO estimated that 84 million
people were suffering from active trachoma, and 7.6 million were
severely visually impaired or blind because of trachoma: this study
provides an updated estimate of the global prevalence of trachoma
based on the most recent information available. A literature search
of recent published and unpublished surveys in the 57 endemic
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L. Ben-Nun King David

countries was carried out: the result of surveys that used the WHO
trachoma grading system and additional information from regional
and country experts served as a basis to determine the prevalence of
trachoma in each country. Population-based surveys provided recent
information for 42 out of 57 endemic countries with 40.6 million
people estimated to be suffering from active trachoma, and 8.2
million are estimated to have trichiasis. In conclusion, the current
estimate of prevalence of trachoma is lower than the previous WHO
estimates: this can be explained by the success in implementing
control strategy, by more accurate data, as well as by socio-economic
development in endemic countries (3).
Leprosy control programs are highly successful. As a result,
leprosy control will be more and more integrated into the general
health services. The existing vertical, specialized control programs
will be dismantled. Eye complications in leprosy have decreased. This
is a result of earlier diagnosis and highly effective MDT of leprosy,
combined with timely treatment of secondary nerve damage by
steroids. Most ocular morbidity is now found among elderly and
disabled leprosy patients who were diagnosed before effective MDT
treatment became available. Many of these patients live in leprosy
settlements. Age-related cataract has become the leading cause of
blindness in leprosy. The second cause of blindness is corneal
opacification, mainly as a result of neglected exposure keratitis and
corneal anaesthesia. The miotic pupils in late multibacillary leprosy,
in combination with small central lens opacities, may lead to
blindness. The Vision 2020 Initiative prioritizes cataract surgery.
Leprosy patients should be actively included. Disabled leprosy
patients can benefit from screening programs for REs and the
provision of spectacles and low vision aids. Determining the most
feasible surgical methods for lagophthalmos surgery remains a
challenge. For all health and eye care staff, training in leprosy and its
eye complications is needed, as well as a change in attitude towards
leprosy patients. Staff must be prepared to welcome them in the
general health services (4).
Of 742 outpatients screened for ocular disease, 177 (24%) had eye
lesions due to leprosy. These were more in the lepromatous
spectrum of the disease and showed increasing trend with age of
patient and duration of the disease. Madarosis was the commonest
lesion (76%). The serious and sight threatening lesions like
lagophthalmos, corneal anaesthesia, corneal opacities and ulcers,
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L. Ben-Nun King David

iritis and complicated cataracts constituted 8.22% of the lesions.


Blindness due to corneal opacity and complicated cataract developed
in six patients, constituting 3.4% of eye lesions with a prevalence rate
of 0.8% among all the leprosy patients. Although the blinding lesions
occurred in a very small percentage of patients, most of these are
preventable through early recognition and institution of appropriate
treatment. The simple techniques of examination to detect
potentially sight threatening lesions should be taught all leprosy
workers to prevent blindness among leprosy patients (5).
This cross-sectional study was aimed at presenting the profile of
ocular lesions observed in the in-mates on MDT, of a leprosy
rehabilitation centre in Nigeria. One hundred patients were selected
by systematic random sampling. The subjects of this study included
69 patients who had ocular involvement. The age range was 15 to 80
years with a mean age of 51 years. There were 57 males (82.6%) and
12 females (17.4%). The range of duration of treatment was two
months to 30 years, with a mean of 15 years. Examination of the
anterior and posterior segments of the globe and its adnexa was
carried out using Penlight, magnifying loupe and direct
ophthalmoscope. VA was recorded using the Snellen charts.
Lepromatous leprosy patients had the greatest incidence of ocular
lesions. Ocular lesions were more in patients who have had leprosy
for ≥15 years. Madarosis (72.5%) and lagophthalmos (29.0%) were
the commonest lesions. Corneal involvement was seen in 36.2%.
Conjunctivitis in 14.5%. trichiasis in 10.1% and ectropion in 8.7%;
17.4% were legally blind (VA≤3/60) in the better eye, and 17.4% had
cataract in at least one eye. There was statistically insignificant
difference in the incidence of ocular lesions among males and
females, and between patients with lepromatous and tuberculoid
leprosy. In conclusion, ocular complications are common and sight
threatening in leprosy patients. Regular screening and outreach
should be incorporated into leprosy care programs (6).
Onchocerciasis results from infestation by the nematode
Onchocerca volvulus and is characterized by troublesome itching,
skin lesions, and eye manifestations. Although partially controlled by
international mass prevention programs, onchocerciasis remains a
major health hazard and is endemic in Africa, Arabia, and the
Americas. Onchocerciasis is spread by bites from infested black flies,
which transmit larvae that subsequently develop into adult filariae.
Skin symptoms are commonly nonspecific and include severe
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pruritus, acute and chronic dermatitis, vitiligo-like hypopigmentation,


and atrophy. Onchocercal ocular disease covers a large spectrum of
manifestations, which in severe cases, may lead to blindness.
Diagnosis is usually made by direct visualization of the larvae
emerging from superficial skin biopsies, "skin snips." In some cases,
the microfilariae can also be directly observed at the slit lamp when
migrating into the anterior chamber of the eye. Ivermectin is the drug
of choice for skin and ocular manifestations. Recent research, using a
chemotherapeutic approach, targets filarial Wolbachia symbionts in
the treatment and control of onchocerciasis, suggests that 100 mg/d
of doxycycline for six weeks might be effective in reducing the filarial
load and preventing ocular symptoms (7).
In the Kaduna State, Nigeria, onchocerciasis focus, the prevalence
of RNB was 12.9%, while the national average reached 1% and in a
control non-onchocercal community 0.83% (p< 0.0001). Risk factors
for RNB were explored. This was an analysis of baseline data from
the phase 3 ivermectin trials in Kaduna (1988-1995); 6,831 subjects in
the onchocercal zone and 1,563 in the control zone were examined.
Ordinal logistic regression was used to assess the relationship
between microfilaria load (uninfected, low (<10 mf/mg), moderate
(10-49 mf/mg) and high (50+ mf/mg)) and likelihood of RNB. Ocular
evidence of vitamin A deficiency (Bitot spots or xerophthalmia) was
absent in both populations. The excess risk of nightblindness
attributable to domicile in this onchocerciasis-endemic area was
11.9% with a population attributable fraction of 92.2%. The
prevalence of RNB and age-AOR increased with higher microfilaria
load (p < 0.0027.) Subjects with onchocerciasis-related ocular lesions
(OND; age-AOR 2.29, 95% CI 1.86-2.83), sclerosing keratitis (OR 2.75,
95% CI 2.10-3.50), and onchocercal chorioretinitis (OR 1.66, 95% CI
1.22-2.26) were significantly more likely to report night blindness.
Overall, subjects with a primary diagnosis of 'ocular onchocerciasis'
were 50% more likely to report night blindness. OND, cataract and
trachoma together accounted for 52% of all RNB but OND
(onchocerciasis-related in 80% of cases) emerged as the single most
common associated pathology in 30% of cases. In conclusion,
onchocercal infection probably accounted for the excess of RNB in
this focus (8).
Ocular findings due to a vitamin A deficiency in a 50-year-old man
are described. The patient had undergone intestinal bypass surgery
two years before. After therapy with oral vitamin A the symptoms
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improved. The incidence of morbid obesity is increasing throughout


much of the developed world, with intestinal bypass surgery the
treatment of choice for most people with the condition. This type of
surgery can lead to a vitamin A deficiency, with remarkable
ophthalmological consequences, which without correct treatment
may ultimately cause blindness. For this reason, the pathology, even
though rare at present, must considered seriously (9).
Vitamin A deficiency remains a major cause of pediatric ocular
morbidity. Over five million children develop xerophthalmia annually,
a quarter million or more becoming blind. It is also a major pathway
for measles-associated blindness, particularly in Africa. Treatment is
practical and inexpensive, based upon the oral administration of
200,000 IU vitamin A on two successive days, at a cost of 10 cents
U.S. Given the potential rapidity of corneal necrosis (keratomalacia)
and the relative inaccessibility of health services to those at greatest
risk, prevention is probably more important than treatment. Oral
administration of high dose supplements (2000,000 IU every three to
six months), vitamin A fortification of commonly consumed items, or
best of all, increased dietary intake of natural sources of vitamin A
will reduce the number of needlessly blind young children. Given
recent evidence that vitamin A deficiency greatly increases overall
mortality, even among children without evidence of xerophthalmia,
the same prophylactic regimen may improve child survival by 35% or
more (10).
Of 216 children with vitamin A deficiency hospitalized in
Hyderabad, India, between 1970 and 1977, 22 died. Of 56 children
who were followed-up, 32 had keratomalacia and 24 corneal xerosis.
In the keratomalacia group, nine died of reasons attributable to
severe protein-energy malnutrition within three to four months after
discharge from the hospital, five became totally blind, nine
monocularily blind, and nine had adequate vision, although four of
these had leucomas. Of the blind children, no change in condition
was noted in the 11 located one year after the initial three to four
month follow-up period. Of the 24 children with corneal xerosis, two
died within three months, 21 retained normal vision, and one had
adequate vision with leucoma. The high death rate, i.e., 30% of the
keratomalacia cases in this study helps to explain the low prevalence
of keratomalacia observed in past and current community surveys.
The high return to normal vision in the corneal xerosis cases after
proper treatment supports the recommendation of treating all
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L. Ben-Nun King David

children with eye involvement before the keratomalacia state


whenever possible, for greater assurance of subsequent eye
improvement (11).
HSV is associated with a variety of ocular diseases, including
epithelial and stromal keratitis. HSV can cause stromal opacification
and is believed to be the leading cause of infectious blindness in the
developed world. An improved understanding of the global burden of
HSV keratitis, including the incidence of severe vision loss, could have
a significant effect on prevention and treatment and place it in
perspective among causes of corneal ulceration. The global incidence
of HSV keratitis is roughly 1.5 million, including 40,000 new cases of
severe monocular VI or blindness each year (12).
The purpose of this retrospective, noncomparative, observational
case series study was to review the clinical characteristics and visual
outcomes of patients with bilateral herpetic keratitis. A retrospective
review of medical records of 544 patients with HSV eye disease
treated between January 1996 and September 2001 was performed
at the Department of Ophthalmology, University of Minnesota. Seven
patients (1.3%) with bilateral herpetic keratoconjunctivitis were
identified. In these seven patients, the age at the initial onset of
corneal disease ranged from seven weeks to 46 years, with a median
of 18 years and a mean of 19.3 years. Five patients had systemic
atopy, and two patients had severe ocular rosacea. Systemic immune
disorders were noted in two patients. Recurrent
blepharoconjunctivitis was noted in eight eyes (57%), epithelial
keratitis in 12 eyes (85.7%), stromal keratitis in nine eyes (64.3%),
necrotizing stromal keratitis in five eyes (35.7%), and progressive
endotheliitis in two eyes (14.2%). Corneal complications included
opacification, neovascularization, and corneal thinning or
perforation. Penetrating keratoplasty was performed in one eye, in
which endophthalmitis subsequently developed, which required
enucleation. Four patients with continued use of oral antiviral
prophylaxis (acyclovir 400 mg twice daily) since September 1999
showed significant decreases in recurrence. The average remission in
these four patients was 1.7 years. The VA at the last follow-up was
20/40 or worse in six eyes (42.8%). In conclusion, in contrast to
unilateral HSV keratitis, patients with bilateral herpetic corneal
infections had underlying atopy or immune deviations and evinced
more protracted clinical courses. Long-term prophylactic antiviral
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L. Ben-Nun King David

treatment has reduced the incidence of recurrence in this group of


patients (13).
Rhegmatogenous retinal detachment is the most common
retinological emergency threatening vision, with an incidence of one
in 10,000 persons per year, corresponding to about 8,000 new cases
in Germany annually. Without treatment, blindness in the affected
eye may result. Selective review of the literature. Indicated that
rhegmatogenous retinal detachment typically presents with the
perception of light flashes, floaters, or a "dark curtain." In most cases,
the retinal tear is a consequence of degeneration of the vitreous
body. Epidemiologic studies have identified myopia and prior
cataract surgery as the main risk factors. Persons in the sixth and
seventh decades of life are most commonly affected.
Rhegmatogenous retinal detachment is an emergency, and all
patients should be seen by an ophthalmologist on the same day that
symptoms arise. The treatment consists of scleral buckle, removal of
the vitreous body (vitrectomy), or a combination of the two.
Anatomical success rates are in the range of 85% to 90%. Vitrectomy
is followed by lens opacification in more than 70% of cases. The
earlier the patient is seen by an ophthalmologist, the greater the
chance that the macula is still attached, so that VA can be preserved.
In conclusion, rhegmatogenous retinal detachment is among the
main emergency indications in ophthalmology. In all such cases, an
ophthalmologist must be consulted at once (14).
Hereditary macular dystrophies are degenerative diseases of the
central area of the retina associating primary anomalies of the RPE
and sensory retina. These conditions, whose hallmark is a loss of VA,
are a major cause of blindness and affect patients at all ages. Macular
dystrophies group diseases that are heterogenous at the genetic
level, as well as at the clinical, histological and physiopathological
levels. Monogenic macular dystrophies are rare autosomal dominant
conditions, with the exception of Stargardt disease in its typical form,
which is not only relatively frequent but is also inherited as an
autosomal recessive trait. During the last few years, the molecular
bases of these conditions have begun to be elucidated with the
identification of several responsible genes. For some macular
dystrophies, this new information has confirmed pre-existing
hypotheses on their pathophysiology, but for others, the discovery of
the disease gene has added further complexity to the disease
process. Two contradictory concepts were particularly highlighted by
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L. Ben-Nun King David

these genetic studies. Several phenotypes previously described as


different clinical entities were brought together by the identification
of mutations in the same gene, and converselyome conditions that
were clinically assigned the same name, often heterogeneous at the
clinical level, appeared genetically and physiopathologically
heterogeneous. In addition, it is worth noting that the monogenic
macular dystrophy genes were often regarded as potential factors for
susceptibility to AMDs. However, to date, only ABCA4 mutations have
been associated with a minority of this frequent multifactorial
condition (15).
CRDs (prevalence 1/40,000) are inherited retinal dystrophies that
belong to the group of pigmentary retinopathies. CRDs are
characterized by retinal pigment deposits visible on fundus
examination, predominantly localized to the macular region. In
contrast to typical RP, called the RCDs resulting from the primary loss
in rod photoreceptors and later followed by the secondary loss in
cone photoreceptors, CRDs reflect the opposite sequence of events.
CRD is characterized by primary cone involvement, or, sometimes, by
concomitant loss of both cones and rods that explains the
predominant symptoms of CRDs: decreased visual acuity, color vision
defects, photoaversion and decreased sensitivity in the central visual
field, later followed by progressive loss in peripheral vision and night
blindness. The clinical course of CRDs is generally more severe and
rapid than that of RCDs, leading to earlier legal blindness and
disability. At end stage, however, CRDs do not differ from RCDs. CRDs
are most frequently non syndromic, but they may be part of several
syndromes, such as Bardet Biedl syndrome and Spinocerebellar
Ataxia Type VII. Non syndromic CRDs are genetically heterogeneous
(10 cloned genes and three loci have been identified so far). The four
major causative genes involved in the pathogenesis of CRDs are
ABCA4 (which causes Stargardt disease and 30% to 60% of autosomal
recessive CRDs), CRX and GUCY2D (which are responsible for many
reported cases of autosomal dominant CRDs), and RPGR (which
causes about 2/3 of X-linked RP and an undetermined percentage of
X-linked CRDs). Highly deleterious mutations in genes that otherwise
cause RP or macular dystrophy may lead to CRDs. The diagnosis of
CRDs is based on clinical history, fundus examination and ERG.
Molecular diagnosis can be made for some genes, and genetic
counseling is always advised. There is no therapy that stops the
evolution of the disease or restores the vision, and the visual
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L. Ben-Nun King David

prognosis is poor. Management aims at slowing the degenerative


process, treating the complications and helping patients to cope with
the social and psychological impact of blindness (16).
RP is an inherited retinal dystrophy caused by the loss of
photoreceptors and characterized by retinal pigment deposits visible
on fundus examination. Prevalence of non syndromic RP is
approximately at 1/4,000. The most common form of RP is a rod-
cone dystrophy, in which the first symptom is night blindness,
followed by the progressive loss in the peripheral visual field in
daylight, and eventually leading to blindness after several decades.
Some extreme cases may have a rapid evolution over two decades or
a slow progression that never leads to blindness. In some cases, the
clinical presentation is a CRD, in which the decrease in VA
predominates over the visual field loss. RP is usually non syndromic
but there are also many syndromic forms, the most frequent being
Usher syndrome. To date, 45 causative genes/loci have been
identified in non syndromic RP (for the autosomal dominant,
autosomal recessive, X-linked, and digenic forms). Clinical diagnosis is
based on the presence of night blindness and peripheral visual field
defects, lesions in the fundus, hypovolted ERG traces, and
progressive worsening of these signs. Molecular diagnosis can be
made for some genes, but is not usually performed due to the
tremendous genetic heterogeneity of the disease. Genetic counseling
is always advised. Currently, there is no therapy that stops the
evolution of the disease or restores the vision, so the visual prognosis
is poor. The therapeutic approach is restricted to slowing down the
degenerative process by sunlight protection and vitaminotherapy,
treating the complications (cataract and macular edema), and helping
patients to cope with the social and psychological impact of
blindness. New therapeutic strategies are emerging from intensive
research (gene therapy, neuroprotection, and retinal prosthesis) (17).

ASSESSMENT: there is a widespread range of diseases, as


mentioned above, that can cause blindness. Although these diseases
cannot be entirely excluded, the King’s medical history indicates that
these diseases were not responsible.
Since the King was afflicted by blindness in his old age, hereditary
eye diseases can be excluded.
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L. Ben-Nun King David

References
1. Whicher JP. Blindness. In: Vaughan D, Asbury T, Riordan-Eva P (eds.). a
Lange medical book. General Ophthalmology, ed. 14. Appleton-Lange, Norwalk.
1995; pp. 396-400.
2. Burton MJ, Mabey DC. The global burden of trachoma: a review. PLoS
Negl Trop Dis. 2009;3(10):e460.
3. Mariotti SP, Pascolini D, Rose-Nussbaumer J. Trachoma: global magnitude
of a preventable cause of blindness. Br J Ophthalmol. 2009; 93(5):563-8.
4. Hogeweg M, Keunen JE. Prevention of blindness in leprosy and the role of
the Vision 2020 Programme. Eye (Lond). 2005;19(10):1099-105.
5. Soshamma G, Suryawanshi N. Eye lesions in leprosy. Lepr Rev. 1989;
60(1):33-8.
6. Ebeigbe JA, Kio F. Ocular leprosy in institutionalized Nigerian patients.
Ghana Med J. 2011;45(2):50-3.
7. Enk CD. Onchocerciasis - river blindness. Clin Dermatol. 2006;24(3): 176-
80.
8. Babalola OE. Onchocerciasis as a risk factor for night blindness.
Ophthalmic Epidemiol. 2012;19(4):204-10.
9. López-Rodríguez N, Faus F, Sierra J, et al. Night blindness and
xerophthalmia after surgery for morbid obesity. Arch Soc Esp Oftalmol.
2008;83(2):133-5.
10. Sommer A. Xerophthalmia, keratomalacia and nutritional blindness. Int
Ophthalmol. 1990;14(3):195-9.
11. Menon K, Vijayaraghavan K. Sequelae of severe xerophthalmia - a
follow-up study. Am J Clin Nutr. 1980;33(2):218-20.
12. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an
epidemiologic update. Surv Ophthalmol. 2012;57(5):448-62.
13. Souza PM, Holland EJ, Huang AJ. Bilateral herpetic keratoconjunctivitis.
Ophthalmology. 2003;110(3):493-6.
14. Feltgen N, Walter P. Rhegmatogenous retinal detachment - an
ophthalmologic emergency. Dtsch Arztebl Int. 2014;111(1-2):12-21.
15. Rozet JM, Gerber S, Ducroq D, et al. Hereditary macular dystrophies. J Fr
Ophtalmol. 2005;28(1):113-24.
16. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007 Feb 1;2:7.
17. Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006 Oct 11;1:40.

TO SUM UP: the elderly have suffered from poor vision or


blindness for thousands of years. This research describes the eye
disease that afflicted King David the Great. The passages “My eye is
consumed…” (Psalm 6:8) and “As for the light of my eyes, it is also
gone from me” (Psalm 38:11) indicate blindness. Among the
numerous causes associated with the blindness, either NVAMD, or
mature cataract, or asymptomatic OAG, or optic atrophy caused by
the end-stage OAG, or RE are the most likely causes in King David’s
case.
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L. Ben-Nun King David

THE DISEASE OF THE BONES


Patients have suffered from pain in their bones, which may be
associated with various diseases, for thousands of years.
Did King David suffer from some disease of the bones? If so, what
are the characteristics of the disease of the bones? What was the
most likely diagnosis? This report analyzes the disease that affected
the biblical King David, the second and greatest of Israel’s Kings, who
ruled the country more than 3537 years ago.

THE BIBLICAL DESCRIPTION


King David, the second and greatest of Israel’s Kings who ruled
that country more than 3537 years ago, suffered from a disease of
the bones “...my strength failed..., and my bones are consumed”
(Psalm 31:11), and “My bones wasted away through my anguished
roaring all day long” (32:3). The first sentence indicates that the
King’s bones were used up, his strength decreased, and he had
become very weak. In the second sentence, the King’s bones have
reached a stage where they are extremely thin and weak, causing
him severe pain.

OSTEOPOROSIS
What does the phrase “...my bones wasted away... ” mean? The
1990 Consensus Development Panel defined osteoporosis as a
“disease characterized by low bone mass and micro architectural
deterioration of bone tissue, leading to enhanced bone fragility and a
consequent increase in fracture risk” (1). In recent years,
osteoporosis is defined as a skeletal disorder characterized by
compromised bone strength predisposing to an increased risk of
fracture. Bone strength reflects integration of bone density and bone
quality (2).
Osteoporosis is the most common skeletal disorder in the elderly,
being characterized by impaired bone strength and increased risk of
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L. Ben-Nun King David

fracture. Severe osteoporosis is currently defined by the threshold of


bone density value below the -2.5 SD of T-score, determined by DXA,
and the presence of one or more fragility fractures. This definition
does not entirely reflect the spectrum of severity of the disease that
provides a variable increase in fracture risk. This manuscript reports
a consensus statement on the diagnostic criteria for severe
osteoporosis in real-life clinical setting, achieved in an event held by
Italian physicians with expertise in osteoporosis and metabolic bone
diseases. A large number of fractures occur in subjects with T-score
above -2.5. In light of recent advances on the structural basis of
skeletal fragility, bone density represents only one of the
contributors to bone strength and number and severity of fragility
fractures. The group suggests that the condition of two or more
fragility fractures should be considered as severe osteoporosis,
independently of bone density. In conclusion, the consensus
statement proposes a more specific definition of severe osteoporosis,
which should consider not only densitometric measurements, but
also the number and severity of fragility fractures. Patients'
management and choice of treatment should take into consideration
the type and severity of osteoporotic fractures, in addition to bone
density (3).
Taking into consideration a multifactorial nature of bone fragility
in osteoporosis, we do not diagnose "osteoporosis" but a total,
individual 10-year fracture risk (AR-10) based on independent and
self-sufficient risk factors. These are: advanced age, previous
osteoporotic fracture, parental history of proximal femur fracture,
low body weight or low BMD, low bone mass, weight loss, physical
inactivity, glycocorticosteroid treatment, androgen deprivation
therapy, RA, smoking, and overuse of alcohol (4,5).
Osteoporosis is a severe public health problem. For example,
there are approximately 700.000 vertebral body compression
fractures in the US each year with approximately 70.000 of these
resulting in hospitalization, with an average hospital stay per patient
of eight days (6).
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L. Ben-Nun King David

Osteoporosis is a disease characterized by a progressive reduction


of bone mass and a simultaneous deterioration of skeletal
microarchitecture leading to a loss of bone strength, resulting in
bone fracture as consequence of even very low traumas.
Osteoporosis has only recently been accorded growing clinical and
pathological importance for its impact on health. This disease, thanks
to considerable increases in life expectancy, is becoming more visible
and is now treated either as a serious public health issue of socio-
economic importance, and as a multifactorial disease. In fact, both in
women and men, osteoporosis is often associated with
hypogonadism as well as with individual traits such as genetic
constitution, cytokines, sex and race, which represent non-modifiable
endogenous risk factors. In addition, modifiable exogenous risk
factors related to lifestyle (e.g. smoking, alcohol consumption, and
diet) can lead to an acceleration in the genesis of osteoporosis (7).
In nine industrialized countries in North America, Europe, Japan,
and Australia, country-specific osteoporosis prevalence (estimated
from published data) at the total hip or hip/spine ranged from 9% to
38% for women and 1% to 8% for men. In these countries,
osteoporosis affects up to 49 million individuals. Standardized
country-specific prevalence estimates are scarce, limiting our ability
to anticipate the potential global impact of osteoporosis. This study
estimated the prevalence of osteoporosis in several industrialized
countries (US, Canada, five European countries, Australia, and Japan)
using the WHO BMD-based definition of osteoporosis: BMD T-score
assessed by DXA ≤-2.5. Osteoporosis prevalence was estimated for
males and females aged 50 years and above using total hip BMD and
then either total hip or spine BMD. Published location-specific data,
using the NHANES III age and BMD reference groups were compiled,
and adjusted for differences in disease definitions across sources.
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L. Ben-Nun King David

Relevant NHANES III ratios (e.g., male to female osteoporosis at the


total hip) were applied where data were missing for countries outside
the USA. Data were extrapolated from geographically similar
countries as needed. Population counts for 2010 were used to
estimate the number of individuals with osteoporosis in each
country. For females, osteoporosis prevalence ranged from 9% (UK)
to 15% (France and Germany) based on total hip BMD and from 16%
(USA) to 38% (Japan) when spine BMD data were included. For males,
prevalence ranged from 1% (UK) to 4% (Japan) based on total hip
BMD and from 3% (Canada) to 8% (France, Germany, Italy, and Spain)
when spine BMD data were included. In conclusion, up to 49 million
individuals met the WHO osteoporosis criteria in a number of
industrialized countries in North America, Europe, Japan, and
Australia (8).
Because the King’s bones were “...wasted away...,” they became
very weak, that is, the bone mass decreased. The decreased bone
mass indicates that the King was suffering from osteoporosis. For the
King, risk factors for bone fragility were: advanced age, low bone
mass, and low BMI. Low BMI indicates the subsequent verses: “My
knees are weak through fasting; and my flesh failed of fatness”
(Psalm 109:24) and “....my bones (the King’s) cleave to my skin”
(102:6).
Contemporary medicine measures reduced bone mass by various
techniques including conventional radiographs, CT, single or DXA,
radiographic measurements of cortical width (radiogrammetry),
resonance frequency of the ulna, total body neutron activation
analysis, and X-ray micro densitometry (9). DXA scans to measure
BMD at the spine and hip have an important role in the evaluation of
individuals at risk of osteoporosis, and in helping clinicians' advice
patients about the appropriate use of antifracture treatment.
Compared with alternative bone densitometry techniques, hip and
spine DXA examinations have a number of advantages that include a
consensus that BMD results can be interpreted using the WHO T-
score definition of osteoporosis, a proven ability to predict fracture
risk, proven effectiveness at targeting antifracture therapies, and the
ability to monitor response to treatment (10). At present, severe
osteoporosis is considered BMD below a T-score of -2.5 existing
together with a prevalent fragility fracture. This is a rough
categorization of a wide range of clinical conditions. In osteoporotic
patients, two different severities include: prognostic severity, i.e., the
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L. Ben-Nun King David

risk of the occurrence of other fragility fractures and clinical severity,


i.e. the degree of pain and disability experienced by the patient (11).
The possible pathologies that cause the loss of bone mass include:
endocrinological, digestive, genetic, hematological, rheumatic, post-
transplant, pharmacological and a wide miscellaneous group (12).
We see that various diseases can be associated with osteoporosis.
What was the disease that affected the King?
Because there is no word in the biblical text about any of the
methods listed above, one can speculate that no methods of
evaluating osteoporosis were in use at that time. Nevertheless, the
biblical sentences quoted above indicate convincingly that the King
suffered from osteoporosis.

References
1. Consensus Development Conference. Prophylaxis and treatment of
osteoporosis. Am J Med. 1991;90:107-11.
2. Kishimoto H. Change in the definition of osteoporosis especially on
bone quality. Clin Calcium. 2005;15:736-40.
3. Nuti R, Brandi ML, Isaia G, et al. New perspectives on the definition
and the management of severe osteoporosis: the patient with two or more
fragility fractures. J Endocrinol Invest. 2009;32(9):783-8.
4. Czrewioski E, Badurski JE, Marcinowska-Suchowierska E, Osieleniec J.
Current understanding of osteoporosis according to the position of the
World Health Organization (WHO) and International Osteoporosis
Foundation. Ortop Traumatol Rehabil. 2007;9:337-56.
5. Liu H, Page NM, Goldzweig CL, et al. Screening for osteoporosis in
men: a systematic review for an American College of Physicians guideline.
Ann Intern Med. 2008;148:685-701.
6. Semionov K, Lieberman IH. Vertebral augmentation in osteoporosis
and bone metastasis. Curr Opin Support Palliat Care. 2007;1:323-7.
7. Stazi AV. Micronutrient deficiencies in osteoporosis. Minerva Med.
2013;104(4):455-70.
8. Wade SW, Strader C, Fitzpatrick LA, et al. Estimating prevalence of
osteoporosis: examples from industrialized countries. Arch Osteoporos.
2014;9(1):182.
9. Rosenblum AL. Connective tissue disorder in diabetes. In: Alberti
K.G.M.M, Zimmet P, DeFronzo R.A, Keen H (eds.). International Textbook
of Diabetes. Vol. 2. 2nd ed. New York, NT: John Wiley & Sons. 1997, pp.
1517-29.
10. Blake GM, Fogelman I. The role of DXA bone density scans in the
diagnosis and treatment of osteoporosis. Postgrad Med. 2007;83:509-17.
11. Trevisan C. New proposals for the definition of severe osteoporosis.
Aging Clin Exp Res. 2007;19(4 Suppl):3-6.
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12. Lafita J, Pineda J, Fuentas C, Martinez JP. Secondary Osteoporosis. An


Sist Sanit Navar. 2003;26 Suppl 3:63-62.

TYPES. Bone loss occurs during the normal aging process. The
term "primary" osteoporosis refers to osteoporosis that results from
the involutional losses associated with aging and, in women,
additional losses related to natural menopause. Osteoporosis caused
or exacerbated by other disorders or medication exposures is
referred to as "secondary" osteoporosis (1).
Involutional or age-dependent senile osteoporosis occurs in men
aged 70 or older and is characterized by trabecular and cortical bone
loss leading to hip, vertebral, proximal humerus, proximal tibia, and
pelvis fractures (2).
Secondary osteoporosis is a common cause of osteoporosis, and
there are many medical conditions associated with osteoporosis.
Many of these present well before osteoporosis develops, and
knowledge of these pre-existing conditions may influence the
decision about whether to test and/or treat for osteoporosis. Men
and premenopausal women with unexplained osteoporosis or a
history of fragility fracture should undergo investigation for
secondary osteoporosis. Postmenopausal women with risk factors for
secondary osteoporosis should be carefully evaluated. Beyond the
well-recognized association with glucocorticoids, an increasing list of
drugs has been implicated in causing bone loss and fractures. With
appropriate consideration of secondary causes and relevant
investigations, many of these conditions are preventable with newer
therapies (3).
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L. Ben-Nun King David

Chronic diseases of many organ systems require long-term (≥ one


year) treatment with glucocorticoids. Owing to the catabolic activity
of glucocorticoid therapy, osteoporosis is a potential complication. A
review of the English-language literature was conducted using the
MEDLINE database and proceedings from scientific meetings. Search
terms including GIO, bone loss, and fracture were used to refine the
search, and preference was given to studies published after 1990.
Long-term glucocorticoid treatment causes bone loss that is most
precipitous in the first six months. Patients treated with
glucocorticoids have additional risk factors for bone loss and
osteoporosis that are associated with their primary disease. Chronic
diseases can cause changes in bone metabolism, leading to bone loss
in addition to that induced by glucocorticoids alone. Bone loss can be
minimized through proper nutrition, weight-bearing exercise, calcium
and vitamin D supplementation, and, where indicated,
bisphosphonate treatment. The American College of Rheumatology
Ad Hoc Committee on GIO guidelines recommend bisphosphonates
for minimizing bone loss and fracture risk in patients at risk for GIO.
Risedronate is indicated for the prevention and treatment of GIO,
and alendronate is indicated for its treatment. Both risedronate and
alendronate increase BMD in patients at risk for GIO. Risedronate
significantly reduces the incidence of vertebral fractures after one
year of treatment (p<0.05). The effectiveness and tolerability of the
bisphosphonates have not been established in pregnant women or
pediatric patients. In conclusion, men and women initiating long-
term glucocorticoid treatment and those with GIO should be
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L. Ben-Nun King David

concomitantly treated with effective osteoporosis therapy to reduce


fracture risk and counseled on preventive lifestyle changes (4).
Glucocorticoids, often regarded as ancient drugs, are still
frequently used in modern medicine because of their strong anti-
inflammatory and immunosuppressive properties. The side effects of
glucocorticoids are well-known and physicians often anticipate on
these side effects. Bone loss is one of the most important side effects
of glucocorticoid use, even in low doses. The main effect of
glucocorticoids on bone is inhibition of osteoblast function, leading to
a decrease in bone formation. Also nongenomic effects (mediated by
glucocorticoid interactions with biological membranes, either
through binding to membrane receptors or by physicochemical
interactions) may have a role in the pathogenesis of GIO. Several
studies and reports show a decrease in BMD and an increased risk of
fractures during glucocorticoid use. Prior and current exposure to
glucocorticoids increases the risk of fractures beyond that explained
by values of BMD. This discrepancy could be explained by osteocyte
apoptosis leading to rapid weakening of bone architecture and
increase in fractures risk. Bone loss starts promptly after initiation of
glucocorticoids and is mainly taking place in the first six months of
treatment. Bone loss is predominantly found in bone with high
trabecular content, like vertebrae. The risk of GIO can be reduced by
general measurements like prescribing glucocorticoids in a low dose
and for a short period. Pharmacological intervention for prevention
of GIO is needed depending on glucocorticoid dose, expected
duration of glucocorticoid treatment, age and gender of the patient
and sometimes BMD at start of the glucocorticoid treatment.
Bisphosphonates seem to be the first choice of pharmacological
intervention for prevention and treatment of GIO and are cost-
effective in subgroups of patients (depending on age, gender,
glucocorticoid dose and fracture history). There is no evidence that
one specific bisphosphonate is superior to another bisphosphonate
due to lacking of head-to-head studies on GIO. A recent study shows
that alendronate is superior to alfacalcidol in prevention of GIO in
patients starting glucocorticoids of 7.5 mg or more on a daily basis.
Calcium and plain vitamin D3 supplementation are considered as
important support for prevention and treatment of GIO. Despite the
increased knowledge on bone loss and fracture risk during
glucocorticoid use and the possibilities of pharmacological
intervention of it, studies indicate that the care given by physicians in
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L. Ben-Nun King David

prevention and treatment of GIO needs to be optimized in future


years. Further training of health care workers in pathophysiology,
general measurements and pharmacological intervention for
prevention and treatment of GIO is needed (5).

References
1. Stein E, Shane E. Secondary osteoporosis. Endocrinol Metab Clin North
Am. 2003;32(1):115-34, vii.
2. Riggs BL, Melton LJ. Medical progress. Involutional osteoporosis. N
Engl J Med. 1986;314:1676-86.
3. Kok C, Sambrook PN. Secondary osteoporosis in patients with an
osteoporotic fracture. Best Pract Res Clin Rheumatol. 2009;23(6):769-79.
4. Boling EP. Secondary osteoporosis: underlying disease and the risk for
glucocorticoid-induced osteoporosis. Clin Ther. 2004;26(1):1-14.
5. De Nijs RN. Glucocorticoid-induced osteoporosis: a review on
pathophysiology and treatment options. Minerva Med. 2008;99(1):23-43.

MALE OSTEOPOROSIS. Osteoporosis in men is a heterogeneous


disease that has received little attention. However, one third of
worldwide hip fractures occur in the male population. This problem is
more prevalent in people over 70 years of age. The etiology can be
idiopathic or secondary to hypogonadism, vitamin D deficiency and
inadequate calcium intake, hormonal treatments for prostate cancer,
use of toxic and every disease or drug use that alters bone
metabolism. Risk factors such as a previous history of fragility
fracture should be assessed for the diagnosis. However, risk factors in
men are very heterogeneous. There are significant differences in the
pharmacological treatment of osteoporosis between men and
women fundamentally due to the level of evidence in published trials
supporting each treatment. New treatments will offer new
therapeutic prospects (1).
Osteoporosis remains underrecognized and undertreated but
more so in men, adding considerably to fracture burden and costs.
Fracture-related morbidity and mortality is higher in men, partly due
to greater frailty. Improved peak bone mass, geometry and turn-over
contribute to lower fracture incidence in men. Bioavailable
androgens and oestrogens regulate these aspects of musculoskeletal
sexual dimorphism, yet the direct cellular and molecular targets of
sex steroids in bone remain incompletely understood. Screening with
clinical risk factors and DXA are advised in men from age 70 years (or
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L. Ben-Nun King David

50 years with additional risk factors). Osteoporosis drugs are equally


effective in men and women, not only to increase bone density but
also to prevent osteoporotic fractures. The use of testosterone or
selective androgen receptor modulators for osteoporosis, sarcopenia,
frailty and falls in men with late-onset hypogonadism requires further
investigation (2).

ASSESSMENT: male osteoporosis is more prevalent in people over


70 years of age. The etiology is idiopathic or secondary to
hypogonadism, vitamin D deficiency, inadequate calcium intake,
hormonal treatments for prostate cancer, diseases or drug use that
alters bone metabolism.
It can be assumed that this type of osteoporosis may have
affected King David’s bones. However, this does not entirely explain
what kind of disease “...consumed...” his bones.

References
1. Herrera A, Lobo-Escolar A, Mateo J, et al. Male osteoporosis: A review.
World J Orthop. 2012;3(12):223-34.
2. Laurent M, Gielen E, Claessens F, et al. Osteoporosis in older men:
recent advances in pathophysiology and treatment. Best Pract Res Clin
Endocrinol Metab. 2013;27(4):527-39.

CUSHING SYNDROME. Cushing’s syndrome refers to metabolic


disorders that result from high levels of glucocorticoids. GIO may be
so severe that collapse of vertebral bodies and pathological fractures
of other bones may occur (1).
Cushing's syndrome is characterized by central obesity,
fatigability, weakness, amenorrhea, hirsutism, edema, hypertension,
impaired glucose tolerance, and osteoporosis due to excessive
production of steroids. Cushing's syndrome is an important cause of
secondary osteoporosis. Patients with Cushing's syndrome have a
high incidence of osteoporotic fractures. At least, 30-50% of patients
with Cushing's syndrome experience fractures, particularly in the
vertebral body. It is consistent with the 50% prevalence of
osteoporosis in patients with Cushing's syndrome. However, reports
of multiple pathological fractures in young patients with Cushing's
syndrome are rare. Thus, the case of a 26-year-old woman with
Cushing's syndrome was accompanied with recurrent multiple
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L. Ben-Nun King David

osteoporotic fractures and being treated by PTH. Careful


consideration for the possibility of Cushing's syndrome will be
necessary in case of young patients with a spontaneous multiple
compression fractures in spine (2).
A 19-year-old woman who had decreased eight centimeters in
stature was diagnosed as Cushing's disease with multiple spine
compression fractures. At the age of 18, the patient had a complex
fracture and gradually presented the features of Cushing's syndrome.
Her plasma adrenocorticotrophic and cortisol levels were extremely
high. Radiological findings and chemical markers for bone
metabolism showed severe osteoporosis. MRI showed the presence
of a pituitary microadenoma. After transsphenoidal surgery, all
endocrine data improved. This case indicates that Cushing's
syndrome should be considered for severe osteoporotic juvenile
patients (3).
Did Cushing’s syndrome affect the King’s bones? In the absence
of characteristic clinical symptoms, and specific laboratory findings
this disease seems unlikely.

References
1. Baker C, McFarland KF. Endocrinology. In: Rakel RE (ed.). Textbook of
Family Practice. 3rd ed. St Louis, Mo: W.B. Saunders. 1984, pp. 949-97.
2. Han JY, Lee J, Kim GE, et al. A case of Cushing syndrome diagnosed by
recurrent pathologic fractures in a young woman. J Bone Metab. 2012;
19(2):153-8.
3. Yoshihara A, Okubo Y, Tanabe A, et al. A juvenile case of Cushing's
disease incidentally discovered with multiple bone fractures. Intern Med.
2007;46(9):583-7.

HYPERTHYROIDISM/HYPOTHYROIDISM. Thyroid hormones


regulate skeletal development, acquisition of peak bone mass and
adult bone maintenance. Abnormal thyroid status during childhood
disrupts bone maturation and linear growth, while in adulthood it
results in altered bone remodeling and an increased risk of fracture.
This review considers the cellular effects and molecular mechanisms
of thyroid hormone action in the skeleton. Human clinical and
population data are discussed in relation to the skeletal phenotypes
of a series of genetically modified mouse models of disrupted thyroid
hormone signaling. In conclusion, euthyroid status is essential for
normal bone development and maintenance. Major thyroid hormone
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L. Ben-Nun King David

actions in skeletal cells are mediated by thyroid hormone receptor α


and result in anabolic responses during growth and development but
catabolic effects in adulthood. These homeostatic responses to
thyroid hormone are locally regulated in individual skeletal cell types
by the relative activities of the type two and three iodothyronine
deiodinases, which control the supply of the active thyroid hormone
3,5,3'-L-triiodothyronine (T3) to its receptor. Population studies
indicate that both thyroid hormone deficiency and excess are
associated with an increased risk of fracture. Understanding the
cellular and molecular basis of T3 action in skeletal cells will lead to
the identification of new targets to regulate bone turnover and
mineralization in the prevention and treatment of osteoporosis (1),
In hyperthyroidism, the bone loss is solely due to elevated thyroid
hormone level (2), occurring as a direct consequence of thyroid
hormone excess acting on bone (3) more on axial than appendicular
(4). Some studies showed that bone loss in thyrotoxicosis is
independent on circulating TSH levels, and mediated predominantly
by thyroid hormone receptor alpha, thus identifying thyroid hormone
receptor as a novel drug target in the prevention and treatment of
osteoporosis (5).
Hypothyroidism is common, potentially serious, often clinically
overlooked, readily diagnosed by laboratory testing, and eminently
treatable. The condition is particularly prevalent in older women, in
whom autoimmune thyroiditis is common. Other important causes
include congenital thyroid disorders, previous thyroid surgery and
irradiation, drugs such as lithium carbonate and amiodarone, and
pituitary and hypothalamic disorders. Worldwide, dietary iodine
deficiency remains an important cause. Hypothyroidism can present
with nonspecific constitutional and neuropsychiatric complains, or
with hypercholesterolemia, hyponatremia, hyperprolactinemia, or
with hyperhomocysteinaemia (6).
Subclinical hypothyroidism or subclinical hyperthyroidism are
defined as normal free T4 and T3 levels associated with elevated
serum TSH levels (subclinical hypothyroidism) or subnormal serum
TSH levels (subclinical hyperthyroidism), respectively. Symptoms and
signs of thyroid dysfunction are scare. In subclinical hypothyroidism,
total cholesterol and LDL-C are modestly elevated and levothyroxine
may influence the lipid levels. There is decreased cardiac contractility
and increased peripheral vascular resistance that improve with
treatment. Subclinical hypothyroidism is associated with atrial
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L. Ben-Nun King David

fibrillation, increased cardiac contractility and left ventricular mass,


diastolic and systolic dysfunction that can be reversed with beta-
adrenergic antagonists (7,8). Depression, panic disorders and
alterations in cognitive testing are frequent in subclinical
hypothyroidism (7). Since bone density is reduced in subclinical
hypothyroidism (7), subclinical hypothyroidism is a risk factor for
osteoporosis (9).
Individuals with subclinical hyperthyroidism demonstrate a 41%
increase in relative mortality from all causes vs. euthyroid control
subjects. Absolute excess mortality depends on age, with an increase
beyond the age of 60, especially in aging men. For patients with
subclinical hyperthyroidism, the relative risk of all-cause mortality is
increased only in patients with comorbid conditions (10).
Measurement of the serum TSH concentration with an assay of
adequate sensitivity is the cornerstone of thyroid function testing; for
untreated population at risk of primary thyroid dysfunction, a normal
TSH concentration rules out an abnormality with a high degree of
certainty (11).
Osteoporosis is mainly associated with hyperthyroidism either
overt or subclinical. This diagnosis as a cause of osteoporosis should
be ruled out in all patients who have bone demineralization (12).

ASSESSMENT: was King David afflicted by hyperthyroidism? In the


absence of nervousness, emotional lability, hyperhydrosis, heat
intolerance, eye symptoms (such as lid lag or exophtalmus), a wide
pulse pressure, sinus tachycardia, atrial arrhythmias (especially atrial
fibrillation), systolic murmurs, cardiac enlargement, CHF, and data on
TSH level in serum, the diagnosis of hyperthyroidism seems unlikely.
We have no data to verify the diagnosis of hypothyroidism,
subclinical hyperthyroidism or subclinical hypothyroidism.

References
1. Wojcicka A, Bassett JH, Williams GR. Mechanisms of action of thyroid
hormones in the skeleton. Biochim Biophys Acta. 2013;1830(7):3979-86.
2. Sun L, Davies TF, Blair HC, et al. TSH and bone loss. An N Y Acad Sci.
2006;1068:309-18.
3. Galliford TM, Murphy E, Williams AJ, et al. Effects of thyroid status on
bone metabolism: a primary role for thyroid stimulating hormone or thyroid
hormone? Minerva Endocrinol.2005;30:237-46.
4. Seeman E, Wahner HW, Offord KP, et al. Differential effects of endocrine
dysfunction and the appendicular skeleton. J Clin Invest. 1982; 69:1302.
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L. Ben-Nun King David

5. Basset JP, O'Shea PJ, Sriskantharajah S, et al. Thyroid hormone excess


rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism.
Mol Edocrinol. 2007;21:1095-107.
6. Roberts CG, Landenson PW. Hypothyroidism. Lancet. 2004;363(9411):
793-803.
7. Romaldini JH, Sgarbi JA, Farah SC. Subclinical thyroid disease: subclinical
hypothyroidism and hyperthyroidism. Arq Bras Endocrinol Metabol. 2004;48:
147-58.
8. Sengupta N, Maji D. Subclinical thyrotoxicosis. J Indian Med Assoc.
2006;104:596, 598-600.
9. Zamrazil V. Subclinical thyroid diseases. Vnitr Lek. 2007;53(7-8):795-8.
10. Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B. Subclinical
thyroid dysfunction and mortality: an estimate of relative and absolute excess
all-cause mortality based on time-to-event data from cohort studies. Eur J
Endocrinol. 2008;159:329-41.
11. Stockigt J. Assessment of thyroid function: towards an integrated
laboratory - clinical approach. Clin Biochem Rev. 2003;24:109-22.
12. Smith TJ. Connective tissue in thyrotoxicosis. In: Braverman LE, Utiger
RD (eds). Werner and Ingbar’s The Thyroid. A Fundamental and Clinical Text.
6th ed. Philadelphia: Lippincot. 1991, pp. 738-41.

ACROMEGALY. Acromegaly is characterized by coarse facial


features as the result of overgrowth of frontal, malar and nasal
bones, enlarged mandible, separated teeth, overgrowth of soft tissue
producing widening of the nose and protrusion of the lips, enlarged
hands and feet, thickened skin, enlarged sebaceous glands, and other
clues that suggest this disease (e.g., CTS, DM, headache [sellar
enlargement], and visual field defects) (1)
A cross-sectional study was carried out in Division of
Endocrinology, Catholic University, Rome. Patients included 40 males
with acromegaly (25 patients with controlled disease and 15 patients
with active disease) and 31 control males, with age and gonadal
status comparable to the patients. Although BMD was insignificantly
different between acromegalic patients and control subjects, the
prevalence of vertebral fractures was higher in acromegalic patients
as compared with the control subjects (57.5% vs. 22.6%, p=0.003).
Fractured and non-fractured acromegalic patients showed
insignificant difference in age and BMD Z-score. Patients with
fractures showed significantly longer untreated hypogonadism as
compared to patients without fractures. The duration of active
acromegaly was the only risk factor that significantly correlated with
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the occurrence of fractures. This study reported a high prevalence of


osteoporotic vertebral fracture in an unselected acromegalic male
population generally considered at low risk of osteoporosis
suggesting that complicated osteoporosis is an important
comorbidity of acromegaly (2).
Over a five-year period, 14 patients with acromegaly and
gigantism were seen at the endocrine clinic of King Edward VIII
Hospital: nine were Blacks and five Indians; eight of the patients were
women. The mean age of the patients was 46 years. Surprisingly, only
two patients complained of acral overgrowth. Symptomatology was
varied and not characteristic of the condition. On examination all
patients had unequivocal signs of soft-tissue and bony overgrowth,
64% had visual abnormalities and 50% hypertension. Radiologically,
88% showed an enlarged pituitary fossa. On biochemical
investigation, the fasting levels of GH were increased in 12 patients
and during oral glucose tolerance tests, the GH levels in these 12
patients were not suppressed. One patient in whom the fasting GH
level was not increased had progressed to the stage of
panhypopituitarism, in the remaining patient challenge with TRH led
to increased GH levels and L-dopa challenge resulted in a paradoxical
decrease in GH levels. Seven patients with increased GH levels who
were challenged with L-dopa showed the typical decrease in GH
levels found in this condition; in five of these patients, challenged
with TRH, GH levels increased. The findings emphasize that despite
the ease of clinical diagnosis, appropriate biochemical investigations
are necessary to confirm the exact status of the disease, which is rare
in the population studied (3).

Acromegaly

Acromegaly is caused by hypersecretion of GH and consequently


of IGF-1 due to pituitary tumor. Other causes, such as increased
GHRH production, ectopic GHRH production, and ectopic GH
secretion, are rare. GH and IGF-1 play a role in the regulation of bone
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L. Ben-Nun King David

metabolism, but accurate effect of growth hormone excess on bone


is not fully explained. The issue of osteoarticular manifestations is still
actual due to development of complications in the majority of
patients with acromegaly. Traditionally, acromegaly is considered as
a cause of secondary osteoporosis. Nowadays, it is discussed if BMD
as predictor of osteoporotic fractures in acromegalic patient is
decreased or even normal. Thus, bone quality remains to be more
important in assessment of fracture risk. GH excess leads to
increased bone turnover, defined by changes of bone markers. The
articular manifestations are frequent clinical complications and may
be present as the earliest symptom in a significant proportion of
acromegalic patients. Articular manifestations are the main causes of
morbidity and immobility of these patients, and they are persistent
even after successful treatment. Quick recognition of osteoarticular
changes and aiming the therapy lead to decrease in complication
number (4).
GH and IGF-1 stimulate proliferation, differentiation and
extracellular matrix production in osteoblastic cells. GH and IGF-1
also stimulate recruitment and bone resorption activity in
osteoclastic cells. A chronic systemic GH and IGF-1 excess produces
an increased bone turn over in acromegalic patients. Osteoporosis,
joint alterations and bone deformities have a great clinical relevance
in acromegalic patients and favor mortality and morbidity. In the
present study, GH/IGF-1 activity on bone, BMD and risk of
osteoporotic vertebral fractures, in relation to gender and gonadal
status in acromegalic patients were evaluated. Of 20 acromegalic
patients (12 females, eight males) ranging 26-64 years, four patients
were hypogonadic (one female, three males), seven women were in
post-menopause and four women eugonadic. The disease was active
in 12 patients and inactive in eight patients. Serum and urinary
24/hours calcium and phosphate and serum PTH, bone formation
(P1NP) and resorption (beta-CTX) markers were assayed. BMD was
measured using DXA at the lumbar spine and femoral neck and bone
quantitative ultrasonography at phalanges. Osteoporotic vertebral
fractures were assessed by A-P and lateral x-ray examinations of the
thoracic and lumbar spine. Serum IGF-1, calcium and phosphate and
24-hours urinary calcium were significantly higher in patients with
active disease in respect to patients with inactive disease. BMD was
reduced in more of 50% of patients, in each skeletal sites measured.
Z-score values were lower in males than in females. Vertebral
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L. Ben-Nun King David

fracture prevalence was 39% (43% in women, 57% in men). Fractured


and non-fractured patients were insignificantly different for BMD, T-
score and Z-score. In conclusion, vertebral fractures are frequent in
acromegaly and, even mild and asymptomatic, play an important role
on QOL and survival, already decreased in acromegalic patients. DXA
and quantitative ultrasonography methods are insufficient for
identifying patients at risk for fracture due to the many possible
interferences (bone deformities, osteoarthritis, joint rigidity and soft
tissue tickening), since BMD is just one determinant of bone fracture.
In the screening of acromegalic complications, it is necessary to
perform a radiographic study of the spine at the time of diagnosis
and during follow up (5).

ASSESSMENT: was King David afflicted by acromegaly? In the


absence of coarse facial features as the result of overgrowth of
frontal, malar and nasal bones, enlarged mandible, separated teeth,
overgrowth of soft tissue producing widening of the nose and
protrusion of the lips, enlarged hands and feet, thickened skin,
enlarged sebaceous glands, and other clues that suggest this disease
(e.g., CTS, DM, headache [sellar enlargement], and visual field
defects), and radiological and biochemical investigations, the
diagnosis of acromegaly unlikely. It would also be ironic if David who
as a youth had slain the pituitary giant, Goliath (6), was visited by the
same disorder in his old age.

References
1. Gregerman RI. Selected endocrine problems: disorders of pituitary,
adrenal, and parathyroid glands; pharmacologic use of steroids;
hypocalcemia and hypercalcemia; water metabolism; hypoglycemia; and
hormone use of unproven value. In: Barker LR, Burton JR, Zieve PD, Finucane
TE (eds.). Principles of Ambulatory Medicine. 5th ed. Baltimore, MD:
Williams & Wilkins. 1999, pp. 1096-121.
2. Mazziotti G, Bianchi A, Bonadonna S, et al. Prevalence of vertebral
fractures in men with acromegaly. J Clin Endocrinol Metab. 2008;93:4649-
55.
3. Jialal I, Nathoo BC, Joubert S, et al. The clinical presentation and
biochemical diagnosis of acromegaly and gigantism. S Afr Med J. 1982;
61(17):617-20.
4. Killinger Z, Kužma M, Sterančáková L, Payer J. Osteoarticular changes
in acromegaly. Int J Endocrinol. 2012;2012:839282.
285
L. Ben-Nun King David

5. Padova G, Borzì G, Incorvaia L, et al. Prevalence of osteoporosis and


vertebral fractures in acromegalic patients. Clin Cases Miner Bone Metab.
2011;8(3):37-43.
6. Berginer VM. Neurological aspects of the David-Goliath battle:
restriction in the giant’s visual field. IMAJ. 2000;2:725-7.

HYPOGONADISM. Some men between the ages 45 and 60 years


develop complaints and symptoms reminiscent of menopausal
complaints in women. Therefore, parallels were sought between the
changes in female and male endocrinology during that period of life.
Indeed, men do show a decline of serum testosterone from age 40 to
50 years onwards but it is a slow decline of 1-2% per year and over
time, it may amount to hypogonadism. The mechanism of a decline
in serum testosterone in men does not resemble the menopause; it is
partially an aging neuroendocrine system with a less efficient
testosterone production but equally or more important, the result of
inhibition of testosterone production by metabolic factors in relation
to visceral obesity. These effects are in part reversible with weight
loss. A hypogonadal state in aging men has deleterious effects.
Mortality of all causes is highest in men with low testosterone
affecting their metabolic state leading to DM, C-V disease,
osteoporosis, and sexual dysfunction. Normalization of testosterone
in aging hypogonadal men has a beneficial effect on the above
pathologies. The fear that testosterone treatment of elderly men
would lead to prostate disease has not been substantiated in studies.
So, while men do not have a 'menopause', testosterone deficiency in
old age deserves serious attention (1).
Male age-related bone loss is caused, at least in part, by
hypogonadism that occurs with advancing age. The study of the
effects of sex steroids on bone physiology in men has recently
highlighted the central role of estrogens on bone pathophysiology.
Aspects of bone physiology and pathophysiology in aging men show
both the similarities to and the differences from female counterparts.
In particular, the role of sex steroids on bone sexual dimorphism in
health and disease (2).
The objective of this study was to investigate the association
between hypogonadal symptoms and total serum testosterone levels
in young men (<40 years of age) with an attempt to determine
whether there exists a clear-cut discriminatory threshold of total
testosterone below which hypogonadal symptoms become more
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L. Ben-Nun King David

prevalent. The charts of 352 men who presented to an outpatient


Men's Health Clinic with chief complaint of "low testosterone" were
reviewed. Sexual, psychological and physical symptoms were
evaluated using the Androgen deficiency in Aging Male (ADAM)
questionnaire. Serum levels of total testosterone were collected on
the same day that men completed their ADAM questionnaires. The
probability of hypogonadal symptoms increased at a serum total
testosterone level of 400 ng/dL. A cluster of symptoms: two
psychological (decreased energy, sadness), and three physical
(decreased strength and endurance, decreased ability to play sports,
and deterioration in work performance) were most strongly
associated with total serum testosterone levels of <400 ng/dL. On
multivariable analysis, only 'lack of energy' predicted a total
testosterone of less than 400 ng/dL. In conclusion, hypogonadal
symptoms in men <40 years of age can be associated with a total
testosterone level of less than 400 ng/dL. Of the hypogonadal
symptoms evaluated with the ADAM questionnaire, lack of energy
appears to be the most important symptom that predicts a total
testosterone level <400 ng/dL (3).
Hypogonadism is characterized by hypospadias, cryptorchism in
childhood, delayed puberty, gradual loss of male secondary sex
characteristics and libido, impotence, and signs or symptoms of a
disease that can produce hypogonadism (e.g., severe headache,
indicating intracranial tumor) (4).
Osteoporosis and osteoporotic fractures are generally considered
to mainly affect older postmenopausal women, but up to 20% of
symptomatic vertebral fractures and 30% of hip fractures occur in
men. Osteoporotic fractures in men are associated with substantial
morbidity, greater excess mortality than in women and account for
almost 25% of the cost of osteoporotic fractures in the UK. One of
the major secondary causes of osteoporosis in men is hypogonadism,
which is found in up to 20% of men with symptomatic vertebral
fractures and 50% of elderly men with hip fractures. The
pathogenesis of osteoporosis in men places particular emphasis on
the importance of sex steroids in the maintenance of bone health.
Hypogonadism affects the skeleton, as well as there are the
consequences of androgen deprivation therapy in men with prostate
cancer. Testosterone replacement in hypogonadism is essential and
there are other options for the treatment of osteoporosis secondary
to loss of sex steroids in men (5).
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L. Ben-Nun King David

Thus, hypogonadism is associated with osteoporosis (6,7). The


majority of older men develop hypogonadism that can be reversed
by testosterone replacement (8-11).
A prospective, randomized, trial assigned 53 hypogonadal men to
the following treatment groups: mesterolone 100 mg p.o. daily,
testosterone undecanoate 160 mg p.o. daily, testosterone enanthate
250 mg i.m. every 21 days, or a single subcutaneous implantation of
1,200 mg crystalline testosterone. The BMD was determined by
peripheral quantitative CT. At baseline, men with secondary
hypogonadism (n=33) had a lower BMD (-1.52 +/- 0.23 SDS; Z-scores)
than men with primary hypogonadism (n=20, -0.87 +/- 0.23 SDS,
p<0.01). In men with primary hypogonadism, the BMD increased
dose dependently (crystalline testosterone +7.0 +/- 1.3%,
testosterone enanthate +4.8 +/- 0.2%, testosterone undecanoate
+3.4 +/- 2.5%, mesterolone +0.8 +/- 1.6%) after six months of
therapy. Only secondary hypogonadal men treated with testosterone
enanthate experienced an increase of the BMD. In conclusion, in
primary hypogonadal men the BMD responds dose dependently to
testosterone substitution, while in secondary hypogonadism only
testosterone enanthate treatment increases the BMD (12).
The purpose of this review was to examine the role of
testosterone in skeletal health in men. Evidence from recent studies
shows that the contributing role of testosterone to osteoporosis is
modest and likely trumped by other factors such as estradiol levels. A
few studies have documented an association between low
testosterone levels and lower BMD, increased prevalence of
osteoporosis of the hip and low bone mass-related fractures. Other
studies, however, have found that testosterone levels are not
independent predictors of bone resorption or formation markers,
BMD at the hip or incident fractures. Curiously, hypogonadism does
not account for the increased osteoporosis seen in men with
Klinefelter Syndrome. Regardless of hypogonadism status, two recent
clinical trials have found fewer new morphometric vertebral fractures
in men treated with ZOL and increased BMD in men treated with
denosumab. Denosumab was also shown to modestly increase bone-
metastasis-free survival in men with castration-resistant prostate
cancer. In conclusion, although male hypogonadism is associated
with osteoporosis, estradiol is likely to be the more important
hormone for bone health. Although a few large RCTs have been
conducted in men with low bone density (a subset of whom have
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L. Ben-Nun King David

hypogonadism), more trials are needed, particularly with fractures as


the main outcome (13).

ASSESSMENT: Was King David affected by hypogonadism? In the


absence of hypospadias, cryptorchism in childhood, delayed puberty,
gradual loss of male secondary sex characteristics and libido,
impotence, and signs or symptoms of a disease that can produce
hypogonadism (e.g., severe headache, indicating intracranial tumor),
and total serum testosterone levels, this diagnosis is unlikely.

References
1. Saad F, Gooren LJ. Late onset hypogonadism of men is not equivalent
to the menopause. Maturitas. 2014 Jun 30. pii: S0378-5122(14)00212-6.
2. Rochira V, Balestrieri A, Madeo B, et al. Osteoporosis and male age-
related hypogonadism: role of sex steroids on bone (patho)physiology. Eur J
Endocrinol. 2006;154(2):175-85.
3. Scovell JM, Ramasamy R, Wilken N, et al. Hypogonadal symptoms in
young men are associated with a serum total testosterone threshold of
400ng/dL. BJU Int. 2014 Oct 23.
4. Gregerman RI. Selected endocrine problems: disorders of pituitary,
adrenal, and parathyroid glands; pharmacologic use of steroids;
hypocalcemia and hypercalcemia; water metabolism; hypoglycemia; and
hormone use of unproven value. In: Barker LR, Burton JR, Zieve PD,
Finucane TE (eds.). Principles of Ambulatory Medicine. 5th ed. Baltimore,
MD: Williams & Wilkins. 1999, pp. 1096-121.
5. Tuck SP, Francis RM. Testosterone, bone and osteoporosis. Front
Horm Res. 2009;37:123-32.
6. Riggs BL, Melton LJ. Medical progress. Involutional osteoporosis. N Engl J
Med. 1986;314:1676-86.
7. Miller PD. Musculoskeletal diseases. Osteoporosis and other metabolic
bone diseases. In: Schrier RW (ed.). Geriatric Medicine. St Louis Mo: W.B.
Saunders. 1990, pp. 324- 40.
8. Morley JE. Andropause: is it time for the geriatrician to treat it ? J
Gerontol Medical Sci. 2001;56A(5):M263-5.
9. Morley JE, Kaiser FE, Perry P, et al. Longitudinal changes in testosterone,
luteinizing hormone, and follicle-stimulating hormone in healthy older men.
Metabolism. 1997;46:410-3.
10. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on
serum total testosterone levels in healthy men. J Clin Endocrinol & Metab.
2001;86:724 -31.
11. Yassin AA, Saad F. Improvement of sexual function in men with late-
onset hypogonadism treated with testosterone only. J Sex Med. 2007;
4(2):497-501.
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L. Ben-Nun King David

12. Schubert M, Bullmann C, Minnemann T, et al. Osteoporosis in male


hypogonadism: responses to androgen substitution differ among men with
primary and secondary hypogonadism. Horm Res. 2003;60(1):21-8.
13. Irwig MS. Male hypogonadism and skeletal health. Curr Opin
Endocrinol Diabetes Obes. 2013;20(6):517-22.

PRIMARY HYPERPARATHYROIDISM. PHPT is a generalized


disorder of calcium, phosphate, and bone metabolism due to an
increased secretion of PTH. The excessive concentration of PTH
usually leads to hypercalcemia and hypophosphatemia. Symptoms
are usually associated with the degree of hypercalcemia; however,
the patient may be asymptomatic. In advanced cases manifestations
of hypercalcemia include: CNS - lassitude, fatigability, poor memory,
depression, and obtundation; ophthalmic - band keratopathy; C-V –
hypertension; digestive - anorexia, vomiting, constipation;
genitourinary - renal stones, decreased urine - concentrating
capacity, and renal insufficiency; musculoskeletal - weakness,
osteoporosis, fractures, bone pain, brown tumors, bone cysts, and
joints - pseudogout (1,2).
Today, PHPT in the developed countries is typically a disease with
few or no obvious clinical symptoms. However, even in the
asymptomatic cases the endogenous excess of PTH increases bone
turnover leading to an insidious reversible loss of cortical and
trabecular bone because of an expansion of the remodeling space
and an irreversible loss of cortical bone due to increased endocortical
resorption. In contrast trabecular bone structure and integrity to a
large extent is maintained and there may be a slight periosteal
expansion. Most studies have reported decreased BMD in PHPT
mainly located at cortical sites, whereas sites rich in trabecular bone
only show a modest reduction or even a slight increase in BMD. The
frequent occurrence of vitamin D insufficiency and deficiency in PHPT
and increased plasma FGF23 levels may also contribute to the
decrease in BMD. The effect of smoking is unsolved. Epidemiological
studies have shown that the relative risk of spine and nonspine
fractures is increased in untreated PHPT starting up to 10 years
before the diagnosis is made. Successful surgery for PHPT normalizes
bone turnover, increases BMD and decreases fracture risk based on
larger epidemiological studies. However, 10 years after surgery
fracture risk appears to increase again due to an increase in forearm
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L. Ben-Nun King David

fractures. There are no RCTs demonstrating a protective effect of


medical treatment on fracture risk in PHPT. Less conclusive studies
suggest that vitamin D supplementation may have a beneficial effect
on plasma PTH and BMD in vitamin D deficient PHPT patients. HRT
and may be SERM appear to reduce bone turnover and increase
BMD. However, their nonskeletal side-effects preclude their use for
this purpose. Bisphosphonates reduce bone turnover and increase
BMD in PHPT as in osteoporosis and may be a therapeutical option in
selected patients with low BMD. There is a need for larger RCTs with
fractures as end-points that appraise this possibility. Calcimimetics
reduce plasma calcium and PTH in PHPT but has no beneficial effect
on bone turnover or BMD. In symptomatic hypercalcaemic PHPT with
low BMD when curative surgery is impossible or contraindicated a
combination of a calcimimetic and a bisphosphonate may be an
therapeutical option that needs further evaluation (3).

Hyperparathyroidism

Patients (n=48) afflicted by PHPT, Sanata Crisitina, Madrid had


elevated PTH levels and 87% had normal or moderately increased
hypercalcaemia, The most common clinical presentation was renal
colic (34%), while 22.8% was asymptomatic. In 70.4% of patients,
osteopenia was found, and osteoporosis in 81.3%. Fractures
developed in 21.8% of the patients. Osteoporosis was a common
finding (4).
In PHPT, PTH is produced by an adenoma in 80% of patients.
Ectopic adenomas occur in a small proportion of cases. A 72-year-old
woman with a delayed diagnosis of primary PHPT, produced by an
intrathoracic adenoma with a longstanding course, presented with
severe osteoporosis, multiple fractures, bone deformities, and
neurological impairments. Persisted hypercalcaemia, high levels of
ALP, and PTH were documented and a paratracheal mass was found
on a helicoids tomography of the thorax. After surgical removal, the
histopathological examination confirmed an ectopic adenoma of the
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L. Ben-Nun King David

parathyroid gland and the patient achieved some improvement in


her clinical course (5).
PHPT results from the excessive secretion of PTH and typically
produces frank hypercalcaemia. With the advent of multiphasic
screening of serum chemistries, it has been recognized that PHPT is a
prevalent disorder. A 32-year- old woman with burning to colicky
recurrent upper abdominal pain, polyuria, polydipsia associated with
anorexia, dyspepsia, generalized body ache, joint pain, constipation
and weight loss has been described. An initial abdominal ultrasound
was performed at hospital and revealed features of cholelithiasis and
bilateral nephrocalcinosis. Serum biochemistries revealed that her
serum calcium was 12.60 mg/dl, serum PTH was 222.80 ng/dl, serum
creatinine was 0.90 mg/dl, 99 Tc-sestamibi scanning for parathyroid
evaluation revealed features suggestive of parathyroid adenoma
adjoining the lower pole of right lobe of thyroid gland. Bone
densitometry of femur and spine by DXA showed osteoporosis with T
score value <-3.5 SD. Right hemithyroidectomy with parathyroid
adenoma excision was performed. Patient was closely monitored.
Serum calcium and PTH levels were markedly reduced near to the
normal range within two weeks of surgery. Following five months
after surgery, serum PTH was 29.59 ng/dl, six months after surgery
serum calcium was 9.2 mg/dl. Patient is in good physical condition
and under regular follow up (6).
Hyperparathyroidism can be primary, secondary or tertiary
depending on its etiology. Parathyroid adenoma accounts for 80% of
cases of PHPT. A case of a 41-year-old female patient presented with
severe osteoporosis and pathological fracture of right acetabulum
and left intertrochanteric region. The patient had diffuse
osteoporosis and multiple well-defined lytic lesions. A diagnosis of
hyperparathyroidism apart from MM and metastasis was made
based on the findings of diffuse osteoporotic changes with multiple
lytic lesions. A skeletal survey was performed in view of the
pathological fracture of the femur; findings of the skeletal survey
favored the diagnosis of hyperparathyroidism. An ultrasound of the
neck was performed to look for the cause and a parathyroid
adenoma was picked up in the inferior aspect of the left lobe of the
thyroid gland. CT of the neck was also performed for preoperative
localization of the lesion. Based on these findings diagnosis of PHPT
due to parathyroid adenoma was made. The patient underwent
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L. Ben-Nun King David

parathyroidectomy and perioperative and histopathological findings


confirmed the preoperative diagnosis (7).

ASSESSMENT: did the King suffer from hyperparathyroidism?


PHPT is a generalized disorder of calcium, phosphate, and bone
metabolism due to an increased secretion of PTH. It can be
speculated that he may have suffered from this disease leading to
osteoporosis, subsequent fractures and severe bone pain. Did the
King suffer from asymptomatic renal stones, renal failure, or other
asymptomatic manifestations of this disease? There are insufficient
data to answer these questions. If this diagnosis is accepted,
however, there is still no explanation for the disease, which
“...consumed ...” the King’s bones.

References
1. Moore TJ. Hypercalcemia. In: Branch WT (ed.). Office Practice of
Medicine. 2nd ed. St. Louis, MO: W.B. Saunders. 1987; pp. 752-63.
2. Rude PK. Hyperparathyroidism. Otolaryngol Clin North Am. 1996;
29:663-79.
3. Mosekilde L. Primary hyperparathyroidism and the skeleton. Clin
Endocrinol (Oxf). 2008;69(1):1-19.
4. Alcaraz MJ, Lorente R, Del Valle Y, et al. Primary hyperparathyroidism:
current role of bone densitometry. Radiologia. 2008;50:37-45.
5. Souza ER, Scrignoli JA, Bezerra FC, et al. Devastating skeletal effects of
delayed diagnosis of complicated primary hyperparathyroidism because of
ectopic adenoma. J Clin Rheumatol. 2008;14:281-4.
6. Siddiqui NI, Miah AG, Khan NK, et al. Primary hyperparathyroidism: a
case report. Mymensingh Med J. 2014;23(2):375-9.
7. Lachungpa T, Sarawagi R, Chakkalakkoombil SV, Jayamohan AE.
Imaging features of primary hyperparathyroidism. BMJ Case Rep. 2014 Mar
10;2014. pii: bcr2013203521.

PAGET'S DISEASE. Paget’s disease is a relatively common


disorder, resulting from a primary overactivity of osteoclasts, which
leads to excessive resorption of bone and the formation of
disorganized, structurally defective bone. Commonly affected areas
include the skull, spine, pelvis, femur, and tibia. The usual presenting
symptoms are deformity and pain, the latter probably arising from
periostal stretching, microfractures, degenerative joint disease, or
direct neural compression. The skull may become enlarged and
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bowing of the femur and tibia are frequently seen. Increased


warmth and sweating of the skin overlying affected bones are
common. In addition, a high output cardiac failure may develop (1).
Paget's disease of bone is one of the most common diseases to
affect bone, yet it is rare before the age of 50 years. The etiology of
the condition remains unproven. Paget's disease of bone has become
less common, less severe, and less extensive in recent decades.
Isotope bone scans and radiographs remain the most frequent
radiological investigations, demonstrating the extent of the disease
and characteristic appearances in most cases. Recent changes in the
radiological investigation of Paget's disease include increasing use of
CT and MRI imaging for the evaluation of less typical disease or
disease complications; the incidental finding of Paget's disease on CT
or MRI requires recognition to avoid inappropriate investigation. The
presence of sclerotic Paget's disease in the lumbar spine or hip may
elevate BMD measurements at these sites, with consequent potential
to underestimate fracture risk. Awareness of the normal level-to-
level vertebral variation in bone density in the spine, and careful
assessment of the images acquired on DXA or quantitative CT will
help to avoid this pitfall (2).

Paget's disease

Paget's disease is a metabolic bone disease characterized by


excessive bone resorption and formation due to activated
osteoclasts. Although Paget's disease is a high bone turnover state,
the excess bone that is formed lacks the structural stability of normal
bone. Complications from Paget's disease include deformity, fracture,
and pain. Although still unclear, both prevalence and severity of
Paget's disease seem to be declining. Recent progress has focused on
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the environmental as well as genetic etiologies for this disease. Many


studies indicate a role for viral infectious agents, whereas others
point to a recently identified candidate gene on chromosome 18q.
Therapy with bisphosphonate drugs is the treatment of choice. With
newer and more powerful agents from this family now available, the
majority of patients affected by Paget's disease can achieve sustained
remission and avoid complications (3).
Paget's disease of the bone is a disorder in which there is marked
increase in bone turnover by activated osteoclasts in localized parts
of the skeleton. The newly formed bone is abnormal in structure and
mineralization resulting in deformity and increased risk of fracture.
The prevalence of the disease has decreased over the last 20 years to
2% in patients over 55 years of age. The etiology of the disease is still
unknown. There is strong evidence for viral infection, but recently a
genetic disposition has also been discussed. There are important
advances in the understanding of the pathophysiology of Paget's
disease. Increased sensitivity of osteoclast-precursors to 1,25(OH)2
Vitamin D3 and RANKL, mediated by IL6, have been described as a
possible mechanism. For the diagnosis of the disease the finding of
an elevated level of plasma ALP as a marker of increased bone
turnover is of great importance. This parameter is also used for
monitoring disease activity during therapy. Plain radiology and
skeletal scintigraphy are necessary for the diagnosis. CT and MRI can
be useful in specific cases. In the last decade, bisphosphonates have
increasingly assumed, according to their mechanism of action, the
prime role in the management of Paget's disease. Recently,
bisphosphonates that are more potent have been developed and
therefore the goal of therapy has changed. Initial response to
treatment in terms of reducing activity of ALP to normal levels is
associated with increased remission duration. In this respect,
risedronate and alendronate have proved superior to etidronate.
Bisphosphonates have also been used extensively in the form of IV
infusion in patients with Paget's disease. Especially when G-I side
effects occur with oral medication, this might be useful. However, at
present more studies are needed to find the optimal drug, the
optimal dose and intervals of IV therapy (4).
Paget's disease, often an incidental finding, sometimes presents in
the form of pain or signs of complications, such as spinal cord
compression, malignant transformation or fissures. The diagnosis is
established by laboratory tests, but essentially by radiological
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findings, based on three basic criteria: cortical thickening, loss of


cortico-cancellous differentiation and enlargement of the bone,
which deformity is a later sign. The diagnosis can usually be made on
plain x-rays, but CT is useful in the case of early, difficult or unusual
lesions and complications. CT can reveal mouth-eaten, vacuolar,
network, clumped or mixed, fibrillary or ivory images. MRI is a last
resort of examination. Angioma, metastases and ivory vertebrae are
the main differential diagnoses (5).
A retrospective review evaluated the medical records of 51
patients with Paget's disease at a tertiary referral centre in Southern
India, 1995-2003. The symptoms included bone pain (65%), backache
(37%), skeletal deformities (33%), pathological fractures (20%),
neurogenic claudication (4%), deafness, head enlargement (7%), and
renal stones (4%). Five patients (9.8%) were asymptomatic and were
incidentally diagnosed during evaluation of an elevated ALP. Two
patients had neurological symptoms (root pains in one and cauda
equina in the other) (6).
Hypocalcemia is rare in Paget's disease, usually occurring because
of therapy with biphosphonates (7).
Paget's disease of bone, the second most common metabolic
bone disease in the US, is characterized by localized areas of
excessive bone resorption coupled with accelerated bone formation,
resulting in a new bone that is less structurally organized and is
weaker than normal bone. Complications of Paget's disease include
bone pain, osteoarthritis, skeletal deformity, hearing loss, and
fractures. The objective of this review is to provide a comprehensive
overview of current standards of treatment in Paget's disease. A
review of literature from 1974 to 2007 was performed on topics such
as epidemiology, etiology, treatment of Paget's disease of the bone,
and bisphosphonates. Paget's disease affects an estimated 2-7% of
persons of age 55 years or older in North America and Western
Europe. Antiresorptive treatment with bisphosphonates is the
standard treatment, but there may be limitations to oral therapy. IV
pamidronate is efficacious and has long been available, but its use is
hindered by an impractical recommended dosing regimen of 30 mg
IV over four hours for three consecutive days. In two identical,
double-blind, six-month trials, 96% of patients treated with a one-
time IV treatment of ZOL five mg achieved therapeutic response,
compared with 74% treated with 60 days of daily oral treatment with
risedronate 30 mg (p<0.001). In conclusion, the etiology of Paget's
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disease is unclear, but some evidence suggests genetic and viral


components. Bisphosphonates restore normal bone turnover and
relieve bone pain, but oral formulations may be limited by
complicated dosing regimens and poor G-I absorption. The
bisphosphonate, ZOL is administered as a single IV infusion and offers
antiresorptive efficacy and longer-lasting remission (8).
The aim of this study is double: 1] to review the known and less
known radiographic patterns of Paget's disease of bone, employing
the most recent imaging techniques; 2] to propose a rationale
algorithm for the diagnosis and management of the disease.
considering its inconsistency and clinical variability. Forty-eight
patients with Paget's disease of bone (30 males and 18 females, aged
45 and 88 years, mean age 71) were examined in the period 1999-
2003. The patients were classified into two groups: symptomatic and
asymptomatic. The first group, comprising 32 patients with generic
''low back pain'' with or without sciatica, or ''coxarthritis'' underwent
conventional radiography. In the second group (16 patients), bone
disease was discovered in course of radiological and/or scintigraphic
examinations performed for other conditions. Subsequently, all the
patients completed the diagnostic algorithm, consisting of
radiographs of the remaining skeletal areas and those segments with
abnormal scintigraphic uptake. Monostotic Paget's disease was
observed in 31 cases (64.6%), of whom 20 males (64.6%) and 11
females (35.4%), whereas polyostotic disease was found in 17 cases
(35.4%), of whom 10 males (58.8%) and seven females (41.2%). The
sites most frequently affected in the monostotic form were: pelvis,
13 cases (43.3%); femur, five cases (16.7%); lumbar spine, five cases
(16.7%); humerus, two cases (6.7%); tibia, two cases (6.7%); dorsal
spine, skull, radius, patella, one case respectively (3.3%). In the
polyostotic disease (17 cases), the affected bones were
predominantly the skull, vertebral spine and pelvis (see text for their
variable association). Pathologic fractures of the femur were found in
two males. Osteogenic sarcoma (histological diagnosis) developed in
the proximal femur in a 81 year-old male. In conclusion, Paget's
disease is asymptomatic in the majority of affected individuals, and is
discovered incidentally with diagnosis being made on routine
radiographs obtained for other purposes. Sometimes, the x-ray
features are so typical that the diagnosis is straightforward. Bone
scan should be the imaging technique of choice, because tracer
uptake is directly related to degree of activity of disease, and it may
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advance any radiographic evidence. Vertebral involvement is better


evaluated by CT. Both CT and MRI are recommended in spine
complications (pathological fractures, radicular or cord compression
syndromes, and malignant degeneration) (9).

ASSESSMENT: was Paget's disease responsible for the King's bone


pain? In the absence of the deformity of the bones, bowing of the
femur or tibia, enlargement of skull, or warmth and sweating skin
over the affected bones, and appropriate laboratory and radiological
investigation, this diagnosis seems unlikely.

References
1. Brown EM. Osteoporosis and Paget’s disease of bone. In: Branch WT
(ed.). Office Practice of Medicine. 2nd ed. St Louis, MO. W.B. Saunders.
1987, pp. 952-64.
2. Whitehouse RW. Paget's disease of bone. Semin Musculoskelet Radiol.
2002;6(4):313-22.
3. Noor M, Shoback D. Paget's disease of bone: diagnosis and treatment
update. Curr Rheumatol Rep. 2000;2(1):67-73.
4. Sieghart S. Osteitis deformans - Paget's disease. Wien Med
Wochenschr. 2004;154(5-6):97-101.
5. Chrétien J. Vertebral localizations of Paget disease. Ann Radiol (Paris).
1995;38(4):169-76.
6. Anjali Thomas N, Rajaratnam S, Shanthly N, et al. Paget's disease of
bone: experience from a centre in southern India. J Assoc Physicians India.
2006;54:525-9.
7. Kannan S, Mahadevan S, Sathya A, Sriram U. A tale of three disease of
the bone. Singapore Med J. 2008;49(10):e263-5.
8. Abelson A. A review of Paget's disease of bone with a focus on the
efficacy and safety of zoledronic acid 5 mg. Curr Med Res Opin. 2008;
24(3):695-705.
9. Scutellari PN, Giorgi A, De Sario V, Campanati P. Correlation of
multimodality imaging in Paget's disease of bone. Radiol Med. 2005;110(5-
6):603-15.

LACTASE DEFICIENCY. Persons with a lifelong low intake of dairy


products because of lactase deficiency may have an increased
incidence of osteoporosis (1). The potential for lactose intolerance
causes 25-50 million Americans and an unknown number of people
around the world to avoid milk. Milk avoidance is a significant risk
factor for low bone density. Individuals who avoid milk, due to
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intolerance or learned aversion, consume significantly less calcium


and have poorer bone health and probable higher risk of
osteoporosis. Lactose intolerance is easily managed by: 1] regular
consumption of milk that adapts the colon bacteria and facilitates
digestion of lactose; 2] consumption of yogurts and cheeses and
other dairy foods low in lactose; consumption of dairy foods with
meals to slow transit and maximize digestion, and use of lactose-
digestive aids. As dairying spreads around the world to new markets
and dairy foods become the dominant source of calcium in these
markets, the potential for lactose intolerance will grow. Management
of lactose intolerance globally will require both education and
product development (2).
Symptoms of lactose intolerance are unlikely to occur under usual
dietary conditions. Yet, self-described "lactose-intolerant" individuals
often restrict dairy and calcium intake. Such individuals have reduced
peak bone mass and increased incidence of osteopenia, and are at
greater risk of osteoporosis and bone fractures (3).
Intolerance to certain foods can cause a range of gut and systemic
symptoms. The possibility that these can be caused by lactose has
been missed because of "hidden" lactose added to many foods and
drinks inadequately labeled, confusing diagnosis based on dietary
removal of dairy foods. Two polymorphisms, C/T13910 and
G/A22018, linked to hypolactasia, correlate with breath hydrogen
and symptoms after lactose. This, with a 48-hour record of gut and
systemic symptoms and a six-hour breath hydrogen test, provides a
new approach to the clinical management of lactose intolerance. The
key is the prolonged effect of dietary removal of lactose. Patients
diagnosed as lactose intolerant must be advised of "risk" foods,
inadequately labeled, including processed meats, bread, cake mixes,
soft drinks, and lagers. This has important implications for the
management of IBS, and for doctors of many specialties (4).
Lactase intolerance is characterized by abdominal pain, bloating
and diarrhea after lactose ingestion (5). Three men with osteoporotic
fractures have lactase deficiency and low dietary calcium intakes,
decreased urinary calcium, and moderately increased serum
osteocalcin and PTH levels. Histomorphometric studies demonstrated
increases in osteoid parameters and resorption surfaces. The few
studies of the links between osteoporosis and lactase deficiency have
yielded discordant results. In conclusion, a low calcium intake due to
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aversion to dairy products caused by the lactase deficiency may


promote the development of osteoporosis (6).

ASSESSMENT: was lactase deficiency responsible for the King's


bone pain? In the absence of characteristic clinical symptoms
associated with lactose ingestion, and appropriate investigation this
diagnosis seems unlikely.

References
1. Newcomer AD, Hodgson SF, McGill DB, Thomas PJ. Lactase deficiency:
prevalence in osteoporosis. Ann Intern Med. 1978; 89:218-20.
2. Savaiano D. Lactose intolerance: an unnecessary risk for low bone
density. Nestle Nutr Workshop Ser Pediatr Program. 2011;67:161-71.
3. Savaiano D. Lactose intolerance: a self-fulfilling prophecy leading to
osteoporosis? Nutr Rev. 2003;61(6 Pt 1):221-3.
4. Matthews SB, Waud JP, Roberts AG, Campbell AK. Systemic lactose
intolerance: a new perspective on an old problem. Postgrad Med J. 2005;
81(953):167-73.
5. Scheuner M, Yang H, Totter JI. Gastrointestinal manifestations of
specific genetic disorders. In: Yamada T (ed.) Textbook of Gastroenterology.
2nd ed. Philadelphia, PA: J.B. Lippincott. 1995, pp. 2419-81.
6. Laroche M, Bon E, Moulinier L, et al. Lactose intolerance and
osteoporosis in men. Rev Rhum Engl Ed. 1995;62(11):766-9.

BILIARY CIRRHOSIS. Biliary cirrhosis results from injury to or


obstruction of either the intrahepatic or the extrahepatic biliary
system. It is associated with impaired biliary excretion, destruction
of hepatic parenchyma, and progressive fibrosis (1).
PBC is an immune-mediated chronic cholestatic liver disease with
a slowly progressive course. Without treatment, most patients
eventually develop fibrosis and cirrhosis of the liver and may need
liver transplantation in the late stage of disease. PBC primarily affects
women (female preponderance 9-10:1) with a prevalence of up to
one in 1,000 women over 40 years of age. Common symptoms of the
disease are fatigue and pruritus, but most patients are asymptomatic
at first presentation. The diagnosis is based on sustained elevation of
serum markers of cholestasis, i.e., ALP and GGT, and the presence of
serum AMAs directed against the E2 subunit of the pyruvate
dehydrogenase complex. Histologically, PBC is characterized by florid
bile duct lesions with damage to biliary epithelial cells, a dense portal
inflammatory infiltrate and progressive loss of small intrahepatic bile
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ducts. Although the insight into pathogenetic aspects of PBC has


grown enormously during the recent decade and numerous genetic,
environmental, and infectious factors have been disclosed which may
contribute to the development of PBC, the precise pathogenesis
remains enigmatic. UDCA is currently the only FDA-approved medical
treatment for PBC. When administered at adequate doses of 13-15
mg/kg/day, up to two out of three patients with PBC may have a
normal life expectancy without additional therapeutic measures. The
mode of action of UDCA is still under discussion, but stimulation of
impaired hepatocellular and cholangiocellular secretion,
detoxification of bile, and antiapoptotic effects may represent key
mechanisms. One of three patients does not adequately respond to
UDCA therapy and may need additional medical therapy and/or liver
transplantation (2).
PBC is a chronic liver disease characterised by intrahepatic bile-
duct destruction, cholestasis, and, in some cases, cirrhosis. Evidence
supporting the autoimmune nature of this disorder includes the
appearance of highly specific AMAs and autoreactive T cells.
Concordance rates in monozygotic twins, familial prevalence, and
genetic associations underscore the importance of genetic factors,
whereas findings of epidemiological studies and murine models
suggest a possible role for exogenous chemicals and infectious agents
through molecular mimicry. The incidence of PBC has increased over
recent decades, possibly attributable to augmented testing of liver
biochemistry rather than a rise in disease incidence. AMAs remain
the hallmark of diagnosis in most cases and allow detection of
asymptomatic patients. Symptomatic individuals usually present with
either pruritus or fatigue and, more rarely, with either jaundice or
complications of cirrhosis. The prognosis of PBC has improved
because of early diagnosis and use of UDCA, the only established
medical treatment for this disorder. Although not a cure, treatment
can slow disease progression and delay the need for liver
transplantation. However, some patients do not respond adequately
to UDCA and might need alternative therapeutic approaches (3).
PBC is characterized by pruritus, jaundice, hyperpigmentation of
the exposed skin areas, xanthelasmas and tendinous and plantar
xanthomas, hepatomegaly, splenomegaly, clubbing of the fingers,
steatorrhea, easy bruising related to the malabsorption of vitamin K,
night blindness due to vitamin A deficiency, and dermatitis due to
vitamin E and/or essential fatty acid deficiency (1,4).
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L. Ben-Nun King David

Liver cirrhosis at an advanced stage can lead to osteoporosis due


to diminished vitamin D absorption, while deficiency of vitamin K
contributes to bone fragility (1,5). Osteoporosis is a common
complication of chronic liver disease, from cholestatic disorders to
autoimmune, alcoholic, and posthepatitic cirrhosis. Osteoporosis
appears more striking in patients with PBC because the disease
usually affects elderly women, who are naturally prone to
osteoporosis (6).
Osteoporosis is a metabolic bone disease associated with a
reduction in bone mass and deterioration of bone architecture,
leading to increased fragility and subsequent low-trauma fractures in
the vertebral column, hip, forearm and other bones. Metabolic bone
diseases such as osteoporosis and osteomalacia have been
recognized as a complication of chronic liver disease, although the
mechanisms of this association remain unclear. An increasing body of
research data indicates a strong relationship between osteoporosis
and PBC, which mainly results from early diagnosis of the disease,
usually when it is still asymptomatic. The incidence of osteoporosis in
PBC ranges from 20% to 44% and increases with the progression of
the disease. Similarly, the incidence of bone fractures is high in this
group of patients (10-20%) (7).
Metabolic bone disease has been recognized as an important
complication of chronic liver disease particularly in cholestatic
disorders [PBC and primary sclerosing cholangitis] and after liver
transplantation. It includes osteoporosis and more rarely
osteomalacia, which is more frequent in severe malabsorption and
advanced liver disease. The pathogenesis of this disorder is complex
and is likely to be multifactorial. Regardless of the etiology of
osteoporosis in PBC patients, they have an increased risk of
spontaneous or low-trauma fracturing leading to significant patient
morbidity, deterioration of QOL, and even patient mortality. The
development of bone densitometry has allowed assessment of bone
mass and then contributed in estimating the fracture risk. The gold
standard of BMD measurement is currently the DXA.
Recommendations formulated by the WHO have reported the
diagnostic ranges of osteoporosis based on the T-score: patient with
osteoporosis has a T-score less than -2.5 SD, osteopenia has a T-score
between -1.0 and -2.5 SD and a normal individual has a T-score more
than -1.0 SD. The risk of fracture shows a correlation with BMD but
no fracture threshold was determined and the best site of
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L. Ben-Nun King David

characterizing the hip fracture risk is the measure of the BMD of the
proximal femur. The treatment of osteoporosis in patients with PBC
is largely based on trials of patients with postmenopausal
osteoporosis as there are a few and smaller studies of osteoporotic
patients with PBC. Bisphosphonates seem to be effective in biliary
disease and are more tolerated (8).
The aims were 1] to compare the prevalence of osteoporosis (T-
score <-2.5 SD) between PBC patients and a group of age-and sex-
matched controls consisting of healthy subjects from the general
population; and 2] to identify the main risk factors for the
development of bone loss. Thirty-three women with PBC (mean age,
47.3 +/- 10.4 years) and 66 healthy subjects were enrolled in the
study. BMD was assessed at the lumbar spine by DXA. Bone
metabolism was evaluated by measuring serum calcium corrected for
serum albumin, 25-OH vit. D, PTH, and osteocalcin. Vertebral
fractures were analyzed using vertebral fracture assessment. The
mean T-score was lower in the PBC group compared to healthy
controls, with a significant statistical difference (-2.39 +/- 0.93 and -
1.47 +/- 0.99 in lumbar spine and total hip, respectively, in the PBC
group vs. -0.99 +/- 0.51 and -0.56 +/- 1.14 in healthy controls,
p<0.001). The prevalence of osteoporosis was 51.5% in the PBC group
vs. 22.7% in healthy controls with a statistically significant difference
(p=0.004). BMD of the PBC group was significantly correlated
positively with BMI and 25-OH vit. D, and negatively with menopausal
status, duration of disease, and PTH levels. Vertebral fractures were
present in 9% of the patients. Osteoporosis is more prevalent in
women with PBC than in the general population. BMI, menopausal
status, duration of the disease, and vitamin D deficiency are the main
risk factors for osteoporosis in this liver disease (6.

ASSESSMENT: was King David afflicted by biliary cirrhosis? In the


absence of pruritus, jaundice, hyperpigmentation of the exposed skin
areas, xanthelasmas and tendinous and plantar xanthomas,
hepatomegaly, splenomegaly, clubbing of the fingers, steatorrhea,
easy bruising related to the malabsorption of vitamin K, night
blindness due to vitamin A deficiency, and dermatitis due to vitamin
E and/or essential fatty acid deficiency, and appropriate laboratory,
radiological, and pathological investigations, this diagnosis seems
unlikely.
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References
1. Podolsky DK, Isselbacher KJ. Cirrhosis and alcoholic liver disease. In:
Harrison’s Principle of Internal Medicine. 14th ed. New York, NY: McGraw-
Hill. 1998, pp. 1704-9.
2. Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis.
Semin Immunopathol. 2009;31(3):283-307.
3. Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis.
Lancet. 2011;377(9777):1600-9.
4. Rosenblum AL. Connective tissue disorder in diabetes. In: Alberti
K.G.M.M, Zimmet P, DeFronzo R.A, Keen H (eds.). International Textbook
of Diabetes. Vol. 2. 2nd ed. New York, NT: John Wiley & Sons. 1997, pp.
1517-29.
5. Bonjour J-P, Schurch M-A, Rizzoli R. Nutritional aspects of hip
fractures. Bone. 1996;18:139S-44S.
6. Mounach A, Ouzzif Z, Wariaghli G, et al. Primary biliary cirrhosis and
osteoporosis: a case-control study. J Bone Miner Metab. 2008;26(4):379-84.
7. Raszeja-Wyszomirska J, Miazgowski T. Osteoporosis in primary biliary
cirrhosis of the liver. Prz Gastroenterol. 2014;9(2):82-7.
8. Wariaghli G, Allali F, El Maghraoui A, Hajjaj-Hassouni N. Osteoporosis
in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2010;
22(12):1397-401.

WHIPPLE DISEASE. Whipple's disease is a rare, chronic


multisystem disease characterized by the presence of fever, diarrhea,
weight loss, malabsorption, abdominal pain and arthralgia. Arthritis
and arthralgia may be the only presenting symptom, predating other
manifestations by years. The causative organism is the bacterium T.
whipplei. Although Whipple's disease usually involves the small
intestine with the presence of malabsorption, it commonly affects
other organs, especially the heart, brain, eyes and joints. The disease
is fatal unless patients are treated with antibiotics. The characteristic
histopathological features are found most often in the small
intestine. These are variable villous atrophy and distension of the
normal villous architecture by an infiltrate of foamy macrophages
with a coarsely granular cytoplasm, which stain a brilliant magenta
with PAS. These pathognomonic PAS positive macrophages may also
be present in the peripheral and mesenteric lymph nodes and various
other organs (1-5).
Whipple's disease is a chronic, multisystemic, curable, bacterial
infection that usually affects middle-aged men. It has a wide range of
clinical manifestations. In the historical presentation, weight loss and
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diarrhea are the most common symptoms and are preceded in three-
quarters of cases by arthritis for a mean of six years. Long-term,
unexplained, seronegative oligoarthritis or polyarthritis of large joints
with a palindromic or relapsing course is typical. In most patients,
periodic acid-Schiff staining of proximal small bowel biopsy
specimens reveals inclusions within the macrophages, corresponding
to bacterial structures. However, patients may have no G-I
symptoms, negative jejunum biopsy results and negative PCR tests.
Even in the absence of G-I symptoms, Whipple's disease should be
considered in case of negative blood culture endocarditis, and
unexplained central neurological manifestations or unexplained
arthritis. Identification of the causative bacterium, T. whipplei, has
led to the development of PCR as a diagnostic tool, particularly useful
in patients in the early stages of the disease or with atypical disease.
The recent cultivation of T. whipplei and the complete sequencing of
its genome should improve our understanding and treatment of the
disease. The future development of an assay for detection of specific
antibodies in the serum and generalization of the
immunohistochemical detection of antigenic bacterial structures may
allow earlier diagnosis, thereby preventing the development of the
severe late systemic and sometimes fatal forms of this disease (6).

A patient was presented with inflammatory back pain due to


multisegmental spondylitis. Following a vertebral biopsy which failed
to detect an infectious organism, the patient was treated with
etanercept, a TNF-alpha inhibitor, for suspected undifferentiated
spondyloarthritis. The back pain worsened and the spondylitic lesions
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increased. Only in a vertebral rebiopsy with PCR amplification for T.


whipplei, the causative agent of Whipple's disease was identified. T.
whipplei should be considered as a cause of spondylitis even with
multisegmental involvement and in the absence of G-I symptoms. In
this clinical setting, routine PCR for T. whipplei from vertebral
biopsies is recommended (7).
Whipple disease is a rare systemic bacterial infection
characterized by migratory polyarthralgia and chronic diarrhea. In 5%
to 20% of patients with Whipple disease, the infection may present
initially with or eventually develop symptoms related to the CNS.
Although CNS involvement is a known feature of systemic Whipple
disease, intracerebral mass lesions are uncommon. Mass lesions in
these cases are typically deep seated and multifocal.
Corticosubcortical regions are unusual sites of CNS involvement in
cases of Whipple disease. In the present paper, the case of Whipple
disease featured a single corticosubcortical solid frontoparietal mass
lesion that displayed homogeneous contrast enhancement on
neuroimaging and was associated with bone destruction of the
calvaria. Although CNS involvement has been observed in the form of
deep-seated mass lesions in cases of systemic Whipple disease,
unusual manifestations should be kept in mind during diagnosis and
follow-up review in these patients (8).

ASSESSMENT: Whipple's disease is a rare, chronic multisystem


disease characterized by the presence of fever, diarrhea, weight loss
and malabsorption, abdominal pain and arthralgia.
Was King David afflicted by this disease? In the absence of fever,
diarrhea, abdominal pain, arthralgia or arthritis, endoscopic and the
characteristic histopathological findings, the diagnosis of Whipple's
disease seems unlikely.

References
1. Ghitoni G, Valentini G, Spada C, et al. Whipple's disease: progress in
the diagnosis and review of the literature. Minerva Med. 2002;93:447-51.
2. Ratnaike RN. Whipple's disease. Postgrad Med J. 2000;76(902):70-6.
3. Schijf LJ, Becx MC, de Bruin PC, van der Vegt SG. Whipple's disease:
easily diagnosed, if considered. Neth J Med.2008;66:392-5.
4. Eriksen R, Westre B, Bergh K, Qvigstad G. Whipple's disease. Tidsskr
Nor Laegeforen. 2008;128:1406-9.
5. Dancygier H, Scharnke W. Whipple disease - a rare systemic disease.
Praxis (Bern 1994). 2002;91:1691-8.
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6. Puéchal X. Whipple's disease. Rev Med Interne. 2009;30(3):233-41.


7. Spoerl D, Bär D, Cooper J, et al. Multisegmental spondylitis due to
Tropheryma whipplei: case report. Orphanet J Rare Dis. 2009 Jun 3;4:13.
8. Akar Z, Tanriover N, Tüzgen S, et al. Intracerebral Whipple disease:
unusual location and bone destruction. Case report. J Neurosurg. 2002;
97(4):988-91.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD represents one of the main causes of morbidity and


mortality worldwide. According to the WHO, approximately three
million people in the world die because of COPD every year. Tobacco
use remains the main factor associated with development of disease
in the industrialized world, but other risk factors are important and
preventable causes of COPD, particularly in the developing world (1).

COPD is a frequent and progressive disease, which can lead to


severe respiratory impairment. Smoking is the main causal factor.
Therefore, respiratory symptoms should not be underestimated in
smokers. Chronic cough, chronic sputum, persistent dyspnea on
exercise (even for sustained efforts) need further investigations. Each
smoker has to be considered as potentially having COPD. Lung
function measurements are required in these patients (2).
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L. Ben-Nun King David

Chronic obstructive pulmonary disease

COPD is characterized by a history of cough and sputum


production (sometimes with wheezing) over many years, dyspnea,
and signs of right ventricular failure (3).

COPD is being regarded as a heterogeneous disease with clinically


significant pulmonary and extrapulmonary manifestations, such as
emphysema, C-V disease and osteoporosis. Osteoporosis is
characterized by low bone mass and microarchitectural deterioration
of bone tissue, leading to enhanced bone fragility and, consequently,
an increased risk of fracture. Fractures resulting from osteoporosis
might contribute to increased morbidity and mortality, particularly in
COPD patients. The high prevalence of osteoporosis in COPD patients
is assumed to be due to common risk factors, such as older age and
tobacco smoking, and COPD specific risk factors, such as systemic
inflammation, vitamin D deficiency and the use of oral or inhaled
corticosteroids (4).
Increasing evidence indicates that COPD and osteoporosis are
strongly linked. Both diseases share common risk factors like age,
smoking and inactivity but the typical presence in COPD of systemic
inflammation, vitamin D deficiency and the frequent use of
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L. Ben-Nun King David

corticosteroids catalyse ongoing bone resorption. Osteoporosis, in


turn, may cause fragility fractures, which further impair mobility and
increase morbidity and mortality. Vertebral compression fractures
and rib cage fractures in patients with COPD may also reduce
pulmonary function or enhance exacerbations. Early prevention and
treatment of osteoporosis in COPD is, therefore, important and
should be based on integrated risk assessment tools such as fracture
risk assessment tool (FRAX), which take BMD, history of fragility
fractures, and population-specific clinical factors into account. As
long as intervention studies focusing on the bone in COPD are
lacking, a more rigorous application of existing treatment guidelines
of osteoporosis in general is mandatory (5,6).

ASSESSMENT: COPD represents one of the main causes of


morbidity and mortality worldwide. COPD enhances systemic
inflammation, vitamin D deficiency, and the use of systemic steroids
induce bone destruction. Thus, COLD is associated with osteoporosis.
Was King David was afflicted by COLD? In the absence risk factors
for COPD, a history of cough and sputum production (sometimes with
wheezing) over many years, dyspnea, signs of right ventricular
failure, results of spirometry and radiological investigation, this
diagnosis seems unlikely.

References
1. Diaz-Guzman E, Mannino DM. Epidemiology and prevalence of
chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):7-16.
3. Kessler R, Weitzenblum E. COPD: from early symptoms to chronic
respiratory failure. Rev Prat. 2004;54(13):1414-8.
4. Nicholson D, Bower AD. Pulmonary Medicine. In: Rakel RE (ed.).
Textbook of Family Practice. 3rd ed. St. Louis, MO: W.B. Saunders. 1984, pp.
363-400.
5. Romme EA, Smeenk FW, Rutten EP, Wouters EF. Osteoporosis in
chronic obstructive pulmonary disease. Expert Rev Respir Med. 2013;
7(4):397-410.
6. Lehouck A, van Remoortel H, Troosters T, et al. COPD and bone
metabolism: a clinical update. Rev Mal Respir. 2010;27(10):1231-42.
7. Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone
metabolism, and osteoporosis. Chest. 2011;139(3):648-57.
8. Balzarini L, Mancini C, Mouzakiti P, et al. Osteoporosis associated with
chronic obstructive pulmonary disease and other respiratory diseases.
Recenti Prog Med. 2011;102(9):359-66.
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L. Ben-Nun King David

RHEUMATIC DISEASES. Numerous rheumatic diseases, including


RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing
spondylitis, SLE, systemic sclerosis, dermatomyositis/polymyositis
and vasculitis are characterized by osteoporosis and fragility
fractures. Inflammatory cytokines, glucocorticoid treatment,
immobilization and reduced physical activity due to painful joints and
muscle weakness are considered the main risk factors that cause low
BMD values in these diseases. Emerging evidence highlights the role
of inflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-7 and IL-17, in
the regulation of the bone homeostasis. In fact, chronic inflammation
is often characterized by an imbalance between bone formation and
bone resorption with a net prevalence of osteoclastogenesis, which is
an important determinant of bone loss in rheumatic diseases (1).
Bone densitometry should be performed earlier in patients with
inflammatory arthritis, since factors such as inflammation and drug
therapy, in particular treatment with glucocorticoids, have an
important impact on the development of osteoporosis. DXA is
considered the gold standard for bone densitometry. According to
the German guidelines for osteoporosis, bone densitometry plays a
crucial role in the choice of therapy. In patients with RA,
measurement of peripheral bone (forearm) density in addition to
lumbar spine and hip is recommended, since local bone loss is
pathognomonic for this disease. DXA measurements of the hand
enable the diagnosis of juxtaarticular osteoporosis at an earlier stage;
however, this has not yet been established in routine practice. Bone
measurement in patients with ankylosing spondylitis can be
performed in the lumbar spine and the hip at disease onset. In SLE,
bone loss is more frequent in patients with high inflammatory
activity. Patients with psoriasis arthritis frequently have osteoporosis
in the case of a destructive development of the joints (2).

References
1. Maruotti N, Corrado A, Cantatore FP. Osteoporosis and rheumatic
diseases. Reumatismo. 2014;66(2):125-35.
2. Franck H; Kommission Osteologie der Deutschen Gesellschaft für
Rheumatologie, Braun J, Buttgereit F, Demary W, et al. Bone densitometry in
inflammatory rheumatic diseases: characteristics of the measurement site
and disease-specific factors. Z Rheumatol. 2009;68(10):845-50.
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L. Ben-Nun King David

RHEUMATOID ARTHRITIS. RA is a chronic multisystemic disease of


unknown cause characterized by persistent inflammatory synovitis,
usually involving wrists, metacarpophalangeal joints, knees, and feet
in a symmetric distribution. A prodrome of fatigue, weakness, joint
stiffness, arthralgias and myalgias may precede the joint swelling.
Constitutional manifestations include malaise, anorexia, low-grade
fever and an elevated ESR (1).
In addition, RA is an autoimmune disease characterized primarily
by progressive synovial inflammation, resulting in irreversible joint
destruction, enhanced atherosclerosis, respiratory illness and other
extra-articular manifestations (2-4). Juxta-articular osteoporosis
develops in early stages of RA; later bony erosions appear at the joint
margins with the destruction of subchondral bone, and diffuse
osteoporosis develops at an advanced stage (5).
In RA, the major autoantigens in the in the inflamed synovium are
citrullinated peptides. Citrulinated peptides are employed in
diagnostic kits for detection of ACPA, a serological marker with high
specificity and sensitivity in the diagnosis of RA, and have been
included in the new The American College of
Rheumatology/European League Against Rheumatism classification
criteria for RA. ACPA-positive patients suffer from an erosive and
more aggressive disease compared to ACPA-negative patients (6).

Rheumatoid arthritis

A 53-year-old female presented with RA and osteoporosis.


Additional conditions and symptoms included Raynaud syndrome,
fatigue, IBS associated constipation, gastroesophageal reflux,
menopausal symptoms, chronic urinary tract and upper respiratory
infections, and weight gain. She was taking Arthrotec (a combination
of diclofenac and misoprostol - for pain and inflammation), Fosamax
Plus D (alendronate with vitamin D3 - recently prescribed because of
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L. Ben-Nun King David

low bone density), and Catapres (clonidine - for menopausal


symptoms). Against the advice of her rheumatologist, she had
recently discontinued taking Plaquenil (hydroxychloroquine),
methotrexate and prednisone due to significant side effects.
Laboratory tests to identify underlying imbalances and to direct
treatment were ordered. Treatment included dietary, nutritional,
hormonal, and mind/body support. After one year of therapy, the
patient experienced improvement of her presenting conditions and
symptoms, which enabled her to discontinue several medications.
She became versed in identifying and avoiding the environmental
triggers of her disease, including foods (dairy, wheat, eggs, and soy),
molds, and emotional stress. Antinuclear antibodies were
normalized. She experienced a 7.5-percent improvement in left
trochanteric bone density - comparable to bisphosphonate therapy.
Mild improvements were noted in the spine and bilateral femoral
neck (7).
Osteoporosis commonly occurs in the setting of inflammatory
arthritis, whereas there is an inverse relationship with osteoarthritis.
In ankylosing spondylitis, lateral lumbar spine DXA is better at
detecting osteoporosis compared with the anterior-posterior view
and patients receiving treatment with anti-TNF medications had
lower levels of bone turnover markers. With regard to RA,
anticitrullinated peptide positivity without clinical arthritis as well as
higher levels of IL-6 is associated with decreased BMD and
polymorphisms in the vitamin D receptor may predispose to
osteoporosis. With regard to osteoarthritis, results from the Global
Longitudinal Study of Osteoporosis in Women study and several
radiological studies suggest that differences in the distribution of
bone mass at the femoral neck may account for the inverse
relationship of osteoarthritis and osteoporosis, and several studies
suggest that osteoarthritis and osteoporosis have opposing cytokine
and bone metabolism marker profiles (8).
The aim of this study was to obtain information on and to study
an association between the erosive and destructive changes in the
hand and foot joints, and BMD in different parts of the skeleton and
the X-ray alterations in the thoracic and lumbar vertebrae of patients
with RA. The investigation enrolled 66 women with a RA diagnosis,
whose mean age was 51.6 +/- 9.6 years and the disease duration was
13.2 +/- 9.1 years. All the patients underwent clinical, laboratory, and
X-ray studies assessing the progression of joint changes by the
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L. Ben-Nun King David

Sharp/van der Heijde method and estimating the vertebral body


deformity index by the Genant technique, and BMD in three skeletal
regions by DXA employing a Holovic Discovery A device. With X-ray
higher-stage RA and higher Sharp total scores, regardless of age,
there was a decrease in BMD in all skeletal areas and an increase in
the number of patients with deformities of vertebrae and
osteoporosis in at least one of the analyzed skeletal part.
Osteoporosis was found in 29% of the patients with Stages I and II RA
and in 65% of those with Stages IV; deformities of vertebrae were in
12 and 22%, respectively. Comparative analysis of BMD and erosive
and destructive changes in the patient groups different in age at
onset of the disease has established that its young onset (from 16 to
30 years) and long duration have a negative effect on bone status.
Femoral neck BMD in these patients was significantly lower than that
in patients who were ill at older age (31-50 or over 50 years) (0.661
+/- 0.080, 0.739 +/- 0.111, and 0.713 +/- 0.120 g/cm2, respectively)
and the Sharp total score was higher (181.1 +/- 91.3, 100.5 +/- 71.5
and 103.9 +/- 74.5, respectively). The patients' mean age in these
groups at the study inclusion was 46.7 +/- 12.1, 51.9 +/- 6.7, and 60.3
+/- 3.3 years, respectively. In conclusion, with the longer disease
duration, regardless of the age of patients with RA, there are
increases in both Sharp total scores, X-ray RA stage, and the number
of patients with osteoporosis, deformities of thoracic and lumbar
vertebrae (without evidence of significant differences), and BMD
decrease in all skeletal parts (9).

ASSESSMENT: rheumatic diseases, including RA, juvenile


idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, SLE,
systemic sclerosis, dermatomyositis/polymyositis and vasculitis, are
characterized by osteoporosis and fragility fractures.
In the absence of joint involvement accompanied by specific
systemic symptoms, and characteristic laboratory and radiological
findings, the diagnosis of some rheumatic disease is unlikely in King
David.

References
1. Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis.
Autoimmun Rev. 2005;4(3):130-6.
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L. Ben-Nun King David

2. Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on


immunity. Inflammation and autoiimunity. J Autoimmunity. 2010;34(3):
1285-64.
3. McInnes IB, SchettG. The pathogenesis of rheumatoid arthritis. N Engl
J Med. 2011;365:2205-19.
4. Branch WT. In: Branch WT ed. Monoarticular arthritis and acute
nd
polyarticular synovitis. Office Practice of Medicine. 2 ed. St. Lois, MO:
W.B. Saunders. 1987, pp. 829-53.
5. Gilliland BC, Mannik M. Rheumatoid arthritis. Harrison’s Principles of
Internal Medicine. 10th ed. New York, NY: McGraw-Hill Book. 1983, pp.
1977-89.
6. Gertel S, Amital H. Putative approaches to bypass the cytrulline-
specific autoimmune responses in rheumatoid arthritis. IMAJ. 2014;16:587-
590.
7. Fitzgerald K. A case report of a 53-year-old female with rheumatoid
arthritis and osteoporosis: focus on lab testing and CAM therapies. Altern
Med Rev. 2011;16(3):250-62.
8. Clayton ES, Hochberg MC. Osteoporosis and osteoarthritis,
rheumatoid arthritis and spondylarthropathies. Curr Osteoporos Rep.
2013;11(4):257-62.
9. No authors listed. Association between bone mineral density and
erosive and destructive changes in patients with rheumatoid arthritis:
preliminary results. Ter Arkh. 2014;86(5):10-7.

MALNUTRITION. Osteoporosis is a metabolic bone disorder


affecting million of people worldwide. Increased understanding of
bone disease has led to a greater recognition of factors affecting
bones, and consequently many secondary causes of osteoporosis.
The patients with chronic inflammatory disease could be at high risk
for fractures due to bone loss as consequence of malnutrition,
caused by inflammation and hormonal change. Consequently, some
actions could derive from the considerations of these mechanisms: a
change in actual approach of chronic patients that may include the
investigation on the possible presence of osteoporosis, as well as
further research on this topic to find a better therapy to prevent
osteoporosis considering all the mechanisms involved (1).
Undernutrition, particularly protein undernutrition, contributes to
the occurrence of osteoporotic fracture, by lowering bone mass and
altering muscle strength. The rate of medical complications after
fracture can also be increased by nutritional deficiency. The IGF-I
system appears to be directly involved in the pathogenetic
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L. Ben-Nun King David

mechanisms leading to osteoporotic hip fracture in elderly and to its


complications. In the presence of adequate calcium and vitamin D
supplies, protein supplements increasing the intakes from low to
normal, raises IGF-I levels, improves the clinical outcome after hip
fracture, and attenuates the decrease of proximal femur BMD in the
year following the fracture. The nutritional approach is associated
with a significant reduction of the stay in rehabilitation hospital. This
underlines the importance of nutritional supports in preventing and
healing osteoporotic fractures (2).
The prevalence of malnutrition, particularly under nutrition,
increases with age (3). Deficiencies in micronutrients such as calcium
and vitamin D can accelerate age-dependent bone loss (4), while a
deficiency in vitamin K can accelerate bone fracture. A deficiency in
macronutrient (protein) leads to lower femoral neck mineral density
(3). Several factors can cause weight loss leading to a state of
malnutrition in elderly persons. Most of them act by reducing
spontaneous food intake, although malabsorption and increased
metabolism can also be implicated in some situations (5). Reduction
in food intake occur physiologically with aging (6), and this can be
aggravated by various physical and mental disorders, poor appetite
due to consumption of drugs, loss of taste and smell, inadequate
access to foods due to poverty or to impairment of cognitive or
physical functions, and chronic alcohol abuse (5,7).

ASSESSMENT: deficiencies in micronutrients such as calcium and


vitamin D can accelerate age-dependent bone loss; deficiency in
vitamin K can accelerate bone fracture; while deficiency in
macronutrient (protein) leads to lower femoral neck mineral density.
Undernutrition, particularly protein undernutrition, contributes to
the occurrence of osteoporotic fracture, by lowering bone mass and
altering muscle strength.
Did the King suffer from malnutrition or under nutrition? It is
possible that for some reason the intake of food was reduced.
However, it seems unlikely that osteoporosis and possible
subsequent fractures developed solely because of reduced food
intake. Thus, it seems unlikely that malnutrition or undernutrition
per se were the cause of the King’s bone disease.
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L. Ben-Nun King David

References
1. Montalcini T, Romeo S, Ferro Y, et al. Osteoporosis in chronic
inflammatory disease: the role of malnutrition. Endocrine. 2013;43(1):59-64.
2. Rizzoli R, Bonjour JP. Malnutrition and osteoporosis. Z Gerontol
Geriatr. 1999;32 Suppl 1:I31-7.
3. Bonjour J-P, Schurch M-A, Rizzoli R. Nutritional aspects of hip
fractures. Bone. 1996;18:139S-44S.
4. Riggs BL, Melton LJ. Medical progress. Involutional osteoporosis. N Engl J
Med. 1986;314:1676-86.
5. Lipschitz DA. Nutritional assessment in interventions in the elderly. In:
Buerhardt P, Heaney RP (eds.). Nutritional Aspects of Osteoporosis 94.
Challenges of Modern Medicine. Rome: Ares-Seromo Symposia Publications.
1995, pp. 177-91.
6. MacIntosh C, Morley JE, Chapman IM. The anorexia of aging. Nutrition.
2000;16:983-95.
7. Munro HN, Suter PM, Russell RM. Nutritional requirements of the
elderly. Ann Rev Nut. 1987;7:23-49.

MEDICATIONS. Some medications are associated with


osteoporosis. GIO osteoporosis is the leading cause of medication-
induced osteoporosis (1,2). The incidence of new fractures after one
year of glucocorticoid therapy can be high as 17%, and observational
studies suggest that fractures, which are often asymptomatic, occur
in 30-50% of chronic glucocorticoid-treated patients (3). Other
medications include antiepileptic drugs (4,5), thyroid hormone which
is used to suppress TSH because of thyroid cancer, goiters, or nodules
(6), neuroleptics (7), antidepressant medications including SSRIs and
tricyclic agents (8,9), and osteoporotic medications such as IV
ibandronate and calcitonin (10).
Use of antidepressant medications that act on the serotonin
system has been linked to detrimental impacts on BMD, and
osteoporosis. Serotonin receptors are found in all major types of
bone cell (osteoblasts, osteocytes, and osteoclasts), indicating an
important role of the neuroendocrine system in bone. Observational
studies indicate a complex relationship between depression,
antidepressants, and fracture. First, the presence of depression itself
increases fracture risk, in relation with decreased BMD and an
increase in falls. A range of aspects of depression may operate,
including behavioral factors (e.g., smoking and nutrition), biological
changes, and confounders (e.g., comorbidities and concomitant
medications). A substantial proportion of depressed patients receive
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L. Ben-Nun King David

antidepressants, mostly SSRIs. Some of these have been linked to


decreased BMD (SSRIs) and increased fracture risk (SSRIs and tricyclic
agents). Current use of SSRIs and tricyclics increases fracture risk by
as much as two-fold vs. nonusers, even after adjustment for potential
confounders. While there is a dose-response relationship for SSRIs,
the effect does not appear to be homogeneous across the whole
class of drugs and may be linked to affinity for the serotonin
transporter system. The increased risk is the greatest in the early
stages of treatment, with a dramatic increase after initiation,
reaching a peak within one month for tricyclics and eight months for
SSRIs. Treatment-associated increased risk diminishes towards
baseline in the year following discontinuation. SSRIs should be
considered in the list of medications that are risk factors for
osteoporotic fractures (9).
The aim of this study was to determine if fracture and mortality
rates vary among patients initiating different osteoporosis
medications. The Medicare 5% sample was used to identify new
users of IV ZOL (n=1.674), oral bisphosphonates (n=32.626), IV
ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or
PTH (n=549). Beneficiaries who were ≥65 years of age were included,
and were continuously enrolled in fee-for-service Medicare and
initiated therapy during 2007-2009. Outcomes were hip fracture,
clinical vertebral fracture, and all-cause mortality, identified using
inpatient and physician diagnosis codes for fracture, procedure codes
for fracture repair, and vital status information. During follow-up
(median, 0.8-1.5 years depending on the drug), 787 subjects had hip
fractures, 986 had clinical vertebral fractures, and 2.999 died.
Positive associations included IV ibandronate with hip fracture
(adjusted HR 2.37, 95% CI 1.25-4.51), calcitonin with vertebral
fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality
(HR=1.31, 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome
comparisons were statistically insignificant. In conclusion, IV
ibandronate and calcitonin were associated with higher rates of some
types of fracture when compared to IV ZOL. The relatively high
mortality associated with use of calcitonin may reflect the poorer
health of users of this agent (10).
Patients with epilepsy have a two-six times greater risk of bone
fractures compared with the general population. There are several
potential explanations. Some fractures are caused by seizure-related
injuries, or they may be associated with the osteopenic effect of
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L. Ben-Nun King David

reduced physical activity in patients with epilepsy. Antiepileptic


drugs, especially those that affect the liver enzymes, e.g., phenytoin,
carbamazepine, phenobarbital, as well as valproate, are associated
with increased fracture rate and low BMD. Many patients with
epilepsy and general practitioners seem unaware of this problem.
Measurements of bone density should be taken regularly in patients
at risk of developing osteoporosis. Non-pharmaceutical initiatives,
such as partaking in regular physical activity and eating a well-
balanced diet, should be recommended. The risk of developing
osteoporosis should be taken into consideration in the selection of an
antiepileptic drugs for treating a newly diagnosed patient with
epilepsy (11).

ASSESSMENT: a wide range of medications is associated with


osteoporosis. In the absence of appropriate anamnesis, it seems
unlikely that the King took any of the above-mentioned medications.

References
1. De Nijs RN. Glucocorticoid-induced osteoporosis: a review on
pathophysiology and treatment options. Minerva Med. 2008;99:23-43.
2. Devogelaer JP, Goemaere S, Boonen S, et al. Evidence-based
guidelines for the prevention and treatment of glucocorticoid-induced
osteoporosis: a consensus document of the Belgian Bone Club. Osteoporos
Int. 2006;17:8-19.
3. Civitelli R, Ziambaras K. Epidemiology of glucocorticoid-induced
osteoporosis. J Endocrinol Invest. 2008;31(7 Supp):2-6.
4. Ensrud KE, Walczak TS, Blackwell TL, et al. Antiepileptic drug use and
rates of hip bone loss in older men: a prospective study. Neurology. 2008;
71:723-30.
5. Pack AM, Walczak TS. Bone health in women with epilepsy: clinical
features and potential mechanisms. Int Rev Neurobiol. 2008;83:305-28.
6. Greenspan SL, Greespan FS. The effect of thyroid hormone on skeletal
integrity. Ann Intern Med. 1999;130:750-8.
7. Vestergaard P. Skeletal effects of central nervous system, active drugs:
anxiolytics, sedative, antidepressants, lithium and neuroleptics. Curr Drug
Saf. 2008;3:185-9.
8. Bruyère O, Reginster JY. Osteoporosis in patients taking selective
serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine. 2014
Aug 5. [Epub ahead of print]
9. Rizzoli R, Cooper C, Reginster JY, et al. Antidepressant medications and
osteoporosis. Bone. 2012 Sep;51(3):606-13.
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L. Ben-Nun King David

10. Yun H, Delzell E, Saag KG, et al. Fractures and mortality in relation to
different osteoporosis treatments. Clin Exp Rheumatol. 2014 Jul 28. [Epub
ahead of print]
11. Svalheim S, Røste LS, Nakken KO, Taubøll E. Bone health in adults
with epilepsy. Acta Neurol Scand Suppl. 2011;(191):89-95.

IDIOPATHIC. Over the last decade, the increasingly significant


problem of osteoporosis in men has begun to receive much more
attention than in the past. In particular, recent observations from
large-scale population studies in males led to an advance in the
understanding of morphologic basis of growth, maintenance and loss
of bone in men, as well as new insights about the pathophysiology
and treatment of this disorder. While fracture risk consistently
increases after age 65 years in men (with up to 50% of cases due to
secondary etiologies), osteoporosis and fractures may also occur in
young or middle aged males in the absence of an identifiable
etiology. For this category (so called idiopathic osteoporosis), there
are still major gaps in knowledge, particularly concerning the etiology
and the clinical management (1).
The aim of this study was to analyze the clinical characteristics
and etiological factors related to osteoporosis in patients attending
an outpatient rheumatology department during an 11-year period
(1995-2006), as well as to compare them with the observed
characteristics in a previous study performed 12 years ago,
Barcelona, Spain. Males (n=232) aged 21-88 years (mean 56.1 +/-14)
with osteoporosis were included in the study. Of the patients, 67%
had previous skeletal fractures and 51% had vertebral fractures; 57%
had idiopathic and 43% had secondary osteoporosis. The most
frequent causes of secondary osteoporosis were corticosteroid
therapy, hypogonadism and alcoholism; 38% of the patients with
idiopathic osteoporosis had associated hypercalciuria. Patients with
secondary osteoporosis were older, shorter, had lower femoral neck
T score and lower serum values of 25-OH Vit. D and testosterone, as
well as higher gonadotrophin and PTH values than patients with
idiopathic osteoporosis, whereas patients with idiopathic
osteoporosis had higher urinary calcium and more frequently family
history of osteoporosis. Back pain, frequently associated with
vertebral fractures, was the most common cause of referral in all age
groups of patients. Idiopathic osteoporosis was the most frequent
cause of male osteoporosis in this clinical study (2).
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L. Ben-Nun King David

The objective of this study was to determine biochemical,


radiological and micro-architectural bone factors related to fragility
fractures in IMO patients. IMO is a rare disorder characterized by low
areal BMD (Z-score<-2) occurring in men after excluding secondary
causes of low BMD. A case-control study was conducted in 31
patients with fragility fracture (IMO F+) that had occurred after the
age of 40 years and 37 without fracture (IMO F-). IMO group to 40
age-matched disease-free men were compared. Areal BMD and bone
micro-architectural indices at distal radius and tibia sites with a HR-
pQCT scan (XtremeCT) using standard and extended cortical analysis
were measured. Urine and blood samples were collected in order to
determine the levels of bone-turnover markers and the potential
determinant of bone fragility. Compared to their controls, IMO
patients showed marked disturbance of their micro-architectural
parameters at tibia and radius affecting both trabecular and cortical
parameters. IMO F+ subjects were significantly older than IMO F-
subjects (58 ± 8 vs. 53 ± 9 years, p=0.01). BMD Z-score at the total-hip
was significantly lower in IMO F+ (-1.3 ± 0.5 vs. -0.9 ± 0.8 g/cm(2),
p=0.01). After adjustment, trabecular micro-architectural
parameters, biochemical markers and hormonal parameters were
not different in the two groups. At distal tibia, cortical v-BMD was
significantly lower in IMO F+ patients (799 ± 73 vs. 858 ± 60
mg/cm(3), p=0.03), while cortical thickness was not different. In
conclusion, patients with IMO display a marked disturbance of
trabecular and cortical bone micro-architecture, while age and low
cortical density are determinants of the fracture occurrence (3).
Bone mineral loss was evaluated by DXA and its cortical or
trabecular nature in a cohort of IMO with fractures was determined.
Thirty-nine men (mean age 60 ± 13 years), with negative
investigations for the cause of osteoporosis, were studied. All had
fragility fractures: vertebral 51%, peripheral 25%, and both types
24%. Bone density was measured at the lumbar spine (L2-L4), total
hip and whole body. The limb/axial skeleton (spine + hips) and
hip/L2-L4 BMD ratios were calculated. Serum 25-OH Vit. D, PTH, bone
ALP and CTX were measured. Bone mineral loss predominated at the
lumbar spine (mean L2-L4 T-score -3 ± 0.93, mean total hip T-score -
1.87 ± 0.75). Limb/axial skeleton and total hip/L2-L4 BMD were
strongly correlated, but not hip and spine BMD. The ratio values were
widely scattered, indicating markedly heterogeneous bone loss.
Vitamin D, PTH, bone ALP and CTX levels did not differ between
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L. Ben-Nun King David

predominantly trabecular and cortical osteoporosis. BMD


measurement in IMO with fractures demonstrated that bone loss
predominated in the spine and it was very heterogeneous, principally
affecting cortical or trabecular bone depending on the patient (4).

ASSESSMENT: osteoporosis and subsequent fractures that occur


in young or middle aged males in the absence of an identifiable
etiology is called IMO. In IMO with fractures, bone loss predominated
in the spine, principally affecting cortical or trabecular bone.
It can be assumed that idiopathic osteoporosis may have affected
King David’s bones. However, this does not entirely explain what
kind of disease “...consumed...” his bones.

Assessment
1. Gennari L, Bilezikian JP. Idiopathic osteoporosis in men. Curr
Osteoporos Rep. 2013;11(4):286-98.
2. Peris P, Martinez-Ferre A, Monegal A, et al. Aetiology and clinical
characteristics of male osteoporosis. Have they changed in the last few
years? Clin Exp Rheumatol. 2008;26:582-8.
3. Ostertag A, Collet C, Chappard C, et al. A case-control study of
fractures in men with idiopathic osteoporosis: fractures are associated with
older age and low cortical bone density. Bone. 2013;52(1):48-55.
4. Laroche M. Pattern of bone mineral density in idiopathic male
osteoporosis. Rheumatol Int. 2012;32(10):3093-6.

ONCOHAEMATOLOGICAL
DISORDERS
The immunosecretory disorders are a diverse group of diseases
associated with proliferation of an abnormal clone of
immunoglobulin (Ig)-synthesizing, terminally differentiated B cells.
These disorders include MM and its variants, plasmacytoma, WM,
MGUS, and monoclonal Ig deposition diseases, the latter including
primary amyloidosis and nonamyloidotic types. These disorders are
histologically composed of plasma cells, or plasmacytoid cells which
produce Ig that is synthesized and usually secreted and can be
deposited in some diseases. The Ig can be complete or can be
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L. Ben-Nun King David

composed of either heavy or light chains and is termed M-


(monoclonal) protein. In MM, this proliferation overwhelms the
normal cellular counterparts that synthesize and secrete appropriate
levels of Ig. Immunosecretory disorders have been classified in
multiple schemes, mostly morphologic, to such a degree that the
classification of these entities has become a challenge to
pathologists. The WHO in 2001 was helpful because it provided
specific clinicopathologic criteria for diagnosis. However, terms such
as "progressive" disease were not well defined. In 2003, the
International Myeloma Group defined MM as a disease with related
organ and tissue injury, serving to better explain progressive in terms
of deterioration of organ (renal, bone, and bone marrow) function
over time. Therefore, modern classification of immunosecretory
diseases is based on integration of clinical, morphologic, laboratory,
radiographic, and biologic (including molecular) parameters (1).

References
1. Shaheen SP, Talwalkar SS, Medeiros LJ. Multiple myeloma and
immunosecretory disorders: an update. Adv Anat Pathol. 2008;15(4):196-
210.

MULTIPLE MYELOMA
MM is the second most common hematologic malignancy, with
approximately 16.000 new cases per year, and accounts for 11.000
deaths in the USA. It is the most common cancer to metastasize to
the bone, with up to 90% of patients developing bone lesions (1).
MM is a tumor of terminally differentiated plasma cells that home
to and expands in the bone marrow (1). It is a hemato-oncological
disease in the elderly population, with a peak incidence in the eight
decade, and represents a malignant bone marrow neoplasia in which
a monoclonal strain of atypical plasma cells proliferates and may
result in bone destruction. Skeletal metastases represent the most
common malignant bone tumor and are the third most common
location for distant metastases. They occur predominantly in adults,
especially in the elderly population (2,3).
MM is characterized by the accumulation more than 10% of
monoclonal plasma cells in the bone marrow and the production of
large amounts of a monoclonal immunoglobulin or paraprotein (4,5);
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L. Ben-Nun King David

in MM enhanced bone loss is commonly associated with a diffuse


osteopenia, or osteoporosis, focal lytic lesions, pathological fractures,
cord compression, severe bone pain, malaise, hypercalcaemia,
anemia, and renal insufficiency (2,6-9).

Multiple myeloma

MM develops and expands almost exclusively in the bone


marrow, and generates devastating bone destruction. MM cells
produce a variety of cytokines to stimulate RANK ligand-mediated
osteoclastogenesis and suppress osteoblastic differentiation from
bone marrow stromal cells, leading to extensive bone destruction
with rapid loss of bone. Pim-2 kinase as well as growth factor
independence-1 were up-regulated in bone marrow stromal cells by
major inhibitors of bone formation known in myeloma as common
downstream mediators for the suppression of osteoblastogenesis.
The biology of osteocytes is unknown in myeloma bone lesions, but
the reduction of viable osteocytes and their correlation with
osteoclastogenesis have been demonstrated (10).
MM is the malignant disease which most frequently leads to bone
lesions. Approximately 80% of myeloma patients develop
osteoporosis, lytic bone lesions (osteolysis) or fractures during the
course of the disease. Of these patients, 43% suffer pathological
fractures most often of the vertebrae followed by fractures of the
long bones. The methods used in the described articles include, e.g.
gene expression profiling, enzyme-linked immunosorbent assays and
radiological techniques. Myeloma bone disease represents a three-
fold therapeutic problem: 1] per se because of the associated
morbidity, mortality and the accompanying decrease of QOL, 2] as
survival space for (residual) myeloma cells after primarily successful
chemotherapy and subsequently necessary chemotherapeutic
treatment, and 3] the occurrence of bone lesions in asymptomatic
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L. Ben-Nun King David

patients is the most common cause for the initiation of treatment to


avoid myeloma-induced fractures. Myeloma cells harbor a high
median number of chromosomal aberrations and multiple changes in
gene expression compared to normal bone marrow plasma cells
leading to the aberrant production of survival, proliferation, pro-
angiogenic and bone turnover influencing factors or the induction of
those factors in the bone marrow microenvironment. This causes an
imbalanced bone turnover in the sense of an increased number and
activity of osteoclasts while bone formation by osteoblasts is almost
completely suspended. Therapeutic approaches, systemically and
locally therefore aim at stimulation of osteoblasts and inhibition of
bone resorption (11).
Osteolytic bone disease is the most debilitating manifestation of
MM (12). The disease of the spine is a growing problem, affecting
70% of patients with metastatic disease or MM. Tumor-induced
osteolysis may lead to pain, dysfunction, and ultimately vertebral
collapse. If left untreated, vertebral body compression fractures take
place with progressive kyphosis over multiple levels, cord
compression, and intractable pain (13).
Although bone pain related to multiple lytic lesions is the most
common clinical presentation, up to 30% of patients are diagnosed
incidentally while being evaluated for unrelated problems, and one
third of patients are diagnosed after a pathological fracture,
commonly in axial skeleton (5).
Diagnosis of MM should be based on the following tests:
(2,14,15):
*Detection and evaluation of the monoclonal (M) component.
*Serum and urine protein electrophoresis (concentrate of 24-h
urine); quantification of IgG, IgA and IgM immunoglobulins.
*Characterization of the heavy and light chain by immunofixation.
Serum free light chain measurement for identifying and monitoring
non secretory MM; evaluation of bone marrow plasma cell
infiltration; bone marrow aspiration and biopsy to detect quantitative
and/or qualitative abnormalities of bone marrow plasma cells.
*Evaluation of lytic bone lesions.
*Biological assessment is required to differentiate symptomatic
and asymptomatic MM: Hg (and full blood cell count), serum
creatinine and calcium level.
Skeletal radiographs are important in staging MM and revealing
lytic lesions, vertebral compression fractures, and osteoporosis. MRI
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L. Ben-Nun King David

and positron emission tomography or CT emerged as useful tools in


the evaluation of patients with myeloma; MRI is preferred for
evaluating metastatic spinal disease (16) and acute spinal
compression. Nuclear bone scans and DXA have no role in the
diagnosis and staging of MM.
During 1990 at the Mayo Clinic, 787 patients were found to have
monoclonal gammopathy. IgG accounted for 61% of the cases,
followed by IgM (18%), IgA (11%), Bence Jones proteinemia (6%),
biclonal gammopathy (3.5%), and IgD (0,5%). MGUS accounted for
approximately two thirds of patients. This denotes the presence of
monoclonal protein in persons without evidence of MM,
macroglobulinemia, amyloidosis, or other related diseases. During
the long-term follow-up of patients with MGUS, one fourth
developed MM or related disorders. The interval from recognition of
the monoclonal gammopathy to the development of MM ranged
from two to 29 years (median, 10 years). WM developed in seven
patients four to 20 years (median, 8.5 years) after recognition of the
monoclonal protein. Systemic amyloidosis was found in eight
patients, six to 19 years (median, nine years) after the diagnosis of a
serum monoclonal protein. Five patients developed a malignant
lymphoproliferative process six to 22 years (median, 10.5 years) after
the recognition of a monoclonal protein. Minimal criteria for the
diagnosis of MM include the presence of at least 10% abnormal
plasma cells in the bone marrow or histological proof of a
plasmacytoma, the usual clinical features of MM, and at least the
following abnormalities: monoclonal serum protein (usually greater
than three g/dL), monoclonal protein in the urine, or osteolytic
lesions. No single technique differentiates benign from malignant
plasma cell proliferation. The most dependable means is serial
measurement of the monoclonal protein in the serum and urine and
periodic reevaluation of pertinent clinical and laboratory features to
determine whether MM, systemic amyloidosis, macroglobulinemia,
or other lymphoplasma cell proliferative disease have developed
(17).
Manifestations of bone disease - osteopenia, osteolytic lesions,
and fractures are the hallmark of MM and occur clinically in the vast
majority of patients. These abnormalities can have devastating
clinical effects by increasing both the morbidity and mortality of
patients. Bone disease is usually found when patients are diagnosed
with active MM; however, recent data suggest that it is present in
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L. Ben-Nun King David

early myelomagenesis, including patients with myeloma precursor


disease, MGUS. The primary mechanisms of abnormal bone
remodeling are increased osteoclastic activity, which occurs in close
proximity to active myeloma cells, and decreased activity of the
surrounding osteoblasts. Better understanding of the pathogenesis of
bone disease in MM will allow us to enhance current therapeutic
options in the treatment of bone disease. In patients with active MM
and at least one lytic lesion, IV bisphosphonates decrease SREs and
pain, improve performance status, and maintain QOL. Intervention at
earlier stages of disease may prevent SREs at time of progression, but
there is no evidence that bisphosphonates in this setting change the
natural history of the disease (18).
MM must be differentiated from other causes of monoclonal
gammopathy, including MGUS, WM, HCD, osteomyelofibrosis,
amyloidosis, plasmacytoma, and small lymphocyte cell disorders
(2,3,5,17).
Smouldering (asymptomatic) MM is characterized by having a
serum IgG or IgA monoclonal protein of 30 g/l or higher and/or 10%
or more plasma cells in the bone marrow but no evidence of end
organ damage – hypercalcaemia, renal insufficiency, anemia, and
bone lesions (18).

ASSESSMENT: MM is a hemato-oncologic disease of the elderly


population, with a peak incidence in the eight decade, representing a
malignant bone marrow neoplasia in which a monoclonal strain of
atypical plasma cells proliferates and may result in bone destruction.
Was the King afflicted by MM? The diagnosis of MM or other
immunosecretory disorders requires an extensive evaluation
including laboratory, radiological, and histopathological. This is a
contemporary approach to establishing an appropriate diagnosis of
the disease that afflicted the patient. We can assume that such
evaluation was not performed in the King's case.
We have two parameters: the King was an elderly person and he
had severe intractable bone pains. Bone pain related to multiple lytic
lesions is the most common presentation of MM.
Although in King David's case no contemporary diagnostic
evaluation was performed, the biblical words "My bones wasted
away through my anguished roaring all day long” (Psalm 32:3) may
indicate MM.
326
L. Ben-Nun King David

One fourth of the patients with MGUS developed MM or other


related disorders. Was King David afflicted by MGUS that later
developed into MM or other related disorders?
Did King David suffer from smouldering (asymptomatic) myeloma?
In smouldering MM, there is no evidence of end organ damage such
as hypercalcaemia, renal insufficiency, anemia, and bone lesions.
Since the King suffered from severe bone pains as well as from
anemia, as shown in a subsequent section, the diagnosis of
smouldering myeloma seems unlikely.

References
1. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease.
Best Pract Res Clin Haematol. 2007;20:613-24.
2. Nau KC, Lewis WD. Multiple myeloma: diagnosis and treatment. Am
Fam Physician. 2008;78:853-9.
3. Baur-Menyk A, Reiser M. Oncohaematologic disorders affecting the
skeleton in the elderly. Radiol Clin North Am. 46:786-98, vii.
4. Caers J, Vande broek I, De Raeve H, et al. Multiple myeloma – an
update on diagnosis and treatment. Eur J Haematol. 2008;81:329-43.
5. George ED, Sadovsky R. Multiple myeloma: recognition and
management. Am Fam Physician. 1999;59:1885-94.
6. Yeh HS, Berenson JR. Myeloma bone disease and treatment options.
Eur J Cancer. 2006;42:1554-63.
7. Berenson JR, Rajdev L, Broder M. Bone complications in multiple
myeloma. Cancer Biol Ther. 2006;5:1082-5.
8. Itse M, Takagi T. Bone lesions in multiple myeloma. Nuppon Rinsho.
2007;65:2224-8.
9. Huff CA, Matsui W. Multiple myeloma cancer stem cells. J Clin Oncol.
2008;26:2895-900.
10. Abe M. Bone and Calcium Abnormalities in Malignancy. Myeloma
bone disease. Clin Calcium. 2014;24(8):1159-68. .
11. Seckinger A, Hose D. Interaction between myeloma cells and bone
tissue. Radiologe. 2014;54(6):545-50.
12. Epstein J, Walker R. Myeloma and bone disease:"the dangerous
tango". Clin Adv Hematol Oncol. 2006;4:300-6.
13. Siemionov K, Lieberman IH. Vertebral augmentation in osteoporosis
and bone metastasis. Curr Opin Support Palliat Care. 2007;1:323-7.
14. Harousseau JL, Dreyling M. Multiple myeloma: ESMO clinical
recommendations for diagnosis, treatment and follow-up. Ann Oncology.
2008;19 (Supplement 2):ii55-57.
15. Hansmann HJ, Wunsch C, Schneider B, et al. Radiologic diagnosis of
bone metastases. Orthopade. 1998;27:224-30.
327
L. Ben-Nun King David

16. Kyle RA. Diagnostic criteria of multiple myeloma. Hematol Onco Clin
North Am. 1992;6:347-58.
17. Minter AR, Simpson H, Weiss BM, Landgren O. Bone disease from
monoclonal gammopathy of undetermined significance to multiple
myeloma: pathogenesis, interventions, and future opportunities. Semin
Hematol. 2011;48(1):55-65.
18. Pangalis GA, Kyrtsonis MC, Kontopidou FN, et al. Differential
diagnosis of Waldenstrom's macroglobulinemia and other B-cell disorders.
Clin Lymphoma. 2005;5:235-40.
19. Kyle RA, Rajkumar SV. Monocolonal gammopathy of undetermined
significance and smouldering multiple myeloma: emphasis on risk factors for
progression. Br J Haematol. 2007;139:730-43

MONOCLONAL GAMMOPATHY OF
UNDETERMINED SIGNIFICANCE

MGUS denotes the presence of a monoclonal protein (M protein)


in patients, without evidence of MM, macroglobulinemia,
amyloidosis or other related diseases (1). MGUS is characterized by
the serum M-protein less than three g/dl; fewer than 10% plasma
cells in the bone marrow; no, or only small amounts of M protein in
the urine; absence of bone lesions, anemia, hypercalcaemia, and
renal insufficiency; and, most importantly stability of the M-protein
and failure of development of other abnormalities (2).
MGUS is found in approximately 3% of persons older than 70
years and in 1% of those 50 years and older. During long-term follow-
up, approximately one fourth of patients develop MM, amyloidosis,
macroglobulinemia, or a similar malignant lymphoproliferative
disorder (3).
MGUS is a laboratory abnormality, there are no clinical symptoms,
it is common in the older population, it is premalignant for MM,
therapy of MGUS has not been shown to prolong survival, there is no
reason to screen for MGUS, if MGUS is diagnosed, the risk for
progression should be defined (4).

ASSESSMENT: MGUS is characterized by anemia, hypercalcaemia,


and renal insufficiency; the presence of a monoclonal protein (M
protein), without evidence of MM, macroglobulinemia, amyloidosis
or other related diseases.
328
L. Ben-Nun King David

Was old King David afflicted by MGUS? Although MGUS is mostly


a disease of the elderly, the absence of the bone pains and anemia
from which the King suffered makes it unlikely that the King was
afflicted by MGUS.

References
1. Shirota T, Kondo M, Uchida H, Ito H. Benign monoclonal gammopathy.
Nippon Rinsho. 1995;53:720-4.
2. Kyle RA. Monoclonal gammopathy of undetermined significance and
solitary plasmocytoma. Implications for progression to overt multiple
myeloma. Hematol Oncol Clin North Am. 1997;11:71-87.
3. Kyle RA, Rajkumar SV. Monocolonal gammopathy of undetermined
significance and smouldering multiple myeloma: emphasis on risk factors for
progression. Br J Haematol. 2007;139:730-43.
4. Monoclonal Gammopathy of Undetermined Significance (MGUS).
Available 30 December 2014 at mayomedicallaboratories.com
/.../transcripts/2011/03-mgus/21.html.

WALDENSTROM MACROGLOBULINEMIA
WM is a B-cell neoplasm characterized by lymphoplasmacytic
infiltration of the bone marrow and/or other tissues. The symptoms
of WM are attributable to the extent of tumor infiltration and
elevated IgM levels (1,2).
WM is a distinct clinicopathologic entity defined as a B-cell
neoplasm characterized by lymphoplasmacytic infiltrate in the bone
marrow, with an associated immunoglobulin (Ig) M paraprotein.
Clinical manifestations are due to deposition of IgM in the liver,
spleen, and/or lymph nodes, so it presents with anemia,
hyperviscosity, lymphadenopathy, hepatomegaly, splenomegaly and
neurologic symptoms. The main diagnostic criteria are a typical peak
on serum protein electrophoresis and malignant cells in bone
marrow biopsy samples (3).
In the past 36 months, new developments have occurred both in
the understanding of the biology of WM and in therapeutic options
for WM. The symptoms of WM are attributable to the extent of
tumor infiltration and to elevated IgM levels (1,4). The most
common symptom is fatigue attributable to anemia (4). Aside from
uncommon patients with idiopathic IgM peaks, most patients have
329
L. Ben-Nun King David

evidence of an underlying lymphoma, characterized by bone marrow


infiltration, enlargement of lymph nodes and/or spleen, CLL, or a
combination of these features (5). The prognostic factors predictive
of survival include the patient's age, beta(2)-microglobulin level,
monoclonal protein level, Hg concentration, and platelet count (1,4).
Therapy is postponed for asymptomatic patients, and progressive
anemia is the most common indication for initiation of treatment (4).
There is no standard therapy for the treatment of symptomatic WM
and no agents have been specifically approved for this disease (3).
The main therapeutic options include alkylating agents, nucleoside
analogues, and rituximab (3,4). Studies involving combination
chemotherapy are ongoing, and preliminary results are encouraging.
No specific agent or regimen has been shown to be superior to
another for treatment of WM. Novel agents such as bortezomib,
perifosine, atacicept, oblimersen sodium, and tositumomab show
promise as rational targeted therapy for WM (4).

ASSESSMENT: WM is a B-cell neoplasm characterized by


lymphoplasmacytic infiltration of the bone marrow and/or other
tissues. The symptoms of WM are attributable to the extent of tumor
infiltration and elevated IgM levels. The presenting symptom in WM
disease is that of lymphoma including fatigue due to anemia.
Although the King suffered from severe anemia (see the section
below), his severe intractable bone pains cannot be related to WM.
For this reason, the diagnosis of WM seems unlikely.

References
1. Pangalis GA, Kyrtsonis MC, Kontopidou FN, et al. Differential diagnosis
of Waldenstrom's macroglobulinemia and other B-cell disorders. Clin
Lymphoma. 2005;5:235-40.
2. Leleu X, Roccaro AM, Moreau AS, et al. Waldenstrom
macroglobulinemia. Cancer Lett. 2008;270:95-107.
3. Budimir I, Nikolid M, Pusid MS, et al. Waldenström's
macroglobulinemia as a diagnostic challenge: case report. Acta Clin Croat.
2014;53(1):94-7.
4. Vijay A, Gertz MA. Waldenström macroglobulinemia. Blood.
2007;109(12):5096-103.
5. Alexanian R. Plasma cell neoplasms and related disorders. In:
Petersdorf RG, Adams RD, Braunwald E, et al (eds). Harrison's Principles of
Internal Medicine. 10 ed. McGrawn-Hill, New York, St Louis. 1983, pp. 362-
371.
330
L. Ben-Nun King David

HEAVY CHAIN DISEASES


HCD are rare B-cell malignancies that are distinguished by the
production of a monoclonal immunoglobulin heavy chain without an
associated light chain by the malignant B-cells (1,2). The diagnosis is
established by immunoelectrophoresis or immunofixation (2).
HCD are variant types of non-Hodgkin lymphoma: alpha-HCD
presents as an extranodal marginal-zone lymphoma of mucosa-
associated lymph-node tissue, gamma-HCD as lymphoplasmacytoid
non-Hodgkin lymphoma, and mu-HCD as small lymphocytic non-
Hodgkin lymphoma or CLL. Diagnosis of HCD requires documentation
of a deleted immunoglobulin heavy chain without a bound light chain
in the serum or urine. Prognosis is variable, and no standardized
effective treatment programs are available except for alpha-HCD,
which in its early stage may respond to antibiotics (3).
Thus, there are three types of HCD defined by the class of Ig heavy
chain produced: IgA (alpha-HCD), IgG (gamma-HCD), and IgM (mu-
HCG). Alpha-HCD is the most common and occurs most commonly as
intestinal malabsorption in a young adult from a country bordering
the Mediterranean Sea (1,2). The main clinical features are chronic
diarrhea and severe malabsorption syndrome (2,3).
Since the first report of gamma-HCD in 1964, alpha-HCD and mu-
HCD have also been described. The clinical features of gamma-HCD
may vary considerably. By contrast, alpha-HCD primarily involves the
secretory IgA system and mainly the digestive tract. Its clinical
pattern is strikingly uniform. Alpha-HCD is the most common of the
HCD, while mu-HCD are relatively rare. The demonstration of Bence
Jones proteins in the urine in association with lymphoproliferative
disorders and vacuolated plasma cells in the bone marrow deserves
further investigation for mu-HCD. Recently, two disease entities
related to molecular abnormalities of heavy chains have been
reported; heavy-chain-associated amyloidosis and heavy chain
deposition disease (4).
The clinicopathologic features of gamma HCD are heterogeneous
often somewhat similar to macroglobulinemia. Some patients show
no evidence of underlying malignant lymphoproliferation. Gamma
HCD most often present as a lymphoproliferative disorder,
characterized by lymphadenopathies, splenomegaly, constitutional
symptoms, and the absence of bone lesions (5,6).
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L. Ben-Nun King David

mu-HCD are a rare monoclonal lymphoid disorder characterized


by the failure to assemble a complete IgM immunoglobulin (7). mu-
HCD often present as CLL with hepatosplenomegaly and vacuolated
plasma cells on bone marrow smears (1), and thrombocytopenia (8).
Renal failure is a rare disease in mu-HCD (9). The prognosis for
patients with mu-HCD is poor (8).
mu-HCD are rare. A patient with mu-HCD associated with systemic
amyloidosis is reported. The diagnosis of mu-HCD was based on
findings of mu-heavy chain fragments in the serum, Bence Jones
proteinuria and vacuolated plasma cells in the bone marrow.
Systemic amyloidosis led to the patient's death (10).

ASSESSMENT: the heavy chain diseases are rare B-cell


malignancies that are distinguished by the production of a
monoclonal immunoglobulin heavy chain without an associated light
chain by the malignant B-cells. HCD involve the three main
immunoglobulin classes; alpha-HCD are the most common and have
the most uniform presentation, gamma- and mu-HCD have variable
clinical presentations and histopathologic features. The diagnosis is
established by immunoelectrophoresis or immunofixation.
Did some type of HCD afflict the King? In alpha-HCD, the main
symptoms are those of chronic diarrhea and severe malabsorption
syndrome, in gamma HCD the clinical presentation is that of a
lymphoproliferative disorder, characterized by lymphadenopathies,
splenomegaly, and constitutional symptoms, while in mu-HCD the
principal symptoms are those of hepatosplenomegaly and vacuolated
plasma cells on bone marrow smears. Bone pain is not the
characteristic symptom of all these types of HCD. Thus, it seems
unlikely that any type of HCD afflicted the King.

References
1. Witzig TE, Wahner-Roedler D. Heavy chain disease. Curr Treat Options
Oncol. 2002;3:247-54.
2. Seligman M. Heavy chain diseases. Rev Prat. 1993;43:317-20.
3. Wahner-Roedler DL, Kyle RA. Heavy chain diseases. Best Pract Res Clin
Haematol. 2005;18(4):729-46.
4. Nomura S, Kanoh T. Heavy chain disease. Nihon Rinsho.
1995;53(3):730-5.
5. Fermand JP, Brouet JC, Danon F, Seligmann M. Gamma heavy chain
"disease": heterogeneity of the clinicopathologic features. Report of 16
cases and review of the literature. Medicine (Baltimore). 1989;68:321-35.
332
L. Ben-Nun King David

6. Leglise MC, Briere J, Abgrall JF, Hurez D. Non-secretory myeloma of


heavy mu-chain type. Nouv Rev Fr Hematol. 1983;25:103-6.
7. Wahner-Roedler DL, Kyle RA. Mu-heavy chain disease: presentation as
a benign monoclonal gammopathy. Am J Hematol. 1992;40:56-60.
8. Yanai M, Marda A, Watanabe N, et al. Successful treatment of mu-
heavy chain disease with fludarabine monophosphate: a case report. Int J
Hematol. 2004;79Z:L174-7.
9. Preud home JL, Bauwens M, Dumont G, et al. Cast nephropathy in mu
chain disease. Clin Nephrol. 1997;48:118-21.
10. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease
associated with systemic amyloidosis. Hematology. 2004;9(2):135-7.

SMALL LYMPHOCYTE CELL DISORDERS


Small lymphocyte cell disorders include B-CLL, SLL, and LPL/WM
(1). B-CLL patients always have blood and bone marrow involvement
by a CD5+ B lymphocyte. They frequently present with
lymphadenopathy and/or hepatosplenomegaly, although in a
considerable number of patients, no abnormal physical findings are
found. They are prone to develop hypogammaglobulinemia,
autoimmune hemolysis, or autoimmune thrombocytopenia (1).
SLL patients present with lymphadenopathy, usually generalized.
Lymphocytosis is by definition absent and bone marrow involvement,
usually nodular, is found in 25% to 50% of patients. LPL/WM patients
may present either with an accidental discovery of IgM gammopathy,
symptoms related to paraproteinemia, or lymphadenopathy and/or
splenomegaly. The bone marrow is frequently involved and a
leukemic picture may be found (1). Some patients have an indolent
leukemia, with long survival while others experience an aggressive
disease, with early and frequent need of treatment (2).
The presence of IgM paraproteinemia in low-grade lymphomas is
usually considered a clinical syndrome known as WM. In the WHO
classification, WM is associated to LPL; it is a clinicopathologic entity
characterized by a monoclonal expansion of predominantly small B-
lymphocytes with variable plasmacytoid differentiation. LPL
constitutes less than 5% of all NHL and it is associated with hepatitis
C virus infection in 26% of cases. Cells of LPL/WM are B cells positive
for monocytic Ig light chains, IgM, pan-B-cell markers, and negative
for CD3 and CD103. The t(9;14)(p13;q32) is present in 50% of LPL,
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L. Ben-Nun King David

and determines PAX-5 over-expression. 6q21 deletion is observed in


42% of cases. LPL occurs in older adults. Clinical presentation usually
consists of disseminated disease, but extranodal involvement and
leukemic phase are rare. Most WM patients have symptoms
attributable to tumor infiltration and/or monoclonal protein. In fact,
a monoclonal serum paraprotein of IgM type and hyperviscosity
symptoms may occur in more than 20% of cases (WM).
Hyperviscosity syndrome is usually manifested by bleeding, blurring
or loss of vision, dizziness, headache, and neurologic symptoms.
Malignant infiltration of the CNS (Bing-Neel syndrome) is uncommon.
LPL/WM is an indolent malignancy that is not usually curable with
conventional treatments. The median survival of patients with LPL or
WM is 50-60 months, transformation to large cell lymphoma may
occur. Stage definition is irrelevant in WM considering that initiation
of therapy is decided on the bases of prognostic factors and the
development of disease-related symptoms and signs. The main
adverse prognostic factors are older age, B symptoms, anemia, low
albumin serum levels, raised SGOT, and high beta 2-microglobulin
values. Several therapeutic alternatives for newly diagnosed or
relapsed LPL/WM are available; however, the best location for every
strategy is a matter of investigation (3).
Plasma cell myeloma and CLL are both common hematologic
malignancies, sharing many epidemiologic features. Concomitant
detection of the two conditions poses special diagnostic challenges
for the pathologist. The objective of this study was to describe the
pathologic findings in cases of concomitant bone marrow
involvement by myeloma and CD5(+) monoclonal B cells and to
outline the differential diagnostic possibilities, suggest a workup for
correct diagnosis, and examine clinical outcome. Fifteen cases that
met the diagnostic criteria were identified from pathology databases
at four participating institutions. Morphologic findings were
reviewed, additional immunohistochemical stains performed, and
flow cytometric, cytogenetic, and relevant laboratory and clinical
information was summarized. Previously published cases were
searched from electronic databases and cross-references. Most
patients (13 of 15) were older males. Often (11 of 15) they presented
clinically with myeloma, yet had both monotypic plasma cells and B
cells in the diagnostic marrow. In four patients, myeloma developed
24 months or later after CLL. In seven patients, myeloma and CD5(+)
B cells showed identical Ig light-chain restriction. Primary differential
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L. Ben-Nun King David

diagnoses include LPL, marginal zone lymphoma, and CLL with


plasmacytoid differentiation. CD56 and/or cyclin D1 expression by
plasma cells was helpful for correct diagnosis. Most patients in this
cohort and published reports were treated for plasma cell myeloma.
In conclusion, concomitant detection of myeloma and CLL in the
bone marrow is a rare event, which must be carefully differentiated
from lymphomas with lymphoplasmacytic differentiation for correct
treatment (4).

ASSESSMENT: small lymphocyte cell disorders include B-CLL, SLL,


and LPL/WM. B-CLL patients have blood and bone marrow
involvement by a CD5+ B lymphocyte. They present with
lymphadenopathy and/or hepatosplenomegaly although in a
considerable number of patients, no abnormal physical findings are
found. They prone to develop hypogammaglobulinemia, autoimmune
hemolysis, or autoimmune thrombocytopenia.
SLL patients present with lymphadenopathy, usually generalized.
Lymphocytosis is by definition absent and bone marrow involvement,
usually nodular, is found in 25-50% of patients. LPL/MW patients may
present either with an accidental discovery of IgM gammopathy,
symptoms related to paraproteinemia, or lymphadenopathy and/or
splenomegaly.
Was the King afflicted by some disorder as mentioned above? In
the absence of severe bone pains from which suffered the King, the
diagnosis of some type of SLC disorder seems unlikely.

References
1. Pangalis GA, Angelipoulou MK, Vassilakopoulos TP, et al. B-chromic
lymphocytic leukemia, small lymphocytic lymphoma, and lymphoplasmacytic
lymphoma, including Waldenström's macroglobulinemia: a clinical, morphologic,
and biologic spectrum of similar disorders. Semin Hematol. 1999; 36:104-14.
2. Ghia P, Ferreri AM, Galigaris-Cappio F. Chronic lymphocytic leukemia. Crit
Rev Oncol Hematol. 2007;64:234-46.
3. Vitolo U, Ferreri AJ, Montoto S. Lymphoplasmacytic lymphoma-
Waldenstrom's macroglobulinemia. Crit Rev Oncol Hematol. 2008;67(2):172-85.
4. Alley CL, Wang E, Dunphy CH, et al. Diagnostic and clinical considerations
in concomitant bone marrow involvement by plasma cell myeloma and chronic
lymphocytic leukemia/monoclonal B-cell lymphocytosis: a series of 15 cases and
review of literature. Arch Pathol Lab Med. 2013;137(4):503-17.
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L. Ben-Nun King David

OSTEOMYELOFIBROSIS
Osteomylofibrosis and sclerosis are chronic myeloproliferative
diseases of the elderly, with a peak incidence in the sixth and seventh
decade of life (1), in which fibrosis and sclerosis finally lead to bone
marrow obliteration (2). Bone marrow fibrosis, anemia,
splenomegaly and a leuko-erythrobastic blood picture generally
characterize idiopathic MF. Apart from minor hemorrhage and
peripheral thrombosis, patients with early stage of idiopathic MF
present with non-specific symptoms including varying degrees of
leukocytosis (51%), anemia (38%), a platelet count exceeding 600 x
10(9)/l (86%), splenomegaly (15%), increase in LAP (24%) and serum
LDH (20%) (3).
Primary MF is a myeloproliferative neoplasm characterized by
stem cell-derived clonal myeloproliferation, abnormal cytokine
expression, bone marrow fibrosis, anemia, splenomegaly,
extramedullary hematopoiesis, constitutional symptoms, cachexia,
leukemic progression, and shortened survival. Diagnosis is based on
bone marrow morphology. The presence of JAK2, CALR, or MPL
mutations is supportive but not essential for diagnosis;
approximately 90% of patients carry one of these mutations and 10%
are "triple-negative." None of these mutations is specific to primary
MF and are also seen in essential thrombocythemia. Prefibrotic
primary MF mimics essential thrombocythemia in its presentation
and the distinction, enabled by careful bone marrow morphological
examination, is prognostically relevant. Differential diagnosis includes
chronic myeloid leukemia, myelodysplastic syndromes, chronic
myelomonocytic leukemia, and acute myeloid leukemia. The DIPSS-
plus uses eight predictors of inferior survival: age >65 years, Hg <10
g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional
symptoms, red cell transfusion dependency, platelet count <100 ×
10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole
or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-,
12p-, or 11q23 rearrangement). The presence of 0, one, two or three,
and ≥ four adverse factors defines low, intermediate-1, intermediate-
2, and high-risk disease with median survivals of approximately 15.4,
6.5, 2.9, and 1.3 years, respectively. High risk disease is also defined
by CALR(-)/ASXL1(+) mutational status. Observation alone is
adequate for asymptomatic low/intermediate-1 risk disease,
especially with CALR(+)/ASXL1(-) mutational status. Stem cell
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L. Ben-Nun King David

transplant is considered for DIPSS-plus high risk disease or any risk


disease with CALR(-)/ASXL1(+) mutational status. Investigational drug
therapy is reasonable for symptomatic intermediate-1 or
intermediate-2 risk disease. Splenectomy is considered for drug-
refractory splenomegaly. Involved field radiotherapy is most useful
for post-splenectomy hepatomegaly, non-hepatosplenic
extramedullary hematopoiesis, primary MF-associated pulmonary
hypertension, and extremity bone pain (4).
A retrospective study was performed involving 865 bone marrow
biopsies together with the clinical records from patients with CIMF.
Diagnosis was established according to the WHO criteria, and
assessment of MF followed a consensus scoring system that included
four grades (MF-0 to MF-3). Histopathological and clinical evaluations
were carried out in an independent fashion. Prefibrotic and early
CIMF (MF-0/-1) were presented by 565 patients showing borderline
to mild anemia and no or slight splenomegaly, but frequently,
thrombocytosis exceeding 500x10(9)/l was shown. Three hundred
patients with reticulin and collagen fibrosis (MF-2/-3) were
characterized by marked anemia, gross splenomegaly, peripheral
blasts, and normal to decreased platelet and leukocyte counts. The
latter cohort was consistent with findings generally in keeping with
MF with myeloid metaplasia. Regarding the stepwise evolution of
disease, sequential bone marrow examinations showed that in 103
patients, prefibrotic and early CIMF transformed into advanced
stages accompanied by correspondingly developing clinical and
histomorphological features. Survival analysis (univariate calculation)
revealed a significantly more favorable prognosis in prefibrotic vs.
advanced stages of CIMF. On the other hand, higher classes of MF
exerted a higher clinical risk profile (Lille score). In conclusion, the
dynamics of the disease process in CIMF are characterized by
evolving MF in the bone marrow and closely associated changes of
relevant hematological findings (5).
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L. Ben-Nun King David

Osteomyelofibrosis

Until now, scant knowledge was available about the dynamics of


CIMF. However, follow-up studies are in keeping with a stepwise
evolution starting with a prefibrotic (hypercellular) phase that
progressively transforms into the classical fibro-osteosclerotic
endstage with myeloid metaplasia. Prefibrotic CIMF is characterized
by a granulocytic and megakaryocytic myeloproliferation lacking an
increase in reticulin. Most conspicuous are abnormalities of
megakaryopoiesis with regard to their histotopography and
maturation. There is a more than 65% probability of progression from
an early to advanced CIMF accompanied by increasing anemia,
splenomegaly, and leuko-erythroblastosis. A significant relationship is
recognizable among frequency, tortuosity, and luminal dilation of the
microvessels and the extent of MF. Quantity of CD34(+) progenitor
cells in the bone marrow reveals a close association with
advancement of disease (fibrosis, splenomegaly, anemia, and
peripheral blasts) and therefore prognosis. Cell kinetic studies show
increased proliferation associated with a higher rate of apoptosis in
initial (hypercellular) stages, as well as a reduced endoreduplicative
activity of megakaryopoiesis and a blocked synthesis phase of the
erythroid precursors. Prefibrotic and early CIMF often present with a
marked thrombocytosis mimicking essential thrombocythemia.
Regarding prognosis, early CIMF is associated with a significantly
more favorable survival than advanced stages (6).
MF is a clonal hematopoietic malignancy characterized by
constitutional and localized symptoms, progressive splenomegaly,
bone marrow fibrosis, and cytopenias. This study aimed to
characterize symptoms and other clinical features of MF among
patients in the US. A retrospective medical record review of adult
patients with an MF diagnosis between 1 January 2005 and 31 March
2010 was conducted, and stratified by the presence of palpable
338
L. Ben-Nun King David

splenomegaly. Eligible patients had 12 months or more of follow-up


after diagnosis (or after detection of splenomegaly, if present) unless
death occurred. Demographic and clinical characteristics, MF-related
symptoms, and treatments were reported by treating physicians. This
study included 180 MF patients: 102 with splenomegaly, and 78
without. Median age was 66 years, 63% were male, and 82% had
intermediate-2 or high-risk MF (International Prognostic Scoring
System). Fatigue was reported by ~85% of patients; weight loss, night
sweats, and fever (any grade) were each reported by 50% or more of
patients. Generalized abdominal pain, left subcostal pain, and early
satiety occurred more frequently among patients with splenomegaly.
Multiple symptoms were reported by 95% of patients. Common
comorbidities were hypertension, DM, and COPD. In conclusion,
symptoms are common in MF patients, regardless of the presence of
palpable splenomegaly. Careful assessment of symptom burden is an
important aspect of the clinical evaluation of patients with MF (7).
A retrospective clinico-pathological study was performed on 208
consecutively recruited patients (94 males, 114 females, median age
67 years) with idiopathic (primary) osteo-/MF. According to bone
marrow histology (cellularity) as well as extent (semiquantitative
grading) and quality (reticulin/collagen) of MF stages of the disease
process were determined. At closure of this study (observation time
65 months), 133 patients died and 75 alive, while median survival
was 56 months. The wide spectrum of clinical signs and symptoms
and laboratory data on admission was reflected by a corresponding
variety of histological features. Significant differences of
hematological values could be calculated between patients with or
without early reticulin fibrosis (fiber scores 0 and 1) and advanced
fibro-osteosclerotic stages (fiber scores 2 and 3). Evolution of disease
features was elicited by longitudinal follow-up studies and sequential
bone marrow biopsies. Morphometric assessment of fiber density in
patients without preceding chemotherapy revealed an unpredictable
and varying progression of MF associated with alterations of certain
laboratory parameters (Hg level, spleen size, and thrombocytosis).
Differentiation from essential (primary) thrombocythemia was
required in 25 patients who fulfilled the postulated diagnostic
criteria. In fact, this group was consistent with hypercellular, early
stages of IMF without relevant reticulin fibrosis and an excessively
raised platelet count (> 1000 × 109/1). Discrimination was only
feasible by regarding histology carefully, particularly abnormalities of
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L. Ben-Nun King David

megakaryopoiesis and follow-up data. Parameters of predictive value


indicating a significant loss in life expectancy in comparison with a
sex- and age-adjusted normal population included: age (>60 years),
Hg level (<10g/dl), thrombocyte count (<600 × 109/1) and the
presence of myeloblasts and promyelocytes. In the so-called early
stages of idiopathic MF without relevant MF, findings indicative for
extramedullary hemopoiesis or generalization of the disease process
exerted an unfavorable influence on survival (8).
A 62-year-old woman suffering from one-year lasting, non-erosive
peripheral arthritides with general health impairment and high acute-
phase reactant levels was admitted to rheumatology department.
The patient had suffered from chronic polyarthralgia and a
thrombocytosis that had been discovered nine years before, with a
recent increase in platelet count. All immunological blood tests were
negative. Corticosteroid and methotrexate treatments improved
pain, swollen joint count, and systemic inflammation. However, joints
remained stiff and painful with two swollen wrists and persistent
thrombocytosis. An iliac bone marrow biopsy was performed,
showing primary MF. Hydroxyurea treatment (500 mg per day)
allowed to achieve complete and prolonged clinical and biological
remission. After six months, a new disease flare occurred. The patient
reached remission again after hydroxyurea dose increased to
1500 mg per day. This supports the hypothesis of idiopathic MF-
associated seronegative polyarthritis. In this case, haemopathy-
targeted treatment using hydroxyurea induced arthritis remission (9).

ASSESSMENT: osteomylofibrosis and sclerosis are chronic


myeloproliferative diseases of the elderly, with a peak incidence in
the sixth and seventh decade of life, in which fibrosis and sclerosis
finally lead to bone marrow obliteration. Bone marrow fibrosis,
anemia, splenomegaly and a leuko-erythrobastic blood picture
characterize IMF. Apart from minor hemorrhage and peripheral
thrombosis, patients with early stage of IMF present with non-
specific symptoms including varying degrees of leukocytosis, anemia,
a platelet count exceeding 600 x 10(9)/l, splenomegaly, increase in
leukocyte ALP and serum LDH. MF is a clonal hematopoietic
malignancy characterized by constitutional and localized symptoms,
progressive splenomegaly, bone marrow fibrosis, and cytopenias.
Did osteomylofibrosis affect the old King? Although the disease is
prevalent in the elderly, and can manifest as arthralgia or arthritis, in
340
L. Ben-Nun King David

the absence of severe intractable bone pain the King suffered from,
and appropriate investigation the diagnosis of osteomylofibrosis
seems unlikely.

References
1. Baur-Menyk A, Reiser M. Oncohaematologic disorders affecting the
skeleton in the elderly. Radiol Clin North Am. 2008;46:786-98.
2. Böhner H, Rötzscher VM, Tirier C, et al. Splenectomy in
osteomyelofibrosis. Indications and outcome. Chirurg. 1996;67:1016-9.
3. Thiele J. Kvasnicka HM, Zankovich R, Diehl V. Early-stage idiopathic
(primary) myelofibrosis- current issues of diagnostic features. Leuk Lymphoma.
2002;43:1035-41.
4. Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-
stratification, and management. Am J Hematol. 2014;89(9):915-25.
5. Thiele J, Kvasnicka HM. Grade of bone marrow fibrosis is associated
with relevant hematological findings-a clinicopathological study on 865
patients with chronic idiopathic myelofibrosis. Ann Hematol. 2006;
85(4):226-32.
6. Thiele J, Kvasnicka HM. Hematopathologic findings in chronic
idiopathic myelofibrosis. Semin Oncol. 2005;32(4):380-94.
7. Mitra D, Kaye JA, Piecoro LT, et al. Symptom burden and splenomegaly
in patients with myelofibrosis in the United States: a retrospective medical
record review. Cancer Med. 2013;2(6):889-98.
8. Thiele J, Kvasnicka H-M, Werden C, et al. Idiopathic Primary Osteo-
myelofibrosis: A Clinico-Pathological Study on 208 Patients with Special
Emphasis on Evolution of Disease Features, Differentiation from Essential
Thrombocythemia and Variables of Prognostic Impact. Leukemia &
Lymphoma. 1996;22(3-4):303-17.
9. Guillot X, Moldovan M2, Vidon C1, Wendling D1. Myelofibrosis-
related arthritis successfully treated with hydroxyurea. Case Rep Rheumatol.
2014;2014:869743.

AMYLOIDOSIS
Amyloid is a pathologic fibrillar aggregation of polypeptides in a
cross-beta-sheet conformation. More than 29 different amyloid
proteins have been identified. Analysis of a Congo red-stained tissue
section by polarization microscopy is the gold standard for diagnosing
amyloid. Subsequent classification of the amyloid is mandatory and is
increasingly supported by molecular biological analyses (1).
341
L. Ben-Nun King David

The modern classification of amyloid disease tends to use an


abbreviation of the protein that makes the majority of deposits,
prefixed with the letter A. Overproduction of immunoglobulin light
chains is termed AL amyloidosis, continuous overproduction of acute
phase proteins in chronic inflammation can lead to AA amyloidosis,
and amyloidosis caused by transthyretin is termed ATTR (2,3).
An older clinical method of classification refers to amyloidoses as
systemic or localized. Systemic amyloidoses affect more than one
body organ or system. Examples are AL, AA and Aβ2m (4). Localised
amyloidoses affect only one body organ or tissue type. Examples are
Aβ, IAPP, atrial natriuretic factor (in isolated atrial amyloidosis), and
calcitonin (in medullary carcinoma of the thyroid) (4).
Another classification is primary or secondary. Primary
amyloidoses arise from a disease with disordered immune cell
function, such as MM or other immunocyte dyscrasias. Secondary
(reactive) amyloidoses occur as a complication of some other chronic
inflammatory or tissue-destroying disease. Examples are reactive
systemic amyloidosis and secondary cutaneous amyloidosis (4).
Additionally, based on the tissues in which it is deposited,
amyloidosis is divided into mesenchymal (organs derived from
mesoderm) or parenchymal (organs derived from ectoderm or
endoderm) (3).
The fibrils of primary amyloidosis consist of kappa or lambda
monoclonal light chains. Weakness, fatigue, and weight loss are the
most frequent symptoms. Macroglosia occurs in 10%. An M-protein is
found in the serum or urine in 90%. The presence of nephritic
syndrome, renal insufficiency, CHF, orthostatic hypotension, or
sensorimotor peripheral neuropathy, and an M-protein in the serum
or urine suggest the possibility of primary amyloidosis. The diagnosis
depends upon the demonstration of amyloid in tissues (5).
The clinical spectrum of plasma cell dyscrasias includes primary
amyloidosis and MM. These two entities are present at the time of
diagnosis in 10 percent of cases. A 72-year- old female was admitted
to the Institution with oligoanuric renal failure. Renal
ultrasonography revealed normal kidney dimensions, with a slight
decrease in the normal parenchyma-sinus differentiation. The
complementary study identified free kappa light chains in urine (73,9
mg/dL) and bone marrow study fulfilled the criteria for MM. Search
for amyloid fibrils in abdominal subcutaneous fat was positive. The
serum beta-2 microglobulin level was elevated (26 mg/L).
342
L. Ben-Nun King David

Transthoracic echocardiogram revealed no pathologic findings.


Treatment initiation was complicated by hemodialysis catheter-
associated Staphylococcus aureus infection. Primary amyloidosis
associated with light chain myeloma is a rare, and often late
diagnosis with a dismal prognosis. Renal failure is a frequent initial
presentation of the disease and infection is an important cause of
death (6).
Renal involvement with amyloidosis is common and patient
survival is rarely reaching five years. In this study, clinical and
biological characteristics as well as treatments and outcomes of
patients with renal amyloidosis followed for more than five years was
reviewed. Between 1975 and 2003, 485 patients were diagnosed
with renal amyloidosis including 12 patients who were followed more
than five years. The six men and six women of mean age 42.4 years
(range 18 to 66 years) displayed renal signs of lower limb edema in all
cases; hypertension in four cases, proteinuria on urinalysis in all cases
with microscopic hematuria in five cases. Biological tests showed
nephrotic syndrome in 11 patients, normal renal function in nine
patients, and renal failure in three patients whose mean creatinine
was 481.6 micromol/L (range 294 to 726). The amyloidosis was AA
type in 11 cases and non-AA in one case. An etiologic survey revealed
spondylarthropathy in one patient, pulmonary tuberculosis in two
patients, chronic bronchitis in three patients, hepatic hydatic cyst in
one patient, Mediterranean familial fever in two patients, Crohn's
disease in one patient, Hodgkin's lymphoma in one patient, and MM
in one patient. Specific treatment was initiated with colchicine in
seven patients. At a 110-month mean follow-up (range 53 to 153
months), remission of nephrotic syndrome was observed in four
cases, progression to CRF in two patients, and to end-stage renal
failure in five cases (range 53 to 196 months), with stabilization of
renal function in seven patients. In conclusion, primary amyloid
disease should be optimally suppressed in patients with renal
involvement. The role of this treatment in remission of renal
amyloidosis is not well established. This efficacy of the treatment has
been demonstrated in some patients with improved survival (7).
Few data are available from large population-based studies on
survival and renal outcome of patients with renal involvement and
different types of systemic amyloidosis. Of 373 patients, 290 affected
by systemic amyloidosis with renal involvement and diagnosed in
Italy between January 1995 and December 2000, were followed from
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L. Ben-Nun King David

diagnosis to death or until the last available clinical control. Eighty-


three patients were excluded from analysis because either the
amyloid type remained undetermined or they were lost at follow-up.
Clinical and laboratory information was collected according to the
different types of amyloidosis using a specific form which included
renal function with 24 hours proteinuria at diagnosis and at the end
of follow-up, the type and the date of onset of dialysis and the kind
of treatment they underwent. The median time of follow-up was 24
months in primary amyloidosis (AL) (range: 1-88 months), 16 months
in AL with associated MM (MM + AL: range 1-76 months), 30 months
in reactive amyloidosis (AA) (range: 1-99 months) and 52 months in
patients with familial forms (AF: range 14-82 months). Patients with
AL showed a significantly shorter survival than AA. Despite
insignificant differences of renal outcome or survival on dialysis being
observed between the two groups, a lower renal survival with a
higher number of patients who progressed to end-stage renal disease
was observed in patients with AA. Overall survival was markedly
improved in patients with AL who underwent a specific therapy
(conventional chemotherapy or ASCT) even in the absence of a
positive kidney response. Multivariate analysis showed cardiac
involvement and specific therapy to significantly influence survival in
AL whereas age, serum creatinine and heart involvement significantly
affected survival in AA. In both groups, serum creatinine and heart
involvement were the most relevant predictors for renal outcome,
together with urinary protein excretion, in patients with AA. In
conclusion, these results show a worse survival in AL due to the
higher prevalence of heart involvement in this group and emphasize
that a specific therapy significantly prolongs survival and slows the
progression of renal disease in patients with AL. A late nephrological
referral is likely to cause the higher serum creatinine found at
presentation in patients with AA and probably accounts for the lower
renal survival observed in the short term in these patients. Renal
transplantation and ASCT are still rare therapeutic options for renal
patients affected by systemic amyloidosis (8).
Whether it is overload disease or mispleated proteins, amyloid is a
great pretender. This is especially true for all of the osteo-articular
manifestations of AL amyloidosis, which may mimic RA, polymyalgia
rheumatica, a myeloma or a bone tumor. To improve the prognosis,
AL amyloidosis must be considered in front of atypical osteo-articular
manifestations. Amyloidosis Ab2M of chronic haemodialysis
344
L. Ben-Nun King David

(members' arthropathy and destructive spondylitis) is a specific entity


that needs to be differentiated from other osteoarthropathies of CRF.
It has become exceptional since the progress of haemodialysis. ATTR
can be responsible for CTS in its genetic and senile form. Although
amyloidosis is rare, it represents one of the etiologies of cancer stem
cell, regardless of its type. In the specific context of haemodialysis,
this poses no difficulty for the clinician. Yet amyloid light chain
amyloidosis must be considered more often, as must senile ATTR in
the elderly. It seems that the anatomo-pathologic analysis with
specific staining with Congo red should be systematically performed
in the case of surgical neurolysis. Amyloidosis is defined by the
extracellular deposit of proteins which share common tinctorial
affinities, a fibril aspect under electron microscopy and spatial
conformation called beta pleated. Once regarded as a mere overload
disease, it is currently considered as a disease of misfolded proteins.
Abnormalities of spatial pattern play an essential role in the
responsibility for the pathology of many proteins whose amyloid
fibre is the final common way. They involve both changes in the
conformation of proteins and other major in vivo interactions
between amyloid protein and the extracellular matrix. In most cases,
amyloidosis represents the bulk of histopathological lesions and its
pathogenic role is certain. In other cases, it is only one elementary
lesion of the disease and its role is controversial. The amyloidosis
responsible for osteo-articular manifestations is the AL
immunoglobulin amyloidosis, the beta2-microglobulin amyloidosis in
patients under haemodialysis and finally the ATTR (genetic and
senile). Rheumatological manifestations of immunoglobulin
amyloidosis are numerous and often indicative of the disease.
Deposits affect joint and periarticular structures. The most common
presentation is a progressively developing bilateral symmetric
polyarthritis with negative immunology and absent specific structural
abnormalities. CTS is common and should suggest the etiology. Other
clinical representations are rarer as an isolated bone tumour
(amyloidoma) or integrating systemic AL amyloidosis. β 2-
microglobulin amyloidosis occurs in patients under chronic
haemodialysis. It is responsible for CTS, arthralgia and a specific
destructive spondyloarthropathy. The ATTR also causes CTS (9).
345
L. Ben-Nun King David

ASSESSMENT: amyloid is a pathologic fibrillar aggregation of


polypeptides. Amyloidoses are caused by the deposition of amyloid
and may occur as cerebral and extracerebral disease.
Weakness, fatigue, and weight loss are the most frequent
symptoms. Macroglosia occurs in 10%. An M-protein is found in the
serum or urine in 90%. The presence of nephritic syndrome, renal
insufficiency, CHF, orthostatic hypotension, or sensorimotor
peripheral neuropathy, and an M-protein in the serum or urine
suggest the possibility of primary amyloidosis.
The amyloidosis responsible for osteo-articular manifestations is
the AL immunoglobulin, the beta2-microglobulin amyloidosis in
patients under haemodialysis and finally the ATTR (genetic and
senile). Rheumatological manifestations of immunoglobulin
amyloidosis are numerous and often indicative of the disease.
Deposits affect joint and periarticular structures. The most common
presentation is a progressively developing bilateral symmetric
polyarthritis with negative immunology and absent specific structural
abnormalities. CTS is common and should suggest the etiology. Other
clinical representations are rarer as an isolated bone tumor
(amyloidoma) or integrating systemic AL amyloidosis. β 2-
microglobulin amyloidosis occurs in patients under chronic
haemodialysis. It is responsible for CTS, arthralgia and a specific
destructive spondyloarthropathy. The ATTR also causes CTS.
Did primary amyloidosis afflict the King? Although the diagnosis of
amyloidosis cannot be absolutely ignored, amyloidosis does not
entirely explain the biblical words " my bones are consumed…"
(Psalm 31:11) and "My bones wasted away through my anguished
roaring all day long" (Psalm 32:3). Thus, the diagnosis of amyloidosis
seems unlikely.

References
1. Röcken C, Eriksson M. Amyloid and amyloidoses. Pathologe.
2009;30(3):182-92.
2. Dhawan R, Herbert S Diamond ed. AA (Inflammatory) Amyloidosis -
Medscape Reference. Available 10 December 2014 at medicine.medscape.
com/article/335559-overview
3. Amyloidosis. Wikipedia, the free encyclopedia. Available 10 December
2014 at wikipedia.org/wiki/Amyloidosis.
4. Sheppard MR, Vinay K, Abul KA, Nelson F. Robbins Basic Pathology.
Philadelphia: Saunders. 2007. 8th edition ISBN 1-4160-2973-7.
346
L. Ben-Nun King David

5. Kyle RA. Clinical aspects of multiple myeloma and related disorders


including amyloidosis. Pathol Biol (Paris). 1999;47:148-57.
6. Martins RG, Roncon-Albuquerque R Jr, Cabral R, et al. Primary
amyloidosis associated with kappa light chain myeloma. Acta Med Port.
2010;23(2):281-4.
7. Kaaroud H, Boubaker K, Béji S, e al. Renal amyloidosis followed more
than 5 years: report of 12 cases. Transplant Proc. 2004;36(6):1796-8.
8. Bergesio F, Ciciani AM, Manganaro M, et al. Renal involvement in
systemic amyloidosis: an Italian collaborative study on survival and renal
outcome. Nephrol Dial Transplant. 2008;23(3):941-51.
9. M'bappé P, Grateau G. Osteo-articular manifestations of amyloidosis.
Best Pract Res Clin Rheumatol. 2012;26(4):459-75.

PLASMACYTOMA
Solitary plasmacytoma is characterized by a mass of neoplastic
monoclonal plasma cells in either bone or soft tissue without
evidence of systemic disease attributing to myeloma. Biopsy
confirmation of a monoclonal plasma cell infiltration from a single
site is required for diagnosis. The common presentation of solitary
plasmacytoma of bone is in the axial skeleton, whereas the
extramedullary plasmacytoma is usually seen in the head and neck.
The ratio of solitary plasmacytoma seen at males to females is 2:1
and the median age of patients is 55 years. The incidence rate of
solitary plasmacytoma in black race is approximately 30% higher than
the white race. Incidence rate increases exponentially by advancing
age. Solitary plasmacytoma of bone has a significant higher risk for
progression to myeloma, and the choice of treatment is radiotherapy
with curative intent at min. 4000 cGy. By only radiotherapy
application, long-term disease-free survival is possible for
approximately 30% of patients with solitary plasmacytoma of bone
and 65% of patients with extramedullary plasmacytoma (1).
Intracranial plasmacytomas are a rare abnormality in a
neurosurgeon's practice. The plasmacytomas may originate from the
skull bones or soft tissue intracranial structures; they may be solitary
or occur as a manifestation of MM, this type being typical of most
intracranial plasmacytomas. Progression of solitary plasmacytoma to
MM is observed in a number of cases. The final diagnosis of
plasmacytoma is based on a morphological study (2-5).
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L. Ben-Nun King David

A case of multiple plasmacytoma in a woman is described, with a


several-year radicular syndrome and recently, with numerous
pathologic fractures and tumor formation on the head and sternum.
Bone pains, pathologic fractures and tumours – osseous
manifestations characterized this disease (6).

Plasmacytoma

Solitary plasmacytoma of the skull is rare and few cases have been
reported in the English literature. Plasmacytoma of the skull has a
wide spectrum of pathology, including a quite benign, solitary
plasmacytoma, and an extremely malignant, MM at the two ends of
the spectrum. The prognosis for solitary plasmacytoma of the skull
appears to be good when it can be diagnosed on strict criteria. The
clinical features of solitary plasmacytoma of the skull are complex
and not easily identified, resulting in a high misdiagnosis rate. A
comprehensive examination and analysis which includes radiological
examination, immunoglobulin, biochemistry, test for Bence Jones
protein in the urine and bone marrow is needed for correct diagnosis.
If the skull lesion is isolated, with accompanying marked swelling in
the area and tenderness, plasmacytoma must be considered as a
possibility for the cause of solitary skull masses. Two cases of solitary
plasmacytoma of the skull lesions were retrospectively reviewed, in
which a comprehensive examination was used in order to predict the
clinical course of solitary plasmacytoma of the skull. The patients
received postoperative radiation and/or chemotherapy. Survival
following surgery was longer than two years for patient one, and
patient two is alive at the 18-month follow-up (7).
Solitary osseous plasmacytoma rarely involves the distal
extremities. A 64-year-old man presented with swelling, mild pain
and a deformed right index finger. The workup led to the diagnosis of
solitary osseous plasmacytoma and the patient eventually required
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L. Ben-Nun King David

amputation of his finger. With clinical follow-up, the disease spread


to regional lymph nodes and subsequently the patient developed
systemic involvement and received chemotherapy. In conclusion,
solitary osseous plasmacytoma should be considered in the
differential diagnosis of distal extremity neoplasms (8).

ASSESSMENT: solitary plasmacytoma is characterized by a mass of


neoplastic monoclonal plasma cells in either bone or soft tissue
without evidence of systemic disease attributing to myeloma. Biopsy
confirmation of a monoclonal plasma cell infiltration from a single
site is required for diagnosis. The common presentation of
plasmacytoma is in the axial skeleton, whereas the extramedullary
plasmacytoma is usually seen in the head and neck.
Was the King afflicted by plasmacytoma, solitary or multiple?
Since the King suffered from severe bone pains, the diagnosis of a
solitary plasmacytoma seems unlikely. In the case of multiple
plasmacytomas, numerous pathological fractures may indicate this
disease. However, although this diagnosis cannot be absolutely
ignored, the formation of tumors in different bones of the body such
as the head and sternum makes the diagnosis of multiple
plasmacytomas unlikely in the King's case.

References
1. Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, Haydaroglu A. A review for
solitary plasmacytoma of bone and extramedullary plasmacytoma.
ScientificWorldJournal. 2012;2012:895765.
2. Belov AI, Gol'bin DA. Intracranial plasmocytomas: biology, diagnosis,
and treatment. Zh Vopr Neirokhir Im N N Burdenko. 2006;3:43-7.
3. Tanaka M, Shibui S, Nomura K, Nakanishi Y. Solitary plasmocytoma of
the skull: a case report. Jpn J Clin Oncol. 1998; 28:626-30.
4. Bret P, Stan H, Streichenberg N, Sebban C, Guyotat J. Solitary
plasmocytoma of the sphenoid. A case report. Neurochirurgie. 2002;48:431-
5.
5. McLaughlin DM, Gray WJ, Jones FG, et al. Plasmacytoma: an unusual
cause of a pituitary mass lesion. A case report and a review of the literature.
Pituitary. 2004;7:179-81.
6. Georgie a B, Goergiev G. Bone manifestations of multiple
plasmocytoma. Vutr Boles.1980;19:79-81.
7. Dong L, Zhang X, Zhang H, et al. Solitary plasmacytoma of the skull:
Two case reports. Oncol Lett. 2013;5(2):479-482.
8. Daneshbod Y, Nowshadi PA, Negahban S, et al. Solitary plasmacytoma
of the index finger. J Clin Pathol. 2014 Jun 24. pii: jclinpath-2014-202413.
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L. Ben-Nun King David

TO SUM UP: the medical record of the King, that is the biblical
text, documents the patient's complains: “...my strength failed..., and
my bones are consumed” (Psalm 31:11), and “My bones wasted away
through my anguished roaring all day long” (Psalm 32:3). The
anamnestic findings indicate a very serious and lethal disease that
caused the King severe intractable bone pain and a great suffering.
Among the all diagnoses, as presented above, the most likely is MM.

OTHER MALIGNANT DISEASES

LUNG CANCER
Lung cancer is currently one of the most common malignant
diseases and is responsible for substantial mortality worldwide.
Compared with never smokers, former smokers remain at relatively
high risk for lung cancer, accounting for approximately half of all
newly diagnosed cases in the US. Screening offers former smokers
the best opportunity to reduce their risk of advanced stage lung
cancer and there is evidence that annual screening using LDCT is
effective in preventing mortality. Studies are being conducted to
evaluate whether the benefits of LDCT screening outweigh its costs
and potential harms and to determine the most appropriate workup
for patients with screen-detected lung nodules. Program efficiency
would be optimized by targeting high-risk current smokers, but low
uptake among this group is a concern. Former smokers may be
invited for screening; however, if fewer long-term current smokers
and more former smokers with long quit duration elect to attend,
this could have adverse effects on cost and screening test
parameters. To illustrate this point, three possible screening
scenarios with lung cancer prevalence ranging from between 0.62%
and 5.0 % is presented. Cost-effectiveness of lung cancer screening
may be improved if linked to successful smoking cessation programs
and if better approaches are developed to reach very high-risk
patients, e.g., long-term current smokers or others based on more
accurate risk prediction models (1).
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Established environmental risk factors for lung cancer include


smoking cigarettes and other tobacco products and exposure to
secondhand tobacco smoke, occupational lung carcinogens,
radiation, and indoor and outdoor air pollution (2), exposure to
asbestos (3), pesticide exposure, diesel exhaust and meat
consumption. The interaction between asbestos and smoking
regarding lung cancer risk is between additive and multiplicative (4).

Lung cancer

The association between COPD and lung cancer has long been a
subject of intense debate. The high prevalence of COPD in elderly
smokers inevitably strengthens their coincidence. In addition to this
contingent coincidence, recent studies have revealed a close
association between the two diseases that is independent of the
smoking history; that is, the existence of COPD is an independent risk
factor for the development of lung cancer. Molecular-based evidence
has been accumulating because of the efforts to explain the
underlying mechanisms of this association. These mechanisms may
include the following: the retention of airborne carcinogens followed
by the activation of oncogenes and the suppression of tumor
suppressor genes; the complex molecular mechanism associated with
chronic inflammation in the distal airways of patients with COPD; the
possible involvement of putative distal airway stem cells; and genetic
factors that are common to both COPD and lung cancer. The
existence of COPD in patients with lung cancer may potentially affect
the process of diagnosis, surgical resection, radiotherapy,
chemotherapy, and end-of-life care. The comprehensive
management of COPD is extremely important for the appropriate
treatment of lung cancer. Surgical resections with the aid of early
interventions for COPD are often possible, even for patients with
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mild-to-moderate COPD. New challenges, such as lung cancer CT


screening for individuals at high risk, are now in the process of being
implemented (5).
The most common initial symptoms are constitutional, cough, and
chest pain. The most frequent reason for the consultation are
dyspnea and haemoptysis (6).
The objective of this study was to estimate the incidence rate of
bone metastasis and subsequent SREs (radiation to bone, spinal cord
compression, fracture, and surgery to bone) in lung cancer patients
and to quantify their impact on mortality. A nationwide cohort study
of patients diagnosed with lung cancer between 1999 and 2010 in
Denmark was conducted. The cumulative incidence (%) of bone
metastasis and subsequent SREs (treating death as a competing risk)
and corresponding incidence rates (per 1000 person-years) were
computed. Patients (n=29,720) with incident lung cancer (median
follow-up: 7.3 months) were identified. The one-year cumulative
incidence of bone metastasis was 5.9%, and the one -year cumulative
incidence of subsequent SREs was 55.0%. The incidence of bone
metastasis and SREs was higher in patients with NSCLC vs. SCLC. One-
year survival was 37.4% in patients with no bone metastasis; 12.1% in
patients with bone metastasis without SREs; and 5.1% in patients
with both bone metastasis and SREs. When mortality rates between
patients with bone metastasis with and without an SRE were
compared, two-month mortality rates were similar, but the > two-
month adjusted mortality rate ratio was 2.0 (95% CI 1.7-2.2). In
conclusion, bone metastases predict a poor prognosis in lung cancer
patients. The majority of lung cancer patients with bone metastasis
will experience a SRE, which may increase the rate of mortality (7).
In Turkey, of 945 patients with NSCLC, 377 (39.9%) had
metastases. Of the 224 patients with the stage I and II of the disease,
73 had 73 metastases, including bone metastases, with a rate of
10.9% silent metastases (8).
In this study, the correlation between distant metastases and
metastatic organ-specific abnormalities in patients with lung cancer
was evaluated. Of 197 patients who have lung cancer with distant
metastases, 141 (71.5%) were with NSCLC and 56 (28.5%) were SCLC.
While one site of liver, brain and bone metastases were detected in
128 (64.9%) patients, 69 patients (35.1%) had suprarenal, renal,
pancreatic, skin, lung, thyroid, abdominal lymph node metastases.
Organ-specific symptoms, findings on physical examination and
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L. Ben-Nun King David

abnormalities in laboratory data were detected in 121 (56.5%), 45


(21%) and 52 (24.2 %) patients, respectively. Sensitivity of
predilection of organ-specific symptoms for bone, liver and brain
metastases were 67%, 43% and 74% and specificity were 86%, 90%
and 76%, respectively (9).
The skeleton is one of the most common sites of metastasis in
patients with advanced cancer. Bone metastases often cause SREs.
The charts of all 259 patients with NSCLC who consulted the
Department of Medical Oncology at Kinki University School of
Medicine between February 2002 and January 2005 were
retrospectively investigated. Their TNM stage, presence of skeletal
metastases (on bone scintigraphy, MRI, and plain X-ray films), and
outcome parameters such as SREs, analgesic use, and survival were
assessed. Seventy patients (30.4%) have skeletal metastases during
their clinical course and these patients, 35 (50%) had SREs. Among
135 stage IV patients, 56 (41%) had skeletal metastases, and of 56
patients, 25 (45%) had SREs. The most common SREs were the need
for radiotherapy (34.3%) and hypercalcemia (20%). Patients with
SREs tended to have worse survival, while insignificant difference of
survival was observed between patients with and without skeletal
metastases. In conclusion, it is important to prevent SREs during the
treatment of NSCLC, so further studies evaluating bisphosphonates in
combination with chemotherapy are warranted (10).

ASSESSMENT: did lung cancer with metastases to the bones affect


the King? In the absence of risk factors for lung cancer, clinical signs
such as dyspnea, chest pain, chronic cough, sputum production, and
haemoptysis, and appropriate radiological, and histopathological
investigations the diagnosis of lung cancer seems unlikely.

References
1. Tota JE, Ramanakumar AV, Franco EL. Lung cancer screening: review
and performance comparison under different risk scenarios. Lung. 2014;
192(1):55-63.
2. Alberg AJ, Brock MV, Ford JG, et al. Epidemiology of lung cancer:
Diagnosis and management of lung cancer, 3rd ed.: American College of
Chest Physicians evidence-based clinical practice guidelines. Chest.
2013;143(5 Suppl):e1S-29S.
3. Nielsen LS1, Bælum J, Rasmussen J, et al. Occupational asbestos
exposure and lung cancer - a systematic review of the literature. Arch
Environ Occup Health. 2014;69(4):191-206.
353
L. Ben-Nun King David

4. Luqman M, Javed MM, Daud S, et al. Risk factors for lung cancer in the
Pakistani population. Asian Pac J Cancer Prev. 2014;15(7):3035-9.
5. Takiguchi Y, Sekine I, Iwasawa S, et al. Chronic obstructive pulmonary
disease as a risk factor for lung cancer. World J Clin Oncol. 2014;;5(4):660-6.
6. Gonzalez-Barcala FJ, Falagan JA2, Garcia-Prim JM3, et al. Symptoms
and reason for a medical visit in lung cancer patients. Acta Med Port. 2014;
27(3):318-24.
7. Cetin K, Christiansen CF, Jacobsen JB, et al. Bone metastasis, skeletal-
related events, and mortality in lung cancer patients: A Danish population-
based cohort study. Lung Cancer. 2014 Sep 10. pii: S0169-5002(14)00367-5.
8. Metintas M, Ak G, Akcayi IA, et al. Detecting extrathoracic metastases
in patients with non-small cell lung cancer: is routine scanning necessary?
Lung Cancer. 2007;58:59-67.
9. Alpar S, Uçar N, Turgut A, et al. The correlation between the distant
metastases and organ-specific symptoms in the patients with lung cancer.
Tuberk Toraks. 2004;52(1):14-8.
10. Tsuya A, Kurata T, Tamura K, Fukuoka M. Skeletal metastases in non-
small cell lung cancer: a retrospective study. Lung Cancer. 2007;57(2):229-
32.

GASTRIC CARCINOMA
Despite a major decline in incidence and mortality over several
decades, stomach cancer is still the fourth most common cancer and
the second most common cause of cancer death in the world. There
is a 10-fold variation in incidence between populations at the highest
and lowest risk. The incidence is particularly high in East Asia, Eastern
Europe, and parts of Central and South America, and it is about twice
as high among men than among women. Prognosis is generally rather
poor, with five-year relative survival below 30% in most countries.
The best-established risk factors for stomach cancer are Helicobacter
pylori infection, the strongest established risk factor for distal
stomach cancer, and male sex, a family history of stomach cancer,
and smoking. While some factors related to diet and food
preservation, such as high intake of salt-preserved foods and dietary
nitrite or low intake of fruit and vegetables, are likely to increase the
risk of stomach cancer, the quantitative impact of many dietary
factors remains uncertain, partly due to limitations of exposure
assessment and control for confounding factors (1).
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L. Ben-Nun King David

Early symptoms include: heartburn, upper abdominal pain, nausea


and loss of appetite. Later symptoms may include: weight loss, yellow
skin, vomiting, difficulty swallowing and blood in the stool among
others (2). The cancer may spread from the stomach to other parts of
the body, particularly the liver, lungs, bones, lining of the abdomen
and lymph nodes (3).
A 46-year-old female woman patient was presented with a
thoracic vertebral wedge fracture and widespread vertebral
metastatic deposits with marrow infiltration. An acute bleeding into
the extradural space causing spinal cord compression complicated
the infiltration and suppression of marrow function. Gastric cancer,
although far less common than breast, kidney, thyroid, prostate and
bronchial cancers, was a cause of metastases to the bones. It
highlights the complications of bone metastases, marrow
suppression, leukoerythroblastic anemia, and spinal canal hematoma
and cord compression (4).
A 49-year-old man was admitted to the hospital with back pain,
appetite loss, and body weight loss in January 2009. Gastroduodenal
endoscopy, abdominal CT, and MRI revealed type IV advanced gastric
cancer (signet-ring cell carcinoma) with multiple lymph node (No. 16
LNs), right adrenal gland, and multiple bone metastases. Between
February 2009 and April 2011, 20 courses of S-1 (80 mg/m2) plus
CDDP (60 mg/m2) and ZOL hydrate (4 mg/body) were administrated.
Since May 2011, S-1 (70 mg/m2) and ZOL hydrate (4 mg/body) was
continued. The lymph node and adrenal gland metastases showed a
complete response, and the gastric tumor showed a partial response;
however, the bone metastases did not show complete response or
progressive disease for four years after initiation of therapy.
Chemotherapy with ZOL hydrate is considered as a useful therapeutic
option for advanced unresectable gastric cancer with multiple bone
metastases (5).

Gastric carcinoma
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L. Ben-Nun King David

Bone metastasis represents an increasing clinical problem in


advanced gastric cancer as disease-related survival improves. Data on
clinicopathology, skeletal outcomes, SREs, and bone-directed
therapies for 208 deceased gastric cancer patients with evidence of
bone metastasis were statistically analyzed. Median time to bone
metastasis was eight months (95% CI 6.125-9.875) considering all
included patients. Median number of SREs/patient was one. Less
than half of the patients (31%) experienced at least one and only four
and 2% experienced at least two and three events, respectively.
Median times to first and second SRE were two and four months,
respectively. Median survival was six months after bone metastasis
diagnosis and three months after first SRE. Median survival in
patients who did not experience SREs was five months. Among
patients who received ZOL before the first SRE, the median time to
appearance of first SRE was significantly prolonged compared to
controls. Bone metastases from gastric cancer are not rare, are
commonly aggressive and result in relatively early onset of SREs in
the majority of patients. This study, which included 90 patients
treated with ZOL, showed a significant extension of time to first SRE
and increase in the median survival time after diagnosis of bone
metastasis (6).
A case of compressive myeloradiculopathy from extensive
metastases to the spine, which on evaluation originated from
adenocarcinoma of the stomach, is reported. MRI of the spine
showed osteolytic and osteosclerotic metastases. G-I endoscopy
revealed ulcerative growth in the stomach that on biopsy showed
poorly differentiated adenocarcinoma. This case is unique in that the
initial presentation of gastric cancer itself was bony metastases
without any G-I symptoms or liver involvement. Metastases were
osteosclerotic as well, which is against the general belief that gastric
cancer produces only osteolytic secondaries (7).

ASSESSMENT: gastric carcinoma is the third most common G-I


malignancy after colon and pancreatic carcinoma. Patients can suffer
from widespread metastases of the bones. Bone metastases are
commonly aggressive and result in relatively early onset of SREs in
the majority of patients. Literature reports a patient in whom the
initial presentation of gastric cancer was bony metastases without
any G-I symptom or liver involvement.
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In the King's case, two symptoms related to this malignancy are


identified: loss of appetite and weight loss. It is understandable that
the results of gastroscopic evaluation and histopathological
evaluation are unavailable. Did the King suffer from gastric carcinoma
with bone metastases?

References
1. Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach
cancer. Methods Mol Biol. 2009;472:467-77.
2. Stomach (Gastric) Cancer. National Cancer Institute. Available 20
November 2014 at cancer.gov/cancertopics/types/stomach.
3. Gastric Cancer Treatment (PDQ®). National Cancer Institute. Available
20 November 2014 at http://www.cancer.gov/ cancertopics/types/stomach.
4. Hussain S, Chui S. Gastric carcinoma presenting with extensive bone
metastases and marrow infiltration causing extradural spinal haemorrhage.
Br J Radiol. 2006;79:261-3.
5. Kimura Y, Kawase T, Kawabata R, et al. Long-term efficacy of
chemotherapy for unresectable gastric cancer with multiple bone
metastases-a case report. Gan To Kagaku Ryoho. 2013;40(12):2235-7.
6. Silvestris N, Pantano F, Ibrahim T, et al. Natural history of malignant
bone disease in gastric cancer: final results of a multicenter bone metastasis
survey. PLoS One. 2013;8(10):e74402.
7. Basheer A, Daniel J, Padhi S. Compressive myeloradiculopathy from
bony metastasis as the initial presentation of poorly differentiated
adenocarcinoma stomach - a case report. Australas Med J. 2013;6(10):515-
9.

COLORECTAL CANCER
More than 1.2 million patients are diagnosed with CRC every year,
and more than 600,000 die from the disease. Incidence strongly
varies globally and is closely linked to elements of a so-called western
lifestyle. Incidence is higher in men than women and strongly
increases with age; median age at diagnosis is about 70 years in
developed countries. Despite strong hereditary components, most
cases of CRC are sporadic and develop slowly over several years
through the adenoma-carcinoma sequence. The cornerstones of
therapy are surgery, neoadjuvant radiotherapy (for patients with
rectal cancer), and adjuvant chemotherapy (for patients with stage
III/IV and high-risk stage II colon cancer). Five-year relative survival
ranges from greater than 90% in patients with stage I disease to
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L. Ben-Nun King David

slightly greater than 10% in patients with stage IV disease. Screening


reduces CRC incidence and mortality, but organized screening
programs are still to be implemented in most countries (1).
Over 37,000 new CRCs are diagnosed in the UK each year. Most
present symptomatically to primary care. The aim of this study was
to conduct a systematic review of the diagnostic value of symptoms
associated with CRC. MEDLINE, Embase, Cochrane Library, and
CINAHL were searched to February 2010, for diagnostic studies of
symptomatic adult patients in primary care. Studies of asymptomatic
patients, screening, referred populations, or patients with CRC
recurrences, or with fewer than 100 participants were excluded. The
target condition was CRC. Data were extracted to estimate the
diagnostic performance of each symptom or pair of symptoms. Data
were pooled in a meta-analysis. The quality of studies was assessed
with the QUADAS tool. Twenty-three studies were included. PPVs for
rectal bleeding in 13 papers ranged from 2.2% to 16%, with a pooled
estimate of 8.1% (95% CI 6.0%-11%) in those aged ≥50 years. Pooled
PPV estimates for other symptoms were abdominal pain (three
studies) 3.3% (95% CI 0.7%-16%); and anemia (four studies) 9.7%
(95% CI 3.5%-27%). For rectal bleeding accompanied by weight loss
or change in bowel habit, PLRs were 1.9 (95% CI 1.3-2.8) and 1.8 (95%
CI 1.3-2.5), respectively, suggesting higher risk when both symptoms
were present. Conversely, the PLR was one or less for abdominal
pain, diarrhea, or constipation accompanying rectal bleeding. In
conclusion, the findings suggest that investigation of rectal bleeding
or anemia in primary care patients is warranted, irrespective of
whether other symptoms are present. The risks from other single
symptoms are lower, though multiple symptoms warrant
investigation (2).
Patients with metastatic CRC evaluated from 1993 to 2002 at the
Fox Chase Cancer Center, Philadelphia, were identified. The records
of 1,020 patients were reviewed. Incidence of bone and brain
metastases were 10.4% (95% CI 8.6-12.4) and 3% (95% CI 2.2-4.5),
respectively. Patients with primary rectal vs. primary colon cancer
were more likely to develop bone metastases (16% vs. 8.6%, p=0.01).
Patients with lung metastases were more likely to have bone
metastases (16.1% vs. 6.4%, p<0.001) or brain metastases (6.2% vs.
1.2%, p<0.0001) than those without it (3).
This retrospective, multicenter, observational study of 264
patients with CRC involved bone examined cancer treatments, bone
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L. Ben-Nun King David

metastases characteristics, SRE type and frequency, ZOL therapy, and


disease outcomes. Most patients with bone metastases had
pathologic T3/4 disease at CRC diagnosis. The spine was the most
common site involved (65%), followed by hip/pelvis (34%), long
bones (26%), and other sites (17%). Median time from CRC diagnosis
to bone metastases was 11.00 months; median time to first SRE
thereafter was 2.00 months. Radiation and pathologic fractures
affected 45% and 10% of patients, respectively; 32% of patients had
no reported SREs. Patients survived for a median of 7.00 months
after bone metastases diagnosis; SREs affect survival insignificantly.
Subgroup analyses revealed that ZOL significantly prolonged median
time to first SRE (2.00 months vs. 1.00 month, respectively, p=0.009)
and produced a trend toward improved overall survival vs. no ZOL. In
conclusion, this study illustrates the burden of bone metastases from
CRC and supports the use of ZOL in this setting (4).
The purpose of this study was to investigate the clinical features
and prognoses of patients with diagnosed bone metastases from
CRC. This was a 16-year retrospective study of 32 patients with bone
metastases secondary to CRC, who were seen at National Kokura
Hospital between 1993 and 2008. The bone most commonly involved
was the spinal column. The mean disease-free interval was 17.6
months and mean survival from the diagnosis of bone metastases
was 9.3 months. On univariate analysis, the serum CEA level at the
time of diagnosis of bone metastases (p=0.020) and history of
pulmonary metastases (p=0.013) were significant. On multivariate
analysis, a history of bone metastases in the ribs (HR 3.669, p=0.025)
and a history of pulmonary metastases (HR 3.854, p=0.022)
significantly affected survival. In conclusion, it is important to
investigate for bone metastases in patients who complain of back
pain and lumbago after CRC surgery (5).

ASSESSMENT: more than 1.2 million patients are diagnosed with


CRC every year, and more than 600,000 die from the disease. Incidence
varies globally and is closely linked to elements of a so-called western
lifestyle.
Patients with primary rectal vs. primary colon cancer are more likely
to develop bone metastases. Most patients with bone metastases have
pathologic T3/4 disease at CRC diagnosis. The spine is the most
common site involved, followed by hip/pelvis, long bones, and other
sites.
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L. Ben-Nun King David

Investigation of rectal bleeding and anemia in primary care patients


is warranted, irrespective of whether other symptoms are present.
Did the King suffer from CRC? In the King's case we have one
symptom - anemia, see the section below. Cancer-related anemia may
indicate the presence of CRC. Although the results of occult stool
examination, colonoscopic evaluation, and histopathological findings
are unavailable, this diagnosis cannot be absolutely ignored.

References
1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383
(9927):1490-502.
2. Astin M, Griffin T, Neal RD, ET AL. The diagnostic value of symptoms
for colorectal cancer in primary care: a systematic review. Br J Gen Pract.
2011;61(586):e231-43.
3. Sundermeyer ML, Meropol NJ, Rogatko A, et al. Changing patterns of
bone and brain metastases in patients with colorectal cancer. Clin Colorect
Cancer. 2005;5:108-13.
4. Santini D, Tampellini M, Vincenzi B, et al. Natural history of bone
metastasis in colorectal cancer: final results of a large Italian bone
metastases study. Ann Oncol. 2012;23(8):2072-7.
5. Jimi S, Yasui T, Hotokezaka M, et al. Clinical features and prognostic
factors of bone metastases from colorectal cancer. Surg Today. 2013;
43(7):751-6.

HEPATOCELLULAR CARCINOMA
HCC is the most common primary malignancy of the liver. It is the
sixth most common malignancy worldwide and the third cause of
cancer-related mortality. Approximately 90% of HCCs are associated
with a known risk factor, mainly hepatitis B and cirrhosis which is a
true precancerous state, whatever its cause. The incidence of HCC in
a patient with cirrhosis is 3-5% per year. In developed countries,
hepatitis C and alcohol use are the main risk factors, and the
incidence of HCC is growing, owing probably to the hepatitis C
epidemic, the increasing incidence of non-alcoholic steatohepatitis
and the better prevention and treatment of other complications of
cirrhosis. In France, non-alcoholic steatohepatitis is currently the
second cause of cirrhosis with HCC after alcoholIn eastern Asia and
sub-saharan Africa, the dominant risk factor is chronic hepatitis B
infection (together with exposure to aflatoxin B1 in Africa). The high
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mortality of HCC is due to a late diagnosis at an advanced stage. This


is why screening of high risk patients is a major issue. The current
recommendation is a biannual liver ultrasonography for cirrhotic
patients, but only 20% of all HCCs are diagnosed during a surveillance
program. Surgical resection, liver transplantation and radiofrequency
ablation are the three validated curative treatments (1).
This study was undertaken to assess the value of clinical
symptomatology, abdominal ultrasound, TPCT and serum AFP
estimations in predicting presence of HCC among patients with
cirrhosis. In this cross-sectional study, Child's A/B cirrhosis patients
were subjected to clinical evaluation, ultrasound, TPCT and serum
AFP estimation. A high proportion of enrolled subjects had HCC at
first presentation (40.7%). Significantly higher prevalence of
abdominal pain, weight loss, and anorexia was seen in patients with
cirrhosis with HCC compared to those without HCC. Sensitivity and
specificity of any of these symptoms was 73% and 79%, respectively
(PPV and NPV of 65% and 85%, respectively). A 100% agreement
between TPCT and ultrasound was observed for diagnosing HCC
cases. However, TPCT detected a greater number of smaller HCCs.
Sensitivity of AFP at 400 ng/ml cut-off was only 25.7%, too low to be
useful. Best mix of sensitivity (77.2%) and specificity (78.1%) of AFP
was found to be at 10.7 ng/ml cut-off which falls within the
conventional limits of normalcy. In conclusion, this study highlights
the importance of symptomatology of weight loss, abdominal pain or
anorexia as markers for HCC in patients with cirrhosis. AFP was not a
useful screening test. TPCT should be undertaken in all cirrhotics
presenting to the hospital for the first time (2).

Hepatocellular carcinoma

Jaundice occurs in 5-44% of patients with HCC. It is an important


clinical presentation as the different etiological causes of jaundice in
HCC determine the therapeutic approach and the prognosis. A
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Medline search was undertaken to identify articles using the key


words 'hepatocellular carcinoma', 'jaundice' and 'tumour thrombus'.
Additional articles were identified by a manual search of the
references from the key articles. Patients with jaundice due to
hepatic parenchymal insufficiency (hepatocellular type) have a very
dismal prognosis. For patients with biliary obstruction due to HCC
(icteric type), the reported one-, three- and five-year survival rates
after curative resection were 57.1-100%, 20-47% and 6.7-45%,
respectively. The mean survival after palliative biliary drainage alone
was less than six months but when biliary drainage was combined
with other palliative treatment, the mean survival could be up to one
year. In conclusion, it is important to differentiate the hepatocellular
type from the icteric type of HCC. For patients with the icteric type of
HCC, curative liver resection can achieve a survival comparable to
that in patients without jaundice. For patients with unresectable
icteric type of HCC, treatment can provide improvement in patient's
QOL and survival (3).
Changes in the incidence of bone metastases in HCC from 1978 to
1997 and the characteristic clinical features were studied. A total of
673 patients with HCC during the period 1978-1997 were studied.
Bone metastasis was screened by bone scintigraphy, and bone
lesions were confirmed by plain radiography, CT and/or MRI. The
serum levels of the CTX, which represent osteoclastic bone
resorption, were measured. The incidence of bone metastasis during
the decade 1988-1997 was significantly higher than that during the
period 1978-1987. The median survival time of patients with HCC
during 1988-1997 was significantly longer than that during 1978-
1987. Portal thrombus was found in about half of the patients with
bone metastases. The most common site of bone metastases was the
vertebra followed by the pelvis, rib and skull in that order. All bone
lesions depicted by plain radiograph, CT and/or MRI were of the
osteolytic type, and the serum levels of CTX were significantly
elevated in the patients with bone metastases. In conclusion, the
increased incidence of bone metastasis in HCC in the decade 1988-
1997 is attributed to the prolonged survival rate of HCC patients due
to recent progress in both the diagnosis and treatment of the
disease. Dissemination of HCC cells to the vertebra through the
portal vein-vertebral vein plexuses due to the presence of portal
thrombus and/or portal hypertension may be related to a higher
incidence of bone metastasis in HCC. Both an early diagnosis and
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timely treatment of bone metastases are thus called for in the follow-
up of HCC patients (4).
In Japan, the clinical records of 482 patients who had been
diagnosed as having HCC were reviewed, 1995-2001. Extrahepatic
metastases had been detected in 65 patients. The frequent
metastatic sites were lung (53.8%), bone (38.5%), and lymph node
(33.8%). Other metastatic sites were the adrenal gland, peritoneum,
skin, brain and muscle (5). Spinal cord compression was an unusual
cause of metastatic HCC (6,7).
A 65-year old man presented with bone pain and anemia. Skull X-
ray revealed multiple osteolytic lesions. The patient was evaluated
for MM but detailed workup revealed the diagnosis of primary HCC
with osteolytic bone metastases (8).
A case of solitary skull metastasis as the first symptom of HCC is
reported. A 49-year-old male patient was admitted to Jinjiang
Hospital of Quanzhou Medical College with a painless parietal-
occipital scalp mass, while he denied any history of hepatic disease. A
cranial CT demonstrated a hypervascular enhancement with
osteolytic change in the right parietal-occipital region, cranial MRI
indicated a highly enhanced and osteolytic skull tumor, and
abdominal CT showed a huge tumor in the liver. The other
examinations showed no other metastases. Laboratory data showed
no liver dysfunction while hepatitis B surface antigen was positive,
and AFP level was high. A craniectomy was performed and the mass
was totally removed. The histological diagnosis was skull metastasis
from HCC. The patient was subsequently treated by transcatheter
arterial chemoembolization. In a review of published literature, the
incidence of skull metastasis from HCC in the period between 1990
and 2011 has increased significantly. The misdiagnosis rate of skull
metastases as the first symptom from HCC was high. Therefore, it is
necessary to give each patient with a scalp mass that has invaded the
skull a liver ultrasound or CT scan. On the other hand, metastases
that occurred in the calvaria site were more frequent than those that
occurred in the skull base and facial skeleton (9).

ASSESSMENT: HCC is the most common primary malignancy of


the liver. It is the sixth most common malignancy worldwide and the
third cause of cancer-related mortality.
Did the King suffer from HCC, which spread to the bones? In
David's case, we have two symptoms - weight loss, and anorexia. In
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the absence of risk factors such as hepatitis B, hepatitis C, alcohol


use, liver cirrhosis, abdominal pain, jaundice, and appropriate
investigation – laboratory, ultrasound, CT and/or MRI of the
abdomen, and histopathological findings, this diagnosis seems
unlikely.

References
1. Fares N, Péron JM. Epidemiology, natural history, and risk factors of
hepatocellular carcinoma. Rev Prat. 2013;63(2):216-7, 220-2.
2. Paul SB, Gulati MS, Sreenivas V, e al. Evaluating patients with cirrhosis
for hepatocellular carcinoma: value of clinical symptomatology, imaging and
alpha-fetoprotein. Oncology. 2007;72 Suppl 1:117-23.
3. Lai EC, Lau WY. Hepatocellular carcinoma presenting with obstructive
jaundice. ANZ J Surg. 2006;76(7):631-6.
4. Fukutomi M, Yokota M, Chuman H, et al. Increased incidence of bone
metastases in hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2001;
13(9):1083-8.
5. Natsuizaka M, Omura T, Akaike T, et al. Clinical features of
hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol
Hepatol. 2005; 20:1781-7.
6. Doval DC, Bhatia A, Vaid AK, et al. Spinal cord compression secondary
to bone metastases from hepatocellular carcinoma. World J Gastroenterol.
2006;12:5247-52.
7. Melichar B, Voboril Z, Toupková M, Dvorál J. Hepatocellular carcinoma
presenting with bone metastasis. J Exp Clin Cancer Res. 2002;21:433-6.
8. Dovai DC, Bhatia K, Vaid AK, et al. Bone metastases from primary
hepatocellular carcinoma simulating multiple myeloma. Hepatobilliary
Pancrear Dis Int. 2005;4:308-10.
9. Guo X, Yin J, Jiang Y. Solitary skull metastasis as the first symptom of
hepatocellular carcinoma: case report and literature review. Neuropsychiatr
Dis Treat. 2014 Apr 28;10:681-6.

PANCREATIC CANCER
Pancreatic cancer is the fourth most common cause of cancer-
related mortality in the US, with over 38,000 deaths in 2013. The
opportunity to detect pancreatic cancer while it is still curable
depends on the ability to identify and screen high-risk populations
before their symptoms arise. Risk factors for developing pancreatic
cancer include multiple genetic syndromes as well as modifiable risk
factors. Genetic conditions include hereditary breast and ovarian
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L. Ben-Nun King David

cancer syndrome, Lynch syndrome, familial adenomatous polyposis,


Peutz-Jeghers syndrome, familial atypical multiple mole melanoma
syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-
telangiectasia; having a genetic predisposition can raise the risk of
developing pancreatic cancer up to 132-fold over the general
population. Modifiable risk factors, which include tobacco exposure,
alcohol use, chronic pancreatitis, diet, obesity, DM, as well as certain
abdominal surgeries and infections, increase the risk of pancreatic
cancer development (1).
Although only 32,000 new cases of PA occur in the US each year, it
is the fourth leading cause of cancer deaths in this country. The
overall five-year survival rate is four percent, and localized,
resectable disease has only a 17 percent survival rate. Risk factors
include smoking, certain familial cancer syndromes, and familial
chronic pancreatitis. The link between risk of pancreatic cancer and
other factors (e.g., diabetes, and obesity) is less clear. Most patients
present with obstructive jaundice caused by compression of the bile
duct in the head of the pancreas. Epigastric or back pain, vague
abdominal symptoms, and weight loss also are characteristic of
pancreatic cancer. More than one-half of cases have distant
metastasis at diagnosis. CT is the most useful diagnostic and staging
tool. Ultrasonography, MRI, and endoscopic retrograde
cholangiopancreatography may provide additional information. The
majority of tumors are not surgically resectable because of
metastasis and invasion of the major vessels posterior to the
pancreas. Resectable tumors are treated with the Whipple procedure
or the pylorus-preserving Whipple procedure. Adjuvant fluorouracil-
based chemotherapy may prolong survival. For nonresectable
tumors, chemotherapy with gemcitabine prolongs survival. Other
agents are being studied. Radiation combined with chemotherapy
has slowed progression in locally advanced cancers. Throughout the
illness and during end-of-life care, patients need comprehensive
symptom control (2).
The Mayo Clinic Biospecimen Resource for Pancreas Research
database from January 1992 to September 2011 was retrospectively
analyzed. Data collected included demographic characteristics,
history of tobacco or alcohol use, DM, cholelithiasis, pseudocyst, and
details regarding PA. Clinical characteristics and outcomes of PA
patients with pancreatitis were compared with PA patients without
pancreatitis history. Patients (n=2,573) with PA diagnosis were
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L. Ben-Nun King David

analyzed. Among these patients, 195 (8%) who had pancreatitis


diagnosis ≥10 days before PA diagnosis were identified. The cohort
with pancreatitis history included more patients with DM (30% vs.
18%, p<0.001) and more smokers (68% vs. 58%, p=0.02). Compared
with patients without pancreatitis history, these patients received
diagnoses of PA at a younger age (63 vs. 65 years, p=0.005) and
earlier stage (stages I and II, 52% vs. 37%, p<0.001). A greater
percentage had history of surgery with curative intent (50% vs. 43%,
p=0.001) and significantly better survival [median (range), 387 days
(314 to 460 days) vs. 325 days (306 to 344 days), p=0.003]. In
conclusion, patients with PA and pancreatitis had more weight loss
and DM, had PA diagnosis at an earlier stage, were more likely to
have pancreatic surgery, and therefore better survival than PA
patients without pancreatitis, likely due to the earlier diagnosis (3).

Pancreatic tumor

The annual incidence of pancreatic carcinoma has been increasing


worldwide, and the overall five-year survival rate has remained at
approximately 5%. Thirty autopsy cases were histologically diagnosed
as pancreatic carcinoma from 1994 through 2010 at Nippon Medical
School Hospital. The mean patient age was 69.5 years, with
insignificant differences between male and female patients. The
location of the primary tumor was most often the head of the
pancreas (46.7%), followed by the body (36.7%) and tail (16.7%). All
patients had advanced-stage pancreatic carcinoma at diagnosis,
which limited the therapeutic options. Surgical resection, radiation,
and surgical resection with chemotherapy were each performed for a
single patient, and chemotherapy was performed in five patients. The
other patients received only symptomatic therapy. The mean survival
time from the first medical examination to death was short (5.5
months; range, 1-40 months). The cases were classified into 28 ductal
adenocarcinomas, one acinar cell carcinoma, and one IPMN with an
associated invasive carcinoma. Death in most cases was directly
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related to the pancreatic carcinoma, including cachexia,


carcinomatous peritonitis and pleuritis, hepatic failure and ileus due
to metastasis, and malignancy-related disorders, such as coagulation
disorders and immunodeficiency. The most frequent site of
metastasis was the lymph nodes, followed by the liver, peritoneum,
spleen, lung and/or pleura, small intestine, adrenal gland, kidney,
omentum, diaphragm, and bone. All cases with local infiltration were
located in the pancreatic head, but no difference was seen in other
clinicopathological features between cases with local infiltration and
cases with distant metastasis. The autopsies revealed an extremely
poor prognosis for pancreatic carcinoma due to the tumor itself and
malignancy-related disorders. The progression pattern (i.e., local
infiltration or distant metastasis) may correlate with the location of
the primary tumor (4).
Prognosis of pancreatic cancer is one of the worst among various
cancers, however, incidence of bone metastasis has been increased
in pancreatic cancer in recent years. Clinical features of pancreatic
cancer presenting bone metastases were examined, and how to
manage these patients were proposed. Thirteen patients (7.3%) with
pancreatic cancer bone metastases during 2000-2003 were studied.
Among these patients, pancreatic cancer was located at pancreatic
body to tail in 10 cases, while at pancreatic head in three cases. Liver
metastasis was noted in seven of 13 cases with bone metastases.
Radiographical imaging of bone lesions revealed osteolytic bone
destruction, and serum levels of bone resorption marker, 1CTP, were
elevated in these patients. Stimulation of osteoclastic bone
resorption is a critical step for bone metastasis, thus, serum levels of
cytokines (PTHrP, IL-6, and VEGF), which exert a promotive effect on
bone resorption, were measured. Serum levels of IL-6 and VEGF were
elevated in most of patients, while elevation of serum PTHrP levels
was found in three of 13 patients. Survival periods of pancreatic
cancer patients with bone metastases was not long, however,
treatment for bone metastases is important in terms of QOL. An
earlier diagnosis is essential to prevent deterioration in the QOL of
pancreatic cancer patients presenting bone metastases. Periodical
measurement of serum 1CTP in addition to bone scintigraphy is
helpful for the earlier diagnosis for bone metastases (5).
The aim of this study was to systematically characterize specific
pain patterns in the most frequent pancreatic diseases. Pain in
patients with chronic pancreatitis (n=314), pancreatic cancer (n=469),
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L. Ben-Nun King David

and other pancreatic tumors (n=249), including mucinous (n=20) and


serous cystadenoma (n=31), invasive (n=37) and non-invasive IPMN
(n=48), low stage (n=18) and high stage neuroendocrine neoplasia
(n=44), and ampullary cancer (n=51) was registered and correlated
with clinicopathological data. Forty-nine point one percent of
pancreatic cancer patients revealed no pain, and in chronic
pancreatitis, 18.3% were pain free. In contrary, moderate/severe
pain was registered in 15.1% of pancreatic cancer patients that was
increased in chronic pancreatitis with up to 34.2%. Serous
cystadenoma was asymptomatic in most cases (58.1%), whereas
78.9% of all mucinous cystadenoma patients suffered pain. In
neuroendocrine neoplasia pain was not a key clinical symptom since
64% of low stage neuroendocrine neoplasia and 59% of high stage
neuroendocrine neoplasia patients were pain free. Cancer
localization in the pancreatic body and patients with malignant
pancreatic neoplasms were associated with more severe pain. Tumor
grading and stage did not show any impact on pain. Only in
pancreatic cancer, pain was directly associated with impaired
survival. In conclusion, pancreatic pain depicts different patterns of
abdominal pain sensation according to the pancreatic disorder and
does not allow a unification of the term pancreatic pain (6).

ASSESSMENT: pancreatic cancer is the fourth most common cause


of cancer-related deaths in the US, with over 38,000 deaths in 2013.
Prognosis of pancreatic cancer is one of the worst among various
cancers, however, incidence of bone metastasis has been increased
even in pancreatic cancer in recent years.
Risk factors for developing pancreatic cancer include multiple
genetic syndromes as well as modifiable risk factors such as tobacco
exposure, alcohol use, chronic pancreatitis, diet, obesity, DM, certain
abdominal surgeries and infections.
Did the King suffer from pancreatic carcinoma? Here we have two
symptoms – weight loss and cachexia. In the absence of risk factors
related to pancreatic cancer, other clinical symptoms, appropriate
laboratory tests, radiological investigations and pathological data,
this diagnosis seems unlikely.
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L. Ben-Nun King David

References
1. Becker AE, Hernandez YG, Frucht H, Lucas AL. Pancreatic ductal
adenocarcinoma: Risk factors, screening, and early detection. World J
Gastroenterol. 2014 28;20(32):11182-11198.
2. Freelove R, Walling A. Pancreatic cancer: diagnosis and management.
Am Fam Physician. 2006;73(3):485-92.
3. Dzeletovic I, Harrison ME, Crowell MD, et al. Pancreatitis before
pancreatic cancer: clinical features and influence on outcome. J Clin
Gastroenterol. 2014;48(9):801-5.
4. Matsuda Y, Hagio M, Naito Z, Ishiwata T. Clinicopathological features
of 30 autopsy cases of pancreatic carcinoma. J Nippon Med Sch. 2012;
79(6):459-67.
5. Iguchi H, Yasuda M, Matsuo T, et al. Clinical features and management
of pancreatic cancer with bone metastases. Nippon Shokakibyo Gakkai
Zasshi. 2004;101:872-8.
6. D'Haese JG, Hartel M, Demir IE, et al. Pain sensation in pancreatic
diseases is not uniform: the different facets of pancreatic pain. World J
Gastroenterol. 2014;20(27):9154-61.

GIANT CELL TUMOR. GCT of bone is one type of giant cell-rich


lesion of bone. This benign mesenchymal tumor has characteristic
multinuclear giant cells. Mononuclear stromal cells are the
physiologically active and diagnostic cell type. Most GCTs are located
in the epiphyseal regions of long bones. The axial skeleton, primarily
the sacrum, is a secondary site of involvement. Most patients present
with pain, swelling, joint effusion, and disability in the third and
fourth decades of life. Imaging studies are important for tumor
staging and radiographic grading. Typically, these clinically active but
slow-growing tumors are confined to bone, with relatively well-
defined radiographic borders. Monostotic disease is most common.
Metastatic spread to the lungs is rare. Extended intralesional
curettage with or without adjuvant therapy is the primary treatment
choice. Local recurrence is seen in ≤20% of cases, and a second local
intralesional procedure is typically sufficient in cases that are
detected early. Medical therapies include diphosphonates and
denosumab. Denosumab has been approved for use in osteoporosis
as well as breast and prostate cancer metastatic to bone. Medical
therapy and radiotherapy can alter the management of GCT of bone,
especially in multifocal disease, local recurrences, and bulky
central/axial disease (1).
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Giant cell tumor

Over 20 years, 470 cases of GCT of bone were diagnosed at a


tertiary cancer hospital, India. Tumors measured six to 20 cm and, in
402 cases, showed "usual" histology comprising uniformly scattered
multinucleate giant cells amidst mononuclear stromal cells, together
imparting a syncitium-like appearance. The presence of osteoid,
hemorrhage, and aneurismal bone cyst-like areas; spindle cells in
sheets (devoid of giant cells); or storiform pattern and intravascular
osteoclasts were less common (2).
GCTs are rare, usually affecting the epiphyses in long bones of the
extremities. They seldom occur in the skull, where they preferentially
affect the sphenoid and temporal bones. Considered to be benign,
locally aggressive lesions may cause cranial nerve deficits by
compression and infrequently invade the dura and parenchyma of
the brain. Several case reports with follow-up describe gross total
resection of skull base GCT to be curative. Anything short of total
resection usually results in recurrence within four years. Radiation
therapy, although controversial, is reserved for lesions that cannot be
completely resected. Some argue, however, against the use of
radiation because there are reported cases of malignant
transformation. The case of a large GCT that was invaded the dura,
temporal lobe, as well as the third division of the trigeminal nerve, is
described. Gross total resection has been curative for this lesion. The
patient has not undergone radiation therapy (3).
The purpose of this research was to study incidence, clinical,
histological, and radiological features, and outcome of PMGCT. The
authors retrospectively reviewed all cases of GCT in which a diagnosis
of GCT was related to sarcoma treated between 1997 and 2004.
Three cases of PMGCT were found according to the criterion of
Hutter and Dahlin. Histological and radiological records of all the
three cases were reviewed. In these three cases of PMGCT, the initial
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clinical and radiological findings were the same as those for benign
GCT. Wide excision of the tumor was performed in all three cases. In
two cases, knee arthrodesis was performed, and in one case a
custom-made total knee replacement was performed. PMGCT was
diagnosed on initial biopsy in one patient, in the second patient it
was diagnosed in the excised specimen, and in third case it was only
diagnosed after local recurrence six months after initial treatment. All
the patients died within five months of detection of recurrence and
metastasis. PMGCT has a poor prognosis. Histological examination is
highly significant in such cases. Awareness about this entity,
adequate biopsy, and sampling of specimen can aid in early
diagnosis, which may improve the overall prognosis (4).

ASSESSMENT: GCT of bone is one type of giant cell-rich lesion of


bone. Most GCTs are located in the epiphyseal regions of long bones.
The axial skeleton, primarily the sacrum, is a secondary site of
involvement. Most patients present with pain, swelling, joint effusion,
and disability in the third and fourth decades of life.
Did the King suffer from a giant cell tumor of bone? Since the King
suffered from pain in his bones, but not in one bone the diagnosis of
giant cell tumor seems unlikely.

References
1. Raskin KA, Schwab JH, Mankin HJ, et al. Giant cell tumor of bone. J Am
Acad Orthop Surg. 2013;21(2):118-26.
2. Gupta R, Seethalakshmi V, Jambhekar NA, et al. Clinicopathologic
profile of 470 giant cell tumors of bone from a cancer hospital in western
India. Ann Diag Pathol. 2008;12:239-48.
3. Billingsley JT, Wiet RM, Petruzzelli GJ, Byrne R. A locally invasive giant
cell tumor of the skull base: case report. J Neurol Surg Rep. 2014;75(1):
e175-9.
4. Kapoor SK, Jain V, Agrawal M, et al. Primary malignant giant cell tumor
of bone: a series of three rare cases. J Surg Orthop Adv. 2007;16(2):89-92.
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L. Ben-Nun King David

LEPTOMENINGEAL CARCINOMATOSIS
Leptomeningeal carcinomatosis is a rare complication of solid
tumors, e.g., breast, lung and G-I carcinomas. Clinical manifestations
are variable with radicular pains with or without neurological
deficiencies as well as headache and hallucinations. The case of a 57-
year-old patient with urological symptoms caused by a
leptomeningeal carcinomatosis and a spinal metastasis of an
asymptomatic signet-ring cell gastric carcinoma is reported (1).
Leptomeningeal metastasis is discovered at autopsy in
approximately 5% of patients with systemic cancer. Until recently
with the introduction of MRI, premorbid diagnosis was extremely
difficult. In particular, initial CSF cytology is diagnostic in less than
50% of autopsy-verified patients, although repeated CSF
examinations may increase the yield significantly. Leptomeningeal
metastasis in metastatic prostate cancer has been reported in only 14
patients previously. A patient was studied and a correct diagnosis
was based solely on the MRI and the presence of an elevated PSA in
CSF. Only three previous patients with leptomeningeal prostate
metastasis have undergone PSA evaluations in CSF. In conclusion, in
such patients, the combination of MRI and CSF studies can overcome
the lack of sensitivity of CSF cytology (2).
Metastatic prostate carcinoma commonly involves bones and
extrapelvic lymph nodes, with occasional visceral deposits. CNS
involvement is unusual and particularly the occurrence of
leptomeningeal metastasis is extremely rare, with few cases
described in the medical literature. The clinical presentation is
characterized by multifocal neurological deficit and the prognosis is
generally dismal, with survival ranging between three and six
months. A patient affected by leptomeningeal metastasis due to
prostate cancer was treated with a combined-modality approach
consisting of sequential chemotherapy and radiotherapy. A 70-year-
old man was referred to the group for cognitive mental disorder, left-
sided frontal headache and nausea; the patient had a previous
history of metastatic prostate cancer. Leptomeningeal metastasis
was diagnosed neuroradiologically with brain MRI and evidence of a
detectable level of PSA in the CSF. He was treated with docetaxel and
prednisone for three cycles followed by EBRT to the whole brain to a
total dose of 30 Gy in 10 fractions with a simultaneous integrated
boost to the macroscopic disease (total dose of 35 Gy in 10 fractions).
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No acute toxicity was observed. A substantial clinical response was


obtained after EBRT with neurological improvement and
radiologically stable disease at post-treatment imaging until 10 weeks
after radiation. The patient died of sudden general condition
deterioration three months after EBRT. In conclusion, since
leptomeningeal metastasis derived from prostate cancer is likely to
become a more common clinical event, such patients would need to
be included in clinical trials evaluating new therapeutic approaches,
considering that the current treatment strategies are ineffective (3).

ASSESSMENT: leptomeningeal carcinomatosis is a rare


complication of solid tumors, e.g., breast, lung and G-I carcinomas.
Clinical manifestations are variable with radicular pains with or
without neurological deficiencies as well as headache and
hallucinations.
Did the King suffer from leptomeningeal carcinomatosis? In the
absence of severe headache and hallucinations, radiological
evaluation such as CT and MRI of the brain, bone scan evaluation,
and bone histopathological studies, this diagnosis seems unlikely.

References
1. Cresto N, Barth A, Arnold M, et al. Extraordinary manifestation of a
gastric carcinoma by leptomeningeal carcinomatosis and spinal metastasis.
Med Klin (Munich). 2007;102:255-8.
2. Cone LA, Koochek K, Henager HA, et al. Leptomeningeal
carcinomatosis in a patient with metastatic prostate cancer: case report and
literature review. Surg Neurol. 2006;65(4):372-5, discussion 375-6.
3. Cante D, Franco P, Sciacero P, et al. Leptomeningeal metastasis from
prostate cancer. Tumori. 2013;99(1):6e-10e.

RENAL CELL CARCINOMA


In Europe, RCC (that is neoplasia of the kidney, renal pelvis or
ureter) ranks as the seventh most common malignancy in men
amongst whom there are 29.000 new cases each year (3.5%) of all
cancers. RCC may remain clinically occult for most of its course. The
classic presentation of pain, hematuria and flank mass occurs in only
9% of patients and is often indicative of advanced disease.
Approximately 30% of patients with RCC present with metastatic
disease, 25% with locally advanced RCC and 45% with localized
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disease. Metastases are typically found in the lung, soft tissue, bone,
liver, cutaneous sites, and CNS (1).

Renal cell carcinoma

Although metastases are common in patients with RCC, it is


extremely rare for patients to present with metastatic RCC without
evidence of a primary mass in the kidney. Two cases of metastatic
RCC with no detectable primary renal mass are reported. Both
patients had bilateral native kidneys in situ and insignificant prior
urologic history. The first patient presented with a hip fracture and
had multiple radiologic bony and lung metastases. Biopsy of a mass
involving the pubic bone demonstrated clear cell metastatic RCC.
Multiple scans by CT and confirmatory imaging by MRI demonstrated
no renal mass. The first patient had disease stabilization for 18
months on sunitinib and was still alive at last follow-up. The second
patient was diagnosed with clear-cell metastatic RCC after thickened
synovium was discovered and biopsied during a knee arthroplasty.
Multiple scans by CT in this second patient demonstrated no primary
renal mass. Sunitinib and radiotherapy to the knee lesion were
initiated, but unfortunately, the patient deteriorated clinically and
passed away from disease progression shortly after diagnosis.
Because of the rare nature of these cases, a standardized course of
action has not yet been established. However, it is reasonable to
manage metastases in these patients by following established
metastatic RCC protocols (2).
Since the approval of sorafenib in December 2005, several
targeted therapeutic agents have been approved by the FDA for the
treatment of advanced RCC. This study was conducted to find out
whether the improvements in survival of advanced RCC patients with
targeted agents have translated into a survival benefit in a
population-based cohort. The SEER 18 registry database were
analyzed to calculate the relative survival rates for advanced RCC
patients during 2001-2009, 2001-2005, 2006-2007 and 2008-2009.
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L. Ben-Nun King David

The survival rates by age (<65 and ≥65 years) and sex were evaluated.
The total number of advanced RCC patients during 2001-2009, 2001-
2005, 2006-2007 and 2008-2009 were 7,047, 4,059, 1,548 and 1,440,
respectively. During 2001-2009, the one- and three-year relative
survival rates were 26.7 ± 0.6 and 10.0 ± 0.4%, respectively. There
was insignificant difference in one-year relative survival rates for
patients diagnosed during 2006-2007 and 2008-2009 compared to
those diagnosed during 2001-2005. Similarly, the three-year survival
rates for patients diagnosed during 2006-2007 were similar to those
diagnosed during 2001-2005. In conclusion, there was insignificant
improvement in relative survival rates among advanced RCC patients
in the era of targeted agents (3).
In Japan, Nagasaki, bone scan was performed at presentation in
205 patients with confirmed RCC. Overall, bone metastasis was
present in 34 (17%) patients (4).
RCC is an uncommon tumor in adults. Metastasis in the nasal
fossa is rare, and can become apparent because of repeated
epistaxis. A patient with RCC presented epistaxis secondary to a
metastasis in the right nasal fossa. The primary tumor was treated
with nephrectomy and the nasal fossa metastasis was treated
successfully with embolization, chemoimmunotherapy, surgery, and
radiotherapy. The presence of repeated epistaxis may occasionally be
the first symptom of RCC, and systemic treatment combined with
local treatment may enable adequate control the disease (5).
This study utilizes a large contemporary patient cohort to examine
patterns of RCC presentation and their clinical implications.
Retrospective analysis was performed on 721 patients (260 women,
461 men) who underwent 750 nephrectomies for treatment of RCC
between 7/1/89 and 12/31/97; 29 patients required two operations
for bilateral RCC. Median age and follow-up were 63 years and 41
months, respectively. Indicators of symptomatic presentation
included flank pain, flank mass, hematuria, varicocele, constitutional
symptoms, paraneoplastic syndromes, and bone pain related to
metastatic disease. Incidental and symptomatic presentation
occurred in 57% and 42% of cases, respectively. When compared to
incidental cases, symptomatic presentation was predominantly
detected in younger patients (mean age, 59 years, p<0.001), in males
(p<0.04), and in tumors with conventional (clear cell) histology
(p<0.001), larger size (mean, eight cm, p<0.001), and non-organ
confined pathology (p<0.001). In univariate analysis, symptomatic
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L. Ben-Nun King David

cases had a more adverse disease-free (p<0.0001) and disease-


specific (p<0.0001) survival. In multivariate analysis, mode of
presentation was an independent predictor of disease-free
(p<0.0001) and disease-specific survival (p<0.005). In conclusion,
symptomatic presentation correlates with an aggressive histology
and advanced disease. Incidental tumors may be frequently detected
in female and elderly patients, as these groups traditionally seek
general medical care more regularly. Mode of presentation can
independently predict an adverse patient outcome and should be
included in RCC-specific modeling systems (6).
The purpose of this study was to evaluate the impact of
presenting symptoms on survival in a contemporary series of patients
with RCC. Data on the presenting symptoms, pathology, and RCC-
specific survival of 633 consecutive RCC patients who underwent
surgery between 2003 and 2012 were recorded prospectively. Of 433
incidental RCCs (68%), 111 (18%) were associated with local
symptoms, and 89 (14%) with systemic symptoms. Among those with
incidental RCC, 317 patients (73%) were completely asymptomatic
and 116 patients (27%) presented with symptoms unrelated to the
tumor. During a median follow-up interval of 40 months (IQR range:
39-69 months), 77 patients died from RCC. In univariate analyses,
symptom classification was significantly associated with RCC-specific
survival (p<0.001). Patients with incidental RCC and unrelated
symptoms tended to have worse prognosis than did patients who
were completely asymptomatic, although this difference was
statistically insignificant. The symptom classification was associated
with advanced TNM stages (p<0.001) and grade (p<0.001). In
conclusion, presenting symptoms are associated with tumor
characteristics and survival. The majority of RCCs are diagnosed
incidentally in patients without any symptoms or with symptoms not
related to RCC. Patients in the latter group tend to have a worse
prognosis than do patients who are completely asymptomatic. With
the increasing number of incidentally diagnosed RCCs,
substratification of patients with incidental tumors may be
prognostically relevant (7).

ASSESSMENT: RCC is a malignant disease, which spreads to the


bones. The majority of RCCs are diagnosed incidentally in patients
without any symptoms or with symptoms unrelated to RCC.
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L. Ben-Nun King David

Indicators of symptomatic presentation include flank pain, flank


mass, hematuria, varicocele, constitutional symptoms, paraneoplastic
syndromes, and bone pain related to metastatic disease. RCC may
remain clinically occult for most of its course, and even in the advanced
stages of the disease the classical presentation of pain, hematuria and
flank mass occur in only 9% of patients. Since RCC may manifest itself
without any overt clinical symptoms, severe intractable bone pains in
the King's case may indicate RCC with metastases to the bones.

References
1. Kumar RM, Aziz T, Jamshaid H, et al. Metastatic renal cell carcinoma
without evidence of a primary renal tumour. Curr Oncol. 2014;21(3):e521-4.
2. Shah BK, Ghimire KB. Survival Trends among Patients with Advanced
Renal Cell Carcinoma in the United States. Urol Int. 2014 Aug 19. [Epub
ahead of print].
3. Corgna E, Betti M, Gatta G, et al. Renal cancer. Crit Rev Oncol
Hematol. 2007;64:247-62.
4. Koga S, Tsuda S, Nishikido M, et al. The diagnosis of bone scan in
patients with renal cell carcinoma. J Urol. 2001;166:2126-8.
5. Cobo-Dols M, Alés-Díaz I, Villar-Chamorro E, et al. Solitary metastasis
in a nasal fossa as the first manifestation of a renal carcinoma. Clin Transl
Oncol. 2006;8(4):298-300.
6. Lee CT, Katz J, Fearn PA, Russo P. Mode of presentation of renal cell
carcinoma provides prognostic information. Urol Oncol. 2002;7(4):135-40.
7. Hofbauer SL, de Martino M, Seemann C, et al. Associations between
presenting symptoms, clinicopathological parameters, and prognosis in a
contemporary series of patients with renal cell carcinoma. Korean J Urol.
2014;55(8):505-10.

PROSTATE CANCER
Prostate cancer is the second most common cancer in men and
the fifth most common cancer worldwide. In the US, it is more
common in African-American men than in Caucasian men (1).
Due to a combination of earlier detection and better treatments,
survival of adenocarcinoma of the prostate has increased
dramatically. Prostate cancer itself is associated with lower bone
density and increased fractures. This is compounded by the use of
androgen deprivation therapy, which causes dramatic falls in
circulating testosterone and estrogen, resulting in rapid falls in bone
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density, decreased muscle mass, and increased fracture rates.


Bisphosphonates prevent and reverse this bone loss, but there are no
anti-fracture data. Denosumab, a monoclonal antibody to RANKL,
increases bone density and reduces fracture rates. Prostate cancer
commonly metastasizes to bone where it can cause complications
such as fracture and pain. Both ZOL and denosumab reduce SREs.
Comparative studies would suggest that densosumab may have an
advantage over ZOL (2).

Prostate cancer

Bone metastases are often observed in patients with lung cancer,


RCC, breast cancer, MM, and prostate cancer. Bone metastases from
prostate cancer often show characteristics different from those that
originated from other organs: for instance, bone is often the only target
organ for prostate cancer metastases, and bone metastatic lesions from
prostate cancer are more osteoblastic than osteolytic. Metastatic
prostate cancer cells interact specifically with osseous tissue and this
tissue-specific interaction is a critical factor in cancer progression. An
understanding of bone metastasis in prostate cancer may lead to novel
treatments against the disease (3).
The British Association of Urological Surgeons Cancer Registry
2000 and 2001 data were used to identify the clinical features and
outcome of 33 patients with metastatic prostate carcinoma who
presented with serum PSA levels <10 ng/mL. Seventeen patients
(51%) presented with urinary symptoms and/or pelvic pain, 6% with
cachexia and 21% with bone pain. Characteristic bone metastases
were found in 81% of patients, similarly to the men with high serum
PSA levels (4).
This study was conducted to assess the value of bone scan for pre-
treatment staging of asymptomatic treatment-naïve patients with
prostate cancer. A total of 203 consecutive asymptomatic and
treatment-naïve patients with prostate cancer (age: 67.6±6.4 years)
who were referred to the department for whole body bone
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L. Ben-Nun King David

scintigraphy were enrolled in the study. Three hours after IV injection


of 20 mCi (99m)Tc-MDP, all patients underwent whole body bone
scanning using a single head gamma camera. The planar images were
supplemented with SPECT as needed for questionable abnormalities
or those having uncertain location on planar images. The mean
serum PSA levels, serum ALP and Gleason score were 42.41±37.1
ng/ml, 223.9±129.9 IU/L and 6.7±1.1, respectively. Of 203 patients,
55 cases (27.1%) had bone metastases. The univariate analysis
showed that serum PSA levels, Gleason score and ALP were
significant predictors of bone metastases. However, only serum PSA
and ALP levels were independent predictors of bone metastasis in
the multivariate logistic regression analysis. The combination of PSA
and ALP, in which patients with either elevated PSA [>20ng/ml] or
elevated ALP were considered as positive, had the best screening
value, with 98.2% sensitivity and 48.6% specificity. In conclusion,
serum ALP screening can be employed as a tool to detect the
subgroup of patients who are at high risk of bone metastases, while
having a PSA of <20ng/ml. The combination of PSA and ALP can be
used to improve predictability of bone metastasis in newly diagnosed
patients with prostate cancer, without affecting staging accuracy (5).
Prostate cancer frequently metastasizes to bone and the lesions
appear osteoblastic on radiographs. Presentation with diffuse
osteolytic bone lesions is rare. An unusual presentation of metastatic
prostate cancer with diffuse osteolytic bone lesions is described. A
65-year-old Namibian man presented with anemia,
thrombocytopenia and worsening back pains. In addition, he had
complaints of effort intolerance, palpitations, dysuria and mild
symptoms of bladder outlet obstruction. On examination he was
anemic, had a swollen tender right shoulder joint and spine
tenderness to percussion. On digital rectal examination, he had
asymmetrical enlargement of the prostate which felt nodular and
hard with diffuse firmness in some parts. His PSA was greater than
100 ng/mL and he had diffuse osteolytic lesions involving the right
humerus, and vertebral, femur and pelvic bones. His screen for MM
was negative and the prostate biopsy confirmed prostate cancer. In
conclusion, prostate cancer rarely presents with diffuse osteolytic
bone lesions and should be considered in the differential diagnosis
when evaluating male patients with osteolytic bone lesions (1).
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L. Ben-Nun King David

ASSESSMENT: prostate cancer is the second most common cancer in


men and the fifth most common cancer worldwide.
Bone is often the only target organ for prostate cancer metastases,
and bone metastatic lesions from prostate cancer are more osteoblastic
than osteolytic. Metastatic prostate cancer cells interact specifically
with osseous tissue and this tissue-specific interaction is a critical factor
in cancer progression. Prostate cancer commonly metastasizes to bone
where it can cause complications such as fracture and pain.
Was prostate carcinoma responsible for the bone metastases in
the King? The medical record of the King, that is the biblical text, did
not mention any urinary complaints. However, only 51% of patients
afflicted with prostate carcinoma may suffer from urinary symptoms
and/or pelvic pain. Thus, the absence of urinary complains cannot
point to the absence of the disease, in this case the prostate cancer.
For this reason, the diagnosis of prostate cancer is possible for King
David.

References
1. Segamwenge IL, Mgori NK, Abdallahyussuf S, et al. Cancer of the
prostate presenting with diffuse osteolytic metastatic bone lesions: a case
report. J Med Case Rep. 2012;6:425.
2. Tuck SP, Hanusch B, Walker J, Datta HK. Prostate cancer and
osteoporosis. Curr Osteoporos Rep. 2013;11(1):11-20.
3. Uemura M, Nonomura N. Bone and Calcium Abnormalities in
Malignancy. Bone metastasis from prostate cancer. Clin Calcium. 2014;
24(8):1169-75.
4. Birtle AJ, Freeman A, Masters JR, et al. Clinical features of patients
who present with metastatic prostate carcinoma and serum prostate-
specific antigen (PSA) levels < 10 ng/mL: the "PSA negative" patients.
Cancer. 2003;98(11):2362-7.
5. Moslehi M, Cheki M, Salehi-Marzijarani M, et al. Predictors of bone
metastasis in pre-treatment staging of asymptomatic treatment-naïve
patients with prostate cancer. Rev Esp Med Nucl Imagen Mol. 2013;32(5):
286-9.
6. Swierz J, Stawarz B. Bone metastasis in patients with urogenital
neoplasms. Wiad Lek. 1997;50:100-5.
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L. Ben-Nun King David

BLADDER CARCINOMA

Bladder cancer is the most frequently diagnosed cancer involving


the urinary tract and is the seventh most common cancer in the UK.
Delayed diagnosis is associated with high-grade muscle invasive
disease which has the potential to progress rapidly, metastasize and
is often fatal. Urothelial cancer (transitional cell carcinoma) is the
predominant histological subtype in Europe, where it accounts for
90% of all bladder cancers. Haematuria, which is typically
intermittent, frank, and painless and at times present throughout
micturition, is the classical and most common presentation of
bladder cancer. Irritative symptoms such as dysuria, urgency, urge
incontinence and frequency as well as obstructive symptoms can also
be experienced. Fatigue, weight loss, anorexia, renal failure,
respiratory symptoms and a suprapubic palpable mass are usually
signs of advanced or metastatic malignancy. Cigarette smokers have
up to four times the risk of bladder cancer compared with non-
smokers. Other risk factors include exposure to aniline dyes, use of
cyclophosphamide, history of pelvic radiation, exposure to chemical
carcinogens associated with certain industries, spinal cord injuries
requiring long-term indwelling catheters, type 2 DM treated with
pioglitazone, and condylomata acuminata. Frank haematuria has a
high diagnostic yield for malignancies involving the urinary tract and
initial routine tests should be directed towards identifying a variety of
potential non-malignant causes. A thorough physical examination
should be undertaken to identify evidence of bleeding diathesis and
metastatic malignancy. Suggested laboratory investigations include
full blood count, coagulation, creatinine and PSA. The diagnosis of
bladder cancer is based on urine cytology, cystoscopy and
pathological assessment of the bladder biopsy (1).
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L. Ben-Nun King David

The objective of this study was to report the clinical experience


and management of patients with SCC of the bladder, treated in the
Anglia Cancer network from 1992 to 2007, and to review published
studies, as SCC is a rare condition, accounting for <1% of all bladder
tumors, and there is no established treatment strategy for managing
these patients. Data from all patients diagnosed with SCC of the
urinary bladder between 1992 and 2007, with an emphasis on stage,
treatment and overall survival were analyzed retrospectively. Twenty
patients were identified with primary bladder SCC (male: female ratio
3:1; mean age 68 years; mean follow-up 15.8 months). Nine patients
(45%) had extensive-stage disease at diagnosis. Four patients
received best supportive care, three had a radical cystectomy, one
radical radiotherapy and six sequential chemo-radiotherapy. In all, 13
patients were treated with chemotherapy, with six receiving
cyclophosphamide, doxorubicin and vincristine, three receiving
carboplatin and etoposide, and the remainder receiving alternative
platinum-based regimens. For 12 patients with assessable disease, six
had a complete response, three a partial response and three had
progressive disease after chemotherapy. No patient received
prophylactic cranial irradiation. At the time of analysis, 14 (70%)
patients had died, with one (5%) developing brain metastasis. The
median survival was 33 months for patients receiving chemotherapy,
vs. three months with no chemotherapy. In conclusion, SCC of the
bladder tends to occur in an older population, more commonly in
men. It is an aggressive tumor with a propensity for early metastasis.
The response rate to chemotherapy is high but the overall prognosis
is poor. Brain metastases are less common than SCC of the lung and
currently the role of prophylactic cranial irradiation is unclear (2).

Bladder cancer

Haematuria clinics with same day imaging and flexible cystoscopy


are an efficient way for investigating patients with haematuria. The
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L. Ben-Nun King David

principal role of haematuria clinics with reference to bladder cancer


is to determine which patients are 'normal' and may be discharged,
and which patients are abnormal and should undergo rigid
cystoscopy. The aim of the present study was to evaluate the
diagnostic accuracy of CT urography in patients with visible
haematuria aged >40 years and to determine if CT urography has a
role for diagnosing bladder cancer. This study shows that the
optimum diagnostic strategy for investigating patients with visible
haematuria aged >40 years with infection excluded is a combined
strategy using CT urography and flexible cystoscopy. Patients positive
for bladder cancer on CT urography should be referred directly for
rigid cystoscopy and so avoid flexible cystoscopy. The number of
flexible cystoscopies required therefore may be reduced by 17%. The
diagnostic accuracy of voided urine cytology is too low to justify its
continuing use in a haematuria clinic using CT urography and flexible
cystoscopy (3).
The purpose of this study was to evaluate the metastatic pattern
of muscle-invasive bladder cancer and to correlate the findings with
the characteristics of the primary tumor. From a clinic population of
392 patients with muscle-invasive (pT2-4) bladder cancer from
January 2004 through December 2009, 150 consecutively registered
patients with pathologically proven metastatic disease were studied.
Patients were divided into two histological categories, those with
transitional cell carcinoma and those with atypical histological
features. The study group consisted of 150 patients (116 men, 77%),
34 women, 23%); median age 64 years). The transitional cell
carcinoma group consisted of 94 (63%) patients and the atypical
histological features group of 56 (37%) patients. The most common
metastatic sites were lymph nodes (104 patients, 69%), bone (71
patients, 47%), lung (55 patients, 37%), liver (39 patients, 26%), and
peritoneum (24 patients, 16%). Patients with tumors of a more
advanced T category had shorter metastasis-free intervals (p=0.001).
There was insignificant difference in the metastatic patterns of
tumors in the different T categories. Patients with atypical
histological features had a shorter median metastasis-free interval
(three months, range 0-29 months) than patients with transitional
cell carcinoma (12 months, range 0-192 months) (p=0.0001). Patients
with atypical histological features had a significantly higher incidence
of peritoneal metastasis (p<0.0002). In conclusion, lymph nodes,
bones, lung, liver, and peritoneum are the most common sites of
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L. Ben-Nun King David

metastasis from bladder cancer. Tumors in a more advanced


category and those with atypical histological features metastasize
earlier. Tumors with atypical histological features also have a higher
frequency of peritoneal metastasis (4).
A 66-year-old man with superficial bladder cancer was treated
with TURBT in October 2011. The pathological diagnosis was
urothelial carcinoma, grade 2, T1. A second TURBT was performed
one month later. The pathological diagnosis was urothelial
carcinoma, grade III, T1. He was treated with intravesical bacillus
Calmette-Guerin after TURBT. His progress was satisfactory, but a
small superficial bladder cancer was found on cystoscopy in August
2012. He was going to be treated with TURBT, but the serum ALP
level was abnormally high on preoperative evaluation. Bone
scintigraphy showed multiple bone metastases from NMIBC without
local invasion. He was started on combined chemotherapy with 1,000
mg/m2 gemcitabine on days 1, 8 and 15 and 70 mg/m2 cisplatin on
day two every four weeks. He received denosumab for multiple bone
metastases at the same time. Although he subsequently developed
severe hypocalcemia, treatment was continued, and he completed
four courses of chemotherapy. Bone scintigraphy and contrast-
enhanced CT showed reduction of the multiple bone metastases, and
ALP decreased to the normal range. It is rare for NMIBC without local
invasion to metastasize to other organs. Thus, it is necessary to
consider distant metastases in patients with NMIBC (5).

ASSESSMENT: bladder cancer is the most frequently diagnosed


cancer involving the urinary tract and is the seventh most common
cancer in the UK. Delayed diagnosis is associated with high-grade
muscle invasive disease which has the potential to progress rapidly,
metastasize and is often fatal. Risk factors include cigarette smokers,
exposure to aniline dyes; use of cyclophosphamide, history of pelvic
radiation, exposure to chemical carcinogens associated with certain
industries, spinal cord injuries requiring long-term indwelling catheters;
type 2 DM treated with pioglitazone and condylomata acuminata.
Haematuria, which is typically intermittent, frank, painless and at
times present throughout micturition, is the classical and most common
presentation of bladder cancer. Irritative symptoms such as dysuria,
urgency, urge incontinence and frequency as well as obstructive
symptoms can also be experienced. Fatigue, weight loss, anorexia, renal
384
L. Ben-Nun King David

failure, respiratory symptoms and a suprapubic palpable mass are


usually signs of advanced or metastatic malignancy.
Lymph nodes, bones, lung, liver, and peritoneum are the most
common sites of metastasis from bladder cancer.
Was bladder cancer responsible for the bone metastases in the
King? Although the King suffered from fatigue, anorexia, and weight
loss, in the absence of risk factors for this type of cancer and urinary
complains the diagnosis of bladder cancer seems unlikely.

References
1. DeSouza K, Chowdhury S, Hughes S. Prompt diagnosis key in bladder
cancer. Practitioner. 2014;258(1767):23-7, 3.
2. Mukesh M, Cook N, Hollingdale AE, et al. Small cell carcinoma of the
urinary bladder: a 15-year retrospective review of treatment and survival in
the Anglian Cancer Network. BJU Int. 2009;103(6):747-52.
3. Blick CG1, Nazir SA, Mallett S, et al. Evaluation of diagnostic strategies
for bladder cancer using computed tomography (CT) urography, flexible
cystoscopy and voided urine cytology: results for 778 patients from a
hospital haematuria clinic. BJU Int. 2012;110(1):84-94.
4. Shinagare AB, Ramaiya NH, Jagannathan JP, et al. Metastatic pattern
of bladder cancer: correlation with the characteristics of the primary tumor.
AJR Am J Roentgenol. 2011;196(1):117-22.
5. Sasaki Y, Oi H, Oyama T, Kagawa J, et al. Non-muscle invasive bladder
cancer with multiple bone metastasis without local invasion : a case report].
Hinyokika Kiyo. 2013 Oct;59(10):669-72.

METASTATIC BONE DISEASE


Metastatic bone disease develops because of the many
interactions between tumor cells and bone cells. This leads to
disruption of normal bone metabolism, with the increased osteoclast
activity seen in most, if not all, tumor types providing a rational
target for treatment. The clinical course of metastatic bone disease in
MM, breast and prostate cancers is relatively long, with patients
experiencing sequential skeletal complications over a period of
several years. These include bone pain, fractures, hypercalcaemia
and spinal cord compression, all of which may profoundly impair a
patient's QOL. EBRT and systemic endocrine and cytotoxic treatments
are the mainstay of treatment in advanced cancers. The
bisphosphonates provide an additional treatment strategy, which
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L. Ben-Nun King David

reduces both the symptoms and complications of bone involvement.


Ongoing research is aimed at trying to define the optimum route,
dose, schedule and type of bisphosphonate in metastatic bone
disease and in the prevention and treatment of osteoporosis in
cancer patients. In vitro suggestions of direct anticancer activity and
some promising clinical data in early breast cancer have resulted in
considerable interest in the possible adjuvant use of bisphosphonates
to inhibit the development of bone metastases (1).
Certain solid tumors metastasize to bone and cause osteolysis and
abnormal new bone formation. The respective phenotypes of
dysregulated bone destruction and bone formation represent two
ends of a spectrum, and most patients will have evidence of both.
The mechanisms responsible for tumor growth in bone are complex
and involve tumor stimulation of the osteoclast and the osteoblast as
well as the response of the bone microenvironment. Factors that
increase bone resorption, independent of tumor, such as sex steroid
deficiency, may contribute to this vicious cycle of tumor growth in
bone (2).
Metastatic bone disease constitutes a major clinical problem.
Skeletal complications are common and lead to significant morbidity;
patients live with metastatic bone disease for several years,
increasing the prevalence of this problem. Effective management
aims to reduce the incidence of complications and relieve symptoms,
such as severe bone pain, which adversely affects patient mobility
and QOL (3).
Bone is commonly affected in cancer. Cancer-induced bone
disease results from the primary disease, or from therapies against
the primary condition, causing bone fragility. Bone-modifying agents,
such as bisphosphonates and denosumab, are efficacious in
preventing and delaying cancer-related bone disease. With evidence-
based care pathways, guidelines assist physicians in clinical decision-
making. Of the 57 million deaths in 2008 worldwide, almost two
thirds were due to non-communicable diseases, led by C-V diseases
and cancers. Bone is a commonly affected organ in cancer, and
although the incidence of metastatic bone disease is not well defined
it is estimated that around half of patients who die from cancer in the
US each year have bone involvement. Cancer-induced bone disease
can result from the primary disease itself, either due to circulating
bone resorbing substances or metastatic bone disease, such as
commonly occurs with breast, lung and prostate cancer, or from
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L. Ben-Nun King David

therapies administered to treat the primary condition thus causing


bone loss and fractures. Treatment-induced osteoporosis may occur
in the setting of glucocorticoid therapy or estrogen deprivation
therapy, chemotherapy-induced ovarian failure and androgen
deprivation therapy. Tumor SREs include pathologic fractures, spinal
cord compression, surgery and radiotherapy to bone and may or may
not include hypercalcaemia of malignancy while skeletal complication
refers to pain and other symptoms. Some evidence demonstrates the
efficacy of various interventions including bone-modifying agents,
such as bisphosphonates and denosumab, in preventing or delaying
cancer-related bone disease. The latter includes treatment of
patients with metastatic skeletal lesions in general, adjuvant
treatment of breast and prostate cancer in particular, and the
prevention of cancer-associated bone disease. This has led to the
development of guidelines by several societies and working groups to
assist physicians in clinical decision-making, providing them with
evidence-based care pathways to prevent SREs and bone loss (4).
The presence of bone metastases predicts the presence of pain
and is the most common cause of cancer-related pain. Although bone
metastases do not involve vital organs, they may determine
deleterious effects in patients with prolonged survival. Bone
fractures, hypercalcaemia, neurological deficits, and reduced activity
associated with bone metastases result in an overall compromise in
the patient's QOL. A metastasis is a consequence of a cascade of
events including a progressive growth at the primary site,
vascularization phase, invasion, detachment, embolization, survival in
the circulation, arrest at the site of a metastasis, extravasation,
evasion of host defense and progressive growth. Once cancer cells
establish in the bone, the normal process of bone turnover is
disturbed. The different mechanisms responsible for osteoclast
activation correspond to typical radiological features showing lytic,
sclerotic or mixed metastases, according to the primary tumor. The
possible mechanisms of malignant bone pain include: the release of
chemical mediators, the increased pressure within the bone,
microfractures, the stretching of periosteum, reactive muscle spasm,
nerve root infiltration and compression of nerves by the collapse of
vertebrae. Pain is often disproportionate to the size or degree of
bone involvement (5,6).
Bone metastases produce pain because of periostal irritation,
medullar pressure, and fractures. Pain may be produced by the
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L. Ben-Nun King David

growth of tumor in a closed area richly supplied with pain receptors


(nocireceptors). Chest pain occurs when tumor of the lung or the
mediastinum invades the pleura. Certain tumors produce
characteristic types of pain. For example, back pain occurs in MM,
while shoulder pain in patients afflicted by Pancoast's tumor (7).
Bone metastases represent a devastating clinical problem in the
most frequent malignancies, especially in MM, tumors of the breast,
prostate, and lungs. The consequences include pain, which is
refractory to conventional analgesics, osteolysis that often leads to
bone-marrow compression, pathological fractures, and metabolic
disorders (8).
Were any of the above-mentioned mechanisms involved in King
David's case?

Metastatic bone disease

Biochemical bone markers, such as bone isoenzyme, form of ALP,


have been used to assess the bone formation phase of bone turnover
in health and disease. Bone markers could be valuable clinical tools
for the management of patients with metastatic bone disease.
Serum levels of BAP, along with serum levels of beta-CrossLap [type I
collagen degradation fragments (beta-CTX)] that contain the beta-
isomerized octapeptide EKAHD-beta-GGR were measured in a large
group (n=200) of patients with newly diagnosed or progressive
cancer of the prostate, breast, colon, liver and pancreas. Tumor
markers such as CEA, PSA, CA 19-9, AFP, CA 15-3 and bone marker
levels were correlated with the presence or absence of bone scan
documented metastases. Markers of biochemical bone remodeling
can be used in assessing and managing patients with malignancies
that metastasize to the bone (9).
We see that the modern approach requires performing of various
malignancy marker tests. These examinations are useful in
establishing the diagnosis of the tumor. It is understandable that
such tests were not performed in the King's case.
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L. Ben-Nun King David

References
1. Coleman RE. Metastatic bone disease: clinical features,
pathophysiology and treatment strategies. Cancer Treat Rev. 2001;7(3):165-
76.
2. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms
responsible for osteolytic and osteoblastic bone metastases. Clin Cancer
Res. 2006;12(20 Pt 2):6213s-6216s.
3. Coleman R, Heidenreich A, Bell R. Managing metastatic bone disease:
three cases studies. Semin Oncol. 2004;31(5 Suppl10):83-6.
4. Rizzoli R, Body JJ, Brandi ML, et al. International Osteoporosis
Foundation Committee of Scientific Advisors Working Group on Cancer-
Induced Bone Disease. Cancer-associated bone disease. Osteoporos Int.
2013;24(12):2929-53.
5. Mercandane S. Malignant bone pain: pathophysiology and treatment.
Pain. 1997;69:1-18.
6. Twycross RG. Management of pain in skeletal metastases. Clin Orthop
Relat Res. 1995;Mar (312):187-96.
7. Slavik E, Ivanovid S, Grujucid D. Cancer pain (classification and pain
syndromes). Acta Chi Iudosi. 2004;51:9-14.
8. Vincet S, Luis-Ravelo D, Antón I, et al. Bone metastases. An Sit Sanit
Navar. 2006'29:177-88.
9. Oremek GM, Weiss A, Sapoutzis N, Sauer-Eppel H. Diagnostic value of
bone and tumour markers in patients with malignant diseases. Anticancer
Res. 2003;23:987-90.

CLINICAL FEATURES. Skeletal metastases represent the most


common malignant bone tumor. They occur mainly in adults and
even more frequently in the elderly (1). Tumor infiltration of bones is
cited as the most common cause of cancer pain, and is most often
secondary to the primary disease in the prostate, breast, thyroid,
lung, and kidney (2,3).
The clinical features of pathologically confirmed metastatic bone
tumors were analyzed for further improvement of early diagnosis and
treatment. Clinical data of 390 patients with pathologically
confirmed metastatic bone tumors, treated from 1980 to 2003 at the
First Affiliated Hospital of Sun Yat-sen University, were reviewed to
summarize the clinical features, including disease history,
predilection sites, clinical manifestation, and imaging presentations.
Of the 390 patients, the ratio of men to women was 2.12:1; the
median age was 55.7 years, and 81.5% of the patients were over 41
years old. The primary tumors were lung cancer (21.8%), prostate
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L. Ben-Nun King David

cancer (13.1%), breast cancer (7.4%), liver cancer (6.4%), G-I cancer
(5.7%), and unknown cancers (24.6%). The common metastatic sites
were spine (47.7%), pelvis (18.2%), femur (15.4%), and rib (12.6%).
Multiple metastases occurred in 20.5% of the patients. The main
symptoms were skeletal pain (53.3%), pathologic fractures (10.3%),
dysfunction (4.9%), and paraplegia (2.1%). Primary tumor detected
before metastasis accounted for 29.7% of the patients with a median
metastatic time of 319 days, and the metastatic intervals were
uncertain in 70.3% of the patients. Osteolytic types accounted for
80.7% of the cases in radiographic patterns, followed by
osteosclerotic (10.5%) and mixed types. In conclusion, metastatic
bone tumors most frequently occur in patients older than 41 years,
and commonly originate from lung, prostate, breast, and liver.
Vertebrae, pelvis, femur, and rib are the most common sites of
metastases. The clinical manifestation is extensive and nonspecific.
Most lesions present osteolytic patterns. Metastases with unknown
origin account for 24%. In spite of complexity, the clinical features
should be mastered for early diagnosis and treatment (4).

Pathological fracture

One hundred and forty-one cases of metastatic carcinoma in bone


encountered at the People's Hospital Peking University, 1998–2004,
were retrospectively reviewed. Skeletal metastases occurred more
commonly in males (male to female ratio 1.7:1). The age of patients
ranged from 23 to 86 years (mean age 56.5). The presenting
symptoms included pain and dysfunction of the affected bones. The
locations of skeletal metastases were as follows: spine (58), pelvic
bone (46), long bone (34) and others (3). Twenty-three cases suffered
from multiple bone lesions. The primary sites were identified in 130
cases (92.2%), which included lung (37), female genital system and
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L. Ben-Nun King David

breast (25), kidney (18), G-I system (17), liver (12), thyroid (11),
prostate (7), bladder (2) and skin (1). Skeletal metastases occurred
more often in elderly males. Axial bones (spine and pelvis) were
usually affected (5).
The most common metastases in men are from prostate cancer
(60%) while in women from breast cancer (70%). Other tumors
responsible for bone metastases are: lung, kidney, thyroid, G-I,
bladder, and skin. The spine and pelvis are the most common
metastatic sites, due to the presence of red (hematopoietic active)
bone marrow in a high amount. Generally, the radiographic pattern is
lytic type; other aspects are osteosclerotic, mixed, lytic vs. mixed and
osteosclerotic vs. lytic patterns. The main symptom is pain, although
many bone metastases are asymptomatic. The most severe
consequences are pathological fractures and cord compression.
Clinical evaluation of patients with skeletal metastases needs
multimodal diagnostic imaging, able to detect lesions, to assess their
extension and location, and eventually to perform the biopsy (for
histo-morphological diagnosis). These techniques give different
performances in terms of sensitivity and specificity; but none of the
modalities alone seems to be adequate to yield a reliable diagnostic
outcome. Therefore, multidisciplinary cooperation is required to
optimize the screening, clinical management and follow-up of the
patients (6).
There were 124,655-fracture cases and 373,962 ages and gender
matched controls. An increased risk of fractures, primarily within the
first year after diagnosis occurred in patients with primary bone
cancer, MM, metastases to the bones, metastases to other organs
than bone, lung cancer, and cancer of the liver, gall bladder and
pancreas. For patients with prostate cancer an increase in the risk of
fractures occurred with time. Other cancer types were not associated
with an increased risk of fractures. A high-risk group regarding
fractures included cancers primarily affecting the bone, primary bone
cancer, MM, metastases to the bone, metastases to other organs
than bone, lung cancer, and cancer of the liver, gall bladder,
pancreas, and prostate cancer. The main increase in risk of fractures
in this group occurred within the first year following diagnosis. A low
risk group for fractures included all other cancer types (e.g. cancer of
the breast, colon, and skin) (7).
Tumor registry data were collected between 1994-1996 on 11
primary tumor sites and 15 metastatic sites from 4,399 patients.
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L. Ben-Nun King David

Three primary tumors had single, dominant metastatic sites: ovary to


abdominal cavity (91%), prostate to bone (90%), and pancreas to liver
(85%). The liver was the dominant metastatic site for G-I primary
tumors (71% of patients), whereas bone and lung metastases were
noted most frequently in non-GI primary tumors, 43% and 29%,
respectively. In a study of combinations of liver, abdominal cavity,
and bone metastases, 86% of prostate primary tumors had only bone
metastases, and 74% of pancreas primary tumors had only liver
metastases (8).
Clinical charts of 100 cancer patients (70 women and 30 men were
studied; mean age 63 years, range: 55-87). The primary lesions
responsible for bone metastases were located in the breast (51
cases), colon (30 cases), lung (seven cases), stomach (four cases), skin
(four cases), kidney (two men), pleura (one woman), and liver (one
men). The most frequent radiographic pattern was lytic type (52%),
followed by osteosclerotic, mixed, lytic vs. mixed and osteosclerotic
vs. lytic patterns. Skeletal metastases were the most common
malignant bone tumors: among these metastases, the spine and the
pelvis were the most frequent. Pain was the main symptom, even
though many bone metastases were asymptomatic. Pathological
fractures were the most severe consequences. Bone scintigraphy
remains the technique of choice in asymptomatic patients in whom
skeletal metastases are suspected. However, this technique though
very sensitive is poorly specific, and thus a negative bone scan finding
is double-checked with another physical examination: if the findings
remain negative, the diagnostic workup is over. On the contrary, in
patients with a positive bone scan or with local symptoms and pain,
radiography and CT are used for screening of metastatic lesions:
results may be negative (for low sensitivity of conventional radiology)
or questionable (in which case bone biopsy is necessary), or
symptoms may be due to the different causes than metastatic lesions
(i.e., osteoarthritis). Before bone biopsy MRI must be performed,
because it is the only technique that allows to distinguish between
bone marrow components (9).
The aim of this study was to investigate the distribution of bone
metastases in common cancers using bone scintigraphy. One
hundred and sixty consecutive patients with malignancy (prostate
cancer: 32, breast cancer: 107, lung cancer: eight, and G-I: 13)
underwent bone scan. Of the 160 patients, 58 patients (36.3%) had
abnormal bone scans attributable to metastatic tumor. Bone
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L. Ben-Nun King David

metastases were found in 32.7%, 40.6%, 38.5% and 62.5% of patients


with breast, prostate, G-I, and lung cancers, respectively (p=0.35).
The most frequently involved area was the spine, followed by ribs
and pelvic bones. Spine was the most frequent site of bone
metastases in breast and G-I cancers. Except for the spine, common
locations of bone metastases from breast cancer were ribs and
sternum. In prostate cancer, the most frequent sites were spine and
pelvis, with similar incidences. In lung cancer, ribs followed by spine
were most frequent sites of bone metastases. Of the cancer patients
studied, 97 (60.6%) had symptoms of bone pain. The highest
incidence was associated with metastatic lesions in bone scan
(p=0.004). Significant correlation between location of bone pain and
evidence of bone metastasis in the same region was noticed in the
pelvis (p=0.001), skull (p=0.04), sternum (p=0.01), spine (p=0.003)
and femur (p<0.001). In conclusion, the spine and pelvis in prostate
carcinoma and the spine, ribs and sternum in breast carcinoma as
well as ribs and spine in lung cancer are most frequently invaded.
Bone pain in the skull, sternum, lumbar vertebrae, pelvis and
proximal portion of femurs are more important to keep in mind for
metastatic bone involvement (10).

ASSESSMENT: pain is the main symptom in metastatic bone


disease, even though many bone metastases are asymptomatic;
pathological fractures are the most severe consequences. Skeletal
metastases are the most common signs of malignant bone tumors,
and the spine and the pelvis are the most frequent locations for
metastases.
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L. Ben-Nun King David

It seems likely that the King was afflicted by some neoplastic


disease, such as MM, or RCL, or prostate cancer, or gastric
carcinoma, or CRC which metastasized to the bones. Did pathological
fractures occur?
Other neoplastic diseases such as lung, stomach, HCC, pancreatic
cancer and other types, as mentioned above, were excluded from the
differential diagnostic list since it seems unlikely that they afflicted
the elderly King David.
The diagnoses of various thyroid disorders can be excluded, since
there are insufficient data to prove their existence, and it would be
very ironic if the King had been affected by carcinoma of the thyroid.
The diagnosis of breast cancer is unlikely because there are
insufficient signs to indicate the presence of this disease.
The King suffered from severe intractable bone pains, which point
towards metastatic disease. Where were the metastases located?
What was the radiographic pattern of the lesions? Osteolytic?
Osteosclerotic? Did pathological fractures occur? Did cord
compression take place?

References
1. Scutellari PN, Antinolfi G, Gaoleti R, Giganti M. Metastatic bone
disease. Strategies for imaging. Minerva Med. 2003;94:77-90.
2. Galasko CSB. Skeletal metastases. London, Butterworths. 1986; p. 99.
3. Enneking WF, Conrad EU III. Common bone tumors. Clin Sympt. 1989;
41:1.
4. Xu DL, Zhang XT, Wang GH, et al. Clinical features of pathologically
confirmed metastatic bone tumors - a report of 390 cases. Ai Zheng. 2005;
24(11):1404-7.
5. Shen DH, Guo W, Yang Y, et al. Clinicopathologic analysis of 141 cases
of metastatic carcinoma in bone. Zhonghua Bing Li Xue Zhi. 2006;35:324-7.
6. Scutellari PN, Antinolfi G, Gaoleti R, Giganti M. Metastatic bone
disease. Strategies for imaging. Minerva Med. 2003;94:77-90.
7. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk patients with
different types of cancer. Acta Oncol. 2008;4:1-11.
8. Hess KR, Varadhachary GR, Taylor SH, et al. Metastatic patterns in
adenocarcinoma. Cancer. 2006;106:1624-33.
9. Scutellary PN, Addonisio G, Righi R, Giganti M. Diagnostic imaging of
bone metastases. Radiol Med. 2000;100:429-35.
10. Kakhki VR, Anvari K, Sadeghi R, et al. Pattern and distribution of bone
metastases in common malignant tumors. Nucl Med Rev Cent East Eur.
2013;16(2):66-9.
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L. Ben-Nun King David

IN CONCLUSION: this report analyzes the most likely disease


affecting the bones of King David. The sentences “...my strength
failed..., and my bones are consumed..,” and “My bones wasted away
through my anguished roaring all day long” (Psalm 32:11, 32:3)
indicate that King David suffered from osteoporosis, which affected his
bones. Among the many diseases which could have been associated
with osteoporosis, senile osteoporosis, hyperparathyroidism, or
malignant disease can be taken into account. Of these possible
diagnoses, malignancy is the most likely. Among neoplastic diseases,
MM, or RCC, or prostate cancer, or gastric carcinoma, or CRC are the
most likely diagnoses.

HAS THIS PATIENT CANCER?


"Has this patient a cancer?" is a question we frequently ask
ourselves in front of some symptoms, signs of laboratory results like
weight loss, anemia, and high ESR. A retrospective study of the
records of 5,500 patients admitted in the Department of Internal
Medicine, Bucharest, Romania, during 1998, selecting those patients
with weight loss, anemia (Hg <10.5 g/dl) and ESR ≥50 mm/h. The
main conclusion of this study was that any patient admitted to this
department had a 4% probability of having a cancer. Among those
with weight loss, anemia and high ESR, one patient out of two had
cancer; among those with weight loss and anemia, 44% had a cancer;
and among those with weight loss and high ESR, one of three had a
cancer (1).
If the King had been admitted to the Department of Internal
Medicine, he had 4% probability of having a cancer. However if we
look at the other considerations, then a significant loss of weight
combined with anemia increases the probability of having cancer to
44%. This research reinforces the conclusion of the previous
research that some type of cancer afflicted King David (2), adding
that there is a 44% probability that he was afflicted by a neoplastic
disease (2).
Due to the lack of space, it was impossible to discuss about other
neoplastic diseases. Nevertheless, the main types of disease, which
may have afflicted the King, are presented in this research.
The contemporary diagnosis requires an extensive evaluation
including modern evaluation such as laboratory evaluation, CT, MRI,
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L. Ben-Nun King David

bone scan, G-I tract evaluation, and histopathological findings.


Although these investigations were not performed on King David, the
most likely diagnosis is based on the description given in the medical
record, that is the biblical text.
We learn that in spite of his great suffering, pain-killing
medications were not used in the King's case. By comparison,
contemporary patients who suffer from severe bone pains would
receive some medication and therefore their QOL is much better
than those of the patients in ancient times, in this case King David the
Great (3).

References
1. Băicuş C, Tănăsecu C, Ionescu R. Has this patient a cancer? The
assessment of weight loss, anemia and erythrocyte sedimentation rate as
diagnostic tests in cancer. A retrospective study in a secondary university
hospital in Romania. Rom J Intern Med. 1999;37:261-7.
2. Ben-Noun L. What was the disease of the bones that affected King
David? J Gerontol A Biol Med Sci. 2001;57(3):M152-4.
3. Ben-Nun L. In: Ben-Nun L. ed. Approach to a Patients with Severe Bone
Pain from Biblical to Contemporary Times. Israel. 2013.

THE DISEASE THAT CAUSED


WEIGHT LOSS
“My knees are weak through fasting,. my flesh failed of
fatness,...my bones cleave to my skin” (Psalm, Bible)

INTRODUCTION
Elderly patients have suffered from decrease in weight that may
be associated with various diseases for thousands of years. By
studying the causes of weight loss in geriatric persons from ancient
history, modern physicians can expand their knowledge thereby
improving their professional skills.
Who suffered from loss of weight in biblical times? What is the
most likely diagnosis? What are the characteristics of the diseases
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L. Ben-Nun King David

that caused weight loss? This report aims to answer these questions
by evaluating weight loss in geriatric patient as described in the Bible.

WEIGHT LOSS AS DESCRIBED IN THE BIBLE


King David, the second and greatest of Israel’s Kings who ruled
that country more than 3537 years ago, suffered from an eating
disorder. A passage in Psalm 102:4 “..I (the King) forget to eat my
bread” tells us about lack of food intake. This condition indicates
anorexia [from Greek, a + orexis, no appetite]. Anorexia is defined as
lack or loss of appetite, resulting in the inability to eat (1). A
subsequent passage “My knees are weak through fasting; and my
flesh failed of fatness” (Psalm 109:24) shows that David’s anorexia
led to fasting and consequently to unintentional weight loss. The
weight loss was so extreme that “....my bones (the King’s) cleave to
my skin” (Psalm 102:6). The condition is compatible with cachexia.

Reference
1. Hamerman D. Molecular-based therapeutic approaches in treatment
of anorexia of aging and cancer cachexia. J Gerontol Med Sci. 2002;57A(8):
M511-8.

CACHEXIA

The word "cachexia" comes from the Greek words "kakos" and
"hexis", meaning bad condition (1). Cachexia is a complex metabolic
status with progressive weight loss and depletion of host reserves of
adipose tissue and skeletal muscle. Cachexia should be suspected if
involuntary weight loss of greater than five percent of premorbid
weight occurs within a six-month period. Cachexia represents the
clinical consequence of a chronic, systemic inflammatory response,
with high hepatic synthesis of acute-phase proteins resulting in
depletion of essential amino acids. By contrast, in starvation only fat
metabolism is increased while the organism tries to conserve body
mass (1).
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L. Ben-Nun King David

Cachexia sometimes refers to as devastating disease,


malnutrition, or hypercatabolism has been described for centuries
and has always raised ominous thoughts that "the end is near". The
disease is encountered in many malignant and nonmalignant chronic,
and ultimately fatal illnesses. Cachexia is associated with exceedingly
high mortality once the syndrome has fully developed, irrespective of
the definition, and is associated with weakness, weight loss, muscle
wasting, and inflammation. It is not simply an ancillary event, it may
contribute to the death of the patients either through effects on
neuroendocrine and immune defense mechanisms or through
protein calorie malnutrition (2,3).
Cachexia indicates general ill health and malnutrition, marked by
weakness and emaciation, usually associated with a severe disease
such as tuberculosis or cancer (4). What was the disease responsible
for anorexia, fasting, extreme loss of weight and subsequent cachexia
in this particular geriatric patient, who was a member of the highest
socioeconomic stratum?
Cachexia is the most common paraneoplastic syndrome of
malignancy and is characterized by anorexia, early satiety, and severe
body compositional change with weight loss, adipose and muscle
loss, weakness (asthenia), anemia, and edema. Cause of death in as
many as 20% of patients with cancer is associated with tumor-
induced and treatment-related malnutrition and inanition (5).
Cancer cachexia describes a syndrome of progressive weight loss,
anorexia, and persistent erosion of host body cell mass in response to
a malignant growth. Although often associated with preterminal
patients bearing disseminated disease, cachexia may be present in
the early stages of tumor growth before any signs or symptoms of
malignancy. A decline in food intake relative to energy expenditure
(which may be increased, normal, or decreased) is the fundamental
physiologic derangement leading to cancer-associated weight loss. In
addition, abnormalities of host carbohydrate, protein, and fat
metabolism lead to continued mobilization and ineffective repletion
of host tissue, despite adequate nutritional support. Cachectin/TNF
or other host-derived cytokines (produced as a defense against
malignancy) have been implicated as signal molecules in cachexia,
based upon similar metabolic derangements produced by these
cytokines in other chronic wasting illnesses (6).
Cancer cachexia is a complex syndrome that includes host tissue
wasting, anorexia, asthenia, and abnormal host intermediary
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L. Ben-Nun King David

metabolism. It is present in approximately 50% of cancer patients


during treatment and nearly 100% of treated cancer patients at
death. The central problem of cancer cachexia is that energy balance
is not maintained, and the host has a relative hypophagia which
results in host tissue wasting (7).
The concept of cancer-related anorexia/cachexia is evolving as its
mechanisms are better understood. To support consensus processes
towards an updated definition and classification system, the
literature for items and domains associated with involuntary weight
loss in cancer was systematically reviewed. Two search strings
(cachexia, cancer) explored five databases from 1976 to 2007.
Citations, abstracts and papers were included if they were original
work, in English/German language, and explored an item to
distinguish advanced cancer patients with variable degrees of
involuntary weight loss. The items were grouped into the five
domains proposed by formal expert meetings. Of 14,344 citations,
1,275 abstracts and 585 papers reviewed, 71 papers were included
(6,325 patients; 40-50% G-I, 10-20% lung cancer). No single domain
or item could consistently distinguish cancer patients with or without
weight loss or having various degrees of weight loss. Anorexia and
decreased nutritional intake were unexpectedly weakly related with
weight loss. Explanations for this could be the imprecise
measurement methods for nutritional intake, symptom interactions,
and the importance of systemic inflammation as a catabolic drive.
Data on muscle mass and strength is scarce and the impact of
cachexia on physical and psychosocial function has not been widely
assessed. In conclusion, current data support a modular concept of
cancer cachexia with a variable combination of reduced nutritional
intake and catabolic/hyper-metabolic changes. The heterogeneity in
the literature revealed by this review underlines the importance of
an agreed definition and classification of cancer cachexia (8).
Malnutrition, anorexia and cachexia are a common finding in
cancer patients. They become more evident with tumor growth and
spread. However, the mechanisms by which they are sustained often
arise early in the history of cancer. For malnutrition, these
mechanisms can involve primary tumor or damage by specific
treatment such as anticancer therapies (surgery, chemotherapy, and
radiotherapy) also in cancers that usually are not directly responsible
for nutritional and metabolic status alterations (i.e. bone tumors). For
anorexia, meal-related neural or hormonal signals and humoral
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L. Ben-Nun King David

signals related to body fat or energy storage and the interaction of


these signals with the hypothalamus or the hypothalamic
inappropriate response play a pathogenetic role. Some cytokines are
probably involved in these mechanisms. For cachexia, the production
of proinflammatory cytokines by tumour cells is the initial
mechanism; the main biochemical mechanisms include the ubiquitine
proteasome-dependent proteolysis and heat shock proteins.
Treatment includes pharmaceutical and nutritional interventions (9).
Muscle wasting during cancer and ageing share many common
metabolic pathways and mediators. Due to the size of the population
involved, both cancer cachexia and ageing sarcopenia may represent
targets for future promising clinical investigations. Cancer cachexia is
a syndrome characterized by a marked weight loss, anorexia,
asthenia and anemia. In fact, many patients who die with advanced
cancer suffer from cachexia. The degree of cachexia is inversely
correlated with the survival time of the patient and implies a poor
prognosis. In recent years, age-related diseases and disabilities have
become a major health interest and importance. This holds
particularly for muscle wasting, also known as sarcopenia that
decreases the QOL of the geriatric population, increasing morbidity
and decreasing life expectancy. The cachectic factors (associated with
both depletion of fat stores and muscle tissues) can be divided into
two categories: of tumor origin and humoral factors (10).

ASSESSMENT: cachexia indicates general ill health and


malnutrition, marked by weakness and emaciation, usually
associated with a severe disease such as tuberculosis or cancer.
Cachexia is the most common paraneoplastic syndrome of
malignancy and is characterized by anorexia, early satiety, and severe
body compositional change with weight loss, adipose and muscle
loss, weakness (asthenia), anemia, and edema.
It seems that cachexia damaged the old King’s health and even
accelerated his death. What factors were involved in the King's
cachexia?

References
1. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763-73.
2. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002; 2:862-
71.
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L. Ben-Nun King David

3. Lainscak M, Filippatos GS, Gheorghiade M, et al. Cachexia: common,


deadly, with an urgent need for precise definition and new therapies. J
Cardiol. 2008;101(11A):8E-10E.
4. Hamerman D. Molecular-based therapeutic approaches in treatment
of anorexia of aging and cancer cachexia. J Gerontol Med Sci. 2002;57A(8):
M511-8.
5. Ottery FD. Cancer cachexia: prevention, early diagnosis, and
management. Cancer Pract. 1994;2(2):123-31.
6. Kern KA, Norton JA. Cancer cachexia. JPEN J Paenter Enter Nutr. 1988;
12:286-98.
7. Norton JA, Peacock JL, Morrison SD. Cancer cachexia. Crit Rev Oncol
Hematol. 1987;7(4):289-327.
8. Blum D, Omlin A, Baracos VE, et al. Cancer cachexia: a systematic
literature review of items and domains associated with involuntary weight
loss in cancer. Crit Rev Oncol Hematol. 2011;80(1):114-44.
9. Nicolini A, Ferrari P, Masoni MC, et al. Malnutrition, anorexia and
cachexia in cancer patients: A mini-review on pathogenesis and treatment.
Biomed Pharmacother. 2013;67(8):807-17.
10. Argilés JM, Busquets S, Felipe A, López-Soriano FJ. Muscle wasting in
cancer and ageing: cachexia versus sarcopenia. Adv Gerontol. 2006; 18:39-
54.

WEIGHT LOSS IN THE ELDERLY


Aging is generally accompanied by weight loss of both fat mass
and fat-free mass. As more people, including elderly, are overweight
or obese, weight loss improves health. Rapid UWL in elderly is usually
indicative of underlying disease and accelerates the muscle loss,
which normally occurs with aging (1).
UWL is a relatively common problem in clinical practice (2). Low
body weight and UWL predict increased morbidity and mortality,
especially in the elderly population (3-6). A retrospective review of
8,428 hospital admissions shows that underweight is a strong
predictor of in-hospital mortality in patients over 60 years of age (7).
The Framingham Heart Study demonstrates that the relative risk of
death in persons over age 65 who are at the lower extreme of BMI is
twice than that of other individual (8). Data for persons in their
seventies and eighties also suggest that higher mortality rates occur
in those with low body weights (9).
Disease-related malnutrition is highly prevalent in hospital
patients and varies from 25-40%. Early nutritional screening of
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L. Ben-Nun King David

patients at admission helps to improve recognition of malnourished


patients to allow early interventions and enhance clinical outcomes.
A total of 104 preoperative surgical patients with esophageal (34),
stomach (17) or pancreatic cancer (53) were recruited in this study.
The risk of malnutrition was examined using the quick-and-easy
Malnutrition Universal Screening Tool. Anthropometric data and
information on percent weight change over the past six months,
UWL, dietician referrals, and history of nutritional intervention were
collected. A total of 75% of participants were at high malnutrition
risk with a mean (±SD) percentage weight loss of 5.18 (±6.23)%,
despite a mean BMI of 26.09 (±5.73) kgm-2. Participants with a
significantly higher percent weight loss, UWL, dietician referral and
nutritional intervention had a higher risk of malnutrition (p<0.05).
Presence of UWL was the only significant predictor (OR 3.22, 95% CI
1.23-8.40) associated with risk of malnutrition after adjusted for all
confounders. In conclusion, these findings highlight the importance
of routine screening of malnutrition in oncology patients. Medical
personnel must be aware that UWL is an important predictor of
malnutrition risks even if the patient’s BMI is not suggestive of
malnutrition (10).
UWL in persons older than 65 years is associated with increased
morbidity and mortality. The most common etiologies are
malignancy, non-malignant G-I, and psychiatric conditions. Overall,
nonmalignant diseases are more common causes of UWL in this
population than malignancy. Medication use and polypharmacy can
interfere with taste or cause nausea and should not be overlooked.
Social factors may contribute to UWL. A readily identifiable cause is
not found in 16% to 28% of cases. Recommended tests include a
complete blood count, basic metabolic panel, liver function tests,
thyroid function tests, CRP levels, ESR, glucose, LDH, and urinalysis.
Chest radiography and fecal occult blood testing should be
performed. Abdominal ultrasonography may also be considered.
When baseline evaluation is unremarkable, a three- to six-month
observation period is justified. Treatment focuses on the underlying
cause. Nutritional supplements and flavor enhancers, and dietary
modification that takes into account patient preferences and chewing
or swallowing disabilities may be considered. Appetite stimulants
may increase weight but have serious adverse effects and no
evidence of decreased mortality (11).
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L. Ben-Nun King David

Despite the reported benefits, weight loss is not always advised


for older adults because some observational studies have related
weight loss to increased mortality. However, the distinction between
intentional and UWL is difficult to make in an observational context,
so the effect of intentional weight loss on mortality may be clarified
in the setting of a RCT. The objective was to determine the effect of
intentional weight loss on all-cause mortality by using follow-up data
from a randomized trial completed in 1995 that included a weight-
loss arm. The Trial of Non-pharmacologic Intervention in the Elderly
used a 2 × 2 factorial design to determine the effect of dietary weight
loss, sodium restriction, or both on BP control in 585 overweight or
obese older adults being treated for hypertension (mean ± SD age: 66
± 4 years; 53% female). All-cause mortality was ascertained by using
the Social Security Index and National Death Index through 2006.
The mortality rate of those who were randomly assigned to the
weight-loss intervention (n=291, mean weight loss: 4.4 kg) differ
insignificantly from that of those who were not randomly assigned to
this group (n=294, mean weight loss: 0.8 kg). The adjusted HR was
0.82 (95% CI, 0.55-1.22). In conclusion, intentional dietary weight loss
was insignificantly associated with increased all-cause mortality over
12 years of follow-up in older overweight or obese adults (12).

ASSESSMENT: rapid UWL in elderly is usually indicative of


underlying disease and accelerates the muscle loss, which normally
occurs with aging. Low body weight and UWL predict increased
morbidity and mortality, especially in the elderly population. The
most common etiologies are malignancy, non-malignant G-I, and
psychiatric conditions.
Thus, it seems that weight loss that can be considered as
unintentional was associated with a serious disease in old King and
even accelerated his death.

References
1. Miller SL, Wolfe RR. The danger of weight loss in the elderly. J Nutr
Health Aging. 2008;12:487-91.
2. Rabinovitz M, Pitlik SD, Leifer M, et al. Unintentional weight loss. A
retrospective analysis of 154 cases. Arch Intern Med. 1986;146:186-7.
3. Hardy C, Wallace C, Khansur T, et al. Nutrition, cancer and aging. An
annotated review. J Am Geriatr Soc. 1986;24:219-28.
4. Schiffman S, Pasternak M. Decreased discrimination of food odors in
the elderly. J Gerontol. 1979;34:79.
403
L. Ben-Nun King David

5. Liu LJ, Bopp MM, Roberson PK, et al. Undernutrition and risk of
mortality in elderly patients within 1 year of hospital discharge. J Gerontol
Med Sci. 2002;57A(11):M741-6.
6. Lee IB, Blair SN, Allison DB, et al. Epidemiologic data on the
relationships of caloric intake, energy balance, and weight gain over the life
span with longevity and morbidity. J Gerontol Med Sci. 2001;56A(Special
Issue SI):7-19.
7. Potter JF, Schafer DF, Bohi RL. In-hospital mortality as a function of
body mass index: an age-dependent variable. J Gerontol. 1988;43:M59-63.
8. Harris T, Cook EF, Garrison R, et al. Body mass index and mortality
among nonsmoking older persons: The Framingham Heart Study. JAMA.
1988;259:1520-4.
9. Fischer DW. Low body weight and weight loss in the aged. Am Diet
Assoc. 1990;90:1697-705.
10. Loh KW, Vriens MR, Gerritsen A, et al. Unintentional weight loss is
the most important indicator of malnutrition among surgical cancer
patients. Neth J Med. 2012;70(8):365-9.
11. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am
Fam Physician. 2014;89(9):718-22.
12. Shea MK, Nicklas BJ, Houston DK, et al. The effect of intentional
weight loss on all-cause mortality in older adults: results of a randomized
controlled weight-loss trial. Am J Clin Nutr. 2011;94(3):839-46.

PHYSIOLOGICAL ANOREXIA OF AGING


Most men reach maximum body weight in their forties and most
women in their early fifties. Beyond these ages, declining lean body
mass normally accounts for the majority of weight lost. Weight
distribution shifts from muscle mass in the extremities to fat stores in
the trunk (1). Despite the increase in body fat and obesity that
occurs with aging, there is a linear decrease in food intake over the
life span. This conundrum is explained by decreased physical activity
and altered metabolism with aging (2). Since older persons fail to
regulate food intake adequately, they develop a physiological
anorexia of aging (2,3).
Anorexia is a frequent and complex symptom occurring
physiologically in older persons and during acute and chronic
pathology (4). Energy intake is reduced in older individuals, with
several lines of evidence suggesting that both physiological
impairment of food intake regulation and non-physiological
404
L. Ben-Nun King David

mechanisms are important. Non-physiological causes of the anorexia


of aging include social (e.g. poverty, and isolation), psychological (e.g.
depression, and dementia), medical (e.g. edentulism, and dysphagia),
and pharmacological factors (5).
Healthy aging is associated with decreased appetite and energy
intake and this is generally associated with weight loss after about 70
years of age. Many sensory and social factors, including olfactory
changes and economic status, contribute to under-nutrition in older
people; however, normal ageing is associated with a number of
significant changes in G-I function. The control of appetite is complex
but it is clear that G-I signals are important in the regulation of
appetite and food intake (6).
Loss of appetite is frequently observed during ageing, termed the
'anorexia of ageing'. Ageing is associated with the inability to
appropriately increase food intake after under-eating in the short-
and long-term. Older people also report lower feelings of hunger and
increased feelings of satiety and fullness. G-I peptide hormones are a
major part of the appetite regulatory system and are released in
response to nutritional stimuli. They can be classified as: anorexigenic
(satiety) [e.g. peptide tyrosine tyrosine, glucagon-like peptide-1,
pancreatic polypeptide, oxyntomodulin and cholecystokinin] or
orexigenic (hunger) (e.g. ghrelin). Although the control of appetite is
not fully understood, these hormones play an important role, and
may influence the development and treatment of obesity and under-
nutrition. The literature shows a consistent finding that there is a loss
of appetite in those aged over 65 years, although how this loss is
mediated is not yet clear. Some evidence suggests that with
advancing age there is an increase in satiety hormones, such as
cholecystokinin and peptide tyrosine tyrosine, and a decrease in the
hunger hormone, ghrelin. However, not all studies agree,
emphasizing the need for more in-depth research to clarify age-
related changes. This knowledge will enable us to develop therapies
to help prevent under-nutrition during ageing (7).
Anorexia represents a major problem for older persons leading to
weight loss, sarcopenia, functional decline, and mortality. There is
increasing information on the pathophysiological mechanisms that
lead to anorexia. Increasing evidence has shown the importance of
G-I hormones (ghrelin, cholecystokinin, and glucagon-like peptide)
and adipokines in producing the anorexia of aging. Numerous
neurotransmitters are involved in this aging anorexia, but evidence in
405
L. Ben-Nun King David

humans is lacking. The early recognition of anorexia of aging is


important to allow intervention and prevent functional deterioration
in older persons (8).
Physiological anorexia is related to the decreased hedonic
qualities of feeding, altered hormonal and neurotransmitter
regulation of food intake (2), alterations in energy metabolism, loss
of calories in the urine or stools (1), poor absorption from the G-I
tract (9), abnormal G-I contraction and secretion, altered perceptions
of taste or smell, satiety, nausea (1,10,11), poor oral hygiene, ill-
fitting dentures (12), and aversion to specific foods because these
foods no longer seem palatable (1). As many sensory systems decline
with aging, these declines influence food choice and acceptability and
may manifest conditions such as geriatric anorexia (13).
Lack of appetite, absence of caloric intake, and altered
perceptions of taste, smell and satiety indicate physiological anorexia
of aging (14). An excessive loss of weight may point to a serious and
even fatal disease (15).

ASSESSMENT: was King David afflicted by physiological anorexia


of aging? The subsequent words “... I forget to eat my bread” (Psalm
102:4) indicate lack of appetite, absence of caloric intake, and altered
perceptions of taste, smell and satiety. All these factors can be
attributed to physiological anorexia of aging. However, the diagnosis
of physiological anorexia of aging seems unlikely in this case, because
the King’s anorexia led to fasting and subsequent cachexia. An
excessive loss of weight may point to a serious and even fatal
disease. What was the disease that caused cachexia in King David’s
case?

References
1. Reife C. Involuntary weight loss. Med Clin North Am. 1995;79:299-
313.
2. Morley J. Decreased food intake with aging. J Gerontol Med Sci.
2001;56 (Special Issue 2):81-8.
3. Roberts SB, Fuss P, Heyman MB, et al. Control of food intake in older
men. JAMA. 1994;272:1601-6.
4. Bertrand PC, Roulet M. Anorexia and malnutrition. Rev Prat.
2003;53:259-62.
5. Hays NP, Robers SB. The anorexia of aging in humans. Physiol Behav.
2006;88:257-66.
406
L. Ben-Nun King David

6. Parker BA, Chapman IM. Food intake and ageing – the role of the gut.
Mech Ageing Dev. 2004;125:859-66.
7. Moss C, Dhillo WS, Frost G, Hickson M. Gastrointestinal hormones: the
regulation of appetite and the anorexia of ageing. J Hum Nutr Diet.
2012;25(1):3-15.
8. Morley JE. Pathophysiology of the anorexia of aging. Curr Opin Clin
Nutr Metab Care. 2013;16(1):27-32.
9. Geokas MC, Haverback BJ. The aging gastrointestinal tract. Am J Surg.
1969;117:881-92.
10. Hays NP, Robers SB. The anorexia of aging in humans. Physiol Behav.
2006;88:257-66.
11. Mathey MFAM, Siebelink E, de Graaf C, et al. Flavor enhancement of
food improves dietary intake and nutritional status of elderly nursing home
residents. J Gerontol Med Sci. 2001;56A(4):M200-5.
12. Langan MJ, Yaerick ES. The effect of improved oral hygiene on taste
perception and nutrition of the elderly. J Gerontol. 1976; 31:413-8.
13. Elsner RJ. Changes in eating behavior during the aging process. Eat
Behav. 2002;3:15-43.
14. Reynish W, Andrieu S, Nourhashemi F, et al. Nutritional factors and
Alzheimer’s disease. J Gerontol Med Sci. 2001;56(11):M675-80.
15. Gazewood JD, Mehr DR. Diagnosis and management of weight loss
in the elderly. J Fam Pract. 1998;47:19-25.

PATHOLOGICAL CAUSES OF WEIGHT LOSS

Many medical conditions cause weight loss. UWL was


documented in 154 patients (2.8%) admitted to an internal medical
department during two-year period. More than one-third (36.3%)
had a neoplasm, involving preponderantly the G-I tract. Patients with
neoplasia were older and more frequently had abnormal physical
findings and significantly lower values of serum albumin as well as
higher values of ALP than other patients did. Despite extensive
investigations, UWL remained unexplained in 36 patients (23.3%)
even after prolonged follow-up periods. The remaining 62 patients
had a variety of disorders, preponderantly G-I tract (26 patients) and
psychiatric (16 patients) diseases. Endocrine disorders such as DM
and hyperthyroidism were relatively uncommon (3.8%). Thus, UWL is
relatively common problem in clinical practice (1).
407
L. Ben-Nun King David

The cause of weight loss was established in 132 (84%) patients,


Lünenberg, Germany, and remained unclear in 26 (16%). Reasons
were non-malignant (60% of patients) and malignant (24%) diseases.
Psychological disorders represented 11% of the non-malignant group.
A G-I disease caused weight loss in 50 (30%) patients. Of malignant
diseases, 53% were G-I. Amongst the non-malignant group, 39% had
somatic disorders. The prognosis for unknown causes of weight loss
was the same as for non-malignant causes. Contrary to common
belief, weight loss was not usually due to a malignant disease. A G-I
tract disorder accounted for weight loss in every third patient (2).
Weight loss of 101 patients, [age, IQR): 64 (51-71) years, 46%
male], at University Hospital Gasthuisberg, Leuven, Belgium, was
evaluated. Organic causes were found in 57 patients (56%), including
malignancy in 22 (22%). In 44 patients without obvious organic cause
for the weight loss (44%), a psychiatric disorder was implicated in 16
(16%) while no cause was established in 28 (28%), despite vigorous
effort and follow-up of at least six months (3).
In Spain, at University Hospital Marqués de Valdecilla, 328
patients were studied. There were 236 inpatients (72%) and 92
outpatients (28%). Malignancies were the most frequent cause of
UWL (35%), followed by psychiatric disorders (24%) (4).
Patients with hyperthyroidism may experience increased appetite
that leads to increased food consumption. However,
hyperthyroidism, especially in the elderly, may present without
obvious change in appetite, and anorexia as well as loss of weight
may be the predominant symptoms (5-7). Hypothyroidism may cause
weight gain. However, this disorder may also lead to anorexia and
apathy resulting in weight loss, especially in the elderly people (8).
The original Whickham Survey documented the prevalence of
thyroid disorders in a randomly selected sample of 2,779 adults,
which matched the population of Great Britain in age, sex and social
class. Outcomes in terms of morbidity and mortality were
determined for over 97% of the original sample. The mean incidence
of spontaneous hypothyroidism in women was 3.5/1000
survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for
all causes of hypothyroidism and in men 0.6/1000 survivors/year
(0.3-1.2). The mean incidence of hyperthyroidism in women was
0.8/1000 survivors/year (0.5-1.4) and was negligible in men. An
estimate of the probability of the development of hypothyroidism
and hyperthyroidism at a particular time, i.e. the hazard rate, showed
408
L. Ben-Nun King David

an increase with age in hypothyroidism but no age relation in


hyperthyroidism. The presence of goiter was not associated with any
clinical or biochemical evidence of thyroid dysfunction. Increased
values of TSH above 2 mu/l increased the probability of developing
hypothyroidism, which was further increased in the presence of anti-
thyroid antibodies (9).
We see that hypothyroidism is increasing with age. Was the King
afflicted by hypothyroidism or hyperthyroidism? We have insufficient
data to suspect the presence of hypothyroidism. The diagnosis of
hyperthyroidism as a condition that led to extreme weight loss in the
absence of appropriate physical and laboratory findings seems
unlikely. Other endocrine and metabolic diseases such as DM,
Addison’s disease, pheochromocytoma, panhypopituitarism and
hypercalcaemia (8,10) can be excluded, since there are insufficient
data to prove their existence. For the same reason, various
infections such as tuberculosis, fungal disease, amebic abscess, and
subacute bacterial endocarditis can be removed from the list (8). The
use of medications that can interfere with appetite by causing
abdominal discomfort, anorexia, nausea, diarrhea, and inhibition of
gastric emptying seems unlikely (8). Although various G-I diseases
such as peptic ulcer, gastroesophageal reflux, cholelithiasis,
inflammatory bowel disease, hepatitis, pancreatitis, gluten
enteropathy, pancreas insufficiency, Helicobacter pylori infection,
cardiac disease (CHF), respiratory diseases (end-stage lung disease,
chronic bronchitis), renal disease (uremia), connective tissue diseases
(RA, or SLE), and neurological diseases (Parkinson’s disease, or
stroke) (8,10,11) may cause anorexia and subsequent loss of weight,
there are insufficient data to prove their presence.
Malignancy is probably the most common cause of weight loss,
especially when major signs and symptoms are absent (12,6,13). The
sentences “My strength failed...and my bones are consumed” (Psalm
32:11) and “My bones wasted away through my anguished roaring all
day long” (32:3), analyzed in a previous section, indicate that King
David suffered from osteoporosis, which afflicted his bones. Among
the various diseases that may be associated with osteoporosis, the
most likely are senile osteoporosis, hyperparathyroidism, or
malignant disease, and the diagnosis of malignancy is the most
acceptable.
A combination of two factors, cachexia and intractable bone
pains, reinforces a previous conclusion that the King was indeed
409
L. Ben-Nun King David

afflicted by a neoplastic disease (14). It is most likely that the King


was affected either by MM, or by primary RCC, or prostate cancer, or
gastric carcinoma, or CRC with subsequent metastases to the bones.
Weight loss in older persons can be ascribed to one or more of
three major sets of causes: 1) social, 2) psychological, and 3) medical
(10). Social causes include poverty, functional impairment limiting
the ability to perform activities of daily living, social isolation, poor
nutritional knowledge, and institutional factors such as ethnic food
preferences, inability to tolerate other residents’ behavior, the
monotony of institutionalized food, loss of mate, fear of old age and
changing roles, feelings of rejection, all resulting in emotional stress,
strain, and deprivation (10,15,16).
Psychological causes of weight loss include depression,
bereavement, alcoholism, late-life mania, late-life paranoia, anorexia
tardive or nervosa, sociopathy, excessive life burden, cholesterol
phobia, choking phobia, and globus hystericus (10,17).
In older persons, depression is associated with anorexia and
weight loss more than in younger individuals (18).
Were social causes, as mentioned above, responsible for loss of
weight in King David’s case? Subsequent passages in Psalm 22:7,12
“..I am a worm, and not a man; a reproach of men, and despised of
the people” (Psalms 22:7) and “..trouble is near ; for there is none to
help” (6:12) indicate loneliness, social isolation and neglect by others.
It seems, therefore, that these social problems were associated with
the loss of appetite that led to subsequent loss of weight.
Was any psychological cause responsible for the King’s weight
loss? The subsequent passages “..a broken and depressed heart (the
King’s) and “I am feeble and depressed...” (Psalms 51:19; 38:9)
indicate a depressed mood. In older persons, depression is
associated with anorexia and weight loss more than in younger
individuals. Thus, depression probably also contributed to King
David’s anorexia, fasting and subsequent loss of weight. His social
problems can be associated with social isolation, loneliness, and
neglect by other people, while his psychosocial problems included his
depressed mood, see a section - Mental Disorder.

ASSESSMENT: this section analyzes the most likely diseases


associated with loss of weight in King David. The passages “... I forget
to eat my bread” (Psalm 102:4), “My knees are weak through fasting;
and my flesh failed of fatness” (109:24) and “....my bones cleave to
410
L. Ben-Nun King David

my skin”(102:6) indicate that the King suffered from anorexia, fasting,


and extreme loss of weight leading to cachexia. Multiple causes may
be responsible for weight loss in a single patient. For King David, a
combination of multivariate causes such as neoplastic, social and
psychological played a role in the development of cachexia. It is most
likely that the King was affected either by MM, or gastric cancer, or
CRC, or primary RCC, or cancer of prostate with subsequent
metastases to the bones. His social problems can be associated with
social isolation, loneliness, and neglect by other people, while his
psychological problems included his depressed mood.

References
1. Schiffman S, Pasternak M. Decreased discrimination of food odors in
the elderly. J Gerontol. 1979;34:79.
2. Lankish P, Gerzmann M, Gerzmann JF, Lehnick D. Unintentional weight
loss: diagnosis and prognosis. The first prospective follow-up study from a
secondary referral centre. J Intern Med. 2001;249:41-6.
3. Metalidis C, Knockaert DC, Bobbaers H, Vanderschueren S. Involuntary
weight loss. Does a negative baseline evaluation provide adequate
reassurance? Eur J Inten Med. 2008;19:345-9.
4. Henández JL, Matorras P, Riancho JA, González-Macías J. Involuntary
weight loss without specific symptoms: a clinical prediction score for
malignant neoplasm. QJM. 2003;86:649-55.
5. Lee IB, Blair SN, Allison DB, et al. Epidemiologic data on the
relationships of caloric intake, energy balance, and weight gain over the life
span with longevity and morbidity. J Gerontol Med Sci. 2001;56A (Special
Issue SI):7-19.
6. Morley JE, Slag MF, Elson MK, et al. The interpretation of thyroid
function tests in hospitalized patients. JAMA. 1983; 249:2377-9.
7. Foster DW. Gain and loss in weight. In: Isselbacher KJ, Braunwald E,
Winson JD, et al (eds.). Harrison’s Principles of Internal Medicine, ed. 13.
New York: McGraw-Hill. 1994, pp. 221-4.
8. Reife C. Involuntary weight loss. Med Clin North Am. 1995;79:299-
313.
9. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of
thyroid disorders in the community: a twenty-year follow-up of the
Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55-68.
10. Morley J. Decreased food intake with aging. J Gerontol Med Sci.
2001;56 (Special Issue 2):81-8.
11. L. Ben-Noun. Was the biblical King David affected by hypothermia? J
Gerontol Med Sci. 2002; 57:M364-7.
12. Rabinovitz M, Pitlik SD, Leifer M, et al. Unintentional weight loss. A
retrospective analysis of 154 cases. Arch Intern Med. 1986;146:186-7.
411
L. Ben-Nun King David

13. Martignoni ME, Kunze P, Friess H. Cancer cachexia. Mol Cancer.


2003;2:36. .
14. Ben-Noun L. The disease that caused weight loss in King David the
Great. J Gerontol A Biol Med Sci. 2004;59(2):143-5.
15. Kamath SK. Taste acuity and aging. Am J Clin Nutr. 1982;36:766-75.
16. McIintosh WA, Shifflett PA, Picou JS. Social support, stressful
events, strain, dietary intake, and the elderly. Med Care. 1989;27:140-53.
17. Morley JE. Anorexia and weight loss in older persons. J Gerontol
Med Sci. 2003; 58A(2):131-7.
18. Fitten LJ, Morley JE, Gross PL, et al. Depression. J Am Geriatr Soc.
1989;40:365-9.

THE DISEASE THAT CAUSED CHRONIC


WEAKNESS

INTRODUCTION
Patients have suffered from chronic weakness, which may be
associated with various diseases, for thousands of years. Who
suffered from this condition in biblical times? What were the
causes? What was the most likely diagnosis? This research aims to
answer these questions by evaluating diseases that caused chronic
weakness as described in the Bible.

WEAKNESS AS DESCRIBED IN THE BIBLE

King David, the second and greatest of Israel’s Kings who ruled
that country more than 3537 years ago, suffered from diminished
strength “My strength fails…, My heart palpitates, my strength fails
me” (Psalms 31:11; 38:11), “My heart fails me” (38:13), and “My
strength is dried up like a potsherd” (22:16). These passages show
that the King became very weak, and was afflicted by the loss of
energy.
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L. Ben-Nun King David

DEFINITION
Weakness is defined as a reduction in the strength of one or more
muscles (1). It may be generalized (total body weakness) or localized
to a specific area, side of the body, limb or muscle (1,2). Thus,
according to the contemporary definition, the passages mentioned
above, indicate a generalized weakness.

References
1. Aminof MJ. Weakness and paralysis. In: Fauci A, Kasper DL, Longo DL,
Braunwald E, et al. (eds). Principles of Harrison's Internal Medicine. 17th ed.
New York: McGraw-Hill. 2008, pp. 147-150.
2. Plum F. Disorders of motor function. Weakness, asthenia, and fatigue.
In: Benet JC, Plum F. (eds.). Cecil Textbook of Medicine. Saunders.
Philadelphia, London. 1991, pp. 2027-8.

GENERALIZED WEAKNESS
Since David suffered from generalized weakness, all conditions
associated with local weakness were not analyzed. Causes for
generalized weakness include electrolyte disturbances, e.g.,
hypokalemia, hypercalcemia, hypernatremia, hypophosphatemia,
hypermagnesemia, endocrine disorders such as
hypo/hyperthyroidism, Addison’s disease, muscle disorders -
channelopathies (periodic paralyses), metabolic defects of muscle
(impaired carbohydrate or fatty acid utilization; abnormal
mitochondrial function), neuromuscular junction disorders -
myasthenia gravis, Lambert-Eaton myasthenic syndrome, CNS
disorders - transient ischemic attacks, transient global ischemia,
multiple sclerosis, toxic myopathy, fibromyalgia, any infection, such
as infectious mononucleosis, flu, poliomyelitis, botulism, pneumonia,
any serious disease, such as CHF, cirrhosis, CRF, cancer, and
psychiatric conditions, especially depression (1-4).
Did any of the factors listed above play a role in the development
of David’s weakness? The previous report shows that King David
suffered from mild hypothermia (5). It seems unlikely that this
condition led to a generalized weakness. King David also suffered
from intractable bone pains due to osteoporosis. Among the various
diseases that may be associated with osteoporosis, the most likely
413
L. Ben-Nun King David

are senile osteoporosis, hyperparathyroidism, or malignant disease,


and of these causes malignant disease is the most likely (6). David
was also afflicted by anorexia, fasting and extreme weight loss that
led to cachexia (7). A combination of two factors, cachexia and
osteoporotic, intractable bone pains points towards a diagnosis of a
metastatic bone disease (6,7).
With regard to malignancy, it seems that the King was affected by
either MM, or primary RCC, or prostate cancer, or gastric carcinoma,
or CRC with subsequent metastases to the bones. In addition to
physical diseases, David suffered from various psychosocial problems
such as loneliness, social isolation and neglect by others, and
depression (7,8).

References
1. Aminof MJ. Weakness and paralysis. In: Fauci A, Kasper DL, Longo DL,
Braunwald E, et al. (eds.). Principles of Harrison's Internal Medicine. 17th
ed. New York: McGraw-Hill. 2008, pp. 147-150.
2. Plum F. Disorders of motor function. Weakness, asthenia, and fatigue.
In: Benet JC, Plum F. (eds.). Cecil Textbook of Medicine. Saunders.
Philadelphia, London. 1991, pp. 2027-8.
3. Olney RK, Aminoff MJ. Weakness, myalgias, disorders of movement
and imbalance. In: Braunwald E, Fauci AS, Kasper DL, et al. (eds.). Harrison’s
Principle of Internal Medicine. 15th ed. New York: McGraw-Hill. 2001, pp.
118-348.
4. Fietta P. Fibromyalgia: state of art. Minerva Med. 2004;95:37.
5. Ben-Noun L. Was the biblical King David affected by hypothermia? J
Gerontol Med Sci. 2002;57A:M364-7.
6. Ben-Noun L. The disease that caused weight loss in King David the
Great. J Gerontology Med Sci. 2004 59A(2):143-5.
7. Ben-Noun L. What was the disease of bones that affected King David?
J Gerontol Med Sci. 2002;57A:M152-4.
8. Ben-Noun L. Mental disorder that afflicted King David the Great. Hist
Psychiatry. 2004;15:467-76.
9. Hjermstad MJ, Fayers PM, Bjordal K, et al. Health-related quality of life
in the general Norwegian population assessed by European Organization for
Research and Treatment of Cancer Core Quality-of-Life Questionnaire: the
QLQ-C30 (+3). J Clin Oncol 1998;16:188-96.
10. Glaus A. Fatigue in patients with cancer: analysis and assessment.
Heidelberg: Springer-Verlag, 1998.
11. Cella D, Jin-shei L, Vhang C-H, et al. Fatigue in cancer patients
compared with fatigue in the general United States population. Cancer.
2002;94:528-38.
414
L. Ben-Nun King David

FATIGUE IN CANCER PATIENTS


Fatigue occurs commonly in general practice. Approximately 20%
of men and 30% of women in the general population complain of
frequent tiredness (1). Labeling it as healthy fatigue, Glaus found
that 55% of healthy individuals identified a physical sensation of
fatigue/tiredness, 21% complained of an affective sensation of
fatigue, and 24% identified cognitive fatigue (2). However, when
cancer patients experience fatigue, it is different and more extreme
than that experienced by healthy individuals (3).
Fatigue is the most common unrelieved symptom of cancer (4-7).
Fatigue, as a symptom, is a subjective sensation of weakness, lack of
energy, or tiredness (8). As a syndrome, fatigue has been defined as
an overwhelming, sustained sense of exhaustion and decreased
capacity for physical and mental work (9). Criteria for cancer-related
fatigue include diminished energy and mental capacity and increased
need to rest that is disproportionate to any recent change in activity
level and is evident nearly every day during any two-week period in
the past month (5). Fatigue presents at the time of cancer diagnosis
in approximately 50-75% of patients (10).
Many conditions that would not be considered normal in a
younger population are routinely accepted in older people as a part
of so-called "normal" aging. Among these conditions are many
chronic and debilitating conditions such as chronic pain, insomnia,
weakness, fatigue, and anemia. Anemia in the elderly is important
because it can lead to weakness, fatigue, limitations in activity, and
may increase C-V risk. Studies of the effect of erythropoietin in an
aging population support the hypothesis that anemia is associated
with pathologic factors and not with normal aging. While older
individuals admitted to hospitals are more likely to be anemic, these
same individuals have a bone marrow mass and numbers of cultured
progenitor cells that are similar to that of the younger population;
therefore, the predicted response to erythropoietin, and thus the
function of the bone marrow and cellular progenitors, is maintained.
Thus, anemia is a correctable pathologic finding in elderly people. A
number of studies have shown a strong relationship between fatigue
and anemia, but few studies investigate to what degree age is a
factor in weakness and fatigue. In a study of 375 anemic cancer
patients with a median age of 61 years, age as a covariate in multiple
linear regression analysis failed to reach significance for most
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L. Ben-Nun King David

measures of function and QOL, including measures of energy,


activities, mental health, general cancer-related QOL, and overall
QOL. Additional analysis suggests that other factors, including cancer
progression, Hg change, and baseline Hg levels, are much more
important in determining change in functional and QOL scores. In
another set of 2,000 cancer patients and 1,000 controls, cancer
patients experienced significantly more fatigue compared with
controls. There was no correlation between cancer patient age and
fatigue, while in controls the cohort aged 65 or more reported more
fatigue than did younger subjects. Finally, measurement of QOL in
the general population demonstrated, for both the Short-Form 36
and Functional Assessment of Cancer Therapy - Anemia
questionnaires, that age alone insignificantly correlated with QOL.
Chronic conditions such as fatigue and anemia are no more "normal"
in an aging population than in a general population, and all patients
with chronic conditions be adequately treated and counseled for
their condition (11).
Fatigue is one of the most common adverse effects of cancer that
might persist for years after treatment completion in otherwise
healthy survivors. Cancer-related fatigue causes disruption in all
aspects of QOL and might be a risk factor of reduced survival. The
prevalence and course of fatigue in patients with cancer have been
well characterized and there is growing understanding of the
underlying biological mechanisms. Inflammation seems to have a key
role in fatigue before, during, and after cancer-treatment. However,
there is a considerable variability in the presentation of cancer-
related fatigue, much of which is not explained by disease-related or
treatment-related characteristics, suggesting that host factors might
be important in the development and persistence of this symptom.
Indeed, longitudinal studies have identified genetic, biological,
psychosocial, and behavioral risk factors associated with cancer-
related fatigue. Although no current gold-standard treatment for
fatigue is available, a variety of intervention approaches has shown
beneficial effects in RCTs, including physical activity, psychosocial,
mind-body, and pharmacological treatments (12).
Fatigue is one of the most common and distressing side effects of
cancer and its treatment, and may persist for years after treatment
completion in otherwise healthy survivors. Guided by basic research
on neuro-immune interactions, a growing body of research has
examined the hypothesis that cancer-related fatigue is driven by
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L. Ben-Nun King David

activation of the pro-inflammatory cytokine network. In this review,


the current state of the evidence linking inflammation and cancer-
related fatigue, drawing from recent human research and from
experimental animal models probing effects of cancer and cancer
treatment on inflammation and fatigue is examined. In addition, two
key questions that are currently driving research in this area were
considered: what are the neural mechanisms of fatigue, and what are
the biological and psychological factors that influence the onset
and/or persistence of inflammation and fatigue in cancer patients
and survivors? Identification of the mechanisms driving cancer-
related fatigue and associated risk factors will facilitate the
development of targeted interventions for vulnerable patients (13).
Fatigue is a frequent symptom in tumor patients. Although the
phenomenon is well known, there is no homogenous definition.
Decreased QOL, exhaustion, fatigability, tiredness, malaise, and
asthenia are synonymous and overlapping terms used for this
syndrome. Fatigue and exhaustion are present in at least 75% of all
tumor patients. Fatigue and exhaustion are enhanced by
chemotherapy, radiation and immunotherapy as well as surgery.
Fatigue in tumor patients has many reasons and comprises physical,
mental and emotional facets. Cancer anemia, atrophy of the
skeleton muscles and cancer cachexia are the decisive factors for
exhaustion (14).
The body wasting known as cancer cachexia is a complex
syndrome characterized by progressive tissue depletion and
decreased nutrient intake that is manifested clinically as inexplicable,
recalcitrant anorexia, and inexorable host weight loss. Decreased
nutritional intake, increased metabolic expenditure and dysfunctional
metabolic processes, including hormonal and cytokine-related
abnormalities, all appear to play roles in the development of cancer
cachexia. Although this condition of advanced protein-calorie
malnutrition, sometimes is described as the cancer anorexia-cachexia
syndrome, it is not entirely understood. The syndrome appears to be
multifactorial, and is a major cause of morbidity and mortality in
cancer patients that ultimately leads to death. The pathogenesis of
cancer cachexia appears to be related to proinflammatory cytokines,
alterations in the neuroendocrine axis and tumor-derived catabolic
factors (15). Several other possible causes of cancer-related fatigue
consist of altered muscle metabolism, sleep deprivation, stress, and
depression (4,5,16-20).
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L. Ben-Nun King David

ASSESSMENT: the biblical verses “My strength fails…, My heart


palpitates, my strength fails me”, (Psalms 31:11; 38:11), “My heart
fails me” (38:13) and “My strength is dried up like a potsherd” (22:16)
indicate chronic fatigue most likely due to cancer. The following verse
“…I am in trouble, my eye is consumed with grief, my soul and my
body” (31:10) demonstrates a decreased mental capacity.
The identifiable causes for cancer-related fatigue in King’s David
case include malnutrition that led to cachexia, intractable bone pains,
persistent stress associated with various psychosocial problems, such
as loneliness, social isolation, neglect by others, and depression
(21,22). It seems unlikely that mild hypothermia was associated with
the development of cancer-related fatigue.
King David also suffered from insomnia “..All the night make I my
bed to swim; I water my couch with my tears” (Psalms 6:7). According
to DSM-IV, insomnia or hypersomnia is one of the symptoms of
depression (20). Thus, insomnia too can be related to cancer-related
fatigue, and it seems likely that in King David’s case, insomnia was
associated with depression.

References
1. Hjermstad MJ, Fayers PM, Bjordal K, et al. Health-related quality of life
in the general Norwegian population assessed by European Organization for
Research and Treatment of Cancer Core Quality-of-Life Questionnaire: the
QLQ-C30 (+3). J Clin Oncol 1998;16:188-96.
2. Glaus A. Fatigue in patients with cancer: analysis and assessment.
Heidelberg: Springer-Verlag, 1998.
3. Cella D, Jin-shei L, Vhang C-H, et al. Fatigue in cancer patients
compared with fatigue in the general United States population. Cancer.
2002;94:528-38.
4. Cella D. The functional Assessment of Cancer Therapy-Anemia (FACT-
An): a new tool for the assessment of outcomes in cancer anemia and
fatigue. Semin Hematol. 1997;34(Suppl):13-9.
5. Cella D, Peretman A, Passik S, et al. Progress toward guidelines for the
management of fatigue. Oncology 1998;12:369-77.
6. Mooney K, Ferrel B, Nail L, et al. Oncology Nursing Society research
priorities survey. Oncol Nurs Forum. 1991;18:1381-8.
7. Stetz K, Haberman M, Holcombe J, et al. 1994 Oncology Nursing
Society research priority survey. Oncol Nurs Forum. 1995;22:785-9.
8. Stone P, Richards M, Hardy J. Fatigue in patients with cancer. Eur J
Cancer. 1998;34:1670-6.
9. North American Nursing Diagnosis Association. Nursing diagnoses:
definition and classification, 1987-1998. Philadelphia: McGraw-Hill. 1996.
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10. Stasi R, Abriani L, Beccaglia P, et al. Cancer-related fatigue: evolving


concepts in evaluation and treatment. Cancer 2003;98:1786-801.
11. Aapro MS, Cella D, Zagari M. Age, anemia, and fatigue. Semin Oncol.
2002;29(3 Suppl 8):55-9.
12. Bower JE. Cancer-related fatigue-mechanisms, risk factors, and
treatments. Nat Rev Clin Oncol. 2014;11(10):597-609.
13. Bower JE, Lamkin DM. Inflammation and cancer-related fatigue:
mechanisms, contributing factors, and treatment implications. Brain Behav
Immun. 2013;30 Suppl:S48-57.
14. Zahner J. Fatigue and exhaustion in tumor patients. Etiology,
diagnosis and treatment possibilities. Med Klin (Munich). 2000 95:613-7.
15. Palesty JA, Dudrick SJ. What we have learned about cachexia in
gastrointestinal cancer. Dig Dis. 2003;21:198-213.
16. Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation
and management. Oncologist. 1999;4:1-10.
17. Irvine DM, Vincet L, Bubela N, et al. A critical appraisal of the
research literature investigating fatigue in the individual with cancer. Cancer
Nurs. 1991;14:188-99.
18. Portenoy RK, Miaskowaki C. Assessment and management of cancer-
related fatigue. In: Berger A, Portenoy RK, Weissman DE, (eds.). Principles
and Practice of Supportive Oncology. Philadelphia: Lippincott-Raven. 1998,
pp. 109-18.
19. Visser MRM, Smets ERA. Fatigue, depression and quality of life in
cancer patients: How are they related? Support Care Cancer. 1998;6:191-8.
20. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition. Washington, DC: American Psychiatric Association, 1994.
21. Ben-Noun L. The disease that caused weight loss in King David the
Great. J Gerontology Med Sci. 2004 59A(2):143-5.
22. Ben-Noun L. What was the disease of bones that affected King David? J
Gerontol Med Sci. 2002;57A:M152-4.

ANEMIA OF CHRONIC DISEASES


Anemia in elderly patients should never be regarded as a normal
physiological response to aging. The main categories of anemia in
older patients are the nutritional anemia attributed to iron
deficiency, including blood loss, folate and vitamin B12 deficiency,
ACD in patients with cancer, infections and other chronic
inflammation. A further category is the unexplained anemia due most
probably to impaired corrective mechanisms to stress in older
persons. Investigations such as a complete blood count, red cell
indices and morphology, reticulocyte count, iron parameters, vitamin
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L. Ben-Nun King David

B12 and folate will detect the underlying disease in many cases,
when anemia is classified according to red blood cell MCV. Microcytic
anemia is typically for iron deficiency, but normocytic anemia can
also be found in iron deficiency or anemia of chronic disease. Anemia
due to vitamin B12 or folate deficiency is typically macrocytic. The
treatment should aim to correct the underlying cause of disorder.
Recombinant human erythropoietin is a standard treatment of
anemia associated with CRF and tumor-associated anemia, but not in
other forms of anemia. Regular blood transfusions may be required
for elderly patients with chronic anemia (1,2).
In elderly patients, underlying causes of anemia must be
investigated and treated in a similar manner to that used in younger
adults. In addition to a thorough history and physical examination,
basic investigations such as red cell indices and morphology,
reticulocyte count, haematinic assays and occasionally bone marrow
examination, will detect the underlying pathology in most cases.
Anemia may be classified, according to red blood cell MCV, into
microcytic, macrocytic and normocytic types. Anemia with an
absolute reticulocytosis is due either to acute blood loss or
haemolysis. Other anemias, more frequently encountered in elderly
patients, are hypoproliferative, and reflect depressed marrow
production or impaired erythroid maturation. Examples include ACD
and IDA and, less commonly, megaloblastic anemia and anemia due
to primary bone marrow failure. The treatment of anemia should aim
to correct the underlying cause of the disorder and/or to improve the
quality of the blood, e.g. by haematinic replacement therapy.
Recombinant human erythropoietin has revolutionised the treatment
of anemia associated with CRF, while its role in other anemias is
currently under investigation. Regular blood transfusion may be
required for some elderly patients with chronic anemia. However,
the attendant risks of this procedure, such as iron overload and viral
hepatitis transmission, must be considered (2).
Anemia is a frequent finding in the elderly. Hypochromic
microcytic anemia, usually secondary to iron deficiency, is the most
common type. Macrocytic anemia, usually caused by folic acid or
vitamin B12 deficiency, is the next most common. Both iron and
vitamin B deficiencies are easy to treat with supplements, but the
clinician must make a careful search for the cause of the deficiency.
Normochromic normocytic anemia can be caused by a number of
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conditions. The only effective treatment is arrest or cure of the


underlying disorder (3).
Anemia should not be accepted as an inevitable consequence of
aging. A cause is found in approximately 80 percent of elderly
patients. The most common causes of anemia in the elderly are
chronic disease and iron deficiency. Vitamin B12 deficiency, folate
deficiency, G-I bleeding and myelodysplastic syndrome are among
other causes of anemia in the elderly. Serum ferritin is the most
useful test to differentiate IDA from ACD. Not all cases of vitamin B12
deficiency can be identified by low serum levels. The serum
methylmalonic acid level may be useful for diagnosis of vitamin B12
deficiency. Vitamin B12 deficiency is effectively treated with oral
vitamin B12 supplementation. Folate deficiency is treated with 1 mg
of folic acid daily (4).
The aim of the present study was to investigate whether
comorbidities as an additional explanation for the severity of the
anemia are frequent, and might help to explain the anemia severity
in older patients with IDA and the ACD. In the present prospective
study, 191 consecutive hospitalized older patients with IDA and the
ACD were investigated. A peripheral blood count, CRP, standard iron
parameters, serum vitamin B12 and folate, and renal and thyroidal
function tests were analyzed. The attending geriatrician was
responsible for the medical diagnosis and follow up. Of 56 patients
with IDA and 135 with the ACD, 24 patients with IDA had normal
serum folate, vitamin B12 and TSH levels without laboratory evidence
of inflammation or CRF, and one of these patients was diagnosed
with hemolytic anemia. Hence, 23 patients (41%) were diagnosed
with "IDA only". "ACD only" was diagnosed in 104 patients (77%), and
22 patients (16%) with ACD had CRF. A myelodysplastic syndrome
was found in two patients. In conclusion, additional etiologies are
often diagnosed in anemic older patients, but it remains unknown to
what extent these diseases might influence the pathogenesis of the
anemia. Individual and clinical judgment remain crucial to evaluating
and treating older anemic patients (5).

ASSESSMENT: anemia in elderly patients should never be


regarded as a normal physiological response to aging. The main
categories of anemia in older patients are the nutritional anemia
attributed to iron deficiency, including blood loss, folate and vitamin
421
L. Ben-Nun King David

B12 deficiency, ACD in patients with cancer, infections and other


chronic inflammation.
The words “My heart palpitates, my strength fails me” (Psalms
38:11) indicate tachycardia, most probably sinus tachycardia, while
the words "… my strength fails me" indicate fatigue. These two
symptoms – tachycardia and fatigue point anemia. It follows, that
the King suffered from ACD.
What was the disease that caused anemia in the King?

References
1. Ebnöther M. Anemia in the elderly - a diagnostic and therapeutic
challenge? Ther Umsch. 2010;67(5):257-63.
2. Murphy PT, Hutchinson RM. Identification and treatment of anaemia
in older patients. Drugs Aging. 1994;4(2):113-27.
3. Howe RB. Anemia in the elderly. Common causes and suggested
diagnostic approach. Postgrad Med. 1983;73(4):153-60.
4. Smith DL. Anemia in the elderly. Am Fam Physician. 2000;62(7):1565-
72.
5. Joosten E, Lioen P. Iron deficiency anemia and anemia of chronic
disease in geriatric hospitalized patients: How frequent are comorbidities as
an additional explanation for the anemia? Geriatr Gerontol Int. 2014 Sep 26.

CANCER-RELATED ANEMIA. One of many causes of cancer-related


fatigue is the anemia that accompanies the disease, or the ACD (1).
Anemia is a decrease in circulating red blood cells that contributes to
a complex group of symptoms. Anemia may be present in more than
half of all patients with cancer but often is assessed, documented,
prevented, and treated inadequately. Individuals with cancer are
living longer, and the number of cancer treatment options provided
at various points in the cancer continuum is growing; however, many
treatments contribute to anemia. Because anemia can develop from
multiple causes, treatment must be tailored to the underlying
etiology. Cancer-related anemia can significantly affect therapeutic
outcomes and patients' QOL (2).
This study aimed to evaluate cancer-related anemia prevalence of
in a large cohort of cancer patients and whether inflammation and
malnutrition were predictive of its development and severity. The
present study included 888 patients with cancer at different sites
between May 2011 and January 2014. Patients were assessed at
diagnosis before any cancer treatment. The prevalence of anemia
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L. Ben-Nun King David

according to the main clinical factors (tumor site, stage and


performance status) was analyzed. In each patient markers of
inflammation, iron metabolism, malnutrition and oxidative stress as
well as the modified Glasgow Prognostic Score, a combined index of
malnutrition and inflammation, were assessed and their role in
predicting Hg level was evaluated. The percentage of anemic patients
was 63% with the lowest Hg levels in the most advanced cancer and
compromised performance status. Hg differed by tumor site and was
lowest in ovarian cancer patients. Hg negatively correlated with
inflammatory markers, hepcidin, ferritin, erythropoietin and reactive
oxygen species, and positively correlated with leptin, albumin,
cholesterol and antioxidant enzymes. In multivariate analysis, stage,
IL-6 and leptin were independent predictors of Hg. Hg was inversely
dependent on modified Glasgow Prognostic Score. In conclusion,
cancer-related anemia is a multifactorial problem with immune,
nutritional and metabolic components that affect its severity. Only a
detailed assessment of cancer-related anemia pathogenesis may
enable clinicians to provide a safe and effective individualized
treatment (3).
Anemia that is common in patients with cancer is often under-
diagnosed and under-treated. Fatigue is frequently associated with
cancer-related anemia and has a significant impact on patients' QOL.
Many patients regard the treatment of fatigue as more important
than the treatment of pain, in contrast with the opinions of many
physicians. Accurate assessment of anemia and fatigue is essential to
understand the reality of living with cancer-related anemia and to
provide optimal treatment (4).
Symptoms associated with anemia include fatigue, loss of
stamina, breathlessness, and tachycardia, particularly associated with
physical exertion, and depend on age of the patient and the
adequacy of blood supply to critical organs (5).
A large European survey of cancer patients (n=15,367) reported
that 67% had anemia at some point during the survey, and 60% of
these patients did not receive any treatment for anemia. Two other
surveys (the FATIGUE surveys) showed that over 75% of cancer
patients experienced fatigue at least monthly, with over 30%
reporting this symptom on a daily basis. Significantly more patients
regarded fatigue as having a greater negative impact on their daily
lives than many other cancer- or treatment-related complications,
with important emotional and mental consequences including lack of
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self-motivation, sadness, frustration, and mental exhaustion. Indeed,


fatigue was so debilitating that 12% of patients felt their QOL was so
reduced that they did not wish to continue living. Anemia is also an
independent predictor of poor prognosis in cancer patients. A
systematic review evaluating survival showed a 65% overall increase
in the risk of mortality in cancer patients with anemia (6).
Anemia in cancer-related fatigue can be defined as mild – Hg level
between 10.00-11.99 g/dL, moderate (8.00-9.90 g/dL), and severe
(<8.00 g/dL). Severity of anemia, using standard criteria for mild,
moderate and severe anemia, is associated with the degree of
reported fatigue among the anemic cancer patients (7).
As previously noted the King most likely suffered from malignant
disease. Among neoplastic diseases, MM, or RCC, or prostate cancer,
or gastric cancer, or CRC are the most likely diagnoses.
What level did the King’s anemia reach? The words “My heart fails
me” (Psalms 38:13) are compatible with a severe condition, in which
the C-V system has failed. This situation indicates severe anemia.

ASSESSMENT: older people have suffered from weakness,


associated with various diseases, since the dawn of history. This
research is unique in character, as it combines present-day
knowledge with the presentation of a case taken from ancient
history. The main aim of this research was to analyze from a modern
perspective the biblical description of a geriatric patient who suffered
from weakness. Biblical texts associated with the aged were
examined and passages relating to geriatric patient who suffered
from weakness were closely studied. Passages “My strength fails…,
My heart palpitates, my strength fails me,….My heart fails me,
(Psalms 31:11; 38:11) and My strength is dried up like a potsherd”
(22:16) indicate generalized weakness. Among the numerous causes
associated with generalized weakness, cancer related fatigue,
intractable bone pain, malnutrition leading to cachexia, severe ACD,
psychosocial problems associated with loneliness, social isolation,
and neglect by others, and depression are the most likely.

References
1. Cella D, Jin-shei L, Vhang C-H, et al. Fatigue in cancer patients
compared with fatigue in the general United States population. Cancer.
2002;94:528-38.
2. Hurter B, Bush NJ. Cancer-related anemia: clinical review and
management update. Clin J Oncol Nurs. 2007;11:349-59.
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L. Ben-Nun King David

3. Maccio' A, Madeddu C, Gramignano G, et al. The role of inflammation,


iron, and nutritional status in cancer-related anemia: results of a large
prospective observational study. Haematologica. 2014 Sep 19. pii:
haematol.2014.112813. [Epub ahead of print]
4. Fubert J. Cancer-related anemia and fatigue: assessment and
treatment. Nurs Stand. 2006;20:50-7.
5. Adamson JW, Longo DL. Anemia and polycythemia. In: Braunwald E,
Fauci AS, Kasper DL, et al. (ed.). Harrison’s Principles of Internal Medicine.
15th ed. 2001. New York: McGraw-Hill. 2001, pp. 348-51.
6. Harper P, Littlewood T. Anaemia of cancer: impact on patient fatigue
and long-term outcome. Oncology. 2005;69 Suppl 2:2-7.
7. Cella D, Jin-shei L, Vhang C-H, et al. Fatigue in cancer patients
compared with fatigue in the general United States population. Cancer.
2002;94:528-38.

HYPOTHERMIA
INTRODUCTION
Elderly patients have suffered from hypothermia for thousands of
years. It is defined as a core (rectal, esophageal, tympanic) body
temperature equal to or less than 350 C (950 F) (1-5).
The causes of hypothermia are either primary or secondary.
Primary, or accidental, hypothermia occurs in healthy individuals with
inadequately clothing and who are exposed to severe cooling (6).
The term accidental hypothermia is used to imply that the low body
temperature is unintentional (7), environmentally induced, and
distinguished from hypothermia that develops secondary to medical
conditions or surgical treatment (2,4,7-9). Who was the person who
suffered from hypothermia as described in the Bible? What were the
characteristics of this hypothermia? This report aims to evaluate this
subject using the biblical description of hypothermia.

References
1. Editorials. Hypothermia. Ann Intern Med. 1978;89:565-7.
2. Reuler JB. Hypothermia: pathophysiology, clinical settings, and
management. Ann Intern Med. 1978 89:519-27.
3. Davidson M, Grant E. Accidental hypothermia. A community hospital
perspective. Postgraduate Med. 1981;70: 42-9.
425
L. Ben-Nun King David

4. Besdine RW. Accidental hypothermia: the body’s energy crisis.


Geriatrics. 1979;34:51-9.
5. Christensen C. Hypothermia. Physiology, clinical picture and
treatment. Ugerskr Laeger. 1990;152:2295-9.
rd
6. Long WB 3 , Edlich RF, Winters KL, Britt LD. Cold injuries. J Long Term
Eff Med Implants. 2005;15:67-78.
7. Exton-Smith AN. Accidental hypothermia. BMJ. 1973;4:727-9.
8. Petersdorf RG. Hypothermia. Editorials. Arch Intern Med. 1979;
139:399.
9. Thompson MK. The care of the older patient in winter. Practitioner.
1979;223:787-91.

HYPOTHERMIA AS DESCRIBED IN THE BIBLE


King David, the second and greatest of Israel’s Kings, who ruled
the country more than 3537 years ago, was about 70 years old
“David was thirty years old when he began to reign, and he reigned
forty years” (II Samuel 5:4). When the King reached old age, he
suffered from a low body temperature “Now king David was old and
stricken in years, and covered him with clothes, but he gained no
warmth” (I Kings 1:1). Thus, David’s servants summoned Abishag to
warm the King “...let her cherish him, and let her lie in thy bosom,
that my lord the king get heat” (1:2). Do these words indicate
hypothermia? According to the biblical text, King David was a very
old man. Although the King was covered with clothes, his body
gained no warmth. Therefore, the King’s body temperature was
lower than normally accepted, that is, equal to or even less than 950
F. Thus, it is clearly stated that the King was suffering from
hypothermia.

ABNORMAL PHYSIOLOGIC MECHANISMS


Man adapts to cold in a variety of ways: vasoconstriction reduces
peripheral blood flow and maintains the temperature of the body
core, shivering increases heat production, and modification of
behavioral patterns results in better tolerance of abnormally low
temperatures (1). When these mechanisms fail, hypothermia
develops (2,3). Its symptoms include impairment of increased heat
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L. Ben-Nun King David

production and decreased heat loss (4), impaired recognition of


decreased temperature allowing patients to tolerate cold conditions
without discomfort (5), decreased activity of the autonomous
nervous system, decreased resting peripheral blood flow, decreased
vasoconstriction, decreased ability to alter respiratory response to
changes in environmental temperature, decreased mobility,
decreased muscle mass, and decreased or absent shivering (2).
Severe cold affects all organ systems and especially the central
nervous and C-V systems; many biochemical reactions and pathways
become distorted or slowed at low body core temperatures (6).

ASSESSMENT: did any of the mechanisms, mentioned above, play


a role in the old King’s hypothermia? This question remains open,
since there are insufficient documented data to evaluate it.

References
1. Petersdorf RG. Hypothermia. Editorials. Arch Intern Med. 1979;
139:399.
2. Navari RM, Sheehy TW. Hypothermia. In: Calkins E, Davis PJ, Ford AB
(eds.). The Practice of Geriatrics. Philadelphia, PA: W.B. Saunders. 1986, pp.
291-301.
3. Collins KJ, Exton-Smith AN, Dore K. Urban hypothermia: preferred
temperature and thermal perception in old age. BMJ. 1981;282:175-7.
4. MacMillan AL, Corbett JL, Johnson RH, et al. Temperature regulation in
survivors of accidental hypothermia of the elderly. Lancet. 1967;2:165-69.
5. Thompson MK. The care of the older patient in winter. Practitioner.
1979;223:787-91.
6. Sallis R, Chassay CM. Recognizing and treating common cold-induced
injury in outdoor sports. Med Sci Sports Exerc. 1999;31:1367-73.

TYPES OF HYPOTHERMIA
Etiologically, there are three types of hypothermia: immersion,
exhaustion, and subclinical (1). Immersion or accidental hypothermia
may result from exposure to prolonged or extreme cold from
immersion or atmospheric conditions that lead to a body heat deficit
and a fall in the core temperature to 950 F (2). Mountain climbers
inadequately clothed in cold weather and long distance swimmers
exposed to hot and cold waters are prone to this type of hypothermia
(1). Exhaustion hypothermia results from depletion of the body’s
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L. Ben-Nun King David

readily available energy sources. It occurs in long distance runners,


miners, steel workers, manual laborers, and so on. Subclinical
hypothermia is usually found in the elderly, resulting from an
impairment of their temperature-regulating center. Often, older
patients are unable to adjust their body temperatures readily to
extremes. They may have consistently low core body temperatures
due to impaired ambient temperature perception, impaired capacity
to shiver, decreased total body water, and inability to conserve heat
by vasoconstriction (3,1).

ASSESSMENT: how can King David’s hypothermia be classified?


Obviously, the King was not a mountain climber, nor a long distance
swimmer, nor a runner, nor a manual laborer. Thus, immersion and
exhaustion hypothermia can be excluded. Because the King
represents the elderly person, it is most likely that he suffered from
subclinical hypothermia.

References
1. Lloyd L. Treatment of accidental hypothermia. BMJ. 1979;1:413.
2. Birrer R, Wilkerson LA. Sports injuries. Cold injuries. In: Rakel R (ed.).
Textbook of Family Practice. 3rd ed. Philadelphia, PA: W.B. Saunders. 1984,
pp. 689-91.
3. Navari RM, Sheehy TW. Hypothermia. In: Calkins E, Davis PJ, Ford AB
(eds.). The Practice of Geriatrics. Philadelphia, PA: W.B. Saunders. 1986, pp.
291- 301.

ENVIRONMENTAL HYPOTHERMIA
A variety of environmental factors such as poor heating facilities,
particularly during winter, a lack of indoor plumbing, living alone, and
being housebound contribute to hypothermia (1-4). Fox et al. (5),
however, were unable to correlate any environmental factors with
low body temperatures in the elderly. Similarly, Davidson and Grant
show that accidental hypothermia was not confined to the elderly
people, nor it was a winter phenomenon. They found that the
eventual outcome was determined more by the underlying medical
condition than by the severity of hypothermia (6).
Exposure to cold can produce a variety of injuries that occur
because of man's inability to adapt to cold. These injuries can be
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L. Ben-Nun King David

divided into localized injury to a body part, systemic hypothermia, or


a combination of both. Body temperature may fall because of heat
loss by radiation, evaporation, conduction, and convection (7).
Did any of the environmental factors play a role in the
development of King David’s hypothermia? Because the King did not
belong to the lower socioeconomic strata, hypothermia related to
poor housing seems very unlikely. Apparently, the King’s house was
not poor heated. Thus, this type of hypothermia seems unlikely.
More than 650 deaths from hypothermia occur each year in the
United States. Even minor deviation from normal temperature leads
to important symptoms and disability. The most significant risk
factors are advanced age, mental impairment, substance use, and
injury (8).
This retrospective study (1995-2995) conducted in a 1200-bed
tertiary care hospital in southern Israel examined patients' data and
weather conditions (including mean day and low temperatures,
humidity, wind velocity and precipitation) within 48 hours before
admission. Patients (n=169) with hypothermia were admitted. The
mean highest environmental temperature over 48 hours before
admission was 15.3 degrees C in the severe hypothermia nine cases,
5.3%), 21.4 degrees C in the moderate (40 cases, 23.7%), and 29.3 C
in the mild group (120 cases, 71%). Major medical conditions
associated with decreased body temperature were sepsis (65,
38.5%), trauma (34, 30.1%), endocrine disorders (19, 11.2%), and
substance abuse (15, 8.8%). The inhospital mortality rate was 47.3%.
A risk score based on five admission variables - age ≥70 years, mean
arterial BP<90 mm Hg, pH <7.35, creatinine >1.5 mg/dL, and
confusion was generated, predicting inhospital mortality with the
aROCs of 0.8. A prognostication system based upon clinical and
laboratory variables may identify hypothermic patients with
increased risk of death (9).

ASSESSMENT: we see that hypothermia is a significant public


health problem and even may cause death. Did King David suffer
from sepsis, trauma, some endocrine disorder, or substance abuse?
In the absence of appropriate anamnestic, physical, and laboratory
findings, these diagnoses seem unlikely.
429
L. Ben-Nun King David

References
1. Salvosa CB, Payne PR, Wheeler BF. Environmental conditions and body
temperatures of elderly women living alone or in local authority homes.
BMJ. 1971;4:656-9.
2. Emslie-Smith D. Accidental hypothermia: a common condition with a
pathognomonic electrocardiogram. Lancet. 1958;2:492.
3. Duguid H, Simpson RG, Stowers JM. Accidental hypothermia. Lancet.
1961;2:1214-9.
4. Society and Medical Officers of Health. A pilot survey into the
occurrence of hypothermia in elderly people living at home. Public Health.
1968;82:223.
5. Fox RH, Woodward PM, Exton-Smith AN, et al. Body temperature in
the elderly: A national study of physiological, social and environmental
conditions. BMJ. 1973;1:200-3.
6. Davidson M, Grant E. Accidental hypothermia. A community hospital
perspective. Postgraduate Med. 1981;70:42-9.
rd
7. Long WB 3 , Edlich RF, Winters KL, Britt LD. Cold injuries. J Long Term
Eff Med Implants. 2005;15:67-78.
8. Jurkovitz GJ. Environmental cold-induced injury. Surg Clin North Am.
2007;87:247-67, viii.
9. Elbaz G, Etzion O, Delgado J, et al. Hypothermia in a desert climate:
severity score and mortality prediction. Am J Emerg Med. 2008; 26:683-8.

URBAN HYPOTHERMIA
Urban hypothermia is characterized by a poor temperature
discrimination and lack of precision in adjusting the thermal
environment (1). In Zagreb, University Hospital Rebro, Croatia, 18
elderly patients, 11 women and seven men, aged 66-87 years, were
afflicted by urban hypothermia. Ten patients suffered from moderate
hypothermia (rectal temperature 32-35 degrees C), and eight from
severe hypothermia (rectal temperature <32 degrees C). In the group
of patients suffering from moderate hypothermia, three were
somnolent and six in various degrees of comatose states. In the
group of patients with severe hypothermia, three patients were
somnolent or stuporous and five were in comatose states of various
degrees. In the group with severe hypothermia, three presented with
arterial hypotension and five were in a state of shock (2).
430
L. Ben-Nun King David

ASSESSMENT: did the King suffer from urban hypothermia?


Apparently, the King's house was not poorly heated. Thus, the
question arises of whether he suffered from poor temperature
discrimination and lack of precision in adjusting to his thermal
environment?

References
1. Collins KJ, Exton-Smith AN, Dore K. Urban hypothermia: preferred
temperature and thermal perception in old age. BMJ. 1981;282:175-7.
2. Durakovid Z, Misigoj-Durakvid M, Corovid N, Cubrilo-Turek M. Urban
hypothermia and hyperglycemia in the elderly. Coll Antropol. 2000;24:405-
9.

CLINICAL STAGES

In mild hypothermia or the responsive stage, body temperatures


range between 32.20C and 350C (90 to 95 F) (1,2). Patients tend to
generate and retain body heat, hence the term “responsive” phase.
The body’s metabolic rate, BP (3), cardiac rate, cardiac output, and
respiratory rate increase. The patient shivers unless this response is
lost because of aging. Cutaneous vasoconstriction occurs and
renders the skin pale and cold to the touch. Diuresis ensues as
vasoconstriction increases the volume of the central circulation. In
moderate hypothermia or the slowing phase, body temperature
reaches 32.10C to 240C. The ability to generate heat is seriously
impaired. Muscles tend to stiffen and shivering decreases. The
respiratory rate declines, hypoventilation, hypotension, arrhythmia,
and CNS dysfunction such as disorientation, confusion and
hallucinations occur, pupils dilate; and coma may develop (4,2,5).
The lower the body temperature, the more likely the victim is to
become unconscious (6,7). Severe hypothermia or the poikilothermic
phase occurs when body temperature is below 240C (75 F). At this
stage a rigor mortis-like appearance is evident, and patients have
been mistaken for dead (1,7,2). Finally, death may occur (7).
According to the Swiss hypothermia clinical staging, patients with
stage III are unconscious with preserved vital signs, with core
temperature usually between 24° and 28°C. With stage IV, vital signs
are absent with core temperature <24°C. The aim of this study was to
431
L. Ben-Nun King David

describe a patient presenting with hypothermia stage III with vital


signs but a core temperature of <24°C, and to search for similar
patients in the medical literature. MEDLINE was used to search for
cases of deep accidental hypothermia (<24°C) and preserved vital
signs. Twenty two cases were found in addition to this case (n=23).
Median age was 44 years (IQR 36, range 4-83) and median core
temperature was 22°C (IQR 1.7, 17-23.8). Vital signs were often
minimal. Seven patients developed VF. Twenty patients survived with
excellent neurological outcome. In conclusion, vital signs can be
present in hypothermic patients with core temperature <24°C. In
deeply hypothermic patients, a careful check and prolonged check of
vital functions should be made, as vital signs may be minimal. The
clinical Swiss staging remains valuable in the prehospital evaluation
of hypothermic patients; its correlation with core temperature
should be better defined (8).

ASSESSMENT: what stage did King David’s hypothermia reach?


The King was not warmed in spite of covering with clothing, but he
was warmed by Avishag’s body heat. Because other signs of
hypothermia did not develop, it is most likely that King’s hypothermia
reached a mild stage. The absence of shivering can be explained by
an impaired thermoregulation mechanism due to the King’s
advanced age. Although absence of shivering may also indicate
moderate or even severe hypothermia, the occurrence of these two
stages is unlikely.

References
1. Davidson M, Grant E. Accidental hypothermia. A community hospital
perspective. Postgraduate Med. 1981;70: 42-9.
2. Navari RM, Sheehy TW. Hypothermia. In: Calkins E, Davis PJ, Ford AB
(eds.). The Practice of Geriatrics. Philadelphia, PA: W.B. Saunders. 1986, pp.
291-301.
3. Fox RH, Woodward PM, Exton-Smith AN, et al. Body temperature in
the elderly: A national study of physiological, social and environmental
conditions. BMJ. 1973;1:200-3.
4. Petersdorf RG. Hypothermia. Editorials. Arch Intern Med. 1979;
139:399.
5. Collins KJ. Effects of cold on old people. Brit J Hosp Med. 1987;38: 506-
14.
6. Editorials. Hypothermia. Ann Intern Med. 1978;89:565-7.
7. Besdine RW. Accidental hypothermia: the body’s energy crisis.
Geriatrics. 1979;34:51-9.
432
L. Ben-Nun King David

8. Pasquier M, Zurron N, Weith B, et al. Deep accidental hypothermia


with core temperature below 24°C presenting with vital signs. High Alt Med
Biol. 2014;15(1):58-63.

ADDITIONAL SIGNS

Hypothermia should be suspected if any of these signs are


evident: bloated face, pale and waxy skin color (at times oddly pink),
trembling on one side of the body or in one arm or leg, irregular and
slowed heartbeat, slurred speech, shallow, very slow breathing, low
BP, absence of chilliness due to diminished alertness, lessened
reflexes, clumsiness, drowsiness, poor coordination, poor judgment,
slips and falls (1,2-4).

References
1. Besdine RW. Accidental hypothermia: the body’s energy crisis.
Geriatrics. 1979;34:51-9.
2. Collins KJ. Effects of cold on old people. Brit J Hosp Med. 1987;
38:506-14.
3. Medical News. Action needed to prevent deaths from hypothermia in
the elderly. JAMA. 1980;243:407-8.
4. Vaisburg S. Accidental hypothermia in the elderly. Editorials. JAMA.
1978;18:1888.

WAS THE KING'S TEMPERATURE TAKEN?


The thermometer, first invented four hundred years ago by
Galileo and refined for clinical use by Sir Clifford Allbutt in 1866, is
one of the most simple and useful tools available in medicine. The
measurements show the body’s response to a myriad of stresses (1).
King David lived 3000 years ago, before the thermometer was known.
Was temperature measured by another means? Or was it was not
measured at all? This question remains open.

Reference
1. Reuler JB. Hypothermia: pathophysiology, clinical settings, and
management. Ann Intern Med. 1978 89:519-27.
433
L. Ben-Nun King David

EKG CHANGES
There is a pathognomonic EKG pattern - the lengthening of the
RR, PR, QRS, and corrected QT (QTC) intervals, the presence of the
typical J deflection, with or without inversion of T, in leads related to
the left ventricle (1-3), and lethal cardiac arrhythmias (VF and
asystole) (4).

References
1. Emslie-Smith D. Accidental hypothermia: A common condition with a
pathognomonic electrocardiogram. Lancet. 1958;2:492.
2. Aslam AF, Aslam AK, Vasavada BC, Khan IA. Hypothermia: evaluation,
electrocardiographic manifestations, and management. Am J Med.
2006;119: 297-301.
3. Wong FW. J wave and hypothermia. Dynamics. 2005;16:17-8.
4. Southwick FS, Dalgish PH. Recovery after prolonged asystolic cardiac
arrest in profound hypothermia. JAMA. 1980;243:1250-3.

HYPOTHERMIA IN THE KING


The passages “My strength failed.. and my bones are consumed”
(Psalm 31:11) and “My bones wasted away through my anguished
roaring all day long” (Psalm 32:3), analyzed in previous report (1),
indicate the osteoporosis which affected the King’s bones. Among
various diseases associated with osteoporosis, senile osteoporosis,
hyperparathyroidism, or malignancy were the most likely to cause
immobility and subsequent hypothermia in King David. Because the
diagnosis of malignancy is the most acceptable (1), it is very likely
that this disease led to malnutrition and subsequent hypothermia
(1,2). Did he suffer from DM, peripheral vascular disease, arthritis, or
drug-induced hypothermia? In the absence of appropriate
anamnestic, physical and laboratory findings, these diagnoses seem
unlikely.

References
1. Ben-Noun L. What was the disease of the bones that affected King
David? J Gerontol Med Sci. 2002;57A:M152-4.
2. Ben-Noun L. Was the biblical King David affected by hypothermia? J
Gerontol A Biol Sci Med Sci. 2002;57(6): M364-7.
434
L. Ben-Nun King David

THERAPY
The general principals of prehospital management are: 1] prevent
further heat loss, 2] rewarm the body core temperature in advance
to shell, and 3] avoid precipitating VF (1).
Accidental hypothermia is an infrequent and under-diagnosed
pathology, which causes fatalities every year. Its management
requires thermometers to measure core temperature. An esophageal
probe may be used in a hospital situation, although in moderate
hypothermia victims epitympanic measurement is sufficient. Initial
management involves advance life support and body rewarming.
Vigorous movements can trigger arrhythmia which does not use to
respond to medication or defibrillation until the body reaches 30°C.
External, passive rewarming is the method of choice for mild
hypothermia and a supplementary method for moderate or severe
hypothermia. Active external rewarming is indicated for moderate or
severe hypothermia or mild hypothermia that has not responded to
passive rewarming. Active internal rewarming is indicated for
hemodynamically stable patients suffering moderate or severe
hypothermia. Patients with severe hypothermia, cardiac arrest or
with a potassium level below 12 mmol/l may require
cardiopulmonary bypass treatment (2).
For hypothermic victims in the prehospital setting,
cardiopulmonary resuscitation, removing wet clothes, insulating the
victim, stabilization with warmed air/oxygen and IV fluids constitute
the initial treatment modalities (3-7). Individuals with only mild
symptoms of hypothermia may be rewarmed with external active
and passive rewarming techniques such as heating blankets, hot wet
towels, warmed water mattresses, warm packs, warm baths, hot
water bottles, and warm enemas (3,4,8). Hospital management
should include, if necessary, central line replacement, pleural lavage
with warm saline, heated humified oxygen (5), warmed peritoneal
dialysis, and extracorporeal blood warming with partial bypass (4,5).
Post resuscitation complications should be monitored; they include
pneumonia, pulmonary edema, cardiac arrhythmias, myoglobinuria,
disseminated intravascular thrombosis, and seizures (5).

ASSESSMENT: there are varieties of methods that can be used to


treat hypothermia. Because it is more likely that the King suffered
435
L. Ben-Nun King David

from mild hypothermia, slow rewarming, such as covering him with


clothes and providing the shared body heat took place.

References
rd
1. Long WB 3 , Edlich RF, Winters KL, Britt LD. Cold injuries. J Long Term
Eff Med Implants. 2005;15:67-78.
2. Soteras Martínez I, Subirats Bayego E, Reisten O. Accidental
hypothermia. Med Clin (Barc). 2011;137(4):171-7.
3. Besdine RW. Accidental hypothermia: the body’s energy crisis.
Geriatrics. 1979;34:51-9.
4. Part IV. Guidelines for cardiopulmonary resuscitation and emergency
cardiac care. Special resuscitation situations. JAMA. 1992; 268:2242-9.
5. Weinberg AD. Hypothermia. Ann Emerg Med. 1993;22:370-7.
6. Arcangeli A, Cavaliere F, Pennisi MA, et al. Physiology and treatment
of accidental hypothermia. Receti Prog Med. 1990; 81:356-60.
7. Kjaergaard B, Rudolph SF, Lucas A, Holdgaard HO. Treatment of the
hypothermic patients. Ugeskr Laeger. 2008;170:2005-10.
8. Bristow G, Smith R, Lee J, et al. Resuscitation from cardiopulmonary
arrest during accidental hypothermia due to exhaustion and exposure. CMA.
1977;117:247-9.

TO SUM UP: the elderly have suffered from hypothermia for


thousands of years. This research analyses the first documented case
of hypothermia as described in the Bible. The sentence “Now king
David was old and stricken in years, and covered him with clothes, but
he gained no warmth” (I Kings 1:1) indicates hypothermia that
afflicted the biblical King David, the second and the greatest of
Israel’s Kings, who ruled the country more than 3537 years ago.
Environmental factors did not play a significant role in the
development of hypothermia. Among various diseases, the most
likely to cause immobility and subsequent hypothermia are senile
osteoporosis, hyperparathyroidism, or malignancy. Among these
diseases, malignancy is the most acceptable. Viewed by a modern
physician, the story of King David unfolds as possibly the earliest
description of patient affected by hypothermia, features of which
have changed little through the ages.
436
L. Ben-Nun King David

PRESSURE ULCERS
Elderly patients have suffered from pressure ulcers for thousands
of years. This is indicated by the presence of pressure ulcers found
on Egyptian mummified bodies (1). Even today, pressure ulcers
remain a common problem in all health care settings.
Patients with pressure ulcers had significantly more pain,
immobility, lack of energy, more restrictions regarding their social
functioning, less vitality, and limitations with respect their emotional
roles. Other problem areas include restrictions in work capacity,
recreation, social interaction, psychological well-being, as well as
problems caused by treatment regiments, worries and frustrations
and a lack of self-esteem (2-4).
Pressure ulcer in an otherwise sick patient is a matter of concern
for the caregivers as well as the medical personnel. A lot has been
done to understand the disease process. So much so, that US and
European countries have established advisory panels in their
respective continents. Since the establishment of these
organizations, the understanding of the pressure ulcer has improved
significantly. The well-documented and well-publicized definition of
pressure ulcer is somewhat lacking in the correct description of the
disease process. Hence, a modified definition has been presented.
This disease is here to stay. In the process of managing these ulcers,
the basic pathology needs to be understood well. Pressure ischemia
is the main reason behind the occurrence of ulceration. Different
extrinsic and intrinsic factors have been described in detail with
review of literature. There are a large number of risk factors causing
ulceration. The risk assessment scales have eluded the surgical
literature and mostly remained in nursing books and websites. These
scales have been reproduced for completion of the basics on
decubitus ulcer. The classification of the pressure sores has been
given in a comparative form to elucidate that most of the
classifications are the same except for minor variations. The
management of these ulcers is ever evolving but the old age saying of
"prevention is better than cure" suits this condition the most (5).
By studying the causes that led to the development of pressure
ulcers in a case taken from ancient history, modern physicians can
expand the horizons of their knowledge and thereby make their
approach more comprehensive. Who suffered from pressure ulcers
437
L. Ben-Nun King David

in the Bible? What were the most likely causes? This research aims
to answer these questions using a biblical description of pressure
ulcers.

References
1. Clarke M, Kadhom H. The nursing prevention of pressure sores in
hospital and community patients. J Adv Nurs. 1988;13:365-73.
2. Herber OR, Schnepp W, Rieger MA. A systematic review on the impact
of leg ulceration on patient's quality of life. Health Qual Outcomes. 2007;
5:44.
3. Hopkins A, Dealey C, Bale C, et al. Patient stories of living with a
pressure ulcer. J Adv Nurs. 2006;56:345-53.
4. Persoon A, Heinen MM, van der Vleuten CJ, et al. Leg ulcers: a review
of their impact on daily life. J Clin Nurs. 2004;13:341-54.
5. Agrawal K, Chauhan N. Pressure ulcers: Back to the basics. Indian J
Plast Surg. 2012;45(2):244-54.

SKIN ULCERS AS DESCRIBED IN THE BIBLE


King David, the second and greatest of Israel’s Kings who ruled
that country about 3537 years ago, suffered from some type of skin
disease. The passage in Psalm 38:6 “My necrotic ulcers stink” tells us
that the King suffered from necrotic ulcers, which are compatible
with pressure ulcers.

DEFINITION
Pressure sores are complex wounds with clinical appearances
ranging from mild redness of the skin to severe necrosis (1-4). Some
patients develop pressure sores due to many intrinsic and extrinsic
factors (2,5-7), the extent of which may not be apparent on initial
assessment. Intrinsic factors include limited mobility, poor nutrition,
comorbidities, and aging skin while extrinsic factors include pressure,
friction, shear, and moisture (8).
There are many terms used to describe pressure ulcers: pressure
sores, decubitus ulcers, bedsores, pressure necrosis, and ischemic
ulcers (9). Of these terms, the most commonly used was once
“decubitus ulcer.” This term is related to the Latin word meaning “to
lie down” (10) since it was thought that “decubitus ulcers” resulted
438
L. Ben-Nun King David

only from prolonged recumbency (11). However, it is now well


established that prolonged application of pressure in any position can
result in ulceration, so that “pressure ulcer” is now perceived as term
that is more correct.

References
1. Banks V. An educational initiative in pressure area management for
nursing staff. J Wound Care. 1997a;6;9:438441.
2. Banks V. Pressure sore education. J Wound Care. 1997b. 6;10:506507.
3. Dealey C. The care of wounds. Blackwell Scientific Publications:
London. 1994.
4. Maklebust J, Sieggreen M. Pressure Ulcers. Guidelines for prevention
nd
and nursing management. 2 ed. Springhouse Corporation. Springhouse
Pennsylvania, 1996.
5. Bridel J. The aetiology of pressure sores. J Wound Care. 1993;
40:23238.
6. Jones KR, Fennie K. Factors influencing pressure ulcer healing in adults
over 50: an exploratory study. J Am Med Dir Asoc. 2007;8:347-8.
7. Bader DL. Pressured sores. Clinical Practice and Scientific Approach.
Macmillan Press: London. 1990.
8. Bluestein D, Javaheri A. Pressure ulcers: prevention, evaluation, and
management. Am Fam Physician. 2008;78:1186-94.
9. Clinical practice guidelines for the prediction and prevention of
pressure ulcers. Stedman’s Medical Dictionary. 24th ed. Baltimore: Williams
& Wilkins. 1982.
10. Kahn, L.F, Van B, Wilking, S, Phillips T. Pressure ulcers. Am Acad
Dermatol. 1998;8:517-38.
11. Shea JD. Pressure sores: classification and management. Clin Orthop.
1975;112:89-100.

MECHANISM OF DEVELOPMENT

Pressure ulcers are an area of localized damage to the skin and


underlying tissue induced by pressure, shear, friction or a
combination of these factors (1,2). The ulcers occur when soft tissue
is compressed between a bony prominence and an external surface
for a prolonged period of time (3). Pressure ulcers are ischemic
damage to soft tissues due to unrelieved pressure, usually over a
bony prominence (4). Persistent pressure on a bony site obstructs
healthy capillary flow, and therefore leads to tissue necrosis (5).
439
L. Ben-Nun King David

Approximately 70% of pressure ulcers occur in patients over than


70 years of age (6). Of all pressure ulcers, 95% develop on the lower
body, with 65% in the pelvic area and 30% in the legs (7). The most
common sites involved are areas of skin overlying bony prominences
such as the sacrum, ischial tuberosities, greater trochanters, iliac
crest, lateral malleolus (ankle), calcaneous, occiput, chin, ear, elbow,
and scapula areas (8,9-11).
The objective of this study was to assess whether there are racial
and ethnic disparities in the time to development of a pressure ulcer
and number of pressure ulcer treatments in individuals aged 65 and
older after nursing home admission. Multi-level predictors of time to
a pressure ulcer from three national surveys were analyzed using Cox
proportional hazards regression for White Non-Hispanic residents.
Using the Peters-Belson method to assess for disparities, estimates
from the regression models were applied to American
Indians/Alaskan Natives, Asians/Pacific Islanders, Blacks, and
Hispanics separately resulting in estimates of expected outcomes as
if they were White Non-Hispanic, and were then compared with their
observed outcomes. More Blacks developed pressure ulcers sooner
than expected. No disparities in time to a pressure ulcer
disadvantaging other racial/ethnic groups were found. There were no
disparities in pressure ulcer treatment for any group. In conclusion,
reducing disparities in pressure ulcer development offers a strategy
to improve the quality of nursing home care (12).

ASSESSMENT: pressure ulcers are mostly located in the sacrum,


and in the legs. Blacks develop pressure ulcers sooner than expected
compared to other racial/ethnic groups. Disparities in time to a
pressure ulcer development for other racial/ethnic groups are not
found.
Where pressure ulcers located in King David's case?

References
1. Bluestein D, Javaheri A. Pressure ulcers: prevention, evaluation, and
management. Am Fam Physician. 2008;78:1186-94.
2. Bergstrom N, Allman R, Alvarez O, et al. Treatment of pressure ulcers.
Clinical Practice Guidelines No. 15. Rockville, M: Agency for Health Care
Policy and Research, Public Health Service, US Department of Health and
Human Services; 1994;AHCPR No. 95-0652.
3. National Pressure Ulcer Advisory Panel. Pressure ulcers: incidence,
economics, risk assessment. Consensus development conference statement.
440
L. Ben-Nun King David

Decubitus. 1989;2:24-8.
4. Bauer J, Philips LG. MOC-PSSM CME article: Pressure sores. Plast
Reconstr Surg. 2008;121(1Sup-pl):1-10.
5. Lyder CH. Pressure ulcer prevention and management. JAMA. 2003;
289:223-6.
6. Norton D, McClaren R, Exton-Smith AN. An investigation of geriatric
nursing problems in hospital. Edinburgh: Churchill-Livingstone. 1975, pp.
193-236.
7. Odom RB, James WD, Berger TG. Mechanical injuries to the skin.
Pressure ulcers (decubitus). In: Odom RB, James WD, Berger TG (eds.).
Andrews’ Diseases of the Skin. Clinical Dermatology. Philadelphia: W.B.
Saunders. 2000, pp. 41-48.
8. Shea JD. Pressure sores: classification and management. Clin Orthop.
1975;112:89-100.
9. Clarke M, Grace P. Understanding the underlying causes of the chronic
leg ulceration. J Wound Care. 2004;13:215-8.
10. Djarmarajan TS, Ahmed S. The growing problem of pressure ulcers.
Postgrad Med. 2003;113:77- 88.
11. Allman R. Pressure ulcers among the elderly. New Engl J Med. 1989;
320:850-3.
12. Bliss DZ, Gurvich O, Savik K, et al. Are there racial-ethnic disparities in
time to pressure ulcer development and pressure ulcer treatment in older
adults after nursing home admission? J Aging Health. 2014 Sep 25. pii:
0898264314553895. [Epub ahead of print]

EPIDEMIOLOGY
During each of nine surveys conducted between 1989 and 2005,
clinical teams in participating facilities predominantly in the US (some
facilities in Canada, Saudi Arabia, and Australia participated after
2003) assessed admitted on assigned study dates. For this study,
trends using all records (n=447.930; average, 49.770) were reviewed.
The majority of facilities in each survey were in the US (99%) overall.
Nosocomial pressure ulcer prevalence rates ranged from 9.2% and
5.6% in 1989 to 15.5% and 10% in 2003 and 2004, respectively. The
highest prevalence was documented in long-term acute care (27.3%
overall, and 8.5% nosocomial) (1).
In Maryland, 2015 residents aged 65 years and older admitted to
59 long-term-care facilities were studied. Of these residents, 208
(10.3%) had one or more pressure ulcers on admission to a long-
441
L. Ben-Nun King David

term-care facility. The proportion of patients with one or more


pressure ulcers was 11.9% among those who were admitted from a
hospital and 4.7% among those not admitted from a hospital
(p<0.01). Admission from a hospital was significantly associated with
pressure ulcer prevalence on admission. A lower prevalence of
pressure ulcers on admission was significantly associated with being
white; a higher prevalence was associated with being chair bound or
bedridden, being underweight, and having fecal incontinence (2).
In Canada, the data included information from 18 acute care
facilities involving 4,831 patients, 23 non-acute care facilities with
3,390 patients, 19 mixed healthcare settings with 4,200 patients, and
five community care agencies that surveyed 1,681 patients, 1990-
2003. Pressure ulcer prevalence was 25.1% for patients in acute care
settings, 29.9% for those in non-acute care settings, 22.1% for
patients in mixed health settings, and 15.1% for those in community
care. The overall estimate of the prevalence of pressure ulcers in all
healthcare institutions across Canada was 26.9% (3).
In Europe, a convenience sample of university and general
hospital: of Belgium, Italy, Portugal, UK, and Sweden (5,947 patients,
25 hospitals) participated in the study. The pressure ulcer prevalence
(grade I-IV) was 18.1% and if grade I ulcers were excluded, the
prevalence was 10.5%. The sacrum and heels were the most affected
locations (4).
In Germany, a total of 11,584 patients and residents in 66
institutions took part in the study. The prevalence, including grade I
pressure ulcers, was 11.7% (5.2%) for the whole sample, while 24.5%
(11.5%) for the group at risk. The size of the group at risk in the
nursing homes was 63.9% and less than 40% in the hospitals (5). In
another report, the prevalence of pressure ulcers ranged from 4% in
Denmark to 49% in Germany, while the incidence ranged from 38%
to 124%, 2000-2005 (6).
In the Netherlands, the total prevalence of pressure ulcers
reached 28.7% (7) in intensive care units; 10.1% (n=368) in the
university hospital; 13.7% (n=1,541) in the home healthcare setting,
and 83.6% (n=122) in the nursing home. The most common lesions
were on the sacrum and below the knee (heel and malleolus) (8).
In Sweden, the prevalence of pressure ulcers was 23.9%
(university hospital), 23.2% (general hospital) and 20.0% (nursing
home). Most (60-66%) of the pressure ulcers in the hospital were
assessed as grade I (9).
442
L. Ben-Nun King David

In China, the prevalence rate of pressure ulcers in 12 hospitals


was 1.58% (0.94-2.97%). The incidence of hospital-acquired pressure
ulcers was 0.63% (0.20-1.20%). The most common locations
developed pressure ulcers were sacrum, heels, and iliac crests. The
common stages of pressure ulcers were stage I and II (10).

ASSESSMENT: there is a wide variation in the prevalence and


incidence rates of pressure ulcers in different countries.

References
1. Valginger C, Macfarlane GD, Meyer S. Results of nine international
pressure ulcer prevalence surveys: 1989 to 2005. Ostomy Wound Manage.
2008;54:40-54.
2. Baumgarten M, Margolis D, Gruber-Baldini AL, et al. Pressure ulcers
and the transition to long-term care. Adv Skin Wound Care. 2003;16:299-
304.
3. Woodbury MG, Houghton PE. Prevalence of pressure ulcers in
Canadian Healthcare settings. Ostomy Wound Management. 2004;50:22-
4,26,28,30,32,34,36-8.
4. Vanderwee K, Clark M, Dealey C, et al. Pressure ulcer prevalence in
Europe: a pilot study. J Eval Clin Pract. 2007;13:227-35.
5. Lahman NA, Halfens RJ, Dassen T. Prevalence of pressure ulcers in
Germany. J Clin Nurs. 2005;14:165-72.
6. Shanin ES, Dassen T, Halfens RJ. Pressure ulcer prevalence and
incidence in intensive care patients: a literature review. Nurs Crit Care.
2008;13:71-9.
7. Bours GJ, De Laat E, Halfens RJ, Lubbers M. Prevalence, risk factors
and prevention of pressure ulcers in Dutch intensive care units. Results of a
cross-sectional survey. Intensive Care Med. 2001;27:1599-605.
8. Bours GJ, Halfens RJ, Lubbers M, Haaboom JR. The development of a
national registration form to measure the prevalence of pressure ulcers in
the Netherlands. Ostomy Wound Manage. 1999;45:28-33,36-8, 40.
9. Gunninberg L. Risk, prevalence and prevention of pressure ulcers in
three Swedish healthcare settings. J Wound Care. 2004;13:286-90.
10. Jiang Q, Li X, Qu X, et al. The incidence, risk factors and
characteristics of pressure ulcers in hospitalized patients in China. Int J Clin
Exp Pathol. 2014; 7(5):2587-94. eCollection 2014.
443
L. Ben-Nun King David

HOSPITAL COST
Incident pressure ulcers were associated with significantly higher
mean unadjusted hospital costs ($7.288 vs. $13.924, p<0.0001) and
length of stay (30.4 vs. 12.8 days, p=0.0001). Compared with those
who did not develop pressure ulcers, patients who developed
pressure ulcers were more likely to develop nosocomial infections,
and other hospital complications. Length of state for those who
developed pressure ulcers remained significantly greater than for
those who did not develop pressure ulcers ($14,260 vs. $12,382,
p=0.03, and 16.9 vs. 12.9 days, p=0.02, respectively). Incident
pressure ulcers were associated with substantial and significant
increases in hospital costs and length of stay. Nosocomial infections
and other hospital complications were additional significant
independent predictors of health care utilization among patients at
risk for pressure ulcers (1).

Reference
1. Allman RM, Goode PS, Burst N, et al. Pressure ulcers, hospital
complications, and disease severity: impact on hospital costs and length of
stay. Adv Wound Care. 1999;12:22-30.

CLASSIFICATION

EUROPEAN PRESSURE ADVISORY PANNEL. Grade I: Non-


blanchable erythema of intact skin. Discoloration of the skin,
warmth, edema, induration or hardness are used as indicators,
particularly in individuals with darker skin. Grade II: Partial thickness
of skin loss, involving epidermis, dermis or both. The ulcer is
superficial and presents clinically as an abrasion or blister. Grade III:
Loss of full skin thickness involving damage to or necrosis of
subcutaneous tissue that may extend down to, but not through
underlying fascia. Grade IV: Extensive destruction, tissue necrosis, or
damage to muscle, bone, or supporting structures with or without
full thickness of skin loss (1).
444
L. Ben-Nun King David

Reference
1. EPUAP. European Pressure Ulcer Advisory Panel: Review 1.
1999;2:31.

MAKLEBUST & SIEGGREEN CLASSIFICATION SYSTEM.


Grade I: Non-blanchable erythema of intact skin. Grade II: Partial
thickness of skin loss involving epidermis and/or dermis. Presents as
an abrasion, blister or shallow cavity. Grade III: Full thickness of skin
loss involving damage or necrosis of subcutaneous tissue extending
to, but not through the muscle. Clinical presentation is a deep crater
with or without undermining damage. Grade IV: Full thickness of skin
loss with extensive damage or necrosis of muscle, bone or supporting
structures. Closed: A large bursa like cavity extending into fascia or
bone. Drainage is through a small sinus tract (1).

ASSESSMENT: what grade did the pressure ulcers reach in the


King’s case? What were the areas involved? The words “My necrotic
ulcers stink” (Psalm 38:6) indicate grade III or IV. Since there are
insufficient data concerning the extensive damage occurring in the
grade IV, it is most likely that his pressure ulcers reached grade III.

Reference
1. Maklebust J, Sieggreen M. Pressure Ulcers. Guidelines for prevention
and nursing management. 2nd ed. Springhouse Corporation. Springhouse
Pennsylvania, 1996.

PRESSURE ULCER PAIN

Although wound pain often is described as an important clinical


factor by both patients and providers, pain associated with pressure
ulcers is poorly understood. To assess the state of knowledge of pain
with pressure ulcers, a systematic, integrative review of the literature
was conducted to determine: 1] how pain is measured, 2] pain
prevalence/incidence, and 3] factors associated with pressure ulcer
pain. Bibliographic databases including MEDLINE (1966-2005),
HealthSTAR (1975-2005), CINAHL (1982-2005), and seven others were
searched using the terms decubitus ulcers, pressure ulcer, pressure
445
L. Ben-Nun King David

sore, bed sore, and pain and then culled to English-language, clinical
publications. Of the 417 articles recovered, 26 met the study inclusion
criteria, six specifically identified pain prevalence (ranging from 37%
and 100%), and none documented the incidence of pain in patients
with pressure ulcers. Measurement tools used to assess pain included
the Visual Analogue Scale, the Verbal Rating Scale, the Wong-Baker
Facial Recognition Scale, the McGill Pain Questionnaire-Short Form, the
Numerical Rating Scale, and the Present Pain Intensity scale. Pressure
ulcer pain was described as a burning sensation and reported as both
constant and transient. Contrary to often-held clinical opinion, the
studies reviewed suggest that pain increases with pressure ulcer stage.
Although a number of intrinsic and extrinsic factors were studied (e.g.,
age, ulcer stage, and bed surfaces), no conclusions could be drawn from
the available research. Because pain is an issue for individuals with
pressure ulcers and may present a different profile than other sources
of pain, pain assessment should become an integral part of pressure
ulcer care and documented to guide pressure ulcer management (1).
The aim of this study was to estimate the prevalence of UPAR pain
which was defined as pain, soreness or discomfort reported by
patients, on an "at risk" or pressure ulcer skin site, reported at a patient
level. Pain prevalence surveys in two large UK teaching hospital NHS
Trusts (six hospitals) and a district general hospital NHS Trust (three
hospitals) during their routine annual pressure ulcer prevalence audits
were conducted. The hospitals provide secondary and tertiary care
beds in acute and elective surgery, trauma and orthopedics, burns,
medicine, elderly medicine, oncology and rehabilitation. Anonymised
individual patient data were recorded by the ward nurse and pressure
ulcer prevalence team. In nine acute hospitals, 3,397 patients were
included in routine pressure ulcer prevalence audits and, of these, 2010
(59.2%) patients participated in the pain prevalence study. UPAR pain
prevalence was 16.3% (327/2010); 1,769 patients had no pressure
ulcers and of these 223 patients reported UPAR pain, a prevalence of
12.6%. Of the 241 people with pressure ulcers, 104 patients reported
pain, an UPAR pain prevalence of 43.2% (104/241). In conclusion, one
in six people in acute hospitals experience UPAR pain on 'at risk' or
pressure ulcer skin sites; one in every eight people without pressure
ulcers and, more than two out of every five people with pressure
ulcers. The results provide a clear indication that all patients should be
asked if they have pain at pressure areas even when they do not have a
pressure ulcer (2).
446
L. Ben-Nun King David

ASSESSMENT: because pain is an issue for individuals with pressure


ulcers and may present a different profile than other sources of pain,
pain assessment should become an integral part of pressure ulcer care
and documented to guide pressure ulcer management. All patients
should be asked if they have pain at pressure areas even when they do
not have a pressure ulcer.
Did King David suffer from pain of pressure ulcer?

References
1. Girouard K, Harrison MB, VanDenKerkof E. The symptom of pain with
pressure ulcers: a review of the literature. Ostomy Wound Manage.
2008;54(5):30-40, 42. Erratum in Ostomy Wound Manage. 2008;54(6):8.
2. Briggs M, Collinson M, Wilson L, et al. The prevalence of pain at pressure
areas and pressure ulcers in hospitalised patients. BMC Nurs. 2013;12(1):19.

MALODOROUS WOUNDS
Infection may present with increased local pain, cellulitis, local
abscess, necrotizing fasciitis, osteomyelitis, bacteremia, or sepsis (1).
Factors that lead to odor formation include necrotic tissue/slough,
infection that multiplies and thrives in necrotic tissue/slough, and
exudates (2-4).
The smell of the exudates is embarrassing to the patient. If the
pressure ulcer is covered with black necrotic tissue, it is difficult to
establish depth of the tissue damage (5). Infections in non-healing
wounds contain a mixture of organisms, including gram-positive
cocci, gram-negative bacilli, and anaerobes.
Necrotizing soft tissue infections are serious complications that
may arise from pressure ulcers. However, there are few studies on
this important issue. In addition, diagnostic criteria for necrotizing
soft tissue infections developing from pressure ulcers and infected
pressure ulcers are not well established. Necrotizing soft tissue
infections developing from pressure ulcers based on clinical findings
were defined. Based on the definition, the medical records of 24
elderly patients with this condition were retrospectively analyzed to
determine patient age, gender, comorbid disease, laboratory
findings, wound location, bacteriology, and treatment outcomes. In
the examined population, necrotizing soft tissue infections
developed primarily from pressure ulcers over the sacrum. Dementia
447
L. Ben-Nun King David

and DM were also frequently observed in patients with necrotizing


soft tissue infections. The average Laboratory Risk Indicator for
necrotizing fasciitis score was relatively low. Bacterial cultures from
the debrided deep tissues exhibited mixed infections of gram-positive
cocci and gram-negative bacilli, except one case. Anaerobic
pathogens were isolated from 18 patients (72%), and seven patients
(29%) developed bacteremia. None of the cases were preceded by
wounds dominated by granulation tissue. Surgical intervention,
combined with antibacterial therapy involving intravenous
carbapenem or cephem, was successfully used in most cases. In
conclusion, necrotizing soft tissue infections arising from pressure
ulcers are generally caused by mixed pathogens and exhibit
symptoms that are milder than those of necrotizing fasciitis caused
by group A Streptococcus (6).
The use of three separate 16S-based molecular amplifications
followed by pyrosequencing, shotgun Sanger sequencing, and
denaturing gradient gel electrophoresis were utilized to survey the
major populations of bacteria that occur in the pathogenic biofilms of
three types of chronic wound types: diabetic foot ulcer, venous leg
ulcers, and pressure ulcers. There were specific major populations of
bacteria that were evident in the biofilms of three types of chronic
wounds including Staphylococcus, Pseudomonas, Peptoniphilus,
Enterobacter, Stenotrophomonas; Finegoldia, and Serratia spp. Each
of the wound types reveals marked differences in bacterial
populations, such as pressure ulcers in which 62% of the populations
were identified as obligate anaerobes (7).
Bacteriological investigation of infected pressure ulcers in spinal
cord-injured patients, Microbiological and Orthopedics Department,
Abroise Paré University Hospital, Boulogne-Billancourt, France, was
carried out. Tissue samples, sampled at the end of the surgical
intervention from unbridled and cleaned ulcers were analyzed. The
most frequently isolated species were enterobacteria, followed by
staphylococci and streptococci (8).
Coagulase-negative staphylococci are common colonizers of the
human skin and have become increasingly recognized as agents of
clinically significant nosocomial infections. The case of a 79-year-old
male patient with multi-infarct dementia who presented systemic
inflammatory response syndrome is reported. This was attributed to
bacteremia due to Staphylococcus cohnii ssp. urealyticus, which was
grown on blood cultures originating from an infected pressure ulcer.
448
L. Ben-Nun King David

The few cases of Staphylococcus cohnii infection reported in the


literature consist of bacteremia relating to catheters, surgical
prostheses, acute cholecystitis, brain abscess, endocarditis,
pneumonia, UTI and septic arthritis, generally presenting a
multiresistant profile, with nearly 90% resistance to methicillin. In
conclusion, the reported case is the case of true bacteremia due to
Staphylococcus cohnii subsp. urealyticus caused by an infected
pressure ulcer. It shows that this species may be underdiagnosed and
should be considered in the differential diagnosis for community-
acquired skin infections (9).

ASSESSMENT: the words “My necrotic ulcers stink” (Psalm 38:6)


indicate malodorous infected non-healing pressure ulcers with
necrotic tissue/slough. Although data on bacteriological investigation
are unavailable, it is very likely that one or more of the pathogens
described above were responsible.

References
1. Ebright JR. Microbiology and chronic leg and pressure ulces: clinical
significance and implications for treatment. Nurs Clin North Am. 2005;40:
207-16.
2. Hack A. Malodorous wounds-taking the patient’s perspective into
account. J Wound Care. 2003;12:319-21.
3. Haugton W, Young T. Common problems in wound care: malodorous
wounds. Br J Nurs. 1995;4:959-63.
4. Bowler PG, Davies BJ, Jones SA. Microbial involvement in chronic
wound order. J Wound Care. 1999;8:216-8.
5. Russel L. Pressure ulcer classification: defining early skin damage. Br J
Nurs. 2002;11(16 Suppl):S33-4, S36,S40-1.
6. Mizokami F, Furuta K, Isogai Z. Necrotizing soft tissue infections
developing from pressure ulcers. J Tissue Viability. 2014;23(1):1-6.
7. Dowd SE, Sun Y, Secor PR, et al. Survey of bacterial diversity in chronic
wounds using pyrosequnecing, DGGE, and full ribosome shotgun
sequencing. BMC Microbiol. 2008;8:43.
8. Heym B, Rimareix F, Lorta-Jacob A, et al. Bacteriological investigation
of infected pressure ulcers in spinal cord-injured patients and impact on
antibiotic therapy. Spinal Cord. 2004;42:230-4.
9. Soldera J, Nedel WL, Cardoso PR, d'Azevedo PA. Bacteremia due to
Staphylococcus cohnii ssp. urealyticus caused by infected pressure ulcer:
case report and review of the literature. Sao Paulo Med J.2013;131(1):59-61.
449
L. Ben-Nun King David

RISK FACTORS FOR PRESSURE ULCERS


Extrinsic causes for pressure ulceration include pressure, shear,
friction and prolonged contact with moisture (1), especially from
urine and feces (2). Intrinsic factors include age >65 years, male
gender, acute illness, recent weight loss (3), level of consciousness,
malnutrition and/or dehydration (1), limited mobility or immobility
associated with severe and multiple diseases (4), sensory
impairment, severe chronic or terminal illness such as metastatic
carcinoma (5), and vascular disease (1,6). Other medical problems
include spinal cord injury, hip fracture, dementia (2), such as
Alzheimer’s type, CHF, COPD, cerebral vascular accident, DM, deep
vein thrombosis, hip fracture, hip surgery, limb paralysis, lower limb
edema, osteoporosis, Parkinson’s disease, RA, UTI (7,8), and
emotional stress (5).
Nursing home residents (n=4,232) free of pressure ulcers on
admission to 78 nursing facilities, Hebrew Rehabilitation Center for
Aged, were studied. Significant factors associated with the formation
of pressure ulcers in high incident homes (21-month incidence =
19.3%) were ambulation difficulty (OR 3.3, 95% CI 2.0-5.3), fecal
incontinence (OR 2.5, 95% CI 1.6-40), DM (OR 1.7, 95% CI 1.2-2.5),
and feeding oneself difficulty (OR 2.2, 95% CI 1.5-3.3). In the low
incidence homes (21-month incidence = 6.5%) significant factors
associated with pressure ulcer incidence were ambulation difficulty
(OR 3.6, 95% CI 1.7-7.4), feeding oneself difficulty (OR 3.5, 95% CI 2.0-
6.3), and male gender (OR 1.9, 95% CI 1.2-3.6) (9).
According to this study, male gender, ambulation difficulty,
feeding oneself difficulty, fecal incontinence, and DM were risk
factors for pressure ulcers.
One of the variables is malnutrition. With age, there is a decrease
in food intake (10). Paradoxically, however, there is an increase in
body fat and obesity. This conundrum is explained by decreased
physical activity and the altered metabolism that accompanies aging.
Older persons fail to adequately regulate food intake and develop
physiologic anorexia of aging. Physiologic anorexia of aging puts
older persons at high risk for developing protein-energy malnutrition
when they have psychological or physical problems (11).
Malnutrition is associated with skin anergy and with immobility
because of mental apathy and muscle wasting (12).
450
L. Ben-Nun King David

Malnutrition is frequent in geriatric patients: it affects 30% to 60%


of elderly residents in institutions and 30% to 70% patients admitted
for short-term hospitalization. In elderly subjects, multiple and
interlinked factors may trigger or aggravate malnutrition; they may
be physical, psychological or social and may be worsened by drugs
and some diets (13). Malnutrition increases the risk of pressure ulcers
(14), leading to a delay in wound healing (12,15,16). In addition, a
low BMI, low serum albumin, and weight loss are associated with an
increased risk of pressure ulcers (13). Proteins and vitamins B and C
that are often deficient in old age are needed to heal pressure ulcer
(14). Therefore, optimal nutrition is necessary to promote wound
healing (17).
Malnutrition is common in hospitals and is a risk factor for
pressure ulcers. Nutrition care practices relating to the identification
and treatment of malnutrition have not been assessed in patients at
risk of pressure ulcers. The present study describes nutrition care
practices and factors affecting nutritional intakes in this patient
group. The study was conducted in four wards at two hospitals in
Queensland, Australia. Adult patients at risk of pressure ulcers
because of restricted mobility were observed for 24 hours to
determine their daily oral intake and practices such as nutrition
screening, documentation and intervention. Two hundred and forty-
one patients participated in the present study. The observed
nutritional screening rate was 59% (142 patients). Weight and height
were documented in 71% and 34% of cases. Sixty-nine patients (29%)
received a dietitian referral. Predictors of receiving a dietitian referral
included lower BMI and longer length of stay. On average, patients
consumed 73% and 72% of the energy and protein provided,
respectively. Between 22% and 38% of patients consumed <50% of
food provided at main meals. In conclusion, nutrition care practices
including malnutrition risk screening and documentation of
nutritional parameters appear to be inadequate in patients at risk of
pressure ulcers. A significant proportion of these patients ate
inadequately at main meals, further increasing their risk of
malnutrition and pressure ulcers (18).
The purpose was to explore the context of incidence of and
associated risk factors for pressure ulcers amongst the population of
surgical patients. The initial study cohort was conducted with 297
patients admitted to a teaching hospital for a surgical operation from
November 14th to 27th 2006 in Taipei, Taiwan. The Braden scale,
451
L. Ben-Nun King David

pressure ulcers record sheet, and perioperative patient outcomes


free from signs and symptoms of injury related to positioning and
related nursing interventions and activities were collected. The
incidence of immediate and 30-minute-later pressure ulcers was
9.8% (29/297) and 5.1% (15/297), respectively. The statistically
significantly associated risk factors related to immediate and 30-
minute-later pressure ulcers included operation age, type of
anesthesia, type of operation position, type of surgery, admission
Braden score, and number of nursing intervention after adjustment
for confounding factors. In conclusion, admission Braden score and
number of nursing intervention are well-established protected
factors for the development of pressure ulcers. This study shows that
older operation age, type of anesthesia, type of operation position,
and type of surgery are also associated with the development of
pressure ulcers (19).
We see that there is a variety of risk factors related to the
development of pressure ulcers. What were the risk factors
responsible for the development of pressure ulcers in the case of
King David, a particular geriatric patient and the member of the
highest socioeconomic stratum? Was David afflicted by physiological
anorexia of aging that led to malnutrition? As previously shown, a
diagnosis of physiological anorexia of aging seems unlikely since an
excessive loss of weight “…my bones (the King’s) cleave to my skin”
(Psalm 102:6) and “…my flesh failed of fatness” (109:24) indicates
severe malnutrition which led to cachexia due to a serious or fatal
disease (20). The King also suffered from osteoporosis, which
afflicted his bones. Among the various diseases associated with
osteoporosis, the most likely here are senile osteoporosis,
hyperparathyroidism, or malignant disease with the diagnosis of
malignancy as the most acceptable (21). A combination of cachexia
and osteoporotic intractable bone pain points towards a diagnosis of
malignancy. With regard to malignancy, it seems that the King was
afflicted either by MM, or by primary RCC, or carcinoma of prostate,
or gastric carcinoma, or CRC with subsequent metastases to the
bones. Thus, there are two identifiable risk factors for pressure ulcers
- malignancy and malnutrition.
Malodor reduces appetite (22) at a time when good nutrition is
needed for healing and when QOL is important (23). This factor also
contributed to David’s reduced or even absent appetite and
subsequent malnutrition.
452
L. Ben-Nun King David

The King also suffered from dehydration “…my tongue cleaveth to


my jaws…” (22:16), which is a risk factor for pressure ulcers. In
addition, King David was afflicted by mild hypothermia (24), although
it is unlikely that this condition was related to the development of
pressure ulcers.
Psychosocial factors play an important role in the eating habits of
the elderly. Failure to eat among older people may be associated
with endogenous depression, bereavement, and dementia - mild
memory disturbances can cause older people to forget to eat (25). It
follows that depression and various social problems such as
loneliness, social isolation and neglect by others (26) can be
responsible for extreme loss of weight.

ASSESSMENT: the risk factors for the development of pressure


ulcers in King David include: male gender, old age – 70 years,
osteoporosis, dehydration, and malnutrition most probably due to
malignancy, depression, and various social problems.

References
1. Collier M. Effective prevention requires accurate risk assessment. J
Wound Care. 2004;13:3-7.
2. Torpy MJ, Lynn C, Glass E. Pressure ulcers. JAMA. 2003;289:254.
3. Finucane TE. Malnutrition, tube, feeding and pressure sores: data are
incomplete. J Am Geriatr Soc. 1995;43:447-51.
4. Allman RM, Goode PS, Burst N, et al. Pressure ulcers, hospital
complications, and disease severity: impact on hospital costs and length of
stay. Adv Wound Care. 1999;12:22-30.
5. Makleburst J, Magnam M. Risk factors associated with having a
pressure ulcer: a secondary data analysis. Adv Wound Care. 1994;7:25-34.
6. Clinical practice guidelines for the prediction and prevention of
pressure ulcers. Stedman’s Medical Dictionary. 24th ed. Baltimore: Williams
& Wilkins. 1982.
7. Margolis DJ, Knauss J, Bilker, W, et al. Medical conditions as risk
factors for pressure ulcers in an outpatient setting. Age Ageing.
2003;32:259-62.
8. Berlowitz DR, Wilking VB. Risk factors for pressure sores. A
comparison of cross-sectional and cohort-derived data. J Am Geriatr Soc.
1989;37:1943-50.
453
L. Ben-Nun King David

9. Brandeis GH, Ooi WL, Hossai M, et al. A longitudinal study of risk


factors associated with the formation of pressure ulcers in nursing homes. J
Am Geriatr Soc. 1994;42:388-93.
10. Bours GJ, De Laat E, Halfens RJ, Lubbers M. Prevalence, risk factors
and prevention of pressure ulcers in Dutch intensive care units. Results of a
cross-sectional survey. Intensive Care Med. 2001;27:1599-605.
11. Morley J. Decreased food intake with aging. J Gerontol Med Sci.
2001; 56 (Special Issue 2):81-8.
12. Mathus-Vliegen. Old age, malnutrition, and pressure sores: an ill-
fated alliance. J Gerontol A Biol Sc Med Sci. 2004;59:355-60.
13. Fontaine J, Raynaud-Simon A. Pressure sores in geriatric medicine:
the role of nutrition. Presse Med. 2008;37:1150-7.
14. Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin
Nutr. 1997;66:760-73.
15. Holmes, R. Nutrition know-how: combating pressure sores
nutritionally. Am J Nurs. 1987;87:1301-3.
16. Tran C, Rouet M, Guex E, et al. Pressure ulcers and undernutrition-
screening and assessment of nutritional status. Praxis (Bern 1994).
2008;97:261-4.
17. Lyder, C.H. Pressure ulcer prevention and management. JAMA.
2003;289:223-6.
18. Roberts S, Chaboyer W, Desbrow B. Nutrition care-related practices
and factors affecting nutritional intakes in hospital patients at risk of
pressure ulcers. J Hum Nutr Diet. 2014 Jun 27.
19. Fu Shaw L, Chang PC, Lee JF, et al. Incidence and predicted risk
factors of pressure ulcers in surgical patients: experience at a medical center
in Taipei, Taiwan. Biomed Res Int. 2014;2014:416896.
20. Ben-Noun, L. The disease that caused weight loss in King David the
Great. J Gerontology Med Sci. 2004;59A(2):143-5.
21. Ben-Noun, L. What was the disease of bones that affected King
David? J Gerontol Med Sci. 2002;57A:M152-4.
22. Benbow M. Malodorous wounds: how to improve quality of life.
Comm Nurse. 1995;5(1):43-6.
23. Price E. The stigma of smell. Nursing Times. 1996;92: 20:71-3.
24. Ben-Noun L. Was the biblical King David affected by hypothermia? J
Gerontol Med Sci. 2002;57A:M364-7.
25. Morley JE. Nutritional status of the elderly. Am J Med. 1986;8:679.
26. Ben-Noun L. Mental disorder that afflicted King David the Great. Hist
Psychiatry. 2004;15:467-76.
454
L. Ben-Nun King David

DIFFERENTIAL DIAGNOSIS
The differential diagnosis of pressure ulcers includes: ischemic
ulcers, neuropathic ulcers, vasculitides, skin cancers such as
squamous cell carcinoma, basal cell carcinoma, malignant melanoma
(1), radiation injury, RA, infectious diseases that lead to tissue
necrosis and ulceration by microorganisms such as -haemolytic
Streptococcus pyogenes, necrobiosis lipoidica, pyoderma
gangrenosum (2), venous leg ulcers, diabetic foot ulcer, gangrenous
wounds and fungating malignant wounds (3-6).

ASSESSMENT: although all these diagnoses are possible, pressure


ulcers provide the best overall explanation for the King's skin ulcers.

References
1. Grace P. (ed.). Guidelines for the Management of Leg Ulcers in Ireland.
Smith and Nephew. 2002.
2. Moloney C. Understanding the underlying causes of chronic leg
ulceration. J Wound Care. 2004;13(6):213-7.
3. Trémezaygues L, Schmaltz R, Vogt T, Reichrath J. Management of
pyoderma gangrenosum. An update on clinical features, diagnosis and
therapy. Hautarzt. 2010;61(4):345-53; quiz 354-5.
4. Baltzis D, Eleftheriadou I, Veves A. Pathogenesis and Treatment of
Impaired Wound Healing in Diabetes Mellitus: New Insights. Adv Ther. 2014;
31(8):817-36.
5. Misciali C, Dika E, Baraldi C, et al. Vascular leg ulcers: histopathologic
study of 293 patients. Am J Dermatopathol. 2014;36(12):977-83.
6. Allman R. Pressure ulcers among the elderly. New Engl J Med.
1989;20: 20: 850-3.

TO SUM UP: older people have suffered from pressure ulcers


since the dawn of history. This research is unique in character, as it
combines modern medical knowledge with the presentation of a case
taken from ancient history. The main aim of this research was to
analyze from a modern perspective the biblical description of a
geriatric case of pressure ulcers. Biblical texts associated with the
aged were examined and a passage referring to an old person who
suffered from skin ulcers was studied. King David developed pressure
ulcers at the age of 70 years: “David was thirty years when he began
to reign, and he reigned forty years (II Samuel 5:4). The King was not
455
L. Ben-Nun King David

apparently hospitalized, nor was he treated in any long-term


treatment facility, but he remained in home care.
The passage “My necrotic ulcers stink” (Psalm 38:6) indicates
infected pressure ulcers, which have reached the third degree. The
risk factors for these ulcers include male gender, old age - a 70 year
old man in this case, osteoporosis, dehydration, malnutrition and
cachexia most probably due to malignancy, depression, and various
social problems.

ERECTILE DYSFUNCTION
INTRODUCTION

Sexuality is an important part of most men's QOL (1), and is an


important component of emotional and physical intimacy that men
and women experience through their lives. About 60% of the elderly
population expresses their interest for maintaining sexual activity (2).
ED is one of the most common chronic diseases affecting men and
its prevalence increases with aging. It is also the most frequently
diagnosed sexual dysfunction in the older male population. A number
of different diseases potentially worsening sexual function may occur
in elderly people, together with polypharmacy. Related causes of ED
are variable and can include arterial, neurogenic, hormonal,
cavernosal, iatrogenic, and psychogenic causes (3).
ED is one of the most common health problems affecting men and
is most common with increasing age. Who suffered from ED in
biblical times? How can this dysfunction be classified? What factors
were responsible? What were its characteristics? This research
evaluates a case of ED in a geriatric patient as described in the Bible.

References
1. Swendsen KO, Schultz A. Sexual dysfunction in men. Tidsskr Nor
Largeforen. 2008;128:448-52.
2. Camacho ME, Reyese-Otiz CA. Sexual dysfunction in the elderly: age or
disease? Int J Impot Res. 2005;17 Suppl 1:S52-6.
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L. Ben-Nun King David

3. Gareri P, Castagna A, Francomano D, et al. Erectile dysfunction in the


elderly: an old widespread issue with novel treatment perspectives. Int J
Endocrinol. 2014;2014:878670.

THE BIBLICAL DESCRIPTION

King David, the second and greatest of Israel’s Kings who ruled the
country more than 3537 years ago, was about 70 years old at the end
of his reign. When the King reached old age, he suffered from ED:
“Now King David was old, advanced in years; and they covered him
with clothes, but he could not become warm” (Kings 1:1). David’s
servants decided to summon “ a young virgin; and let her lie in thy
bosom, that my lord the king may become warm” (I Kings 1:2). They
“...found Avishag the Shunammite, and brought her to the king. And
the maiden was very fair, and she cherished the king, and ministered
to him: but the king knew her not” (I Kings 1:3-4). These words
indicate that the old King was unable to have sexual relations with
this pretty young woman. We have here the case of an old man,
from a high socioeconomic stratum, who had loved many women
during his long life, had wives, concubines and many children, but in
his old age was afflicted by some type of ED.
In King David’s case the relevant information has been extracted
from the patient’s medical file, the biblical text, recorded more than
3000 years ago. In this case, the pertinent biblical passages studied
should be regarded as the patient’s interview.

DEFINITION
ED is defined by a consistent or recurrent inability to attain and/or
maintain penile erection sufficient for sexual activity (1-3).

References
1. NIH Consensus Development Panel on Impotence. NIH consensus
conference: impotence. JAMA. 1993;270:83-90.
2. Korenman SG. Advances in the understanding and management of
erectile dysfunction. J Clin Endocrinol Metab. 1995;60:1985-8.
3. Giuliano F, Droupy S. Erectile dysfunction. Prog Urol. 2013;23(9):629-
37.
457
L. Ben-Nun King David

EPIDEMIOLOGY
ED prevalence is less than 10% in men aged below 50, while 20%
for men over 60 (1). The prevalence of sexual dysfunction increases
with age; about 20-30% of adult men have at least one manifested
sexual dysfunction (2,3). Sexual dysfunction is common among
individuals with chronic illnesses and is associated with distress and
reduced QOL (4).
The aim of this study was to estimate, by race/ethnicity in the US,
the prevalence of ED and the impact of sociodemographic, health,
relationship, psychological, and lifestyle variables. This cross-
sectional, population-based, nationally representative probability
survey conducted between May 2001 and January 2002 in the
general community setting facilitated equivalent representation
among US non-Hispanic white (n=901), non-Hispanic black (n=596),
and Hispanic (n=676) men aged 40 and older by using targeted phone
lists to oversample the minority populations. Estimated prevalence
of moderate or severe ED, defined as a response of "sometimes" or
"never" to the question "How would you describe your ability to get
and keep an erection adequate for satisfactory intercourse?" The
estimated prevalence was 22.0% (95% CI 19.4-24.6) overall, 21.9%
(95% CI 18.8-24.9) in whites, 24.4% (95% CI 18.4-30.5) in blacks, and
19.9% (95% CI 13.9-25.9) in Hispanics, and increased with increasing
age. The OR increased with increasing age. Probability also increased
with DM, hypertension, and moderate or severe LUTS overall; age
≥70 years and DM in whites; severe LUTS in blacks; and age ≥60
years, moderate LUTS, hypertension, and depression in Hispanics. It
decreased with exercise and college vs. less than high school
education overall; with exercise, good relationship quality, and
according to alcohol intake in blacks; and with high school or college
education in Hispanics. In conclusion, the odds of ED increased with
increasing age across race/ethnicity when controlling for
sociodemographic, health, relationship, psychological, and lifestyle
variables (5).
The inability to achieve or sustain an erection satisfactory for
intercourse in at least 75% of attempts is estimated to affect at least
10 million American men (6). Prevalence increases dramatically in
men over 50 years of age, with at least a quarter of older men being
affected (7). In men aged 40 to 70 years, 52% report some degree of
458
L. Ben-Nun King David

sexual dysfunction, 17.1% - mild, 25.3% - moderate, and 9.6%


complete (8).
According to Willie (9), approximately one in 10 men over the age
of 40 is affected by this condition and the incidence is age related.
Fewer than 2% of men with erection problems report that their first
difficulty occurred before age 40 years, and in 4% it occurred
between ages 40 to 49 years. After the age of 50 years, the
percentage of men with ED increases sharply - from 26% between 50
to 59 years to 40% between 60 to 69 years (10).
The aim of this study was to estimate the prevalence and examine
the association of various sociodemographic, mental health,
comorbid conditions and life style factors with sexual dysfunction in
Iraq/Afghanistan veterans. This exploratory cross-sectional study was
conducted using data from the Veteran administrative database. A
total of 4,755 Iraq/Afghanistan veterans were identified who sought
treatment from the Michael E. DeBakey Veterans Affairs Medical
Center inpatient and outpatient clinic between September 2007 and
August 2009. Sexual dysfunction was determined by ICD9-CM codes
related to sexual health issues and/or by specific medications,
primarily PDE-5i, prescribed for ED. The overall prevalence of sexual
dysfunction was 5.5% (n=265). By age category, it was 3.6% (n=145)
for Iraq/Afghanistan veterans aged 18-40 years and 15.7% (n=120)
for Iraq/Afghanistan veterans aged >40 years, respectively. A
multivariate logistic-regression model revealed that annual income,
marital status, PTSD, and hypertension were significant risk factors of
sexual dysfunction (all p<0.05) among younger Iraq/Afghanistan
veterans, whereas among the older Iraq/Afghanistan veterans, being
African American and having PTSD and hypertension were significant
risk factors of sexual dysfunction (all p<0.05). There was marked
discrepancy between documented ED and prescription of a PDE-5i. In
conclusion, a significant proportion of Iraq/Afghanistan veterans
have sexual dysfunction and the risk factors differ between younger
and older veterans. Sexual dysfunction is likely under-coded. To
better identify the scope of the problem, systematic screening for
sexual dysfunction may be appropriate perhaps as part of an initial
post-deployment health evaluation (11).
The aim of this study was to assess the prevalence of ED in
Western Australia and to examine its associated sociodemographic
factors. Postal questionnaires were sent to randomly selected age-
stratified male population samples obtained from the Western
459
L. Ben-Nun King David

Australia Electoral Roll. In addition to items covering


sociodemographic and clinical information, the Australian Standard
Classification of Occupations, the Socioeconomic Index for Area, and
the five-item International Index of Erectile Function were used. Of
4,228 questionnaires, 1,770 (41.9%) were returned. One thousand
five hundred eighty (89.3%) were completed questionnaires from
men aged 20.1 to 99.6 years (mean 57.9, median 59.1, SD 18.5). The
prevalences of any ED and of severe ED among adult males in
Western Australia, adjusted for age distribution, were 25.1% and
8.5%, respectively. Standardized to WHO World Standard Population,
the corresponding prevalences were 23.4% and 7.4%. Prevalence, as
well as severity, of ED increased with age. Thirty-eight percent of the
participants who were married or had partners experienced ED
(severe ED 19.1%). The prevalence of ED was insignificantly different
between "white-collar" and "blue-collar" workers. Despite the great
majority of the affected participants having experienced ED for > one
year, only 14.1% reported having ever received any treatment for ED.
In conclusion, this study has provided population-based
epidemiological data on ED in Western Australian men covering a
wide range of ages. The finding that ED is age related, highly
prevalent, and grossly underdiagnosed and undertreated is pertinent
to global population aging and a rapidly aging Australian population.
To facilitate comparisons across populations with different age
distributions, all future population-based studies on ED should be
standardized to WHO World Standard Population (12).

ASSESSMENT: ED is a prevalent condition, although different


prevalence rates are observed in different countries.

References
1. Giuliano F, Droupy S. Erectile dysfunction. Prog Urol. 2013;23(9):629-
37.
2. Camacho ME, Reyese-Otiz CA. Sexual dysfunction in the elderly: age or
disease? Int J Impot Res. 2005;17 Suppl 1:S52-6.
3. Lewis RW, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk factors for
sexual dysfunction. J Sex Med. 2004;1:35-9.
4. Barsky JL, Friedman MA, Rosen RC. Sexual dysfunction and chronic
illness: the role of flexibility in coping. J Sex Marit Ther. 2006;32:235-53.
5. Laumann EO, West S, Glasser D, et al. Prevalence and correlates of
erectile dysfunction by race and ethnicity among men aged 40 or older in
460
L. Ben-Nun King David

the United States: from the male attitudes regarding sexual health survey. J
Sex Med. 2007;4(1):57-65.
6. Morley JE. Impotence. Am J Med. 1986;80(5):897-905.
7. Slag ME, Morley JE, Elson MK, et al. Impotence in medical clinic
outpatients. JAMA. 1983; 249:1736-40.
8. Feldman HA, Goldstein I, Hatzichriston DG, et al. Impotence and its
medical and psychological correlates: results of the Massachusetts male
ageing study. J Urol. 1994; 151:54-61.
9. Wylie K. Erectile dysfunction. Adv Psychosom Med. 2008;29:33-49.
10. Bacon CG, Mittelman MA, Kawachi I, et al. Sexual function in men
older than 50 years of age: results from the health professionals follow-up.
Ann Intern Med. 2003;139:161-8.
11. Hosain GM, Latini DM, Kauth M, et al. Sexual dysfunction among
male veterans returning from Iraq and Afghanistan: prevalence and
correlates. J Sex Med. 2013;10(2):516-23.
12. Chew KK, Stuckey B, Bremner A, et al. Male erectile dysfunction: its
prevalence in Western Australia and associated sociodemographic factors. J
Sex Med. 2008;5(1):60-9.

ETIOLOGY
Normal erectile function requires the coordination of
psychological, hormonal, neurological, vascular and cavernosal
factors (1,2). Alteration in any of these factors, or their combination,
is sufficient to cause ED (3). Organic causes are the main factor in
90% of cases in men over age 50, while in younger men psychogenic
causes are more common (4). ED often has multiple causes (5-7).
Diagnostic evaluation should include psychosexual, endocrinological,
neurological, vascular, traumatic, and iatrogenic (drugs and surgery)
factors (7).
ED is a sentinel marker for several reversible conditions including
peripheral and coronary vascular disease, hypertension, and DM.
Endothelial dysfunction is a common factor between the disease
states. Concurrent conditions such as depression, late-onset
hypogonadism, Peyronie's disease, and LUTS may significantly
worsen erectile function, other sexual and relationship issues, and
pen's dysmorphobia (8).
Major causes of ED include: vascular diseases such as C-V
problems, particularly hypertension, peripheral vascular diseases,
atherosclerotic disease of the penile artery, and the venous leakage
461
L. Ben-Nun King David

from the corpora cavernosa; endocrine disorders such as


hyperprolactinemia, hypo/hyperthyroidism, DM, hypogonadism that
occurs with increasing age and is characterized by low levels of
testosterone and luteinizing hormone; neurological conditions
including epilepsy, lacunar infarcts and larger strokes, spinal cord
trauma, herniated lumbar disk injury, sensory neuropathy, multiple
sclerosis, Parkinson’s disease, and Alzheimer’s disease; psychological
factors – stress, depression, anxiety disorders, or widower’s
syndrome; social factors; other diseases - kidney diseases, obesity,
COPD, arthritis/degenerative joint disease, hyperlipidemia, cancer,
the sequelae of various operations such as prostatectomy, and
various ostomies; medications - thiazide diuretics, antihypertensive
agents, digoxin, gemfibrozil (Lopid), cimetidine, tranquilizers,
antipsychotics, anti-arrhythmics, statins, niacin, phenytoin;
nutritional - zinc deficiency; and life style such as cigarette smoking,
alcohol abuse, or lack of exercise (9-19).
ED is an independent risk factor for C-V events sharing mutual risk
factors with coronary artery disease. Several guidelines for the
management of ED in C-V disease have been proposed,
recommending cardiologists to routinely inquire about erectile
function. However, males' specific needs and wishes regarding sexual
health care in cardiology are unknown. Male patients' view
concerning possible improvements in sexual health care and
preferred forms of sexual counseling in the cardiology practice was
evaluated. This is a cross-sectional multicentered survey study
among randomly selected males visiting a cardiologist. Of 388
respondents, 296 questionnaires were eligible for analysis. Mean age
of respondents was 62.9 years. Overall, 56% (n=165) had ED, with up
to 86% in patients with heart failure. Mean bother experienced due
to ED was 5.93 (±2.57) on a 0 to 10 scale. Most respondents indicated
to feel comfortable discussing sexual health with the cardiologists
(88%). Of men with ED (n=165), 46% would like to have a
conversation with the cardiologist about possibilities to improve
sexual function, 55% would be helped if questions could be asked
during consultation with a specialized nurse, and 58% would
appreciate written information. Of all respondents (n=296), 28% ever
tried a PDE-5i; 4% received the prescription of the cardiologists. In
conclusion, ED is highly prevalent in patients with a variety of C-V
diagnosis and care for sexual function is mandatory. Patients
indicated that above consultation with the cardiologist, both
462
L. Ben-Nun King David

consultation with a specialized nurse and written information would


be helpful (20).
There are a significant number of men under 40 who experience
ED. In the past, the vast majority of cases were thought to be
psychogenic in nature. Studies have identified organic etiologies in
15-72% of men with ED less than 40 years. Organic etiologies include
vascular, neurogenic, Peyronie's disease, medication side effects and
endocrinologic sources. Vascular causes are commonly due to focal
arterial occlusive disease. Young men with multiple sclerosis, epilepsy
and trauma in close proximity to the spinal cord are at increased risk
of ED. It is estimated that 8% of men with Peyronie's disease are less
than 40 years; with 21% of these individuals experiencing ED.
Medications causing ED include antidepressants, NSAIDs and
finasteride (Propecia), antiepileptics and neuroleptics. Hormonal
sources are uncommon in the young population, however possible
etiologies include Klinefelter's syndrome, congenital
hypogonadotropic hypogonadism, and acquired hypogonadotropic
hypogonadism. The workup of young men with ED should include a
thorough history and physical examination. The significant
prevalence of vascular etiologies of ED in young men should prompt
consideration of nocturnal penile tumescence testing and penile
Doppler ultrasound. Treatment options that may improve ED include
exercise and oral PDE-5i (21).
Most men experience an age-related testosterone decline, which
accounts for some decline in sexual interest and coital frequency
occurring even in healthy older men (22). Testosterone deficiency
may result in a reduction of trabecular smooth muscle content
concomitant with increased accumulation of extracellular matrix and
deposition of adipocytes in the subtunical region. All this can lead to
corporal veno-occlusive dysfunction (23). Androgens exert a direct
effect on penile tissue to maintain erectile function while androgen-
deficiency produces a metabolic and structural imbalance in the
corpus cavernosum, resulting in venous leakage and ED (24). In
humans, androgen-deficiency manifestations include: inadequate
development of the penis and loss of erectile function in prostate
cancer and benign prostatic hyperplasia in patients managed with
medical or surgical castration or antiandrogen therapy (25).
Aging in men is accompanied by a decrease in libido and sexual
activity. A significant proportion of men > 60 years have biochemical
hypogonadism. Hypoandrogenism, which is associated with other
463
L. Ben-Nun King David

conditions that negatively influence erectile activity, may be an


important cofactor in the induction of ED and in the response to
PDE-5i in aging. Measuring plasma testosterone levels in aged men
with ED is essential and treating them (with testosterone) barring
clinical contraindications (26).
Hypogonadism should be considered a medical problem, termed
late onset hypogonadism or testosterone deficiency syndrome, only
when symptoms are present. One of the most common symptoms of
late onset hypogonadism/testosterone deficiency syndrome is sexual
dysfunction. The prevalence of hypogonadism in men with ED ranges
from 1.7% to 35%. In ED patients, hypogonadism is often associated
with reduced sexual desire and nocturnal erections, while association
with sex-induced erection is less evident. This is because
testosterone regulates not only cyclic guanosine monophoshate
formation, through nitric oxide synthase stimulation, but also its
catabolism, through PDE-5i activity. The androgen-dependent PDE-5i
expression could explain the reduced effectiveness of PDE-5i in the
treatment of ED in hypogonadal patients. Recognizing hypogonadism
in patients with ED is essential in order to appropriately treat the
disease (27).
Hypogonadism may play a significant role in the pathophysiology
of ED. A threshold level of testosterone may be necessary for normal
erectile function. Testosterone replacement therapy is indicated in
hypogonadal patients and is beneficial in patients with ED and
hypogonadism (28). It is important to screen all men with ED for
hypogonadism, especially those with history of inadequate response
to prior PDE-5i. The combination of testosterone plus PDE-5i may be
considered for the treatment of ED in men with low to low-normal
testosterone levels, who had inadequate response to treatment with
PDE-5i inhibitors (29). The diagnosis of late onset hypogonadism in
men requires biochemical and clinical evaluation (30).
A definite role of testosterone in ED has been controversial;
however, recent evidence is becoming available which substantiates
a key function for this hormone. Testosterone deficiency is
associated with a decline in ED and testosterone levels are inversely
correlated with increasing severity of ED. ED can be caused by
multifactorial pathologies. ED may be the first symptom of C-V
disease. Testosterone increases the expression of nitric oxide
synthase and PDE-5i, both principal enzymes involved in the erectile
process (31). The effects of testosterone upon sexual function are
464
L. Ben-Nun King David

dose-dependent up to a threshold level that is consistent within an


individual, but markedly variable between individuals, ranging from 2
to 4.5 ng/ml (32).
Did King David suffer from testosterone deficiency and because of
this a decline in erectile function?
Low libido may be secondary to organic ED, or androgen
deficiency, and it may be due to systemic illness, depression or other
psychological problems. ED, androgen deficiency, and decreased
libido appear distributed independently, but overlap to some extent
(33). Since testosterone levels correlate with libido in both sexes,
therapy with testosterone may enhance libido (34). Since “…the king
knew her not” (I Kings 1:4) it is most likely that the King suffered from
low or absent libido relating to some organic disease and/or mental
disorder.
Premature ejaculation is generally acknowledged largely as a
psychogenic dysfunction, usually due to anxiety (35). This type of ED
can be excluded since the King had no sexual relations with the
pretty young woman at all.
Peyronie's disease consists of an acquired penile deformity,
caused by the formation of fibrous plaques within the tunica
albuginea (36), which alter penile anatomy (37). Peyronie's disease
results from a predisposing genetic susceptibility combined with an
inciting event such as micro trauma during intercourse. During the
initial acute phase (6-18 months), the condition may progress,
stabilized, or regress (38). Clinical presentations of this disease
include penile pain, angulation, penile deformities or shortening
during erection, painful erection, palpable plaque or induration
throughout the length of the penile shaft and ED (36,38).
The absence of specific clinical symptoms makes it unlikely that
the King suffered from this disease. There is no data arouse suspicion
that other penile disorders such as priapism, and other anatomical
defects were a cause of his ED (39).
ED is associated with treatable C-V risk factors; therefore,
screening for ED and its C-V risk factors is of clinical importance. The
Sexual Health Inventory for Men questionnaire was handed out to
military personnel aged 25-55 years during routine examinations, in
Israel. Men (n=19,131), a mean age of 34.0 +/- 7.1 years, participated
in routine physical examinations during the years 2001-2005. One of
every four men (25.2%) suffered from ED, which was mild in 18.9%,
mild to moderate in 4.4%, moderate in 1.1%, and severe in 0.7%.
465
L. Ben-Nun King David

Even though treatable C-V risk factors were quite prevalent in the
study group, 45.2% of men suffered from dyslipidemia, 4.2% from
essential hypertension, 1.6% from DM, and 25.6% smoked. ED was
significantly associated with age and DM alone (p<0.0001). In
conclusion, there is a high prevalence of ED and associated treatable
C-V risk factors in Israeli men aged 25-55 years, especially in those
with DM (40).
The medical record of the King, that is the biblical text, gives no
details about the existence of C-V risk factors such as dyslipidemia,
hypertension, DM, or smoking.

References
1. Wagner G, Saenz De Tejada S. Update on erectile dysfunction. BMJ.
1998;316: 678-82.
2. Lue TF. Erectile dysfunction. New Engl J Med. 2000; 342:1802-13.
3. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. N Engl J Med.
1989;321:1648-9.
4. Morley JE. Management of impotence. Diagnostic considerations and
therapeutic options. Postgrad Med. 1993;93:65-72.
5. NIH Consensus Development Panel on Impotence. NIH consensus
conference: impotence. JAMA. 1993;270:83-90.
6. Morley JE. Impotence in older men. Hosp Pract. 1988;23:139-42, 145-
6.
7. Kirby RS. Impotence: diagnosis and management of male erectile
dysfunction. BMJ. 1994;308:957-60.
8. Wylie K. Erectile dysfunction. Adv Psychosom Med. 2008;29:33-49.
9. Giuliano F, Droupy S. Erectile dysfunction. Prog Urol. 2013;23(9):629-
37.
10. Wagner G, Mulhan J. Pathophysiology and diagnosis of male erectile
dysfunction. BJU Int. 1991;88(Suppl)3:3-10.
11. Feldman HA, Goldstein I, Hatzichriston DG, et al. Impotence and its
medical and psychological correlates: results of the Massachusetts male
ageing study. J Urol. 1994;151:54-61.
12. Morley JE, Kaiser FE. Sexual function with advancing age. Geriatr
Med. 1989;73:1483-95.
13. Korenman SG, Morley JE, Mooradian AD, et al. Secondary
hypogonadism in older men: its relation to impotence. J Clin Endocrinol
Metab. 1990;71:963-9.
14. Nephra A, Moreland RB. Neurologic erectile dysfunction. Urol Clin
North Am. 2001;28:289-305.
15. Sullivan, ME, Keoghane SR, Miller MAW. Vascular risk factors and
erectile dysfunction. BJU Int. 2001;87:838-45.
466
L. Ben-Nun King David

16. Phanjoo AL. Sexual dysfunction in old age. Adv Psychiat Treat.
2000;6:270-7.
17. Parmet S, Lynm C, Glass RM. Male sexual dysfunction. JAMA.
2004;291:307
18. Camacho ME, Reyese-Otiz CA. Sexual dysfunction in the elderly: age
or disease? Int J Impot Res. 2005;17 Suppl 1:S52-6.
19. Lewis RW, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk factors
for sexual dysfunction. J Sex Med. 2004;1:35-9.
20. Nicolai MP, van Bavel J, Somsen GA, et al. Erectile dysfunction in the
cardiology practice - a patients' perspective. Am Heart J. 2014;167(2):178-
85.
21. Ludwig W, Phillips M. Organic causes of erectile dysfunction in men
under 40. Urol Int. 2014;92(1):1-6.
22. Martin CE. Factors affecting sexual functioning in 60-79 year old
married males. Arch Sex Behav. 1981;10:399-420.
23. Pan LJ, Xia XY, Huang YF. Androgen deficiency and erectile
dysfunction. Zhonghua Nan Ke Xue. 2006;12:1030-4.
24. Traish A, Kim N. The physiological role of androgens in penile
erection: regulation of corpus cavernosum structure and function. J Sex
Med. 2005;2:759-70.
25. Traish AM, Guay AT. Are androgens critical for penile erections in
humans? Examining the clinical and preclinical evidence. J Sex Med. 2006;
3:382-404.
26. Caretta N, Ferlin A, Palego PF, Foresta C. Erectile dysfunction in aging
men: testosterone role in therapeutic protocols. J Endocrinol Invest. 2005;
28(11 Suppl Proceedings):108-11.
27. Morellli A, Corona G, Filippi S, et al. Which patients with sexual
dysfunction are suitable for testosterone replacement therapy? J Endocrinol
Invest. 2007;30:880-8.
28. Shabsigh R, Rajfer J, Aversa A, et al. The evolving role of testosterone
in the treatment of erectile dysfunction. Int J Clin Pract. 2006;60:1087-92.
29. Shabsigh R. Testosterone therapy in erectile dysfunction and
hypogonadism. J Sex Med. 2005;2:786-92.
30. Stanworth RD, Jones TH. Testosterone for the aging male; current
evidence and recommended practice. Clin Interv Aging. 2008;3:25-44.
31. Blute M, Hakimian P, Kashanian J, et al. Erectile dysfunction and
testosterone deficiency. Front Horm Res. 2009;37:108-22.
32. Buvat J, Bou Jaoudé G. Significance of hypogonadism in erectile
dysfunction. Words J Urol. 2006;24;657-67.
33. Fine SR. Erectile dysfunction and comorbid diseases, androgen
deficiency, and diminished libido. JAOA. 2004;104(1Suppl 1):S9-15.
34. Morley J. Endocrine factors in geriatric sexuality. Clin Geriatr Med.
1991;7:85-93.
467
L. Ben-Nun King David

35. Gottfried LA, Richie JP. Sexual problems. Premature ejaculation. In:
Branch WT (ed.). Office Practice of Medicine. Philadelphia, Toronto: W.B.
Saunders. 1987, pp.1407-14.
36. Briganti A, Salonia A, Deho F, et al. Peyronie’s disease: a review. Curr
Opin Urol. 2003;13:417-22.
37. Hellstrom WJ. History, epidemiology, and clinical presentation of
Peyronie's disease. Int J Impot Res. 2003; Suppl 5:S91-2.
38. Hellstrom WJ. Medical management of Peyronie's disease. J Androl.
2009;30:397-405.
39. Wagner G, Mulhan J. Pathophysiology and diagnosis of male erectile
dysfunction. BJU Int. 1991;88(Suppl)3:3-10.
40. Heruti RJ, Steivil A, Shochat T, et al. Screening for erectile dysfunction
and associated cardiovascular risk factors in Israeli men. Isr Med Assoc J.
2008;10;686-90.

KING DAVID'S CASE


It appears that ED dysfunction afflicted the aged King, and since
he was unable to have sexual relations with a young, pretty woman –
he “knew her not” (I Kings 1:4), his ED was severe, or complete.
Can ED be related to the King's biological changes of aging? These
changes can be included among the factors relating to ED (1).
Although this possibility may exist, the presence of serious disease
and social problems, as described below, rules out advanced age as
the cause of ED in this case.
Previous research indicates that the King suffered from mild
hypothermia (2). It seems very unlikely that this disease was
responsible for ED. King David also suffered from a disease of the
bones “My strength failed…and my bones are consumed” (Psalm
31:11) and “My bones wasted away through my anguished roaring all
day long” (32:3). The first passage indicates that the King’s bones
were used up, his strength was decreased, and he had become weak.
In the second passage, the King’s bones had reached a stage where
they were extremely thin and weak, causing him severe pain. A
condition is compatible with osteoporosis, which affected his bones.
Among the various diseases that may be associated with
osteoporosis, the most likely in this case are senile osteoporosis,
hyperparathyroidism, or malignant disease. An extensive evaluation
468
L. Ben-Nun King David

of these conditions indicates that the diagnosis of malignancy is the


most acceptable (3).
Malignancy is found to be related to the development of ED (1).
In this connection, it seems that the King was affected by either MM,
or carcinoma of the kidney, or prostate, or gastric carcinoma, or CRC
with subsequent metastases to the bones. It follows that one of
these malignant diseases was related to ED in the old King.
The King also suffered from anorexia, fasting, extreme weight loss,
and subsequent cachexia. Among the numerous causes associated
with weight loss, we can consider malignancy, psychosocial problems
such as depression, loneliness, lack of close relationships and friends
on whom he could rely, loss of power and control over his people,
feelings of neglect and negative interpersonal relationships as playing
a part (4).
Common causes of psychogenic ED include performance anxiety,
or a strained relationship and lack of sexual arousal (5,6). King
David's rich sexual history and his high socioeconomic status make
these causes of ED unlikely. Males may also function poorly with
their regular partners while finding the excitement of a new
encounter sufficiently stimulating to allow adequate functioning (7).
This cause of ER can be excluded, since the King was unable to
perform sexual relations with his new sexual partner, a young, pretty
woman.
Depression, deep-seated social factors or relationship conflicts are
identified as causes of ED. The risk of ED associated with depression
is particularly striking, with 90% of severely depressed patients
having moderate to complete ED (5,6,8-12). It has been reported
that King David suffered from MDD (13). It can be concluded
therefore that this mental disorder was also partly responsible for his
ED. Numerous social problems, as listed above, also played a part in
the development of ED as well.
Statistical analysis of data from the 2005-2006 National Social Life,
and Aging Project (NSHAP), a nationally representative US probability
sample of 1,550 women and 1,455 men aged 57-85 years at the time
of interview was carried out. Sexual problems among the elderly
were not an inevitable consequence of aging, but instead responses
to the presence of stressors in multiple domains. This impact may
partly be gender differentiated, with older women's sexual health
more sensitive to their physical health than for men. The mechanism
linking life stress with sexual problems is likely to be poor mental
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L. Ben-Nun King David

health and relationship dissatisfaction. NSHAP results demonstrate


the consistent impact of poor mental health on women's reports of
sexual problems and the less consistent association with men's
problems. The results point to a need for physicians who are treating
older adults experiencing sexual problems to take into account not
simply their physical health, but also their psychosocial health and
satisfaction with their intimate relationship (14).
We see that ED afflicts old patients who suffer from various
psychosocial problems. Thus, an evaluation of each particular
patient, including organic problems and psychosocial extensive
evaluation is recommended.

TO SUM UP: the elderly have suffered from ED since the dawn of
history. The main objective of this research was to evaluate from a
contemporary perspective the biblical description of a geriatric
patient who suffered from ED. This report analyzes the sexual
disorder that affected the biblical King David, the second and
greatest of Israel’s Kings, who ruled the country more than 3537
years ago. A passage “And the maiden was very fair, and she
cherished the king, and ministered to him: but the king knew her not”
(I Kings 1:4) indicates ED that afflicted the biblical King David. Among
various types of sexual dysfunction, ED combined with low or absent
libido was most likely responsible. The numerous possible causes of
King David’s ED include malignancy such as MM, or RCC, or prostate
cancer, or gastric carcinoma, or CRC with metastases to the bones,
MDD and various social problems such as loneliness, lack of close
relationships with friends on whom the King could rely, feelings of
neglect, and loss of power and control over his people. The story of
King David unfolds as possibly the earliest description of an elderly
patient who suffered from ED.

References
1. Phanjoo AL. Sexual dysfunction in old age. Adv Psychiat Treat. 2000;
6:270-7.
2. Ben-Noun L. Was the biblical King David affected by hypothermia? J
Gerontol Med Sci. 2002;57A:M364-7.
3. Ben-Noun L. What was the disease of the bones that affected King
David? J Gerontol A Biol Sci Med Sci. 2002; 57A:M152-4.
4. Ben-Noun L. The disease that caused weight loss in King David the
Great. J Gerontol A Biol Sci Med Sci. 2004;59A: M143-5.
470
L. Ben-Nun King David

5. Araujo AB, Durante R, Feldman HA, et al. The relationship between


depressive symptoms and male erectile dysfunction: Cross-sectional results
from the Massachutes Male Male aging Study. Psychosomat Med.
1998;60:458-65.
6. Shabsigh R, Klein LT, Seidman S, et al. Increased incidence of
depressive symptoms in men with erectile dysfunction. Urology. 1998;52:
848-52.
7. Morley JE. Impotence. Am J Med. 1986;80(5):897-905.
8. Lue TF. Erectile dysfunction. New Engl J Med. 2000; 342:1802-13.
9. Morley JE. Management of impotence. Diagnostic considerations and
therapeutic options. Postgrad Med. 1993;93:65-72.
10. Wagner G, Mulhan J. Pathophysiology and diagnosis of male erectile
dysfunction. BJU Int. 1991;88(Suppl)3:3-10.
11. Johnson LE, Morley JE. Impotence in the elderly. AFP. 1988;38:225-
40.
12. Makhlouf A, Kparker A, Niederberger CS. Depression and erectile
dysfunction. Urol Clin North Am. 2007;34:565-74, vii.
13. Ben-Noun L. Mental disorder that afflicted King David the Great. His
Psychiatry. 2004;15:467-76.
14. Laumann EO, Waite LJ. Sexual dysfunction among older adults:
prevalence and risk factors from a nationally representative U.S. probability
sample of men and women 57-85 years of age. J Sex Med. 2008;5:2300-11.

MENTAL DISORDER
INTRODUCTION
Patients have suffered from mental disorders since the dawn of
history. There is an indication of this in the book of Deuteronomy,
which talks of God’s punishment for those who violate divine
commands: “The Lord shall smite thee with madness, and blindness,
and astonishment of heart” (Deuteronomy 28: 28). Thus, we learn
that even in those ancient times there was a negative attitude
towards some mental illnesses.
Contemporary interpretation of the currently available literature
on mental disorders is important since it may give us a better
understanding of the roots of modern psychiatry. By studying the
mental disorder of a patient from ancient history, modern physicians
can expand their knowledge and thus improve their professional
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L. Ben-Nun King David

skills. Building a bridge to the remote past can be a way of better


coping with today’s psychiatric patient.
The purpose of this article is to determine whether the second
and greatest King of Israel, King David, was affected by some mental
disorder. The study focuses on biblical passages associated with the
King’s mental state, and evaluates his mental status using
contemporary diagnostic criteria. Viewed by a modern physician, the
story of King David unfolds as possibly the earliest description of
mental illness. This case highlights the challenges encountered in the
diagnostic experience.

HISTORICAL BACKGROUND

King David, who ruled Israel more than 3537 years ago, was
“...the son of Ephrathite of Beth-lehem-judah, whose name was Jesse;
and he had eight sons” (I Samuel 17:12). David was the youngest and
tended his father’s sheep. He was a ruddy and handsome young man
(17:42), and even in his youth was already very strong, showing his
skills by killing a lion and a bear. Subsequently, David killed Goliath, a
terrifying giant from the area of Gat, and defeated the Philistines.
Participating in numerous wars, he built a great empire located
between Mesopotamia and Anatolia in the north and Egypt in the
south. King David was an enigmatic warrior, whose name evokes a
mystical power almost like that of a deity (1). Even today, after
thousands of years, King David continues to live in the heart of the
Israeli people. One very popular song proclaims that “David, the King
of Israel, lives, lives and exists.” We can assume that medical
information relating to this great leader is important to many people.
In his old age King David began to suffer from a number of
physical ailments (2,3). Was he also afflicted by some mental
disorder? This article aims to answer this question by studying all
biblical passages relating to the King’s mental state.
The passages “....My soul in distress...” (Psalm 31:8), “...having
agony in my heart daily” (13:3), “My soul is alarmed..” (6:4), “...Heal
my soul ; because I sinned..” (41:5), and “The troubles of my heart are
widened;. bring thou me out of my distress” (25:17) indicate that the
King had some mental problem. What was the mental disorder that
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afflicted King David in his old age? Are mental disorders prevalent in
contemporary days?

References
1. David. In: Encyclopedia of Tanach. The Jerusalem Publishing House
Ltd. 1987, pp. 172-74.
2. Ben-Noun L. What was the disease of the bones that affected King
David? J Gerontol A Biol Sci Med Sci. 2002; 57:M152-4.
3. Ben-Noun, L. Was the biblical King David affected by hypothermia? J
Gerontol A Biol Sci Med Sci. 2002;57: M364-7.

PSYCHIATRIC EPIDEMIOLOGY
US population estimates, based on combined site data, indicate
that 15.4% of the population 18 years of age and over fulfilled criteria
for at least 1 alcohol, drug abuse, or other mental disorder during the
period one month before interview. Men had higher rates of
substance abuse and antisocial personality, whereas women had
higher rates of affective, anxiety, and somatization disorders (1). In
addition, men have a significantly higher rate of cognitive impairment
than women did after controlling for the effects of age, race or
ethnicity, marital status and socioeconomic status (2).
The objective of this study was to present estimates of the
lifetime prevalence of DSM-IV mental disorders with and without
severe impairment, their comorbidity across broad classes of
disorder, and their sociodemographic correlates. The National
Comorbidity Survey-Adolescent Supplement (NCS-A) is a nationally
representative face-to-face survey of 10,123 adolescents aged 13 to
18 years in the continental US. DSM-IV mental disorders were
assessed using a modified version of the fully structured WHO CIDI.
Anxiety disorders were the most common condition (31.9%),
followed by behavior disorders (19.1%), mood disorders (14.3%), and
substance use disorders (11.4%), with approximately 40% of
participants with one class of disorder meeting criteria for another
class of lifetime disorder. The overall prevalence of disorders with
severe impairment and/or distress was 22.2% (11.2% with mood
disorders, 8.3% with anxiety disorders, and 9.6% behavior disorders).
The median age of onset for disorder classes was earliest for anxiety
(six years), followed by 11 years for behavior, 13 years for mood, and
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L. Ben-Nun King David

15 years for substance use disorders. In conclusion, these findings


provide the data on a broad range of mental disorders in a nationally
representative sample of US adolescents. Approximately one in every
four to five youth in the US meets criteria for a mental disorder with
severe impairment across their lifetime. The likelihood that common
mental disorders in adults first emerge in childhood and adolescence
highlights the need for a transition from the common focus on
treatment of US youth to prevention and early intervention (3).
In Great Britain, data were from the Psychiatric Morbidity Survey
(2000), covering a sample of 8.500 responders aged 16-74 years.
Prevalence rates for having any common mental disorder in men
aged 65-69 years (5%, 95% CI 2.7-7.3) were lower than in the age
group 60-64 years (14.5%, 95% CI 10.6-18.5). Prevalence rates in
women peaked at age 50 years and declined thereafter; but no large
changes in the prevalence were evident around age 60 or 65 years.
In men, leaving work early (aged 50-64 years), the prevalence of
common mental disorders remains high until the conventional
retirement age (4).
In France, 36,000 people aged 18 years and older were
interviewed using the Mini International Neuropsychiatric Interview.
Anxiety disorders were most common (17% in men and 26% in
women), while prevalence estimates for mood disorders were 10% in
men and 14% in women. Prevalence of troubles was consistently
higher among those in the lowest occupational categories. Among
those reporting mental disorders, in about 50% their work was
affected (5).
In Austrian tertiary care hospital, two one-year surveys (2003-
2005) were compared. In Survey A, the most common psychiatric
diagnoses were adjustment disorders (21.4%), depressive disorders
(18.5%), and delirium (18.1%). The most prevalent diagnoses in
Survey B were adjustment disorders (24.5%), delirium (18.8%), and
depressive disorders (14.3%) (6).
The prevalence of mental disorders in inpatients in general
hospitals, Germany and Austria, ranges from 41.3% to 46.5%. The
most prevalent groups of psychiatric disorders among general
hospital inpatients are organic mental illness, depressive disorders,
and alcohol dependence or abuse. The prevalence rates of organic
brain syndromes, adjustment disorders with depressed mood, and
alcohol dependence in general hospital inpatients are above of the
general population (7).
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Adults (n=1,394) systematically sampled from Al Ain community,


the United Arab Emirates, were assessed with a modified version of
the CIDI as well as with other psychiatric instrument, Self-Reporting
Questionnaire, and the Structured Clinical interview for DSM-IV Axis
one disorders screening module. Overall prevalence of ICD-10
psychiatric disorder was 8.2% (95% CI 6.7-9.7); while the one-week
prevalence rate of mental distress was 15.6% (95% CI 11.8-19.5) and
the life prevalence rate of mental distress was 18.9% (95% CI 11.5-
25.9). Mood disorders and anxiety (neurotic) disorders were more
common in women while alcohol and substance use disorders were
exclusively confined to men. Female sex, young age, quality of
marital relationship, life events over past year, chronic life difficulties,
physical illness, family history of psychiatric disorders and past
history of psychiatric treatment were associated with ICD-10
psychiatric disorders. Age, sex, exposure to chronic difficulties and
history of psychiatric treatment were the most significant predictors
of ICD-10 psychiatric disorders, while exposure to chronic difficulties,
past history of psychiatric treatment and educational attainment
were the significant predictors of lifetime ever and current mental
distress (8).
In Australia, according to the National Mental Health and Well-
being Survey, of 1,792 elderly responders, 13% reported symptoms
consistent with a mental disorder in the past one month, and 16%
reported symptoms consistent with a mental disorder in the past 12
months. Women experienced higher rates of affective disorders and
GAD and had lower rates of substance abuse compared with men.
After excluding cognitive disorder, increasing age was associated with
less likelihood of having symptoms of any mental disorder. Older age
and never having been married were associated with less likelihood
of having symptoms of an affective disorder (9).
In Chile, of the 2,659 interviewed 352 were over age 64 years.
Elderly adults had lower prevalence rates of lifetime mental disorders
than the younger population, 20% in comparison with 34%.
Dysthymia, agoraphobia, simple phobia, and alcohol dependence
disorders were less common among elderly subjects. Those over the
age of 64 years in comparison with those over the age of 74 had
higher prevalence rates of mental disorders. One third of elderly
responders with major depression had a late onset disorder (10).
Multistage stratified clustered sampling of households in the
Yoruba-speaking parts of Nigeria. Face-to-face interviews used the
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L. Ben-Nun King David

WMH-CIDI. Of the 4,984 people interviewed (response rate 79.9%),


12.1% had a lifetime rate of at least one DSM-IV disorder and 5.8%
had 12-month disorders. Anxiety disorders were the most common
(5.7% lifetime, 4.1% 12-month rates) but virtually neither GAD nor
PTSD were identified. Of the 23% who had seriously disabling
disorders, only about 8% had received treatment in the preceding 12
months. General medical practitioners mostly provided treatment;
only alternative practitioners such as traditional healers treated a
few. In conclusion, the observed low rates seem to reflect
demographic and ascertainment factors. There was a large burden of
unmet need for care among people with serious disorders (11).
A two-phase total population survey of 1,544 adults in an urban
and rural area of Timor Leste was carried out. Phase two yielded a
DSM-IV point prevalence estimate of 5.1% (including psychosis,
1.35%; and PTSD, 1.47%). Psychotic disorders were most disabling,
primarily attributed to supernatural causes and treated mainly by
traditional healers. Those with depression and PTSD experienced
substantial disability but had received little treatment. They
attributed their mental problems to social and traumatic causes (12).
The literature on mental health disorders in Bangladesh was
reviewed to summarize the available data and identify evidence gaps.
Relevant literature on mental disorders within Bangladesh published
between 1975 and October, 2013 through a systematic and
comprehensive search was identified. Relevant information from the
selected articles was extracted. Thirty-two articles met pre-defined
eligibility criteria. The reported prevalence of mental disorders varied
from 6.5% to 31.0% among adults and from 13.4% to 22.9% among
children. Some awareness regarding mental health disorders exists at
community level. There is a negative attitude towards treatment of
those affected and treatment is not a priority in health care delivery.
Mental health services are concentrated around tertiary care
hospitals in big cities and absent in primary care. In conclusion, the
burden of mental disorders is high in Bangladesh, yet a largely
unrecognized and under-researched area. To improvise the mental
health services in Bangladesh, further well-designed epidemiological
and clinical research are needed (13).
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ASSESSMENT: mental disorders are prevalent in the general


population and their pattern varies in different countries.

References
1. Regier DA, Boyd JH, Burke JD Jr, et al. One-month prevalence of
mental disorders in the United States. Based on five Epidemiology
Catchment Area sites. Arch Gen Psychiatry. 1988;45:977-86.
2. Regier DA, Farmer ME, Rae DS, et al. One-month prevalence of mental
disorders in the United States and sociodemographic characteristics: the
Epidemiologic Catchment Area study. Acta Psychiatr Scand. 1993;88:35-47.
3. Merikangas KR, He JP, Burstein M, et al. Lifetime prevalence of mental
disorders in U.S. adolescents: results from the National Comorbidity Survey
Replication - Adolescent Supplement (NCS-A). J Am Acad Child Adolesc
Psychiatry. 2010;49(10):980-9.
4. Melzer D, Buxton J, Villamil E. Decline in common mental disorder
prealence in men during the sixth decade of life. Evidence from the national
psychiatric morbidity survey. Soc Psychiatry Psychiatr Epidemiol. 2004;
39:33-8.
5. Cohidon C, Imberson E, Goldberg M. Prevalence of common mental
disorders and their work consequences in France, according to occupational
category. Am J Ind Med. 2008;52:178.
6. Rothenhäusler HB, Stepan A, Kreiner B, et al. Patterns of psychiatric
consultation is an Austrian tertiary care center - results of a systematic
analysis of 3.307 referrals over 2 years. Psychiatr Danub. 2008;20:301-9.
7. Rothenhäusler HB. Mental disorders in general hospital patients.
Psychiatr Danub. 2006;18:183-92.
8. Abou–Saleh MT, Ghubash R, Daradkeh TK. A1 Ain Community Survey.
I. Prevalence and sociodemographic correlates. Soc Psychiatry Psychiatric
Epidemiol. 2001;36:20-8.
9. Trollor JN, Andeson TM, Sachdev PS, et al. Prevalence of mental
disorders in the elderly: the Australian National Mental Health and Well-
Being Survey. Am J Geriatr Psychiatry. 2007;15:455-66.
10. Kohn R, Vicente B, Salvidivia S, et al. Psychiatric epidemiology of the
elderly population in Chile. Am J Geriatr Psychiatry. 2008;16:1020-8.
11. Gureje O, Lasebikan VO, Kola L, Makanjuola VA. Lifetime and 12-
month prevalence of mental disorders in the Nigerian Survey of Mental
Health and Well-Being. Br J Psychiatry. 2006;188:465-71.
12. Silove D, Bateman C, Brooks RT, et al. Estimating clinically relevant
mental disorders in a rural and an urban setting in postconflict Timor Leste.
Arch Gen Psychiatry. 2008;65:1205-12.
13. Hossain M, Ahmed H, Chowdhury W, et al. Mental disorders in
Bangladesh: a systematic review. BMC Psychiatry. 2014;14(1):216.
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DEPRESSION. MDD is often a chronic, recurrent, and debilitating


disorder with a lifetime prevalence of 16.2% and a 12-month
prevalence of 6.6% in the US. The disorder is associated with high
rates of comorbidity with other psychiatric disorders and general
medical illnesses, lower rates of adherence to medication regimens,
and poorer outcomes for chronic physical illness. While 51.6% of
cases reporting MDD received health care treatment for the illness,
only 21.7% of all MDD cases received minimal guideline-level
treatment. Because the overwhelming majority of patients with
depressive disorders are seen annually by their primary care
physicians, the opportunity to diagnose and treat patients early in
the course of their illness in the primary care setting is substantial,
though largely unfulfilled by our current health care system. The goal
of treatment is two-fold: early and complete remission of symptoms
of depression and eventual recovery to premorbid levels of
functioning in response to acute-phase treatment, and prevention of
relapse during the continuation phase or recurrence during the
maintenance phase. However, only 25% to 50% of patients with MDD
adhere to their antidepressant regimen for the length of time
recommended by depression guidelines, and nearly 50% of
depressed patients referred from primary care to specialty care
treatment fail to complete the referral. Patients with chronic or
treatment-resistant depression often require multiple trials using an
algorithm-based approach involving more than one treatment
strategy. Under conditions of usual care, 40% to 44% of patients with
MDD treated with antidepressants in the primary care setting show a
≥50% improvement in depression scores at four-month follow-up,
compared with 70% to 75% of those treated using collaborative care
models. This demonstrates the importance of factors other than
antidepressant medication per se for achieving treatment
effectiveness (1).
Potential solutions for barriers to improved organization of care of
depressive illness were identified. These included 1] aligning efforts
to improve depression care with broader strategies for improving
care of other chronic conditions; 2] increasing the availability of
depression case management services in primary care; 3] developing
registries and reminder systems to ensure active follow-up of
depressed patients; 4] achieving agreement on how depression
outcomes should be measured to provide outcomes-based
performance standards; 5] providing greater support from mental
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health specialists for management of depressed patients by primary


care providers; 6] campaigns to reduce the stigma associated with
treatment of depressive illness; 7] increased dissemination of
interventions that activate and empower patients managing a
depressive illness; 8] redefining the lack of time of primary care
providers for high-quality depression care as issues in organization of
care and provider training; and 9] development of incentives
(organizational or financial) for high-quality depression care.
Research needs were identified according to what has been learned
to date. Identified research needs included: studies of approaches to
organization of case management, research in new populations (e.g.,
new diagnostic groups, rural populations, the disadvantaged, the
elderly, and those with chronic medical illnesses), research on
stepped care and relapse prevention strategies, evaluation of the
societal benefits of improved depression care, and multisite trials and
meta-analytic approaches that can provide adequate statistical
power to assess societal benefits of improved care (2).
Depression is associated with high morbidity, and (with the
exception of serious heart disease) causes greater impairment to
physical and social functioning, more pain (apart from arthritis) (3),
high medical utilization and more functional impairment than most
chronic medical illnesses. This mental disorder occurs in 2-4% of
persons in the community, 5-10% of primary care patients, and in 10-
14% of medical inpatients (4).
In the US and worldwide, depression is the most common mental
disorder among older adults. This descriptive, correlational study of
314 older adults with chronic conditions examined three measures to
assess depressive symptoms: the CES-D, the CES-D-10, and an ESC.
About 12% of the older adults exceeded the CES-D criteria for severe
depressive symptoms, with the greatest percentage among those
aged 75 to 84 years. The most frequently reported negative emotions
were sadness (by women and elders through age 84) and loneliness
(by men and elders aged 85 and over) (5).
Although effective treatments exit, individuals with depressive
and anxiety disorders can remain ill for years. In the US, in a
community-based cohort study (n=1,642), the estimated national
prevalence of a persistent depressive or anxiety disorder was 4.7%. In
this subgroup, 87% had a chronic comorbid condition. Between
baseline and follow-up, the percentage using appropriate medication
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increased (21% to 29%), but there was insignificant change in the use
of appropriate counseling (19% to 23%) (6).
In a community-based study, Amsterdam, The Netherlands, the
prevalence of depressive symptomatology and risk indicators were
assessed in 2,850 participants aged 75 years or more. The
prevalence of depressive symptoms was 31.1% (7).
The aim of this study was to determine the association between
physical fitness and depressive symptoms among young adults. The
study population consisted of 5,497 males and females, members of
the Northern Finland birth cohort of 1966, who at age 31 completed
fitness tests and filled in a questionnaire including questions about
depressive symptoms (Hopkins' Symptom Checklist-25) and physical
activity. Cardiorespiratory fitness was measured by a four-min step
test and muscular fitness by tests of maximal isometric handgrip and
isometric trunk extension. The OR with 95% CI for having depressive
symptoms were calculated for quintiles groups of physical fitness
using the third, median quintile as reference group, and the results
were adjusted for potential confounding variables. Depressive
symptoms were most common among males and females in the
lowest quintile group of trunk extension test (OR 1.58, 95% CI 1.07-
2.32 for males and OR 1.43, 95% CI 1.03-2.0 for females) and among
males in the lowest quintile group of handgrip strength (OR 1.64, 95%
CI 1.11-2.42) compared to the reference group. Level of self-reported
physical activity was inversely associated with depressive symptoms
both for males (OR 1.74, 95% CI 1.25-2.36) and for females (OR 1.36,
95% CI 1.05-1.75). The cardiorespiratory fitness was not associated
with depressive symptoms (OR 1.01, 95% CI 0.68-1.49 for males and
0.82, 95% CI 0.57-1.16 for females). In conclusion, low level of
isometric endurance capacity of trunk extensor muscles is associated
with high level of depressive symptoms in both sexes. In males, also
poor handgrip strength is associated with increased levels of
depressive symptoms. The physical activity level is inversely
associated with the prevalence of depressive symptoms among
young adults (8).
This cross-sectional study was conducted to determine prevalence
of current depressive, anxiety, and stress-related symptoms on a
Dimensional and Categorical basis among young adults in Ranchi city
of India. A stratified sample of 500 students was selected to be
representative of the city's college going population (n=50,000) of
which 405 were taken up for final analysis. Data were obtained using
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Depression, Anxiety, and Stress Scale to assess symptoms on


dimensional basis and using Mini International Neuropsychiatric
Interview to diagnose on categorical basis. Mean age of students was
19.3 years with an average education of 14.7 years. Ranging from
mild to extremely severe, depressive symptoms were present in
18.5% of the population, anxiety in 24.4%, and stress in 20%. Clinical
depression was present in 12.1% and GAD in 19.0%. Comorbid
anxiety and depression was high, with about 87% of those having
depression also suffering from anxiety disorder. Detecting
depressive, anxiety, and stress-related symptoms in the college
population is a critical preventive strategy, which can help in
preventing disruption to the learning process. Health policies must
integrate young adults' depression, stress, and anxiety as a disorder
of public health significance (9).
Depression is common among elderly in developed countries and
it is more pronounced in institutional settings. The objectives of this
study are to report the magnitude of depression among elderly
having two different residential arrangements and to examine the
association of depression and its established demographic factors in
Pakistan. Data were collected from 141 respondents, 108 were
community residents (Male = 57 and Female = 51) and 33 were living
in the care homes (Male = 29 and Female = 4). Prevalence of
depression as assessed by GDS among community and Care Homes
participants was 31.5% and 60.6%, respectively. On CES-D, 42.6
percent of the community and 69.7 percent of the Care Homes
respondents were deemed depressed. Before adjusting for any other
potential risk factors the odds of being depressed was significantly
increased if the study participants were living in Care Home,
relatively older, female, not currently married, had low educational
level, had lower MMSE scores, and reported lower perceived
emotional and practical support. In a partially adjusted logistic
regression model, an increased risk of depression was not
confounded by any of the above mentioned risk factors. The risk
associated was insignificant when it was adjusted for social support.
In conclusion, these findings are consistent with previous research
and throws light on the dire need for interventions to address mental
health needs of Pakistani elderly (10).
The purposes of this study were: 1] to compare the extent of
depression in the nursing home and community-dwelling elderly
people, and 2] to find the variables including residential status and
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other related variables explaining depression in Korea. Two sets of


secondary data were combined and used to achieve the objectives of
this study. One data set relating to elderly people in nursing homes
was from a part of 2002 Kyunggi Long-term Care System Construction
Study by Kyunggi Research Institute, Kyunggi province, Korea. The
other data set for community-dwelling elderly people was from a
part of 2001 National Long-term Care Study by Korea Institute for
Health and Social Affairs. The data set for this study included 307
elderly people living in nursing homes and 166 elderly people living in
the community. Depression was measured and determined using the
GDS-short form Korean version, with scores of eight or higher to
indicate possible depression. A total of 39.3% (95% CI 32.1-46.9%) of
the sample in the community elderly showed symptoms of
depression, higher than the rate found in the nursing home elderly
(24.0%) (95% CI 19.5-29.2%). The mean (SD) GDS-SF score for the
elderly in the nursing home was 6.1 (3.4), and 7.4 (4.3) for elderly in
the community, the difference being statistically significant (p<001).
In multiple logistic regression analysis, residential status has
appeared as an important predictor after controlling other related
variables. The AOR of depression associated with the nursing home
residents in residential status, all other factors being equal, was 3.14
(95% CI 1.30-7.58). Community-dwelling elderly people have higher
odds of depression. These findings suggest that there is a need to
provide adequate health-related care services for the elderly people
in the community (11).
Geriatric depression is often difficult to recognize as patients tend
to present with somatic complaints, anxiety, or loss of concentration
and memory problems (12,13) rather than depressed mood. When
strict DSM-III criteria are applied, approximately 3% of the elderly
living in the community suffer from MDD (14,15) and 15-20% exhibit
clinically significant depressive syndromes (16,17).
The objective of this study was to determine the prevalence and
correlates of depression among school-going adolescents in Malaysia.
Data from the Malaysia Global School-based Health Survey 2012
were analyzed with additional data from the validated DASS21
(Depression, Anxiety, and Stress) questionnaire. The study revealed
that 17.7% of respondents had depressive symptoms. Multivariate
analysis further showed that feeling lonely (AOR 2.99, 95% CI 2.57-
3.47), Indian ethnicity (AOR 2.00, 95% CI 1.63-2.44), using drugs (AOR
1.85, 95% CI 1.21-2.82), and being bullied (AOR 1.79, 95% CI 1.60-
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L. Ben-Nun King David

1.99) were significantly associated with depressive symptoms. Lack of


parental supervision, alcohol use, and tobacco use were also
significant risk factors. Addressing depressive symptoms among
adolescents may have implications for managing their risks of being
bullied and substance use. This study also highlights the need to
further investigate depressive symptoms among adolescents of
Indian ethnicity (18).

ASSESSMENT: depression is a prevalent mental disorder


worldwide, and its prevalence varies in different countries.

References
1. Trivedi MH, Lin EH, Katon WJ. Consensus recommendations for
improving adherence, self-management, and outcomes in patients with
depression. CNS Spectr. 2007;12(8 Suppl 13):1-27.
2. Von Korff M, Katon W, Unützer J, et al. Improving depression care:
barriers, solutions, and research needs. J Fam Pract. 2001;50(6):E1.
3. Wells K.B, Burman M.A. Caring for depression in America: lessons
learned from early findings of the Medical Outcomes Study. Psychiatr Med.
1991;9:503-19.
4. Katon W, Schulberg H. Epidemiology of depression in primary care.
Gen Hosp Psychiatry. 1992;14:237-47.
5. Zauszniewsky JA, Morris DL, Preechawong S, Chang HJ. Reports on
depressive symptoms in older adults with chronic conditions. Res Theory
Nurs Pract. 2004;18(2-3):185-96.
6. Young AS, Klap R, Shoai R, Wells KB. Persistent depression and anxiety
in the United States: prevalence and quality of life. Psychiatr Serv. 2008;
59:1391-8.
7. van't Veer-Tazelaar PJ, van Marwijk HW, Jansen AP, et al. Depression
in old age (75+), the Piko study. J Affect Disord. 2008;106:295-9.
8. Suija K, Timonen M, Suviola M, et al. The association between physical
fitness and depressive symptoms among young adults: results of the
Northern Finland 1966 birth cohort study. BMC Public Health. 2013 Jun 3;
13:535.
9. Sahoo S, Khess CR. Prevalence of depression, anxiety, and stress
among young male adults in India: a dimensional and categorical diagnoses-
based study. J Nerv Ment Dis. 2010;198(12):901-4.
10. Qadir F, Haqqani S, Khalid A, et al. A pilot study of depression among
older people in Rawalpindi, Pakistan. BMC Res Notes. 2014 Jun 28;7:409.
11. Chung S. Residential status and depression among Korean elderly
people: a comparison between residents of nursing home and those based
in the community. Health Soc Care Community. 2008;16(4):370-7.
12. Georgotas, A. Affective disorders in the elderly: diagnostic and
483
L. Ben-Nun King David

research considerations. Age Ageing. 1983;12:1-10.


13. Fogel BS, Kroessler D. Treating late-life depression on a medical-
psychiatric unit. Hosp Community Psychiatry. 1987; 38:829-31.
14. Lebowitz BD. Diagnosis and treatment of depression in late life: and
overview of the NIH consensus statement. Am J Psychiatry. 1996;4(1
Suppl):3S-6S.
15. Bland JRM, Newman SC, Orn H. Prevalence of psychiatric disorders
in the elderly in Edmonton. Acta Psychiatr Scand. 1988;77(338 Suppl):57S-
63S.
16. Copeland JRM, Dewey ME, Wood, et al. Range of mental illness
among the elderly in the community: prevalence in Liverpool using GMS-Age
cat package. Br J Psychiatry. 1987;150:815-23.
17. Gurland BJ, Cross PS, Katz S. Epidemiological perspective on
opportunities for treatment of depression. Am J Geriat Psychiatry. 1996;4(1
Suppl) 7S-13 S.
18. Kaur J, Cheong SM, Mahadir Naidu B, et al. Prevalence and
Correlates of Depression Among Adolescents in Malaysia. Asia Pac J Public
Health. 2014;26(5 Suppl):53S-62S.

CRITERIA FOR MAJOR DEPRESSION


The well-known criteria of DSM-IV are presented here as a means
for evaluating biblical verses relating to mental distress in King David.
Major depressive syndrome is characterized either by a severely
depressed mood [1] or by loss of interest or pleasure in nearly all
activities [2], with the change in previous level of functioning lasting
for at least two weeks. At least four additional symptoms are
required for a definite diagnosis of the disorder, including changes in
appetite or weight [3], insomnia or hypersomnia [4], psychomotor
agitation or retardation [5], fatigue or loss of energy [6], feelings of
worthlessness or excessive or inappropriate guilt [7], diminished
ability to think or concentrate or indecisiveness [8], and recurrent
unfocused thoughts of death or suicide, or suicide attempt (1,2).
The words “...a broken and depressed heart..”.(Psalm 51:19) and
the verse “I am feeble and depressed: I have groaned by reason of the
suffering of my heart” (38:9) indicate a depressed mood (criterion 1).
The verse “My knees are weak through fasting; and my flesh failed
of fatness” (109:24) describes a significant loss of weight. This loss
may indicate criterion 3.
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L. Ben-Nun King David

The verse “..All the night make I my bed to swim; I water my couch
with my tears” (6:7) points to insomnia during which the King wept
so much that his bed was wet with tears (Criterion 4).
The passages “Fearfulness and trembling are come upon me...”
(55:6), “My heart is shivering within me ..” (55:5) and “..Like a deaf
man I would not hear and like a mute I would not speak..” (38:14)
indicate psychomotor agitation or retardation that are compatible
with criterion 5.
The verse ”My strength failed because of mine iniquity...” (31:11)
indicates fatigue or loss of energy (criterion 6).
The subsequent passages “But I am a worm, and no man; a
disgrace of men, and despised of the people” (22:7) and “I am
forgotten as a dead man out of mine mind: I am like a lost tool”
(31:13) express feelings of worthlessness (criterion 7).
Fear of death and recurrent thoughts of death (criterion 9) are
found in numerous passages: ”...has brought me into the dust of the
earth to death” (22:16), “... the terrible fears of death had fallen
upon me” (55:5), “The sorrows of death compassed me...” (18:5) and
“...The mines of death preceded me..” (18: 6).
This study found 7 criteria for major depression in King David.
Criterion 3 can be related either to depression or to physical illness
such as bone diseases, with the diagnosis of malignancy as the most
probable (1). Since cancer may have a link to depression, this
criterion is removed. Criterion 6 can also be attributed to physical
illness, for example anemia. If criteria 3 and 6 are dropped, there are
still sufficient criteria (5) for a diagnosis of major depression.

References
1. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
2. American Psychiatric Association. Practice Guideline for the Treatment
of Patients with Major Depressive Disorder (Revision). Am J Psychiatry.
2000;157:1-45.

SUBSTANCE-INDUCED MOOD DISORDER


Did King David suffer from a substance-induced mood disorder,
characterized by prominent and persistent mood disturbances
associated with the direct physiological consequences of drug abuse,
or the use of medication such as glucocorticoids, anabolic steroids,
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L. Ben-Nun King David

reserpine in high-dose, and cocaine or amphetamine withdrawal, or


toxic exposure (1-6). In the absence of appropriate anamnestic data,
the diagnosis of substance-induced mood disorder seems unlikely.

References
1. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
2. Goodwin FK, Bunney, W.E Jr. Depressions following reserpine: a
reevaluation. Sem Psychiatry. 1971;3:435-8.
3. Kronke, K. A 75-year-old man with depression. JAMA. 2002;287:1568-
76.
4. Lewis DA, Smith, R.E. Steroid-induced psychiatric syndromes: a report
of 14 cases and a review of the literature. J Affect Disord. 1983;5:319-32.
5. Pope HG Jr, Katz DL. Affective and psychotic symptoms associated
with anabolic steroid use. Am J Psychiatry. 1988;145:487-90.
6. Uzych L. Anabolic-androgenic steroids and psychiatric-related effects:
a review. Can J Psychiatry. 1992;37(1):23-8.

GENERAL MEDICAL CONDITION


A variety of other general medical conditions, apart from
depression, may cause mood symptoms, including neurological
ailments such as Parkinson’s disease, Huntington’s disease,
dementia, stroke, metabolic conditions such as vitamin B12
deficiency, endocrine disorders such as hyper- and
hypoparathyroidism, hyper- and hypoadrenocorticism, C-V disease,
arthritis, autoimmune diseases such as SLE, viral or other infections
such as hepatitis, mononucleosis, HIV, carcinoma of the pancreas,
and sensory loss (1-4). Did the King suffer from any of these medical
conditions? Although it has been previously shown that King David
suffered from mild hypothermia (5), it seems unlikely that this
disorder was the cause of his depression. In the absence of
appropriate anamnestic, physical, and laboratory findings, other
diagnoses seem equally unlikely.

References
1. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
2. Kronke, K. A 75-year-old man with depression. JAMA. 2002;287:1568-
76.
486
L. Ben-Nun King David

3. NIH Consensus Development Panel on Depression in Late Life.


Diagnosis and treatment of depression in late life. JAMA. 1992;268:1018-24.
4. Rothenbacher D, Jaensch A, Mons U, et al. Prognostic value of one-
year course of symptoms of anxiety and depression in patients with
coronary heart disease: Role of physical activity and unmet medical need.
Eur J Prev Cardiol. 2014 Jul 28. pii: 2047487314545317. [Epub ahead of
print]
5. Ben-Noun L. What was the disease of the bones that affected King
David? J Gerontol A Biol Sci Med Sci. 2002; 57:M152-4.

DYSTHYMIC DISORDER
This disorder refers to a chronic mild depressive syndrome, with
insidious onset often commencing in childhood or adolescence,
characterized by less acute, less severe, and less disabling depressive
symptoms, symptomatically subsyndromal and psychologically
intractable to change, which are present for at least two years and
may last for many years (1-5). Dysthymic disorder is a chronic
condition with a protracted course and a high risk of relapse. Almost
all patients with dysthymic disorder eventually develop
superimposed MDD. Although patients with dysthymic disorder
show mild to moderate symptoms, from a longitudinal perspective,
the condition is severe (6,7).
The diagnosis of dysthymic disorder was created in DSM-III and
maintained in DSM-IV to describe a depressive syndrome of mild to
moderate severity of at least two years' duration that did not meet
criteria for MDD. The prevalence of dysthymic disorder is
approximately 2% in the elderly population where subsyndromal
depressions of lesser severity are more common. Dysthymic disorder
was replaced in DSM-V by the diagnosis of "persistent depressive
disorder" that includes chronic major depression and dysthymic
disorder. In older adults, epidemiological and clinical evidence
supports the use of the term "dysthymic disorder." In contrast to
young adults with dysthymic disorder, older adults with dysthymic
disorder commonly present with late age of onset, without major
depression and other psychiatric disorders, and with a low rate of
family history of mood disorders. They often have stressors such as
loss of social support and bereavement, and some have
cerebrovascular or neurodegenerative pathology. A minority has
487
L. Ben-Nun King David

chronic depression dating from youth with psychiatric comorbidity


similarly to young adults with dysthymic disorder. In older adults,
both dysthymic disorder and subsyndromal depression increase
disability and lead to poor medical outcomes. Elderly patients with
dysthymic disorder are seen mainly in primary care where
identification and treatment are often inadequate. Treatment with
antidepressant medication shows marginal superiority over placebo
in controlled trials, and problem-solving therapy shows similar
efficacy. Combined treatment and collaborative care models show
slightly better results, but cost effectiveness is a concern (8).

ASSESSMENT: did King David suffer from this syndrome? The


following verses indicate severe mental distress and significant
suffering: “...a broken and depressed heart (Psalm 51:19); I am feeble
and depressed: I have groaned by reason of the suffering of my heart
(38:9); All the night make I my bed to swim; I water my couch with
my tears (6:7); ...having agony in my heart daily (13:3); .. I am a
worm, and no man; a disgrace of men, and despised of the people"
(22:7); and "I am forgotten as a dead man out of mine mind: and I am
like a lost tool” (31:13). Since dysthymic disorder refers to a mild to
moderate depressive syndrome, the diagnosis of dysthymia seems
unlikely.

References
1. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
2. Akiskal HS. Dysthymic disorder: psychopathology of proposed chronic
depressive subtypes. Am J Psychiatry. 1983;140:11-20.
3. Akiskal HS. Mood disorders: clinical features. In: Sadock B J, Sadock
VA (eds.). Comprehensive Textbook of Psychiatry, 7th ed. Philadelphia:
Lippincott Williams & Wilkins. 2000, pp. 1338-44.
4. Lehmann, H.E. Affective disorders. In: Kaplan HI and Sadock BJ (eds.).
Comprehensive Textbook of Psychiatry, 4th edn. Baltimore: Williams &
Wilkins. 1985, pp. 786- 811.
5. McCullough JP, Kasnetz MD, Braith JA, et al. A longitudinal study of an
untreated sample of predominantly late onset characterological dysthymia.
J Nerv Mental Dis. 1988;176:658-67.
6. Klein DN, Schwartz JE, Rose S, Leader JB. Five-year course and
outcome of dysthymic disorder: a prospective naturalistic follow-up study.
Am J Psychiatry. 2000;157:931-9.
488
L. Ben-Nun King David

7. Klein DN, Shankman SA, Rose S. Ten-year prospective follow-up study


of the naturalistic course of dysthymic disorder and double depression. Am J
Psychiatry. 2006;163:872-80.
8. Devanand DP. Dysthymic disorder in the elderly population. Int
Psychogeriatr. 2014;26(1):39-48.

MINOR DEPRESSION
Did King David suffer from minor depression? Subsyndromal
subthreshold (minor) depression is common and associated with
symptoms of impairments of clinical importance (1). This depression
is a condition in which a person has depressive symptoms but does
not meet the criteria for a depressive disorder. Subthreshold
depression has serious consequences for the QOL, but not as serious
as in the case of a depressive disorder. Subthreshold depression has
considerable economic consequences for the individual concerned,
although again less severe than if the individual had a MDD (2).
Major depression, defined according to DSM IV TR criteria, is less
common in older subjects, while other types of depression are two to
three times more prevalent. This heterogeneous group of
disturbances has received different names: depression not otherwise
specified, minor depression, subthreshold or subsyndromal
depression. Moreover, each condition has been defined using
heterogeneous criteria by different authors. The term of
subthreshold depression will be adopted in this position statement.
Subthreshold depression has been associated with the same negative
consequences of major depression, including reduced well being and
QOL, worsening health status, greater disability, increased morbidity
and mortality. Nevertheless, there is a dearth of clinical trials in this
area, and therefore older patients with subthreshold depression are
either not treated or they are treated with the same non-
pharmacological and pharmacological therapies used for major
depression, despite the lack of supporting scientific evidence. There
is an urgent need to reach a consensus concerning the diagnostic
criteria for subthreshold depression as well as to perform clinical
trials to identify effective and safe therapies in this too long
neglected patient group (3).
DSM-IV criteria for this disorder include two to four depressive
symptoms, such as depressed mood or anhedonia, causing significant
impairment in social, occupational or other important areas of
489
L. Ben-Nun King David

functioning for at least two weeks (4,5). Minor depression, an


unofficial diagnosis that has been designated for further research
study, is defined as a mental disorder with an insufficient number of
symptoms for a diagnosis of major depression (4-6).
Subsyndromal symptoms in bipolar disorder are strongly
associated with both social and occupational functioning (7,8), but
not as serious as in the case of a depressive disorder. Subjects with
subthreshold depression have an increased risk of developing a major
depression (9).
Was King David afflicted by minor depression? Since this study
found sufficient diagnostic criteria for major depression, the
diagnosis of minor depression is disregarded in King David’s case.

References
1. Lyness JM, Kim J, Tang W, et al. The clinical significance of
subsyndromal depression in older primary care patients. Am J Geriatr
Psychiatry. 2007;15:214-23.
2. Cuijpers P, Smit F. Subclinical depression: a clinically relevant
condition? Tijdscr Psychiatr. 2008;50:519-28.
3. Cherubini A, Nisticò G, Rozzini R, et al. Subthreshold depression in
older subjects: an unmet therapeutic need. J Nutr Health Aging.
2012;16(10):909-13.
4. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
5. Williams JW, Hitchcock P, Cordes JA, et al. Is this patient clinically
depressed? JAMA. 2002;287:1160-70.
6. Pincus HA, Davis WW, McQueen LE. “Subthreshold” mental disorders:
a review and synthesis of studies on minor depression and other “brand
names”. Br J Psychiatry. 1999;174:288-96.
7. Marangell. LB. The importance of subsyndromal symptoms in bipolar
disorder. J Clin Psychiatry. 2004;65 Suppl 10:24-7.
8. Altshuler LL, Gitlin MJ, Mintz J, et al. Subsyndromal depression is
associated with functional impairment in patients with bipolar disorder. J
Clin Psychiatry. 2002;63:807-11.
9. Cuijpers P, Smit F. Subclinical depression: a clinically relevant
condition? Tijdscr Psychiatr. 2008;50:519-28.
490
L. Ben-Nun King David

STRATEGIES FOR DIAGNOSING DEPRESSION


There are a number of strategies for diagnosing depression. In
DSM-III-R and DSM-IV, the approach of counting symptoms toward
depression is “etiological”. According to this strategy, symptoms are
counted towards the diagnosis of depression only if the clinician
decides that a particular symptom is not due to “..a physical
condition” (DSM-III-R) or “.. a general medical condition “ (1,2). The
reliability of this method is poor given the lack of a standard for the
decision (3).
In King David’s case all the relevant information was extracted
from the patient’s medical file (the biblical text), recorded more than
3,537 years ago. Since the clinical diagnosis of depression is usually
based on an interview with the patient (4), the pertinent biblical
passages should be regarded as interviews. According to the
“etiological” strategy, King David was afflicted by MDD.
The “inclusive” approach counts all depressive symptoms towards
the diagnosis of depression, regardless of whether the clinician
judges that any symptom is due to medical or psychological causes
(5). This approach is highly sensitive and reliable, since the only
decision needed is whether the relevant symptom is present or not
(6). When the two approaches are compared, the etiological
approach is found to be less reliable than the inclusive approach (5).
The “inclusive” strategy, however, has been criticized as having poor
specificity and for inflating rates of depression (6), since all relevant
symptoms, regardless of cause, are taken into account in the
diagnosis of depressed mood. If this approach is adopted, King David
was certainly afflicted by major depression.
A third strategy, called the “substitutive” approach, eliminates
symptoms that are most likely to be confused with medical illness,
such as loss of energy, weight loss, psychomotor changes and
impaired concentration (7). In place of these symptoms,
consideration is more likely to be given to symptoms that are
cognitive or affective in their origin, such as irritability, tearfulness,
feelings of being punished, or social withdrawal (7,8). Irritability is
identified in the passage “...Why hast thou forgotten me? why go I
mourning because of the pressure of the enemy? (Psalm 42:10).
Tearfulness is shown by ” I water my couch with my tears”(6:7).
Feelings of being punished can be seen in the passage “...neither is
there any rest in my bones because of my sin” (38:4). Social
491
L. Ben-Nun King David

withdrawal is indicated by the passage “But I am a worm, and no


man; a disgrace of men, and despised of the people.” (22:7). Thus,
the substitutive approach also indicates that King David suffered
from depression.
An additional simple method for diagnosing depression is a case
finding instrument. A single question “Have you felt depressed or
sad much of the time in the past year?” is asked to elicit a yes or no
response (9). The simple question strategy was compared with a 20-
item Questionnaire from the Center for Epidemiological Studies of
Depression that focuses on depressive symptoms within the last
week (10). The simple question strategy was found to have similar
performance characteristics to the longer questionnaire and is more
feasible because of its brevity (11). If the simple question had been
posed to the King, the answer would have been “...a broken and
depressed heart..” (Psalms 51:19) and “I am feeble and depressed ”
(38:9). Such answers are a convincing indicator of depression.
Although no time spans are given for the duration of the depression,
it is most likely that the King had suffered from the depression for a
long time.

ASSESSMENT: according to different diagnostic strategies, King


David was afflicted by MDD causing clinically significant mental
distress.

References
1. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
2. Koenig HG, George, L.K., Peterson, B.L, et al. Depression in medically ill
hospitalized older adults: prevalence, characteristics, and course of
symptoms according to six diagnostic schemes. Am J Psychiatry.
1997;154:1376-83.
3. Cohen-Cole S, Stoudemire A. Major depression and physical illness:
special considerations in diagnosis and biologic treatment. Psychiat Clin
North Am. 1987;10:1-17.
4. Kronke, K. A 75-year-old man with depression. JAMA. 2002;287:1568-
76.
5. Williams JW, Hitchcock P, Cordes JA, et al. Is this patient clinically
depressed? JAMA. 2002;287:1160-70.
6. Koenig HG, George LK, Peterson BL, et al. Depression in medically ill
hospitalized older adults: prevalence, characteristics, and course of
symptoms according to six diagnostic schemes. Am J Psychiatry. 1997;154:
1376-83.
492
L. Ben-Nun King David

7. Endicott J. Measurement of depression in patients with cancer.


Cancer. 1984;53:(10 suppl):2243-49.
8. Cavanaugh S, Clark D, Gibbon R. Diagnosing depression in the
hospitalized medically ill. Psychosomatics. 1983;24:809-15.
9. Rost K, Burman MA, Smith GR. Development of screeners for
depressive disorders and substance disorder history. Med Care.
1993;31:189-200.
10. Radloff LS. The CES-D scale: a self report depression scale for
research in the general population. Appl Psychol Meas. 1977; 1:385-401.
11. Williams JW, Mulrow CD, Kroenke K, et al. Case-finding for
depression in primary care: a randomized trial. Am J Med. 1999; 106:36-43.

MECHANISM OF DEPRESSION DEVELOPMENT


Stressful and adverse life events are a potent factor in predicting
major depression (1-4). Certain cognitive personality characteristics
also indicate susceptibility to depression (5). Beck’s cognitive theory
of depression proposes that the cognitive personality characteristics
of sociotropy and autonomy act as “vulnerability markers for
depression by sensitizing individuals to certain types of negative life
experiences” (5). Interactions between sociotropy (or interpersonal
dependency), characterized by a strong need for close relationships
and concern over disapproval (6) and negative interpersonal events,
such as the death of a loved one, have been reported to predict
depression (7). In addition, the major factors associated with major
depressive episode include urban residency, smoking, alcohol
intoxication, chronic medical conditions for both sexes, and being
single and obese only for males (8).
The aim of this study was to determine whether, in a general
population sample, different categories of adverse life events were
associated with different patterns of depressive symptoms. A total of
4,856 individuals (53% female) who experienced depressive
symptoms in the previous year were assessed in up to four waves
over a maximum of 12 years. At each wave, participants reported the
severity of 12 symptoms disaggregated from the nine DSM-III-R
criteria for major depression and the self-identified cause of these
symptoms, which were classified into nine categories of adverse life
events. The patterns of depressive symptoms associated with the
nine categories of adverse life events differed significantly. Deaths of
loved ones and romantic breakups were marked by high levels of
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L. Ben-Nun King David

sadness, anhedonia, appetite loss, and (for romantic breakups) guilt.


Chronic stress and, to a lesser degree, failures were associated with
fatigue and hypersomnia, but less so with sadness, anhedonia, and
appetite loss. Those who reported that no adverse life events caused
their dysphoric episodes reported fatigue, appetite gain, and
thoughts of self-harm, but less sadness or trouble concentrating.
These symptom patterns were found in a between-persons analysis
of participants who had a single dysphoric episode, and they were
replicated in an independent within-persons analysis of episode-
specific symptom deviations among individuals with multiple
episodes. Similar results were obtained when the sample was
restricted to those meeting DSM-III-R diagnostic criteria for major
depression. In conclusion, depression is a pathoplastic syndrome.
Different types of life events are related to different depressive
symptom profiles. The results from the within-persons analysis
suggest that these relationships are causal (9).
As mentioned previously, depressive symptoms are highly
prevalent in the elderly population and increase with age. This
increase seems to be attributable to age-related changes in risk
factors rather than to ageing itself (10).
Patients with depression often go under diagnosed or are
misdiagnosed. The evidence suggests a multifactorial etiology for this
problem. Many patients with depression selectively focus on the
somatic components of their depressive syndrome and minimize or
even deny affective and cognitive symptoms. Depression and medical
disorders also often occur concomitantly with depression causing
amplification of somatic complains (11).
Evolved mechanisms, and underpinning attachments and social
rank behavior are the basis for some forms of major depression,
especially those associated with chronic stress. Some of depression
core symptoms, such as behavioral withdrawal, low self-esteem and
anhedonia, may have evolved in order to regulate behavior and
mood and convey sensitivity to threats and safety. Focusing on the
evolved mental mechanisms for attachment and social rank helps to
make sense of depression's common early vulnerability factors (e.g.,
loss of close relationships, being defeated and/or trapped in low
socially rewarding or hostile environments), and the psychological
preoccupations of depressed people (e.g., sense of unloveliness, self
as inferior and a failure) (12).
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L. Ben-Nun King David

The extent to which loneliness is a unique risk factor for


depressive symptoms was determined in two population-based
studies of middle-aged to older adults, and the possible causal
influences between loneliness and depressive symptoms were
examined longitudinally in the second study. In study one, a
nationally representative sample of persons aged 54 years and older
completed a telephone interview as part of a study of health and
aging. Higher levels of loneliness were associated with more
depressive symptoms, net of the effects of age, gender, ethnicity,
education, income marital status, social support, and perceived
stress. In study two, detailed measures of loneliness, social support,
perceived stress, hostility, and demographic characteristics were
collected over a three-year period from a population-based sample of
adults' ages 50-67 years from Cook County, Illinois. Loneliness was
again associated with more depressive symptoms, net of the effect of
age, gender, ethnicity, education, income, marital status, social
support, and perceived stress. Latent variable growth models
revealed reciprocal influences over time between loneliness and
depressive symptomatology. These data suggest that loneliness and
depressive symptomatology can act in a synergistic effect to diminish
well-being in middle-aged and older adults (13).
A study investigated relationships between loneliness, health, and
depression in 216 older men (>65 years). A diagnosis of illness or
disability was unrelated to depression, however, self-reported health
was associated with depression, with those reporting poorer heath
experiencing greater depression. Social support variables were
unrelated to depression. The most significant relationship to
depression was that of loneliness. Although depression is often a
response to declining health and functional impairment in the older
adult, the present finding suggest that social isolation may influence
the experience of depression. Age-related losses such as loss of
professional identity, physical mobility and the inevitable loss of
family and friends can affect a person's ability to maintain
relationships and independence, which in turn may lead to a higher
incidence of depressive symptoms (14).
Within a prospective population-based study of 85-year-olds, the
15-item Geriatric Depression Scale and the Loneliness Scale were
annually applied to 476 participants with a MMSE score of 18 points
or more, the Section of Gerontology and Geriatrics, The Netherlands.
Depression was present in 23% and was associated with marital
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L. Ben-Nun King David

status, institutionalization, and perceived loneliness. When


depression and perceived loneliness were assessed during follow-up,
neither depression nor perceived loneliness had a significant effect
on mortality. However, those who suffered from both depression and
feelings of loneliness had a 2.1 times higher mortality risk (15).
The intense focus on major psychiatric disorders in both
contemporary psychiatric research and clinical practice has resulted
in the relative neglect of less definable constructs such as loneliness
and how such entities might affect health outcomes. The purpose of
this review is to raise awareness among physicians and psychiatrists
of the medical impact and biological effects of loneliness as well as
making the argument that loneliness should be a legitimate
therapeutic target. Using Pubmed the literature for research and
review papers was looked at loneliness as a construct, how it is
measured and its health effects. The relevant papers were reviewed
and have summarized their main findings. Loneliness has strong
associations with depression and may in fact be an independent risk
factor for depression. Loneliness appears to have a significant impact
on physical health being linked detrimentally to higher BP, worse
sleep, immune stress responses and worse cognition over time in the
elderly. There is a relative deficiency in adequate evidence based
treatments for loneliness. In conclusion, loneliness is common in
older people and is associated with adverse health consequences
both from a mental and physical health point of view. There needs to
be an increased focus on initiating intervention strategies targeting
loneliness to determine if decreasing loneliness can improve QOL and
functioning in the elderly (16).
The impact of recent life events in the provoking of depressive
episodes is well established, but their weight in the course of
depression has not been frequently studied. Firstly, life events
occurring before the beginning of the episode are predicative neither
of the response to treatment, nor of the long-term evolution of
major depressive episodes. Reactional depression is more sensitive
to placebo than non-reactional depression, and, minor reactional
depression could have a better spontaneous course. Secondly,
stressful life events and long-lasting difficulties are contemporary
with the episode and are some of the most important clues for
durability, and sometimes chronicity, of depressive symptoms. Some
of those events are independent (not controlled by the subject), but
some are dependent, produced by the subject and his depressive
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L. Ben-Nun King David

state. On the other hand, certain types of life events (like


"neutralizing events" or "fresh start events") and the stress reduction
of long-lasting difficulties seem to favor remission of minor
depression. Thirdly, weight of life events in relapse and recurrence of
depression is significant, but seems to be less important than the
release of first depressive episodes. The interaction between life
events and the genesis of depression can be observed from
sociological, psychological or biological point of view (17).

ASSESSMENT: the mechanisms of the development of depression


in King David’s case are demonstrated by the passages “Be not far
from me; for trouble is near; for there is no help “ (Psalm 6:12), “I am
helpless” (25:16) and “I am wretched..” (6:3). Here we learn about
the King’s loneliness, need for close relationships and lack of friends
on whom he can rely. Additional passages: “But I am a worm, and
no man; a disgrace of men, and despised of the people” (22:7) and “I
am forgotten as a dead man out of mine mind. I am like a lost tool”
(31:13) show loss of power and control over his people, feelings of
neglect and negative interpersonal relationships. Thus, persistent
negative stress and negative interpersonal experiences played a role
in the development of his major depression. The King was aware of
his iniquity, wickedness and sin “...my strength failed because of mine
iniquity” (31:11) and “Save me from all my sins...” (39:9). All these
causes acted together in the development of the King’s mental
disorder. The interaction between life events and the genesis of
depression involves sociological and psychological dimensions.

References:
1. Bebbington P, Tennant C, Hurry J. Adversity and the nature of
psychiatric disorder in the community. J Affect Disord. 1981; 3:345-66.
2. Roy A, Breier A, Doran AR, Pickar D. Life events in depression:
relationships to subtypes. J Affec Disord. 1985;9:143-8.
3. Shrout, P, Link B, Dohrenwend B, et al. Characterizing life events as
risk factors for depression: the role of fateful loss events. J Abnorm Psychol.
1989;95:460-67.
4. Mazure CM, Bruce ML, Maciejewski PK, et al. Adverse life events and
cognitive-personality characteristics in the prediction of major depression
and antidepressant response. Am J Psychiatry. 2000;157:896-903.
5. Beck AT. Cognitive model of depression. Journal Cogn Psychother.
1987;1:2-27.
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L. Ben-Nun King David

6. Clark D, Beck AT, Brown G. Sociotropy, autonomy, and life event


perceptions in dysphoric and nondysphoric individuals. Cogn Ther Res.
1992;16:635-62.
7. Hammen, C, Ellicot, A., Gitlin, M. et al. Sociotropy/autonomy of
relapse and vulnerability to specific life events in patients with unipolar
depression and bipolar disorders. J Abnorm Psychol. 1989;98:154-60.
8. Lindeman S, Hämäläinen J, Isometsä E, et al. The 12-month prevalence
and risk factors for major depressive episode in Finland: representative
sample of 5993 adults. Acta Psychiatr Scand. 2000;102:178-84.
9. Keller MC, Neale MC, Kendler KS. Association of different adverse life
events with distinct patterns of depressive symptoms. Am J Psychiatry.
2007;164(10):1521-9; quiz 1622. Erratum in Am J Psychiatry. 2008;
165(3):401.
10. van'tVeer-Tazelaar PJ, van Marwijk HW, Jansen AP, et al. depression
in old age (75+), the Piko study. J Affect Disord. 2008;106:295-9.
11. Katon W. The epidemiology of depression in medical care. Int J
Psychiatry Med. 1987;17:93-112.
12. Sloman L, Gilbert P, Hasey G. Evolved mechanisms in depression: the
role and interaction of attachment and social rank in depression. J Affect
Disord. 2003;74:107-21.
13. Cacioppo JT, Hughes ME, Waite LJ, et al. Loneliness as a specific risk
factor for depressive symptoms: cross-sectional and longitudinal analyses.
Psychol Aging. 2006;21:140-51.
14. Alpass FM, Neville S. Loneliness, health and depression in older
males. Aging Ment Health. 2003;7:212-6.
15. Stek ML, Vinkers DJ, Gussekloo J, et al. Is depression in old age fatal
only when people feel lonely? Am J Psychiatry. 2005;162:178-80.
16. Luanaigh CO, Lawlor BA. Loneliness and the health of older people.
Int J Geriatr Psychiatry. 2008;23(12):1213-21.
17. Hardy P, Gorwood P. Impact of life events in the course of
depression. Encephale. 1993;19 Spec No 3:481-9.

OUTCOME

Information on the naturalistic outcome of MDD is important in


developing rational clinical practices. The Vantaa Depression Study is
a prospective, naturalistic cohort study of 269 secondary-level care
psychiatric outpatients and inpatients diagnosed with a new episode
of DSM-IV MDD. The median length of time that patients met full
criteria for a major depressive episode was 1.5 (95% CI 1.3-1.7)
months, and the median time to full remission was 8.1 (95% CI 5.2-
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L. Ben-Nun King David

11.0) months after entry. During the follow-up, 38% had a


recurrence. Although numerous factors predict outcome of MDD to
some extent, severity of depression and current comorbidity were
the two most important predictors of longer episode duration and
recurrence. The course of MDD in modern psychiatric settings
remains unfavorable. Any estimates of duration of depressive
episodes and rates of recurrence are likely to be dependent on the
severity of depression and level of comorbidity. At least among a
population of mostly outpatients with MDD in medium-term follow-
up, severity of depression and comorbidity appears to be more useful
predictors of recurrence than does the number of prior episodes (1).
In Dublin, 100 consecutive depressed inpatients were followed
prospectively over 18 months. The cumulative probabilities of
remission onset by three and 18 months were 0.67 (95% CI 0.57-0.77)
and 0.82 (95% CI 0.74-0.90). The cumulative probability of relapse
was 0.25 (95% CI 0.15-0.35); 53% of those relapsing did so in the first
two months. Younger age at onset, longer illness length, and higher
depression and anxiety ratings predicted delayed remission onset (2).
Inpatients and outpatients (n=150) 60 years and older with major
depression were enrolled in a naturalistic treatment study and
followed up for 10 years; 34.8% of the patients had comorbid MDD
and dysthymia at baseline enrollment. Compared with those with
major depression alone, they had longer time to both partial (median
number of days = 175 vs. 106) and full remission (median number of
days = 433 vs. 244) from MDD. The effect of having comorbid
dysthymia was not consistent over time, with patients with both
disorders having higher predicted scores after initial response. Older
patients with comorbid major depression and dysthymia have a less
favorable trajectory of recovery compared with those with
depression alone (3).
Major depression can affect up to 10% of older adults in clinical
samples. Longitudinal studies of older adults with major depression
report that a significant proportion of patients do not fully recover.
Partial remission or symptoms of major depression that do not meet
criteria for major depression, is predicted by 1] clinical factors, such
higher number of symptoms at diagnosis, presence of comorbid
dysthymia, and health problems; 2] social variables, such as high
levels of perceived stress and low levels of perceived social support;
and 3] perceived health/well-being variables, such as limitations in
mobility or instrumental activities of daily living, poorer self-
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L. Ben-Nun King David

perceived health, finding life not satisfying, and looking back over life
and finding it unhappy. Treatment options include antidepressants
(alone or in combination) and psychotherapy (4).
Screening surveys of depressive symptoms were conducted
among primary care patients at six sites in different countries.
Subjects aged 18 to 75 were recruited from participating primary
care facilities in Beer Sheva (Israel), Porto Alegre (Brazil), Melbourne
(Australia), Barcelona (Spain), St Petersburg (Russian Federation) and
Seattle (USA). Depressive symptoms were measured by CES-D. A
total of 18,489 patients were screened, of whom 37% overall (range
24-55%) scored ≥16 on the CES-D and 28% (range 17-42%) scored ≥
20. Overall, 13% reported current treatment for depression (range 4-
23%). Patients with higher depressive symptoms scores had worse
health, functional status, QOL, and greater use of health services
across all sites. Among those with a CES-D score ≥16, subjects
reporting treatment for depression were more likely than those
reporting no treatment to be satisfied with their health (except St
Petersburg), and have higher depressive scores. Higher depressive
symptom scores in primary care patients were consistently
associated with poorer health, functional status and QOL, and
increased health care use, but not with demographic variables (5).
An association between major and subsyndromal depression on
QOL and attitudes toward aging was examined in a large
international sample. A cross-sectional study assessed 4,315
responders in 20 countries from five continents. The study used the
WHOQOL Assessment for Older Adults, known as the WHOQOL-OLD;
the brief version of the WHOQOL instrument, known as WHOQOL-
BREF; and the Attitudes to Ageing Questionnaire. Even relatively
minor levels of depression were associated with a significant
decrease in all QOL domains and with a pattern of a negative
attitudes toward aging (overall WHOQOL-OLD R(2) change = 0.421).
QOL and attitudes toward aging scores were lower as depression
intensity is increased, even in subsyndromal levels (overall WHOQOL-
OLD mean scores of 97.7 vs. 86.4, p<0.001). This phenomenon
happened not only for clinically depressed individuals but also for
subsyndromic individuals (6).
QOL in depression could be of great value as an outcome
measure, especially in determining the effectiveness of treatment
strategies. However, for this aim to be accomplished, it is important
to clarify the relationship between QOL and a number of potentially
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mediating factors, such as sociodemographic and clinical variables.


For this purpose, 140 depressed outpatients with the Mini
International Neuropsychiatric Interview, the WHOQOL BREF, and the
BDI were assessed. After standard and stepwise multiple regression
analyses, the following variables predicted independently QOL: BDI
score for the physical (adjusted R(2)=0.125) and psychological
(adjusted R(2)=0.23) domains, and for the overall QOL estimate
(adjusted R(2)=0.226); age, suicidality according to the MINI and BDI
score for the social relations domain (adjusted R(2)=0.244); and
ethnicity, psychiatric comorbidity, psychotic symptoms and BDI score
for the environmental domain (adjusted R(2)=0.328). Limitations of
the study include its cross-sectional design, relatively small sample
size, and lack of objective measures of depressive symptomatology.
Sociodemographic and clinical variables explain less than 32.8% of
the variance of QOL in subjects with depressive disorders (7).
The objective this study was to evaluate the association between
depressive symptoms and social functioning in individuals (n=2.201)
at primary care services, Porto Alegre, Brazil. The intensity of
depressive symptoms (measured by CES-D) was 20.2 for women and
16.2 for men. Depressive symptoms have a strong association with
poor social functioning and QOL and a high utilization of health
resources in primary care patients (8).
An additional cross-sectional study was carried out in a primary
care clinic also in a Brazil. The cases were divided into three groups
according to the severity of depressive symptoms: 1] subjects with
MDD; 2] subjects with subsyndromal depression; 3] subjects without
depressive symptoms - controls. The sample consisted of 438
primary care users (35.2% of them had subsyndromal depression).
The subjects with MDD presented the worst impairment of QOL,
which was measured by the WHOQOL- BREF and the QLDS. The
patients with subsyndrome depression have a smaller impact on their
QOL and the subjects without depression presented an even lower
impact. The hierarchical linear regression involving demographic
variables and the severity of depressive symptoms showed that the
severity of depression was the variable with higher correlation with
QOL dimensions, presenting increased variation in the domains (from
9% to 24%) (9).
Predictors of depression severity and functional impairment at 10-
year outcome include older age, less education, concurrent anxiety
disorder, greater familial loading for chronic depression, a history of a
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L. Ben-Nun King David

poorer maternal relationship in childhood, and a history of childhood


sexual abuse (10).

ASSESSMENT: a significant proportion of older adults with MDD


do not fully recover. Severity of depression and current comorbidity
are the two most important predictors of longer episode duration
and recurrence. Younger age at onset, longer illness length, higher
depression and anxiety ratings, predicted delayed remission onset.
The course of MDD in modern psychiatric settings remains
unfavorable.
Higher depressive symptom scores in primary care patients are
consistently associated with poorer health, functional status and
QOL, and increased health care use, but not with demographic
variables.
Even relatively minor levels of depression are associated with a
significant decrease in all QOL domains and with a pattern of
negative attitudes toward aging. Depressive symptoms have a strong
association with poor social functioning and QOL and a high
utilization of health resources in primary care patients.
These studies show that both major depression and subsyndromal
depression cause severe impairment of the QOL. We can conclude
that the QOL, as well as functional status and health were impaired
significantly in the King's case, who was afflicted by MDD.
Was social functioning impaired in King David's case? The
passages: “But I am a worm, and no man; a disgrace of men, and
despised of the people” (Psalms 22:7) and “I am forgotten as a dead
man out of mine mind. I am like a lost tool” (31:13) indicate a severe
impairment of social functioning due to loss of power and control
over his people.
What was the outcome of MDD in King David's case? The King's
medical record, that is the biblical text, did not show any
improvement in the King's mental status. We can assume that
outcome of his mental disorder was poor.

References
1. Melartin TK, Rytsälä HL, Leskelä US, et al. Severity and comorbidity
predict episode duration and recurrence of DSM-IV major depressive
disorder. J Clin Psychiatry. 2004;65:810-9.
2. O'Leary D, Costello F, Gormley N, Webb M. Remission onset and
relapse n depression. A 18-month prospective study of course for 100 first
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admission patients. J Affect Disord. 2000;57:158-71.


3. Hybels CF, Pieper CF, Blazer DG, et al. The course of depressive
symptoms in older adults with comorbid major depression and dysthymia.
Am J Geriatr Psychiatry. 2008;16:300-9.
4. Hybels CF, Blazer DG, Steffens DC. Partial remission. A common
outcome in older adults treated for major depression. Geriatrics.
2006;61(4):22-6.
5. Herrman H, Patrick DL, Dieh P, et al. Longitudinal investigation of
depressive outcomes in primary care in six countries: the LIDO study.
Functional status, health service use and treatment of people with
depressive symptoms. Psychol Med. 2002;32:889-902.
6. Chachamovich E, Fleck M, Laidlaw K, Power M. Impact of major
depression and subsyndromal symptoms on quality of life and attitudes
toward aging in an international sample of older adults. Gerontologist.
2008;48:593-602.
7. Berlim MT, McGirr A, Fleck MP. Can sociodemographic and clinical
variables predict the quality of life of outpatients with major depression?
Psychiatry Res. 2008;160(3):364-71.
8. Fleck MP, Lima AF, Louzada S, et a. Association of depressive
symptoms and social functioning in primary care services, Brazil. Rev Saude
Publica. 2002;36:431-8.
9. De Silva Lima AF, de Almeida Fleck MP. Subsyndromal depression: an
impact on quality of life? J Affect Disor. 2007;100(1-3):163-9.
10. Klein DN, Sakman SA, Rose S. Dysthymic disorder and double
depression: prediction of 10-year course trajectories and outcomes. J
Psychiatr Res. 2008;42:408-15.

GENERALIZED ANXIETY DISORDER


GAD is characterized by at least six months of excessive
uncontrollable worry accompanied by symptoms of motor tension
and vigilance and scanning. As with other anxiety disorders, GAD is
less prevalent in older adults than younger adults. GAD has a high
level of comorbidity with other psychiatric disorders and this has a
bearing on estimates of its prevalence. GAD that is comorbid with
another psychiatric disorder has a period prevalence of
approximately 4% in community-dwelling older adults. On the other
hand, "pure" GAD is less common, with a period prevalence of
approximately 1% (1).
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L. Ben-Nun King David

The objective of this study was to determine the current


prevalence, impairment, and comorbidity of anxiety disorders in
primary care and to evaluate a brief measure for detecting these
disorders. Criterion-standard study was performed between
November 2004 and June 2005 in 15 US primary care clinics.
Participants included 965 randomly sampled patients from
consecutive clinic patients who completed a self-report questionnaire
and agreed to a follow-up telephone interview. Seven-item anxiety
measure (GAD-7 scale) in the clinic, followed by a telephone-
administered, structured psychiatric interview by a mental health
professional who was blinded to the GAD-7 results. Functional status
(Medical Outcomes Study Short Form-20), depressive and somatic
symptoms, and self-reported disability days and physician visits were
also assessed. Of the 965 patients, 19.5% (95% CI 17.0-22.1%) had at
least one anxiety disorder, 8.6% (95% CI 6.9-10.6%) had PTSD, 7.6%
(95% CI 5.9-9.4%) had a GAD, 6.8% (95% CI 5.3-8.6%) had a panic
disorder, and 6.2% (95% CI 4.7-7.9%) had a social anxiety disorder.
Each disorder was associated with substantial impairment that
increased significantly (p<0.001) as the number of anxiety disorders
increased. Many patients (41%) with an anxiety disorder reported no
current treatment. ROC analysis showed that both the GAD-7 scale
and its two core items (GAD-2) performed well (aROCs, 0.80-0.91) as
screening tools for all four anxiety disorders. In this nonrandom
sample of selected primary care practices, anxiety disorders are
prevalent, disabling, and often untreated in primary care. A two-item
screening test may enhance detection (2).
There has been increased interest in the impact and treatment of
anxiety disorders. However, one type of anxiety disorder, GAD, has
received less attention than other disorders, such as panic disorder,
despite the prevalence and amenability of this disorder to treatment
in the primary care setting. Rates of GAD estimated at 2.8% and 8.5%,
with a median prevalence of 5.8% at least twice the rate reported in
the National Comorbidity Survey. Up to one third of patients
presenting to primary care clinics with somatic complaints had a
mood or anxiety disorder. GAD is linked to the overuse of medical
services: emergency department visits, hospitalizations, diagnostic
and laboratory tests, pharmacy costs, and so on. Recognition of
anxiety and depression in primary care is poor, with only 23% of pure
anxiety cases being recognized compared with 56% of depression
cases. The various stakeholders (patients, family members,
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L. Ben-Nun King David

employers, and insurers) in a patient's outcome often complicate


treatment of anxiety. Barriers to effective treatment include time
constraints, acute disease orientation of most care systems, lack of
planned follow-up and monitoring, and relative unavailability of
specialist access. The collaborative care approach is designed to
overcome these barriers. With this approach, the patient is provided
with additional educational materials, physicians are supported by
physician extenders (nurses, social workers, or expert consultants)
who provide case-based feedback, follow-up, extra visits, and
telephone calls to patients. Providing efficacious treatment to
primary care for GAD will require improving knowledge of providers
and increasing patient engagement (3).
Did King David suffer from GAD? Some passages such as ”...having
agony in my heart daily.” (Psalms 13:3), “My soul is alarmed..” (6:4),
“The troubles of my heart are widened; ..bring thou me out of my
distress” (25:17) “...My soul in distress..”(31:8) and “Be not far from
me; for trouble is near; for there is no help “ (6:12) indicate
restlessness, and “..All the night make I my bed to swim; I water my
couch with my tears” (6:7) show sleep disturbances, while ”My
strength failed because of mine iniquity...” (31:11) and “...My heart
failed me” (40:13) indicate fatigue or loss of energy. The last two
passages can also be attributed to physical illness. Thus, although
some symptoms may be attributed to GAD, in general there are
insufficient criteria for a diagnosis of this mental disorder.
Similarly, there are insufficient data to suspect other types of
anxiety disorder such as social phobia, obsessive-compulsive
disorder, separation anxiety disorder, anorexia nervosa, somatization
disorder or hypochondriasis. For panic attack, only three criteria
were found [diagnosis requires four]: trembling: “Fearfulness and
trembling are come upon me...”, (55:6) palpitations: “My heart is
shivering within me ..”, (55:5) and fear of death: “... the terrible fears
of death had fallen upon me” (55:5). In the absence of other
symptoms, such as sweating, shortness of breath, chest pain, feeling
of choking, derealization, fear of losing control, paresthesia, chills or
hot flashes (4), the diagnosis of panic attack seems unlikely.

ASSESSMENT: King David’s mental status taken as a whole


indicates that he was afflicted by some kind of a mental condition.
Among the many disorders, which could have affected the King,
MDD, minor depression, or dysthymic disorder are the most likely.
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L. Ben-Nun King David

Of these diagnoses, MDD provides the best explanation (5). An


examination of the biblical King David’s mental illness from a
contemporary perspective shows that features of mental illness have
changed little through the ages. Although new diagnostic and
treatment strategies have been developed over time, both ancient
and modern psychiatric patients deserve similar diagnostic
investigation and subsequent treatment. We need to increase our
knowledge of ancient history and learn from the psychiatric cases we
find there, in order to improve our treatment of contemporary
patients.

References
1. Flint AJ. Generalized anxiety disorder in elderly patients:
epidemiology, diagnosis and treatment options. Drugs Aging. 2005;22:101-
14.
2. Kroenke K, Spitzer RL, Williams JB, et al. Anxiety disorders in primary
care: prevalence, impairment, comorbidity, and detection. Ann Intern Med.
2007;146(5):317-25.
3. Roy-Byrne PP, Wagner A. Primary care perspectives on generalized
anxiety disorder. J Clin Psychiatry. 2004;65 Suppl 13:20-6.
4. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Washington, DC: American Psychiatric Association, 1994.
5. Ben-Noun L. Mental disorder that afflicted King David the Great. Hist
Psychiatry. 2004;15(4):467-76.
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L. Ben-Nun King David

SUMMARY OF MEDICAL RECORD


In the end, King David was an old, sick man suffering from
multiple diseases and affected by various psychosocial problems.
King David died in old age, and was buried in the city of David.
The King's medical record indicates:
Blindness due to either neovascular age-related macular
degeneration, or non-neovascular age-related macular degeneration
that progressed to neovascular age-related macular degeneration, or
mature cataract, or asymptomatic open angle glaucoma, or optic
atrophy caused by the end-stage open angle glaucoma, or ischemic
optic neuropathy due to atherosclerosis or giant cell arteritis, or
refractive error.
Osteoporosis
Intractable bone pain due to multiple myeloma, or renal cell
carcinoma, or prostate cancer, or gastric carcinoma, or colorectal
carcinoma with metastases to the bones
Unintentional, excessive weight loss
Loss of appetite
Fasting
Malnutrition
Dehydration
Cachexia
Generalized weakness
Chronic fatigue
Mild hypothermia
Anemia of chronic diseases
Pressure ulcers, grade III
Persistent stress
Insomnia
Social problems: loneliness, social isolation and neglect by others
Erectile dysfunction
Major Depressive Disorder
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L. Ben-Nun King David

ABBREVIATIONS

ACD Anemia of chronic diseases


ACPA Anti-citrullinated protein antibodies
AFP Alpha-fetoprotein
AIDS Acquired immunodeficiency syndrome
AION Anterior ischemic optic neuropathy
AL Amyloid light chain
ALP Alkaline phosphatase
AMAs Antimitochondrial antibodies
AMD Age-related macular degeneration
AN Anorexia nervosa
AOR Adjusted odds ratio
A-P Antero-posterior
aROCs Areas under receiver operator characteristic curves
ASCT Autologous stem cell transplantation
ATTR Transthyretin amyloidosis
BAP Bone specific alkaline phosphatase
BBV Blood-borne viruses
B-CLL B-chronic lymphocytic leukemia
BCVA Best corrected visual acuity
BDI Beck Depression Inventory
BED Binge eating disorder
BMD Bone mineral density
BMI Body mass index
BN Bulimia nervosa
BP Blood pressure
CAG Closed angle glaucoma
CAR Carcinoma-associated retinopathy
CCR Coordinated Community Response
CDC The Centers for Disease Control and Prevention
CES-D Center for Epidemiological Studies Depression Scale
CES-D-10 Short form of the Center for Epidemiological
Studies Depression Scale
CI Confidence intervals
CIDI Composite International Diagnostic Interview
CIMF Chronic idiopathic myelofibrosis
CHD Congenital heart disease
CHF Congestive heart failure
CLL Chronic lymphocytic leukemia
CMV Cytomegalovirus
CNS Central nervous system
COPD Chronic obstructive pulmonary disease
CRC Colorectal cancer
CRD Cone rod dystrophy
CRF Chronic renal failure
Crl Credible intervals
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L. Ben-Nun King David

CRP C reactive protein


CSF Cerebrospinal fluid
CT Computed tomography
C. tetani Clostridium tetani
C. trachomatis Chlamydia trachomatis
1CTP The carboxy-terminal telopeptide of type 1 collagen is a marker of bone
resorption
CTS Carpal tunnel syndrome
CTX C-telopeptide of type I collagen
C-V Cardiovascular
D. Diopter/s
DALYs Disability-Adjusted Life Years
DES Dissociative Experiences Scale
DESNOS Disorders of extreme stress not otherwise specified
DIPSS-plus Dynamic International Prognostic Scoring System-plus
DM Diabetes mellitus
DOA Dominant Optic Atrophy
DRC Democratic Republic of Congo
DSM Diagnostic and Statistical Manual of Mental Disorders
DXA Dual energy x-ray absorptiometry
EBRT External beam radiotherapy
ED Erectile dysfunction
EDNOS Eating Disorders not Otherwise Specified
ELBW Extremely low birth weight
ERG Electroretinogram
ESC Emotional Symptom Checklist
ESR Erythrocyte sedimentation rate
FNA Fine-needle aspiration
FSWs Female sex workers
FT-AGA Full term Appropriate for gestational age
FT-IUGR Full term intrauterine growth retardation
GA Gestational age
GAD Generalized anxiety disorder
GCT Giant cell tumor
GDS Geriatric depression scale
GGT Gamma-glutamyl transferase
GH Growth hormone
GHRH Growth-hormone releasing hormone
G-I Gastrointestinal
GIO Glucocorticoid-induced osteoporosis
GON Glaucomatous optic neuropathy
GRADE Grading of Recommendations Assessment, Development and Evaluation
HCC Hepatocellular carcinoma
HCD Heavy chain diseases
H. ducreyi Haemophilus ducreyi
Hg Hemoglobin
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L. Ben-Nun King David

HIV Human immunodeficiency virus


HPV Human papilloma virus
HR Hazard ratio
HRT Hormone replacement therapy
HSV Herpes simplex virus
IBS Irritable bowel syndrome
ICD International Classification of Diseases
IDA Iron deficiency anemia
Ig Immunoglobulin
IGF-1 Insulin-like growth factor-I
IL Interleukin
i.m. Intramuscular
IMF Idiopathic myelofibrosis
IMO Idiopathic male osteoporosis
ION Ischemic optic neuropathy
IOP Intraocular pressure
IPMN Intraductal papillary mucinous neoplasm
IPV Intimate partner violence
IQR Interquartile range
IUGT Intrauterine growth retardation
IV Intravenous
IVH Intraventricular hemorrhage
LBW Low birth weight
LDCT Low-dose computed tomography
LDH Lactate dehydrogenase
LHON Leber hereditary optic neuropathy
LOCS Lens Opacities Classification System
LPL Lymphoplasmacytic lymphoma
LR+ Positive likelihood ratio
LR- Negative likelihood ratio
LUTS Lower urinary tract symptoms
MCV Mean corpuscular volume
MDD Major Depressive Disorder
MDT Multidrug treatment
MF Myelofibrosis
M. genitalium Mycoplasma genitalium
MGUS Monoclonal gammopathy of
undetermined significance
M. hominis Mycoplasma hominis
MM Multiple myeloma
MMSE Mini Mental State Examination
MRI Magnetic resonance imaging
MSA Military sexual assault
MST Military sexual trauma
MSVI Moderate and severe vision impairment
NAION Nonarteritic anterior ischemic optic neuropathy
NEC Necrotizing enterocolitis
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N. gonorrhea Neisseria gonorrhoeae


NHANES National Health and Nutrition Examination Survey
NICU Newborn intensive care unit
NM Neonatal mortality
NMIBC Non-muscle invasive bladder cancer
NPV Negative predictive value
NS Neurosyphilis
NSCLC Non-small cell lung cancer
NSSI Nonsuicidal self-injury
NT Neonatal tetanus
NV Neovascular
NVAMD Neovascular age-related macular degeneration
OAG Open angle glaucoma
OCT Optical coherence tomography
25-OH Vit. D 25-hydroxyvitamin D
OND Optic nerve disease
ONH Optic nerve head
OR Odds ratio
PA Pancreatic adenocarcinoma
PACG Primary glaucoma with angle-closure
PBC Primary biliary cirrhosis
PCR Polymerase chain reaction
PCVA Pinhole corrected visual acuity
PDE-5i Phosphodiesterase type 5 inhibitors
PEP Post exposure prophylaxis
PHPT Primary hyperparathyroidism
PHQ-9 Patient Health Questionnaire
PID Pelvic inflammatory disease
PLR Pooled positive likelihood ratio
PMGCT Primary malignant giant cell tumor
PMWI Psychological Maltreatment of Women Inventory
p.o. Orally
POAG Primary open-angle glaucoma
PPROM Pre-term premature rupture of membranes
PPV Positive predictive value
PROM Premature rupture of membranes
PSA Prostate-specific antigen
PSC Posterior subcapsular
PTH Parathyroid hormone
PTHrP Parathyroid hormone-related peptide receptor
PTSD Post-traumatic stress disorder
PTSS Posttraumatic stress symptomatology
PUFA Polyunsaturated fatty acids
PVA Presenting visual acuity
QALYs Quality-adjusted life years
QOL Quality of life
RA Rheumatoid arthritis
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RAAB Rapid Assessment of Avoidable Blindness


RCC Renal cell carcinoma
RCDs Rod cone dystrophies
RCT Randomized controlled trial
RDS Respiratory distress syndrome
RE Refractive error
RGC Retinal ganglion cells
RNB Reported night blindness
RNFL Retinal nerve fiber layer
ROC Receiver-operating characteristic curve
RP Retinitis pigmentosa
RPE Retinal pigment epithelium
RPR Rapid plasma reagin
RRR Ratio of rate ratios
SCC Small cell carcinoma
SCLC Small cell lung cancer
SCOFF A brief screening instrument for eating disorders
SD Standard deviation
SE Standard error
SEER Surveillance, Epidemiology and End Results
SERM Selective estrogen receptor modulators
SIDS Sudden infant death syndrome
SLE Systemic lupus erythematosus
SLL Small lymphocytic lymphoma
SRE Skeletal-related event
SRQ Self-Reporting Questionnaire
SSRIs Selective serotonin reuptake inhibitors
STD Sexually transmitted disease
STI Sexually transmitted infection
SVAWS Severity of violence against women scales
SVI Severe visual impairment
TNF Tumor necrosis factor
T. pallidum Treponema pallidum
TPCT Triple-phase CT
TPPA Treponema pallidum particle agglutination
TRH Thyrotrophin-releasing hormone
TSH Thyroid-stimulating hormone
TT Tetanus toxoid
TURBT Transurethral resection
T. vaginalis Trichomonas vaginalis
T. whipplei Tropheryma whipplei
UPAR Unattributed pressure area related
URE Uncorrected/undercorrected refractive error
URTI Upper respiratory tract infection
UTI Urinary tract infection
UV Ultraviolet
UWL Unintentional weight loss
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VA Visual acuity
VEGF Vascular endothelial growth factor
VF Ventricular fibrillation
VI Visual impairment
VLBW Very low birth weight
WBC White blood cell
WHO World Health Organization
WHOQOL World Health Organization Quality of Life
WM Waldenström's macroglobulinemia
WMH-CIDI World Mental Health version of the
Composite International Diagnostic Interview
WWII World War Two
ZOL Zoledronic acid
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L. Ben-Nun King David

PICTURES

Boaz meets Ruth. Julius Schnorr von Carolsfeld. German, 1794 – 1872. Due to this
marriage, a son, Obed, the grandfather of King David, was born.

David & Goliath. Peter Paul Rubens, 1577


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L. Ben-Nun King David

David and Goliath. Caravaggio.

Amnon and Tamar. Giovanni Francesco Barbieri called Guercino.


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L. Ben-Nun King David

Batsheba with David's messenger, as the King watches


from his roof. Jan Massys. 1562.

King David. Gottlieb Welté.


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L. Ben-Nun King David

King David in Prayer.


Pieter de Grebber. 1635.

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