Neuro

Gr. T. Popa Publisher, U.M.F.
Iai
Iai, 2015
Descrierea CIP a Bibliotecii Naionale a Romniei
POPESCU, CRISTIAN DINU
Neurology for medical students / Cristian Dinu Popescu (ed.) - Iai: Gr. T.
Popa Publisher, 2015
Bibliogr.
ISBN 978-606-544-288-7
Scientific reviewers:
Prof. BAJENARU OVIDIU ALEXANDRU, M.D., Ph.D.
Professor of Neurology at the University of Medicine and Pharmacy Carol Davila
Bucharest and Chairman of the Neurology Department of the University Hospital of
Emergency Bucharest
Director of the Department of Neurology, Neurosurgery and Psychiatry University of
Medicine and Pharmacy Carol Davila Bucharest
Honorary President of the Romanian Society of Neurology
Prof. SIMU MIHAELA ADRIANA, M.D., Ph.D.

Professor of Neurology at the University of Medicine and Pharmacy Victor Babes
Timisoara
Chairman of the Neurology Department of the Emergency Clinical County Hospital,
Timisoara
List of contributors
Professor Cristian Dinu Popescu, MD, PhD (editor)
Associate Professor Aurora Constantinescu, MD, PhD
Lecturer Emilian-Bogdan Ignat, MD, PhD
Lecturer Daniela Matei, MD, PhD
Assistant Professor Daniel Alexa, MD, PhD
Assistant Professor Orest Bolbocean, MD, PhD
Assistant Professor Cristina Grosu, MD, PhD
Assistant Professor Dragos Popescu, MD, PhD
Front cover: Marius ATANASIU
Gr. T. Popa Publisher

University of Medicine and Pharmacy Iai
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FOREWORD TO THE SECOND EDITION ..............................................................12
ETIOLOGY OF THE NERVOUS SYSTEM PATHOLOGY. ...........................................14
CRISTIAN DINU POPESCU

I. CONGENITAL DISEASES .......................................................................................14
II. DEGENERATIVE DISEASES ....................................................................................15
III. TRAUMA .......................................................................................................15
IV. VASCULAR DISEASES .........................................................................................16
V. BRAIN TUMORS ...............................................................................................16
VI. INFECTIOUS DISEASES .......................................................................................17
VII. AUTOIMMUNE AND INFLAMMATORY DISEASES ......................................................17
VIII. METABOLIC AND ENDOCRINE DISEASES ..............................................................18
IX. CSF CIRCULATION DISORDERS .............................................................................18
X. DEFICIENCY DISEASES.........................................................................................19
SELECTIVE BIBLIOGRAPHY .......................................................................................19
NEUROANATOMY DATA ...................................................................................20

THE NEURON.......................................................................................................20
GLIAL TISSUE AND THE BLOOD-BRAIN BARRIER .............................................................22
THE SYNAPSE ......................................................................................................23
NEUROPLASTICITY ................................................................................................24
CNS AND STEM CELLS ............................................................................................26
DISEASES OF THE MOTOR NEURONS.................................................................28

UPPER MOTOR NEURON SYNDROME .........................................................................28
UPPER MOTOR NEURON DISEASE..............................................................................30
PRIMARY AMYOTROPHIC LATERAL SCLEROSIS (PALS) ......................................................... 30
HEREDITARY SPASTIC PARAPLEGIA ................................................................................... 30
LOWER MOTOR NEURON SYNDROME .......................................................................30
GENERAL PROBLEMS ..................................................................................................... 30
TYPES OF DEFICIT .......................................................................................................... 31
LOWER MOTOR NEURON DISEASE .............................................................................32
ANTERIOR ACUTE POLIOMYELITIS ..................................................................................... 32
POSTPOLIO SYNDROME .................................................................................................. 32
WEST NILE VIRUS INFECTION .......................................................................................... 33
3
KENNEDY SYNDROME .................................................................................................... 33
SPINAL MUSCULAR ATROPHIES (SMAS) ........................................................................... 34
DISEASES OF BOTH UPPER AND LOWER MOTOR NEURONS...............................................35
AMYOTROPHIC LATERAL SCLEROSIS (ALS) ........................................................................ 35
PERIPHERAL PARALYSIS OF THE LIMBS..............................................................41
DRAGOS POPESCU
PHERIPHERAL PARALYSES OF UPPER LIMBS .......................................................41
BRACHIAL PLEXUS PARALYSIS ...........................................................................42
MONONEUROPATHIES OF THE UPPER LIMB ......................................................45
MUSCULOCUTANEOUS NERVE PARALYISIS. ........................................................................ 45
AXILLARY (CIRCUMFLEX) NERVE PARALYISIS. ...................................................................... 45
RADIAL NERVE PARALYSIS. .............................................................................................. 45
ULNAR NERVE PARALYSIS. .............................................................................................. 46
MEDIAN NERVE PARALYSIS. ............................................................................................ 47
PARALYSIS OF THE LOWER LIMBS......................................................................48
FEMORAL (ANTERIOR CRURAL) NERVE PARALYSIS............................................................... 48
OBTURATOR NERVE PARALYISIS. ...................................................................................... 50
SCIATIC NERVE PARALYSIS............................................................................................... 50
COMMON PERONEAL (EXTERNAL POPLITEAL) NERVE PARALYSIS. ........................................... 51
POLYNEUROPATHIES ........................................................................................53
CRISTINA GROSU
GENERAL DATA ....................................................................................................53
1) MOTOR MANIFESTATIONS .......................................................................................... 54
2)ALTERED SENSIBILITY .................................................................................................. 54
3) TROPHIC DISORDERS .................................................................................................. 54
4) VEGETATIVE DISORDERS ............................................................................................. 55
5) CRANIAL NERVE DISORDERS ........................................................................................ 55
LABORATORY INVESTIGATIONS ................................................................................55
HEREDITARY NEUROPATHIES ............................................................................56
I. THE HEREDITARY SENSORY-MOTOR NEUROPATHIES: ...................................................56
1,2) CHARCOT MARIE TOOTH DISEASE (HSMN TYPE I AND II) ............................................ 56
3) DERJERINE SOTTAS DISEASE (HSMN TYPE III) ............................................................... 57
4) SENSORY-MOTOR PRESSURE SENSITIVE HEREDITARY NEUROPATHY .................................... 57
5) REFSUM DISEASE (HSMN TYPE IV).............................................................................. 57
II. PREDOMINANTLY SENSORY HEREDITARY NEUROPATHIES ARE DIVIDED INTO: ....................58
1) HSN TYPE I (DENNY BROWN) ..................................................................................... 58
4
METABOLIC NEUROPATHIES .............................................................................59
DIABETIC POLYNEUROPATHY ................................................................................... 59
UREMIC POLYNEUROPATHY..................................................................................... 60
AMILOIDOSIS POLYNEUROPATHY ............................................................................ 61
PORPHYRIC POLYNEUROPATHY ............................................................................... 61
IMMUNE-MEDIATED NEUROPATHIES ...............................................................62
1) GUILLAIN BARRE SYNDROME ...................................................................................... 62
2) CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP) .............................. 64
3) MULTIFOCAL MOTOR NEUROPATHY ............................................................................. 65
INFECTIOUS NEUROPATHIES .............................................................................66
1) LYME DISEASE (NEUROBORELIOSIS) .......................................................................... 66
2) HIV NEUROPATHY. ............................................................................................... 66
3) DIPHTERIC POLYNEUROPATHY............................................................................. 67
4) LEPROUS POLYNEUROPATHY ............................................................................... 67
5) BOTULISM NEUROPATHY ..................................................................................... 67
AUTOIMMUNE NEUROPATHIES ........................................................................67
PERIARTERITA NODOSA AND OTHER NECROTIZING VASCULITIS (CHUNG STRAUSS, WEGENER) .... 67
LES (ERITHEMATOUS SYSTEMIC LUPUS) ........................................................................... 68
SJOGREN SYNDROME..................................................................................................... 68
DEFICIENCY POLYNEUROPATHIES .....................................................................68
ALCOHOLIC POLYNEUROPATHY ............................................................................... 68
B12 DEFICIENCY POLYNEUROPATHY ........................................................................ 69
OTHER DEFICIENCY POLYNEUROPATHIES: ............................................................... 70
TOXIC NEUROPATHIES ......................................................................................70
LEAD POISONING ..................................................................................................... 70
ARSENIC POISONING ................................................................................................ 70
THALIUM POISONING .............................................................................................. 70
ORGANOPHOSPHORUS POISONING ........................................................................ 71
MERCURY POISONING.............................................................................................. 71
DRUGS ...................................................................................................................... 71
SPINAL CORD PATHOLOGY ...............................................................................73
CRISTIAN DINU POPESCU, CRISTINA GROSU

GENERAL DATA ....................................................................................................73
SPINAL CORD PATHOLOGY ...............................................................................78
DEGENERATIVE DISEASE SYRINGOMYELIA .................................................................78
SPINAL CORD TRAUMA ..........................................................................................79
COMBINED SCLEROSIS OF THE SPINAL CORD ................................................................81
SPINAL CORD COMPRESSIONS ..................................................................................82
VASCULAR DISEASES OF THE SPINAL CORD ..................................................................84
5
MYELITIS............................................................................................................87
PATHOLOGY OF BRAINSTEM. CRANIAL NERVES. CEREBELLUM. FRIEDREICH

DISEASE ...........................................................................................................90
DANIEL ALEXA, DRAGOS POPESCU

BRAINSTEM ISCHEMIC SYNDROMES...........................................................................90
NOTIONS OF ANATOMY ................................................................................................. 90
DESCENDING PATHWAYS ................................................................................................ 91
ASCENDING PATHWAYS ................................................................................................. 92
CRANIAL NERVES NUCLEI ................................................................................................ 92
BULBAR SYNDROMES ............................................................................................93
PONTINE SYNDROMES ...........................................................................................95
PEDUNCULAR SYNDROMES .....................................................................................96
RETICULAR SYNDROMES .........................................................................................98
NOTIONS OF ANATOMY ................................................................................................. 98
CLINICAL PICTURE ....................................................................................................... 100
I. DISORDERS OF CONSCIOUSNESS .......................................................................... 100
COMA ...................................................................................................................... 101
SYNCOPE ................................................................................................................... 110
II. DISORDERS OF THE SLEEP-WAKE RYTHM ............................................................... 112
III. PSYCHIATRIC DISORDERS ................................................................................. 115
IV. MUSCLE TONE DISORDERS ............................................................................... 115
CRANIAL NERVES PATHOLOGY ............................................................................... 115
OCULOMOTOR NERVES PARALYSES ................................................................................ 115
SUPRANUCLEAR PARALYSIS ........................................................................................... 117
NUCLEAR PARALYSIS .................................................................................................... 118
INFRANUCLEAR PARALYSIS ............................................................................................ 119
INTERNUCLEAR PARALYSIS ............................................................................................ 119
CRANIAL NERVE III (COMMON OCULOMOTOR NERVE) ................................................. 119
CRANIAL NERVE IV (TROCHLEAR OR PATHETIC NERVE) ................................................. 121
ANATOMO-FUNCTIONAL DATA: ..................................................................................... 121
SEMIOLOGY OF LESIONS: .............................................................................................. 121
CRANIAL NERVE VI (EXTERNAL OCULOMOTOR OR ABDUCENS NERVE) .............................. 122
ANATOMO-FUNCTIONAL DATA: ..................................................................................... 122
SEMIOLOGY OF LESIONS: .............................................................................................. 122
CONJUGATE MOVEMENTS OF THE OCULAR GLOBE ....................................................... 122
PARALYSIS OF VERTICAL CONJUGATE MOVEMENTS:........................................................... 122
PARALYSIS OF LATERAL MOVEMENTS: ............................................................................. 123
INTRINSIC PUPILLARY MOTILITY .............................................................................. 123
EXAMINATION OF THE PUPILLARY MOTILITY ..................................................................... 124
6
PATHOLOGY OF THE PUPIL ............................................................................................ 124
TRIGEMINAL NEURALGIA AND PARALYSIS.................................................................. 125
CLINICAL EXAMINATION ............................................................................................... 125
ESSENTIAL TRIGEMINAL NEURALGIA (TROUSSEAU DISEASE) ........................................... 126
ETHIOPATHOGENESIS: ................................................................................................. 126
PATHOGENETIC MECHANISMS: ...................................................................................... 126
CLINICAL PICTURE: ...................................................................................................... 126
EVOLUTION ............................................................................................................... 127
POSITIVE DIAGNOSIS ................................................................................................... 127
DIFFERENTIAL DIAGNOSIS ............................................................................................. 128
TREATMENT............................................................................................................... 128
FACIAL NERVE PALSY ........................................................................................... 129
ANATOMY ................................................................................................................. 129
CLINICAL ENTITIES: ...................................................................................................... 131
FACIAL PARALYSIS OF PERIPHERAL TYPE:.......................................................................... 131
FACIAL PARALYSIS OF CENTRAL TYPE: .............................................................................. 133
PRIMITIVE FACIAL HEMISPASM: ..................................................................................... 133
CEREBELLUM ..................................................................................................... 133
NOTIONS OF ANATOMY ............................................................................................... 133
SEMIOLOGY OF THE CEREBELLAR SYNDROME ................................................................... 135
CEREBELLAR SYNDROMES: ............................................................................................ 136
ETIOLOGY .................................................................................................................. 136
FRIEDREICH'S DISEASE ......................................................................................... 138
CLINICAL EXAMINATION: .............................................................................................. 139
LABORATORY INVESTIGATIONS: ..................................................................................... 140
PATHOLOGY............................................................................................................... 140
DIFFERENTIAL DIAGNOSIS ............................................................................................. 140
TREATMENT............................................................................................................... 141
SELECTIVE BIBLIOGRAPHY ..................................................................................... 141
MOVEMENT DISORDERS ................................................................................ 143
AURORA CONSTANTINESCU
MOVEMENT DISORDERS....................................................................................... 143
PARKINSONS DISEASE ........................................................................................ 144
STADIALIZATION ......................................................................................................... 144
ETIOLOGY .................................................................................................................. 145
CLINICAL ASPECTS ....................................................................................................... 145
NONMOTOR SYMPTOMS IN PD ..................................................................................... 147
DIAGNOSTIC .............................................................................................................. 149
PRINCIPLES OF TREATMENT IN PARKINSONS DISEASE ....................................................... 150
7
PHARMACOLOGICAL MANAGEMENT OF ADVANCED PD PATIENTS WITH MOTOR COMPLICATIONS
............................................................................................................................... 153
CONTINUOUS DOPAMINERGIC STIMULATION ................................................................... 154
DEEP BRAIN STIMULATION............................................................................................ 155
PHYSICAL THERAPY IN PARKINSONS DISEASE ................................................................... 155
HEPATOLENTICULAR DEGENERATION (WILSON DISEASE) ............................................. 156
DEFINITION ............................................................................................................... 156
HISTORY.................................................................................................................... 156
CLINICAL SYMPTOMS ................................................................................................... 156
BIOCHEMISTRY ........................................................................................................... 157
NEUROPATHOLOGIC CHANGES ...................................................................................... 157
DIAGNOSIS ................................................................................................................ 158
TREATMENT............................................................................................................... 158
HUNTINGTON CHOREA ........................................................................................ 158
CLINICAL SYMPTOMS................................................................................................... 159
PATHOLOGY............................................................................................................... 159
NEUROPATHOLOGIC CHANGES ...................................................................................... 160
DIAGNOSIS ................................................................................................................ 160
TREATMENT............................................................................................................... 161
SELECTIVE BIBLIOGRAPHY: .................................................................................... 163
CEREBRAL LOBES. HIGHER CEREBRAL FUNCTIONS. DEMENTIA......................... 166
EMILIAN-BOGDAN IGNAT, DANIELA MATEI

GENERAL ARCHITECTURE OF THE CEREBRAL LOBES ...................................................... 166
THE FRONTAL LOBE ............................................................................................. 168
TEMPORAL LOBE ................................................................................................ 170
PARIETAL LOBE .................................................................................................. 172
OCCIPITAL LOBE ................................................................................................. 174
DEMENTIA........................................................................................................ 176
ALZHEIMER'S DISEASE ......................................................................................... 179
LEWY BODY DEMENTIA ........................................................................................ 181
FRONTOTEMPORAL DEMENTIA .............................................................................. 181
VASCULAR DEMENTIA.......................................................................................... 182
EPILEPSY ........................................................................................................ 186
EMILIAN-BOGDAN IGNAT
DEFINITIONS ..................................................................................................... 186
EPIDEMIOLOGY .................................................................................................. 187
ETIOLOGY......................................................................................................... 187
8
CLASSIFICATION ................................................................................................. 188
CLINICAL PICTURE ............................................................................................... 188
DIFFERENTIAL DIAGNOSIS ..................................................................................... 192
LABORATORY WORKUP ........................................................................................ 192
TREATMENT OF EPILEPSY ...................................................................................... 194
GENERAL RULES.......................................................................................................... 194
DRUG THERAPY .......................................................................................................... 195
INTERVENTIONAL TREATMENT APPROACHES .................................................................... 197
SPECIAL ISSUES AND TREATMENT CESSATION ................................................................... 197
PAINFUL SYNDROMES: NEUROPATHIC PAIN, HEADACHE................................. 200
CRISTIAN DINU POPESCU, EMILIAN-BOGDAN IGNAT

NEUROPATHIC PAIN ............................................................................................ 200
DEFINITION, CLASSIFICATION ........................................................................................ 200
PATHOPHYSIOLOGY ..................................................................................................... 201
PERIPHERAL NEUROPATHIES HYPERALGESIA ..................................................................... 202
CNS HYPERALGESIC PATHOLOGY ................................................................................... 204
TREATAMENT ............................................................................................................. 205
HEADACHE ....................................................................................................... 205
VASCULAR HEADACHE ................................................................................................. 205
TRAUMATIC HEADACHE ............................................................................................... 206
DISORDERS OF CSF FLOW ............................................................................................ 207
ASSOCIATED WITH HYPERTENSION ................................................................................. 208
MIGRAINE ........................................................................................................ 208
DEFINITION ............................................................................................................... 208
ETIOLOGY AND PATHOGENY.......................................................................................... 209
CLASSIFICATION .......................................................................................................... 211
TREATMENT............................................................................................................... 212
CLUSTER HEADACHE ............................................................................................ 214
TENSION HEADACHE ........................................................................................... 215
CEREBROVASCULAR DISEASES ........................................................................ 217

GENERAL DATA .................................................................................................. 217
CEREBRAL INFARCTION ........................................................................................ 219
CEREBELLAR INFARCTION ............................................................................................. 222
TRANSIENT ISCHEMIC ATTACK (TIA) ............................................................................... 224
9
CAROTID TIAS............................................................................................................ 225
THE EMBOLIC STROKE .................................................................................................. 226
LACUNAR CEREBRAL INFARCTION ................................................................................... 228
DISECTION OF CERVICO-CEREBRAL ARTERIES .................................................................... 229
CEREBRAL THROMBOPHLEBITIS .............................................................................. 231
PROCOAGULABILITY STATE IN STROKE ...................................................................... 232
PRO-COAGULANT FACTORS .......................................................................................... 233
INTRACRANIAL HEMORRHAGES .............................................................................. 235
CEREBRAL HEMORRHAGE ............................................................................................. 235
SUBARACHNOID HEMORRHAGES ................................................................................... 237
TREATMENT IN STROKE ........................................................................................ 239
ANTIAGGREGANT AND ANTICOAGULANT THERAPY IN NEUROLOGICAL DISEASES ..................... 240
MULTIPLE SCLEROSIS ..................................................................................... 245

DEFINITION....................................................................................................... 245
EPIDEMIOLOGY AND GEOGRAPHICAL DISTRIBUTION .................................................... 245
AGE OF ONSET AND PROGNOSIS ............................................................................. 245
PATHOGENY ..................................................................................................... 246
CLINICAL PICTURE ............................................................................................... 247
DIAGNOSIS ....................................................................................................... 248
CLASSIFICATION OF MS ACCORDING TO THE CLINICAL EVOLUTION .................................. 251
CLINICALLY ISOLATED SYNDROME ........................................................................... 251
RELAPSING REMITTING MULTIPLE SCLEROSIS (RRMS) ................................................. 251
SECONDARY PROGRESSIVE MS (SPMS) ................................................................... 252
PRIMARY PROGRESSIVE MS (PPMS) ...................................................................... 252
PROGRESSIVE RELAPSING MULTIPLE SCLEROSIS (PRMS) .............................................. 252
OTHER DEMYELINATING DISEASES .......................................................................... 252
DIFFERENTIAL DIAGNOSIS ..................................................................................... 253
EDSS (EXPANDED DISABILITY STATUS SCALE) ........................................................... 256
TREATMENT ...................................................................................................... 256
TREATMENT OF RELAPSE ...................................................................................... 257
DISEASE MODIFYING THERAPY ............................................................................... 257
SYMPTOMATIC TREATMENT AND REHABILITATION ...................................................... 261
INFECTIOUS DISEASES OF THE NERVOUS SYSTEM............................................ 265

GENERAL DATA .................................................................................................. 265
10
CNS AFFECTATION IN BACTERIAL INFECTIONS ............................................................ 266
SYPHILIS .................................................................................................................... 268
BACTERIAL NEUROPATHIES ................................................................................... 269
CNS INVOLVEMENT IN VIRAL INFECTIONS ................................................................. 271
RABIC ENCEPHALOPATY ............................................................................................... 272
VIRAL NEUROPATHIES.......................................................................................... 272
FUNGAL INFECTIONS OF THE NERVOUS SYSTEM .......................................................... 274
NERVOUS SYSTEM INVOLVEMENT IN PROTOZOAR, HELMINTHS AND PRION INFECTION ......... 274
NEUROLOGICAL COMPLICATIONS OF HIV INFECTION ................................................... 275
THE NEUROLOGIC COMPLICATIONS OF HIV ..................................................................... 276
MUSCULAR PATHOLOGY ................................................................................ 282
OREST BOLBOCEAN
GENERAL DATA .................................................................................................. 282
I.A. PROGRESSIVE MUSCULAR DYSTROPHY ............................................................... 284
A) DUCHENNE MUSCULAR DYSTROPHY: .......................................................................... 285
B) BECKER-KIENER MUSCULAR DYSTROPHY: .................................................................... 286
C) SCAPULAR AND PELVIC MUSCULAR DYSTROPHY: ........................................................... 286
D) FACIO - SCAPULAR HUMERAL DYSTROPHY (DEJERINE):................................................ 286
I.B. CONGENITAL MYOPATHIES .............................................................................. 287
I.C. METABOLIC MYOPATHIES ............................................................................... 288
I.D. PERIODIC KALEMIC PARALYSES ......................................................................... 288
II. DERMATOMYOSITIS AND POLYMIOSITIS ............................................................... 290
III. ENDOCRINE AND METABOLIC MYOPATHIES........................................................... 292
IV. TOXIC MYOPATHIES ....................................................................................... 293
MYOTONIA .................................................................................................... 293
MYOTONIC DYSTROPHY (STEINERT) ............................................................................... 293
CONGENITAL MYOTONIA (THOMSEN DISEASE) ................................................................. 295
MYASTENIA GRAVIS ....................................................................................... 295
CLASSIFICATION (OSSERMAN):...................................................................................... 296
LABORATORY FINDINGS ARE: ........................................................................................ 296
EVOLUTION AND COMPLICATIONS.................................................................................. 297
TREATMENT............................................................................................................... 298
ABBREVIATIONS............................................................................................. 300
INDEX ............................................................................................................ 303
11
Foreword to the Second
Edition
The first course of neurology for students studying in English at "Gr.

T.Popa "Iasi was written in 1998 and is now surpassed by the many novelties
in this specialty.
The present edition aims to respect the traditions of Neurology in Iasi
that goes from simple to complex and reaches the beginning, studying the
diversity of cells and fibers, then pathophysiology and consequences of
morphological destruction, but also reviews the most common pathology of
cells, fibers, circuits and various components of the central and peripheral
nervous system.
It covers theory starting from peripheral pathology and the spinal
cord, brainstem, cerebellum, basal ganglia plus cerebral hemispheres.
The updated edition aims to transmit to the students the neurological
knowledge that will be part of the basic training of any doctor facilitating the
understanding of the nervous system involvement both in its own pathology
but also in the accompaniment pathology of general diseases. It is intended
that this edition to be at least the same with the course of neurology which
addresses students from other countries preparing students in English.
Also we want this work to form the basis for further training in
neurology and other specialties in which the nervous system involvement is
important. The course includes new chapters according to the specialty
training program in neurology, wanting to bring it up to date with news
regarding etiology, investigations and treatment.
The course is edited by Prof. Dr. CD Popescu, and among authors is
the faculty who is part of the Neurology Clinic inside the Clinical
Rehabilitation Hospital Iasi.
Special attention was paid to the chapters dedicated to
cerebrovascular diseases, demyelinating diseases and pathology of the
extrapyramidal system consistent with the current therapies and guidelines
for these disorders.
12
Any suggestion is welcome because we want future generations to
benefit from a competent and ongoing support comparable to the evolution
of this specialty.
13
Chapter I.
Etiology of the Nervous System
Pathology.
Cristian Dinu Popescu
Congenital diseases Infectious

Degenerative diseases Autoimmune and inflammatory
Traumatic Metabolic and endocrine
Vascular CSF Circulation disorders
Tumors Toxic and deficiency
The nervous system can be affected by several mechanisms, with its

various component-specific vulnerabilities central, peripheral and autonomic.
The functions and integrity of the central nervous system depends largely on
the system and the blood-brain or spinal barrier. The brain and spinal cord
are protected in case of trauma by especially the skull and the spinal canal.
The neuronal body (gray matter) develops a special pathology especially due
to infectious and degenerative mechanisms. The myelinated fibers (white
matter) are vulnerable to immune, toxic and ischemic pathologies.
The peripheral nervous system is vulnerable to trauma, exogenous or
endogenous toxics, demyelination, ischemia and infectious agents. Central
and peripheral myelin antigens are different, this is why demyelinating
pathology interests only one component. CSF secretion and resorption may
be disrupted resulting in specific different clinical pictures.
Diseases of the nervous system can have the following etiologies:
I. Congenital diseases
Congenital diseases are the result of developmental abnormalities,
which can be highlighted and identified soon after birth or later in life.
Nervous system abnormalities may be of interested or may be associated
with bone changes that will contribute to the development and worsening of
deficits. Among the best known are those of the cervico-cephalic junction
malformations, such as basilar impression and Arnold-Chiari malformation.
14
Chiari malformation presence and basilar impression may signal the
existence or development of cavities leading to syringomyelia. The same
class of pathology also include arterial and arteriovenous malformations or
myelomeningocele.
II. Degenerative diseases

Changes in the demographic composition of the population confirms
the increasing number of older population. Increasing longevity reveals the
degenerative pathology which is dominated by Alzheimer's disease and
Parkinson's disease.
Neurodegenerative processes precede the clinical expression and the
deficits are manifested when endogenous compensatory mechanisms have
been exhausted. The same group also includes hereditary ataxia, chronic
chorea and spastic familial paraplegia. Transmission variants can be
dominant or recessive but also sporadic cases are described. One can speak
of a programmed lifespan of some cell populations who are in so-called
strategic places. Exceeding the a certain threshold makes it possible for the
clinical expression to set in.
Current therapy manages to maintain a certain quality of life
prolonging patients' autonomy with a number of years. Older or newer
studies emphasizes the negative influences of the environment, without being
able to prove some clear pathogenic mechanisms.
Changes occur in the synthesis of extracellular molecules that will
initiate a processes of accumulation, disruption of functions and shortening
the life of neuronal populations. It is now the so-called process of
anticipation so that the disease occurs in the next generations at a more
younger age.
III. Trauma
Trauma may interest peripheral nerves, spinal cord and brain,
resulting in dysfunction of also other systems. The most frequent injuries of
the nervous system are the result of road accidents, attacks, falls, domestic
accidents, sports. Traumatic brain pathology is dominated by bleeding
events, dilacerations, various fractures, which may occur in the same
individual.
The spinal cord may be additional aggressed by falls from height,
bruising, contact with hard objects. Immediate or remote, trauma can be
complicated by CSF fistula, meningitis, thrombophlebitis, abscess.
The peripheral nervous system can be aggressed by compression,
elongation, section, infectious or toxic mechanisms, dysmetabolic, immune
15
or vascular pathologies. An important role both in inducing pathology and
repair processes is held by vasa nervorum. Regeneration of peripheral nerve
fibers is a natural process that reduces dysfunction or even leads to "restitutio
ad integrum".
IV. Vascular diseases

Vascular diseases are a major health problem being the second cause
of death worldwide. They induce a significant disability that adversely affect
the quality of life. The number of patients with this pathology will increase
in the upcoming years in relation to the overall aging of the population. The
World Health Organization announced that in 2005 5.8 million people died
of stroke and the forecast is up to 6.5 million by 2015 and 7.8 million until
2030. Approximately two thirds of the cases from neurology services is
made of cerebrovascular diseases that can have a high incidence in the
population of Hispanic, Asian or African origin.
Medical advances in recent years have led to the prevention of such
diseases in a large number of individuals. Proper and timely treatment of risk
factors has led to the postponement of the start of such pathology avoiding
fatal outcome in a large proportion of individuals. Early diagnosis of
vascular aging phenomena type, highlighting degenerative arterial
atherosclerotic changes, the emergency attitude taken in case of transient
stroke, application of thrombolysis and efficient recovery made it possible to
change the evolution of ischemic stroke patients.
The second version of the stroke, the hemoragic or bleeding one is
uncommon (20% of cases) and implies the existence of arteriovenous
malformations pre-existing or acquired, plus some blood diseases and
disorders.
V. Brain tumors
Brain tumors may be glial, astrocytomas, oligodendrogliomas,
gliomas, ependymomas, non glial (meningiomas, meduloblastomas, CNS
lymphoma), schwannomas, neurofibromas and metastatic.
The main symptoms consist of intracranial hypertension and focal
deficits. Deficits are the consequence of tissue infiltration or mass effect.
They can sometimes be present with signs of seizures, which may indicate
the existence of a benign or malignant brain tumor. Tumor processes in the
spinal canal can cause spinal cord or root compression.
Intracranial hypertension may be exacerbated by obstruction or
malfunction of a valve mechanism in the CSF circulation.
16
It should be taken into account also some clinical signs of cognitive
impairment or personality disorder. The existence of the current
neurosurgical techniques ensure complete removal of the tumor and cancer
therapy extends the lifespan of the patient. Single or multiple metastases can
induce a similar clinical picture.
VI. Infectious diseases

Infectious diseases have as causes viruses, bacteria, protozoa, or
rickettsiae and prions. The way they get into the body may be respiratory,
oral, nasal, genital or sanguine. The nervous system can be affected by
sanguine way by expanding of the neighboring infections or even retrograde
following the peripheral nerve sheaths. It can also affect the meninges, white
matter, gray matter, arteries or veins of the brain, myelin sheaths of nerve
root or peripheral nerve. There is an additional selective vulnerability of the
gray matter, which is a metabolic four times more active than the white
matter. Such patients may develop meningitis, brain abscess, subdural
empyema, epidural abscess, septic thrombophlebitis, encephalitis in many
cases. Infections can affect many parts of the nervous system. The
Mycobacterium tuberculosis can cause meningitis or abscess (tuberculomas).
Treponema pallidum may result in central nervous system as encephalic
stroke, encephalopathy with seizures and in spinal injury (tabes dorsalis) and
significant neuropsychological changes like delirium or dementia.
Last century but also the current one is faced with the multitude of
neurological complications of HIV, which may include inflammatory
demyelinating polyneuropathy, multiplex mononeuropathies, myelopathies,
cognitive dysfunction, aseptic meningitis or encephalitis. The clinical picture
is compounded by the many variants of opportunistic infections.
VII. Autoimmune and inflammatory diseases

In this group of diseases systemic lupus and Sjogren syndrome can be
included. These diseases may be accompanied by significant clinical signs of
neurological and psychiatric disorders, including impairment of brain and
spinal cord.
Patients may have motor deficits that can be added to seizures and
psychosis. The presence of neurological clinical signs can become diagnostic
criteria. The brain and cortex can be especially altered through the vascular
system, which will develop cerebral vasculitis phenomena.
From the same group of demyelinating diseases belong multiple
sclerosis and its variants, which is why immunological investigation is
required to establish a positive and differential diagnosis.
17
Another example of autoimmune disease is myasthenia gravis. The
muscular deficit is determined by subtracting the number of acetylcholine
receptors. The decrease in muscle strength is due to the action of the
antireceptor antibody of acetylcholine. Thymic ablation of tumor formation
(thymoma) has a favorable effect on the disease.
VIII. Metabolic and Endocrine Diseases

Metabolic diseases are linked on the one hand by a mitochondrial
dysfunction and on the other hand by a disturbance of the functions of
certain organs. Mitochondrial diseases are transmitted to daughters, which in
turn may forward the mutation to the next generations. It produces a
disturbance of mitochondrial energy metabolism, especially in muscles,
myocardium, CNS and the symptoms may worsen with different types of
dysfunction. Chronic progressive external ophthalmoplegia, myoclonic
epilepsy associated with lactic acidosis and stroke-like epilepsies (MELAS),
Leber optic atrophy are some examples.
For these conditions are typical is the proximal motor deficit,
ophthalmoplegia, dementia, muscle weakness and weight-stature deficit. In
the same group is also subacute porphyria with polyneuropathic episodes of
false acute abdomen and seizures.
There are also acquired metabolic diseases such as uremic
encephalopathy, hepatic or hyponatremia. Among the endocrine diseases,
thyroid and parathyroid pathologies are accompanied by neurological signs.
Hypothyroidism is associated with polyneuropathy and cerebellar ataxia.
Hyperparathyroidism generates an encephalopathy associated with disorders
of muscle contraction, numbness and seizures.
IX. CSF circulation disorders

Elements of pathology occurs mainly due to compression of the
ventricular cavities and the aqueduct of Sylvius or disorders of resorption of
the CSF. The induced clinical entities include normal pressure
hydrocephalus, pseudotumor cerebri syndrome, idiopathic CSF hypertension.
Enlargement of the one of the lateral ventricle is due to obstruction of the
Monro foramen. Dilatation of both lateral ventricles may be caused by
disruption of CSF flow through the aqueduct of Sylvius and the third
ventricle. Dilatation of the Sylvian aqueduct and ventriculs signifies a
disturbance of CSF flow in the fourth ventricle. Neurosurgical techniques are
ment to assure the CSF drainage and they have greatly improved the
prognosis of this condition.
18
X. Deficiency diseases
Deficiency diseases are caused by toxic and nervous system exposure
to physical agents, chemical or biological. Already today, several hundred
have been identified that have potential neurotoxic effect. These agents can
be classified into: pharmaceutical, biological, neurotoxic chemicals in the
environment, industrial chemical, self-managed. They may produce heavy
metal poisoning (arsenic, lead, manganese, mercury), organophosphorus
agents, poisonous industrial toxins (toluene, carbon disulphide - CS2),
household accidents (carbon monoxide), bacterial toxins (tetanus), plant
toxins.
Deficiency and the toxic effects is specific to chronic alcohol
consumers. It can induce a genuine ethanolic encephalopathy as a result of
direct action of the toxin and its metabolites on neurons and the myelin
sheath. The consequences are cognitive deficits, manic states (jealousy),
psychosis, hallucinations. The most common pathology is the
polyneuropathy and then more rare myopathy.
Selective bibliography
1. Adams and Victors Principles of Neurology, Ropper HA, Brown
RH Editors, Eighth Edition, McGraw Hill, Medical Publishing
Division, 2005;
2. Bradleys Neurology in clinical practice, Daroff BR, Fenichel
GM, Jankovic J, Maziotta JC, Editors, Sixth Edition, Elsevier,
2012;
3. Harrisons Neurology in Clinical Medicine, Hauser SL Editor,
Second Edition, McGraw Hill, Medical, 2010;
4. Hufschmidt A, Lcking CH, Neurologie integral, De la simptom
la tratament, Editor Popescu CD, Edit. Polirom, Ia i, 2002;
5. Popescu DC, Neurology for medical students, Psihomnia
Publishing House, 1998;
6. Popoviciu L, A gian B, Bazele semiologice ale practicii
neurologice i neurochirurgicale, Edit. Medical, Bucure ti,
1991;
19
Chapter II.
Neuroanatomy Data
Neuron Sinapse
Glial tissue Neuroplasticity
Blood brain barrier CNS and stem cells
The neuron
The cell component of the nervous system are the neurons and glial
cells, which together will form the so-called functional units. Neurons are
specialized cells that receive a certain type of information, transmit to other
similar structures by effector tissues. These cells show a pattern consistent
with the location of structural change and the function they perform.
The neuron is composed of a cell body and one or more extensions
(axons or dendrites) bounded by a membrane. Inside the body is a nucleus
surrounded by the cell cytoplasm. Nuclear bodies form what we call gray
matter, white matter and myelinated extensions.
The neuronal membrane has a lipoprotein structure and is bearing the
pores and voltage-gated ion channels or selective substance whose passage is
assured. Inside the cell are the cell type-specific structures, but also
nonspecific, found in other tissues. The specific differences are the presence
of neurotangles, microtubules and Nissl body.
The neurotangles are oriented axonal and dendritic, along with being
responsible for transmitting and maintaining the trophicity of nervous cells.
Microtubules are a genuine pipe with a diameter of 200 microns for the
passage of molecules that are located in the axonal hilum and dendrites.
Nissl body are located mainly in the cytoplasm of the proximal part of the
dendrites, in axons they are absent. At this level, but also through free
ribosomes necessary for protein synthesis the neuronal functions are
20
occuring and for providing cellular integrity. Their number diminishes with
aging as an argument in favor of decreasing cerebral metabolism. Other
neuronal cell specific components are melanin, lipofuscin, some metals (Cu,
Zn, Fe). The organelles that are not specific are: mitochondria, Golgi
apparatus, pigments (red nucleus, substantia nigra), lipids and protein
inclusions.
The extensions of the neurons are the axons and dendrites, the last
ones having different structural elements. The axon emerges from the cell
body at the level of the axonal hilum, where there are also found the
axoplasmatic neurotangles for slow or quick flow.
The number and distribution of neuronal dendrites contributed to
classification. The most common pattern is that of a bipolar neuron that has a
cell body, axon and a dendrite placed at 180 degrees for the single extension.
Other neurons are unipolar, pseudounipolar, multipole, polar-oposed and
dendritic dual crown.
Unipolar neurons have a single extension: axon, the dendrites
function by being replaced with some growths located on the perikarya. The
pseudounipolar neuron has only one extension which is divided into a axonal
and dendritic component. The polar-oponent neuron has two complex
dendrites located at 180 degrees between the place where the axon emerges.
Neurons with dual crown have a multitude of connections with surrounding
cells.
Neurons are part of circuits that provide transportation of
information, its processing, integration, dissemination or cancellation,
making processes as: inhibition of convergence, divergence, occlusion,
facilitating reciprocal innervation and feedback control.
The properties of neurons are excitability and conductivity.
Excitability means that the neuron is able to develop a response to a received
stimulus. Conductivity can be achieved by some variants: the great circle -
orthodromic, isolated antidromic and decremential.
According to the neural doctrine of Santiago Ramn y Cajal, the
neuron is a anatomical, genetic, functional, pathological and regenerative
unit. Each neuron develops from an independent embryonic cell having a
genetic code, a specific structure, metabolism and proper connections.
Through embryogenesis almost twice as many neurons are developed as
compared with those of the mature brain. It produces an increased number of
neurons until around 24 weeks of gestation, afterwards appears a process that
induces death (loss) of selective neurons. The process is called apoptosis,
and consists of programmed cell death, or their inclusion within a
programmed life. This type is active, assuming among other intracellular
DNA fragmentation. For a normal brain function it requires a certain density
21
of neurons, a number of axonal or dendritic branches, plus a sufficient
number of synapses. These conditions are present after 2-3 years after birth.
Neurons may die in this cell necrosis that was determined by
purchased pathology. Other mechanisms of neuronal death are transsynaptic
degeneration and excessive calcium influx. Transsynaptic degeneration
refers to the existence of a programmed number of contacts with neighboring
cells until the cell dies. The occurrence of abnormal intracellular protein
synthesis can lead to cellular depopulation, and this variation is characteristic
of degenerative diseases (Alzheimer, Parkinson, cerebellar atrophies,
dementia with Lewy bodies).
There are also possibilities of response of the adult brain neural
networks, and also in the childs one, among them being neuroplasticity.
This requires the entry into service of unused neural circuits and new
synaptic pathways. Peripheral motor neuron axons are renewable in certain
conditions.
Glial tissue and the blood-brain barrier

The cells of this tissue components do not realize the potential of
action being specialized in receiving and transmitting signals. Their primary
role is to ensure stability and normality into the perineuronal space, offering
a genuine structural support. Only astrocytes are involved in modulating
synaptic afferents by performing the neuron-astrocyte-capillary complex.
There are glial cells in the central nervous system and the peripheral
nervous system. The central glial tissue consists of macroglia (protoplasmic
astrocytes, fibers and mixed), microglia, oligodendroglia and epithelial cells.
The macroglia includes large cells (20 microns) called astrocytes. There are
protoplasmic astrocytes associated with the gray matter, fibrous astrocytes
designed for support and nutrition for white matter and mixed located at the
boundary between white and gray matter. These cells modulate synaptic
activity by releasing molecules of glutamate. Astrocytes have the so called
perivascular feet located on the external surface of the capillaries
specializing in transfers between neurons and the circulatory system. To go
to the CNS the cells, substances, metabolites, even drugs, must pass through
the so-called blood-brain barrier. Some pass through this barrier like oxygen,
carbon dioxide, some amino acids, some drugs (Levo Dopa) stopping the
passage of larger molecules, especially proteins. The membrane transport
mechanisms are operating both active and passive. Microglia is another
important cell belonging to the glial tissue. It is of mesoderm origin, which
explains the phenomenon of multiplication and the possibility of exercising
the role of macrophage. This type of phagocytic cells have a remarkable
22
potential. Microglia is located around blood vessels and preferably in the
white matter. Microglial cells play an important role in immune effector
being involved in inflammatory processes of the CNS.
Oligodendrocytes are other nervous glial cells of relatively small size
which do not have multiple connections. They are distributed both in the
white and gray matter. Among the most important roles of these cells we
mention myelination. The role of oligodendrocytes is disrupted specifically
in the so-called demyelinating diseases (eg. Multiple sclerosis).
The nevroglia is epitheliasing the ventricular cavities and the
ependimar channel realizing what is called enchephalo fluid barrier. The
epithelial cells are connected by so-called tight junction, which gives it a
certain strength and permeability of exchanges between brain parenchyma
and cerebrospinal fluid. In the ventricles (I and II) by fusion of the epithelial
cell with the pia mater will be formed the choroid plexus which will produce
CSF. The rupture of the epithelial cell layer with the point of starting
cerebral lead to so-called flooding hemorrage of the ventricles.
The peripheral nevroglia is made out of support cells for the
vegetative and peripheral nervous system. There are described the so-called
satellite cells and Schwan cells. The satellite astrocytes cells have similar
roles and the Schwan ones take the role of oligodendrocytes (myelination).
They are located near the neuronal bodies of sensory and autonomic neurons.
Schwan cells are distributed around the axon of the peripheral neurons.
These cells produce myelin and are located around the axons of
unmyelinated fibers.
The synapse
The functional connection between two neurons is through synapses.
Synaptic connections can be made between axons, dendrites, cell bodies,
realizing several combinations (axono-dendritic, dendro-dendritic, axial-
axonal, axons or dendrites of the next cell body, axial-somatic, dendro-
somatic).
Normal variants are known as electrical and chemical synapses.
Under certain conditions it can establish unsynaptic contact between two
neighboring nerve fibers. This contact is pathological, possibly after the
destruction of myelin sheaths and Schwann cells and it is called efapsa.
The chemical synapse involves interneurons communication through
a neurotransmitter with the presynaptic membrane, the synaptic space and a
postsynaptic membrane. The interneuronal transmission is characterised by a
biological sequence of events leading to some delay in the passage of
information. Synaptic transmission delays can be between 0.5-1.2 msec. For
23
this reason nerve impulses transmitted by multisynaptic ways are delayed
according to the number of synapses. The best known neurotransmitters are
dopamine, norepinephrine, acetylcholine, gamaminobutiric acid (GABA)
VIP, etc.
The 20-60 nm synaptic space may be sealed by a glial cell. Electrical
synapses allow nerve transmission without using a mediator. Distance
between neurons is about 2nm and the transmission is based on "electrical
bridge" low resistance formed by neural endings involved in transmission.
Usually the synaptic transmission is in one direction but there are
exceptions. These include the case of the reciprocal synapses in which the
membranes can function as both the presynaptic and the postsynaptic. It is
possible that part of the synapse to transmit in one direction and the other in
the opposite direction. There are serial synapses made through an axon in its
way to another neuron or effector organ and make connections with other
neighboring neuron or muscle cells.
The number of synapses of a neuron varies between 50-100000.
Pyramidal cells of the cerebral cortex can have up to 500,000 synapses.
Synaptic transmission requires the existence of a mediator and the sequence
of events that will happen presynaptic, synaptic space and in the post
synaptic membrane.
For the event to occur there must exist the presynaptic vesicles
(storage medium), so that a membrane depolarization will be achieved
through action potential after which calcium ion penetrates through voltage-
gated calcium channels in the neuron. The influx of calcium causes vesicles
mediating presynaptic membrane to reach near and mediator to be released
in the synaptic space. The most important postsynaptic events are related to
the activation of postsynaptic receptors.
A separate entity is the neuromuscular plaque which enables nerve
transmission to skeletal muscle fibers. Mediation is conducted by
acetylcholine. The muscle fiber of this complex has a number of folds
bordering these channels. It is known as the "neural apparatus of Coateaux".
The folds are less than 1 micron in size and distance from each other is 0, 5
microns. The synaptic space is 20 to 30 microns being sealed by a Schwann
cell. One peripheral motor nerve fiber and the number of muscle fibers
innervated form a motor unit. The best known pathology is myasthenia
gravis, characterized by loss of postsynaptic acetylcholine receptors.
Neuroplasticity
Neuroplasticity is the ability of the nervous system to generate
changes in behaviour adapted to the changes that occur both in the internal
24
and external environment. Basically, certain cortical projections can
"migrate" being taken from other areas. One of the best known examples is
related to the areas involved in speech.
From this point of view, the phenomenon can be regarded as positive,
based on the neurological recovery. Not to be ignored, however, that there
are situations when neuroplasticity may take a less favorable path, eg pain, in
which case certain changes may lead to chronic pain syndromes.
In the prenatal period, cells are undifferentiated (stem) and able to
transform into any cell type depending on the embryonic region in which
they are. After birth, the brain grows in size until the end of puberty, based
on multiplying the number of synapses, axonal myelination, nerve
conduction velocity increases and the increase in dendritic extensions. In
adulthood, however, there neurogenesis is still happening through
neurological rehabilitation following illness, which is just relying on
functional reorganization or through acquisition of new motor schemes or by
inactivation of some brain structures. The changes that underlie adaptive
plasticity are actually the same biological processes that lead to the
development of the nervous system. Even from the physiologically
perspective we can talk about this phenomenon of plasticity linked to
learning.
One of the known mechanisms of neuroplasticity (together with
synaptic plasticity, axonal growth and regeneration, sensory or motor cortex
neuroplasticity) is the Hebb law: repeated or persistent stimulation of cell A
to B causes metabolic changes in one or both neurons and possibly axo
dendritic changes that modulate the synaptic transmission efficiency.
Neuroplasticity in recovery of the motor deficit due to stroke can be
modulated by applying the principles of motor learning/physical therapy
coupled with the administration of neurotrophic substances (pharmacological
neuroprotection), which will have as goal the acquisition of new motor skills.
The application of a therapeutic strategy will aim to functional
reorganization in the primary motor area by learning new motor schemes
through repetition.
This phenomenon is continuously throughout the entire life and
occurs in normal and pathological conditions, enabling learning and adapting
to emerging situations, both by exposing to already existing connections and
by forming new connections, proving the dynamic character of the synapses
and their particularly important role in recovery.
25
CNS and stem cells
In the embryonic period, together with the formation of the neural
plaque, some of the non-differentiated or stem cells will be programmed to
become nerve cells. This complex development will include several phases:
neuronal proliferation, migration outward from the ventricular zone (based
on the chemical affinity, the action of adhesion molecules and/or chemical or
electrical topographic gradient axonal guidance), aggregation (which leads to
the formation of specific structures, the presence of adhesion molecules) as
well as programmed cell death, useful for removing those cells not included
in any circuit or migrated into the wrong areas.
Stem cells are not found in the body only in the embryonic period,
but are also found in adults, in the adult CNS and can be activated as a result
of injury having the ability to help regenerate the damaged tissues. They are
cells with the potential to form precursors of various cell lines in the body,
may be pluripotent, when the potential to give precursors to multiple cell
types or unipotent, i.e. dedicated to a single cell line. Great attention has
been paid in recent years to the hematopoietic stem cells derived from the
bone marrow, which have been shown to be a potential source of neural cells
in the transplant application.
There are currently recorded several attempts to obtain stem cells.
Thus, starting from the observation that human fetal CNS is able, in the
presence of growth factors, to make differentiation into cells with specific
morphology of neurons, astrocytes or oligodendrocytes, the cells were
implanted in the mouse brain tissue resulting in the occurrence of neural
copies. Another strategy tested in recent years is the somatic cell nuclear
transfer, placing it in the enucleated oocytes and then differentiation in stem
cells identical to the donor, as already tested in experimental animal studies
with Parkinson's disease. The use of growth factors such as BDNF to
promote stem cell proliferation and migration of endogenous neural areas
destruction is another approach that has passed and is in continuing research.
The results so far suggest the possibility for future therapeutic
approach with such cell cultures of Parkinson's disease, spinal trauma,
Huntington's disease and even multiple sclerosis, the drawback so far is
mainly represented by obtaining specific neuronal subtypes. This way it
might reduce the persistence of undifferentiated cells and the risk of tumors,
one of the major problems reported so far. In addition to the risk of
malignancies there are a number of ethical considerations taken into account,
especially related to the use of fetal tissue.
Still, stem cell therapy remains a therapeutic alternative to follow.
26
1. Mummenthaler M, Mattle H, Fundamentals of Neurology, Georg
Thieme Verlag, 2006;
2. Netters Neurology, Jones HR, Editor, Elsevier Saunders, 2012;
3. Neurology Board Review, An Illustrated Study Guide, Mowzoon
N, Flemming KD, Editors, Mayo Clinic Scientific Press, 2007;
5. Rusu V, Dic ionar medical, Edit. Medical, Bucure ti, 2007;
6. Wilkinson I, Lennox G, Essential Neurology, Fourth Edition,
Blackwell Publishing, 2005.
27
Chapter III.
Diseases of the Motor Neurons

Upper motor neuron syndrome Lower motor neuron disease

- General issues - Acute anterior polyomyelitis
- Types of deficit - Postpolio Syndrome
Upper motor neuron disease - West Nile virus infection
- Primary amyotrophic lateral - Kennedy syndrome
sclerosis - Spinal Muscular Atrophy
- Hereditary spastic Diseases of both upper and lower
paraplegia motor neurons
Lower motor neuron syndrome - Amyotrophic lateral sclerosis
- General problems
- Types of deficit
Upper motor neuron syndrome

General issues
The upper motor neuron (UMN) is located in the primary motor

cortex (Brodmann area 4) and the premotor area 6. The motor neurons
located in the primary motor cortex are responsible for the voluntary
contraction of the striate muscle groups that realize voluntary movements.
The descendent axons of the neurons from the motor area will form
the corticospinal and the corticonuclear tracts. The corticopinal tract contains
descendent fibres which will decussate at bulbar level to form the pyramidal
lateral tract, which will make synapse with the lower motor neuron (LMN) in
the anterior horn of the spinal cord. There is also a fibrillary component that
will not decussate, out of which the anterior corticospinal tract will result.
The corticonuclear (corticobulbar) component will project bilaterally on the
motor nuclei of the cranial nerves V, VII, IX, X, XI and XII.
The clinical signs of affect of the upper motor neuron are:
Loss of muscle ability is one of the first signs that appears and can
manifest by the impossibility of performing certain movements, installing of
28
spasticity, and is characterized by slow and imprecise movements. The
affectation can initially be symmetrical.
Loss of dexterity is a common sign of upper motor neuron
pathology. It manifests by clumsiness and stiffness while performing
voluntary skillful motor actions. The normal function of these actions in
normal individuals is dependent on the integrated activation of interneuronal
circuits within the spinal cord, controlled by the corticospinal tract. An UMN
lesion will produce difficulty for the patient in performing rapid repetitive
movements.
Loss of Muscle Strengh (weakness) is another symptom of upper
motor neuron disorders. This behaviour is much more obvious on extensor
muscles of the upper limbs and flexor muscles of the lower limbs.
Spasticity is another marker of UMN disorders and can be evident
during passive movements. The muscles will induce the so called clasp-knife
response.
Pathological signs are: the Babinski sign, the Hoffmann sign and the
disappearance of abdominal cutaneous reflex.
The Babinski sign is the most important one, and once identified, it
has the significance of an affectation of the pyramidal tract. It can be absent
in case of a long evolution in some illnesses that are associated with toe
extensor muscle atrophy and also disorders of the anatomic foot.
Osteotendinous hyperreflexia is another sign of affectation of
UMN. This kind of hyperreflexia can be present even in case of an atrophic
limb.
Pseudobulbar palsy occurs whenever the corticobulbar tract is
involved in the pathologic process, manifesting supranuclear control upon
speech, mastication or deglutition. The term pseudo is intended to
differentiate with an authentic bulbar syndrome caused by the implication of
bulbar cranial nerves pathology.
Speech, deglutition and fonatory dysfunctions are accompanied by
the so called affective incontinence (emotional lability), which manifests
by spastic cry and laughter.
Types of deficit
Hemiplegia/hemiparesis loss of voluntary mobility of half of the
body, determined by central lesions of the pyramidal tract; the causes can be
vascular, tumoral, encephalitic or traumatic.
UMN lesions can induce the following types of deficits:
- Paraplegia/paraparesis motor deficit of the lower limbs by
central cause;
- Diplegia/diparesis motor deficit of the upper limbs by
central cause;
29
- Triplegia/triparesis motor deficit present in 3 limbs;
- Tetraplegia/motor deficit of all the 4 limbs;
- Monoplegia/monoparesis motor deficit of only one limb
(either superior or inferior).
Based on the cause and the time interval from the acute episode,
paresis can be either flaccid (hypotonia) or spastic (hypertonia).
Upper motor neuron disease
Primary Amyotrophic Lateral Sclerosis (PALS)

PALS usually occurs in patients below 50 years of age, and is
characterized by the presence of a lent progressive paraparesis, with
predisposition of ascension towards the upper limbs and inducing of
characteristic elements for pseudobulbar paralysis.
In some cases, the onset can be either bulbar or descendent in the
Mills form (hemiplegia). Cramps and fasciculations may also be present.
Deficits manifest by spasticity, loss of muscle ability and walking
disturbances. Muscle atrophy usually occurs late during the evolution.
Cognitive impairment can also be present, but without reaching the
dementia stage.
The prognosis is much more favorable than in Amyotrophic Lateral
Sclerosis (ALS).
Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegia (Familial) is one of the progressive
forms of illnesses, in this case, the adult person is affected by a genetic
autosomal dominant disease.
An important clinical criteria for the diagnosis of this pathology are
the sensory modifications and sphincter dysfunction, which usually occur
during the late stages of the disease.
Many of these patients suffer from cerebellar ataxia and dementia.
Lower Motor Neuron Syndrome

General problems
The LMN is located in the anterior spinal horn, where on the
vertically it realizes longitudinal columns. There is also a certain somatotopy
of the neuronal distribution, so that the neurons destined to the dorsal
muscles are located in the dorsal area, and those destined to the proximal
30
muscles in the anterior area. Alfa neurons for the muscular fibers, and beta
and gamma neurons for the neuromuscular cones, leave from the anterior
horn towards extremities.
Clinical signs are: weakness, atrophy, hyporeflexia, hypotonia,
fasciculations and cramps. One of the most known diseases of the anterior
horn is the acute anterior poliomyelitis.
Muscle hypotonia is the result of the loss of innervation of the motor
unit. Peripheral motor neurons are located in the motor nuclei of the cranial
nerves and in the anterior horns of the spinal cord. Alfa motor neurons are
the main neurons that innervate the muscular fibers. They are among the
largest cells of the nervous system.
Muscle atrophy is the consequence of denervation and is
accompanied by the osteotendinous hyporeflexia.
Muscle hypotonia is observed when applying passive movements and
even when palpating the affected muscular groups.
Fasciculations are caused by the contraction of muscle fibers
belonging to a motor unit. They are produced by the hyperexcitability type
activation of motor neurons from the anterior horn.
Muscle cramps seem to have the same mechanism as fasciculations.
They are characterized by involuntary contraction and denervation of some
muscle groups. They can be found also in healthy subjects.
Types of deficit
At peripheral level there is a deficit that is proportional with the
affected motor units. From topographical point of view, the lesions can be
located at the motor pericarion level, at the anterior roots, at plexus level and
at the peripheral nerve level.
Paraplegia and tetraplegia in LMN lesions can be found in: subacute
or subchronic poliomyelitis, Charcot-Marie amyotrophy, spinal progressive
amyotrophies, polinevritis and other polyneuropathies, polyradiculoneuritis.
- Mononeuritis isolated affection of one peripheral nerve in case of
troncular paralysis of a nervous trunk.
- Mononeuritis multiplex simultaneous or successive affection of two
or more nervous trunks, in the course of the same pathology.
- Multinevritis clinically syndrome that consists in affection of more
distinct peripheral nerves, in regions apart from each other. It
manifests by pains, paralysis and atrophy of correspondent muscles.
- Polyneuropathy simultaneous affection of the nervous terminations.
It can have numerous causes: intoxications, alcoholism, diabetes,
toxi-infectious diseases, congenital or idiopathic causes. It is
characterized by the existence of a sensory-motor bilaterally deficit.
31
- Polyradiculoneuritis . peripheral neuropathy characterized by
bilaterally and symmetrically affection of a certain number of
rachidian nerve roots and the correspondent peripheral nerves.
Depending on its evolution, there are acute forms, Guillan-Barr
syndrome, subacute and chronic forms.
Lower motor neuron disease

Anterior acute poliomyelitis
Syndrome of Acute Anterior Poliomyelites can be caused by the
infection with poliomyelitis viruses, but also with Coxackie A and B, West
Nile or Japanese encephalitis viruses, these being the mainly incriminated
pathogens for the appearance of this illness in countries with a well
organized vaccination programs for the population.
The poliomyelitis virus is a small RNA virus that prefers the human
intestinal tract, the main way of getting infected being the fecal-oral path.
The symptoms may vary according to the severity of the infection
and also by the degree of nervous system involvement, from general
symptoms such as: fever, nausea, vomiting, myalgia, neck stiffness, to
symmetrical limb paralysis, similar to Guillan-Barr syndrome.
Fasciculations can also be encountered, diminished or absent reflexes, and
also flaccidity of the affected muscles. Muscle atrophy occurs at
approximately 3 weeks from the onset of the paralyisis, becoming permanent
after 12 weeks.
There is a high mortality rate in the extreme age categories. The main
risks are referring to respiratory and deglutition difficulties, the treatment
dealing mainly with these situations and the supportive therapy for these
functions. The natural evolution of the disease after the acute phase is over,
leads to almost fully recovery of deficits and the installation of the postpolio
syndrome.
Postpolio syndrome
Patients that had poliomyelitis develop after several years a
progressive dysfunction, characterized by fatigue, pain, dysphagia, dysarthria
and sleep disorders. This clinical symptomatic complex occurs in 27 up to
60% of the patients, without a clear explication at the moment. Most patients
develop this syndrome at about 10 years after the initial infection. There
seems to be an affection of the muscles that werent initially affected, by
fasciculations, muscle cramps and amyotrophies.
32
The diagnosis is established based on the history and initial clinical
and electromyographic signs, and also excluding pathologies such as:
asymmetrical radiculopathies, compression neuropathies, diabetic, endocrine
and vasculitic manifestations as well. There isnt any effective
pharmacotherapy at the moment, the treatment being mainly symptomatic,
physical and weight loss recommendations. Imbalances caused by
asymmetrical atrophies can lead in time to both articular and respiratory
decompensation.
West Nile virus infection

The West Nile virus infection can determine meningitis, encephalitis
and also an acute syndrome similar to the one induced by poliomyelitis. The
virus is endemic in the USA, but similar infections have appeared in
Romania, Russia, Hungary, Italy or Israel. The disease appears after the sting
of the Culex mosquito and is most likely to spread due to birds migration.
The human transmission can be done by transfusions, organ
transplantation, intrauterine and breast feeding. Respiratory insufficiency
that occurs during the infection can cause death.
Beside clinical signs and epidemiological context, identifying the anti
WNV IgM in the CSF contributes to diagnostic.
The treatment is symptomatic and supportive, especially in the
conditions of a respiratory insufficiency.
Kennedy syndrome
The Kennedy syndrome is a X-linked recessive bulbospinal
pathology, common in men, manifesting by gynecomastia. Initially
considered a strictly LMN affection, it is now referred to with the term
bulbospinal neuronopathy.
It is asymptomatic until around the age of 30, and is characterized by
a slowly progressive limb-girdle muscle weakness, tremor, slowly
progressive moderate bulbar dysfunction, muscle cramps and facial
fasciculations, gynecomastia and endocrinological manifestations (testicular
atrophy, feminization, diabetes mellitus), dysarthria and dysfagia.
The diagnostic is possible due to nervous conduction studies, as well
as the detection of elevated level of CK and abnormal level of feminine
hormones, but also genetic anomalies regarding cytosine-adenine-guanine
(CAG) among androgen gene receptors.
The treatment is symptomatic, targeting the muscle cramps, diabetes,
dysphagia, and also including logopedic therapy. Gastrostomy may be
necessary as the nutritional management is very important.
33
Genetic counseling is essential in families with history of the disease.
Spinal Muscular Atrophies (SMAs)

30 years ago, Werdnig and Hoffman were describing a pediatric
pathology that manifested through a progressive loss of muscle strength,
leading to death after only a short evolution and histopathologically
characterized by neuronal loss in the anterior spinal horns.
Later, the genes and the mutations responsible for it were described
(the SMN1, NAIP and BFT2p441 genes).
Today we know that the SMA is a progressive neuromuscular
autosomal-recessive transmitted disease, characterized by progressive loss of
muscle strength and atrophy, resulted from motor neurons degradation in the
spinal cord and brainstem. It is the second most frequent hereditary disease
after cystic fibrosis. In more than 95% of the cases it is determined by
mutations of the SMN1 gene.
The classification of SMAs is considering the age of onset, muscle
hypotonia characteristics and life expectancy, into the following forms:
- SMA type 1, Werdnig-Hoffman;
- SMA type 2, chronic infantile;
- SMA type 3, chronic juvenile, Kugelberg Welander;
- SMA type 4, adult form.
SMA type 1, Werdnig-Hoffman is characterized by the deterioration
of the motor neurons from the anterior horns of the spinal cord and also of
the nuclei from the brainstem. The onset is often around the age of 6 months,
and manifests by a symmetrical progressive loss of muscle strength; at the
age of 3 months only, hypotonia being visible. Hypotonia may also be
present in the intrauterine life, sometimes articular or skeletal deformities
being present. In other cases the diseases manifestations can be present
since the first days of life.
From the clinical point of view, fasciculations can be observed,
especially at the tongue, and rarely postural tremor of the fingers,
osteotendinous reflexes being absent. The evolution is fast progressing from
the muscles of the back to the girdle ones, and finally affecting the distal
segments of the limbs, facial muscles being usually respected.
Death usually occurs before the age of 2, by bulbar lesions that will
eventually lead to respiratory insufficiency. The cases with onset after the
age of 6 months have a better life expectancy, usually until around the age of
14.
SMA type 2, chronic or Dubowitz has its onset around 6 and 12
months and presents a slow evolution, the symptomatology progressing from
mild muscle strength deficit in the limbs, to difficulties in the acquisition of
34
walk, the upper limbs muscles being less affected. Fasciculations can be
present and also skeletal deformities.
Physical development can be normal, also cognition, life expectancy
in this case being around 30 years. Death usually occurs by respiratory
infections, as a result of respiratory muscles impairment.
SMA type 3, juvenile, Kugelberg-Welander appears after one, one
and a half years of life and has a better prognosis. The disease manifests
predominantly in the lower limbs. If the disease manifests before the child
learns to walk, he will lose the ability of walking until around 14-16 years. It
the onset is after the walk acquisition is complete, the patient will be able to
maintain it until 30-40 years.
The illness evolves slowly compared to the first two forms. The
muscle weakness in this case interests more the proximal segments,
electrophysiological examination being most useful for differential diagnosis
with other myopathic syndromes.
SMA type 4, adult form manifests in the second or third life decades.
Clinically it resembles to type 3, but patients have a normal life expectancy.
Another type of disease in the adult is the Finkel type Slow
Progressive Spinal Muscle Atrophy, which is an autosomal dominant
transmitted disease, with deterioration of the neurons in the anterior spinal
horns, force deficit and symmetrically muscle atrophy. The onset is usually
situated around the third or the fourth life decade, but there are mentions
made in literature about cases with onset around the age of 50. The prognosis
is good.
Clinically, there is a muscle strength deficit, initially in the lower
limbs, later in the superior limbs, the osteotendinous reflexes being either
diminished or absent. Generalized fasciculations are also present. EMG can
establish the neurogenic etiology of the disease.
Diseases of both upper and lower motor neurons

Amyotrophic Lateral Sclerosis (ALS)
ALS is a degenerative disease that affects both central and peripheral
neurons, sporadic and familial forms being also described. The disease is
also known by the name of Charcot, the name of the first scientist that
described it back in 1869, as well as Lou Gehrig disease, being diagnosed in
1939 at the famous baseball player.
The symptomatology is progressive and is characterized by
associating the motor deficit with the muscular atrophy. The disease may
have different types of onset, based on which there are several types
described. Classically, the spinal symmetric form is ALS characteristic, other
35
forms being hemiplegic (Mills), pseudonevritic (pseudopolynevritic), flail
arm presentation and the monoparetic type. The onset can be by the presence
of UMN, LMN, bulbar or dyspneic form. Other forms have also been
described: progressive muscle atrophy, primary lateral sclerosis and
progressive bulbar paralysis.
The name of ALS suggests the link between amyotrophy and the glial
sclerosis of the anterior and lateral pyramidal tracts.
The incidence and prevalence of the sporadic form of ALS is uniform
in the world. In Europe there is an incidence of 2 cases for 100000
inhabitants, with a prevalence of 6 cases for 100000 inhabitants. The female
population seems to be more exposed, the proportion men/women is about
1.2 to 1.4. The diseases onset is located after midlife, with a higher
incidence, between the ages of 65 and 74. Life is significant shortened with a
life expectancy of only 3 years after the diagnosis, some patient however
surviving up to 5 or even 10 years.
The diseases etiology is still not known at the moment, therefore it
doesnt benefit from an effective treatment. Morphopathological researches
identified the degeneration and the neuronal loss, the astrocitary gliosis and
the microglial proliferation. The cellular loss is located in the motor cortex
(UMN), the spinal anterior horn and the motor nuclei of the cranial nerves.
Morphopathological modifications can also be identified in other areas, such
as the fronto-temporal cortex, hippocampus, thalamus, the spinocerrebellar
tract, the posterior tracts and substantia nigra. There is suspected a selective
neuronal degeneration related to some excitotoxines, oxidative stress,
neurofilamental anomalies, or regarding anomalies of the ionic channels of
the mythocondria and proinflammatory cytokines.
The clinical picture reveals the association of progressive motor
deficit with amyotrophies. It is possible identifying a motor deficit associated
with osteotendinous hyperreflectivity, spasticity and pathological reflexes.
The presence of amyotrophies and fasciculations proves the involvement of
the LMN.
The onset is usually monofocal, with possible localization at the
lower limbs level as well as in the upper limbs. An important percentage of
patients, 25% can have bulbar onset, and in a reduced percentage of 1-2%
the onset can be with dyspnea or hemiparesis.
A deficit that affects the superior limbs can be another variety of this
disease. Depending on the onset, afferent clinical signs can be identified. The
onset located in the superior limbs can be signaled by the loss of muscle
ability and strength for everyday activities. The affect of the lower limbs is
signaled by falls, limited walking distances and walking instability.
The bulbar onset or the extension of the symptomatology is signaled
by deglutition and fonatory problems. The pseudobulbar symptomatology is
36
characterized by spastic laughter and cry. Fasciculations may not be present
from the beginning, but visible next in evolution. Their absence is
whatsoever a signal for reconsidering the diagnosis.
Muscle cramps can be associated with AMS onset, being a regular
presence in the clinical picture afterwards. Spasticity is usually present, but
does not influence in a negative way the clinical aspect of the disease,
however, it may induce painful spasms of the flexor muscles of the limbs.
Deglutition problems increase the risk for aspiration pneumopathies,
but also to the installation of a ponderal deficit or even cachexy.
Atrophies and the tonic disequilibrium lead to abnormal usage or
joints which can cause pain or induce deformities.
The presence of cognitive impairment can be followed by
frontotemporal dementia, thus suggesting the involvement of other CNS
structures in the ALS specific degenerative pathology.
Other clinical manifestations can be: sleep disorders, depression,
anxiety, extrapiramidal signs, sphincter disorders or abnormal eye
movements.
The primary lateral sclerosis and the progressive muscle atrophy have
a better prognosis.
Paraclinical exams can either help diagnose AMS or exclude this
diagnosis. Biochemistry analysis, electromyography and MRI may help in
the differential diagnosis.
Biochemistry analysis is formed by a battery of test containing: CK,
complete hemogram, VDRL, anti-GM1, ESR, electrophoresis, glicozilate
hemoglobin, thyroid hormones and vitamin B12. CK may be elevated in
ALS patients, the other tests helping eliminate other etiologies. CSF fluid
can provide data about an eventual basal meningitis, lymphoma or CIDP.
Muscle biopsy can only say if the atrophic process is similar to other
neurogenic illnesses. Electrodiagnosis is useful for investigating the
conductibility of certain nervous truncks and the reactivity of the partially
dennervated muscle.
Nerve conduction velocities can be either normal or slightly
diminished, based on the number of damaged axons.
The disappearance of an important number of axons may lead to
Generalized Low Motor Normal Sensory EDX pattern, which has a bad
prognosis meaning.
EMG exam can reveal 2 processes. One is characteristic to the initial
phase, manifesting by sharp waves, the other to the chronic phase: a low
number of contractions is associated with an amplitude increase and also an
increase of the time to add motor polyphasic potentials. Fasciculation
potentials are also characteristic for this disease, their absence suggesting
investigating for another possible diagnosis than ALS.
37
MRI (FLAIR and T2, Weighted Fast Spin) are not ALS specific, even
though they show elements for frontal and parietal cortical atrophy. Much
more useful seem to be the MTR (Magnetization Transfer Ratio), Magnetic
Resonance Voxel Based Morphometric Spectroscopy and Diffusion Tensor
MRI (DTI) variants.
Some information about the functional state of the corticospinal tract
can be obtained with the help of TMS.
Diagnosis
Knowing the difficulty for an onset diagnosis, there are criteria for
situating the patient in one of the ALS types: definite, probable, probable
lab-supported, possible and familial lab-supported.
The first criteria was elaborated at El Escorial (Spain) in 1990, being
later completed by Airlie House, USA, Virginia, in 1998.
Criteria for the clinical diagnosis of ALS
Definite clinical UMN and LMN in at least 3 regions (bulbar + 2

ALS spinal locations/ 3 spinal locations without bulbar
affect)
Probable clinical UMN and LMN in 2 regions, with UMN signs

ALS rostral to LMN signs
Probable ALS, UMN and LMN signs in one region, UMN signs in
Laboratory- another area + EMG proof of LMN affect in at least
Supported 2 limbs
Possible ALS UMN and LMN signs in one region/ or UMN signs
in 2 or more regions/ or LMN signs rostral to UMN
signs
Familial ALS, Unexplained UMN or LMN signs in at least 1

Laboratory- region, SOD1 mutation present or family history
Supported with SOD-1 mutation disease
Table 1. Criteria for the clinical diagnosis of ALS
38
The differential diagnosis is performed with neurological disorders
that affect the hemispheres, the brainstem, the spinal cord, the anterior horn,
the nervous roots, the neuromuscular junctions and muscles.
Some specific signs can be also found in cervico-arthrosic
myelopathy, syringomyelia and syringomyelobulbia, multiple sclerosis,
CIDP with demyelinating lesions, bulbar progressive paralysis, miastenia
gravis, multisystemic atrophy, paraneoplastic syndromes or hyperthyroid.
ALS therapy should be multidisciplinary because of the multitude of
complications. This team should be composed by neurologists,
pneumologists, rehabilitation specialists, social counselors, psychologists,
dieticians, logopedy therapeuts and dentists.
The neuroprotector treatment available is Riluzol, an assumed
antagonist of glutamate release, which seems to have a benefic role in
delaying the evolution of the disease. Oral administration of 100 mg/day
increases the life expectancy with approximately 3 months after 18 months
of treatment. The benefit can be extended up to 6-20 months. Nevertheless,
the benefit is very much reduced in late stages of the disease.
The symptomatic treatment in ALS has a main objective:
improvement of the quality of life.
Frequent Symptomatic treatment

symptoms in ALS
- Amitriptilin 25-50 mg 2-3 times/day or
Sialorrhea - Atropin, sublingual drops, 0.26 0.75 mg 3
times/day or
- Hioscin (scopolamin), transdermal patch, 1.5
mg every 3 days
Bronchi secretions - Guaifenesin or N-acetilcistein and/or
- Ipatropium + mechanic devices for cough
assist
Pain - Paracetamol or tramadol or even morphine
Cramps - Mg2+, carbamazepin, fenitoin, verapamil or
gabapentin.
- Gabapentin (900-2400 mg/day)/ Memantine
Spasticity (10-60 mg/day)/ Dantrolen (25-100 mg/day)/
Diazepam (10-30 mg/day).
Depression, anxiety - Amitriptyline/ Sertraline/ Fluoxetine/
and insomnia Paroxetine for anxiety and depression;
- Amitriptyline/ Zolpidem for insomnia.
Table 2. The ALS treatment
39
In spite the risk for venous thrombosis in patients with lower limbs
paralysis, prophylactic treatment is not recommended whatsoever,
compression stockings and physiotherapy being recommended instead.
Selective Bibliography
1. Adams and Victors Principles of Neurology, Ropper HA, Brown RH
Editors, Eighth Edition, McGraw Hill, Medical Publishing Division,
2005;
2. Bradleys Neurology in clinical practice, Daroff BR, Fenichel GM,
Jankovic J, Maziotta JC, Editors, Sixth Edition, Elsevier, 2012;
4. Hufschmidt A, Lcking CH, Neurologie integral, De la simptom la
tratament, Editor Popescu CD, Edit. Polirom, Ia i, 2002;
5. Ghiduri de diagnostic i tratament n neurologie, Bjenaru O, Edit.
Amaltea, Bucure ti, 2010;
8. Neurology Board Review, An Illustrated Study Guide, Mowzoon N,
Flemming KD, Editors, Mayo Clinic Scientific Press, 2007;
9. Popoviciu L, A gian B, Bazele semiologice ale practicii neurologice
i neurochirurgicale, Edit. Medical, Bucure ti, 1991;
10. tefanache F, Popescu CD, Neurologie clinic, UMF Ia i, 1997;
40
Chapter IV.
Peripheral Paralysis of the

Limbs
Dragos Popescu
Pheripheral Paralysis of Upper Limbs Paralysis of the Lower Limbs
- Brachial Plexus Paralysis - Femoral (Anterior Crural)

Mononeuropathies of the Upper nerve paralysis
Limb - Obturator nerve paralyisis
- Musculocutaneous nerve - Sciatic nerve paralysis
paralyisis - Peroneal and tibial nerve
- Axillary (circumflex) nerve paralyses
paralyisis - Tibial nerve paralysis
- Radial nerve paralysis - Common peroneal
- Ulnar nerve paralysis (external popliteal) nerve
- Median nerve paralysis paralysis
PHERIPHERAL PARALYSES OF UPPER LIMBS

The peripheral paralysis of the upper limbs are the result of lesion of
the spinal nerve roots, brachial plexus and peripheral nerves.
The peripheral nerves are: the median, ulnar, radial, musculo-
cutaneous.
Paralyses of some collateral branches, such as the nerves to serratus
anterior, pectoralis major, subcapsular and supraspinatus and infraspinatus
muscles, are added.
The spinal nerve roots pathology is caused by vertebral-medullary
traumas, disc herniations, benign and malignant tumors, vertebral
malformations and arterial-venous malformations in this territory.
41
By the functional assessment of roots C5, C6, C7, C8 and T1, the
motor deficits caused by spinal nerve roots lesions can be determined. Thus,
C5 root makes possible the abduction of arm, flexion of forearm, rotation
and adduction of arm, and C6 root the extension of hand and ulnar extension
of hand. Root C7 makes possible the extension of the elbow and fingers. C8
root innervates the flexors of the fingers and the intrinsic muscles of the
hand, innervated by the median nerve. Root T1 innervates the intrinsic
muscles of the hand through the cubital nerve.
Paralyses are characterized by motor deficits in the muscles or
muscle groups innervated by these roots. Tendon reflexes are diminished or
absent.
The laboratory diagnosis is made by anterior-posterior, lateral,
oblique radiographs of the spine, lumbar puncture, magnetic resonance
(MR), computer tomography.
Detection electromyography may determine the injured root territory
and the progression.
BRACHIAL PLEXUS PARALYSIS

The brachial plexus is formed by the ensemble of the ventral
branches of roots C5, C6, C7, C8, T1, with the participation of some
anastomoses from C4 and T2. The roots pass through the thoracic outlet
subsequently combining to form three trunks. The upper trunk is formed by
the union of C5 and C6 roots. The middle trunk is formed by C7 root alone
and the lower primary trunk by the union of C8 and T1 roots. Each trunk
divides into an anterior and a posterior division. From these divisions will
result the lateral, median and posterior cords.
Cord Nerves Function

Lateral musculo-cutaneous Motor:
elbow flexion, pronation
lateral head of the median nerve radial flexion of wrist
extrinsic flexion of hand
Sensory:
lateral board of forearm
Medial medial head of median nerve Motor:
ulnar intrinsic muscles of
medial brachial hand
cutaneous ulnar flexion of wrist
Sensory:
medial bord of forearm
42
and hand
Dorsal radial axillary Motor:
extension of ulna, hand,
fingers;
supination;
abduction of upper limb
Sensory:
shoulder and hand
Table 1. Functions of the brachial plexus
The lateral cord is formed by the anterior divisions of the upper and
middle trunk. This cord gives rise to the musculocutaneous nerve and the
outer branch of the median nerve. The anterior division of the lower trunk
forms the median cord which gives off the ulnar nerve and the inner branch
of the median nerve.
The three posterior divisions of the trunk unite to form the posterior
cord, which splits to become the radial and axillary nerves. The lesions of
the cords may be diagnosed by the presence of motor deficit and sensitivity
disturbances.
The automatic innervation is situated between segments T1 and T8,
providing the regulation of vasomotricity, piloerection and glandular
secretion.
The etiology of brachial plexus paralyses is diverse. Direct and
indirect trauma, gunshot wounds, surgical trauma, elongations, compression
due to the use of crutches, all may cause lesions of the brachial plexus.
Paralyses of the brachial plexus are also met in lateral-cervical tuberculous
adenopathies, neoplasms, following serotherapy for neoplasms in the apex of
the lung, aneurysms of subclavian artery.
The paralyses of the brachial plexus are classified into: complete,
partial and dissociated.
In the complete paralysis the upper limb cannot perform any
movement. Anesthesia is present. Tendon reflexes are absent, and atrophies
make the upper limb to be skeleton-like.
Partial paralyses are of upper plexus, lower plexus, and middle plexus
type. The upper plexus type paralysis occurs when the upper trunk (C5 and
C6) is involved. Hypotonia and motor deficit will affect the deltoid, biceps,
brachialis, rhomboideus, supraspinatus and infraspinatus muscles, with
resulting loss of abduction and external rotation of the shoulder and ulnar
flexion. Sensation is disturbed in the shoulder, lateral aspect of upper limb
and thumb. Bicipital and radial relexes (at C5-C6 level) are diminished or
absent.
43
The middle plexus type paralysis is caused by lesions of the trunk
itself or C7 root. Motor disturbances are represented by triceps paralysis and
weakening of the extensors of the wrist and fingers. Hypoesthesias are
located on the dorsal aspect of the forearm and hand. Triceps reflex
conducted by C7 root is diminished.
Injuries to the lower plexus determinate paralysis, hypotonies and
atrophies of the intrinsic muscles of the hand. Loss of the flexion of fingers
and ape hand deformity are common. Sensation is diminished or lost on
the inner aspect of the upper limb and on the cutaneous territory of the
cubital nerve in the hand. The cubital-pronator reflex is absent. When roots
C8-T1 and Budges ciliospinal center are involved, the symptoms of
Horners syndrome (characterized by enophtalmos, miosis and ptosis) are
added to the deficit.
Dissociated paralyses are rarely met in medical practice, being
occasionally associated with one of the above mentioned types of paralysis.
Thoracic outlet syndrome. Before reaching the axilla, the nerve
roots and subclavian artery cross the thoracic outlet formed by the first
thoracic rib, clavicle, anterior and posterior scalenus muscle.
This outlet narrows both with age (mild shoulder drop) and presence
of a rudimentary cervical rib or hypertrophy of transverse process of vertebra
C7. Of the nerve trunks, the compressive effect is more common to the lower
trunk (C8-T1), vascular-nervous (diminuation of the flow through the
subclavian artery and the neurologic signs), and purely vascular.
The clinical symptoms consist in paresthesia of the last fingers of the
hand, motor deficit and atrophy of thenar eminence, no pulse in the radial
artery, and in case of forced extension of upper limb the Raynaud
phenomenon is also present. Frequently, remission or slow progression may
occur.
Cervical radiographs (anterior-posterior and oblique views) and
Doppler examination of subclavian artery make the diagnosis.
Surgical removal of cervical ribs, division of fibrus bands, or section
of the scalenus muscle may give permanent relief.
Amyotrophic neuralgia (Parsonage-Turner syndrome) is a bilateral,
symmetrical or asymmetrical brachial plexus neuritis of the adult, probably
caused by an immune-allergic mechanism. The age at which it occurs ranges
between 25 and 60 years. The onset is with pains in the shoulder girdle
followed by myopathies of the deltoid, biceps, triceps, serratus,
supraspinatus and infraspinatus muscles.
44
MONONEUROPATHIES OF THE UPPER LIMB
Musculocutaneous nerve paralyisis.
The musculocutaneous nerve originates from the lateral cord of the
brachial plexus. It is formed of fibers from C5 and C6 segments. The
muscles it innervates are: the coracobrachialis, biceps and brachialis.
The musculocutaneous nerve may be involved in fractures of the
humerus, aneurysms of the axillary artery, stab wounds, gunshot wounds.
Toxic, diabetic and infectious paralysis are exceptional.
The paralysis of the musculocutaneous nerve has the following
clinical features: weakened flexion of the forearm when it is in supination,
weakened forearm supination. Biceps jerk is lost. Sensory disturbance
consists in hypoesthesia on the anterolateral surface of the forearm.
Axillary (circumflex) nerve paralyisis.

The axillary nerve derives from the posterior cord of the brachial
plexus. Its motor branches innervate the deltoid and teres minor muscles.
The sensory branches supply the skin of the lower area of the deltoid muscle.
Paralyisis of this nerve may be due to fractures and dislocations of the
femoral head, trauma to the shoulder girdle, stab or gunshot wounds. An
abnormal position of the arm during sleep or anesthesia may induce axillary
nerve paralysis. In the paralyisis by impossibility to contract the muscles, the
inability to protract and retract the arm or to raise the arm to the horizontal
position are present.
Radial nerve paralysis.

The radial nerve has a role in extension and supination. It begins at
the lower border of the pectoralis minoris being the continuation of the
posterior trunk. The fibers of the radial nerve derive from C6, C7 and C8 and
T1 roots. The radial nerve accompanies the profunda artery winding around
the humerus, and enters the musculospiral groove. It becomes anterior in the
vicinity of ulnar articulation, where it divides into the deep radial nerve,
superficial radial nerve and dorsal antebrachial cutaneous nerve. Above the
spiral groove split the branches for the triceps brachii muscle. As the nerve
emerges from the spiral groove, it supplies the anconeus, extensor carpi
radialis longus and brachioradialis muscles.
The deep radial nerve is distributed to the extensor-supinator group
of muscles. The nerve supplies the radial, extensor policis brevis, extensor
carpi radialis brevis, extensor digitorum communis, extensor digiti quinti,
extensor indicis, abductor pollicis longus muscle.
45
Lesions affecting the radial nerve may occur at the level of axilla,
spiral groove, deeps radial nerve, and above the external epicondylus.
Of all peripheral nerves the radial nerve is the most commonly
affected. Lesions to the trunk are the result of shoulder dislocation, fracture
of the humerus, callus formation around a fracture of humerus, compression
over the spiral groove, trauma of the arm, tuberculosis of the arm and
forearm bones, fracture of the neck of the radius. Paralysis of the radial nerve
are also described in association with lead or arsenic poisoning.
The axilla and supracondylar area are rarely affected. The
involvement of axilla may be due to pressure incurred from crutches and
adenopathies. To the weakness of the triceps, extension and supination
deficits are added, the paralysis being of complete type.
The spiral groove is most commonly affected, compression during
sleep being the most frequent cause. The absence of reaction is explained by
the deep sleep, due to tiredness, drunkenness or sedatives. The affection of
the deep branch usually results from a neurofibroma, synovial cyst or stab
wound in the forearm.
The clinical picture includes: motor, sensory and trophic signs.
Motor signs: in the complete palsy there is an inability to extend the
thumb and proximal phalanges, wrist and elbow, accompanied by pronation
of the hand. With the arm raised and forearm flexion the position termed
wristdrop is noticed. The adduction of the thumb, absence of contraction
in the supinator muscle, and inability to grasp objects are other signs of
motor dysfunction characteristic to radial nerve palsy.
Sensor signs: sensory loss is slight on the dorsal surface of the arm,
forearm and hand. The most marked hypoesthesia is on the dorsal surface of
the hand. In the complete paralysis the triceps reflex is absent. Atrophies are
manifest after 2 to 3 weeks involving the brachial triceps and the extensor
supinator group of muscles in the forearm.
The compressive palsies do not induce atrophies, but often cause
neuropraxia.
Ulnar nerve paralysis.

The ulnar nerve is composed of fibers from C8 and T1 segments. It
orders the flexion of the wrist, flexion in abduction of the last two fingers,
adduction of the thumb, and abduction and adduction movements of the
fingers. The sensory branches supply the skin of the little finger, the medial
half of the hand, and the ring finger.
Following its formation at the lower border of the pectoralis minoris,
the nerve crosses the medial side of the arm entering a groove on the medial
head of the triceps. On its way to the territory of distribution, the nerve
46
descends on the anterior side of the forearm passing below the anterior
ligament of the carpus into the hand. It innervates the following muscles:
flexor carpi ulnaris, ulnar portion of flexor digitorum profundus, adductor
pollicis, flexor pollicis brevis, interossei, the ulnar lumbricales, palmaris
brevis, abductor digiti quinti, and flexor digiti quinti.
The etiology of ulnar nerve palsies is most often traumatic or
compressive. Ulnar nerve palsies are most frequently caused by lesions of
the elbow or wrist. At the elbow, direct and indirect trauma (elongation,
wrenching), compressions, but also the entrapment of the channel of medial
epicondyle are responsible of palsies. At the same level, the lower fracture of
the humerus, dislocation of the elbow, repeated occupational microtrauma
may injure the trunk of the ulnar nerve. At axilla, stab wounds or aneurysms
of the axillary artery, and the wrist, minor and repeated trauma, carpal
fracture, and carpal tunnel syndrome may cause ulnar nerve palsies.
The clinical symptoms consist in motor deficits, sensory
disturbances, atrophies, vasomotor and trophic disturbances. Clawhand and
inability to grasp objects are the main motor deficits. Clawhand results from
tonus discrepancies between the extensor digitorum communis and the
flexors of the fourth and fifth fingers. The first phalanges of these fingers
remain extended, while the second and distal ones cannot be extended,
remaining flexed. Abduction and adduction of the fingers is restricted or
impossible.
The inability to abduct the thumb at normal strength and the weak
flexion of the wrist are other motor signs.
The secondary disturbances are loss of sensation over the little finger
and on the ulnar side of the ring finger and hand.
Amyotrophies are found at the level of hypothenar eminence and
interosseous spaces. Trophic and vasomotor disturbances are found in the
little finger and hypothenar eminence. The skin is colder and drier. The nail
of the little finger may be deformed, and ulcerations may occur following
minor trauma or burns.
Median nerve paralysis.

The median nerve is formed by two roots. The inner root and the
external root unite at the lower margin of the pectoralis minor muscle. The
trunk derives its fibers from C6, C7, C8 and T1 segments of the spinal cord,
and has a role in flexion and pronation, innervating the forearm and hand
muscles. In the arm it has no branches, descending along the course of the
brachial artery, then passing on the volar side of the forearm where it gives
numerous muscular branches. It reaches the hand below the anterior ligament
of the carpus and terminates with muscular and cutaneous branches.
47
In the forearm, the median nerve innervates the pronator teres,
palmaris longus, flexor digitorum sublimis, flexor digitorum profundus (for
fingers II and III), flexor pollicis longus, and pronator quadrates muscles. In
the hand, it innervates the abductor pollicis brevis, flexor pollicis brevis,
opponens pollicis, and the first and second lumbricales.
The secondary branches supply the skin of the thenar area, thumb,
second and third fingers, and the radial of the ring finger. On the dorsal
side it supplies the last two phalanges of the index finger, the middle finger
and half of the ring finger.
The paralysis of the median nerve occur in laceration of the arm,
forearm, wrist and hand resulting from car accidents, stab wounds, gunshot
wounds, carpal tunnel syndrome.
Most frequently, the lesions are at the level of the elbow and wrist.
The clinical features are: motor deficits, sensory disturbances,
atrophies, vasomotor and trophic changes.
The motor deficit is represented by paralysis of the flexor-pronator
muscles and thenar eminence muscles. Pronation of the forearm is lost or
weak. The hand slightly deviates to the ulnar side, and the thumb is in the
plane of the other fingers, especially following the onset of thenar atrophy.
Flexion of the index and middle fingers is weak or lost. The thumb
remains in abduction, and is unable to oppose or abduct.
There is also inability to grasp objects and a weakened grip especially
in thumb and index finger. The index finger shows a tendency to remain
extended and the thumb adducted. The sensory disturbances affect the
thumb, index and middle fingers, and half of the ring finger on the palmar
side. On the dorsal aspects, the loss of sensation is most commonly over the
last two phalanges of the index, middle and ring fingers. In the cutaneous
area of the middle finger causalgia may occur. Atrophies of the thenar
eminence and flexor-pronator group of muscles in the forearm are present.
The atrophy of the thenar eminence occurs within a few weeks, and that of
the flexor-pronator group of muscles over a few months.
The vasomotor changes are a dry, cold, discolored and hyperkeratotic
skin of the palm, and nail changes. Ulcerations at the level of the index
finger may also occur.
PARALYSIS OF THE LOWER LIMBS

Femoral (Anterior Crural) nerve paralysis
The femoral nerve conducts the nerve impulses for the flexion of the
thigh and extension of the leg. The femoral nerve arises from the three
48
posterior divisions of the lumbar plexus which derive from the second, third
and fourth lumbar nerves (L2, L3, L4).
It innervates the following muscles: iliacus, psoas major, pectineus,
adductor longus, sartorius and quadriceps. The secondary branches supply
the anterior and medial surfaces of the thigh, and the medial side of the leg
and foot (the femoral cutaneous branch to the thigh, and the saphenous nerve
to the leg and foot). It has important relationships with the psoas muscle,
inguinal ligament and femoral artery. It emerges from the lateral border of
the psoas, then descends and enters the femoral trigone where it divides into
terminal branches.
It ensures the flexion of the leg on the abdomen (iliopsoas), flexion
and external rotation of the leg (sartorius) and the extension of the leg on the
thigh (quadriceps).
Femoral nerve palsy is caused by some spinal cord, cauda equine,
lumbar plexus and nerve trunk lesions. Thus, pelvic tumors, psoas abscess,
fractures of the pelvis and femur, obstetrical surgery (forceps injury),
reduction of congenital hip dislocation, aneurysms of the femoral artery may
all cause femoral nerve paralyses. Diabetes mellitus and inguinal hematoma
occurring during the anticoagulant treatment must also be considered.
Motor symptoms, sensory disturbances and atrophic lesions are
present.
The complete paralysis also involves the iliopsoas muscle. In this
circumstance, the flexion of the thigh on the trunk becomes impossible. If the
iliacus muscle is solely involved, the flexion of the thigh on the trunk is
weakened. The extension of the leg on the thigh is lost, and rising from a
seated position, orthostatism and gait become difficult.
In the high nerve trunk paralysis, the patient use a dragging gait.
Walking forward becomes difficult or even impossible. The patient cannot
climb stair or raise from a seated position. Walking backward is easier.
Lesions of the low femoral nerve trunks (inguinal) cause paralysis of
the quadriceps muscle and sensory disturbances at the level of internal
saphenous nerve
Sensation is lost in the cutaneous distribution of the femoral nerve.
Femoral neuralgia is caused by affections of vertebrae or discs, tumors or
infections of the pelvis. Sensation of pain is lost on the anterior aspect of the
thigh and inner aspect of the leg. Knee jerk is diminished or absent.
Atrophy develops over the anterior aspect of the thigh. The disturbed
tonicity of the knee may determine genu recurvatum with thigh
algodystrophy.
49
Obturator nerve paralyisis.
The obturator nerve forms by the fusion of the anterior divisions of
roots L2, L3 and L4. From the median border of the psoas, the nerve passes
on the lateral of the ureter descending through the obturator canal in the
obturator foramen situated on the median side of the thigh. The nerve divides
into anterior and posterior branches. Motor rami from the posterior branch
innervate the obturator extremis and adductor magnus muscles, while those
from the anterior branch supply the adductor longus and brevis, adductor
brevis and gracilis muscles.
Obturator nerve paralysis may occur by pressure from a gravid
uterus, tumors or obturator hernia. The external rotation and adduction of the
thigh are impaired. Crossing of the legs is difficult.
Sciatic nerve paralysis.

The sciatic nerve is formed by roots L5, S1, S2, S3. It is the largest
nerve of the body, crossing the pelvis, deep gluteal area, posterior surface of
thigh, and popliteal space. At the neck of peroneus it divides into its terminal
branches: the peroneal nerve (external popliteal nerve) and its tibial nerve
(internal popliteal nerve).
Its most important relationships are with the sciatic foramen, ischial
tuberosity, the greater trochanter, gluteal muscles, pyramidalis muscle,
semitendinous and semimembranous muscles, and the long and short head of
the biceps. In the popliteal space it has relationships with the popliteal artery.
Practically, the sciatic nerve is made up by two separate nerves,
namely the tibial and peroneal ones, which originate from the same roots, but
in one sheath.
Motor branches are to the posterior muscles of the thigh (biceps
femoris, semitendinous and semimembranous), and to the leg, through the
common peroneal nerve, and tibial nerve. By innervation, the sciatic nerve
realizes the flexion of the leg on the thigh, flexion, extension, adduction,
abduction and rotation of the leg. The sensory distribution is that of roots L5,
S1 through S3.
The etiology of sciatic nerve paralysis varies with the site of the
lesion. Paralysis of the nerve roots (L5 and S1), nerve trunks (high and low)
and terminal branches (common peroneal and tibial nerves) are described.
Injury to the nerve roots results from herniated intervertebral disk
(L4-L5 and L5-S1). It is worth mentioning that a L5-S1 disk herniation may
induce lesions in both roots.
The higher nerve trunk paralysis result from gluteal trauma, femur
and pelvis fractures, injection of drugs near the nerve. During delivery, both
the mother and the newborn may develop sciatic nerve injuries. The sciatic
mononeuritis may the result of pelvic ostheoarthritis and sacroiliitis. The low
50
nerve trunk paralysis are caused by injury to the dorsal areas of the thigh
during car accidents. Gunshot wounds determine paralysis of the low sciatic
trunks.
Peroneal and tibial nerve paralyses are a result of compression,
wounds, osteoarticular trauma, tumors, occupational and sports accidents.
High nerve trunk paralysis is often complete and causes the paralysis
of the posterior muscles of the thigh, with inability of flexion of the leg on
the thigh and absence of the voluntary movements of the leg. Hypotonia and
atrophy affect the dorsal muscles of the thigh, the muscles of the leg and
foot. The Achilles jerk is lost. Hypoesthesia is present in the posterior area of
the thigh and most of the legand foot.
Trophic changes, such as ulcerations, hyperhydrosis, skin thinning,
migratory edema, cyanosis or erythema are seen.
Tibial nerve paralysis. The tibial nerve seems to continue the course
of the sciatic nerve entering the dorsum of the leg to the dorsomedial aspect
of the ankle. From this point it gives off its terminal branches which continue
into the foot.
Its motor branches are to the gastrocnemius, soleus, plantaris, tibialis
posterior, flexor digitorum longus pedis, flexor hallucis longus muscles.
Tibial paralysis may result from sacral plexus and sciatic nerve
injuries.
Clinical features: the patient cannot stand on tiptoe, walking is
difficult and sometimes painful. Ankle jerk reflex is absent. A clawfoot,
atrophies of the calf and foot muscles, and tendon retraction may also occur.
Common peroneal (external popliteal) nerve paralysis.

This nerve is formed by the fusion of the posterior divisions of roots
L4, L5, S1, S2. Once formed, it is part of the sciatic nerve trunk, crossing the
thigh as far as the popliteal space. From this point it becomes independent,
descending to the head of fibula where it divides into its terminal branches.
These terminal branches are: the recurrent articular nerve, superficial and
deep peroneal nerves. The superficial peroneal nerve innervates the peroneus
longus and brevis muscles. The deep peroneal nerve is distributed to the
tibialis anterior, extensor digitorum longus, extensor hallucis longus and
peroneus tertius muscles.
Lesions causing common peroneal nerve paralysis may be located at
the level of sacral plexus or sciatic nerve.
Slow or rapid compressions, direct trauma, fractures of the knee or
leg, sports accidents, all may induce paralysis of this nerve. The clinical
picture includes: motor deficits, sensory disturbances and trophic changes.
The motor signs are: paralysis of the extensor-abductor muscles of
the foot, steppage gait, characteristic deformity of the foot (footdrop).
51
Hypoesthesia or anesthesia is located over the dorsum of the foot and the
anteroexternal side of the leg.
Trophic changes in the anteroexternal muscles of the leg and
moderate vasomotor changes do occur.
2012;
2. Kuhlman K.A., Hennessy W.J.: Sensitivity and specificity of
carpal tunnel syndrome signs. Am J Phys Med
Rehabil. 76:838 1997
3. Landry G.J., Moneta G.L., Taylor L.M., et al.: Long-term
functional outcome of neurogenic thoracic outlet syndrome in
surgically and conservatively treated patients. J Vasc
Surg. 33:312-3172001
4. Lawrence T., Mobbs P., Fortems Y.: Radial tunnel syndrome. A
retrospective review of 30 decompressions of the radial nerve. J
Hand Surg [Br]. 20:454-459 1995
52
Chapter V.
Polyneuropathies
Cristina Grosu
General data Amiloidosis Polyneuropathy

Laboratory Investigations Porphyric Polyneuropathy
Hereditary Neuropathies Immune-mediatedNeuropathies
- Charcot Marie Tooth - Guillain Barre Syndrome
Disease HSMN I & II - Chronic Inflammatory
- Dejerine Sottas Disease Demyelinating
- Sensory-motor pressure Polyneuropathy
sensitive hereditary Infectious Neuropathies
neuropathy Autoimmune Neuropathies
- Refsum disease Deficiency Polyneuropathis
Predominantly sensory hereditary Toxic Neuropathies
neuropathies
Metabolic neurpathies
- Diabetic Polyneuropathy
- Uremic Polyneuropathy
General data
Polyneuropathy is a symmetrical process, usually distal and graded,
affecting the peripheral nerve trunks. Peripheral nerves consist of motor,
sensory and autonomic fibers. Each of these fibers has a specific metabolism,
fact explaining the differences in vulnerability. There are a number of motor,
sensory, reflex, autonomic and trophic symptoms and signs, more or less
specific to peripheral nerve diseases, which provide diagnostic criteria.
Often, either motor or sensory symptoms prevail, and are associated, at least
for a while, with deficits or irritative manifestations. Motor deficits consist in
quadric or paraparesis (sometimes even tetraplegia), distal atrophies and
hypotonia in some muscular area in the distal segments of the limbs. The
irritative elements, which precede the impairment, consist in muscle cramps.
General clinical data about the peripheral nervous system pathology:
53
1) motor manifestations
force deficit - typical onset in the lower limbs, distal, symmetrical,
affecting mainly the anterolateral region of the leg, ascending to
proximal, possibly involving upper limbs but to a lesser extent
(retrograde axonopathy); the variants are: generalized force deficit
(diphtheria, PNP toxic forms Guillain Barre), initially affecting the
upper limbs and face (acute or chronic demyelinating inflammatory
neuropathies), brachial deficit (Sjogren, demyelinating neuropathies,
paraneoplasic), paraparesis (inflammatory/infectious lesions of the
horsetail, Lyme disease, CMV infection) cranial nerve paralysis
(Guillain Barre, Lyme disease, metabolic PNP).
muscle atrophy - appears in weeks/months, the degree of atrophy is in
proportion to the number of motor fibers affected; it can also cause
muscle volume decrease by 75-80% (the difference from nonusage
atrophy is that it occurs late in time and the muscle mass decreases by
25-30%); if reinnervation appears in less than one year muscle function
and mass are likley to be restored
abolition of reflexes - damage occurs at the level of thick myelinated
fibers (the afferent pathway of reflexes) frequently disproportionate to
shortages of force; it coincides with impairment of deep sensibility (the
same type of fiber conduction)
fasciculations, muscle cramps, spasms - atypical, but sometimes
appear in reinnervation stages
2)altered sensibility
subjective: paresthesia which is distal, symmetric, initial distal to lower
limbs, upper limbs and then upward; burns, bites, cuts
objective: hypoesthesia distal, symmetric, initial upward trend from the
lower limbs and then to the upper limbs; affects all types of sensibility
and can sometimes appear with syringomyelic dissociation
when deep sensitivity is involved appears gait ataxia (polyneuropathy
with impairment of the posterior cranial roots - diabetes, Fisher
syndrome) or discrete tremor of the fingers
3) trophic disorders
dry, scaly, hair loss, brittle nails, ribbed, plantar ulcers
the early onset polyneuropathy - "claw foot" aspect due to early
atrophy of the muscles of the anterior external region of the foot that
can no longer oppose the posterior muscle contraction and atrophy of
the small muscles of the leg and foot in the training period can cause
plantar flexion of the foot, flexion of the distal phalanges
54
4) vegetative disorders
vasomotor disturbances, orthostatic hypotension, impaired intestinal
motility, sphincter disorders such as retention or incontinence,
anhydrosis, sweating, salivation, pupil disorders (diabetes,
amyloidosis)
5) cranial nerve disorders

quite rare; retrobulbar neuritis from alcoholic, saturnian, pregnant,
diabetic polyneuropathy, cochlear neuritis, nerve 3 or 7 paresis in
diabetic polyneuropathy.
Laboratory investigations
Electrophysiological: nerve conduction velocity measurements
- In demyelination: decrease in nerve conduction velocity, partial or
complete conduction block, prolongation of distal latency
- In axonal lesions: normal or moderately slow nerve conduction
velocity, reducing the amplitude of sensory nerve potentials or
muscle action potential
- EMG: Fibrillation potentials at rest, slow denervation fasciculations,
in contraction abnormal spatial and temporal recruitment with
decreasing amplitude of the motor unit potentials
- Somestesic and motor evoked potentials
CSF exam: usually normal; in diabetes and diphtheria -
hyperalbuminorahia; albumin-cytological dissociation in
polyradiculoneuritis
Other biological exams: glucose, blood count, liver and kidney samples,
infllamatory panel, electrolytes, thyroid hormone, dosage B12 and folic
acid, muscle enzymes and other tests depending on the suspected
etiology.
Muscle biopsy - confirming the neurogenic character, nerve biopsy: for
cases with unclear etiology
There are many and various criteria to divide neuropathies, but the
most used one is based on the area affected: the neuron cell body
(neuronopathy) and their peripheral processes (peripheral neuropathy). The
neuronopathies include anterior horn cell disorders, which are named motor
neuron disease and dorsal root ganglion disorders, which are named
sensory neuronopathies or ganglionopathy. The peripheral neuropathies can
be subdivided into two major categories: primary axonopathies and primary
mielinopathies.
55
HEREDITARY NEUROPATHIES
The most commonly used classification is the one made by Dyck
which includes:
Hereditary sensory-motor neuropathy (HSMN);
Hereditary sensory neuropathies (HSM)
I. The hereditary sensory-motor neuropathies:

1) HSMN type I - Charcot Marie Tooth disease hypertrophic form
2) HSMN type II - Charcot Marie Tooth disease neuronal form
3) HSMN type III - hypertrophic neuropathy Derjerine Sotas
4) Hereditary sensory-motor neuropathy pressure sensitive
5) HSMN Refsum disease type IV
1,2) Charcot Marie Tooth disease (HSMN type I and II)

The epidemiology is 1/2500 cases in the general population with AD,
AR or X linked transmission ( the most malignant variant is AR) with
mutation on chromosome 1 or 17. The pathology consists in peripheral
nerves hypertrophic myelin sheath alterations with the proliferation of
Schwann cells and appearance as "onion bulb"-like, axonal degeneration
predominantly in the large fibers and especially distal, demyelinating lesions,
with secondary muscular denervation. It is a hereditary polyneuropathy,
slowly progressive, characterised by muscular weakness and atrophy of the
anterior external region of the legs, small muscles of the feet and hands.The
onset is in the childhood or adolescence, with a peak incidence in the first
and second decade with motor deficit of the lower limbs, especially antero-
external region of the calf, symmetrical stepping walk; muscle atrophies
which can cause the leg to deformate showing a rooster leg; the atrophies
stop in the lower third of the thigh ("in garter") and in the upper limbs in the
small muscles of the hand and wrist ("the bracelet").
The atrophies are greater than the motor deficit and the reflexes are
abolished. The sensitive disorders are expressed as muscle cramps,
numbness, pain, tactile hypoesthesia, distal, symmetric "socks" or "glove"
type.
Autonomic disturbances are rare and they give out cyanosis or edema
of the extremities, hypothermia, nystagmus, pupillary abnormalities, cardiac
arrhythmias. Other signs possibly related are optic atrophy, retinal
degeneration, pyramidal or cerebellar syndrome
Electrophysiological studies show a marked decrease in nerve
conduction velocity in the peripheral nerves in type I and in type II a
moderate lowering conduction velocities in the lower limbs; the CSF exam is
normal or may show moderate proteins
56
Treatment is made with group B vitamins, painkillers, exercises
and medical gymnastics, orthotics.
3) Derjerine Sottas disease (HSMN type III)

It is the most severe form of HSMN with AD or AR transmission .
Clinically the onset is in the childhood (1-10 years) with late somatic
development, with important disorders of all types of sensitivity, especially
vibratory and propioceptive, with ataxia, pain flashing.
The hypertrophy of nerve trunks that can be felt under the skin and
are not painful (tendons) at the ulnar, median, radial, peroneal nerves.
Usually the cranial nerves are not affected, but if ciliary or optic nerve
hypertrophy occurs it may lead to ptosis, miosis, photomotor lazy reflex,
pupillary disorders. The autonomic manifestations are gastrointestinal
disturbances (epigastric pain, superior digestive hemmorage), sphincter
disorders.
Electric exam shows decreased nerve conduction velocities. The
differential diagnosis is made with progressive spinal amiotrophies, muscular
dystrophies and acquired polyneuropathies. Treatment include group B
vitamins, painkillers, medical gymnastics, orthotics.
4) Sensory-motor pressure sensitive hereditary neuropathy

The transmission is AD and the mutation is on chromosome 17.
Clinically it debutes in tge second and third decade with truncal paralysis,
recurrent episodes of paresthesia that occur by nerve compression (can be
mild, of short duration, possibly postural), resolve in hours, days or months,
rarely leaves sequelae as moderate atrophies; the most commonly affected
nerves are the external popliteal, the sciatic, the ulnar, the radial, the median,
cranial nerves are rarely involved (mainly the facial nerve).
Laboratory findings: EMG with trails of denervation in the affected areas
and reduced conduction velocities achieved in the affected nerve trunks.
5) Refsum disease (HSMN type IV)

The transmission is AR and it is produced by the accumulation in the
blood and tissues of the fitanic acid (a fatty acid)by metabolism enzyme
deficiency; so far it is not clear the relationship with neuropathic impairment.
The pathology is expressed by hypertrophic changes of peripheral nerves
(though not palpable) with appearance of "onion bulb" , segmental
demyelination and lesions of the Schwann layer. Clinically it has an onset in
the childhood or up to 20 years with a sensorymotor, distal, symmetrical
polyneuropathy in the lower limbs with all types of sensitivity altered,
especially the proprioceptive one; the reflexes are abolished. Other clinical
symptoms may include: retinitis pigmentosa, cerebellar ataxia, deafness,
ichtiosis, loss of smell, cardiomyopathy, skeletal disorders.
57
Laboratory findings are centered on the fitanic acid-dosing levels (high) and
on the electrophysiology exam with lowered conduction velocities in the
affected nerves.
The treatment must firest include a low fitanic acid diet and
symptomatic treatment; plasmapheresis is considered in some cases.
II. Predominantly sensory hereditary neuropathies are

divided into:
HSN type I (Denny Brown)
HSN type II (Morvan)
HSN type III (Riely-Day)
HSN tipIV (congenital sensory neuropathy)
1) HSN type I (Denny Brown)

The transmission is AD and the onset in the second decade or later.
Morfopathology findings include wallerian degeneration of myelinated and
amyelinated fibers, demyelinating lesions, lesions of the spinal posterior
roots and peripheral nerves.
The clinical picture shows discrete alteration of the pain and thermal
sensitivity in the lower limbs which progresses with trophic disorders and
ulcers leading to osteomyelitis and osteo-articular damage; the upper limbs
are not affected. Deep sensitivity disorders are associated with the absence of
sweating, abolition of reflexes and atrophies of the anterolateral region of the
calf resulting in stepping gait.
2) HSN type II (Morvan)

This type is more rare, with early onset and its clinical features are
more general including pressure ulcers and abolition of reflexes, affecting
mainly the upper limbs
3) HSN type III (Reily Day) - familial dysautonomia

It is AD transmited and affects mostly Hebrew children. It debuts at
birth when the new born has sucking difficulties, unexplained fever and
episodes of pneumonia without a certain etiology. The neurologic features
include: alteration or loss of thermal and pain sensitivity, with relative
preservation of touch and pressure one. The general symptoms overshadow
the evolving neurological pathology including repeated infections, lack of
tears with corneal ulcer, non reactive pupils, impaired thermoregulation,
excessive sweating, blood pressure variability, orthostatic hypotension,
58
swallowing disorders, emotional instability, gastrointestinal disorders. The
morfopathological lesions consist of alteration of small caliber myelinated
and amyelinated fibers, lesions of sympathetic and parasympathetic ganglia.
Laboratory findings may show homovanillic acid in urine in large amounts,
vanilmandelic acid in small amounts. The treatment is merely symptomatic.
METABOLIC NEUROPATHIES
DIABETIC POLYNEUROPATHY
Diabetic polyneuropathy is the most frequent form of peripheral

neuropathy, accounting for 50% of the patients with diabetes. If
electromyographic and SEP investigations are used, the specific changes are
found in 90% of the diabetics. Its an axonal and demyelinating neuropathy
with unclear pathogenesis; the hypothesis include vascular lesions (of the
vasa nervorum), metabolic (persistent hyperglycemia lowers intraneuronal
mioinositol with impact on myelin phospholipid metabolism) and
immunological disturbances (inflammatory infiltrates in autonomous
ganglia).
The clinical forms, manifestated acute or chronic, symmetric or
asymmetric, sometimes overlapping include:
Sensory polyneuropathy (most common) - chronic and symmetric form
with insidious onset of loss of sensation and proprioceptive sensitivity ,
abolition of Achilles reflex, tingling, burning and flashing pain character
in the distal lower limbs, distal hypoesthesia objectived as "socks" type
predominantly on the thermal and pain sensitivity; in evolution,
paraesthesia and hypoaesthesia of the trunk and upper limbs may appear
together with trophic disorders
Ataxic sensory polyneuropathy (pseudotabetic) with deep sensitivity
disturbances; . In these patients disturbances of equilibrium, more severe
when dark and gestural inabilities in the upper limbs may develop.
Sensorimotor polyneuritis with distal and symmetric deficit in
association with other pathologies (eg, alcoholism).
Diabetic polyradiculoneuritis is rare, difficult to differentiate from
Guillan Barre
Autonomic neuropathy (isolated or associated with other clinical forms)
with vaso-motor disorders like postural orthostatic hypotension and
syncope, abnormal sweat,anhydrosis of the feet with hyperhidrosis in
other territories, urinary incontinence, impotence, diarrhea, bowel
disorders, nocturnal nausea, bloating or severe constipation, abnormal
pupillary reflex, abolish photomotor reflex, trophic disorders especially of
59
the lower limbs with dry skin, brittle nails, hair alteration, plantar ulcers (
due to an abnormal pressure distribution and associated with altered
sensitivity) especially in the metatarsal phalanges or interphalangeal
articulations, loss of pain sensation with zones that can lead to amputation
or deformations of bones and articulations.
Diabetic mononeuritis usualyy with acute onset that affects the femoral,
sciatic, peroneal, cubital nerves; the cranial nerves can also be affected
and lead to diabetic ophthalmoplegia , peripheral facial paresis,
hypoesthesia in the trigeminal nerve, generally with regressive evolution
Diabetic multineuritis which frequently occur in the transition of diabetes
(eg marked hyperglycemia, initiation or adjustment of insulin therapy,
etc) and appear especially at thepelvic belt or with thoracic radiculopathy
Garland syndrome which is defined as diabetic proximal muscular
atrophy and clinically it presents with amyotrophic motor deficit that
affects mainly the quadriceps, hip adductors, psoas, symmetrical or
asymmetrical, abolition of reflexes and muscle twitching.
Laboratory findings in diabetic polyneuropathy should include
glycemic profile, glycated hemoglobin, albumin and glucose in CSF;
Electric exams to be done are EMG and nerve conduction velocity with show
lower conductions velocities especially in distal symmetrical forms with
demyelination and axonal damage in the asymmetrical forms.
The treatment consists in a strict diabetes control and a symptomatic
treatment for pain manily with analgesics, carbamazepine, amitriptyline,
antidepressants (sertraline, fluoxetine), in severe cases - epidural injections
and nerve block for the neuropathic pain, neurotrophics, distal vasodilators;
also there are studies concerning the administration of endothelial and
neuronal growth factor.
UREMIC POLYNEUROPATHY
Occurs in up to 50% of dialysis patients and it is an axonal
neuropathy with secondary demyelination of unknown cause; theories argue
about neurotoxic molecules that accumulate in the renal system (mioinozitol,
azide) that are not removed by hemodialysis but filtered by the transplated
kidney (for example post-transplant there is an improvement in the
neuropathy)
The clinical picture consists in an subacute or chronic sensorimotor
distal symmetric neuropathy with paraesthesia, nocturnal leg cramps,
burning, tingling improved with movement, restless legs syndrome. The only
treatment available is hemodialysis and renal transplant.
60
AMILOIDOSIS POLYNEUROPATHY
The amyloid is a protein derived material (proteins altered by genetic
defects )which is deposited in the form of filaments in the tissues.
Amyloidosis has three forms:
- familial form (autosomal dominant transmission, afecting both sexes
with amyloid deposits in vessel and nerve walls, spinal and vegetative
ganglia; many forms according to the region: portuguese, Iowa or with
certain characteristisc: carpal tunnel syndrome, corneal dystrophy)
- sporadic form (associated with monoclonal gamapathies when genetic
mutations cause synthesis of abnormal proteins that are deposited in
tissues as amyloid which cause sensorimotor neuropathy, renal, cardiac
and gastrointestinal disturbances)
- form associated with chronic inflammatory diseases which is very
rare and does not associates neuropathy
The features for all forms of amyloidosis are the fact that especially
neuropathic amyelinic fibers and small diameter myelinated fibers are
affected (the ones that lead pain and thermal sensitivity and have a main role
in autonomous system) leading to sensory-motor polyneuropathy dominated
by pain and dysautonomia disturbances; also amyloid infiltration affects
multiple organs (heart, kidney, gastrointestinal tract). The treatment consists
in imunomodulators, imunosupressants, plasma exchange, stem cell therapy.
PORPHYRIC POLYNEUROPATHY
Porphyries are genetically determined metabolic disorders. The
biochemical disturbance of hem metabolism in the liver leads to the two
variants: acute intermittent porphyria and porphyria varigata (cutaneous).
Motor deficit evolves over a period of several hours to several days, having
as precipitating factors: infections, pregnancy, alcohol abuse, barbiturates,
benzodiazepines, other anticonvulsant drugs, sulphamides, meprobramate,
chloramphenicol and rifampicin. The forms are: acute intermittent
porphyria with predominantly motor polyneuropathy with acuteinstallation
in a few hours, typically displaying loss of force in the distal part of the leg
with upward trend, affecting muscles of the upper torso even respiratory
muscle; severe forms affect even the cranial nerves; the sensitivity pattern is
proximal respecting proprioceptive sensitivity with vegetative disturbances
(sphincter, cardiovascular-tachycardia, hypertension, leukocytosis, fever)
The cerebral phenomena include confusion, delirium, visual field
defects and even seizures, in severe cases. Other symptoms include: intense
abdominal pain, colicky nature-looking acute abdomen but no signs of
peritoneal irritation or transit disorders; the condition has evolution in crisis
with mild symptoms that regress within weeks, but severe cases can lead to
61
death by respiratory or cardiac failure; the evolution can be with complete or
partial recovery in a few months. As to laboratory investigations, the main
diagnostic criteria is the presence in urine of more than 1500 micrograms of
porphobilinogen per liter in 24 hours which colors red-brown; the
determination of porphobilinogen long after the porphyric episode be
misleading; the attack of porphyria may cause death by cardiac and
respiratory paralysis; in the stool the level of porphyrins is normal
(differential from porphyria varigata).
Treatment consists in trigger discontinuation and suppression of
heme synthesis with high dose iv glucose (inhibits synthesis of delta amino
levulinic acid), with hematin carbohydrate diet without protein, prednison in
severe cases, beta blockers for tachycardia and hypertension, and in severe
cases respiratory support; seizures can be treated with sodium valproate;
pains and mental disturbances may be relieved by administering
chloropromazine.
IMMUNE-MEDIATED NEUROPATHIES
1) Guillain Barre syndrome
It is a sensory-motor quadriplegia resulting from extensive,
systematic and simultaneous inflammation of spinal nerve roots and
sometimes cranial nerves. The epidemiology is about 1.7 cases / 100,000
persons / year occuring at all ages and both sexes.
According to the etiology it can be divided into: seconday infectious
polyradiculoneuritis that occurs after an infectious episode(respiratory,
gastro-intestinal, etc. due to bacterial or viral), vaccins (rabies, typhoid) or
serum therapy (tetanus, diphtheria), surgery, blood transfusion, preceding the
neurological pathology with 1-3 weeks- primitive polyradiculoneuritis with
pathological context currently unknown or primary where the pathogenesis is
not yet clear, but it is assumed that it exists a cell-mediated immune response
against neuronal components of peripheral nerve (the role of Ly T, which are
activated in GB, TNF-alpha, IL-2 and complement) with data supporting this
hypothesis ( clinical and pathological similarities with experimental allergic
neuritis that looks identical regardless of the initial infectious disease, also
identification of autoantibodies against neuronal gangliozide (Ac anti
g1b)play an important role).
The pathologcal lesions include interstitial inflammatory lesions with
perivascular lymphocytic infiltrates around small vessels and nerv,local and
segmental demyelination lesions in areas with the inflammatory infiltrate,
62
damage to the vessel system and cerebral inflammatory lesions of the
meninges togheter with moderate Wallerian degeneration
The onset is often 1-3 weeks after an infectious episodewith
important distal paresthesias and pain in the legs, then an upward trend from
lower and distal symmetric, involving the distal and proximal muscles
equally to the trunk and upper limbs possibly cranial nerves (facial diplegia
occurs most frequently - 50% , also oculomotor and trigeminal nerves may
be lessioned, bulbar dysphagia, dysarthria may appear) and in some cases
may reach to flaccid tetraplegia with respiratory failure (Landry ascending
form). The reflexes are abolished and sensitivity disturbances occur with
pain and discomfort in the lower limb muscles, back muscles with an upward
trend, accentuated by compression of the muscle mass, with positive
elongation maneuver. Autonomous disorders may be found like sphincter
disorders with urinary retention, abnormal heart rhythms (tachycardia or
bradycardia), decreased sweating, trophic disorders. There are quite a few
forms of polyradiculoneuritis depending on manifestations (general or
limited; with impariment of the cranial nerves; limited to the pharyngeal
muscles; encephalomyelopolyradiculoneuritis ; Miller Fisher syndrome=
oculomotor paralysis, ataxia, abolished reflexes without power deficit of
limbs, but with albumino-cytological dissociation in CSF; pseudomyopatic
form; pure sensory or motor form; axonal form) or depending on their
progress ( the most frequent is when symptoms evolve upward from distal
lower torso, upper limbs and cranial nerves, reach a peak in 4-6 weeks and
then in a plateau phase for 2-3 weeks and restauration take place in reverse
order to the initial damage; the Landry form has a fatal outcome).
The laboratory findings include: CSF with albumino-cytological
dissociation, that is albuminorahia is normal in the first few days, grows,
reaches maximum concentration in 4-6 weeks, persist for several weeks, no
cellularity in most cases, in 10% cases it may go up to 50 at/microliter
(mostly lymphocytes), but disappear within 2-3 days; persistence suggests
another diagnosis (HIV, Lyme). Electrofisiological examination shows low
nerve conduction velocity, low amplitude action potentials, motor
conduction blocks in motor nerves, delayed F wave which means nerve root
demyelination, delayed or absent H reflex. Biochemistry should include liver
tests (CMV infection, Ebstein Barr), electrolytes (frequent hyponatremia
with inappropriate secretion of ACTH), inflammation tests, serology for
viruses: CMV, Ebstein Barr, herpes simplex, HIV, Ac anti GQib (Miller
Fisher), GM1 (worse prognosis), stool for Campylobacter jejuni. The MRI
with gadolinium shows hyperfixation of the contrast substance in the spinal
roots by altered brain blood barrier (commonly hyperintense image of the
cauda equina). It musta also be done muscle biopsy, ECG (AV block, T
63
wave abnormalities, ST depression, arrhythmias), measurements of vital
capacity to appreciate the need for artificial ventilation.
Differential diagnosis should be done with: acute spinal cord
pathology (myelitis, trauma, spinal expansive processes) - level of sensitivity
and motor deficit limit without affecting the cranial nerves, polyneuropathy -
no dissociation in CSF, negative elongation maneuvers, polio infection -
fever, CSF pleocytosis, predominantly motor paralysis asymmetric distal
areflexia with atrophies and fasciculations without sensitivity problems,
carcinomatous meningitis-deficit unevenly distributed, with the unilateral
onset and asymmetric evolution due to neoplastic infiltration of nerve roots,
muscular diseases (myastenia gravis, acute myopathies), infectious diseases
(botulism, Lyme disease, encephalities), poisoning (heavy metals,
organophosphorus neurotoxins from fish and seafood).
The treatment includes general measures ( mechanical ventilation if
required; electrolytes imbalances; correction of autonomous anomalies),
prevention of complications of prolonged decubitus - nursing measures, low
molecular weight heparin, IV immunoglobulin are indicated if there is a
gradually severe clinical picture, important motor deficit with walk distance
<5m, significant reduction in vital capacity, severe oropharyngeal symptoms,
disease duration <14 days; the dosage used is 0.4 g / kg / day, 5 days; the
complications that may appear are kidney failure, proteinuria, aseptic
meningitis manifested by severe headache. Plasma exchange has similar
indications and it is used in 4-6 sessions on alternate days, removing a total
of 200-250 ml/kg of plasma; studies show no differences between plasma
exchange and IVIG eficinenta. Relapses may occur after IVIG or
plasmapheresis; in this case another cure of IVIG is performed in a dose
of2g/kg for 2-5 days or plasmapheresis; if the relapse occurs after 9 weeks it
is considered the onset of chronic demyelinating polyneuropathy (CIDP).
Corticosteroids are ineffective as monotherapy, iv methylprednisolone is
moderately effective in combination with IVIG, but does not alter the long-
term prognosis.
2) Chronic inflammatory demyelinating polyneuropathy (CIDP)

There are 2 forms: idiopathic and secondary (associated with other
diseases like monoclonal gammopathy, lupus, sarcoidosis, diabetes,
lymphoma, HIV, chronic active hepatitis, thyroid disease, inflammatory
bowel disease, glomerulonephritis, organ or bone marrow transplant, etc.).
Clinically we find a progressive polyradiculoneuropathy,
symmetrical or asymmetrical, which was in clinical remission period and
relapsed or progressive over 2 months (16% of patients are initially
diagnosed with Guillan Barre syndrome, but the continuous degradation over
2 months from the onset or occurring more than 3 fluctuations in therapeutic
64
response), associated disorders and vibratory sensitivity especially
proprioceptive and areflexia.
The diagnosis is made according to international criteria which are
clinical ones (for typical CIDP the patient should present progressive chronic
muscle weakness or recurrent symmetric proximal and distal associated with
sensory dysfunction in all extremities, which develops over 2 months and
may involve cranial nerves, with the absence or reduction of reflexes in all
extremities), laboratory ones (EMG with multifocal conduction blocks,
segmental demyelination, prolonged distal latent, low conduction velocities,
reduced amplitude of the action potential (specific criteria for EMG), CSF
with albumin-cytological dissociation, biopsy of sural nerve, MRI with
gadolinium), exclusion and supportive criteria.
After gathering all these the disease can be classified in defined,
possible or probable CIDP. The differential diagnosis is made with diabetic
neuropathy, vasculitis, collagen disease, amyloidosis, leukodystrophy,
syphilis, HIV, multiple sclerosis.
The treatment includes corticosteroids (oral prednisone starting with
60mg/zi, 6 weeks or a single iv dose of 2g/kg), iv immunoglobulins for
moderate or severe forms of the disease (dose=2 g/kg, 2-5 days -
improvement lasting 2-6 weeks, or 2-4 days then 1g/kg, then 2g/kg 1-2 days
every 3 weeks, improvement in 24-48 weeks), plasmapheresis (clinical
improvement in 2/3 patients then rapid deterioration), immunosuppression
and immunomodulation (alemtuzemab, azathioprine, cyclophosphamide,
cyclosporine, etanercept, interferon alfa, mycophenolate mofetil,
methotrexate, rituximab), stem cell transplant (very few studies).
3) Multifocal motor neuropathy

It is a pure motor neuropathy, asymmetrical, with multifocal
conduction blocks. Clinically there are diagnostic criteria, with:
major criteria (progressive decline of muscle strength in the limbs,
asymmetric spatial distribution or motor impairment in at least two
nerve territories, lasting more than a month
no sensitivity problems objected except for mild impairment of
vibration sensitivity in the lower limbs)
supporting criteria ( predominantly affecting the upper limbs, reflexes
diminished or absent in the affected extremity, absence of cranial
nerve damage, cramps and fasciculations in the affected extremity)
exclusion criteria (motor neuron signs such as marked bulbar
disturbances,marked sensitivity disorders, which involves more than
vibratory sensitivity in the lower limbs).
65
Laboratory findings should show: conduction motor block ( lower
amplitude or compound muscle action potential area obtained by proximal
versus distal motor nerve stimulation in the absence or in the presence of
abnormal temporal dispersion only temporal dispersion of focal
abnormalities) and other specific electrofphysiological criterias, CSF with
proteins> 1g / l, Ac anti GM1, MRI ( increased intensity in T2-weighted
sequences in brachial plexus), nerve biopsy (to determine other causes).
The treatment is made with: IVIg (2g/kg for 2-5 days) is the preferred
when disability is severe enough to justify treatment; if initial treatment with
IVIg is effective, some patients may receive repeated courses with frequency
of maintenance depending on the response. Corticosteroids are not indicated.
Immunosuppressive therapy (Cyclophosphamide, cyclosporine, azathioprine,
interferon beta 1a or rituximab) is an alternative.
INFECTIOUS NEUROPATHIES
1) LYME DISEASE (neuroboreliosis)
It is produced by Borellia burgdorferi a bacteria which is transmitted
by tick bite. The biting site becomes reddish and 10-15% of patients with
borreliosis develop neurological symptoms. The neurological manifestations
may be:
Acute (1-3 weeks after the sting) with cranial nerve disturbances -
most commonly bilateral facial paresis, then polyradiculoneuritis
possibly aseptic, meningoradiculoneuritis
Chronic appeared at months after infection includes
mononeuropathies, lumbar or brachial plexopathy, predominantly
sensory polyneuropathy in the lower limbs, polyneuropathy with
encephalopathy, polyradiculoneuritis.
Diagnosis is made by observing the initial erythema, then by noticing
the neurological manifestations and the positive diagnosis is made by
determing the antiborelia antibodies in blood and CSF. Tratement is done
with ampicillin or third-generation cephalosporins.
2) HIV NEUROPATHY.
HIV affects all structures of CNS and PNS causing several clinical
forms of nerve damage. Early stage is characterised by sensory axonal
neuropathy detected by SEP or mononeuropathies which mainly affects the
cranial nerves, most commonly facial nerve (facial diparesis); all this may
regress spontaneously or progress to multineuritis or polyneuropathy; we can
also find multifocal subacute forms expressed by asymmetrical distal
paresthesias in the lower limbs evolving to the superior ones with sensitivity
66
and motor deficit disorder, abolished or exaggerated reflexes; aso
polyradiculoneuritis may be the first manifestation. In the late stage a distal
axonal polyneuropathy can be found predominantly sensitive, especially at
lower limbs affecting thermal and pain sense with significant pain; the
evolution is slowly progressive and associates motor deficit; rare autonomic
manifestations are found.
3) DIPHTERIC POLYNEUROPATHY
Beside motor impairment, which may be as severe as tetraplegia,
deglutition, phonation and vision disorders are present. Demyelination
without inflammatory reaction of spinal roots, sensory ganglia and adjacent
spinal nerves is found.
4) LEPROUS POLYNEUROPATHY
Among its characteristic symptoms are: hypertrophy of nerve trunks,
motor and sensory disturbances. Sensory disturbances consist in
hyperesthesias followed by distal anesthesia with trophic disturbances and
resorption and loss of phalanges.
5) BOTULISM NEUROPATHY
It is due to the infection with Clostridium botulinicum (food
poisoning) which produces a exotoxin which prevents the release of
acetylcholine in the synaptic gap. Clinically the onset is at 12-36 hours after
ingestion, manifested by anorexia, nausea, vomiting. The neurological
symptoms are oculomotor paralysis with ptosis and strabismus, fixed non
reactive mydriasis, dysphagia, dysarthria, force deficiency of neck muscles.
By day 2-4 flaccid paralysis of the limbs is installed, including respiratory
muscles, abolished reflexes without sensitivity changes, transit disorders
(constipation) because of the smooth muscle paresis of the intestine.
Electrophysiologically we can find increment on the EMG of the affected
muscles.Treatment is done with botulinum antitoxin, guanidine, support for
the respiratory function.
AUTOIMMUNE NEUROPATHIES
Periarterita nodosa and other necrotizing vasculitis (Chung
Strauss, Wegener)
The mechanism is ischemic with nerve damage. The most typical is
mononeuritis multiplex which has an acute onset of pain in a nerve territory
and lack of strength in the same area, then random involvement of other
nerves. The most commonly affected are the limbs, cranial nerves and spinal
cord. The CSF exam is normal, the nerve biopsy shows necrotizing arteritis
67
of vasa nervorum (fibrinoid necrosis of the vascular wall, eosinophilic
infiltration) and the muscle biopsy shows perivascular inflammatory
infiltrate and necrosis. Other organs affected are the kidneys with rapidly
progressive glomerulonephritis and the lungs with pulmonary hemorrhage.
The treatment is made with corticosteroids, cyclophosphamide (alternative:
azathioprine, methotrexate). The evolution may be spontaneous with
remission, but sometimes (rarely) improved under treatment with damage
that may persist after controlling neuropathic disease.
LES (Erithematous Systemic Lupus)

The neuronal damage apperas in 10% of patients and it can be found
most commonly in the advanced stages, rare in the initial stage. The
polyneuropathy is symmetrical, sensory and motor, progressive with onset in
the distal part of the lower limbs, affecting predominantly vibratory and
proprioceptive sensitivity.
Sjogren syndrome
Sjogren syndrome gives out a predominantly sensory
polyneuropathy, symmetric, with distal paresthesias, usually moderate,
possibly hypoesthesia, with altered proprioceptive sensitivity and limb and
gait ataxia, abolished reflexes. Other forms may include mononeuropathies
(most commonly the trigeminal nerve), autonomic neuropathy, sensorimotor
polyneuropathy, poliradiculopathy.
DEFICIENCY POLYNEUROPATHIES
ALCOHOLIC POLYNEUROPATHY
It is an axonal neuropathy with secondary demyelination, common in
men with chronic alcoholism; its severity is proportional to the amount of
ethanol and it is associated with liver pathology, cerebral atrophy,
cardiomyopathy due to alcohol consumption. Its mechanisms are: direct
toxic effect of the alcohol which causes axonal damage and indirect by
thiamine deficiency and malabsorption secondary to chronic ethanol-
induced pancreatic disorders which causes demyelination more pronunced in
the long fibers.
Clinical picture includes an insidious onset in weeks or months with
nocturnal muscle cramps in the calf and distal paresthesia. The classic form
is the sensorimotor polyneuritis which is characterized by force deficit in the
antero-external region of the calf with stepping, pain when the muscles are
compressed, muscle cramps, distal paresthesia, sensitivity disorders,
burns,socks type hypoesthesia, anesthesia dolorosa, ataxic gait, plantar
68
trophic disorders (ulcers). Rare forms are with sensory disturbances,
abolished Achilles reflex, force deficit of toe; subacute forms are with large
paralysis, fast installation involving proximal and distal limbs; forms with
neuro-psychiatric disorders, confabulations (Korsakoff syndrome),
confusion, oculomotor palsy, cerebellar syndrome (Wernicke
encephalopathy), pontine central myelinolisis. Strachan syndrome is a rare
and particular form of alcoholic polyneuropathy that includes sensory, visual
and cochlear disturbances together with hypoesthesia in the face and trunk.
The diagnosis is made from the clincal and laboratory signs of
alcohol intoxication (erythrosic face, trembling extremities and biomarkers
like macrocytosis, GGT increased). The treatment consists first in stopping
the ethanol consumption, B group vitamins and physiotherapy for the
prevention of tendon retraction.
B12 DEFICIENCY POLYNEUROPATHY

The etiology is the depletion of B12(pregnancy, anorexia), impaired
absorption (anti intrinsic factor antibodies, gastrectomy, pancreatic
insufficiency, resection of the ileum)
and certain drugs (biguanide, nitrofurantoin, primidone, phenylbutazone,
phenobarbital, cytostatics).
The pathogenesis consists in subacute degeneration of posterior and
lateral cords of the spinal cord, vacuolation of the myelin sheath, axonal loss,
gliosis, all of this occurring in lower cervical/upper dorsal spine; there is also
demyelinating of the optic nerve, the optic chiasm, subcortical white matter,
but also demyelination of peripheral nerves.
Clinical picture is characterized by a sensory-motor polyneuropathy
with symmetrical or asymmetrical motor deficit, limb numbness and cramps,
abnormal deep sensitivity leading to ataxia and gait disturbance, altered
touch sensibility, areflexia in the lower limb, autonomous symptoms like
bowel disorders, sphincter disorders, potency and libido disorders.
The gastrointestinal symptoms include Hunter glossitis, stomach pain,
diarrhea, weight deficit; also we can find psychiatric symptoms like
psychosis or hallucinations. The laboratory findings include megalocytic
anemia, thrombocytopenia, low serum B12, Schilling test (it tests the
difference between the lack of intrinsic factor and other etiologies).
Electrophysiologic studies include sensory evoked potentials,
transcranial magnetic stimulation. Treatment: B12 = 1mg/day im one month,
then 1mg twice / week, a year, then 1mg / month for a long time. The
evolution of the neurological signs may be good with full recovery if the
treatment is initiated in the first 3 months.
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OTHER DEFICIENCY POLYNEUROPATHIES:
B1 deficiency (polyneuropathy with cardiac disturbances), PP
deficiency (sensitive polyneuropathy with psychiatric and cutaneous
manifestations.
TOXIC NEUROPATHIES
LEAD POISONING
It can happen through professional intoxication (lead paints in
printing, paint, batteries) or consumption of drinks distilled in lead pipes.
Clinically we can find a motor polyneuropathy predominant in the upper
limbs in the radial nerve territory, sometimes lower limbs in the antero-
external region of the calf and it can associate saturnine encepahlopathy
expressed by irritability, slowness in ideation, seizures.As far as general
symptoms characteristic is the blue coloration of the gums (Burton gums),
abdominal colic with constipation, hypertension.
Laboratory findings show anemia with basophilic granulations,
dotted red blood cells, elevated blood and urine lead, deltaaminolevulinic
acid in urine (precursor in the synthesis of hem, accumulates when hem
synthesis is interrupted by enzymatic inhibition by poison). Treatment is
done with chelator EDTA calcium.
ARSENIC POISONING
The acute form (ingestion of a single high dose) is characterised by a
rapidly progressive sensorimotor polyneuropathy, which occurs in 8-12 days
after poisoning, associated signs of CNS involvement (seizures, confusion,
coma), important kidney and liver failure. The chronic form (prolonged
ingestion of small quantities) is expressed by a sensory-motor
polyneuropathy installed in weeks-months associated with gastrointestinal
pathology, brown pigmentation of the skin, hyperkeratosis of palms and
soles. For diagnosis the amount of arsenic in appendages (hair, nails) and
urine is dosed. Treatment includes dimercaptol for chelation and
symptomatic one.
THALIUM POISONING
Thalium can be found in pest control substances or depilatory cream.
Poisoning can cause a sensorimotor polyneuropathy with significant pain,
associated optic atrophy, optic neuritis, difuse hair loss (15-30 days after
ingestion) with gradual recovery in months.Diagnosis is made by dosating
the toxic in urine.
70
ORGANOPHOSPHORUS POISONING
Organophosphorus can be found usually in insecticides. These
substances have anticholinesterase effects in acute intoxication consisting in
nausea, vomiting, abdominal cramps, headache, increased sweating,
excessive salivation, bronchial spasm, miosis and after 2-5 weeks CNS and
PNS injury occur. Polyneuropathy or predominantly sensory-motor
development motor with acute or subacute onset is found at the clinical
examination with slow regression and sequels (possible progression to
muscle atrophy). It can also associate digestive disorders.The treatment
includes neurotrophics and B group vitamins.
MERCURY POISONING
Clinically we can find polyneuropathy in the four limbs or upper
limbs associated with ataxia, tremor, impaired vision, stomatitis, psychiatric
disorders. The diagnosis is made by dosing mercury in blood and urine.
Treatment is done with chelators (BAL, penicillamine).
DRUGS
Drugs have different mechanisms of neurotoxicity: metabolic
(vitamin deficiencies-HIN), allergic (gold salts, sulfonamides), toxic-axonal
or myelinic. The toxicity is dose dependent therefore toxic interruption may
improve recovery. The polyneuropathy accuired from medicine has different
forms:
demyelinating forms: predominantly proximal neuropathy, cranial
nerve damage, reduced visual acuity, papiloedema; given by
Amiodarone, Chloroquine
axonal forms given by Cliochinol (parasite medication), Thalidemida
(leprosy, erythema nodosum, ulcerations in Bechet and HIV).
TB medication (Izoniazid) may produce nerve damage in 10% of
patients, predominantly sensory ployneuropathy with painful distal
paresthesias, tingling, burning; Nitrofurantoin, streptomycin,
gentamycinmay produce initial distal paresthesias of the lower then higher
limbs. Vincristine (lymphoma, leukemia) produces a sensitive neuropathy
possibly deficient especially on extensor forearm and hand, then lower on the
external anterior region of the leg; vegetative visual disorders, orthostatic
hypotension, urinary retention, paralytic ileus.
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2. Chance P.F., Windebank A.J.: Hereditary neuralgic
amyotrophy.Curr Opin Neurol. 9:343-347 1996
3. Guarantors of Brain: Aids to the Examination of the Peripheral
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4. Hughes R.A., Cornblath D.R.: Guillain-Barr
syndrome. Lancet.366 (9497):1653-1666 2005 Nov 5
5. Jaeckle, K.A.: Neurologic manifestations of neoplastic and
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2622010
6. Kim K.K.: Acute brachial neuropathyelectrophysiological
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8. Misulis K.E.: Essentials of Clinical Neurophysiology. third
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9. Misulis K.E., Head T.C.: Netters Concise
Neurology. 2007 ElsevierPhiladelphia
14. Rudnicki S.A., Dalmau J.: Paraneoplastic syndromes of the
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72
Chapter VI.
Spinal Cord Pathology
Cristian Dinu Popescu, Cristina Grosu
General data Syringomyelia

Lesional topography Spinal trauma
Types of medular dysfunctions Combined sclerosis
Vascular spinal diseases
Mielitis
General data
The spinal cord is part of the central nervous system, with a length of
43-45 cm. It starts conventionaly fron an horizontal plane passing through
atlas, and ends at L2 vertebra, where the spinal canal is occupied by roots
part of the pony tail.
It is composed of cords up and down (white matter), gray matter,
disposed around the ependimar channel, with anterior, posterior and lateral
horns.
In the vertical plane it is composed of 31 myelomas distributed to the
same number of myotoms and dermatomes. There are 8 pairs of cervical
roots, 12 thoracic, 5 lumbar, 5 sacral and 1 coccygeal. From each myelomer
anterior roots (motor) and posterior (sensory) detach.
The point of detachment of these roots and the damage to the
sensitive cords are important for the clinician, who seeks the so-called
"sensitivity level", which may signal the affected spinal segment. The level
of sensitivity can be unilateral, bilateral, symmetrical or asymmetrical.
Identifying this level enables laboratory targeted examinations in order to
identify the location and etiology of the disease.
The spinal cord ends at the L2 vertebra creating discrepancies
between the spinal level. At the cervical region there is a consistency
between the spinal myelomer and the vertebral body (Chipault's law). In the
upper dorsal region the myelomer number is by decreasing the number 1
from the number of the corresponding vertebra. For the lower dorsal region
73
the affected myelomer can be identified by subtracting the number two from
the vertebra in which a pathological process develops. Behind the T12
vertebra we can find the L2, L3, L4 myelomers. L1 vertebra corresponds to
the L5, S1, S2 and S3 myelomers, and behind the L2 vertebra are the S4 and
S5 myelomers.
The ending of the spinal cord at the L2 vertebra makes possible the
practice of the lumbar punctures at this level, avoiding the aggression of the
spine. If the spinal tab is practiced in the D12-L1 and L1-L2 areas than there
is a high to damage the spine and to induce a medullary cone syndrome
associated with urinary incontinence.
The spinal cord generates syndromes related to the cords or the gray
matter. Another important milestone is the location of the pathological
processes generating specific features for the cervical, dorsal or lumbar-
sacral cord. The posterior or anterior horn separately or together with root
components can be affected. The clinical picture consists of the characteristic
signs of the lesion plus sublesional signs located both on the same side and
the controlateral.
There can be an anterior horn syndrome, central syndrome, the
posterior horn syndrome, and combinations of the sufferings of gray matter
to white matter (lateral or posterior cords). Medullary lesions may be
complete or partial.
Complete cervical lesion above the C5 vertebra is very serious,
sometimes incompatible with survival. Installing a flaccid quadriplegia with
respiratory disorders by affecting the phrenic nerve and diaphragm function.
The lesion located at C5-C6 is in most cases compatible with
survival, generating a quadriplegia with signs of damage roots of C5 and C6,
including radicular pain.
Lesions located at C7-T1 generate pain and radicular syndrome to the
upper limb interesting the sensitivity of the cubital ("ulnar side") of the arm,
forearm and peripheral nerves. Lesions at this level may be associated with
Claude Bernard Horner syndrome by affecting the spinal center of Budge
(miosis, enophthalmos, lower palpebral fissure).
Complete thoracic lesions generate a flaccid paraplegia (shock phase)
associated with radicular pain and sublesional complete anesthesia. Togheter
with the spasticity special reflexes like crossed extension reflex, extensor
thurst, mass reflex can be added. In the final stage the patient will install a
triple limb flexion position.
L1 medullary cone lesions are characterized by multiradiculare
dysfunction associated with Babinski sign and will generate motor deficit
with hypotonia, absence of tendon reflexes in the legs and the so-called
,,saddle anesthesia".
74
Horse tail lesions (Fig. 1) generate a purely peripheral motor neuron
syndrome characterized by muscular weakness, hypotonia, areflexia and
sensory pain in different variants.
Figure.1 The horse tail (with the courtesy of The Anatomy Museum of the
University of Medicine and Pharmacy Gr. T. Popa Iasi
The medullary cone syndrome and ponytail syndrome and may be

involved in sclerosis processes, lower limb muscles atrophies, in association
with gait disturbance and bulbar dysfunction.
Incomplete transverse lesions of the spinal cord generates the Brown
Sequard syndrome. This entity is rarely encountered in pure version. The
syndrome is characterized by unilateral hemi or monoparesis plus loss of
sensation and perception of vibrations and segments motion. Controlateral,
75
below the lesion the perception of pain and temperature dissapears. The
Brown Sequard syndrome can have multiple etiologies including traumatic
and by firearm and assault with weapons. The level lesioned can predicted
by the characteristic of the affected root and the zones of dermal anesthesia.
Anterior horn syndrome is characterized by dysfunction induced by
impairment of the junction between the central and peripheral motor neuron
and also by the involvement of the peripheral motor neuron. It is
characterized by moderate paresis, atrophy, hypotonia, decreased or lack of
osteo-tendinous reflexes. The distribution of clinical signs depends on the
involvement which can be uni or bilateral, segmental or multisegmental. It is
can be present in spinal atrophies, poliomielitis, myelopathy due to artrosis
in the cervical spine. Similar clinical pictures can be found in ALS,
syringomielia, anterior spinal artery syndrome, tumors, trauma.
Posterior horn syndrome is caused by the suffering of the Goll and
Burdach cords, event which occurs for several diseases, such as furuncular
mielosis, tabes dorsalis, Friedreich ataxia. The symptoms are loss of
profound sensation and vibretion sublesional, loss of discriminative
sensitivity, astereognosia, adermolexia, sensory ataxia with positive
Romberg, feeling constraint. A separate entity is the L'hermitte sign which
means that the patient is feeling a shocked cervico-dorsal irradiation in
upper limbs triggered by the neck flexion. It is a characteristic sign
encountered in patients with MS and is due to the demyelination plaques
location to the neck and posterior cords.
Posterior horn syndrome occurs when the main neurons of the
spinothalamic tract are injured. In this are take place the processed of pain
modulation, which makes this symptom predominant. To this dissociated
disorders of the distribution of multisegmentary sensitivity may be added.
Pain may be of of afferent type due to the damage of the inhibitoring
structures at this level. Centro-medullary syndrome is generated when
damage occurs to the commissure, to the anterior or posterior horns and even
to the posterior pyramidal tract. It is determined by centro-medullary tumors,
traum or syringomyelia. The disorder is characterised by syringomyelic
dissociation, which means the inability of pain and thermal perception in the
suspended territory.
The most common types of medullary dysfunction are complete
section, hemisection, centromedullar damage, damage of the long pathways
and of the anterior horn and lateral cords (Table 1).
76
Spinal cord lesion Affected
Etiology Main Symptoms
localization structures
Hemiparesis/hemiparalysis
Brown-
Hemi- ,
Sequard
section paresthesias/dysesthesias
Syndrome
in the controlateral limb.
Tetraplegia (when the

Complete Trauma or lesion is located above C5)
section myelitis or paraplegia (when lesion
is below T2).
Absent reflexes, loss of

Syringo
Central position and vibratory
mielia or
structures sense, pain, bladder
tumors
dysfunction, scoliosis.
Tabes
Posterior dorsalis Paresthesias, loss of
columns (syphilitic coordination, wide-base
and horns myelo- gait, loss of reflexes.
pathy)
Dorsal
Ataxia, absence of
columns,
Spino- reflexes, disarthria,
pyramidal
cerebellar head/hand tremor,
tracts and
degene- horizontal nistagmus
spino-
ration (varying according to the
cerebellar
diseases type)
tract
May vary within slapping

Pyramidal Amio-
gait, weakness or wasting
tracts and trophyc
of intrinsic hand muscles,
anterior Lateral
reduced finger dexterity,
horns Sclerosis
spasticity.
Table 1. The most frequent types of spinal cord pathology
77
SPINAL CORD PATHOLOGY
Spinal cord pathology is due to degenerative disorders, trauma, some
deficiences, compressions, vascular and infectious diseases.
Degenerative disease syringomyelia

Syringomyelia is a degenerative disorder of the spinal cord and
medulla oblongata. Characteristic to this disease are the loss of pain and
temperature senses, atrophies of the muscles of the upper limb, and, below
the level of the lesion a syndrome dominated by pyramidal signs.
Intramedullary and downward, one or more cavities localized in the cervical
region or thoracic or lumbar segments are seen. When the process extends
into medulla oblongata, the disease is termed syringobulbia.
Several theories on the etiology of this disease have been suggested.
Thus, the infectious, tumoral, vascular, traumatic, malformation,
dysembryoplastis theories have partially explained the ocurrence of this
disease. Each of these theories aim at explaining the cavitation of the spinal
cord, but it seems the dysembryoplastic theory is closest to the truth.
Among the arguments supporting this theory is the presence of other
malformations in the upper cervical portion of the spinal cord, base of the
skull, and brainstem. Syringomyelia may be associated with cervical fusion
syndrome (Klippel Feil), platybasia, basilar invagination, and abnormaly
low position of the fourth ventricle and brainstem. Another theory,
suggested by Gardner, is the congenital absence of communication between
the fourth ventricle and the pericerebral fluid spaces. In this circumstance,
the fourth ventricle continues with the central canal of the cord. As a result, a
pulse wave of cerebrospinal fluid (CSF) pressure is transmitted into the cord
from the fourth ventricle through the central canal, a cavity being formed
probably duet o a decreased resistance of the central spinal tissues. With
time, the cavity increases in width and length, symmetrically or
asimmetrically, affecting the anterior and posterior horns, and the lateral and
posterior funiculi of the spinal cord. The cavities are lined with astrocytes
and a few thick walledblood vessels.
The syringomyelic syndrome may be induced by intramedullary
tumors, trauma, hematomyelia, spinal ischemia, and irradiation myelopathy.
The syringomyelic syndromes may be classified into the following 4 types:
Type I syringomyelia with obstruction of the foramen
magnum and dilatation of the central canal;
Type II syringomyelia without obstruction of foraman
magnum;
Type III syringomyelia with spinal cord tumors, traumatic
myelopathy, spinal arachnoiditis and pachymeningitis;
78
Type IV pure hydromyelia with or without hydrocephalus.
Clinical picture: the disease equally affects both sexes, symptoms

usually beginning between 25 and 35 years. Occasionally, the first sign is in
adolescence. The onset is insidious, with amyotrophies of the upper limbs,
loss of pain sense for burns, and trauma in the hands. Sometimes, the patient
notices an increased tolerance at handling hot objects. As the disease
progresses, the atrophies of the upper limbs become more marked, gait
disturbances and bulbar dysfunctions do occur.
The neurological examination reveals a specific sensory syndrome
which is suspended over a cervical, dorsal or lumbar territory. In these
territories there is a loss of pain and temperature senses with the preservation
of touch sense. Tendon reflexes are absent in the limbs with deficits of pain
and thermal senses. In the upper limbs fasciculations and atrophies are
present. Below the original lesion, the injury to the lateral organs causes a
pyramidal syndrome , and sometimes disturbances of deep sensitivity in the
lower limbs. The extension of the cavities to medulla oblongata causes
tongue paralysis, dysarthria and deglutition disturbances.
Pathophysiologically, the sensory dissociation is due to the
interruption of the crossing pain and temperature fibers by the appearance of
the central cavity. The enlargement of this cavity towards the anterior and
posterior horns, posterior and lateral funicului of the spinal cord determines
pyramidal and tabetic symptoms below the level of the lesion. The thermal
and pain sensations are diminished or absent in the suspended territories
sensory inervated by the myelomeres in which the syringomyelic cavity is
sited.
Laboratory findings: radiographs of the skull for detecting a
platybasia or basilar invagination are required. Axial computed tomography
and MRI may detect the cavity.
The disease progresses slowly and irregularly. A few cases progress
to a severe disability within 3 to 5 years following the onset of the
symptoms.
Treatment is only surgical, and is directed at decompressing the
foramen magnum and upper cervical canal.
Spinal cord trauma

The spine protects the spinal cord in the trauma not causing fractures
or dislocations of the vertebral bodies. More commonly, vertebral
dislocations are found in the cervical area. More commonly, vertebral
dislocations are found in the cervical area. The spinal cord injuries may be
severe even though the radiographic images obtained immediately following
the accident suggest normal or minor aberration in the position of the
79
vertebrae. A few millimeter displacement followed by the return to the
original position due to the work of the elastic structures may cause severe
concussions of the cervical spine.
The fractures cause spinal cord lesions by the displacement of
vertebral bodies or the action of some bone fragments. The vertebral
dislocations and fractures occur as a result of direct or indirect mechanisms.
Indirectly, the spinal cord may be affected by head trauma or falls on the
ischial bones. The lesions of the spinal cord may be complete (complete
transection) or incomplete (incomplete transection). Complete transection of
the spinal cord above C5 vertebra is very severe. Initially, a flaccid
tetraplegia with respiratory disturbances due to the involvement of the motor
nuclei and phrenic nerves, followed by complete paralysis of the diaphragm
do occur.
Vertebral fractures at C5-C6 level are more common and also involve
the C6 and C7 roots. A lesion at this level is compatible with survival.
Complete dorsal transection causes a flaccid paralysis with complete
anesthesia below the level of the lesion. Later on, hypertonia with
hyperreflexia and spinal automatic reflexes (mass reflex, cross extension
reflex, extensor thurst) occur. In the end, a triple flexion emerges.
Injuries at L1 cause a conus medullaris syndrome. A positive
Babinski sign and associate dysfunctions of the peripheral nerves are
characteristic to the lesions at this level.
The lesions of the vertebral bodies between L2-L5 vertebrae
determine the cauda equine syndrome. Both the conus medullaris and
cauda equine syndromes are accompanied by sphincteral disturbances.
Lesions above L1 determine an urinary pattern specific to central
bladder. Lesions of L1-L2 vertebral bodies determine an urinary pattern
specific to peripheral bladder.
X-ray examination of the cervical spine is essential; it reveals
fractures of the lateral masses of the atlas, fractures of the axis and odontoid
process, fractures of the spinous processes, compression fractures,
subluxations, reversal of the normal cervical spine curvature, etc.
The examination with contrast agents is required when a spinal cord
damage is suspected and the radiological examination is normal. The
aggravation of the neurological deficits require myelography. In the thoracic
and lumbar cord fractures, teardrop fractures, anterior or posterior
subluxation, with or without ligament disruption, and fracture-dislocation
may be seen.
Treatment: Reduction, stabilization and laminectomy techniques are
used.
The tetraplegic and paraplegic patient is at cutaneous, urinary,
digestive and thromboembolic risk.
80
The cutaneous risk consists in the occurrence and aggravation of
decubitus ulcers, the urinary risk in retention, incontinence and infections.
Intermittent drainage of the bladder by cathether, close cytobacteriologic
follow-up of urine, acidification of urine, and a dieresis of over 2 liters per
day are the most recommended steps.
Paralytic ileus, peptic esophagitis and gastric ulcer are the digestive
complications that may occur in a tetraplegic and paraplegic patient.
Pulmonary embolism is common, with thrombophlebitis of the lower limbs
as a starting point.
The prognosis is good for the incomplete lesions with the
preservation of some senses and tendon reflexes. Sensory impairment
following trauma is also a favorable sign. The presence of complete
transection signs (tetraplegia with hypotonia, areflexia and anesthesia) which
do not improve with time, except for hypotonia, are indicative for a poor
prognosis. Cervical lesions above C5 are incompatible with life.
Combined sclerosis of the spinal cord

In Biermer anemia, caused by vitamin B12 deficiency, dysfunctions
of the spinal cord, brain, optic nerves, and peripheral nerves do occur. Given
the presence of autoantibodies, gastric intrinsic factor, the disease is
believed to be autoimmune.
The absence of the intrinsic factor secreted by the gastric mucosa
disturbs the absorption of the extrinsic factor (vitamin B12) inducing its
deficiency. Mental, visual, peripheral nerves and spinal cord disorders do
thus occur.
Mental signs range from emotional instability, somnolence,
irritability, apathy to psychosis. The ophtalmological examination reveals
scotomas and optic atrophy in the cases with long progression. Visual
impairments due to retrobulbar neuritis may be early or the only sign of
disease.
The lesion of the peripheral nerves are quite frequent and induce
paresthesia, absence of tendon reflexes, pain, blunt peripheral touch and pain
sensations. The conduction velocity through the peripheral nerves is
significantly lowered.
The combined sclerosis or the subacute combined degeneration of
the spinal cord develops a complex clinical picture indicative for motor and
sensory disturbances. After the occurrence of symmetrical paresthesia in the
extremities, the neurological examination reveals characteristic signs of
lateral and posterior funiculi involvement. The lesions of lateral funiculi (the
corticospinal tracts) cause loss of muscle strength, spasticity, hyperreflexia,
clonus and positive Babinski sign. The Achilles and pattelar reflexes may be
diminished, absent or exaggerated, depending on which of the lateral or
81
posterior funiculi is predominantly involved. Loss of vibration sense is more
pronounced in the legs, but may be also present in arms and over the trunk.
Position sense is not altered. The neurological signs are prevalent in the
lower limbs. The involvement of the pyramidal fascicles and posterior
funiculi make the gait ataxic and spastic.
The morphophysiologic changes characteristic to vitamin B12
deficiency take the form of some degenerations of the white matter in the
spinal cord and brain. The early changes are the swelling of the myelin
steaths, formation of vacuoles, and separation of myelin lamellae. The small
foci coalesce giving the tissue a vacuolated aspect. The myelin steath and the
axons are involved in the pathologic processes impairing nerve impulse
transmission. Fibrous gliosis in the early lesions is also described. The
changes first occur in the posterior columns, fact making the term subacute
combined degeneration more appropriate.
The diagnosis is difficult because there is no parallelism between the
hematologic and neurologic picture. Thus, anemia may be absent several
months after the onset of neurological signs. The diagnosis relies on the
clinical signs, blood tests and determinations of vitamin B12 blood levels.
Treatment is with 1000 g vitamin B12 per day for several weeks.
Then, 100 g are administered daily for a week per month. The maintainance
dose is 1000 g per month.
Spinal cord compressions

The compressive spinal disorders may be acute, subacute or chronic.
Downward, the compression causes symptoms at or below the level of the
lesion. The compressive syndrome may be complete or partial. A cervical
compressive lesion induces hemiplegia or tetraplegia, while a dorsal lesion
causes a crural monoplegia or paraplegia. Compression may have a starting
point in the extramedullary spaces or intramedullary areas. The epidural
space is formed between the bony vertebral canal and dura mater.
The subdural space is formed between dura mater and arachnoid.
Through the subarachnoid space flows the cerebrospinal fluid. The pia mater
closely surrounds the spinal cord, penetrating between its septa.
Extramedullary, compression will be exerted by meningiomas,
neurinomas, primitive tumors and metastases of the spine, parasitoses,
epidural hematoma, absecess, lipoma and disc herniations. One of the most
common comprehensive syndromes is Brown-Sequard syndrome which
consists in the lesion of the lateral half of the cord. The characteristic
symptoms are:
- ipsilateral lower motor neuron paralysis in the segment of the lesion;
- ipsilateral upper motor neuron paralysis below the level of the lesion;
- ipsilateral zone of cutaneous anesthesia in the segment of the lesion;
82
- ipsilateral hyperesthesia below the anesthetic zone;
- ipsilateral loss of proprioceptive, vibratory and 2-point discrimination
sense below the level of the lesion;
- controlateral loss of pain and temperature sense below the lesion.
Other causes of hemisection may be: syringomyelia, hematomyelia,
spinal cord tumor,
bullet or stab wounds.
In the intramedullary processes, the signs of radicular involvement
may be initially absent, the tumors beginning with deep sensory
impairments, syringomyelic dissociation, pyramidal syndromes. The most
common intramedullary tumors are astrocytoma, oligodendroglioma, and
ependymoma. Acute spinal cord compression may be due to epidural
hematoma and disc herniation.
Rachidian epidural hematoma may occur following physical
exercise, local trauma and during anticoagulant treatment. Hypertension may
precipitate the occurrence of this hematoma. First, the patients complain of
radicular pains, followed after several hours by deficits below the level of the
lesion. Most commonly the hematoma has a dorsal site.
Spinal cord compression by disc herniation may have a cervical or
dorsal location. The disc herniation causing most frequently spinal cord
compression is the cervical one. The motor deficit of hemiparesis or
tetraparesis type occurs acutely or subacutely. Dorsal herniation of the
cervical intravertebral disc may be precipitated by ample head movements.
Slow spinal cord compression is due to tumors, metastases,
abscesses, parasitosis, arachnoidites.
The onset is by manifest radicular syndrome and pain at coughing or
other maneuvers increasing the cerebrospinal fluid pressure. The persistence
and amplification of radicular pain is an argument suggesting an organic
affection, requiring a through investigation.
Epidural metastases result from breast cancer, bronchial, prostate,
digestive and other tumors. A single metastasis or multiple metastases may
cause vertebral fractures with resulting spinal cord compression or
transection.
Spinal epidural abscess develop from a neighboring infection or
following lumbar puncture. The compressive phenomena progress
subacutely or chronically being accompanied by radicular syndromes,
ipsilateral and controlateral motor and sensory deficits below the level of the
lesion.
Hydatid cyst may be sited within the vertebral bone canal. As the cyst
enlarges, radicular signs of spinal cord compression occur. A single cystor
multiple cysts may be present.
83
The laboratory tests include: lumbar puncture, vertebral radiographs,
myelography with contrast substance, magnetic resonance and computer
tomography.
Lumbar puncture reveals an increased albumin level, xanthochromic
aspect and changes in CSF pressure during manometry and Queckenstedt-
Stookey test.
Radiographs of the lumbar cord may show changes in the shape of
vertebral body, erosions, areas of osteolysis, hyperostosis, widening of
intravertebral foramen, and more distant vertebral pedicles. These signs are
evocative for the pathologic vertebral processes determining spinal cord
compression.
Contrast myelography brings additional evidence especially in the
partial and variable compressions.
Magnetic resonance imaging is extremely useful for the diagnosis.
The sagital sections give detailed evidence on spinal cord involvement and
the relationships with the neighboring structures. Single or multilevel
compressions may be thus seen.
Vascular diseases of the spinal cord

Extramedullary arteriovenous malformations
Extramedullary arteriovenous malformations determine over 60% of
the vascular accidents in this nervous formation. They are most often found
between T3 T4 or T10 L5 vertebra. The sacral location is exceptional,
and the cervical area seems to be spared. The malformation has an arterial
pedicle trough which it receives blood and a network of draining veins
carrying away arterial blood. The disease manifests by intermittent spinal
claudication, which induces gait stop or even transient spinal cord ischemia
with its characteristic deficits and presence of some disequilibrium
phenomena.
Sometimes, the episodes resemble the drop attacks, the paraparesis
being transient. Posterior column type pains and intermittent sphincter
disturbances are also described. The age at the onset ranges between 30-80
years. Beside the ischemic claudication syndrome, subarachnoid
hemorrhages and hematomas causing motor deficits, meningeal irritative
syndromes, sensory and sphincter disturbances may occur.
Extramedullary hemorrhage
Extramedullary hemorrhage may have epidural, subdural, and
subarachnoid localization.
84
Epidural hemorrhage
Epidural hemorrhage as a sudden onset with signs of acute spinal
cord compression. The symptoms are similar to those in epidural hematoma,
and require neurosurgery.
Subdural hemorrhage
May result from moderate trauma to the spine. It may occur after a
symptom free interval or may recur causing spinal compressions.
Subarachnoid hemorrhage
Subarachnoid hemorrhage may cause meningeal irritation and
radicular pains. It is either the result of trauma, or anticoagulant treatment.
Intramedullary arteriovenous malformations

These are more rare, but also more severe . If ruptured, they cause
hematomyelia or meningeal hemorrhage. They are located in the thoracic
and lumbar spinal cord. When rupture is present, the symptoms are those of
hematomyelia.
The investigations performed include contrast myelography, selective
angiography, magnetic resonance and computed tomography.
The spinal cord has a segmentary blood supply depend on the
radiculomedullary arteries. After penetrating the spinal canal, these arteries
divide into the anterior and posterior radicular arteries. Round each
myelomere, a perimedullary anastomotic network, which develops
anstomoses in transverse and vertical directions, is formed.
Downward, the links are realized by the anterior spinal artery and
the two posterior spinal arteries. The anterior spinal artery lies in the anterior
median fissure from the cervical area to filum terminale.
Each myelomere receives from the anterior spinal artery a pair of
sulcocommissural arteries wich supply the two halves of the anterior region
of the spinal cord. Both the sublcocommisural arteries and the arteries
derived from the perimedullary anastomotic system and penetrating the
spinal cord are of terminal type, so they do no longer develop and receive
anastomoses. The two posterior spinal arteries have relationships with the
dorsal roots of the spinal nerves. The posterior spinal arteries supply the
lower third of the cord third of the cord, while the anterior spinal artery
nourishes, through the sulcocommisural, the anterior two thirds of the
spinal cord.
The anterior and posterior spinal arteries have their rostral origin in
the anterior arteries, receiving anastomoses through the paired
radiculomedullary arteries. In the young adult , there is only a reduced
number of radiculomedullary arteries that remain functional (3 to 10 for the
anterior axis and 6 to 25 for the posterior one). The upper cervical cord is
85
supplied by branches of the vertebral artery. The last cervical segments and
the first thoracic ones are supplied by the cervical arteries, branches of the
subclavian arteries and intercostal arteries. Between T3T7, the thoracic
cord is supplied by a T4 or T5 single radicular artery, representing a true
critical area. Between T8 and L2 the blood supply comes from the
Adamkiewicz artery, aortic branch. The thrombotic occlusion of this artery
causes infarction of the anterior spinal territories.
As compared to the incidence of stroke, the vascular disease causes
infarctions of the spinal cord are quite rare, being grouped into infarction of
the spinal cord, hemorrhage into the spinal cord, and the spinal canal and
vascular malformations.
Spinal cord ischemia may be acute or chronic, the deficit being
localized either in the territory supplied by the anterior spinal artery, or by
the posterior cerebral arteries. The acute spinal cord infarct occurs as a result
of embolic or thrombotic occlusion of the spinal arteries or of the important
arteries they derive from. Thus, aortic thrombosis or dissections may cause
cord infarction by affecting the radicular arteries and intrerupting the
anastomoses of the anterior spinal system with the posterior one. The infarct
is most commonly located at the level of the lower thoracic cord, where,
between the vascularization dependent on the vertebral arteries and the origin
of the artery of Adamkiewicz, a critical supply area exists.
The anterior spinal cord artery syndrome has an acute onset, often
following surgical interventions requiring clamping of proximal aorta for
more than 30 minutes. The symptoms are: motor deficit under the form of
rapidly developing flaccid paraplegia and accompanying local pain. Spinal
cord infarcts following system arteritis, immune reactions of serum sickness,
angiitis have also been described. In the young adults who practice sports or
have trauma to the dorsal plane, cord infarction caused by microscopic
fragments of nucleus pulposus detectable at the level of intramedullary
arteries may occur.
Complete softening in the territory supplied by the anterior spinal
artery results the infarction of the anterior and lateral funiculi, anterior and
even part of the posterior horn. The cervical localization determines a
tetraplegia with a syringomyelic type dissociated sensory loss and,
possibly, atrophies of the muscles dependent on the neurons in the injured
anterior horns. The dorsal site determines paraplegia with syringomyelic
dissociated sensory loss and sphincteric disturbances. Infarction in the
territory of a subcommisural artery induced a hemicord syndrome (Brown
Sequard) by the involvement of anterior horn and of the anterior or lateral
columns (funiculi) on the affected side.
86
Adamkiewicz Artery Syndrome
Infarction of the thoraco-lumbar cord results in paraplegia with
sphincter dysfunction and sensory disturbances at vertebral level (T10
T11).
Softening in the territory of posterior spinal arteries is rare. By the
involvement of the posterior columns, posterior horns, and a portion of the
lateral columns a tabetic syndrome with anesthesia for the various sensations
vehicled through the lateral columns and, sometimes, pyramidal signs
appear.
Chronic spinal cord ischemia determines cervical spondylitic
myelopathy.
Hemorrhage into the spinal cord is known under the name of
hematomyelia. Hematomyelia is usually traceable to a ruptured
arteriovenous malformation or newly formed intratumoral vessels, and
particularly to the administration of anticoagulants. Some direct or indirect
vertebrospinal trauma (elongation, torsion) may cause both hematomyelia
and extramedullary hemorrhage.
At the level of the lesion a syndrome characteristic to the involved
spinal cord segment develops. A severe radicular pain, indicative for the site
of hemorrhage, may precede by minutes or hour the onset of motor and
sensory deficits. Most commonly, the segment affected by hematomyelia is
the cervical one. The sensory disturbances are of syringomyelic type. The
involvement of the motor and sensory roots causes a uni- or multiradicular
syndrome accompanied by muscular hypotonia, diminution or absence of
tendon reflexes. Later on, atrophies due to peripheral motor neuron injury,
component of the anterior root, may develop.
Below the level of the lesion, unilateral or bilateral pyramidal deficits
and sphincter disturbances are found. The cervical lesions cause tetraplegia,
the thoracic or lumbar ones paraplegia. Spinal shock, tendon hyperreflexia
and sequel phases are described.
Laboratory investigations: lumbar puncture (bloody fluid), computed
tomographic examination, magnetic resonance imaging and selective
angiography.
Myelitis
The spinal cord has a selective tropism for infections and
inflammatory processes which causes destruction of the neurons and involve
the meninges. If the inflammatory process is confined to the gray matter, the
disease is better termed poliomyelitis, and if to the white matter,
leukomyelitis. If both the white and gray matter are involved, there is
transverse myelitis, which may have a cervical, thoracic or lumbar site. The
87
lesion may also be diffuse, the signs of neurological involvement not being
clearly systematized. The dissemination of the infections to the meninges or
neighboring nerve roots may generate meningomyelitis or
meningoradiculitis.
An important role is played by the blood system which vehicles the
infections agents or which, by thromboses amplifies the dysfunctions of the
meninges spinal cord.
Myelitis are due to filterable viruses, bacteria, fungi, parasites, and
may also have undetermined etiologies.
Among the filterable viruses causing myelitis are poliomyelitis
virus, Coxackie virus, echovirus, rabies virus, virus B, HTLV- 1 or HTLV-
3.
The most common myelitis secondary to bacterial, parasitic and
fungal disease are: syphilitic myelitis, suppurative myelitis, tuberculous
myelitis and parasitic myelitis.
Syphilitic myelitis has the following clinical forms: chronic
meningoradiculitis (tabes dorsalis), chronic meningomyelitis,
meningovasclar syphilis, syphilitic meningitis.
Suppurative myelitis progresses acutely or subacutely, and may
even become an abscess of the spinal cord.
In the recent years the incidence of tuberculous myelitis has
increased, so that special investigations and long-term treatment are required.
Trabeculoma of the spinal cord, tuberculous osteitis of the spine (Potta
disease) may compress the cord.
The fungal and parasitic infections may induce epidural granuloma,
localized meningitis, meningomylitis, or abscesses.
To the group of myelitis of undetermined etiology belong:
postinfectious mylitis, postvaccinal myelitis, necrotizing myelitis.
Clinical picture
The onset of myelitis due to filterable viruses is acute. The clinical
picture develops within several hours or days and consists in: motor deficits,
sensory disturbances, retention-type sphincter dysfunctions. Trophic changes
and urinary infections may occur with time.
In acute anterior poliomyelitis, as the virus has an affinity for the
motor neurons of the anterior horn, asymmetric paralyses with muscular
hypotonia and areflexia do occur. In herpes-zoster infection, the lesions are
at sensory roots rather than at spinal cord level. The presence of the
characteristic vesicles is an important diagnostic sign.
Postinfectious and postvaccinal myelitis may occur following
measles, chickenpox, and smallpox or vaccinations. The specific cutaneous
88
manifestations of these diseases or recent vaccination may orient the
diagnosis.
Diagnosis
Beside clinical sign, the cerebrospinal fluid examination is
compulsory. In myelitis, the CSF contains several hundred elements per
cubic millimeter. Serological tests for identifying the responsible virus need
also be performed.
In syphilitic myelitis a positive CSF and a positive serologic test are
diagnostic. The decrease of glycorrhachia is characteristic to tuberculous
meningitis. The bacteriological examination of the cerebrospinal fluid may
demononstrate the responsible microbial agent.
Treatment
The drugs of choice are: prednisone in viral myelitis, antibiotics in
bacterial myelitis, tuberculostatics in tuberculous myelitis and penicillin in
syphilitic meningomyelitis.
89
Chapter VII.
Pathology of Brainstem.
Cranial Nerves. Cerebellum.
Friedreich Disease
Daniel Alexa, Dragos Popescu
Brainstem ischemic syndromes Cranial nerves pathology

Notions of anatomy Oculomotor nerves paralyses
Bulbar syndromes Trigeminal neuralgia and paralysis
Pontine syndromes Facial nerve paralysis
Mesencephalic syndromes
Reticular syndromes Cerebelum

Notions of anatomy Notions of anatomy
Disorders of consciousness Semiology of the cerebellar
Coma syndrome
Syncope Cerebellar syndromes
Disorders of the sleep-wake rythm Etiology
Psychiatric disorders
Tone disorders Friedreich Disease
Brainstem ischemic syndromes

Notions of anatomy
The brainstem is situated between diencephalon and spinal cord,
being composed of bulb (medulla oblongata), pons ( protuberance) and
mesencephalon (cerebellar peduncles). It is delimited at the superior end by
a plane that passes the posterior part of the mammillary tubercles and on the
anterior end by the anterior quadrigemini tubercles; and at the inferior end by
a horizontal plane traced through the pyramidal decussation. It presents
inferior relationes with the great occipital hole (through which can be
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produced the hernia of the cerebellums amygdalian lobes), posterior reports
with the drainage pathways of the CSF (ventricle IV, Sylvius aqueduct) and
behind these with the cerebellum to which is connected through cerebellar
peduncles, superior reports with Bichat's fissure (the possibility of
compressing the brainstem through engaging the temporal lobe through the
cleft) and with the epiphysis; while posterolateral report with ponto-
cerebellar angle, entry space of the cranial nerves VI, VII, VIII.
In longitudinal plane, it is formed by tectum (posterior; does not
contain nuclei of the cranial nerves, of the reticular formation or of the
ascending and descending pathways), tegmentum and basis (anterior,
containing most of the nervous pathways and formations). The base contains
descending tracts and, only at the pontine level, nuclei (that belong to the
descending cortico-ponto-cerebellar pathways). At bulbar level, the base
contains bulbar pyramids (hosting the pyramidal pathways). The tegmentum
is found between tectum and base, and it hosts all cranial nerves nuclei, of
the reticular formations and nucleus proprius, as well as all the other nervous
leasing pathways. At the tegmentums level, the nuclei with efferent somatic
component, efferent visceral and afferent visceral are clustered in the
posterior third (median towards lateral, respectively), and the nuclei proprius
with motor component in the anterior third (ventral).
The most important structural elements are:
Descending pathways
- pyramidal fascicles that descend ventrally, through the bulbar
pyramids, cross at the bulbs caudal limit (pyramidal decussation)
and descend towards the spinal cord (corticospinal); some issue fibers
in the brainstem for cranial nerves nuclei, after they previously
crossed (corticonuclear);
- cortico-oculo-cephalogyr fibers and posterior longitudinal bandelette
(also named median longitudinal fascicle in the anglo-saxon
literature) complex system with ascending as well as descending
fibers that complete the connection between the cerebellar crust
(frontal and parieto-occipital fields), oculomotor and vestibular
nuclei, containing also internuclear fibers; have a role in adjusting
conjugated motility of head and ocular globes and their correlation
with the postural tone
- the central fascicle of the calotte formed by fibers between the
diencephalon, red nucleus, olivary bulbar;
- sympathetic iris-dilating fibers that begin from the posterior
hypothalamus and continues towards the spinal cord to the ciliospinal
center
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- vestibulospinal and reticulospinal fascicles with a role in controlling
muscle tone.
- corticopontine fascicles belonging to the cortico-pontocerebellar
pathways.
Ascending pathways
- median lemniscus (Reils median ribbon) leads the conscious
proprioceptive sensibility and is formed from crossed fibers
originated from Goll and Burdach nuclei, where they arrive from the
spinal cord fascicles with the same name (spinobulbary); is situated
dorsally within the brainstem tegment.
- anterior and lateral spinothalamic fascicles control the tactile
sensibility of protopathic and pressure type
- sensitive fibers from cranial nerve nuclei (quintothalamic from pair
V, solitary fascicle from pairs IX, X, XI), lead through brainstems
tegment
- spinocerebellar Flechsig (direct) and Gowers (indirect) fascicles
control the unconscious proprioceptive sensibility
Cranial nerves nuclei

Bulb (Medulla oblongata) somatomotor nuclei: hypoglossal nucleus (XII)
equivalent to the base of the medullary anterior horn; ambiguous nucleus
(IX, X, XI) equivalent to the head of the medullary anterior horn;
o somatosensitive nuclei: trigemini nucleus (V) (thermo-
analgesic sensibility of the face) corresponding to the head of
the medullary posterior horn; solitary fascicle nucleus
corresponding to the base of the posterior horn and contains
sensitive fibers of the glossopharyngeal (IX), Wrisberg
intermediary (VII bis), vague (X);
o vegetative nuclei: situated under the platform of the ventricle
IV: dorsal nucleus of the vague (X), salivary inferior nucleus
(IX).
Pons somatomotor nuclei: abducens nerve nucleus (VI), homologue to the
base of the anterior horn; facial nucleus (VII), masticatory nucleus (V); are
homologue to the head of the medullary anterior horn;
o somatosensitive nuclei: sensitive nucleus of the trigemini (V)
(tactile sensibility of the face);
o acusticovestibular nuclei at the limit between the bulb and
the pons;
o vegetative nuclei: salivary superior nucleus, lacrimal nucleus
(VII);
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Mesencephalon somatomotor nuclei: the trochlear nerve nucleus (IV),
common oculomotor nucleus (III); in tight connection with this one is the
Edinger-Westphall nucleus (ocular parasympathetic);
- somatosensitive nuclei: trigemini nucleus (V) the
mesencephalon portion (myoarthrokinetic sensibility of
the face).
Vascular ischemic etiology is most often involved in brainstem

syndromes. There are three irrigation zones of the brainstem: the median
territory irrigated by the paramedian arteries, lateral territory tributary to
short circumferential arteries, posterior dependant on the long
circumferential arteries. Besides the vascular etiology, few of the brainstem
syndromes are due to other causes: cerebellar tumors, hemispheric
hemorrhage, subarachnoid haemorrhage, which can be accompanied by
secondary haemorrhage in the mesencephalon-pontine calotte. The pontine
syndromes can appear also in the evolution of cerebellar tumors or of the
ponto-cerebellar angle. Other syndromes, such as in central pontine
myelinolysis, are due to a few general factors (alcoholism, too fast
hydroelectrolytic re-adjustment after hyponatremia). Other causes of the
brainstem syndromes are the infectious, degenerative, traumatic and toxic
ones; but ischemic syndromes realise quasi-stable lesions, while other
etiologies lead to a greater variability of clinical manifestations, explained
through the lack of lesions correspondence with arterial territories and their
modifications in dynamic.
Bulbar syndromes
1. Median syndrome (interolivary). It is determined by the
occlusion of the paramedian arteries that arise, usually, from the anterior
spinal arteries and in rare cases from the vertebral artery. Hemiplegia appears
contralateral with respecting the face (ventral injury of bulbary pyramids)
and sensibility disorders with tabetic dissociation (interesting the Reil ribbon
and the anterior spinothalamic fascicle with maintaining the integrity of the
posterior spinothalamic fascicle) and the tongues homolateralparalysis with
atrophies and fasciculations (touching the nucleus XII).
2. Lateral bulbar syndrome (Wallenberg, retro-olivary, of the
bulbs lateral fossette), it is one of the most frequent vascular syndromes of
the brainstem. Its onset is usually sudden, through powerful vertigo
accompanied by vomiting, hiccup, without consciousness disorders.
Homolaterally it is registered as a hemianesthesia of the face often with
syringomyelic dissociation, associating paresthesis and diminishing the
corneal reflex (nucleus V and quintothalamic fibers), veil, pharynx and vocal
cords paralysis objectified through disorders in deglutition, phonation
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(lesions of the ambiguous nucleus IX, X, XI), vestibular syndrome
expressed through vertigo, horizontal-gyrating nystagmus and tonic
deviation (vestibular nuclei), static cerebellar hemisyndrome, with
predominance in the inferior limb (injury to the dorsal spinocerebellar
fascicle and the restiform bodies), Claude-Bernard-Horner syndrome (injury
to the sympathetic irisdilation fibers). Clinical contralateral manifestations
include thermo-alesic hemihypesthesia that respects the face and can
associate vasomotor disorders (injuring the posterior spinothalamic fascicle).
Lateral bulbar syndrome can be determined by the occlusion of the
vertebral artery or postero-inferior cerebellar, of lateral fossette artery of the
bulb or even by the obstruction of the brachiocephalic trunk (theft
syndrome).
3. Hemibulb syndrome. Babinski and Nageotte have described a so-
called hemibulb syndrome caused by the obstruction of the vertebrobasilar
artery, which is in fact a lateral bulbar syndrome that associates elements of
the paramedian syndrome, usually hemiparesis. Thus the resulted clinical
picture contains homolateral cerebellar syndrome and Claude-Bernard-
Horner syndrome, and contralateral hemiplegia that observe the face and
total hemi-anaesthesia.
4. Cestan-Chenais syndrome consists of a Babinski-Nageotte
syndrome with homolateral paresis of IX, X, XI.
5. Posterior syndrome can be given by the interest in the postero-
inferior cerebellar artery and can appear often in association with lateral
syndrome. Homolaterally appears cerebellar hemisyndrome (injury to the
restiform bodies) and cochleovestibular syndrome, and contralateral hemi-
anaesthesia for profound sensibility (injury to the Goll and Burdach nuclei
and/or the median lemniscus)
6. Pyramidal decussation syndrome can occur through the
appearance of small, unilateral, paramedical lesions to the inferior portion of
the bulb at the decussation level. It is characterised by crossed hemiplegia
(hemiparesis). It interests the fibers destined for the superior limbs after
crossing and fibers destined for inferior limbs before the crossing so that
homolaterally it appears the monoplegia of a superior limb and
heterolaterally the monoplegia of the opposite inferior limb.
7. Avellis syndrome (ambiguous nucleus syndrome). It is
homolaterally recorded the paralysis of the palatine veil and of the vocal
cords (affecting the nerve X and of the internal branch of XI), and
contralateral a hemiplegia.
8. Schmidt syndrome in clinical manifestations from the Avellis
syndrome is added the homolateral paralysis of the trapezoid and
sternocleidomastoid (external branch XI)
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9. Jackson syndrome consists in contralateral hemiplegia and
homolaterally the paralysis of the palatine veil and of the vocal cords,
paralysis of trapezoid and of sternocleidomastoid, and the tongues
homolateral half paralysis and atrophy (Schmidt syndrome and affecting the
nerve XII)
Pontine syndromes
1. Median syndrome (paramedian, anterior pontine) constitutes
the most frequent form of the vascular pontine syndromes. The lesion is
located at the middle third or inferior level of the protuberances leg, two
situations being distinguished:
- -unilateral lesions contralateral hemiplegia with brachial or
crural predominance in case of small size ischemic accidents
- -bilateral lesions paraplegia or tetraplegia in case of most
extended accidents
2. Millard-Gubler alternate syndrome (peripheral facial paralysis,
eventually with paralysis of the ipsilateral external right, associated with
contralateral hemiplegia); rarely appears in pure form and expresses a
frequent hemorrhagic or tumoral etiology.
3. Foville syndromes (median and inferior) are syndromes that
consist in paralysis of lateral movements to the right, left respectively. They
are usually associated with contralateral hemiplegia. Median Foville
syndrome (or pontine superior) contains oculo-cephalogyr fibers after the
crossing that happens in the superior side of the pons, realising on the same
side with the lesion a lateral paralysis of the sight, and on the opposite side, a
hemiplegia with facial paralysis of central type (the diseased is looking at
his own paralysed limbs). The inferior Foville syndrome manifests in the
same manner as the above mentioned one, with the exception of facial
paralysis which will become of peripheral type and will be situated
ipsilateral to the lesion (the nerve VII nucleus being injured and not the
corticonuclear tracts).
A ventral or posttraumatic vascular pontine lesion can trigger a
locked-in syndrome: tetraplegia, paralysis of the inferior cranial nerves,
horizontal paralysis, anarthria, with preserved consciousness; can
communicate with the surroundings through verticality movements of the
ocular globes and of the eyelids. It does not present severe disorders of
superficial sensibility (feels it is being touched).
4. Lateral or Pierre-Marie-Foix syndrome is determined by lesions
that contain the median cerebellar peduncle, the root of the pair V and
sometimes part of the pyramidal fibers or lateral lemniscus. Clinically it is
manifesting through homolateral neocerebellar syndrome, with or without
hemiparesis or thermo-algesic hemihyposthesis. This syndrome is the
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consequence of obliterating short circumferential arteries or of the median
cerebellar artery (antero-inferior).
5. Foville-Millard-Gubler syndrome (of the calotte or the inferior
pontine tegment) presents homolaterally the face anaesthesia with paralysis
of the masticatory muscles (V sensitive and motor) peripheral paralysis of
pairs VI and VII, and the paralysis of the ocular globes movement towards
the lesions part, and contralateral hemiplegia (pyramidal tracts) and thermo-
algesic hemianaesthesia (lateral spinothalamic fascicle). To this could also
be associated the rhythmic myoclonus of the veil, larynx and face (central
fascicle of the calotte) and anterior or posterior internuclear paralysis
(posterior longitudinal bandelette)
6. Raymond-Cestan syndrome (of superior pontine tegmentum):
Homolaterally the lesion is of interest to the oculocephalogyr pathways
above their crossing, clinically consisting in a lateral paralysis of the sight
accompanied by hemiplegia and facial paralysis of central type, all on the
opposite side of the lesion (the diseased is looking at the lesion). To these
it is added cerebellar syndrome (superior cerebellar peduncle before the
crossing), choreo-athetoid movements (dentorubric fascicle) with or without
the Claude-Bernard-Horner syndrome (sympathetic irisdilating fibers),
horizontal and vertical nystagmus (posterior longitudinal bandelette),
akinetic mutism or rigidity through decerebration (reticulated substance).
Contralaterally is being noticed a global hemihyposthesia (median lemniscus
and lateral spinothalamic fascicle). Posterior syndrome appears as a
consequence of obliterating the long circumferential arteries, with an
important role being played by the superior cerebellar artery.
7. Internuclear ophthalmoplegia is due to multiple lesions of the
posterior longitudinal bandelette. In the case of anterior internuclear
ophthaloplegia, within the lateral movements it is disrupted the contraction
of an internal right muscle along with the contraction of the external right on
the opposite side. On the other hand, in the case of convergence movements,
the internal right contraction is possible. Posterior internuclear
ophthalmoplegia have as characteristic the blocking of the external right
muscle contraction that can no longer realise the abduction.
Peduncular syndromes
1. Weber median (ventral) syndrome the infarction contains the
median part of the leg (ventral part of the mesencephalon), being of interest
also to the nerve III, realising the contralateral hemiplegia with facial
paralysis of central type, and the partial or total ipsilateral paralysis of the
common oculomotor. The syndrome is the consequence of obliterating the
paramedian vasa detached from the basilar, of certain tumoral or traumatic
lesions. A fake Weber syndrome can be caused by an aneurism of the
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posterior communicating or cerebellar artery that compresses the pair III and
the peduncular leg.
2. Red nucleus syndromes appear by engaging the red nucleus and
the surrounding formations: the posterior longitudinal bandelette, nuclei and
fibers of nerves III, IV, median lemniscus with oculo-cephalogyr fibers,
nuclei of the reticulated substance. The following are described:
- Benedikt syndrome (the lesion contains the inferior part of
the red nucleus, nucleus III and sometimes efferent fibers
from the black substance): homolateral paralysis of the
common oculomotor, associated with contralateral
involuntary movements (choreoathetosis, posture or
intentional tremor).
- Claude syndrome (the superior cerebellar peduncle are
injured after the crossing, the inferior part of the red nucleus,
nucleus III, eventually IV): homolateral paralysis III, rarely
also IV, contralateral nerocerebellar hemisyndrome
(intentional tremor, dysmetria, adiadochokinesia, ataxia)
- superior red nucleus syndrome (Foix and Masson):
neocerebellar syndrome and contralateral choreoatheotic
movements.
Red nucleus syndromes are due to obliterating the retromammillary
peduncle, but the etiology is rarely ischemic, more often being due to some
tumoral processes. The red nucleus is well vascularised, which makes
bleeding relatively frequent at this level.
3. Mesencephalic tegmentum syndrome. Here are involved the
superior cerebellar peduncle, the median and lateral lemniscus, the
periaqueductal grey matter, the quadrigemini tubercles, the posterior white
commissure, the reticulated substance. From a clinical point of view the
following are described:
- Parinaud syndrome paralysis of the voluntary and
automatic verticality movements with or without paralysis of
convergence and pupillary areflexion. The injured ones are
the anterior quadrigemini tubercles and the posterior white
commissure, most often through obliterating the posterior
cerebellar artery or the retromammillary peduncle.
- the periaqueductal grey matter syndrome (Kestenbaum)
is usually the consequence of occlusion to the periaqueductal
arteries which originate from the posterior cerebellar artery. It
manifests through paralysis of the ocular globes verticality
movements, retracting nystagmus constant sign and which
appear especially when looking upwards, convergence and
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vertical nystagmus, pupillary anomalies, convergence spasms
and sometimes, eyelid pathologic contraction (Collier sign).
- posterior cerebellar artery syndrome: on the same side of
the lesion it is noticed the cerebellar hemisyndrome, Claude-
Bernard-Horner syndrome, eventually myoclonus and on the
opposite side the thermo-algesic hypoesthesia. To this it can
be added the moderate hypoacusis (posterior quadrigemini
tubercles); contralateral paralysis of nerve IV (the only cranial
nerve that crosses with another).
If an embol reaches into the basilar artery, it can stop at its
bifurcation level in the two posterior cerebellar arteries, causing a
mesencephalic infarction which can be confused for transtentorial uncal
engagement: uni- or bilateral paralysis of nerve III, hemiplegia or tetraplegia
with rigidity through decerebration (top of the basilar syndrome) and
negative vital prognosis.
Reticular syndromes
Notions of anatomy
Reticulated formation occupies the space outside the specific
pathways and segmentari and intersegmentari nuclei of brainstem
tegmentum. It is presented as a vast network of nerve fibers in the eyelets of
which many cell groups make up the reticulated formation nuclei. It lies
between diencephalon and spinal cord. It is the main structure who deals
with information integration in brainstem. Having receiving numerous
information from various sources, reticulated formation transforms them into
general, nonspecific messages projected towards the most of central
nervous system structures. In the reticulated formation of the brainstem are
distinguished 4 groups of neurons:
1. Dorsal nuclei are located in the dorsal part of the bulb and the
pons. They are involved in running of important vegetative functions that
segmental centers couldn t done alone. Thus in the bulb, on the ventricular
floor, breathing centers are symmetrically arranged about the center line.
Each center has a respiratory and expiratory fraction interconnected through
nerve connections so that excitation of one leads to inhibition of the other.
Inspiratory centre is maintained active by a pontine center called apneustic
center; its action is suppressed by another pontine respiratory center called
pneumotaxic center. Also in the bulb are vascular constrictors and dilators
centers and cardio-inhibitory center.
2. Lateral nuclei are located in the side and top of the bulb. They
maintain two-way connections with the cerebellum
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3. Central nuclei are distinguishe by their citoarchitecture and also
by their topography and form. In bulb the ventral reticular nucleus is in the
lower half of the bulb and giganto-cell nucleus in the upper half of the bulb.
In pons we find inferior and superior pontine reticular nucleus. Between
these two nuclei there are groups of neurons that are forming the center of
Jouvet (or paradoxal sleep center). At midbrain level we discover
mesencephalic reticular nucleus. All these nuclei receive afferents from all
the specific lemniscale ways on their side and send efferents to medial side
either upwards or downwards direction.
The descending axons goes down towards spinal motoneurons as
the tracts reticulospinale. They synapse with gamma motor neurons. Central
nuclei from whom these tracts originate belongs to descending reticular
formation. Its bulbar segment exerts a strong inhibitory activity on spinal
motoneurons. Therefore, it is known as the inhibitory bulbar reticular
formation. Pontomezencefalic segment of the descending reticular formation
exerts a strong facilitatory action on motoneurons of spinal cord. It is called
therefore facilitatory downward reticulated formation.
Ascending axons breaktrough brainstem tegmentum. They make a
slow, non-specific multisinaptic way, which goes up to the thalamus reticular
nuclei forming synapses with them. This is called ascending reticular
formation and is concentrated mainly in the midbrain. Together with
reticular nuclei of the thalamus they form a functional unit ascending
reticular activating system (ARAS). This system is responsible for
maintaining wakefulness.
4. Medial nuclei comprise a group of nuclei called raphe nuclei and
occupy even the midline of the brainstem. They are best represented in
bulbo-pontine segment. They are very rich in serotonin which is their
chemical mediator. Raphe nuclei in bulbo-pontine segment and Jouvet's
nucleus are the structures responsible for installing and maintaining sleep.
Reticulated formation takes part in the most complex brain functions
(memory, learning) and in regulation of sleep-wake rhythm.
Wakefulness is the state in which brain function is characterized by
increased ARAS tone, concomitant with the orientation of consciousness to a
certain activity.
Alternative to wakefulness is sleep. Switching from sleep to waking
and vice versa, is achieved by stimulating or, on the contrary, inhibition of
the ARAS. Sleep is a state of brain activity characterized by cessation of
conscious analysis and suppression of voluntary stimuli. It is a state of rest of
brain regions, while maintaining or enhancing the activity of others. It is
reversible. There are two types of sleep: deep, dreamless, and paradoxically,
accompanied by dreams and rapid movements of the eyeballs. These phases
are cycled several times during sleep.
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Consciousness can be defined as the ability to be informed, to have or
take notice of something, to know the right way and objectives surrounding
phenomena (the surrounding reality).
Clinical picture
Lesion of reticulated formation can manifest clinically by:
I. Disorders of consciousness:
- Comatose states;
- Syncope
- Akinetic mutism;
- Locked-in syndrome;
II. Disorders of the sleep-wake rythm
- Sleepiness: the patient may be awakened by strong stimuli, hearing,
understanding and
performing with some slowness orders then rejoin sleep;
- Lethargy: the patient can wake up by violent excitement but
reactions are inadequate;
- Periodic hypersomnia - Kleine Levin syndrome(lesion of
diencephalon);
III. Psychiatric disorders:
- Peduncular hallucinosis;
IV. Muscle tone disorders
V. Vegetative disorders: hyperpyrexia, cardiac arrhythmia, periodic
breathing
I. Disorders of consciousness
The main aspects of assessment of consciousness are:
A. level of consciousness;
B. contents of consciousness;
C. wakefulness or alertness;
A. Disorders of consciousness level: it is estimated type reactions
(adequate / inadequate, timely, delayed, absent) to verbal and painful stimuli,
and observation of spontaneous behaviour:
- Dizziness: awake, but slowed reactions;
- Sleepiness: sleepy, easy to wake, delayed reactions to verbal stimuli,
prompt and adequate reaction to painful stimuli;
- Stupor: hard to wake, significantly delayed or absent response to
verbal stimuli, delayed defense, adequate to painful stimuli;
- Coma
B. Disorders of consciousness comprise:
Confusion: syndrome which translates clinically an acute cerebral
suffering of multiple etiology and variable topography, it is defined as a
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disturbance of consciousness, a state of "intermediate" between waking and
comatose or stuporous moods;
appearance of patient expresses a global disorder of mental
functions, facies "stunned" on vague absence;
psychomotor behaviour characterized by the absence of
initiative, with slowness and clumsiness or disorderly
agitation imposes strict supervision;
attention can not be fixed, adapted or extended;
hesitant language reduced to brief phrases often inconsistent,
clumsy gestures;
altered perceptual data (visual, auditory) leading to
identification errors or defects and even delusions, very poor
intellectual performance;
mnemonic altered temporal-spatial disorientation global and
false recognitions;
affective-emotional disorders (which can manifest as mental
confusion, false foreground appreciated as "inorganic
psychiatric disorder") can perform two opposite aspects:
continue perplexity or interrupted by periods of lucidity with
anxiety and agitation or oniric state manifested by a "dream"
pathologically with visual and sometimes auditory and tactile
hallucinations that can be triggered by the slightest external
stimulation;
etiology: cranio-cerebral traumatisms, epilepsy, deficiency
encephalopathy (Wernicke), meningitis, encephalitis, , stroke,
brain tumors, fever, alcoholism, drug addiction, poisoning,
metabolic encephalopathy, endocrine disorders;
Delirium: is a specific confusional syndrome with various cognitive
and behavioural symptoms, acute onset (install in hours or days),
characterized by disorder of attention and perception, with visual
hallucinations, agitation, autonomic disturbances and fluctuations in the
intensity of symptoms (worsening in the evening) caused by diffuse organic
lesions of cerebral cortex. Common causes are metabolic disorders,
poisoning, febrile syndromes, severe dehydration, epilepsy. It occurs after
surgery, especially in the elderly;
C. alertness disorders: narcolepsy, hypersomnia
Coma
Coma is the alteration of consciousness associated with loss of
function of sensory-motor relationship and alterations of autonomic function.
Coma etiology involves humoral factors, biochemical
(hypoglycemia, hypoxia, hierglicemia acidosis, uremia) compression
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mechanical factors (space substitute formations over and subtentorial),
ischemia in the vertebrobasilar territory, brainstem hemorrhage etc. The
disorders that cause comatose states are represented by diseases that does
not assume the existence of neurological signs of focalization or changes in
CSF (intoxication, metabolic disorders and brain contusion); diseases with
meningean syndrome- cell reaction or the presence of blood in CSF
(subarachnoid hemorrhage after ruptured aneurysm or trauma, meningitis,
encephalitis, some viral hemorrhagic leucoenkephalitys); and conditions that
show signs of neurological focalization and inconsistent changes of CSF
(vascular diseases, infections, tumors)
After etiology coma may be classified as:
- Neurological conditions that impaires structures of brain by
vascular, infectious, traumatic or tumor mechanisms
- Metabolic: diabetic coma, hypoglycemia, hepatic, endocrine;
- Toxic;
Consequently, the main causes that produce coma are:
- Isolated injury of the cerebral cortex - hypoxia (cardiac and
respiratory episode narcotic) poisoning with barbiturates;
- Isolated lesion of the brainstem - ischemia in the vertebrobasilar
territory, traumatic lesion to the brainstem, central pontine
myelinolysis, Wernicke encephalopathy;
- Combined disorders involving the reticulo-cortical pathways: acute
metabolic encephalopathy (diabetic coma, hepatic, uremic), bilateral
infarction and bleeding, poisoning, encephalitis, venous thrombosis
or venous sinuses, intracranial hypertension, severe, diffuse traumatic
brain injury
Pathophysiology of coma
Brain function is dependent on cerebral blood flow (CBF) to supply
with oxygen and glucose. CBF is approximately 100g for 55 ml / min in
healthy subjects. If CBF falls below 25 ml/min for 100 g EEG recording
show a slowing global electrical activity (metabolic encephalopathy). When
CBF values drops below 15 ml/min for 100 g EEG electrical activity
disappears and at values below 10 ml/min for 100 g appear irreversible brain
damage. Stop of CBF cause sudden loss of consciousness in 8-10 seconds.
Normal oxygen consumption is 3.5 ml/min for 100 g and consumption of
glucose is 5 mg/min for 100 g. Cerebral glucose reserves are sufficient two
minutes after stopping CBF.
Reticular activating system in midbrain is responsible for waking and
her tone is provided by trigeminal afferents, impulses from the cerebellum,
humoral factors (arterial concentration of CO2 and O2, plasma levels of
catecholamines), diffuse nonspecific thalamic system (Thalamic midline and
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intralaminari nuclei). Neural groups of ARAS use as neurotransmitters
acetylcholine, norepinephrine, serotonin; activity of these systems is
controlled by excitatory (glutamatergic) and inhibitory (GABAergic)
neurotransmitters.
Metabolic disorders that can lead to coma are: hipo and
hyperosmolarity, hypercapnia, encephalopathy in liver failure and renal
diabetic ketoacidosi,s hypercalcemia, hypothyroidism, deficiency in B12
vitamine, CNS depressant drugs, anesthetics. The main pathophysiological
mechanisms involved are altered blood-brain barrier with altered neuronal
electrical operation
Examination of comatose patient

- History - a history of trauma, ingestion of toxic substances, diseases
known;
- General physical examination - important to assess the skin,
temperature, respiratory rate and type of respiration, pulse and BP
- Fundus eye examination (subhialine bleeding), hypertensive
encephalopathy (exudates, hemorrhages), raised intracranial pressure
(papilledema);
- Global neurological assessment considering the:
o signs of meningism - may be absent in children and the
elderly;
o type of breathing: apnea posthyperventilation: 5-6 breaths
then forced 12-30 sec apnea (in diffuse hemispheric lesion );
Cheyne Stokes breathing (in suffering diencephalon);
Kussmaul breathing: 40-70 resp / min; breath apneustica: 3-5
resp / min, irregular, with long pauses (pathognomonic in
damaged pontine respiratory center); breathing Biot (in
bursts) respiratory movements grouped, rapid alternating with
periods of apnea (low pontine lesion with poor prognosis);
ataxic respiration (in bulbar compression and infectious
processes);
o motility disorders: monoplegia, hemiplegia, facial paresis of
central type, myoclonus (the stigma of being disseminated
metabolic disorders like uremic coma or the hypercapnia)
flapping tremor or tremor (in metabolic encephalopathies or
poisoning), focal seizures (in suffering hemispheric) core or
athetosis type movements, hemiballismus (lesion in the
hypothalamus and basal ganglia);
o motor reflex responses: stiffness of decortication (serious
damage to both hemispheres) or of decerebration (midbrain
lesion);
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Ocular Semiology:
a) blinking movements
Spontaneous: their absence means lesion of the brainstem;
Reflexe:
to threat - have cortical integration;
strong acoustic stimulus (located low pontine);
strong luminous stimulus ( located in geniculate body);
Corneal reflex - testing the functionality of the mesencephalic
tegmental area of lower pons
b) pupillary changes
miosis in healthy subject is produced under the action of
parasympathetic fibers from oculomotor nerve ( Eddinger-Westphall
nucleus);
reactive miosis (<2.5 mm) appears in: metabolic
encephalopathy, bilateral lesion of hemispheres
(hydrocephalus, hemorrhage), ingestion of barbiturates,
narcotics,
Claude Bernard Horner syndrome (miosis, enophthalmos,
smaller palpebral fissure unilateral) lesion in the bulb;
mydriasis in healthy subjects appears under the action of
sympathetic nerve fibers V
mydriasis (> 5 mm) occurs in midbrain lesion, ingestion of
drugs with anticholinergic action;
c) fotomotor reflex originating in nerve III nucleus - abolition of this reflex
in a patient with miotic pupils irregular (Argyll Robertson sign) occurs in
syphilis, diabetes.
d) changes in ocular motility
Eye Ball (EB) position: frontal cortex (area 8) and occipital cortex
(areas 18,19) are responsible for conjugate movements of laterality
and verticality of EB;
lateral deviation
supratentorial single sided lesion (affecting cortical centers
and oculomotor pathways)
EB deviate from lesion. (the tonic influence of controlateral
centers);
irritating supratentorial lesion (in the cerebral hemorrhage) -
in the early hours adversive deviation of the EB followed by
deviation towards the lesion
brainstem lesion (pons) - deviation of the eyes toward the
hemiplegia;
the vertical deviation
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physiological - sleep and intentional eyelid occlusion;
pathology: up (in Cheyne Stokes apnea, seizures - but
oculomotor pathways are intact);
down ( hepatic coma);
oblique deviation (a deviated eye up and one down) - lesion
posterior longitudinal bandelete of the brainstem;
e) spontaneous motility EB:
a comatose patient present slow spontaneous conjugate movements
of EB, which takes place regularly in the horizontal and vertical plan
and are involuntary, may not be reproduced (in healthy subjects
appear only in sleep) and means the integrity of brainstem;
diversion of unconjugated EB - mesencephalo-pontine lesions;
sudden conjugate movement down to return to the starting position
("bow") pontine lesion
swinging movements of EB diencephalon lesion
f) EB reflex motility of the comatose patient
1) oculo-cephalic reflexes shall be examined by a sudden rotational
movement of the head flexion-extension resulting in a deviation in
the opposite conjugated EB ("doll eyes");
reflex afferents are in the cervical musculature;
in healthy subject these reflexes are not obtained due to the
inhibitory action of frontal oculomotor areas;
lesion occur in bilateral hemispheres (in unilateral
hemispheric lesion is difficult to
obtain due to the EB conjugate deviation);
2) oculo-vestibular reflexes
to test those who do not respond to r. oculo-cephalic or in
cases of difficulty of mobilizing head (ie. those with neck
stiffness);
apply a caloric stimulus in labyrinthine (cold water in the ear
canal); this maneuver in healthy subjects lead to ear
nystagmus with fast phase controlateral; in comatose patient
tonic conjugate deviation of EB towards the irrigated ear
indicate a lesion in the brainstem, and the absence of
deviation indicates a lesion of paramedian pontine reticulated
formation;
Glasgow Coma Scale or GCS is a neurological scale that aims to give a

reliable, objective way of recording the conscious state of a person for initial
as well as subsequent assessment. The scale is composed of three tests: eye,
verbal and motor responses. The three values separately as well as their sum
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are considered. The lowest possible GCS (the sum) is 3 (deep coma or
death), while the highest is 15 (fully awake person):
Eye opening:
1. absent;
2. to painful stimuli;
3. to order;
4. spontaneously;
Verbal response:
1. absent;
2. unintelligible sounds;
3. inappropriate words without meaning;
4. confused;
5. prompt oriented;
Motor response:
1. absent;
2. posture in extension (decerebration);
3. flexion posture (shelling);
4. withdrawing member flexion (reflex removal) to painful stimuli;
5. Locate nociceptive stimulation (defensive gesture);
6. limbs mobilized to order or executes moves spontaneously;
Interpretation:
.
Minor, GCS 13 - lack of response to verbal stimuli,
inadequate response, global movement to painful stimuli;
Moderate, GCS 8 or 912 response only to strong stimuli,
inadequate defense moves to painful stimuli;
Severe, with GCS < 8-9 absence of reaction to painful stimuli,
possibly triggering crises of flexion-extension or generalized
extension;
Clinical syndromes:
diencephalic syndrome: reticulo-cortical connections disruption and
interruption of cortico-bulbar tract by vascular lesion, space
replacement processes in the hemispheres (hemorrhage, diffuse
cerebral edema, etc.) and pupillary sympathetic innervation deficit;
Clinical: stupor to mild coma, extension of lower limbs amplified by
painful stimuli, miosis, divergent strabismus, oculocefalic reflex
diminished;
mesencephalic syndrome: impaired midbrain reticulated formation,
cortico-bulbar and rubro-spinalways (innervate flexor muscles)
maintaining intact the pontine vestibulo-spinal tract (extensor muscle
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innervation), deficit of sympathetic and parasympathetic pupillary
innervation caused by stroke or midbrain hemorrhage, tentorial
herniation; Clinical: coma, position in decerebration, moderately
dilated pupils, less reactive, oculo-cephalic reflex absent;
bulbar syndrome: deficit of all brainstem functions that can be caused
by vertebral basilar artery occlusion, compression or herniation;
Clinical: coma, generalized hypotonia, non reactive mydriasis,
strabismus divergent, ataxia breathing to respiratory arrest.
Investigation needed:
Laboratory blood gas meter, glucose, CBC, coagulation, electrolytes, urea,
creatinine, urine summary, CK, ALT, specific reactions to drugs;
Imaging: CT or MRI;
ecoDoppler: basilar thrombosis, obstruction of other major arteries;
CSF examination: unless there is an indication of a ICH,
EKG;
EEG: focal lesions characteristic to potential epilepsy, coma grade
estimation or prognosis, for the control of status epilepticus in evolution,
delimitation of psychogenic coma to organic coma or locked-in syndrome;
auditory evoked potentials: useful in controlling evolution, appreciable
only when wave I is present;
sensory evoked potentials: useful in excluding supplementary, peripheral or
spinal lesion; coma prognosis.
Differential diagnosis of comatose states

1. apalic syndrome (vegetative status)
occurs through lesion of the bilateral cerebral hemispheres
with extensive loss of cortical function; The most common
injuries are on thalamic and subthalamic level;
in the first week the patient is in coma, can open his eyes to
noxious stimuli; in the coming weeks the patient is apparently
awake, with spontaneous movements of EB, fixation target
can give erroneous impression that recognize people or
objects and winking at threat;
position of decerebration with minimal spontaneous
movements;
pathognomonic are stereotyped motor responses of mouth lips
touch to any stimulus, and the tendency to grip the mouth,
without discrimination, to that stimulant (similar to those of
infants);
may develop a false grip reflex (grasping);
frequently divergent strabismus, anizocorie and gaze palsy;
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no response to verbal stimuli, absent language;
important vegetative disorders: incontinence, sweating,
tachycardia, tachypnea;
respiratory automatism is preserved and swallowing
movements is possible, but due to lack of effective
masticatory movements it requires nasogastric tube feeding;
EEG is often flattened, areactiv to external stimuli;
cortical evoked potentials are unanswered;
signs of remission: reactions to pain with grimaces and
defense inadequate fixation and tracking eyes, mouth opening
moves at perioral or optical stimuli, prehension movements,
development of SDR. Korsakow;
vegetative state lasting more than 3 months in patients with
nontraumatic brain injuries and more than 12 months in
patients with traumatic brain injury were called persistent
vegetative state;
2. akinetic mutism
occurs through bifrontale, cingulate gyrus or limbic system
lesions caused by bifrontale traumatic brain injury, ACA
bilateral syndrome, tumors of the posterior cerebral fossa or
V3, decompensated hydrocephalus;
consciousness is preserved, inability to initiate voluntary
movements and verbal expression even on nociceptive
stimulation, lack of emotional events, expressionless facies;
are maintained EB movements, swallowing, skin reflexes;
this sphincter incontinence;
no perceptual disturbances, so after improvement not find
amnesia;
Clinical and pathologic there are described two forms:
o reticular (mesencephalic): akinesia generalized
catching also the face muscles, but respecting ocular
motility, reactivity to intense stimuli is absent,
voluntary phase of swallowing is abolished, while
reflex phase is preserved, the presence of neurological
signs of distress brainstem (tonic seizures of limbs);
o cingulate (frontal): akinesia dress mild or stuporous
appearance, absence of brainstem neurological signs,
better recovery capabilities;
EEG: reactivity maintained at optical and acoustic stimuli;
frontal suffering;
MRI: fronto mesodiencephalic lesion or hydrocephalus;
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3. Locked-in syndrome
cortical efferent pathways affected by interrupting
corticonuclear and corticospinal pathways bilateral, abducens
nuclei, trigeminal fibers, paramedian pontine reticular
formation through a bilateral lesion of the ventral part of the
pons;
causes: basilar artery occlusion with infarction in the ventral
region of the protuberance, pontine hemorrhage, encephalitis
or brain stem abscess, pontine myelinolysis, pontine tumors,
TBI;
Clinical: Full quadriplegia or minimal voluntary movements,
muscle paralysis mutism by phonation, conservation of
vertical movements of eyeballs and eyelids and use of these
movements in order to establish a form of communication
with the examiner and the environment, the appearance of
decerebration crises application of noxious stimuli, absence of
corneal reflex, swallowing disorders; consciousness,
sensitivity and respiratory rate are preserved;
EEG: alpha activity;
prognosis depends on the size and pontine lesion etiology,
most patients die in the acute phase; total dependent in case
of survival, care and communication is limited to a code using
eye movements;
4. Psychogenic disorder of consciousness (catatonia)
quantitative neurological damage associated with disorders of
consciousness;
patient seems conscious, with open eyes, do not perform
voluntary movements, resists to passive opening slots eyelid;
presents a "waxy flexibility" in which members remain in
position printed by the examiner;
advocates for organic causes: EB fluid displacement, EEG
slowing basis;
advocates against organic causes: the eyelid reflex maintained
during the absence of reaction to pain stimuli, optokinetic
nystagmus currently maintained in EEG alpha blocking;
5. Hypersomnia
pathological sleep duration and depth by the patient to be
awake and asleep again;
lesion occurs mesodiencephalic (epidemic enkephalitis,
tumors, etc.);
6. Global aphasia
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Comatose patient care:
release the airway to allow ventilation, endotracheal intubation or
tracheostomy
removing dental prosthesis;
moistening the mouth;
pharyngeal aspiration of bronchial secretions in excess;
eyes should be protected by locking and eye drops disinfectants
should be instilled in the conjunctival sac;
skin should be clean, avoiding creases linen;
prevention of bedsores by changing the patient's position within 2
houres, compressions followed by massaging the exposed areas;
bladder and bowel evacuation
sounding 2-3 days;
ensuring nutritional caloric and electrolyte balance;
supervision vein thrombophlebitis due to the increased risk of
pulmonary embolization source;
Indicators of a poor prognosis (with high probability of a fatal outcome or
apalic syndrome):
- After 24 hours no corneal reflexes and pupillary reactions;
- Within 48 hours absence of motor reactions;
- After 7 days absence of EB movements
Syncope
Syncope is a generalized weakness accompanied by autonomic

phenomena (pale / skin cyanosis, cold sweats, filiform pulse, bradycardia,
vertigo) followed by loss of postural tone and loss of consciousness for a few
seconds or minutes due to a nonepileptic cause; usually stored sphincter
control. Syncopal reflex afferents takes information from sensory and
sensorimotor pathways of V, VII bis, IX, X cranial nerves; stimuli reach the
vegetative centers connected to reticulated formation and by efferent vagal
(cardioinhibitorii), sipathetic (pressor) or motor pathways (for respiratory
muscles) are distributed to formations with role in regulating heart rate,
blood pressure, respiratory function. Cardioinhibitory and vasodepressor
either individually or mixed mechanisms will lead to cerebral anoxia and
unconsciousness.
Classification of syncope:
orthostatic: by hypovolemia or poor adjustment orthostatic BP
(hypertension, neuropathy, autonomic failure,
antihypertensive drugs);
heart: by arrhythmias, mitral or aortic stenosis, pulmonary
embolism;
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vasovagal: the taking of blood, pain, fear;
reflex: carotid glomus syndrome (bradycardia or asystole
local compression), micturition syncope (by decreasing
sympathetic), the Valsalva maneuver;
cerebrovascular: debut as a symptom of ischemia or cerebral
hemorrhage;
Syncope of orthostatic hypotension: occurs in sudden or prolonged
orthostatic; orthostatic hypotension occurs in Shy-Drager disease, anemia,
Addison's disease, polyneuropathy (diabetic acetate) under vasodilator
medication.
Adam-Stokes syndrome: association represents a neurologic event
(syncope) with atrioventricular block (or other arrhythmias).
Shy-Drager disease - common in men between 55-60 years; but
sporadic cases with dominant transmission; Clinical: syncope, orthostatic
hypotension, anhidrosis, sphincter disorders (nocturnal urinary frequency),
sexual impotence, increased catecholamines in the absence of standing,
pyramidal, extrapyramidal and cerebellar signs; neurological signs preceding
syncope 2 to 20 years; degenerative lesions found in dorsal nucleus of
vague, intermedio-lateral tract substantia nigra, cerebellum.
Micturition syncope is pretty rare. Occurs more frequently in men
after 40 years, after drinking the night prior access. After a variable time of
sleep the patient awakes and immediately after urination occurs a brief loss
of consciousness that sometimes can be accompanied by 1-2 minutes of tonic
or tonic-clonic seizures. Patient accuse postictal headache, dizziness, fatigue,
anxiety. It is considered that this type of syncope is favored by standing in a
phase of night hipervagotony in vagotonic individuals.
Syncope of glossopharyngeal neuralgia: glossopharyngeal
neuralgia pain in bouts lasting 20-30 sec occur spontaneously or triggered by
swallowing (pain at the base of the tongue, tonsil and angle of the jaw),
ended through syncopal attacks. There is the a trigger sinocarotidian area of
which irritation induce syncope crisis.
Investigation necessary for diagnosis of syncope (which is a
diagnosis of exclusion):
EEG, ECG, echocardiography, vascular Doppler, TA measurement
after 4 minutes of supine and 3 minutes standing (pathological result in the
drop of 20 mmHg systolic or with minim 10 mmHg diastolic BP).
To reproduce in the laboratory a syncopal access these maneuvers are
cited:
ocular compression (oculo-cardiac reflex testing) for 10-15 seconds
while a recording is being performed (EEG, EKG, pneumograma,
pletismograma); maneuver is positive if there are minim 5 sec cardiac
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pause, slow heart rate by at least 50%, presyncope or syncope
manifestations;
carotidan sinus compression;
Valsalva maneuver;
Differential Diagnosis with:
seizures;
attacks of hypersomnia with brutal and brief appearance
(narcolepsy, catapletic access, in which the patient suddenly
collapses as a result of sudden loss of postural muscle tone
including factors related to affective-emotional but with
preservation of consciousness, sleep paralysis) ;
the fall during the attacks of Meniere's disease, sometimes
accompanied by loss of consciousness with vertiginous
disorders and hearing;
drop attack seizures pathognomonic for vertebrobasilar
circulatory failure;
psychogenic seizures
II. Disorders of the sleep-wake rythm
Sleep - is a physiological condition characterized by abolition of

consciousness (the result of periodic suppression of reticulo-cortical
impulses that activate the cortex - ARAS inactivation by a physiological
process). Its role is not fully understood, but current theories claim that it is
involved in replenishing the body's energy and metabolic storages and in
reorganizing information acquired during wakefulness, with memory
consolidation. It is an active process generated and modulated in the CNS
under the control of many neural systems located in the hypothalamus,
brainstem and thalamus.
Structure of sleep: REM (rapid eye movements) (with rapid electrical
activity, disappearance of muscle tone, rapid eye movement, is dependent on
latero-dorsal structures activity of pontine tegmental area) and non-REM
sleep (at least partial maintenance of muscle tone, is dependent on the
activity of raphe) that has 4 stages (I-IV) defined by distinct EEG brain
activity. Sleep architecture is composed of sleep cycles representing a
successive transition from one sleep stage to another; stages I and II are
superficial, III and IV are deep and REM sleep occur in most dreams; There
are about 4-5 cycles of sleep a night, a cycle lasts on average 90-100
minutes.
Sleep disorders are classified:
by etiology: primary and secondary;
by duration and quality of sleep: insomnia and hypersomnia;
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The international classification of sleep disorders has 8 categories:
1. insomnia;
2. Sleep related breathing disorders;
3. Secondary hypersomnia disorders not associated with sleep
breathing;
4. Circadian rhythm disorders;
5. Parasomnias;
6. Motility disorders associated with sleep;
7. Isolated symptoms;
8. Other sleep disorders;
1. Insomnia - the most common sleep disorder, affecting one third of the
population, and more females, incidence is increasing with age; is defined as
repeated difficulty for initiation, duration, consolidation or sleep quality
despite the existence of necessary time and opportunity to sleep and
translates into daytime functioning impairment. It is characterized by
difficulty in initiating or maintaining sleep, insufficient sleep, interrupted or
having a poor quality. It is frequently associated with neurological diseases.
Classification of insomnia:
1. Transient - from one night to several weeks;
2. Intermittent - episodes of insomnia that occur from time to time;
3. Chronic - occurs in most nights and lasts several months;
Transient or intermittent insomnia occurs more frequently in
individuals undergoing stress and extreme environmental conditions
(extreme temperature, noise environment, etc.), change the time zone,
adverse drug effects; most often do not require treatment, but prescription of
sleep inductors with short-acting for limited periods improves sleep and,
therefore, ameliorates somnolence and difficulty concentrating during the
day.
Chronic insomnia is caused by a complex of factors, usually
secondary to systemic disorders or psychological (depression, heart failure,
asthma and other lung diseases, hyperthyroidism, arthritis, Parkinson's
disease) or after prolonged excess of stimulants (caffeine, alcohol ). It is
necessary to diagnose the underlying disease that causes insomnia to
establish therapeutic possibilities. The treatment may be associated with
hypnotics but with caution due to the adverse effects of chronic treatment
with them.
2. Sleep related breathing disorders (SBD) - is characterized by abnormal
breathing during sleep occurring; are classified as:
a. obstructive sleep apnea syndrome - is characterized by recurrent
episodes of partial obstruction (produces hypopnea - this is defined
by decrease of more than 50% of airflow during sleep, evident
decrease in the amplitude of breathing associated with peripheral
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blood desaturation over 3% or produce an awakening from sleep, this
event should last more than 10 sec) or complete (produces apnea -
defined as cessation of ventilation beyond 10 sec) occurring during
sleep, often waking the patient
b. apnea / hypopnea central sleep - defined by recurrent episodes of
sleep apnea (> 5 episodes per hour) without the presence of airway
obstruction, with decreased air flow> 50% and duration of apnea> 10
sec.
c. Cheyne-Stokes syndrome breath - breathing cycle fluctuations with
periods of apnea or hypopnea alternating with periods of hyperpnea;
appears particularly in acute cerebrovascular diseases usually during
sleep and in severe cases during wakefulness;
d. syndromes hypoventilation / hypoxemia associated with sleep -
defined as decrease in ventilation associates alveolar hypoventilation
which translates into increased blood pressure of CO2 and
hypoxemia; is associated with erythrocytosis, HTP, right cardiac
failure, respiratory failure and excessive daytime sleepiness,
hypertension and cardiac arrhythmias.
3. Hypersomnia not associated with breathing disorders during sleep -
defined as the inability of the individual to remain alert and awake during the
day resulting in involuntary bouts of sleep; hypersomnia occurs frequently in
neurological diseases and may be a consequence of sleep centers
degeneration, sleep fragmentation or medication side. The most common
manifestations include:
Restless Legs Syndrome - sleep disorder characterized by primary
rhythmic movements, stereotyped in the big toe, ankle or knee,
slower than myoclonus (duration of 1-5 seconds) that correspond to
the intervals of 30-40 seconds and occurring during non-REM sleep
in the early hours of sleep.
Narcolepsy - part of primary sleep disorders; The main symptom is
daytime sleepiness accentuated with short sleep episodes that occur
suddenly and can not be controlled; they are accompanied by
cataplexy (sudden episodes of loss of muscle tone triggered by
emotions -anger, laughter- without loss of consciousness).
4.Circadian rhythm disorders - refers to the misalignment between the
pattern of the patient's sleep and sleep pattern seen as desirable or acceptable
as social norm. It is caused by external factors associated with social factors.
There are neurological diseases that destroy afferents in the suprachiasmatic
nucleus (bilateral lesions of the retina, optic nerves, chiasm or hypothalamic
lesions).
5. Parasomnias - are strictly sleep disorders (do not give symptoms during
wakefulness) and is associated with undesirable physical or external events
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occurring in sleep and waking. Partial or pathological transition waking
between sleep stages. In involves abnormal behaviour occurring in sleep.
III. Psychiatric disorders

Peduncular hallucinosis is a rare neurological disorder that causes
vivid visual hallucinations that typically occur in dark environments, and last
for several minutes. The hallucinations are very realistic and often involve
people and environments that are familiar to the affected individuals.
Because the content of the hallucinations is never exceptionally bizarre,
patients can rarely distinguish between the hallucinations and reality.
Peduncular hallucinosis is attributed to a range of various pathologies such
as vascular and infectious midbrain, pontine and thalamic lesions, local
subarachnoid hemorrhage, compression by tumors, basilar migraine, basilar
vascular hypoplasia, and following regional surgical or angiographic
interventions. The lesions that disturb brainstem reticular formation or
thalamic targets seem to be the source behind peduncular hallucinosis
IV. Muscle tone disorders

Rigidity by decerebration: occurs after midbrain transsection under
the red nucleus suppressing cortico-subcortical reticulated pathways with
facilitating role of inhibitory structures. Clinical manifestations ere trunk
extension with opisthotonus, stiffness in extension of members, altered
consciousness and autonomic function disorders (respiratory,
thermoregulatory, increased salivation, fixed bilaterally mydriasis);
Crisis of drop attacks: falls without loss of consciousness for
a few seconds and after that patient resumes walking. They
are caused by transient ischemia of facilitator descending
reticular system;
Stiffman syndrome is controversial by some authors;
progressive hypertonia comprising the trunk, limbs and neck,
sparing at least for a while respiratory muscles and muscles
of the face, hypertonia disappears in sleep and after
administration of diazepam. It is assumed that an impairment
brainstem encephalitis-like leads to a hyperactivation of the
gama motor system by affecting supraspinal centers;
Cranial nerves pathology

Oculomotor nerves paralyses
Ocular movement is functionally systematized to perform lateral and
vertical eye movements. The combination of these two types of movements
results in rotary and oblique movements. It is the combined action of six
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muscles innervated by three nerves that permits eye movements in all
directions. The oculomotor nerve (III) innervates the medial, superior, and
inferior rectus muscles, the inferior oblique muscles, and the levator muscles
of the superior eyelids. The abducens nerve (VI) innervates the lateral rectus
muscle, and the trochlear nerve (IV) the superior oblique muscle.
At rest (during sleep) the eyeballs are at equilibrium, deviating
upward and outward. A rather complicated central mechanism controls the
fine synergism of the various eye muscles and their nerves. The eye can be
moved both voluntarily and by reflex. They can, however, move only
conjugately. that is in whatever position the eyes move, all eye muscles
participate in the action, in part by increasing muscle strength, in part by
relaxation.
The frontal lobe (area 8) is the center for voluntary conjugate
movements of the eyes, while the occipital lobe (area 19) and temporal lobe
(auditory pathway) are centers for reflex eye movements. The impulse for
voluntary and reflex eye movements is sent via the descending visual
pathway to the intermediate ocular motor centers in the brainstem. These
centers produce and send impulses to the motor nuclei of nerves III, IV, and
VI. From here, via the ocular motor nerves, the impulses reach the ocular
motor muscles, and the movement is realized.
The supranuclear pathway, originating in the left frontal cortex,
subserves the conjugate horizontal gaze to the right, and the pathway
originating in the right frontal cortex the conjugate horizontal gaze to the
left. The impulses are mediated through the paramedian pontine reticular
formation, the supranuclear pathways crossing at pontine level. The medial
longitudinal fasciculus provides intimate connections among the nerves in
charge of ocular movements, and is involved in vertical as well as right-left
eye movements. The medial longitudinal fasciculus runs bilaterally parallel
to the midline from tegmentum of the midbrain down the cervical cord, and
interconnects the nuclei of the motor nerves of the eye muscles.
The most important symptoms occurring during paralysis ot ocular
motor nerves are diplopia, strabismus, eyelid ptosis, changes in pupil
diameter.
Diplopia consists in double vision. Horizontal diplopia is due to
innervation deficits of a medial or lateral rectus muscle. In vertical diplopia
the innervation deficit is in the superior or inferior rectus muscle. In oblique
diplopia there is a deficit of innervation in a superior or inferior oblique
muscle. Diplopia may be mild or occurs when eyes look in a certain
direction. To identify the eye with movement deficit and the paralyzed
muscle, red-white glass test is used. The double image of an object appears
in the direction in which the paralyzed muscle normally would pull the eye.
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When the patient looks in that direction, the distance between the double
images is the greatest.
The deviation of the eyeballs as a result of an acquired ocular motor
nerve palsy causes a converging strabismus (paralysis of the abductors) or
diverging strabismus (paralysis of the adductors). Limited abduction of an
eyeball is due to lesion in a lateral rectus muscle innervated by the fourth
nerve, and limited adduction is the result of paresis of a medial rectus muscle
innervated by the third nerve. Limited vertical movements are due to damage
to the superior and inferior rectus muscles.
Ptosis (lid drop), caused by paralysis of the levator muscle of the
superior lid, results in the absence of binocular vision. The changes in
pupillary diameter consist in mydriasis (paralysis of the parasympathetic
fibers of the thirdnerve) and, with the interruption of the sympathetic fibers,
in miosis, enophthalmos, lid retraction (Bernard-Horner syndrome).
Paralysis of the ocular motor nerves is termed ophthalmoplegia.
Extrinsic (ocular motor muscles), intrinsic (sphincter muscle of the pupil and
ciliary muscle), and complete paralyses are described.
If the cranial nerves in the peduncle (third and fourth) and pons
(sixth) are taken as reference points, eye muscle palsies can be divided into:
supranuclear (involving the supranuclear structures of the brainstem),
nuclear, intranuclear, and internuclear.
Supranuclear paralysis
Supranuclear Iesions that cause dysfunctions of the ocular nerves
may have frontal or occipital location. Paralyses of the conjugate horizontal,
vertical, and reflex movements are described. Paralysis of conjugate
horizontal gaze is known in medical practice as Foville's syndromes. This
syndrome results from a frontal lobe lesion (area 8). It consists, of an
ipsilateral facial paralysis owing to the involvement of the root fibers, an
ipsilateral paralysis of lateral gaze because of involvement of the center for
lateral gaze or medial longitudinal fasciculus, and a contralateral
corticospinal hemiplegia.
These supranuclear palsies are bilateral, symmetrical, and diplopia is
absent. There is a contralateral deviation of the eyes, and sometimes of the
head as well, paresis of conjugate gaze, and lateral rotation of the head
contralateral tothe lesion, with ipsilateral deviation resulting from
involvement of the aberrant oculogyric and cephalogyric pyramidal fibers.
Paralysis of conjugate upward gaze is also known as Parinaud's
syndrome. The lesion is located in the periaqueductal gray matter of the
midbrain, posterior commissure, and Darkschewitscb nuclei. Paralysis of
conjugate upward gaze may be total or partial. The lesion may extend to the
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paramedian pontine reticular formation. In some cases, the unilateral upward
gaze palsy is the result of partial oculomotor nerve palsy.
Reflex movement paralysis is caused by lesion of the occipital
oculogyric pathways, the reflex movements in response to visual, vestibular,
or acoustic stimuli being lost. Thus, pursuit and fixation movements become
impossible. Balint's syndrome ("psychic" paralysis of optic fixation, optic
ataxia, and alterations in visual attention) is said to be caused by bilateral
parieto-occipital lesions.
Neoplasms, vascular lesions (ischemic or hemorrhagic),
inflammations, trauma, and degenerative changes of the cerebrum may all
affect the ocular nerves.
Nuclear paralysis
In this type of paralysis the lesions are at the level of the peduncle tor
nerves III and IV, and at pontine level for the abducens nerve. The nuclear
paralysis of the sixth nerve may be either partial, as its nucleus is made up of
five joined fragments with vertical extension, or complete, by the total
involvement of the nuclei of nerves III, IV and VI.
A complete nuclear palsy of the oculomotor nerve results in ptosis,
inability to rotate the eyes upward, downward, or inward, to which dilated
pupil not reacting to tight is added.
Partial palsy consists in the limitation or inability of upward, downward, or
inward movements.
In complete paralysis, although the eyes are in strabismus, the patient does
nor complain of double vision, because eyelid ptosis prevents image
perception.
In partial palsies red-white glasses test is very useful. Diplopia may
occur when the examiner rises the eyelid, a divergent strabismus and
possibly mydriasis by the involvement of the parasympathetic fibers
originating in the Edinger-Westphal nuclei being also detected.
Nuclear paralysis of the oculomotor nerve are met in Weber's syndrome and
Benedict and Claude's syndrome (see the brainstem).
In trochlear nerve paralysis, when the patient is looking straight
ahead the axis of the diseased eye is higher than that of the other eye. When
the patient is looking downward and inward, the eye rotates. Diplopia occurs
with every direction of the gaze except upward. As in the paralysis of the
oculomotor nerve, head tilting to the shoulder on the unaffected side ablates
the diplopia. Nuclear paralysis of the trochlear nerve is rare and is often
caused by trauma, usually by a fall on forehead or vertex.
Nuclear paralysis of the abducens nerve results in paralysis of
abduction, convergent strabismus, and horizontal diplopia. The etiology
maybe vascular, tumoral, or, more rarely, inflammatory. The most common
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such syndrome is Millard-Gubler syndrome. It is characterized by ipsi lateral
lateral rectus paralysis, probably because of nuclear involvement, with
ipsilateral facial paralysis, probably due to involvement of the root fibers,
and contralateral hemiplegia from involvement of the corticospinal fibers.
Infranuclear paralysis
Infranuclear involvement may result from extranevraxial lesions,
aneurysms, diseases of the base of the skull, orbital trauma, tumors, diabetes,
sarcoidosis, panarteritis nodosa. Paralysis of every nerve causes specific
symptoms, and beside impaired eye movements, nerves in the vicinity, such
as the trigeminal and optic nerves, may also be involved.
Progressive infranuclear paralysis of the ocular motor nerves is
caused by tumors of orbital apex, sphenoidal fissure, cavernous sinus.
Acute infranuclear palsies have ruptured aneurysm of inner carotid
artery or traumatic orbital hematoma among their causes.
Internuclear paralysis
Symptoms consists in the complete paralysis of eyeball, adduction
with preserved convergence, associated with monocular nystagmus in the
other eye which is in abduction. The coexistence of these anomalies makes
the diagnosis of internuclear paralysis. There are unilateral and bilateral
forms. The lesion is situated in the posterior portion of median longitudinal
bundle between the nucleus of the oculomotor nerve and the abducens nerve.
Unilateral internuclear ophtalmoplegia suggest a vascular cause, particularly
in an elderly person. Bilateral ophtalmoplegia is usually the result of multiple
sclerosis.
Cranial Nerve III (common oculomotor nerve)

Anatomo-functional data:
Edinger-Westphall Nucleus: responsible for parasympathetic
function of nerves III.
Innervated Muscles:
Extrinsic eyeball muscle structure, 5 muscles:
1. levator palpebrae superioris
2. superior rectus
3. inferior rectus
4. medial rectus
5. inferior oblique (small)
Intrinsic muscle structure (parasympathetic innervation from
Edinger-Westphall nucleus):
1. ciliary muscle
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2. iris sphincter (circular fibers of the iris muscle)
Semiology of lesions:
I) Palpebral Ptosis: dropping of the superior eyelid and the ocular
globe is totally or partially covered.
II) Divergent Strabismus: due to the motor deficit of the medial
rectus muscle, the ocular globe is deviated to external angle of the
palpebral slit, under the influence of the lateral rectus muscle,
should this be unsteady.
III) Diplopia: caused only if ptosis is incomplete. It is due to
strabismus, which causes ocular axes to not be parallel anymore;
objects will be projected on asymmetric retinal points, thus
cortical images are no longer overlapping. Therefore, two images
appear, one real, obtained by the normal eye, and one false,
transmitted by the retina of the affected eye, this appears lateral to
the real image, on the opposite side of the injured eye.
IV) Paralytic Mydriasis: the accentuated and permanent dilation of
the pupil due to injury of parasympathetic fibers with consecutive
paralysis of pupillary sphincter and action of the sympathetic,
which is unsteady and determines the activation of iris radial
fibers photomotor reflex is paralysed.
V) Paralysis of lifting and dropping movements of the ocular
globe: at the invitation to follow upward and downward
movements of the examiners finger, the injured part of the eye
remains stationary in the external angle of the palpebral slit.
Unilateral Lesions can be:
partial->motor deficit is of interest to only a part of the innervated
muscles, within a paresis degree
total->motor deficit is of interest to both, intrinsic muscle structure as
well as extrinsic muscle structure; appears rarely isolated; usually it
appears together with lesions of other cranial nerves:
- sphenoid slit syndrome->injury to nerves III,IV,VI and the
ophthalmic branch of nerve V
- orbital apex syndrome->injury to nerves II,III,IV,V,VI
- cavernous sinus syndrome->different clinical aspects depending
on the location of the pathologic process within the cavernous
sinus.
- Garcin syndrome->lesions to all cranial nerves from half of the
cranium base
- in intranevraxial affections injury to nerve III is associated
usually with lesion of other cerebral structures, constituting
clinical entities of alternate type with high locating value
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- Weber syndrome->homolateral paralysis to nerve III +
contralateral hemiparesis
- Benedikt syndrome ->homolateral paralysis to nerve III +
extrapyramidal hemisyndrome
- Claude syndrome
Bilateral Lesions appear usually in peduncular affections
1. Acute Hemorrhagic Polioencephalitis Gayet-Wernicke:
- infectious processes with germs or neurotropic viruses, that
determine the appearance of hemorrhagic focal points in
oculomotor nuclei
- privileged role have chronic ethylism, stages of dis-
assimilation and vitamins deficit (especially of thiamine)
- is extremely severe
2. Chronic progressive ophtalmoplegia: insidious, progressive onset
of a symmetric bilateral ophthalmoplegia, that ultimately leads to
total paralysis of the ocular globes.
Cranial Nerve IV (trochlear or pathetic nerve)

Somatic motor nerves.
Is the only cranial nerve that emerges on the dorsal part of the
brainstem and presents an integral decussate of the radiating
fibers.
Innerves: the superior oblique muscle (great) - moves the ocular
globe in a downward and outward movement.
Diplopia: especially with looking downward and outward, on the
injured nerve side (e.g. when climbing down stairs).
The false image is formed underneath the real image. Lesion to nerve
IV can be singular (mononeuritis->diabetes) or in the context of injuring
nerve III.
The position of the ocular globe is not altered, if the other oculomotor
nerves are intact. Exploration of ocular globes motility provides very little
information to lesions exclusive to IV (even none), movements ordered
through trochlear nerve (pathetic) being very well compensated by
movements ordered through III (inferior rectus muscle) and VI (lateral rectus
muscle). Therefore, the diagnosis of lesion is more an issue of ruling-out,
after eliminating the possibility of injuring nerves III and VI. The diplopia
examination is relevant when performed at an ophthalmology office.
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Cranial Nerve VI (external oculomotor or abducens
nerve)
Somatic motor nerves.
Innervates: lateral rectus muscle > mobilizing the ocular globe
towards the external angle of the palpebral slit.
I) Convergent strabismus->the globe is deviated to the internal angle
of the palpebral slit, under the influence of an unsteady medial rectus
muscle
II) Diplopia: homonym (the false image appears on the same side as the
injured eye, medial to the real image). There can be present a
particular attitude: tilting the head in the direction in which an ocular
globe movement is not possible. The lesion can be uni- or bilateral,
associated or not with lesions to other cranial nerves.
- lesions can be on the following courses:
1. extracerebral ->more frequent with simultaneous injuring of
nerves III and IV
Gradenigo syndrome->paralysis of nerves VI, neuralgia of
nerve V (osteitic affections of the petrous apex.)
paratrigeminal Raeder syndrome->neuralgia of nerve V,
paralysis of nerve VI, Claude Bernard-Horner syndrome -
appears in vascular and tumoral processes from Gasser
ganglion slits area on the antero-superior aspect of the
petrous apex.
2. intracerebral (intrapontine)
Millard-Gubler syndrome->homolateral paralysis of nerves
VI and VII of peripheral type; heterolateral
hemiparesis/hemiplegia
Little disease
isolated nuclear ophthalmoplegia->rare
Conjugate movements of the ocular globe

Paralysis of vertical conjugate movements:
A) Parinaud syndrome: in lesions to peduncular tegmentum and to the
diencephalic-mesencephalic ones, including impossibility of performing
these movements; is often accompanied by the paralysis of conjugate
movements of convergence
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B) Kestenbaum periaqueductal syndrome: appears in lesions to the grey
matter surrounding the Sylvius aqueduct.
- paralysis of verticality
- retractor and convergent disjunctive nystagmus
- partial paresis to nerve III
Paralysis of lateral movements:

Lesions of the centers or paths that are responsible for performing
these movements provoke the impossibility to direct both eyes
simultaneously either to the right or left. The lesion is found on the opposite
side to the one that the diseased can not look to. When the eyes deviation is
accompanied by the head deviation, towards same side, we speak about
conjugate head - eye deviation or oculocephalogyric deviation, characteristic
to Foville syndromes:
1. of peduncular type->lesion situated above the pontine
decussation
-the diseased is looking at the lesion->hemiplegia on the opposite
side to the lesion
2. of protuberantial type->lesion situated underneath the pontine
decussation
- the diseased is looking at the hemiplegia
superior->lesion above nerve VII nucleus and paralysis VII of
central type
inferior->lesion at the nucleus level in nerve VII and
peripheral paralysis VII on the same side as the lesion
Oculogyric crises (can be oculocephalogyric): consists in tonic and

involuntary orientations of the ocular globes (perhaps of the head as well),
upwards (particularly) or lateral. The diseased is incapable to influence this
position over a period of minimum 20-30 minutes. Crises are painful and
unbearable. Signifies extrapyramidal discharges on the supranuclear
oculogyric centers (subcorticals), with prognosis of severity.
Rhythmic ocular myoclonus: are continuous myoclonus, with
frequency of 60-90/minute, that appear in lesions to the olivarydentorubric
triangle. Appear frequently within myoclonic velo-palato-faringo-laringo-
oculo-diaphragmatic syndrome.
Intrinsic pupillary motility

Definitions:
- Mydriasis: pupillary diameter over 4-5 mm.
- Miosis: pupillary diameter under 2 mm.
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- Anisocoria: pupillary diameters are unequal; always has
an explanation (must not be neglected) in case it appears
suddenly!
Examination of the pupillary motility

I) Photomotor reflex: the suffering person is placed facing the light,
eyes are covered; after 10-15 seconds each eye is uncovered one by
one, observing the miosis.
II) Accommodation reflex (convergence): the diseased, placed facing
the light, follows the examiners finger that is approaching and
distancing from the base of the nose.
III) Consensual reflex: one eye is being covered and the others pupil is
observed, which will suffer of miosis when uncovering the covered
eye, mydriasis when covering it, respectively.
Pathology of the pupil

I) Claude Bernard-Horner Syndrome: appears in lesions to
sympathetic-pupillary dilation pathways especially at cervical
level
- anisocoria through homolateral miosis
- enophthalmy
- partial palpebral ptosis
II) Pourfour-du Petit Syndrome: is an excitation syndrome of
the cervical sympathetic
- unilateral mydriasis
- exophthalmy
- enlargement of the palpebral slit
III) Argyll-Robertson Syndrome:
- anisocoris
- irregularity of the pupillary contour
- abolishing the photomotor reflex, but preserving
the accommodation-convergence one
- characteristic to tabes, but also appears
posttraumatic, in multiple sclerosis etc.
IV) Adie syndrome:
- pupillary tonia (slow pupillary reactions to light
and convergence)
- abolishing deep tendon reflexes
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Trigeminal neuralgia and paralysis
The trigeminal nerve has a sensory and a motor component. The first
sensory neuron arises in the gasserian ganglion, directing to the pons where
it synapses, via the ascending fibers, with the mesencephalic nucleus
(subserving touch), and via the descending fibers with the inferior nucleus of
trigeminus (subserving pain and temperature). Sensory proprioceptive fibers
arises from unipolar cells within the mesencephalic nucleus, and the
peripheral processes pass to nerve spindles in the muscles of mastication.
The gasserian (semilunar) ganglion is the equivalent of a spinal ganglion,
receiving via the ophthalmic, maxillary and mandibular nerves sensory
information from the craniofacial territory.
Via the ophthalmic nerve, the sensory fibers supply sensation from
the forehead, eyes, nose, temples, meninges, paranasal sinuses, and nasal
mucosa. The nerve penetrates the orbit trough the sphenoidal fissure.
Via the maxillary nerves, the sensory fibers supply sensation from the
maxillary sinuses, upper teeth, cheeks, upper lip, hard palate, and nasal
mucosa. It penetrates intracranially through the foramen rotundum.
Via the mandibular nerve the sensory fibers supply sensation from
the lower jaw, lower lip and teeth, buccal mucosa, tongue, meninges,
external ear, and part of auditory meatus. Intracranially it penetrates, together
with a motor root, through the foramen ovale.
The motor root arises from the masticatory nucleus of trigeminus in
the pons. The motor root supplies the masseter, temporal, internal and
external pterygoid, tensor tympani, tensor veli palatini, mylohyoid, and
anterior belly of digastric muscles.
The syndromes involving the trigeminal nerve are sensory of
essential and secondary type. Syndromes with motor dysfunctions may also
appear. The acquired disorders may be due to syringobulbia, malignant,
benign or metastatic tumors of the brain and base of the skull, skull fracture,
aneurysm of the carotid artery, syphilis, tuberculosis, cavernous sinus
thrombosis.
Clinical examination
I) Sensitive function: superficial sensibility (tactile, thermic,
painful) on tegumentary regions and innerved mucous.
II) Motor function:
- inspecting the masticatory region
- observing the lifting, lowering, forward projecting and
retracting the mandible can decelerate an eventual
diminishing of muscle force in the mandible lifter (the patient
is gripping a spatula between the teeth at pre-molar level, and
the examiner tries to remove it)
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- sometimes spasms are underlined, especially on mandibles
lifter trismus, which can signify extrapyramidal discharges
or masticatory nuclei irritation in infectious context (bruxism
consists of trismus episodes during sleep, which can be the
expression of an epileptic context)
Reflexes:
1. Corneal, conjunctival: trigeminofacial, mucous
2. Maseterin: trigeminotrigeminal, myotatic.
Essential trigeminal neuralgia (Trousseau disease)

Refers to trigeminal algia that meet 6 criteria, so that they are:
1. Paroxysmal
2. Challenging
3. Unilateral
4. Strictly localised on nerve V territory
5. Without organic suffering signals at the level of nervous
structure
6. Fragmented by free periods there are no intercritical
residual pains.
Ethiopathogenesis:
Appears in the second half of the day, most frequent after the
age of 50.
Onset under 20 years is exceptionally.
Female:Man ratio = 3:2.
The familial character is not proven.
Hypothetical etiologic factors, whose action seems to have
place intra- and extranervous:
- degenerative
- vascular and hormonal changes
- arachnoid cysts at the level of trigeminal roots or of
Gasser ganglion (vacuoles, cellular shadows in Gasser
ganglion)
Pathogenetic mechanisms:
- intra-neuraxial
- extra-neuraxial
Clinical picture:
1. Paroxystic, fulgurant pain with a duration up to 2-3 minutes, in
crises, of extremely high intensity (described as knife strokes,
electric pulse, burn with red iron), sometimes unbearable,
surfacing at intervals of irregular periods. The number of crises
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varies between 1-2 a day and ten crises a day; crises can occur
anytime, day or night. The violence of the pain determines a
facial rictus (palpebral spasm or ipsilateral labial of pain-
>painful facial tic).
2. Challenging pains: triggered by a minimum stimulus, that the
patient can notice or not. The triggering stimuli can be tactile,
vibrating, of distortion (mastication and speech movements). The
areas in which these stimuli need to action in order to provoke
pain are called trigger zones and can be unique or multiple in the
same patient (facial skin, labial mucous, oral, gingival, teeth;
zones that can be stimulated by tongue movements, cough, sneeze
etc.). The presence of the trigger zones imprints the patient a
characteristic attitude and behaviour: he becomes obsessed by the
crises reappearance and avoids any known triggering stimulus
(avoids alimentation, oral hygiene, speech, does not come out for
air, takes preventive anti-analgesic drugs->toxicomany->suicide);
the intensity of pain is comparable with the one in myocardial
infarction or renal colic
3. Pains are unilateral; never overpass the facial medial line. Tend
to predominate in the right trigeminal area.
4. Strict localisation at the level of trigeminal innerved territory, in
one or multiple branches area. Most frequent is affected branch II
(superior maxillary), then III (mandible) and ultimately branch I
(ophthalmic), rare.
5. Objective modifications are missing at the level of trigeminal,
with the exception of the cases in which surgical interventions
were done for pains. However, vegetative manifestations appear
in innerved territory, only in crisis: weeping, salivation, skin
congestion, nasal congestion, hypersudation.
6. Symptoms are lacking between the painful episodes.
Evolution
Evolution is discontinuous, painful periods alternate with those of
calm. The painful periods have a profound impact on the psyche state, until
self-mutilation or suicide.
Positive diagnosis
Positive diagnosis is more a ruling-out diagnosis, after is being
rejected the possibility of a secondary symptomatic trigeminal neuralgia
through complementary examinations (EEG, dental examination, CT, NMR,
CRL examination, ORL examination). It is based on described characteristic
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symptomatology and lack of any objective organic modifications of nervous
structures associated with nerved V pathology.
Differential diagnosis
Differential diagnosis with all the other affections that go along with
trigeminal suffering of neuralgic type (secondary trigeminal neuralgia).
Treatment
Treatment takes into account the evolution stage, previous treatments,
precise topography of pain and triggering zone (zones), patients physical
and psychological stage. Is:
A. Medication: is made of primary intention in any essential trigeminal
neuralgia. The classes of drugs used:
1. Antiepileptic:
- carbamazepine 600-800 mg / day
- clonazepam->0.5-2 mg
Efficiency is good, with progressive diminishing of algic
episodes, even periods of calm-> progressive over time of dosage or
even their removal for varying periods.
2. Central Myorelaxants: Baclofen, Lioresal 60 mg/day
3. Phenothiazine neuroleptic: Chlorpromazine 60 mg/day,
Levomepromazine 25-100 mg/day
4. Common Analgesic.
5. Antidepressants.
6. Neurotonic->vit.B
B. Surgical: only in the case of medication therapy failure. May consist of:
1. Chemical blocking of peripheral trigeminal branches with alcohol,
procaine
2. Alcoholisation, electrocoagulation, thermocoagulation or Gasser
ganglion gangliosis.
3. Partial sectioning of trigeminal roots-> retrogasserian
rhizotomy/juxtapontine
4. Trigeminal tractotomy->bulbar, pontine, mesenchemical
5. Gasserian and retrogasserian decompression.
-complications-> painful anaesthesia, de-innervation hyperesthesia
C. Physiotherapeutic: ionizations with aconitine nitrate with antianalgesic
purpose, antiinflammatory
D. Rntgen therapy: antianalgesic.
E. Acupuncture.
F. Mesotherapy (trigger point injection): intradermic injection with high
delicate needles of some minimum dosage of medicamentary prepared
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drugs (e.g. chlorpromazine) at the place that triggers the symptomatology
appearance
Facial nerve palsy

Anatomy
The facial nerve is made up of motor, sensory, autonomic and
parasympathetic fibers. The motor neuron of the facial nerve lies in the
caudal portion of the pons. The motor fibers loop around the nuclei of the
abducens nerves (VI) then proceeding toward the facial canal up to the level
of the geniculate ganglion. The motor fibers of the facial nerve supply the
superficial musculature of the face and forehead, the stylohyoid muscle,
platysma and posterior digastric muscle.
The motor nucleus of the facial nerve may be subdivided into a
superior and an inferior nucleus. The nucleus receives crossed and uncrossed
libers from the ipsilateral and contralateral corticobulbar and extrapyramidal
tracts. The contralateral corticobulbar tract alone innervates the inferior
nucleus of the facial nerve. A contralateral lesion to the corticobulbar
fascicle causes a central facial palsy (supranuclear) characterized by motor
deficit of the cheek area and loss of platysma contour. The superior part of
this nucleus receives a double corticobulbar innervation. The contralateral
lesion may lead, in the worst case and inconstantly, to a facial paresis
extended toward the upper temporofacial branch. This extension may
develop a lagophthalmos (inability to close the eyelids completely) manifest
for several hours.
The sensory fibers originate from the neuron in the geniculate
ganglion and carry taste from the anterior two-thirds of the tongue, and
sensation from part of the parotid area. These fibers form the nervus
intermedins of Wriesberg. Taste sensation follows the route of the lingual
nerve, chorda tympani nerve, and nervus intermedium of Wriesberg up to the
nucleus of the tractus solitarius in the brainstem.
The supranuclear sensory fibers are connected with the cortex via the
medial lemnisci and thalamus. The parasympathetic fibers arise from the
superior salivary nucleus, being distributed to the lacrimal glands, sublingual
salivary glands, and oral and nasal glands and mucous membranes. They
follow two directions:
- the first direction: via the great superficial petrosal nerve and
sphenopalatine ganglion to the lacrimal glands and nasal mucosa.
- the second direction: via the chorda tympani nerve and submaxillary
ganglion to the sublingual salivary glands and glands of the oral
mucosa.
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After leaving the pons, the facial nerve crosses the pontocerebellar angle,
enters the internal auditory meatus, passes through the middle ear and leaves
the skull via the stylomastoid foramen. Then it enters deep into the parotid
gland where it divides into its two terminal branches: temporofacial nerves
(supplies the frontalis and orbicularis oculi muscles)
cervicofacial nerves (supplies the cutaneous muscles of the nose, cheek area,
orbicularis oris, mentalis, and platysma muscles).
Clinical picture
Clinical evaluation (modifications characteristic to paralysis of peripheral
type):
I) Motor functions:
A) Static examination:
- lagophthalmy (enlarged palpebral slit)
- tears do not drip through the nasolacrimal duct (Horner
muscle paralysis), but gather in the internal corner of the eye
from where they drip on the cheek, realising the epiphoric
aspect.
- the eye seems moved upwards (Negro sign)
- hemifrontal creases are erased
- nasogenian groove is erased
- oral commissure is lowered
- absent blinking on the same side
B) Dynamic examination:
- The eyelid from the same side does not close and is noticed
the sign of Charles-Bell (physiological synkinesis of pointing
the ocular globe upwards and outwards at the moment when
eyelids are closing)
- when wrinkling the forehead there are no folds on the injured
side
- when moving to show teeth the mouth deviates on the healthy
side
- the diseased can not blow straight ahead, can not whistle
- consonants B, P, M can not be correctly pronounced
- when masticating food drops on the injured side
- if the eye can be closed and patient is invited to do so, the
eyes genes on the side with deficit are hiding less among the
tight closed eyelids folds, seem longer (Souques sign)
- the diseased can not close the injured eye in an isolated
manner (Revillod sign), even if he manages to close it,
partially at least, along with the healthy one
C) Reflexes:
130
- nasopalpebral: moving the base of the nose normally
determines bilateral blinking; in the case of VII lesions, this
reaction does not produce on the injured eye side
- opticopalpebral: sudden projection towards the eye of a bright
stimulant causes bilateral blinking, reaction being absent in
the injured side
- cohleopalpebral: the same reaction, with same pathologic
alterations, with regards to applying a sound stimulant
- corneal reflex: abolished
II) Sensitive functions:

Taste alterations in 2/3 anterior parts of the tongue, determined by
applying on the hemioral mucous of tampons impregnated with substances
having all tastes: sweet, salty, sour.
Hypogeusia, ageusia: diminishing intensity or loss of taste sensation.
Dysgeusia: confusing tastes.
Clinical entities:
Facial paralysis of peripheral type:

The motor deficit is of interest to the muscles of entire hemiface
(affecting the temporo-facial branch as well as the cervico-facial
branch)
Etiology:
- unknown, most of the times.
- if it can be specified, the paralysis is most of the times a frigore
(Bells palsy): is possibly due to a viral infection, that initiates an
inflammatory process at the nerve level, which determines an
increase in its volume, thus compressing itself in the petrous
channel. The consequence is a periaxial segmentary neuritis, with
walerian degeneration, should no measures are taken.
- there are also cases with clear causes (more rare), in a traumatic,
tumoral, infectious context (proven, precised infections).
Clinic: above described alterations appear (from a motor, sensitive-
sensory and vegetative points of view) on the entire hemiface on the
same side as the lesion.
Investigations:
- electric examination: reveals the neuromuscular hyperexcitability
and total or partial degeneration of nerves or muscles
- electromyographic examination (detection and stimulo-
detection): important for the prognosis
Particular forms:
131
Foville inferior protuberantia syndrome
-homolateral->peripheral VII paralysis, lateral paralysis of sight
-heterolateral->hemiplegia
Millard-Gubler Syndrome->vascular lesions of facial nucleus
-homolateral->peripheral VII paralysis
-heterolateral->hemiparesis
Mebus Syndrome: simple or double facial paralysis, associated with
oculomotor paralysis. It is a congenital entity.
Facial diplegia (double facial paralysis): appears in encephalitis,
polyradiculoneuritis, basal meningitis, infiltrative processes at the
cranium base
Melkerson-Rosenthal syndrome: relapsed peripheral facial paralysis,
facial edema, plicated tongue with faded margin. Etiology is
imprecise.
Evolution (available especially for a frigore one):
- highly available, from case to case
- healing takes place within 6-8 weeks, in average
- there are often relapsed
Complications (available especially for a frigore one):
1. Postparalytic facial hemispasm: contraction of the paralysed
hemiface, context in which appear involuntary movements with
paroxystic character or synkinesis.
2. Corneal ulcerations: due to lagophthalmos, through the lack of
protection from the eyelid.
3. Crocodile tears syndrome: homolateral hyperlacrimation
triggered by the alimentation act. It appears that it is due to an
aberrant regeneration of certain salivary fibers that reach to
sphenopalatine ganglion and lacrimal gland.
Treatment:
- etiological, if possible
- for the a frigore one:
1. antiinflammatory treatment with the most powerful
prepared drugs tolerated by the patient (corticosteroids-
>prednisone 1 mg/kg/day if there are no contraindications:
HTA, DZ, ulcer; if such contraindications are present AINS
will be administered)
2. neurotonics: milgamma, vitamins of B group
3. physiotherapy: it should be mandatory; has antiinflammatory
and nervous stimulation purpose-> ultrashort rays,
ionizations, delta currents
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Facial paralysis of central type:
Lesions are of interest to the descendant motor pathways, between
crust and facial nuclei.
Manifestations appear only within the territory of the cervicofacial
branch (inferior hemiface),being practically unapparent superior
quadrant of the hemiface (territory of motor innervation of the
temporo-facial branch that has a double homo- and heterolateral
innervation)
Usually it is accompanied by a hemiparesis or contralateral
hemiplegia of vascular, tumoral, traumatic, inflammatory origin, due
to reports of the corticonuclear pathways with the corticospinal tract.
Usually it is unilateral; it is bilateral in the case of injuring both
hemispheres (pseudobulbar syndrome), that appear over time.
Causes: traumatic, tumoral, inflammatory, vascular.
Primitive facial hemispasm:

It is a rare entity, characterised by tonic and clonic seizures of the
muscles innerved by the facial nerve.
Onset is usually made with blepharospasm.
Spasm is favoured by automatic voluntary movements of the face.
Should a cause not be identified, it is called essential spasm.
Sometimes definite causes are being reported, when we talk about a
secondary spasm: brainstem tumors, vascular malformations,
compressions in the cerebellopontine angle, osseous chiari
malformations, aneurisms, mega-dolicho-basilar brainstem
Treatment->decompressions or partial alcoholisation of the nerve
-carbamazepine
Cerebellum
Movements coordination assumes the entrance in action of all
nervous systems levels. Practically, more frequently met coordination
disorders (ataxias) are due to: lesions of cerebellum and cerebellar pathways
(cerebellar ataxia) and lesions to profound sensibility pathways
(pseudotabetic ataxia)
Notions of anatomy
Cerebellum is found in the posterior fossa, covered by tentorium (tent of
the cerebellum), that separates it from the inferior face of the occipital lobes.
133
It is situated in a posterior position towards the brainstem, being separated
by this through the IV ventricle. Anatomically it is formed by vermis (medial
portion) and two lateral portions (cerebral hemispheres). From an anatomo-
functional point of view the cerebellum is divided into 3 delimited segments
by 2 creases: the antero-superior one or primary and posterior fissure, found
on the inferior face; the 3 segments are:
- anterior- paleocerebellum lobe,
- posterior- neocerebellum lobe and
- flocculo-nodular-arhicerebellum lobe.
Within the cerebellum structure are found white substance and grey
substance. The grey substance forms the cerebellum crust with the 3 layers:
molecular, big Purkinje cells and internal granular, and 4 pairs of nuclei
situated symmetric in white substance: indented nuclei or olivary cerebral,
roof or fastigial nuclei, globose and embolifrom nuclei. The white substance
is formed by cerebral connections: afferent, efferent and intercerebellar
connections:
1. archicerebellum (vestibular cerebellum, flocculo-nodular lobe), the
oldest part of the cerebellum, receives afferents from the vestibular
nuclei, from the lateral geniculate bodies and from the
quadrigeminal superior colliculus (visual pathway). Sends efferents
through fastigial nucleus back to the vestibular nuclei and to the
reticular substance, which is connected to the peripheral motor
neurons through reticulo-spinal tract. Coordinates the body
equilibrium and head and ocular globes movements to modify
position, relating with these afferents;
2. paleocerebellum (spinal cerebellum here are projected the direct
and crossed spinocerebellar tracts, from the peripheral
proprioceptors level sensible to the position of articulations and
muscule tone, while the efferants are made through globose and
emboliform nuclei at red nucleus (and then through the rubrospinal
fasciculus) and at the reticulate formation (reticulo-spinal
fasciculus); has a role in controlling the muscle tone and in the
synergy of the muscle activity in orthostatism and walking.
3. neocerebellum (cerebral cerebellum) has connections with the
cerebral crust through afferent cortico-ponto-cerebellar and
efferent fibers through (via indented nucleus) cerebello-rubro-
thalamo-cortical pathways. Intervenes in coordinating movements
of the limbs, first of all of fine and precised movements of the
superior limbs (hands and fingers) and of the speech motor
apparatus.
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The cerebellum connections are contained within the 3 cerebellar
peduncles: the superior ones unite the cerebellum with metencephalon, the
middle ones with the pons and the inferior ones with the rachidian bulb.
Semiology of the cerebellar syndrome
Cerebellar ataxia is characterized through dysmetria with

hypermetria, asynergy, adiadochokinesia, cerebellar tremor and disorders of
the muscle tone.
Hypermetria consists of increased amplitude of movement, due to
lack of timely contraction of antagonists. These are underlined through the
index-nose test for the superior limbs and heel-knee for the inferior limbs.
The diseased can not touch with the tip of the index the tip of the nose,
crossing the target and reaching with the tip of the index the cheek on the
opposite side, and at the inferior limbs the movement takes the heel above
the knee, on the thigh.
At the bottle test the diseased can not put the index into the neck of
the bottle due to hypermetria.
The tonic-dynamic asymmetry test consists in asking the diseased to
lift at the same time the superior limbs extended forward, stopping them
suddenly when they reached horizontal plane. The superior limb on the
cerebellar syndrome side will lift higher, passing over the horizontal plane,
due to delayed entering in action of the antagonistic.
Asynergy the diseased being in the dorsal decubitus position is
asked to raise in breech with crossed arms. He raises the inferior limbs
instead of using them to help by bending them on the beds plane. In
unilateral cerebellar lesions the inferior limb on the injured side is tossed
upwards and the healthy one leans on the heel against the bed.
In Holmes and Stewart test, the diseased bends the forearm
powerfully, movement to which the examiner opposes to by keeping the
diseaseds fist; the examiner suddenly releases the fist, the diseased can not
restrain the movement in time (through the delayed entrance in action of the
triceps) and his fist hits the shoulder or thorax.
The cerebellar tremor alters movements continuity. Movement is no
longer slow, continuous and becomes discontinuous, sequential. The index-
nose test points out the cerebellar tremor. At the beginning of the movement
the tremor is slightly visible. As the index gets closer to the nose the tremor
increases in amplitude. The tremor is well noticed also when the diseased
takes the glass full of water to the mouth. This tremor affects writing, speech,
walking, etc.
Muscle tone disorders are translated through muscle hypotonia
underlined by increased amplitude of passive movements and through the
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presence of pendular rotulian reflexes (after the extension caused by rotulian
tendon percussion, the calf does not return immediately in rest position, but
describes a few oscillations).
All these coordination disorders are found in the orthostatic
equilibrium (it is done through the enlarged support base), in the diseaseds
walking (walking is insecure, waddling, stagger), in speech (cerebellar
dysarthria is characterized through slow, broken speech, with pauses
between syllables, sometimes explosive) and in his writing (which is shaken,
with unequal letters and of great amplitude, often with ink stains).
Cerebellar syndromes:
1) rostral vermis syndrome, paleocerebellar syndrome: it manifests

itself through stationary and walking disorders explained through
incoordination of trunk and inferior limbs. Walking is waddled with an
enlarged support base, with tendencies to fall backwards (forwards in
exceptionally cases).
Causes: alcoholism, vascular lesions, congenital malformations (Dandy-
Walker).
Dandy-Walker malformation consists of enlarged posterior recess,
hypogenesis or agenesis of the cerebellar vermis, cystic dilatation of IV
ventricle, hydrocephalus, agenesis of corpus callosum, occipital
encephalocele, facial, ocular, cardiovascular anomalies.
2) caudal vermis syndrome (arhicerebellar syndrome): is
characterized through disorders with equilibrium, walking with enlarged
support base, oscillations in antero-posterior sense and nystagmus.
Causes: medulloblastoma.
3) hemispheric cerebellar syndrome (neocerebellar syndrome):
predominate disorders in coordinating with precision the cerebellar
ipsilateral lesions of the superior limbs. There are dissymmetry, asynergy,
adiadochokinesia, hypotonia and intentional tremor.
Causes: infarct, neoplasm, abscess
Etiology
Cerebellum tumors
Medulloblastoma predominates in children, that develops into
vermis, appears at the ages 5-10, with cephalalgia, vomiting, papillary stasis,
ataxia. Seizures called cerebellar fits appear along with increase in
intracranial pressure and consists in sudden hyperesthesia of the head and
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limbs, deviation of the ocular globes upwards, stertor and bradycardia. The
crises mark the involvement of the cerebellar amygdala and appear in the late
stages of the disease. The tumor is radiosensitive.
Cerebellar and retina hemangioblastomas (Von Hippel Lindau
disease) is a vascular tumor, it manifests itself through dizziness, ataxia, ICH
(intracranial hypertension), and associates sometimes with a retina angiomas,
hepatic and pancreatic cysts. Sometimes it is associated with a renal
carcinoma. Heredity is dominant. Children whose parents have cerebellar
hemangioblastomas must be examined periodically to notice ocular and renal
lesions.
The paraneoplastic cerebellar carcinomatosis degeneration appears in
pulmonary, ovarian, uterine, bowel cancers, Hodgkin disease, etc. The
evolution of the cerebellar syndrome is progressively slow (weeks, months).
Sometimes it precedes the clinical diagnosis of the primary tumor. CT and
MRI examinations are strictly necessary. Treatment is surgical.
Cerebellar atrophies can be primitive and secondary (infections, toxics,
traumas, vascular causes).
Primitive cerebellar atrophies:
- Congenital cerebellar atrophies manifest themselves clinically within
the first months after the birth.
- The most common heredo-familial cerebellar atrophies are: olivary
cerebellar atrophy of Holmes type: clinical signs appear in IVth
decade and consists in a progressively slow cerebellar syndrome,
myoclonic cerebellar syssynergia Ramsay Hunt: convulsive crises,
cerebellar syndrome, facial and superior limb level myoclonies and
progressive intellectual deterioration, olivo-ponto-cerebellar atrophy
of Menzel type is hereditary and besides the cerebellar syndrome
associate lesions of spinal cord, mesencephalon and basal nuclei;
onset is at 20-30 years and evolves over a period of 15-20 years,
spinocerebellar atrophies characterized through cerebellum and
pathways and cerebellar connections degeneration, with dominant
autosomal transmission or seldom recessive autosomal and to which
other symptoms can be associated such as peripheral neuropathies,
extrapyramidal or long fibers syndromes, cognitive disorders and
even convulsions.
Cerebellum intoxications can appear in the treatment with phenobarbital,
phenytoin, diazepam, etc. Mercury, lead and thallium can induce cerebellar
ataxia. Chronic alcoholism can lead to a cerebellar degeneration.
Cerebellar infections (cerebellitis) appear in rubeola, scarlet fever, flu,
pneumonia, typhoid fever, etc.
Cerebellar abscess can be the starting point from ears, mastoid, sinus
infections.
137
Tuberculoma appears more frequently in children.
The cerebellar syndrome in multiple sclerosis is frequent.
Cerebellar stroke can be of hemorrhagic or ischemic type. Cerebellar
hemorrhage has a noisy clinical picture that consists of cephalalgia, nausea,
vomiting, meningeal sign, marked ataxia to which is being added certain
sufferings of the brainstem such as: myosis, oculomotor disorders, different
variants of periodic breathing and coma. Cerebellar hematoma has a reduced
frequency, but can determine phenomena of immediate intracranial
hypertension, in two times or progressively slow producing the involvement
of the cerebellar amygdala in the occipital hole. Pure cerebellar ischemia is
rarely encountered in clinic environment having a higher frequency in the
territory of antero-superior cerebellar artery.
Traumatic brain injuries, depending on ampleness, determine cerebellar
syndromes that subsequently become sechelar.
Friedreich's disease
It is the most common type of spinocerebellar degeneration, with a
prevalence of 0.4 to 4.7 / 100,000 inhabitants. The mode of transmission is
autosomal recessive gene located on the long arm of chromosome 9 and
encoding a mitochondrial protein (frataxin) involved in the respiratory chain
(triplet repeat in the first intron of the gene), but sporadic forms are quite
common. biochemical disorder - is questionable (is accused an abnormality
of pyruvate kinase enzyme complex that induces a disorder of incorporation
of linoleic acid in the cell membrane). Another hypothesis is that frataxin is a
mitochondrial matrix whose function is the prevention of mitochondrial iron
overload.
Lesions are prevalent in spinal cord and consist of simultaneous
alteration of axons and myelin sheath, concomitant with an important
process of gliosis. There are affected the large cells of posterior root
ganglion, large myelinated fibers of peripheral nerves, cords posterior
spinocerebellar tracts, cortico-spinal pathways and cerebellum (cortex and
dentate nucleus).
The clinical picture is dominated by ataxia. The disease begins
around the age of 12 years by progressive gait disturbance and evolve slowly
. Difficulties in maintaining posture and running are the first symptoms
subsequently affecting the upper limbs (intentional tremor), then the trunk,
rarely the head. Cerebellar syndrome is dominant, vertical stance remains
broad-based with support oscillations, walking is wide-based "drunken
sailor". Gestures are poorly coordinated, sudden clinical examination
highlighting dysmetria, asinergia, adiadococinezia and intentional tremor.
Finally appears the cerebellar dysarthria type. Exceptionally ataxia begins
138
abruptly after a febrile illness. Proprioceptive disorders translate into
worsening instability while closing their eyes (Romberg sign).
There are skeletal deformities (hollow leg and kyphoscoliosis), but
they are relatively independent of neurological disorders. Characteristic
deformation is described as retraction metatarsophalangeal tendon and
flexion of interphalangeal tendon leading to ascension of plantar arch.
Cardiac disorders, particularly detectable by ECG, appear early; in
late stages more than half of patients suffer from hypertrophic obstructive
cardiomyopathy. Many patients can die because of arrhythmias or congestive
heart failure. Cardiomyopathy develops slowly, insidiously, patients
requiring assessment and ecocardiography, EKG. Kyphoscoliosis causing
restrictive respiratory dysfunction is another additional factor of mortality.
About 10% of patients associates diabetes mellitus or impaired
glucose tolerance.
Dementia is not part of the clinical picture, but in some cases there is
a low intelligence, emotional lability. Speech is slow and in the final stages
incompressible. Muscles of the face and arms may sometimes present
choreiform movements. In the final stages may occur disorders of
swallowing, amyotrophy, language incompressible and paraparesis or even
paraplegia.
In about a third of cases occur optic atrophy and oculomotor
disorders (pulse fixation, fixation suppression reduced vestibuloocular
reflex) and 10% of patients have sensory deafness.
Clinical examination:
Sometimes nystagmus is present: the most commonly horizontal, the
vertical and rotator are rare. Babinski sign is present, but the tone is normal.
Profound sensitivity is affected (mioartrokinetic sense, perception of
vibration, and, to some extent, the pressure sensitivity). Tendon reflexes are
diminished or absent; pupillary reflexes are normal. Usually sphincter
control and abdominal reflexes are spared.
The evolution is progressive, more or less disabling. Relatively
frequent coexistence of diabetes mellitus does not worsens prognosis,
however, cardiac disorders may influence the vital prognosis. Death occurs
by intercurrent infections or as a result of heart failure, exceptionally by a
brutal autonomic crisis.
There have been described some morbid associations:
- Amyotrophy forms similar to those of hereditary neuropathy Charcot
Marie-Tooth;
- Forms associated with optic atrophy (Behr's disease);
- Forms associated with retinal degeneration;
- Forms associated with cataracts.
139
Laboratory investigations:
- EMG appearance in this disorder is chronic denervation.
- VCM are normal, and VCS are normal or slightly low.
- Histological aspects of muscle biopsy on optical microscopy are
common type denervative amyotrophy with chronic evolution and
certain regenerative resources.
- Nerve biopsy takes aspects of axonal degeneration preferentialy of
large myelinated sensitive fibers and in late stages of the disease of
small myelinated fibers.
- Somatosensory evoked potentials: delayed peripheral and (rarely)
central driving.
- Transcranial magnetic stimulation: central motor driving time
extended.
- MRI: the cervical spinal atrophy.
- EKG and ecocardiography can show ventricular hypertrophy.
Pathology
Lesions are interesting a certain groups of neurons and their axons
showing characteristics of hereditary systemic degeneration - neurons dying
retrograde from the axon to the cell body and in the periphery the
degenerative process involve simultaneously the myelin sheath and the
cilindrax with a nevroglial fibrillar secondary proliferation.
Degeneration affects:
- Spinal ganglia neurons and their fibers ascending in the posterior
spinal cords (Goll tract is affected first and worst).
- Clarke column cells and spinocerebellar fibers, cerebellar cortex and
dentate nucleus.
- Pyramidal tract.
- Nuclei of cranial nerves VIII, X and XII.
- Lesions less important can be found in ventral horns of the spinal and
other brainstem neuronal groups.
Positive diagnosis: clinical picture of ataxia and genetic testing
Differential diagnosis should be done with:
- Ataxia caused by deficiency of vitamin E;
- Hereditary sensorimotor neuropathy type I and III;
- Exogenous intoxication (alcohol, phenytoin, heavy metals, lithium);
- Paraneoplastic syndrome;
- Cerebellar encephalitis;
- Demyelinating diseases.
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- Cerebellar cortical atrophy, spastic paraparesis, Lewy-Roussy
syndrome, peroneal muscular atrophy.
- Tropical spastic paraparesis (spinocerebellar degeneration)
Treatment
- Neuroprotective - antioxidants (N acetylcysteine, selenium) and
vitamin E;
- Symptomatic - physiotherapy;
- Amantadine - to combat ataxia, but without confirmed success;
- Verapamil - treat abnormal heart rhythms and obstructive
cardiomyopathy.
- Surgical treatment for kyphoscoliosis and foot deformities
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Chapter VIII.
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Movement Disorders
Aurora Constantinescu
General data
Parkinsons disease
Wilsons disease
Huntington chorea
Movement disorders
Movement is produced and coordinated by several interacting brain
centers,such as motor cortex,cerebellum,basal ganglia.
Voluntary motor commands begin in the motor cortex,generating
electrical signals which pass along upper motor neurons through the
midbrain to the spinal cord,connecting to lower motor neurons which convey
the signals out of the spinal cord to the surface of the muscles involved
,generating contraction. Voluntary contraction of one muscle is automatically
accompanied by blocking the antagonistic muscle.The cerebellum deals with
the exact timing and coordination of different body parts. Motor cotex and
cerebellum send information to basal ganglia which send output messages to
the motor cotex,helping to initiate movements.Circuits within basal ganglia
are complex.There are complicated feedback circuits and their disruption
cause distinct movement disorders.In the last decades,it has become
generally accepted that basal ganglia arrange a wide array of functions
ranging from pure sensoriomotor to cognitive-executive and emotional-
motivational behaviours.
The variety of symptoms caused by an inadequate response selection
of motor,cognitive,and affective responses to internal and external stimuli
represent movement disorders.
Movement disorders in the presence of clear consciousness include:
1. hypokinetic motor behavioural disorders with scarcity of
movements: Parkinsons disease, multiple system atrophy,
progressive supranuclear palsy, corticobasal degeneration.
2. hyperkinetic motor behavioural disorders with excess of
movements: dystonia, tremor, myoclonus, chorea, ballism, tics,
akathisia, athetosis
3. dyskinetic motor behavioural disorders with abnormal executed
movements: ataxia
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Diagnosis of movement disorders requires a careful medical history and
a thorough physical and neurological examination,with the exclusion of other
conditions that may cause the disorder.
Genetic testing is available for some forms of movement
disorders.Routine blood and urine analyses are required.Imaging techniques
as CT-scan,MRI,PET and lumbar puncture are necessary.In some
cases,nerve conduction studies with EMG of the affected muscles may be
performed to evaluate the nerve and muscle function. EEG may be
performed to detect seizures,to analize general brain function and to measure
brain activity associated with movement disorders. Video recording of the
abnormal movement is often used to analyse movement patterns
Parkinsons Disease
Parkinsons disease (PD) is a progressive alpha-synucleinopathic
neurodegenerative disease affecting peripheral and central nervous system,
characterized by motor and non-motor symptoms and pathologically defined
by presence of Lewy bodies and loss of dopamine in parts of the brain.The
agreed definition of PD describes rest tremor (pill rolling) , bradykinesia
(slownwss of movement),hypokinesia (reduced movement) ,rigidity of the
limbs,impairment of the postural reflexes , asymmetric onset , absence of
other neurological or cognitive deficits in the beginning and a good
response to dopamine therapy.
The average age on onset in PD is established at about 60 years ,but PD
cases are reported at all ages, with an incidence 13.4 in 100,000 with a
significant higher rate for man.Younger patients are often found to suffer
genetic parkinsonism.
According to H.Braak,the degenerative pathology in PD patients starts
in the peripheral autonomic nervous system,dorsal motor vagal nucleus and
olfactory bulb(representing stage 1 and 2),then reaches the substantia nigra
and the brainstem sensory relay centers (stage 3 and 4). Finally,the
degeneration spread to the neocortex in stage 5-6.
Stadialization
The stages of PD are:
- presymptomatic phase of more than 5 years duration,during which
nigral neurons are being lost at least 50%,but the number of
remaining neurons is sufficient to prevent the onset of symptoms;
- pretreatment phase when the patient begin to notice symptoms, but
without significant impact on quality of life,and so,do not require
treatment;
- early treatment phase-using monotherapy which is sufficient to restore
lost function,with minimal side effects;
144
- complex treatment phase,when the patient requires multiple drugs to
restore function;the response to therapy is not constant and side-
effects and complication of therapy are common;
- palliative phase with loss of mobility and other bodily function,with
psychosis and dementia and complications of advanced disease
causing death.
The duration of each phase is highly variable from one person to the
other.in the condition of a good therapy.
In 1960, Margaret Hoehn and Melvin Yahr published a detailed
description of the progression of PD ,modified in 1967,very used nowadays
too:
Stage 0-no signs of disease
Stage 1- unilateral disease
Stage 1.5-unilateral plus axial involvement
Stage 2-bilateral disease,without any impairment of balance
Stage 2.5-mild bilateral disease,with recovery of balance at pull test
Stage 3-mild to moderate bilateral disease with abnormal pull
test;physically independent
Stage 4- severe disability;still able to walk or stand unassisted
Stage 5- wheelchair bound or bedridden unless aided
Etiology
Causes of PD are unknown.A number of theories try to explain the
condition of a levo-dopa responsive parkinsonian syndrome,but none of them
has been sustained.The various hypotheses include a genetic abnormality,a
viral infection,a result of some environmental toxin,or a combination of
environmental and genetic factors which might lead to selective death of the
dopamine-containing nerve cells.There are a few rare families in which PD is
inherited because of a clear genetic defect.Abnormalities at seven possible
sites across the genome have been linked with inherited forms of the
disease.Families with these inherited forms of PD often have slightly
atypical disease features in younger age than normal and with unusual
response to therapy.
Clinical aspects
PD may be diagnosed when first signs of motor parkinsonism are present
and levo-dopa test is found to be positive, reducing these symptoms. The
most common presenting complaints of PD patients are:
- resting tremor, mostly unilateral at the hand
- change in the handwriting,with micrographia
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- decrease in dexterity of the affected hand when using a knife,in doing
up buttons and so on..
- general slowing up
- loss of facial expression
- a frozen shoulder
Parkinsonism (the parkinsonian syndrome) means the striatal
dopaminergic denervation-induced dysfunction of the basal ganglia.
The parkinsonian syndrome may be degenerative (primary)in the
following conditions:
- Parkinsons disease (PD)
- dementia with Lewy Bodies (DLB)
- multiple system atrophy (MSA)
- progressive supranuclear palsy (PSP)
- cortico-basal degeneration (CBD)
- Alzheimers disease (AD)
- fronto-temporal dementia with parkinsonism (FTDP)
- Huntingtons disease (HD)
- spino-cerebellar atrophies (SCA)
- neuroacancythosis
The secondary(symptomatic) parkinsonian syndrome may be found in
the following conditions:
- iatrogenic: lithium, alpha-metildopa, phenothiazine, rezerpine,
sodium-valproate, tetrabenazine
- toxic: CO, manganese, methyl-phenyl-tetrahydropyridine,
organophosphorates
- infectious: encephalitis, HIV, prion infection
- metabolic: Wilsons disease, hypoparathyroidism
- normal-pressure hydrocephalus
- cerebrovascular infarction
- CNS tumors and/or trauma
Importance of a correct PD diagnosis in the first instance.It is
possible for a suspected PD patient to present one or two of the classical
features of PD and only a correct history and examination may reveal other
characteristic symptoms.Differential diagnosis for the tremor is sometime
difficult for essential and cerebellar tremor,hyperthyroidism,drug
exposure,alcohol abuse.Regarding bradykinesia,it is important to be
demonstrated in the hand and foot and to see if other causes of increased
muscle tone are eliminated.Postural instability generating falls when
turning,hesitation on starting are clinical criteria for diagnostic. Very
important is to test the symptomatic response to L-dopa or apomorphine
which increase the likelihood of a correct diagnosis of PD.
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Nonmotor symptoms in PD
Recently recognized as important features for PD are the non-motor
symptoms which may generate negative effects on the quality of life and may
lead to frequent hospitalizations, though they are not part of the diagnostic
criteria for PD.
1.Neuropsychiatric symptoms
- depression, delirium,hallucinations and psychosis
- cognitive dysfunction and dementia
- obsessional behaviour
Depression-with a prevalence of 25-40% may be present in any stage
of PD,even in premotor phase.The symptoms of depression
are:fatigue,apathy,poor motivation,sleep disturbance,anorexia or
hyperphagia,suicidal ideation.Depression is mediated by
noradrenergic,serotonergic and dopaminergic neuronal loss;depressed PD-
patients have lower CSF 5-hydroxy-indoacetic acid levels than non-
depressed PD-patients.
Delirium is an acute or subacute change of consciousness or
cognition associated with illusions and/or hallucinations.
Hallucinations are more common at night and are exclusively
visual.They may occur at any time in the course of the disease.When
hallucinations appear in the early stages of the disease ,the diagnostic mast
be reevaluated,thinking mostly to LBD.
Psychosis(serotonin may pay a role) with hallucinations and/or
illusions and/or delusions make the patient an agrssive and agitated one.
In all these situations any recent changes of medications,including the
addition of new agents should be investigated,together with electrolyte
imbalance and infections.
Cognitive dysfunction with slowing of attention span and
fluency,impaired color discrimination,impaired executive functions leading
to apathy are commonly associated with depression and may be present
because of the disruption of thalamic projections to the dorso-lateral,anterior
cingulate and orbitofrontal areas.
Dementia occurs in the late stages of PD,including as risk factors
advanced age,severe motor disability and depression.When it occurs early in
the evolution of the disease, the reevaluation of the diagnosis of PD must be
done.Standardized dementia rating scales (Mattis Dementia Rating Scale)
are useful tools for assessing cognitive abilities including executive function
and attention.Dementia is associated with pathological changes of brain
regions involved in memory and cognitive processes.
Obsessional disorders with persistent ideas,thoughts,impulses that
cause anxiety or distress may be present. Compulsions are described as
147
repetitive behaviuors or mental acts;this disorder can include excessive
amounts of time spent performing rituals,disrupted family and social
relationship,impaired work or academic performance with a decrease in
quality of life.
2.Gastrointestinal dysfunction
Dysphagia and a variety of swallowing abnormalities(poor lingual
control of swallowing,esophageal dilatation,gastro-esophageal
reflux,achalasia) are present because of alterated cholinergic mechanisms.
Sialorrhea(excessive saliva in the mouth) is the consequence of
inefficient and infrequent swallowing.
Gastroparesis(delayed gastric empting) may occur in PD ,producing
early satiety,abnormal discomfort with bloating,nausea,vomiting,weight
loss,malnutrition.The delayed gastric emptyng may contribute to the
fluctuations in levo-dopa plasmatic levels,generating the clinical motor
fluctuations in advanced stages of the disease.
The disorder of gastrointestinal autonomic function generates
prolonged orocecal transit time,constipation being the most frequent
symptom complained of by PD patients.
Weight loss is a frequent feature of PD.The patients have impairment
of olfaction with consequent reduction in sense of taste,together with
dysphagia that may lead to reduced caloric intake and weigt loss.
3.Autonomic dysfunction in PD
Autonomic dysfunction in PD has multiple components:sympathetic
noradrenergic and cholinergic,parasympathetic cholinergic,enteric and
adrenomedullary components.
The non-motor symptoms related to autonomic dysfunction may be:
- gastro-intestinal as we mentioned above
- bladder dysfunction.PD patients complain of urgency , frequency and
nocturia which may be severe.Benign prostatic hyperplasia may be a
common coexistent disorder in men,contributing to bladder
dysfunction.
- cardiac sympathetic denervation leading to orthostatic
hypotension,post prandial hypotension,orthostatic tachycardia,that
may generate frequent cardiologic consultations.
- sexual dysfunction with loss of libido,erectile dysfunction,vaginal
dryness.Sometimes,related to dopaminergic agonists,PD patients may
experience hypersexuality.
- thermoregulatory disturbances with hyperhidrosis and seborrhea
- pupilomotor abnormalities
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4. Sleep disorders
Sleep disorders with sudden and irresistible sleep attacks are reported
in PD patients in relation with ropinirol and pramipexole.Difficulties in
initiating sleep and fragmented sleep are most frequent symptoms observed
.In advanced stages, excessive daytime
sleepness,insomnia,nightmares,restless leg syndrome,parasomnias,nocturnal
akinesia painful cramps may aggravate sleep disorders.Parasomnias occur
during sleep including vivid dreams,nightmares,night terrors,nocturnal
vocalizations, REM-sleep behavior disorder (RBD),sleep-talking,nocturnal
hallucinosis ,somnambulism ,panic attacks.
5.Sensorial symptoms
Pain and paresthesia in limbs may be unpleasant
complaints,contributing to sleep disorders.
Diagnostic
In conclusion, a correct diagnosis of PD is made according UK
Brain Bank Criteria:
Step 1:Diagnosis of parkinsonian syndrome:bradykinesia and at least one

of the following
- muscular rigidity
- 4-6 Hz resting tremor
- postural instability without other cause
Step 2:Exclusion criteria for PD:
- hystory of repeted strokes,head injury and encephalitis
- cerebral tumor and hydrocephalus on CT scan
- exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- oculogyric crises
- cerebellar signs
- Babinsky sign
- persisting strictly unilateral parkinsonism
- early severe autonomic involvement
- early dementia or psychotic signs,requiring treatment
- negative response to large doses of levodopa
Step 3.Supportive prospective positive criteria for PD(almost three
required for a definite diagnosis of PD):
- unilateral onset
- rest tremor
- progressive disorder
- good response to levo-dopa for 5 years or more.
- clinical course of 10 years or more
149
- levo-dopa induced dyskinesias
Imaging in Parkinsons Disease

Functional and structural imaging are not used for PD diagnosis,but
they are important in differential diagnosis.(22,23)PET scan uses fluoro-dopa
which is taken up by the remaning dopamine cells within the brain.In PD,
striatal uptake of fluoro-dopa dopaminergic markers tends to decrease
assimetrically ,in the posterior putamen.SPECT technology using a
radioligand-[123-I]-FP-CIT is also taken up in the striatum of normal brains
These scans are commercially reffered to as DaTSCANs.The resolution
produced by these scans is not as high as that seen in PET scan,but the
equipment is more widely available in nuclear medicine department,being
used in individuals where clinical diagnosis is in doubt.PET and SPECT
scans do require patients to be free from dopaminergic therapies,but
cessation of treatment may be associated with increased morbidity.
Transcranial sonography might be useful as a trait marker .
Limitations are associated with each of these technical
approaches,none of them being specific for PD.
There are no biochemical markers available in PD
diagnosis.Sometimes,the disorder clinically diagnosed as PD is post mortem
without Lewy-body pathology.
Principles of treatment in Parkinsons Disease

Once the diagnosis has been made,the treatment has to be
started.There are guidelines for the management of PD treatment,but they
should be used as an aid rather than being followed obsessively.
The treatment has to be appreciated by the specialist and then
continued for a period of time under GP supervision.Any change in therapy
belongs to the specialist.
The choise of the antiparkinsonian drug depends on 1) the age of the
patient in the moment of the diagnosis and 2) the clinical aspect of PD in the
moment of the diagnosis(which may be not in the first stage of the disease at
that moment)
For the management in Parkinsons disease the available therapy
consists of: 1.pharmacological therapy, 2.surgery, 3.rehabilitation.
1.The main mechanisms of action of pharmacological agents available
are:
- dopaminergic
o promote dopamine synthesis:Levo-dopa(gold standard of
treatment)
150
o activate specific receptors:Dopaminergic agonists(DAgs)These
may be
non-ergot (pramipexole, ropinirole, rotigotine, apomorphine,
piribedil), and
ergot(bromocriptine,cabergoline,pergolide,lisuride)
o prolong dopamine availability: MAO-B inhibitors
(selegiline,rasagiline)
o prolong levodopa bioavailability: COMT Inhibitors
(entacapone,tolcapone)
- antiglutamatergic (the mechanism of action is not fully known,the
antiglutamatergic action being only part of the drugs effect):
Amantadine
- anticholinergic : Trihexyphenidyl.
2.Surgical treatment .In the last years,the lesional

surgery(thalamotomy,pallidotomy and subthalamic nucleotomy) was
replaced byDBS regarding pallidum and subthalamic nucleus.
3.Rehabilitation therapy consists in physical therapy,occupational
therapy and speech therapy.
Choice of therapy depending on age and clinical picture
I - Early clinical onset, patient without functional impairment we start

with MAO-B inhibitors.
II - Patient recently diagnosed with PD, with recent clinical onset and
functionally impaired
a) Patient under 65 years old and socio-professional situation does not
require a rapid motor improvement,we may start with dopaminergic
agonists. Over time,if the clinical response becomes unsatisfactory,we
may increase the agonist dose,or add another agonist (rotigotine
patch).If the dopaminergic agonist was a standard one,it may be
replaced with a prolonged released. When clinical response becomes
unsatisfactory,we add levo-dopa, and the doses may be escalated until a
good response.In the situation of unsatisfactory clinical response,we add
COMT-inhibitors (STALEVO).
b) Patient under 65 years old and socio-professional situation requiring a
rapid motor improvement; Patient over 65 years old, recently
diagnosed with PD,with recent clinical onset and functionally impaired;
PD recently diagnosed,in the advanced stage
In all these last 3 situations we start with levo-dopa,replaced in time
with levo-dopa triple association(STALVEO).If the clinical response
becomes unsatisfactory,dopaminergic agonist may be added(standard or
151
prolonged release),to which it may be added in time
Rotigotine(dopaminergic agonist that support association at another
dopaminergic agonist)
III - Advanced stage of PD which has been treated as I and II,

The clinical response is unsatisfactory and motor and non-motor
fluctuations appear,we may adjust levo-dopa dosage or add
STALEVO.Another therapeutical strategy is to increase the agonist dose,or
to associate Rotigotine patch.When dyskinesia is more invalidant than
motor fluctuations, Amantadina may be a solution,or adjustment the doses
of dopaminergic agonists/levo-dopa,or the use of apomorphine.
IV - Advanced stage of PD,trated as above,with unsatisfactory response

,with persistent motor fluctuations and/or dyskinesia,we have two
alternatives:enteral pump and DBS
The dopaminergic agonist is a drug that directly binds and activates

dopamine receptors,,mimicking the effects of dopamine.They were
introduced in clinical practice in 1970.Dopamine receptors are divided into 5
types;D1 and D5 stimulate the adenylate cyclase pathway,whereas D2,D3
and D4 inhibit it.
D1 and D2 receptors are concentrated in the striatum and substantia
nigra,and have a largely postsynaptic localization.D3 receptors are located in
mesolimbic structures(nucleus accumbens).The major motor effects of
dopaminergic agonists arise from D2 stimulation.D1 stimulation works
together with D2 stimulation to mediate motor activity.
As a general rule,we start with low dose of dopaminergic
agonist,increasing towards the maximum dose required by clinical
status,over weeks.
Levo-dopa is the precursor of dopamine which is released by the
nigral neurons in the striatum.Levo-dopa therapy requires a number of intact
presynaptic dopaminergic neurons in order to be metabolized to
dopamine;then the dopamine is released from these surviving nerve
terminals to compensate for the dopamine deficiency in PD.Levo-dopa is
initially started in low doses,then gradually increased until side-effects or
benefits are reported by the patient.Higher levo-dopa doses are associated
with an increased risk of motor complications,but may be justified if required
to provide a satisfactory clinical response.Levo-dopa is metabolized by the
enzyme dopa decarboxylase in the periphery,and that is why they are
manufactured together with an inhibitor of dopa decarboxylase as carbidopa
(in Sinemet,Isikom,Nakom) or benserazide (in Madopar).It is not allowed to
reccomand levo-dopa at less than 2 hours intervals.There are different types
152
of Madopar or Sinemet in order to allow flexibility in the treatment and also
CR preparations which release levo-dopa slowly (8-12 hours) and normal
preparations which have a short period to release.The majority of patients
have a therapy with a dopaminergic agonist and a levo-dopa drug,both being
titrated to improve and maximize the patients response.
Over time,increasing amounts of levo-dopa are required in order to
minimize the progression of functional disability.The duration of levo-dopa
response becomes increasingly shorter and the patients experience these 3
major complications of levo-dopa long-term therapy:motor and non-
motor fluctuations, dyskinesias and neuropsychiatric
complications(formation of toxic free radicals).
Motor and non-motor fluctuations and dyskinesias are present up to
80% of PD patients after 5-10 years of treatment with levo-dopa.
Pharmacological management of advanced pd patients with motor

complications
Motor fluctuations
End-of dose deterioration(wearing-off phenomenon)
- levo-dopa doses may be increased(if dyskinesia is not invalidant)
- the frequency of administration of levo-dopa may be increased when
dyskinesia is invalidant(with lower individual doses)
- dopaminergic agonist or COMT-inhibitors may be tried if not added
until then
- we may try IMAO-B
- S.c.injections of apomorphine
- continuous dopaminergic infusion with apomorphine or lisuride
- attention to the dietary protein
Delayed-on and no-on response
- levo-dopa may be taken on an empty stomach or reducing the protein
concentration
- COMT inhibitors if not added
- continuous intraintestinal infusion of levo-dopa (duodopa-pump)
Unpredictable OFF episodes
- similar to wearinf-off episodes(they are more difficult to treat)
- Duodopa or DBS
Freezing
- when appers during OFF state ,we may increase the dose of
dopaminergic medication
- when appears in connection with the peak levo-dopa effect,we try to
underdose the medication,or to change combination
- anxiolitics ,if necessary
153
- try to use sensory cues or devices
Dyskinesia
peak-dose dyskinesia
- small reduction in levo-dopa doses(avoid CR forms of levo-
dopa)
- dopaminergic agonists if not added,together with levo-dopa
reduction
- Amantadine,but it has transient effects
- Duodopa or DBS
diphasic dyskinesia
- -more frequent or higher doses of levo-dopa
- -avoid CR-forms of levo-dopa and COMT inhibitors
- -s.c.apomorphine
- -Duodopa or DBS
Dystonia
Peak-dose dystonia
o similar to peak-dose dyskinesia
o dopaminergic agonists if not added
o surgical treatment
Continuous dopaminergic stimulation

Apomorphine is an dopaminergic agonist acting by direct
stimulation of striatal postsynaptic dopamine D1 and D2 receptors.Used in
s.c injection,it is rapidly absorbed ,but has a short half-life (about 40 min).Its
effects appear in 5-15 minutes.This characteristic allow its use as a
pharmacological test for the positive diagnosis of PD and in the treatment of
OFF stages when oral therapy is of no use(or impossible to administrate).
The continuous subcutaneous apomorphine infusion is an effective option
for patients with advanced form of disease. Dyskinesia improvement is not
satisfactory under this method,its reduction being obtained after weeks or
months of use as a result of a wider therapeutic window.Patients who use
long-term apomorphine (for a 16 h/day,24 months)may develop impulse
control disorders. The use of apomorphine can be limited by poor
compliance and local skin reactions at the site of injection.
Continuous levodopa delivery by intestinal infusion.

Levodopa/carbidopa intestinal gel (LCIG) is recommended for
patients with advanced stages of PD with severe on-off fluctuations and
dyskinesias unresponsive after optimized oral treatment.LCIG provides a
stable plasma levo-dopa levels ,leading to less severe and fewer periods of
154
dyskinesia,impoves ontime and avoid fluctuations,and may improve non-
motor symptoms.Adverse events can occur related to the device or surgical
procedure:dislocation,occlusion and a kink/knot in the tube,secretion from
the stoma,infection and recent raports describe a polyneuropathic
syndrome(an imbalance in vitamin 12/homocysteine)Regarding the
polyneuropathic syndrome,there are suggested two mechanisms:axonal
degeneration and inflammatory damage.
Deep brain stimulation

The ideal indication for DBS is idiopathic PD,genetic parkinsonism
reaching in the advanced stage,after a gold period of good response to levo-
dopa,but with motor fluctuations and dyskinesias,uncontrollable with oral
medication.A condition for the patient is the absence of cognitive decline,
psychiatric complications,and any major comorbidity.The targets for DBS
are STN (subthalamic nucleus) and GPi (globus pallidus internal segment).
The main method of targeting is MRI and/or CT.Image guided STN DBS
without microelectrode recording leads to important improvement in motor
disability.Intraoperative MRI facilities will enable improved guidance and
successful implantation under general anaesthesia.There is an important
decrease of dyskinesias after bilateral STN DBS.After surgery,stimulation
settings are progressively increased.
As adverse effects of this method,less than 2% consists of
perioperative intracranial haemorrhage and ischemia; 2% electrode
misplacement or migration,3% skin erosions and device malfunction,2%
infection.Post operative motor dysfunction consists of persistence of
dysarthria and gait difficulties;sometimes ,reduced verbal fluency is noted.
Physical therapy in Parkinsons disease

It is an important part of therapy which 1)enhances patient
mobility,encouraging for an active lifestyle and 2) may enhance
dopaminergic pathways in PD. In early stage of PD,the aim is to teach the
patient some exercises in order to prevent motor impairment,maintaining
functional capacities. In moderate stage,the goal is to delay progression of
the disease.Different techniques may be used:gait training,attention strategies
and sensory cueing,compensatory mobility strategies.Patients family mast
cooperate. In advanced PD, the patient require assistance in almost all
activities of daily living;the presence of cognitive changes affect
independence of the patient.Physical therapy provide appropriate
compensation strategies in order to optimize functional
independence:behavioural strategies,daily exercise programme,pain
control,instruction for positioning. Familial support is wery important.
155
Hepatolenticular Degeneration (Wilson Disease)
Definition
It is an eredodegenerative metabolic disease with autosomal
recessive transmission characterized by degenerative changes in the brain,
particularly in the basal ganglia, and cirhhosis of the liver,because of the
accumulation of copper.
History
Wilson was the first to recognize this anatomoclinical entity in 1912.
He had under his care a patient who died after a long illness characterized by
muscular rigidity, tremor and forced grimacing. Cirrhosis of the liver and
gross degenerative changes in the lenticular nucleus of the brain were found
at necropsy. A similar neurologic disorder had been described previously by
Westphal (1883) and Strmpell (1898) as pseudocirrhosis. Kayser, in
1902, and Fleischer, in 1903, described a peculiar ring of pigmentation of the
cornea, which later on was recognized as copper deposition, a characteristic
feature of the disease. Rumpel had demonstrated the greatly increased copper
content in the liver and brain in 1913. Mandelbrote (1948) found that the
urinary excretion of copper was elevated in Wilson disease. In 1952,
Scheinberg and Gitlin discovered that ceruloplasmin, the serum enzyme that
binds copper, is consistently reduced in Wilson disease.
Clinical symptoms
Hepatolenticular degeneration is usually characterized by the triad of
neurologic symptoms, cirrhosis of the liver and Kayser-Fleischer ring of the
cornea. Most patients develop symptoms in adolescence or early adulthood,
although onset of symptoms has been described between 5 and 30 years of
age. Two forms of neurologic involvement are recognized in hepatolenticular
degeneration:
- the dystonic form corresponds to classic lenticular degeneration and
is characterized by spasticity, rigidity, drooling of saliva, dysartria
and dysphagia; tremor is less pronounced
- the pseudosclerosis form shows flopping tremor of the wrists and
shoulders as the major disabling symptom, whereas rigidity and
plasticity are less marked
In all instances, the first expression of the disease is a deposition of
copper in the liver. This may be asymptomatic. The hepatic manifestations of
hepatolenticular degeneration vary greatly and have been described acute
hepatitis, fulminant hepatitis and chronic active hepatitis.
156
With further progression of neurologic disease, the Kayser-Fleischer
ring becomes more evident. It takes the form of a rusty-brown decoloration
of the deepest layer of the cornea (Descemets membrane). A slit-lamp
examination may be necessary for its detection, particulary in brown-eyed
patients.
The patient becomes mute, immobile, extremely rigid, dystonic and
slowed mentally.
Biochemistry
Copper is an essential nutrient element for human beings and for
other species as well. An excess of copper is toxic. Copper exerts its toxic
action mainly as a potent inhibitor of a wide variety of enzymes. Suppression
of microsomal membrane ATP-ase activity is probably the primary effect.
Copper absorbed from gastrointestinal tract is distributed to the tissue by the
blood. The liver plays a central role in the maintenance of copper
homeostasis. The release of copper from the liver occurs through two main
routes: incorporation of copper into ceruloplasmin and release into blood,
and excretion in the bile.
Ceruloplasmin is a glycoprotein containing alpha-2-globulin,
carbohydrates and six to seven atoms. The mean serum concentration of
ceruloplasmin in adult humans is 31 mg/100 ml. In hepatolenticular
degeneration one of the most constant biochemical abnormalities is low level
of blood ceruloplasmin (below 20 mg/100 ml). The urinary excretion of
copper is significantly elevated.
Many tissues, particularly the liver, brain, kidney and cornea show a
marked increase in copper content. The liver is the first site to accumulate
copper. Excessive amounts of copper are also present in the brain with
maximum of accumulation in the basal ganglia, in glial cells rather then in
neurons. Wilsons disease is a monogenic, autosomal recessive condition.
The causative gene, ATP7B, encodes a copper transporting P-type ATPase.
More than 500 ATP7B mutations have now been identified. Most of these
are missense mutations, small deletions or insertions in the coding region, or
splice junction mutations.
Neuropathologic changes
In the rapidly advancing and fatal form, there is frank cavitation in
the lenticular nuclei. In the more chronic form there is a light-brown
discoloration of these structures. Nerve cell loss and some degree of
degeneration of myelinated fibers in lenticular nuclei, substantia nigra and
dentate nuclei are usually apparent.
157
Diagnosis
The diagnosis is virtually certain when there is an
extrapyramidal,cerebellar and cerebral-related symptoms conjoined with
liver disease and the corneal rings. The findings of :
- low ceruloplasmin level (less than 20 mg/dl)
- low serum copper level (less than 80Ng/ml)
- increased urinary copper excretion (more than 100 Ng in 24 hours)
make the diagnosis in most cases.
Early in the course of illness the most reliable diagnostic findings are
a high copper content in biopsy of liver tissue (more than 250 Ng per dried
weight) and a failure to incorporate Cu64 into ceruloplasmin.
Liver function tests are normal.
Cranial CT scans are abnormal, even in the hepatic stage and are
invariable so when the neurologic disorder intervenes. The lateral ventricles
and often the third ventricle are enlarged, the brainstem appears shrunken
and the lenticular nuclei become hypodense. With treatment these radiologic
changes become less marked.
Cerebral MRI (is an even more sensitive mean of visualizing the
structural changes, particulary those in the subcortical white matter,
midbrain, pon and cerebellum.
Treatment
Treatment is available and effective in hepatolenticular degeneration
when started before advanced cirhhosis has developed. It consists of :
- reduction of dietary copper less than 1 mg/day by avoiding food with
a high copper content (liver, nuts, mushrooms, cocoa, chocolate,
shellfish)
- administration of the copper chelating agent D-pecillamine (1-
2g/day)
- the rare patients who cannot tolerate pencillamine may be treated
with the chelating agent triethylene tetramine hydrochloride. Hepatic
transplantation may be considered in patients with very advanced
disease.(31)
Huntington Chorea
Huntington chorea is an autosomal dominant neurodegenerative
disease distinguished by the triad: coreic movements, personality changes
158
and dementia.The incidence is 0.38 per 100,000 per year,in Europe being a
prevalence of 5.70 per 100,000 inhabitants.
This disease commemorates the name of George Huntington, a
medical practitioner of Ohio. In 1872, Huntington gave a succinct account of
the disease.
Clinical Symptoms
The typical age of onset is between 30 and 40 years; however there
are many exceptions, such as early onset below 20 year of age in the
juvenile type of disease or late onset, over 60 years of age.
The memory alterations may represent the earliest manifestation of
Huntington chorea. Patients may be suspicious, irritable, impulsive, eccentric
or excessively religious. These emotional disturbances and changes in
character may reach such proportions as to constitute a virtual psychosis.
Disturbances of mood, particularly depression, are common and may
constitute the most prominent symptoms early in the disease.
The abnormality of movement is at first slight, involving the hands
and face. The patient is merely considered to be fidgety or restless and
nervous;slowly it becomes more pronounced until the entire musculature is
implicated. Voluntary movements are initiated and executed more slowly
than normal. Muscle tone is variable. The speech becomes dysarthric and
explosive.
In particular, the patients with juvenile Huntington chorea show the
rigid, akinetic variant of the disease, also known as the Westphal variant.
The epileptic seizures, usually of grand mal type, are more frequently
in this form of the disease.
The course of the disease is inexorably progressive with worsening of
choreic movements, severe mental deterioration and cachexia. During the
last years of their life, many Huntington chorea patients are completely
helpless and have to be admitted to an institution prepared for total care of
the patient.
Pathology
Huntington disease (HD) is caused by a CAG repeat expansion in the
huntingtin (HTT) gene on chromosome 4 that codes for polyglutamine in the
huntingtin protein. Some of the earliest steps in the pathogenic cascade of
HD include misfolding of huntingtin to a -sheet structure, and post-
translational alterations, such as cleavage or altered phosphorylation. The
mutant huntingtin protein has many effects in cells, including abnormalities
in cellular proteostasis mechanisms. The mutant protein can enter the
nucleus and alter gene transcription. Mutant huntingtin can also affect
cellular metabolism; in particular, mitochondrial function, which may lead to
159
the production of abnormal metabolites and markers of oxidative stress.Age
of onset and rate of progression of HD are both likely to be influenced by
environmental and genetic modifiers. Neuronal death is the hallmark of HD,
but neuronal dysfunction manifesting in clinical features probably occurs
before actual cell death. Chorea has been suggested to reflect neuronal
dysfunction, while motor impairment (bradykinesia/fine motor dysfunction)
seems to be best correlated with neuronal cell death. Mutant huntingtin is
likely to have cell-autonomous toxic effects, but there may also be elements
of cell interaction, which could be mediated in several different ways,
including excitotoxicity, spread of abnormal mutant huntingtin from cell to
cell in a prion-like fashion, and loss of trophic support from brain-derived
neurotrophic factor or other trophic molecules.
Neuropathologic changes
Gross wasting of the head of the caudate nucleus and putamen
bilaterally is the characteristic abnormality, usually accompanied by a
moderate degree of gyral atrophy in the frontal and temporal regions. The
caudatal atrophy alters the configuration of the frontal horns of the lateral
ventricles.
The light microscopic findings include degenerative in nerve cells,
particularly in the small neurons of the neostriatum. Many ultrustructural
abnormalities have been demonstrated to affect the membranes, ribosomes,
lysosomes and mithocondria.
Diagnosis
Once the disease has been observed in its fully developed form, it
requires no great clinical wit to recognize. Dominant inheritance, choreic
movements and dementia are the main features of the disease.
The CT scans show the bicaudate-cranial index increased in the
majority of patients.
PET-scan shows a characteristic decrease in glucose utilization, which
appears early in the disease and precedes the loss of tissue.
Chorea that begins in late life, with only mild or questionable
intellectual impairment and without a family history of similar disease is a
source of difficulty; referring to it as a senile chorea does not solve the
problem. Indeed, senile chorea may have more than one cause; it appears
with infections and drug therapy, only to disappear after a few weeks.
Recurrent chorea in early adult life always raises the question of a late form
of Sydenham chorea and illness in which neither family history nor mental
deterioration are seen.
160
Treatment
Chorea is a prominent and troublesome motor symptom of
Huntington's disease (HD). Frequent, large amplitude choreic movements
contribute to impairments in balance, walking, and daily activities, such as
getting up and down from a chair, and may increase fall rates. Symptomatic
treatment of chorea has the potential to improve motor function, safety, and
quality of life. Several neuroleptics and tetrabenazine have been shown to
decrease chorea but there are only limited studies of their effects on other
motor functions in HD. The administration of the neuroleptic haloperidol to
individuals affected by HD reduced chorea but showed no effects on gait.
Studies in a small number of individuals with HD on high doses of some
atypical neuroleptics (i.e., olanzapine, zotepine) have documented
improvements in chorea as well as fine motor tasks, oral functions, and gait.
Tetrabenazine is a vesicular monoamine transporter 2 (VMAT-2) inhibitor
that causes a depletion of monoamines, particularly dopamine, in the brain.
At the end of 2012 evidence-based medicine guidelines for the
pharmacological treatment of chorea in HD was published and you may find
these in figure 1.
Cognitive dysfunction in HD is characterized by slowness in
thinking, called sub-cortical dementia. Patients also lose their mental
flexibility, their capability to distinguish between which issues are more or
less important and have difficulties in planning or making mental
adjustments in their lives. Memory seems to remain unaffected for longer.
The most common psychiatric feature of HD is depression, which competes
and is often confused with apathy. Treatment of depression in HD does not
differ from standard treatment of depression and is based on the usage of
selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine
reuptake inhibitors (SNRIs) with venlafaxine, which has confirmed efficacy.
Psychosis such as irritability or obsessive compulsive behaviors could be
treated with antipsychotics (Table 1)
161
Fig. 1 Decision tree of different recommended treatments for chorea in
Huntingtons disease. Physicians may choose between antipsychotic
drugs(APD) and tetrabenazine(TBZ). If monotherapy with either APDs or
TBZ is unsatisfactory, then combination therapy should be considered.
( Reilmann R)
Table 1 Recommended first-choice antipsychotic drugs for the treatment of

Huntingtons disease and their recommended starting doses and maximal
doses
APD Respondents Starting dose, mg Maximal dose,

% mg/d
Risperidone 43 0.5-2 16
Olanzapine 39 2.5-10 20
Tiapride 29 50-200 900
Haloperidol 24 0,5-2 10
Quetiapine 12 25-200 400
162
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Chapter IX.
Cerebral Lobes. Higher

Cerebral Functions. Dementia
Emilian-Bogdan Ignat, Daniela Matei
Cerebral lobes. Higher cerebral Occipital lobe

functions - Visual field defects
General architecture of the cerebral - Visual agnosia
lobes - Positive symptoms
The frontal lobe (hallucinations and
- Motor function illusions)
- Speech and language. Motor
aphasia Dementia
- Lesions of the prefrontal areas Definition, general aspects,
Temporal lobe pathogeny, differential
- Language understanding. diagnosis, investigations,
Sensory aphasia treatment
- Memory Major types of dementia
- Control of emotions - Alzheimer disease
- Other functions - Dementia with Lewy
Parietal lobe bodies
- Sensation - Fronto-temporal
- Agnosia dementia
- Apraxia - Vascular dementia
General architecture of the cerebral lobes

The cortex is considered to be the higher most structure that
coordinates and guides us in all activities. Each part of the brain has specific
abilities, receiving information from within the body and from the
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environment, working with it and generating actions that integrate in this
larger picture.
Each cerebral hemisphere is responsible for the opposite half of the
body.
Large anatomical boundaries were used to trace divisions on the
hemispheres, and further work has only partially supported an unitary
activity of each of the large morphological entities described.
The lateral fissure (Sylvius) separates the frontal and temporal lobes
(on the basal surface and also on the dorsolateral surface) and, in its posterior
part, the parietal and temporal lobes. The central sulcus (fissure of Rolando)
separates the frontal and parietal lobes, and the parieto-occipital fissure
separates on the internal aspect of the hemisphere the parietal and occipital
lobes.
Traditionally, motor functions are related to the frontal lobe,
sensation to the parietal lobe, while the occipital lobes are dedicated to visual
information and temporal lobes to memory, affect and speech (fig.1). More
complex functions have less precise and often multi-lobe distribution, as they
depend on integration of multiple input types. Furthermore, each hemisphere
assumes specific functions in our individual evolution, with the left
("dominant" ) hemisphere being responsible for language processing and
the right ("nondominant") hemisphere for "attention", visual imagery,
emotions.
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Fig. 1. Cortical areas
The frontal lobe

The frontal lobe is the largest and the newest of all the lobes of the
brain. It lies anteriorily to the rolandic sulcus (which separates the frontal
and parietal lobes), and above the sylvian fissure (that separates the frontal
and temporal lobes).
It has important attributions in voluntary motion activity (being
connected to all the major structures involved in generation and control of
movement), but also speech and language, cognitive functions (attention,
concentration, ability for sustained mental activity, ability to shift from one
line of thought to another, initiative, spontaneity) and personality (especially
mood and self control) or emotion, as it is connected to the limbic/paralimbic
structures.
Motor function
The frontal lobe is involved in all spheres of motor activity, from
planning stages to ultimate execution. Motor functions are related to the
primary motor area (area 4) located in the most posterior part of the frontal
lobe. Electrical stimulation of this area generates contraction of the
corresponding muscle groups on the opposite part of the body, and, if precise
enough, even movement of individual muscles. Stimulation of the
supplementary motor cortex (part of area 6) generates larger, coordinated
movements. Activation of area 8 triggers head and eyes turning towards the
opposite side.
Lesions in the posterior part of the frontal lobe (area 4) cause
controlateral spastic hemiparesys.
Lesions in more anterior and medial motor parts of the frontal lobe
(area 6 and area 8 the premotor cortex) also lead to motor deficit, but less
pronounced, associated with increased spasticity and release of the sucking,
groping and grasping reflexes ("instinctive grasping", normally inhibited by
the frontal lobe). These areas are involved in planning and initiation of
sequences of movement; other clinical signs generated by dysfunction in
these territories are imitation and utilization behaviour, reduced and delayed
motor and mental activity (abulia), motor impersistence (right hemisphere
lesions) or motor perseverance (left hemisphere lesions), paratonia
(resistance to passive manipulation of the limbs). Paralysis of head/eye
turning towards the opposite side appears after lesions of the 8th area (usually
with favourable evolution).
Seizures originating from motor areas appear as involuntary
movements of the corresponding body parts either tonic or clonic
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contractions. Abnormal activity of premotor areas might generate curious
postures or gestures, and seizures that affect the frontal eyes areas lead to
forced deviation of the eyes and head.
Other motor disturbances that appear in frontal lobes dysfunction
(mainly in bilateral lesions) are ataxia of gait (also referred as gait apraxia,
frontal gait disturbance) resulting in a short stepped, slowed, imbalanced
gait, with lack of correct positioning of body parts during gait stances;
astasia-abasia and cerebral paraplegia in flexion (as more advanced stages),
pseudobulbar palsy, incontinence.
Speech and language

Speech and language are related to areas 44 and 45 on the dominant
hemisphere (Broca's area), as well as to the neighbouring parts of the insular
and motor cortex. Lesions in these areas lead to reduction or loss of motor
speech, agraphia, apraxia of the face, lips and tongue. Less severe lesions
generate abnormalities as laconic speech, lack of spontaneity, telegraphic
speech (agrammatism), loss of fluency, perseveration of speech, dysarthria.
In a recovering patient, the first to reappear are the short, habitual phrases
("hi", "yes", "no", counting or naming the days of the week).
The function of the anterior, inferior and inner parts of the frontal
lobe are less clear they seem to be responsible for quickly and efficiently
helping the individual to act appropriately (and choose among possible
different responses). It integrates both past experiences and concepts and the
current conditions and accordingly generates the best future projected
actions.
Prefrontal areas
Lesions of the prefrontal areas are accompanied by mood changes
(slight elevation of mood, increased talkativeness, tendency to joke
inappropriately (moria), lack of tact, difficulties in adaptation and reaction
adjustement, loss of initiative. Apathy and loss of initiative seem to be
connected to lesions in the sagital or medial frontal cortex, while lesions in
the orbital or dorsolateral frontal cortex are associated with a socially
inappropriate state.
Abulia or akinetic mutism (the patient lies still, motionless and silent
for days although he is alert and capable of movement and speech), lack of
ability to sustain attention and solve complex problems, rigidity of thinking,
impairment of abstract thinking, blunt affect, social ineptitude, behavioural
disinhibition, impulsiveness, perseveration, inability to anticipate, labile
mood, utilization behaviour are associated with prefrontal lesions.
Psychological tests used in frontal lobe function evaluation are
Wiscosin card sorting test, the Stroop color naming test, "trial making" test,
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the alphabet-number test, sequencing of pictures, the three step hand posture
test of Luria (the examiner performs a sequence of three gestures a.e. arm
thrusting forward, fist clenching and forming a ring with the first two fingers
that the patient is asked to imitate and then perform on his own). Less
specific for frontal lobe dysfunction are serial subtraction test, interpretation
of proverbs, test of rapid motor response.
Temporal lobe
The temporal lobe lies in the lateral part of the hemispheres, with the
sylvian fissure separating it from the frontal and (partially) from the parietal
lobe. The limits between the occipital lobe and the posterior part of the
parietal lobe have less clear anatomic boundaries.
It includes the temporal gyri (superior, middle and inferior), the
hippocampal, parahippocampal and lingual convolutions, the lateral
occipitotemporal gyrus, and the transverse gyrus of Heschl.
The most important functions of the temporal lobe are connected to
memory (the hippocampus), affection and emotions (the lymbic system),
hearing (primary auditory area (41), secondary auditory area (42) and
association areas 20, 21, 22, 38), speech (areas 41 and 42 on the dominant
hemisphere). Overall, the temporal lobe seems to integrate all sensory
modalities into ultimate self awareness, in close connection with the
instinctive and emotional life.
Lesions of the temporal lobe might cause hemianopia or upper
quadrananopia (due to damage of the optic radiations, part of the
geniculocalcarine pathway).
Bilateral lesions of the transverse gyri of Heschl cause cortical
deafness, while unilateral lesions usually cause discrete deficits, detectable
only upon careful testing. Lesions of the association areas (21, 22) of the
auditory cortex do not influence the perception of pure sounds, but impair
the interpretation and perception of complex combinations of sounds, leading
to auditory agnosias auditory sensations cannot be differentiated or
associated to specific sources. Lesions of the right hemisphere impair
recognition of melody and harmony. Amusia (impaired recognition or
production of melodies or of their characteristical features) is not necessarily
associated with word deafness.
Language understanding
The left hemisphere (dominant) is responsible for recognition of
language translation of the coded information into thought. The source of
coded information comes either from auditory or visual sources, but the final
stage of comprehension depends on the temporal lobe. Lesions of the
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supramarginal and angular gyri (areas 37, 39, 40) and of the posterior part of
the superior temporal gyrus (area 22) in the dominant hemisphere lead to
sensory (receptive or fluent) aphasia (also called Wernicke aphasia). In this
situation the patient is unable to understand what is said to him and is unable
to read (alexia), to write comprehensible language (agraphia), and is
displaying fluent paraphasic speech. Paraphasic patients produce clear,
fluent and melodic speech, but its content is unintelligible because of
frequent errors of word choice, inappropriate use of words, use of made-up
nonsense words (sometimes called "world salad"). Word deafness (auditory
verbal agnosia) can occur separately from Wernicke aphasia, as can alexia or
agraphia, in more discrete localized lesions that damage the prerequisite
steps to final understanding (a.e. occipital lobe lesions for alexia).
It is presumed that the cortical control of emotions originate from
the cingulate and hippocampal regions, and that their influence is conveyed
to the mammilary body of the hypothalamus via the fornix. The medial
mammilary nucleus projects to the anterior nucleus of the thalamus, and then
to the cingulate gyrus. This anatomic pathway is called "the Papez circuit".
Bylateral temporal lobe lesions that damage the amygdaloid complex
cause an association of behavioural changes the Kluver-Bucy syndrome.
The patient is no longer able to recognize objects by sight (visual agnosia),
and may also show tactile and auditory agnosia. He explores and examines
objects exclusively by mouth (hyperorality), and tends to compulsively
explore the immediate environment and to overreact to visual stimuli.
Placidity is characteristically seen. The subject may eat in excessive amounts
(hyperphagia) even when not hungry, and may eat objects that are not food
or are not appropriate for its species (a.e. a human may eat leaves, or a
monkey may eat meat). There is also striking augmentation in sexual
behaviour (hypersexuality). Depending on the extent of the damage in the
neighbouring areas, amnesia, dementia or aphasia appear.
Memory
Stimulation of posterior parts of the first and second temporal
convolutions can arouse complex memories, visual and auditory images,
some with strong emotional content.
An important function of the hippocampal formation seems to be
consolidation of immediate and short term memories into long term
memories. Patients with hippocampal dysfunction (a.e. in Alzheimer's
disease) are able to perform a task for seconds or minutes, but, if distracted,
they are not able to return to what they were doing. In Korsakof syndrome
(due to thiamine deficiency, usually in alcoholics) the mammillary bodies are
involved (but also the dorsomedial nucleus of the thalamus , fornix,
hippocampus). These patients show a deficit in short term memory, and
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consequently in long term memory for events happening after the onset of
the disease, they are prone to confabulation they tend to string together
fragments of memory from different separate events to form a new
"memory" that never occurred.
Other functions
Balance, and especially taste and smell have less precise anatomical
locations, although disturbances of equilibrium, olfaction and ability to
perceive taste appear in temporal lobe dysfunction. Epileptic discharges in
the temporal lobes can take the form of olfactory hallucinations, usually
accompanied by dreamy state (uncinate fits).
Auditory hallucinations may be elementary (murmurs, sirens, running
water) or complex (musical themes, voices). They appear isolated or in
association with visual, gustatory or another disorders, or in hallucinations
based on past experiences.
In temporal lobe seizures patients can experience disturbances of
time perception time may seem to stand still or to pass with great speed
and also disorders of recognition and recall phenomena like "deja vu"
(already seen), "jamais vu" (never seen), when the patient feels that the
context is familiar and known to him, or reversely, he fails to recognize
things normally known to him.
Parietal lobe
The parietal lobe lies on the outer part of the hemispheres, behind the
central sulcus (Rolando) and above the lateral fissure (Sylvius) that separate
it from the frontal and temporal lobes. Posterior limits are less clearly
marked only on the medial side of the hemisphere the boundary between
parietal and temporal lobes is set by the parieto-occipital fissure.
Sensation
The parietal lobe is the final stage of sensory integration. It houses
the primary sensory area (areas 3,2,1 in the postcentral gyrus) and the
sensory association areas (both unimodal and multimodal). It integrates all
type of sensory (and motor) information, generating a state of awareness of
ones own body and of its relations with the surrounding extrapersonal space.
The postcentral suclus separates the primary somesthetic area from
the rest of the parietal lobe. The intraparietal sulcus separates the rest of the
lobe in an superior (areas 5,6) and an inferior lobule (including the
supramarginal (area 40) and angular (area 39) gyri). The association parts of
the parietal lobe attain their full functionality late in life (around 7 years of
age), together with the neighboring areas in the occipital and temporal lobes.
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The postcentral gyrus receives most its afferent projections from the
ventroposterolateral nucleus of the thalamus. The controlateral part of the
body is represented somatotopically; spindle afferences project to area 3a,
cutaneous afferences to area 3b and 1, and joint afferences to area 2.
Sensory deficits most often take the appearance of a sensory
discrimination deficit, with impairment of the ability to localize tactile,
thermal and noxious stimuli, to distinguish objects by their shape, size or
texture (astereognosis), to recognize figures drawn on the skin, to detect the
direction of a moving stimulus. This type of sensory impairment is often
called "cortical" and the perception of pain, touch, pressure, vibratory stimuli
and thermal stimuli is relatively intact. Tactile inattention (or extinction)
represents the tendency to disregard stimuli on the affected side when the
healthy side is stimulated simultaneously (the patient perceives only the
stimuli on the healthy side). Sensory seizures may appear as paresthesiae or,
less often, as painful sensations.
Effects of parietal lobe dysfunction include disturbed sensitivity,
agnosia, apraxia, and also problems of language, motricity, vision.
Agnosia
Agnosia refers to failure to identify an entity, failure that cannot be
attributed to a defect in primary sensory modalities.
Visual and sensory information is synthesized during development
into a schema of the body (perception of the body and of the relations of
bodily parts). This ability (to recognize one's parts of the body) is called
somatognosia. Patients with parietal lesions may show asomatognosia,
meaning that they ignore their opposite half of the body (a loss of stored
body schema). Unilateral asomatognosia is more frequent on the left side
(only partially due to aphasia masking the symptoms on left hemisphere
lesions).
The disturbance extends to the perception of the surrounding space,
as the patient does not pay attention to objects or stimuli in half of the
environment (on the opposite side to the lesion). He may fail to dress, shave
or groom one side of the body (if dressing is impaired on both sides of the
body one speaks of a "dressing apraxia"), and he may bump into large
objects on that side of the visual field.
Another disorder that appears in parietal lobe lesions (much more
often in lesions of the nondominant hemisphere) is anosognosia the patient
does not acknowledge the disease on a conceptual level, he acts as if nothing
is the matter, does not recognize the paralyzed limbs as his limbs, and may
even ask the staff to remove from the bed "that other person". Anosognosia
usually associates with blunted emotionality, apathy, various degrees of
inattention, confusion, and sometimes with visual and tactile illusions,
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hallucinations of movement. Anosodiaphoria means that the patient is
emotionally indifferent to his disease.
Visual disorientation and disorders of spatial localization include
topographic agnosia (the patient is not able to draw a map of a room,
describe a familiar route), inability to orient in a virtual environment (a map).
They tend to appear in nondominant parietal lobe disorders. Prosopagnosia
(inability to recognize familiar faces) and simultanagnosia (difficulties in
relating to one another different visual stimuli) are
Lesions in the dominant parietal lobe may lead to Gerstmann
syndrome (probably the most striking instance of bilateral asomatognosia)
it associates finger agnosia (inability to designate the names of the fingers),
right-left agnosia, dyscalculia, and dysgraphia.
Apraxia
Constructional apraxia is a special type of spatial neglect, in which
the patient is unable to reproduce a geometric figure an inability to
summate a series of "spatial impressions" into understanding the spatial
relations between the parts of a whole. It is more frequent in nondominant
perietal lobe lesions. Tests used for this disorder include placing the hand of
a clock (or drawing one), reproducing a blocks or sticks construction or a
drawing.
Patients with lesions of the dominant hemisphere exhibit ideomotor
apraxia an impossibility to perform learned motor activities (on command
or by imitation) in the absence of motor or sensory deficits. The patient is no
longer able to use tools (in relation to their bodies (like in brushing teeth or
combing hair) or in relation to other aspects of the environment (key,
doorknob, hammer). the disorder appears as a disorder of action sequence.
Visual disturbances include hemianopia or quadrantanopia due to
geniculocalcarine radiations lesions, visual neglect (sometimes as part of
hemispatial neglect).
Motor disturbances can occur in parietal lobe lesions (a large
contingent of the corticospinal tract originates in the parietal lobe) from a
mild hemiparesys to poverty of movement, pseudocerebellar syndrome,
clumsiness in reaching for and grasping an object under visual guidance. The
affected limbs tend to remain hypotonic and the musculature may undergo
atrophy of a degree not explained by nonuse alone (parietal amiotrophy).
Occipital lobe
The occipital lobes are the final destination of geniculocalcarine
pathway, concentrating and making available the visual information. Their
surface is limited on the medial surface of the hemispheres by the
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parietooccipital fissure, but less clear anatomical boundaries separate it from
parietal and temporal lobes on dorsolateral and basal parts of the
hemispheres. It is important to acknowledge that association and
interpretation functions are also less well delimited in these multimodal
association areas. The calcarine scissure creates a clear landmark from the
occipital pole to the corpus calosum, and the primary visual cortex lies on its
borders (area 17). Associative areas 18 and 19 are concentrically distributed
more distally to the calcarine fissure.
Each of the occipital cortices receives information from the opposite
visual field. The macular area projects towards the occipital pole, and
sometimes receives special blood supply from the middle cerebral artery.
Separate locations can be identified in the visual areas for different visual
characteristics (form, location, movement and shape).
Visual field defects

Complete destruction of one of the occipital lobes leads to opposite
side homonymous hemianopia, while partial lesions result in different
degrees of visual loss, accompanied by positive phenomena (visual
hallucinations in the defective visual fields). The pupillary light reflexes are
preserved.
If destruction is bilateral (area 17 on both sides), cortical blindness
(loss of sight and loss of visual protective reflexes) is found. Patients
maintain visual imagination and dreams. A special situation is the Anton
syndrome, when the patient denies the visual loss and acts as if he could see.
Another visual disorder linked to occipital lobe dysfunction is the
Anton syndrome. Patients suffer from a disorder of visual attention (affecting
mainly the periphery of the visual fields) that prevents them from perceiving
"the whole" although attention for individual elements and for other sensory
modalities is maintained. A second feature of the syndrome is deficiency in
reaching or grasping objects under visual guidance, while another disorder
consists in an inability to voluntarily direct gaze to explore the peripheral
space (psychic paralysis of fixation gaze), despite the fact that voluntary
movement of the eyes is fully possible.
Visual agnosia
Visual agnosia refers to failure to properly identify (recognize) an
object (or some of its characteristics) upon visual examination. The same
object is efficiently identified by tact or other senses. Visual object
recognition depends on two stages in Lissauer's concept: the construction of
a perceptual image from vision and then mapping of this perceptual
representation onto stored engrams that identify the object's functions and
associations.
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Prosopagnosia and simultanagnosia (the patient is not able to
perceive simultaneously all the aspects of a scene and its global meaning,
and only sees isolated elements) (both discussed in parietal lobe dysfunction)
are usually signalling dysfunctions of multimodal association areas
(parietooccipital and temporooccipital). Colour agnosia takes either the form
of inability to name or point colours that are correctly perceived (probably
resulting from disconnection of visual and speech areas), or the form of
impaired perception of colours (central achromatopsia) it usually affects
the upper quadrants and is associated with other visual disturbances.
Positive symptoms
Positive symptoms linked to visual cortices in the occipital lobes are
visual illusions and hallucinations.
Illusions present as distortions of the images existing in the visual
fields, in matter of form, size, shape, color or movement. They appear both
as consequences of lesions restricted to the occipital lobes, but also of
occipitoparietal or occipitotemporal areas, more frequently if the right
hemisphere is involved. Other types of visual illusions are changes in color
(erythropsia or achromatopsia), multiple images of the same object
(polyopia), persistence of an image after the object has moved/dissapeared
from view (palinopsia), and in other instances misperceptions of spatial
relationship and of movement.
Hallucinations represent appearance of inexisting images in the visual
fields. They are either perceived by the patient as false, either he believes
they represent real items and reacts to them. Elemental hallucinations take
the appearance of flashes of light, stars, light points, lines and other
geometric forms, while formed (complex) hallucinations may represent
persons, objects, animals, or more complex settings, of normal or distorted,
unnatural appearance. Hallucination may be stationary or in movement, in
visually normal parts of the visual field or in areas with defective vision.
Dementia
Dementia is a syndrome that comprises the acquired loss/impairment
of some or all of the superior intellectual abilities, as are memory, linguistic
abilities, numerical abilities, visuoapatial perception, capacity to abstractize
and solve problems, social abilities and perception and integration of self,
musical and artistic ability.
In some situations these impairments associate with other
neurological disturbances (as in Parkinson's disease or in stroke) , but there
are diseases that have as sole (or dominant) feature dementia (as is
Alzheimer's disease).
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Pathogeny
Dementia is caused by either diffuse loss of functional brain tissue,
either by a more selective pathology that damages key areas involved in
cognitive functions. This is a consequence of either primary degenerative
disorders, or of other pathologies (in this case one might speak of a
"symptomatic dementia").
Depending on the location of the pathological process one of the
features might predominate over the others, but as the disease progresses
most situations would end with a global impairment, culminating with the
vegetative state. Most types of dementia are slow and progressive. By the
time the person shows signs of the disease, the process in the brain has been
happening for a long time.
Classification
Cortical and subcortical dementias have been described, referring to
the primary site of involvement cortical dementia include Alzheimer's
disease, frontotemporal dementias, while subcortical dementias refer to
Huntington's disease, Parkinson's disease, thalamic or other basal ganglia
pathology.
Generally (but not as an absolute rule), cortical dementias manifest
with memory impairment, language impairment, apraxia, agnosia,
mathematical and abstract thinking abnormalities, while in subcortical
dementias features as slowed thinking, depression, lack of initiative,
eventually associating movement disorders, are more prominent.
Frontal dementia is characterized by a loss of abstract thinking,
planning, judgement,, initiative, lack of control of impulses or lack of drive,
personality disorder.
An etiologic classification could distinguish between degenerative
disorders (taupathies, alpha synucleinopathies) and vascular dementia.
Memory and amnestic syndromes

The amnesic syndrome refers to a disorder of memory and learning.
Based on its characteristics, amnesia can be retrograde affecting the ability
to recall information stored (and firmly established) before the onset of the
causing disease or anterograde impairing the accumulation (learning) of
new memories. In a degenerative disorder, more recent memories will suffer
first Ribot's law long before old, firmly established retained information.
Note that accumulation of memories can also be impaired in other
types of pathology (affecting attention, volition, perception) without a true
retentive memory dysfunction.
Different structures of the brain are essential for memory function,
but central to this are parts of the medial structures of the temporal lobes (the
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hippocampus, parahippocampal gyrus, enthorinal cortex, dentate gyrus,
subiculum), and antero-rostral parts of the diencephalon (the medial portions
of the dorsomedial nuclei of the thalamus, the midline nuclei of the thalamus,
septal gray matter). Other regions of the cortex are important for specific
types of memory (modality based memory).
Procedural memory refers to the ability to unconsciously learn simple
mechanical skills (a.e. riding a bicycle) (the patient knows how to do a
certain task but does not know when or how he had acquired that), as
opposed to declarative memory (nonprocedural memory), that refers to
memories that can be consciously recalled such as facts and knowledge.
Declarative memory is memory that a patient can state in words, while
explicit memory is the deliberate recall of information that the patient
recognizes as a memory.
Differential diagnosis of dementia

Differential diagnosis of dementia should exclude treatable
conditions, and should help differentiate among types of dementias as
treatment approach varies with etio-pathogeny. Infectious diseases (HIV-
AIDS, prion diseases, viral encephalitis, syphilis), toxic conditions (heavy
metals, carbon monoxide, alcohol, medication), metabolic or endocrine
pathology (hypothyroidism, hypoglycaemia, B12 deficiency, pellagra,
hepatic encephalopathy, Wernicke encephalopathy), hydrocephalus, Wilson's
disease, paraneoplastic encephalopathies, psychiatric conditions (depression,
hysteria, schizophrenia) are some of the pathologies that may present with
marked cognitive symptoms. Isolated neuropsychological disturbances
(aphasia, apraxia or agnosia) are not considered dementia.
Mild cognitive impairment

Mild cognitive impairment refers to patients with subtle cognitive
impairment, that are still able to function correctly and manage their day-to-
day activity.. Even if most of these persons will eventually develop
dementia, there are patients who's disease will never evolve enough to
support that diagnosis. They may have some difficulties with memory,
speech or other cognitive functions (difficulties that are perceived by the
patient or his relatives), but overall they are able to cope with usual tasks.
Diagnosis of MCI is often difficult, as cognitive testing may be normal.
Often, more in-depth neuropsychological testing is necessary to make the
diagnosis. It is thought that antidemential treatment should be initiated early,
in some cases even during the MCI stade.
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Diagnostic
Diagnostic evaluation of dementia relies primarily on a thorough
neuropsychological testing, oriented by history (taken from the patient and
family) and physical examination.
Imagistic investigation (MRI is preferred) help establish the presence
of vascular or other specific pathologies (tumour, abscess, encephalitis), or
show non-specific atrophy (either generalized or focal). Functional imagery
(PET, SPECT) are useful in showing location-specific metabolic
dysfunction.
EEG can be of help.
Laboratory tests (including HIV testing, B12 vitamin, thyroid
hormones, CSF examination) are necessary for the differential diagnosis.
Treatment
There is no cure for dementia. Treatment should be targeted on the
causative factors if that is possible.
Symptomatic management aiming at cognitive dysfunction is rather
disappointing, with only modest benefit from existing anti-dementia drugs.
Cholinesterase inhibitors such as donepezil are often used and may be
beneficial in mild to moderate disease. It is important to stress out that early
intervention is crucial in achieving some efficacy, as severe dementia is most
of the times beyond therapeutic benefit. Nootropic drugs and vasodilators (as
ginkgo biloba extracts) are thought to be helpful, but supporting evidence is
scarce.
Control of the behavioural and psychiatric components that
accompany dementia is important and achievable, and it improves the quality
of life of both patients and carers.
Cognitive and behavioural interventions may be appropriate. Support
and counselling for families and patients are important in coping with long
time consequences. Planning in advance the management of care or of legal
issues can spare the family of unpleasant situations.
Exercise programs are beneficial with respect to activities of daily
living and potentially improve outcomes.
Alzheimer's disease
It is a degenerative disease, and the most common cause of dementia
incidence is 1-4% in people aged 65-70 and increases up to 40% in people
85 or older.
The causes of the disease are unknown, although genetic factors play
an important role. Familial Alzheimer's disease may be related to mutations
in the amyloid precursor protein, presenilin 1 or presenilin 2 genes and has
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an autosomal dominant inheritance. Sporadic Alzheimer's disease correlates
with the presence of Apo E4 alleles 2 and 4, age, feminine sex, but also with
a low level of education and other cases of the disease in the family.
The disease is generated by accumulation of beta amyloid amyloid
precursor protein is normally cleaved by alfa secretases, but in Alzheimer's
disease beta and gamma secretases generate insoluble aggregates neuritic
plaques . Pathological aggregation of hyperphosphorylated tau-protein,
forming tangles or paired helical filaments, is another hallmark of
Alzheimer's disease. These changes lead to neuronal suffering, inflammation,
reduction of synaptic density, abnormal neurotransmitter levels and neuronal
death.
Clinical pictures it is a slowly progressing cortical dementia, with
memory impairment as the first and most prominent feature. Patients present
with memory (especially recent memory) dysfunction, abnormal spatial
orientation, sometimes depression, and rarely with more focal cortical
dysfunction (aphasia, apraxia or acalculia). In evolution amnesia accentuates,
and other features appear visual-spatial processing dysfunction, naming.
Psychiatric features (psychosis), circadian rhythm perturbations, depression
may appear. Usually personality, initiative and alertness are spared until late.
In the final stages of the diseases the patient presents with severe global
cerebral function diminishment, mutismus, akinesia, incontinence.
Diagnosis is made on clinical grounds (psychological evaluation with
memory impairment Mini Mental Scale or Alzheimer Disease State
Assessment Scale, Wechsler Adult Intelligence Scale - Revised are useful
tools). Cerebral CT or MRI would show non specific cortical atrophy, and
possible more characteristic hyppocampal atrophy. Functional imagery
(PET, SPECT) migtht show hypofunction of basal temporal structures.
Psychiatric evaluation is necessary to rule out other confounding pathologies
(as depression). A biological evaluation (B12 vitamin, thyroid function, HIV,
inflammation) is necessary for the differential diagnosis.
Drug treatment is centered on symptomatic acetylcholinesterase
inhibitors donepezil, rivastigmine and galantamine - and memantine.
Memantine is useful in moderate Alzheimer disease, while ACI work mostly
in mild disease. All of these drugs have fairly similar effect.
Until now, all tentative to stop or reverse the degenerative processes
has failed active or passive immunization against amyloid, neurotrophic
approaches, E vitamin, etc but research is intense and would hopefully lead
to an effective way to control the disease.
Pharmacological treatment can be helpful in controlling the psychiatric
symptoms agitation, hallucinations, delusions, depression.
Alternate approaches include physical exercise, creation of a safe and
supporting environment, nutrition, sensory therapies (art therapy, music
180
therapy). They can improve daily living and facilitate better function over a
longer period of time.
Lewy body dementia

Lewy body dementia (and also Parkinson's disease dementia) are
characterized by alfa synuclein aggregates in neurons, that take the form of
Lewy body, and by dystrophic neurites. Abnormal cholinergic and
dopaminergic synthesis are important in the pathogeny of dementia.
Dementia with Lewy bodies is the most frequent degenerative
dementia after Alzheimer dementia.
Clinical picture includes fluctuating cognition, recurrent visual
hallucinations and parkinsonian features. Suggestive features are also REM
sleep behaviour disorder, pathologic sensitivity to neuroleptics, autonomic
dysfunction, depression and other psychiatric disturbances.
Cognitive impairment takes the form of a severe dysexecutive
syndrome associated to memory deficits and impaired abstract thinking.
Differential diagnosis has to be made with Parkinson's disease
dementia, and also with Parkinson's plus syndromes (MSA, CBD),
Creutzfeld-Jakobs disease, vascular dementia, Wilson's disease or
Huntington's. PET/SPECT might help differentiate from Alzheimer disease.
Treatment has to keep balance between therapy for extrapyramidal
symptoms and cognitive impairment. Anticholinergic drugs have the
potential to facilitate further deterioration of memory and executive
functions. Atypical antipsychotics (clozapine, quetiapine, aripiprazole) might
be useful in controlling psychiatric manifestations. Acetylcholinesterase
inhibitors (especially rivastigmine) have been shown to produce similar
improvements as those seen in Alzheimer.
Frontotemporal dementia
It is characterized by frontal and temporal lobe atrophy and
dysfunction. It is the third most frequent degenerative dementia.
Frontotemporal dementia includes different pathological entities, and may
also be a result of other major dementing diseases. It is considered that
taupathies are frequently associated with primary progressive aphasia, while
ubiquitinopthies are behind frontal lobe dementia with motor neuron
syndrome and semantic dementia.
Clinical (and diagnostic) characteristics are the
behavioural/dysexecutive syndrome (early personality and conduct
abnormalities) and speech problems (progressive non-fluent aphasia or
semantic dementia).
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The behavioural dysexecutive syndrome is characterized by early
behavioural dysfunction, including impairment and decline in regulation of
social interpersonal conduct, loss of insight and emotional blunting,
ritualistic and repetitive behaviours, diminished capacity for abstraction,
attention, problem solving (executive functions).
Primary progressive non-fluent aphasia associates early annomia,
agrammatism, phonemic paraphasias, with telegraphic speech and writing
and reading problems. The speech is effortful, but there is a relative
preservation of the comprehension of the meaning of words.
Semantic dementia is the least frequent, and is characterized by
impaired comprehension of the verbal and visual message meaning. Fluent
aphasia (grammatically correct and fluent speech) are accompanied by visual
agnosia, prosopagnosia, loss of word meaning (leading to impairment of
comprehension and naming tests).
Memory, spatial orientation are relatively well preserved, and if
found early they should orient the diagnostic towards another type of
dementia.
Treatment of the behavioural symptoms with serotoninergic
medication significantly improves them, but does not have any impact on
cognitive deficits. Acetylcholinesterase inhibitors have not been useful in
FTD, as the cholinergic system seems to be relatively spared. They have
been reported to produce agitation in such patients.
Vascular dementia
Vascular dementia (VaD) covers cognitive dysfunction caused by
cerebrovascular disease. Although there are instances when pure vascular
dementia is diagnosed, the current trend states that mixed (vascular and
Alzheimer) dementia is a much more frequent situation, with at least 15-20%
of all dementia cases. In many cases vascular lesions and features of
Alzheimer coexist, making impossible a very clear separation of the two
etiologies.
According to current definition and diagnostic criteria, a VaD
diagnosis can be made if in a demented there is evidence of the vascular
lesion (either clinical or by imagery) and if a clear temporal relationship can
be established between the onset of dementia (3 months after a stroke
according to the NINDS-AIREN criteria). A stepwise progression of
cognitive impairment is also suggestive for a vascular etiology.
Cognitive impairment can appear due to a variety of lesional
mechanisms generally accepted as the most important lesional patterns are
strategic area lesions, multiple lesion accumulation or widespread subcortical
ischemia.
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Large strokes in critical brain areas (angular gyrus, thalamus, basal
forebrain, the territories of the anterior or posterior cerebral arteries,
temporal areas) would manifest differently depending on the location (and
corresponding function loss).
Multiple repeated infarcts (even if not individually responsible for a
marked cognitive decline) add their deficits and cognitive status gradually
worsens (might or might not be clearly stepwise). Focal neurological signs
are usually present. Multi-infarct dementia often has the features of a
subcortical dementia.
Diffuse subcortical ischemia (Binswanger disease subcortical
atherosclerotic encephalopathy) is characterized by multiple diffuse ischemic
areas and small lacunar infarcts in the white matter. It has a strong
association with arterial hypertension. Subcortical dementia features are
usually found (bradipsichia, attention deficit, reduced spontaneity, apathy),
together with neurological signs (gait apraxia, incontinence, imbalance,
different focal deficits) and psychiatric disorders (iritability, depression).
Cerebral amyloid angiopathy also causes diffuse white matter lesions,
hemorrhage that may lead to progressive cognitive decline. Characteristic
risk of mycrohemorrhage in cerebral amyloid angiopathy can increase if the
disease is mistaken to a common type of atherosclerotic pathology and
antiplatelet or anticoagulant therapy is used.
Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is a genetic condition that leads to
white matter changes and silent strokes. The clinical picture includes
repetitive strokes, migraine and subcortical dementia.
Treatment of vascular dementia associates prevention of cerebral
vascular disease with symptomatic treatment of dementia.
Treatment of the risk factors (arterial hypertension, dyslipidemia,
smoking, diabetes) and antiplatelet agents (or anticoagulants in case of
embolic strokes) are the available measures to prevent further
cerebrovascular damage.
Data support the use of memantine, and less clearly of
acetylcholinesterase inhibitors in the symptomatic treatment of VaD.
Although they are widely used, no clear efficacy of cerebral vasoactive drugs
and nootropics has been established, and their availability differs from
country to country.
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Kalaria RN. Vascular Risk Factors and Neurodegeneration in Ageing
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related Dementias: Alzheimers Disease and Vascular Dementia.
Curr Alzheimer Res. 2013;10:642653
2. Al-Qazzaz NK, Ali SH, Ahmad SA, Islam S. Cognitive assessments
for the early diagnosis of dementia after stroke. Neuropsychiatric
Disease and Treatment 2014;10:1743-1751.
doi:10.2147/NDT.S68443.
3. Bond, M; Rogers, G; Peters, J; Anderson, R; Hoyle, M; Miners, A;
Moxham, T; Davis, S; Thokala, P; Wailoo, A; Jeffreys, M; Hyde, C
(2012). "The effectiveness and cost-effectiveness of donepezil,
galantamine, rivastigmine and memantine for the treatment of
Alzheimer's disease (review of Technology Appraisal No. 111): a
systematic review and economic model.". Health technology
assessment (Winchester, England) 16 (21): 1470.
4. Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid
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clinical spectrum. J Neurol Neurosurg Psychiatr. 2012;83:124137.
5. De Souza LC, Guimares HC, Teixeira AL, et al. Frontal lobe
neurology and the creative mind. Frontiers in Psychology
2014;5:761. doi:10.3389/fpsyg.2014.00761.
6. Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber
R, Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, OBrien
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elderly: molecular pathology suggests origin from chronic
hypoperfusion injury. Stroke. 2006;37:13911398.
7. FOLSTEIN MF, FOLSTEIN SE, MCHUGH PR: Mini-mental
status: A practical method for grading the cognitive state of patients
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10. Iadecola C. The pathobiology of vascular dementia. Neuron
2013;80(4):10.1016/j.neuron.2013.10.008.
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11. Kim WS, Kgedal K, Halliday GM. Alpha-synuclein biology in
Lewy body diseases. Alzheimers Research & Therapy 2014;6(5):73.
doi:10.1186/s13195-014-0073-2.
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14. Madhusoodanan S, Ting MB. Pharmacological management of
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16. Riedl L, Mackenzie IR, Frstl H, Kurz A, Diehl-Schmid J.
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Chapter X.
Epilepsy
Emilian-Bogdan Ignat
Definition. Differential diagnosis

Epidemiology Laboratory workup
Etiology - Electroencephalogram
Classification - Functional imagery
Clinical picture - Structural imagery
- Absences - Blood tests
- Myoclonic seizures Treatment
- Tonic-clonic seizures - General rules
- Partial simple seizures - Drug treatment
- Partial complex seizures - Interventional treatment
- Status epilepticus approaches
- Special issues and treatment
cessation
Definitions
In normal conditions information flows within the nervous system
through well delimited and regulated channels. It takes the form of
bioelectrical activity different structures in the brain exchange data (from
individual neurons communicating through synapses at the smallest scale, to
large structures that work together and interconnect). The material form of
electrical activity in humans is the variable ionic concentration across
biomembranes, with Na+, K+ and Cl- as the most important actors on this
stage.
Epilepsy is a disorder characterized by recurrent seizures.
Epilepsy is quite a nonunitary notion, since it generically gathers
together different types of pathology that have one common feature:
seizures.
Seizures are characterized by paroxistic abnormal electrical activity
episodic, sudden, fast and excessive discharge of a more or less extensive
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neuronal population of the grey matter of the brain (Jackson). They may
involve either a part or the whole brain. Depending on the exact location and
function of the affected part of the brain (the "epileptic focus"), seizures can
take various clinical aspects from motor convulsions if happening in motor
parts of the brain to psychic paroxistical manifestations in other parts.
It is important to differentiate between simple seizures and epilepsy.
Current diagnostic criteria require that at least 2 seizures are documented (or
one episode and suggestive electric abnormalities) at a minimum interval of
2 months before a diagnosis of epilepsy can be made and treatment started.
An unique episode of epileptic activity (seizure) does not imply that
that individual has epilepsy! Symptomatic seizures, even if repeated, are not
sufficient to diagnose epilepsy.
Symptomatic seizures can be the result of various pathological
conditions, and they are a reaction of the brain to momentary (non persistent)
changes. Stroke, trauma, toxics, infection, fever, extremely elevated blood
pressure and other noxious stimuli can lower the seizure treshold, but if no
other seizure episode appears after they have ceased their influence, it cannot
be said that the subject has epilepsy and therefore he needs no special
treatment but the prevention of the causal factor.
Epidemiology
The incidence of epilepsy is somewhere between 50 and
120/100000/year. It tends to have a bimodal distribution over age intervals
incidence is higher in children and in the elderly. Etiology and type of
seizures are also different in these two patient categories.
Generalized seizures account for more than half of the seizures in
persons younger than 15, and absence seizures (accounting for maybe 15%
of pediatric patients) tend to decrease dramatically after adolescence. Partial
and partial complex seizures' incidence increases with age (in individuals
over 35 they account for almost half of the new cases).
A particular individual may present with one ore more types of
seizures in a precise point of the evolution of the disease, and the clinical
aspect can change over the course of the disease.
Etiology
The cause of most cases of epilepsy is unknown, although some
people develop epilepsy as the result of brain injury, stroke, brain tumour,
and drug and alcohol misuse. Genetic mutations are linked to a small
proportion of the disease
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Causes of epilepsy are different in different age spans. In children
and young people epilepsies are often idiopathic (more than 70%), while in
adults and older persons they tend to be acquired.
Secondary epilepsies appear in hereditary diseases (progressive
myoclonic epilepsy, Lafora bodies disease), or in acquired lesions (scars due
to stroke, trauma, encephalitis, vasculitis; tumors; parasitic lesions; vascular
malformations).
Classification
The International Classification of Epileptic Syndromes and
Epilepsies (ILAE 1989) classifies the epilepsies upon 2 criteria: (1) partial
(localization-related) versus generalized and (2) idiopathic versus
cryptogenic or symptomatic.
The classification of seizures is based on their clinical and electrical
character.
Seizures can be generalized or partial. Generalized seizures involve
both hemispheres symmetrically and synchronously (fig. 1). In partial (focal)
seizures the abnormal electrical activity is restricted to a limited area. In
secondarily generalized seizures the abnormal activity involves only a
restricted area at the beginning, but then spreads in the neighboring regions
and eventually they would generalize and involve the whole brain.
Clinical picture
Absences (petit mal) are characterized by a short period of suspended
consciousness. The duration ranges from a few seconds to tens of seconds. It
usually involves children. The patient is "absent" interrupts all activities,
stares blankly, in a vacant state, does not respond, eyes might roll upwards,
and after the seizure had passed he would continue his activity as if nothing
happened, with no recollection of the absence period. They can be very
frequent, some patients experiencing hundreds absence seizures per day.
In some patients absence seizures might associate palpebral
myoclonies, atonic or tonic muscle activity or automatic behaviours.
Myoclonic seizures do not associate alterations of consciousness.
They consist of short, symmetrical, and synchronous muscle jerks. They tend
to involve more the upper part of the body. EEG recordings show bilateral
polispike-wave activity.
Tonic-clonic seizures (grand mal) associate loss of consciousness
with specific motor activity that usually lasts for 5-10 minutes.
The seizure might be preceded by an "aura" abnormal sensations or
feelings that the patients learns to associate with the coming seizure. Aura
could be identified as a focal beginning of a secondary generalized seizure.
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The generalized tonic-clonic seizure starts with the patient losing
consciousness and falling on the ground. There is no control of the fall, so it
may generate injuries. the seizure itself har 2 phases: the tonic and then the
clonic phase, followed by a recovery phase.
During the tonic phase all muscles contract and the limbs and the
body are tense. The patient may emit sounds (scream) due to the air that is
forcefully expelled from the lungs due to contraction of the body muscles. It
is the shortest phase of the seizure, with a duration of seconds to tenths of
seconds. The patient is cyanotic, as there is apnea during this phase.
During the next phase (clonic phase) the muscles will start to contract
rapidly and briefly, in a random manner, causing convulsions. The clonic
phase lasts a few minutes. Movements include twitches of the limbs, shaking
or vibrating of the stiffened extremities. The eyes typically roll back or close.
Uncontrolled contractions of the masticatory muscles and of the tongue
might lead to lacerations or bruises. Relaxation of the sphincters appears
during these phases.
International classification of epileptic seizures

1. Generalized 2. Partial (focal) seizures
seizures
1.1 Absences 2.1 Simple partial seizures (no alteration of
- Typical consciousness)
- Atypical - with motor signs
1.2 Myoclonic seizures - with somato-sensory or sensitive signs
1.3 Clonic seizures - with vegetative signs
1.4 Tonic seizures - with psychological signs
1.5 Tonic-clonic 2.2 Complex partial seizures (with alteration of the
seizures state of consciousness)
1.6 Atonic seizures - simple partial evolving to complex partial
seizures
- with altered consciousness from the
beginning, with or without automatic behaviour
2.3 Secondarily generalized seizures
- secondarily generalized simple partial seizures
- secondarily generalized complex partial
seizures
- simple partial seizures evolving to complex
partial and then to generalized seizures
3. Unclassified seizures
Table 1: International classification of epileptic seizures (after Thomas and
Genton, 1993)
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a b c
Figure1. Abnormal electrical activity in partial seizures (a) (localized),
primarily generalized (b) (a deep epileptic focus with generalized spreading
of abnormal activity) and secondarily generalized (c) (initial focal activity
spreads in the neighbouring areas and eventually take over the whole brain)
The contractions reduce in frequency and amplitude and the patient

slowly regains consciousness. During the recovery phase there is
hypotonicity and stertorous breathing. Confusion follows most often, with
complete amnesia of the ictal period. Frequently there is post ictal sleep or a
prolonged confusional status.
Partial simple seizures are characterized by normal consciousness.
Abnormal activity involves a limited part of the brain, with unimodal clinical
picture. The patient does not have amnesia and can describe the seizure,
usually being aware of its unreal character.
If the motor area is involved, the clinical manifestation of the seizures
consist in motor behaviours, ranging from simple, repeated contractions of a
muscle group (characterizing the principal motor area), to more complex
automatisms and gestures that originate from the supplementary motor areas.
The "versive" seizures originate in the supplementary motor area, with tonic
deviation of the head and eyes away from the side of the epileptic focus,
sometimes with repetitive vocalisation or abnormal postures (lifting) of the
upper limb.
In some situations the abnormal activity spreads progressively to the
neighbouring areas, and eventually takes over the pathways that allow it to
spread to the controlateral hemisphere. The patient would present with
initially with involuntary movements that affect a limited part of the body
a.e. the hand and then spread to the whole upper limb, then half of the body
and finally, the whole body, when the patient also loses consciousness (the
seizure becomes generalized). This pattern of spreading was described by
Jackson and hence the name of "jacksonian seizures". It can also involve non
motor areas (a.e. somatosensory).
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Sometimes the partial motor seizure is followed by transient motor
deficit of the affected parts of the body (Todd paralysis).
Somatosensory area seizures present as paroxystical abnormal
sensation (paresthesiae) that involve part of the body. Symptoms depend on
the location in the sensory strip. More anterior parts of the sensory area
generate simple sensations, while more posterior associative cortex seizures
manifest as more complex sensations (movement of a body part).
Any part of the cortex can be affected by epileptic activity and
manifestations reproduce the normal function of that area, but out of the
normal context. More information about specific manifestations in seizures
that involve specific areas can be found in the "cerebral lobes" chapter.
Pathological change in the respective areas can lead to gustatory seizures
(the rolandic opercule), auditory seizures (ranging from noises - roaring,
whistling, humming or buzzing - to music and words, depending on the site
affected in the temporal lobe), olfactory seizures (originate from the inferior
posterior frontal cortex and consist in the perception of an abnormal smell,
usually unpleasant), visual seizures (in the occipital areas; elemental or more
complex visual illusions).
Seizures that involve the temporal lobe or the lymbic system present
with memory or affective signs. Extreme fear, vegetative changes, changes
of the perception of reality sensation of already seen ("deja vu") or never
seen ("jamais vu"), sensation of familiarity (the patient feels familiar with an
environment or situation) or alienation (he perceives the known environment
as non familiar), panoramic vision of the past, changes in the perception of
time can appear in temporal lobe seizures.
Partial complex seizures associate an altered consciousness with
various automatic behaviours. The patient might suddenly stop his activity,
seeming dazed and confused and then start behaving abnormally chewing,
swallowing, simple gestures or more complex behaviours feeding,
exploring, ranging, dressing, grooming, ambulating.
Status epilepticus is a neurological emergency and consists in
seizures that last longer that 15 minutes or in recurrent seizures that do not
allow the patient to regain consciousness between them. It has to be
remembered that status epilepticus is not always convulsive, and that non
motor seizures can be involved. Electrical status epilepticus means that
seizures continue in the absence of motor signs; it can follow after prolonged
convulsions, when the the motor neurons have been exhausted, and it has the
same prognosis and implications as if the motor activity had continued.
Over activation of neurons leads to exhaustement of energy and
oxygen resources. If it is not approached properly and in time irreversible
changes occur, with neuronal death. General vegetative changes
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(hyperthermia, vasomotor and respiratory depression) further darken the
prognosis, with a high death rate.
Treatment of status epilepticus is done immediately with intravenous
administration of clonazepam, fenitoin, or intrarectal diazepam, and must be
continued in an intensive care unit.
Partial status epilepticus doesn't have the same severe implications
there is continuous epileptiform activity that involves a limited part of the
brain. A special situation is Kojevnicow's epilepsia partialis continua.
Most often differential diagnosis is necessary upon the first reported
seizure in a previously healthy subject.
It includes on one hand other sudden and brief alterations of
consciousness (as syncope, metabolic (hypoglycemic) coma, intoxications)
and on the other hand diseases that associate involuntary movements. A
special situation is represented by psychogenic pseudoseizures, that are
sometimes hard to differentiate from true epileptic activity.
Symptomatic seizures need to be differentiated from epilepsy, since
treatment approaches might be completely different.
Laboratory workup
A patient with suspected seizures has to be evaluated in order to find
out whether it is truly an epileptic episode, and if so to differentiate within an
idiopathic and a secondary epilepsy and to eventually find out the cause.
Electroencephalography is the technique that provides the most
useful information in seizure disorders. It is a functional technique, as it
gives information about what happens in the brain and not about structural
abnormalities. EEG is recorded through electrodes on the scalp, in different
settings. Interictal EEG is most often normal it is important to remember
that a normal EEG recoding does not rule out epilepsy. On the other hand,
finding an abnormal pattern interictally confirms epileptiform activity and
offers information about the location of the pathological process. EEG
should be performed as soon as possible after the seizure (in the first 24 h) as
it has a greater sensitivity during this period. A definitive diagnosis of
epilepsy can be made if a seizure occurs during an EEG recording and
electrographic ictal discharges can be correlated with habitual clinical signs
and symptoms.
EEG raw data can be used directly or it can be put in the form of
voltage or frequency maps that make easier the identification of
asymmetrical activity.
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Procedures that would increase the chances that abnormal elements
are found on EEG are used on a regular base as hyperpnoea, flash light
stimulation during the recording, repeated EEG, or sleep deprivation. High
definition EEG (using 50 to 300 electrodes on the scalp) provides quality
data about the electric activity. Video-EEG monitoring is the criterion
standard for classifying the type of seizure or syndrome or for diagnosing
pseudoseizures, and it increases the chances to find abnormal changes. still,
although it can be performed to rule out an epileptic etiology with a
reasonable degree of confidence, it is limited by the possibility that nothing
happens during the monitoring time. Video-EEG is also used to characterize
the type of seizure and epileptic syndrome to optimize pharmacologic
treatment and for presurgical workup. Different approaches are used before
surgery for example implanted electrodes that would better characterize
the exact location of the epileptic focus and its behaviour.
However, video-EEG monitoring is an expensive and laborious
study. In a normal clinical setting monitoring all patients is impractical, and
only those whose condition does not respond to treatment, legal cases or
patients in whom pseudoseizures are suspected should undergo video-EEG,
usually in an epilepsy referral center.
Typical absence seizures are characterized by bilateral, symmetrical,
synchronous and generalized 3 Hz spike-wave complexes on the EEG.
Different EEG patterns characterize atypical absence seizures.
EEG recording during the tonic-clonic seizure would show initial
bursts of generalized multiple spike and wave complexes. During the tonic
phase there can be desynchronization of the background for up to 3 seconds
and 10 hertz surface negative spikes with duration of approximately 10
seconds. The jerks tend to occur simultaneously to the spikes. Clonic phase
can show slow waves intermixed with the 10hz spikes, rhythmic jerks
associated with spikes, muscular relaxation will be associated with the slow
waves and as the jerks decrease in frequency the spike and wave will
diminish. Postictal EEG will show a flattening of the EEG followed by low
voltage delta that will gradually increase in frequency and voltage.
In simple partial seizures EEG shows focal spike activity over
corresponding brain area.
Interictal EEG can show focal spikes or sharp waves with or without
focal slowing, while ictal EEG can show rhythmic, hypersynchronous beta
(13-30Hz). Amplitude will progressively increase as frequency decreases.
Rhythmic activity gradually replaced by spike and wave activity.
Functional imagery PET, SPECT or functional MRI would
eventually show abnormal activity in a specific territory, but due to costs and
low availability are usually reserved for special cases, usually when surgery
is discussed.
193
Structural imagery is necessary in all cases of newly appeared
seizures in adults, as it has to rule out secondary epilepsy due to tumors or
vascular changes. MRI is the better choice (with the use of contrast media),
with CT only for the cases where MRI cannot be performed or for the initial
screening. High power MRI performed by a trained radiologist can show
structural abnormalities of the cortex (double cortex, hippocampal sclerosis,
lissencephaly, pachygyria, band or laminar heterotopias, heterotopias, focal
cortical dysplasia polymicrogyria) that can cause epilepsy and that are
surgically approachable.
Metabolic screening for uremia, hypoglycemia, drug intoxications,
and electrolyte disorders should be conducted for patients with first seizure
who present to the emergency department. A pregnancy test might be
needed. Perform other laboratory investigations as indicated for specific
clinical situations (previous intake of drugs, medical history, alcohool
consumption or withdrawal). Prolactin is occasionally used in the diagnosis
of seizure (a prolactin level greater than 3 times normal might help
differentiate generalized tonic-clonic seizures versus nonconvulsive syncope
versus pseudoseizures).
Neuropsychological testing is useful for characterizing functional
deficits for psychosocial prognosis and rehabilitation.
In the case of a first seizure that has clinical characteristics that can
suggest a syncope, cardiological evaluation should be performed, including
ECG (long QT syndrome, arrhytmia) and long time ECG recording (Holter
monitoring).
Treatment of epilepsy
General rules
There are a few general rules that have to be respected when treating
an epileptic patient.
The treatment aims at a seizure free period as long as possible
(ideally with no recurrence at all).
Therapy includes general measures (diet, sleep hygiene, avoidance of
precipitating factors). Diet must avoid stimulating substances found in
coffee, cocoa, green and black tea (coffeine, teobromine), cola. Some
seizures might be potentiated by intermittent light stimulation (as in driving
during night or during exposure to fast changing images in TV, video
games).
For their own protection persons with epilepsy must avoid situations
when a sudden loss of consciousness might endanger them (swimming,
climbing). They must also avoid driving (which is generally prohibited, but
194
subjected to special regulations that may vary in different countries),
operating machinery (the seizure recurrence risk is added to the sedative
effect of some of the antiepileptic drugs).
Drug therapy
Drug therapy is usually initiated when an epilepsy diagnosis is
certain that is when 2 seizures have occurred at more than 2 months space
(or there are EEG signs that confirm epileptic activity in the same
conditions) and the seizures are not connected with a specific situation
(symptomatic seizures a.e. in connection with alcohol consumption,
hypertensive encephalopathy, etc).
Drug therapy is initiated with the most appropriate AED
(antiepileptic drug) for the type of epilepsy of each patient, or with a large
spectrum AED.
Drugs are usually up-titrated relatively fast until the lowest
therapeutic dose is reached (to avoid side effects), and then slowly until
efficacy is met, or until the maximum dose is reached, or until intolerable
side effects appear.
If there is no efficacy at the highest tolerated dose, a second AED
may be introduced (second line therapy).
Usually, when a therapeutic concentration of the second AED is
attained, the first one (that has proven inefficient) starts to be slowly down-
titrated while the dose of the new drug is increased.
Down titration of AED MUST be performed slowly, in a matter of
months. Sudden arrest of a drug, even if apparently inefficient, might trigger
a rebound phenomenon or even status epilepticus. Before considering a drug
as inefficient one must be sure of the treatment compliance of the patient (no
drug can be of use if the patient fails to administer it), and the maximum
tolerated (or admitted) dose must have been reached.
Up to 50% of the epilepsy patients are well controlled with the first
AED, if chosen correctly. A further 10-20% respond to the second AED, and
less then 5% to the third AED. Politherapy (association of 2 or more AEDs)
helps another 5% of the patients. A high number of patients (up to 30%) fail
to respond to any oral therapy, and other methods must be tried.
AEDs have complex side effects and interactions (a.e. valproate can
cause weight gain, hair loss, liver damage, pancreatic damage, cognitive
slowness; topiramate might cause weight loss, kidney litiasys, and it is an
enzyme inductor, as is carbamazepine; lamotrigine can cause severe skin
hipersensitivity reactions and liver damage; phenytoin causes gingival
hyperplasia). When choosing an AED the practician must take all the
possible interactions into consideration.
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Type of epilepsy 1st line AED 2nd line AED
Generalised Sodium valproate, Topiramate, Levetiracetam,
epilepsy, tonic- Lamotrigine Carbamazepine
clonic seizures
Absence Ethosuximide Sodium valproate
seizures
Partial epilepsy Lamotrigine, Phenitoin, gabapentin,
carbamezepine, topiramate, valproic acid,
oxcarbazepine, pregabalin
levetiracetam
Status Diazepam 5 mg IV, Tiopental, Pentobarbital,
epilepticus Fenitoin 20 mg/kg, Propofol
Fenobarbital 20 mg/kg,
Acid valproic 20 mg/kg
Lorazepam 2 mg i.v.
Fosfenitoin 20 mg/Kg
Midazolam 0,1-0,4
mg/Kg/hour
Table 2. Drugs used in the treatment of epilepsy
Status epilepticus needs emergency treatment, starting with O2

administration. Glucose and B6 vitamin should also be administered. First to
administer (first 10 minutes) are diazepam (0.15 mg/kg) (intravenously or
intrarectally) or lorazepam (0.1 mg/kg) IV over 5 minutes, followed by
fosphenytoin or phenytoin. Phosphenytoin provides the advantage of a more
rapid rate of administration with less risk of venous irritation
Failure to respond to optimal benzodiazepine and phenytoin defines
refractory status epilepticus. If the patient has not awakened yet (bedside
EEG can differentiate seizure persistence of the sleepiness and confusion that
frequently follow prolonged convulsions) he must be transferred to an
intensive care unit, where vital functions can be supported and disbalances
can be addressed. If seizures continue after 20 minutes, phenobarbital (15
mg/kg IV) must be given. Barbiturates coadministration with
benzodiazepines may potentiate ventilatory failure. If seizures continue over
30 minutes, consider administering general anesthesia with medications such
as propofol, midazolam, or pentobarbital. These agents are given by IV drip
and titrated to a burst-suppression pattern in the EEG trace.
Third line therapy for drug resistant epilepsies include cetogenic diet
(complete/almost complete removal of glucides from diet seems to reduce
the seizure frequency in many patients), vagal stimulation, surgery and
(mostly experimental) other brain stimulation techniques.
196
Interventional treatment approaches
Vagal stimulation implies placing of a stimulating electrode on the
vagus nerve. It is connected to a pulse generator places under the skin.
Stimulation is intermittent. Efficacy tends to increase over time (in a study
by Morris (1999) 43% of the patients showed a reduction of the number of
seizures with more than 50% after 3 years, compared to 23% at 3 months).
Usually the adverse effects are manageable and are not severe.
Surgery is performed in specialized centres, and aims to separate the
epileptic focus or to suppress it in certain cases. Preoperative evaluation is
complex and needs to correctly identify the source of abnormal discharges
and the spreading pathway. In some situations radical interventions are
performed lobectomy or even hemispherectomy, when the patient gains
due to the reduction in seizure frequency even at the cost of deficits.
Calosotomy is an intervention that stops seizures to generalize.
Stimulation techniques include trigeminal nerve stimulation (a new
technique that seems to be effective despite its simplicity).
Deep brain stimulation - different teams have tried cerebellar,
hyppocampal, subtalamic nucleus, caudate, centromedial and anterior nuclei
of the thalamus stimulation, with mixed results. Procedures are costly and
complicated, and must be reserved to cases where all other approach has
failed and that are not eligible for surgery.
Special issues and treatment cessation

Pregnancy is a special issue for women with epilepsy. All AEDs have
the potential to trigger abnormalities in the foetus, but the risk is not
extremely high and if the treatment is properly conducted it can be said that
the risks associated with a generalized tonic clonic seizure is higher than that
generated by treatment.
Antiepileptic treatment can be reduced or even interrupted under
supervision after a long seizure free period (usually 5 years). If seizure
reappear treatment must be continued indefinitely.
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overview. J Pharm Pharm Sci. 2013;16(4):564-76
2. Aneja S, Sharma S. Newer anti-epileptic drugs. Indian Pediatr. 2013
Nov 8;50(11):1033-40.
3. Banerjee PN, Filippi D, Hauser WA. The descriptive epidemiology of
epilepsy-a review. Epilepsy research 2009;85(1):31-45.
doi:10.1016/j.eplepsyres.2009.03.003.
4. Commission on Classification and Terminology of the International
League Against Epilepsy: Proposal for revised clinical and
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electroencephalographic classification of epileptic seizures. Epilepsia
22:489, 1981.
5. Commission on Classification and Terminology of the International
League Against Epilepsy: Classification of Epilepsy and Epileptic
Syndromes. Epilepsia 30:389, 1989.
6. Cox JH, Seri S, Cavanna AE. Clinical utility of implantable
neurostimulation devices as adjunctive treatment of uncontrolled
seizures. Neuropsychiatric Disease and Treatment 2014;10:2191-
2200. doi:10.2147/NDT.S60854.
7. EADIE MJ, TYRER JH: Anticonvulsant Therapy: Pharmacological
Basis and Practice, 3rd ed. New York, Churchill Livingstone, 1989.
8. ENGEL J JR: Surgery for epilepsy. N Eng J Med 334:647, 1996.
9. Espinosa-Jovel CA, Sobrino-Meja FE. Clinical approach to the first
epileptic crisis in adults. Rev Neurol 2014;58 (08):365-374
10. Harrisons Neurology in Clinical Medicine, Hauser SL Editor, Second
Edition, McGraw Hill, Medical, 2010;
12. Lee SK, Kim D-W. Focal Cortical Dysplasia and Epilepsy Surgery.
Journal of Epilepsy Research 2013;3(2):43-47.
doi:10.14581/jer.13009.
13. Lisak RP, Truong DD, Carroll WM, Bhidayasiri R. International
Neurology A Clinical Approach. Wiley-Blackwell, 2009
15. Nair P P, Kalita J, Misra U K. Status epilepticus: Why, what, and how.
J Postgrad Med 2011;57:242-52
16. NIEDERMEYER E: The Epilepsies: Diagnosis and Management.
Baltimore, Urban and Schwarzenberg, 1990.
17. PORTER RJ: Epilepsy: 100 Elementary Principles, 2nd ed.
Philadelphia, Saunders, 1989.
18. Ropper AH, Adams and Victor's Principles of Neurology, Eighth
Edition, McGraw-Hill, 2005
19. Rossetti AO, Kaplan PW. Seizure semiology: an overview of the
'inverse problem'. Eur Neurol. 2010;63(1):3-10. doi:
10.1159/000258634. Epub 2009 Nov 14.
20. Schmidt Dieter, Schachter Steven C. Drug treatment of epilepsy in
adults BMJ 2014; 348:g254
21. Sendrowski K, Sobaniec W. Hippocampus, hippocampal sclerosis and
epilepsy.Pharmacol Rep. 2013;65(3):555-65
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22. Sharma S, Jain P. The ketogenic diet and other dietary treatments for
refractory epilepsy in children. Annals of Indian Academy of
Neurology 2014;17(3):253-258. doi:10.4103/0972-2327.138471.
23. So EL. Classifications and epidemiologic considerations of epileptic
seizures and epilepsy. Neuroimaging Clin N Am 1995;5:51326
24. Zhao F, Kang H, You Li, Rastogi P, Venkatesh D, Chandra M.
Neuropsychological deficits in temporal lobe epilepsy: A
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2014;17(4):374-382. doi:10.4103/0972-2327.144003.
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Chapter XI.
Painful Syndromes:
Neuropathic Pain, Headache
Cristian Dinu Popescu, Emilian-Bogdan Ignat
Neuropathic pain Migraine and cluster headache

Definition, clasification General data
Physiopathology Etiology
Hyperalgesic peripheral neuropathies Clinical signs
Hyperalgesic CNS pathology Clasification
Treatment Treatament
Headache Tension headache

Vascular
Traumatic
CSF disturbances
HTA associated
Neuropathic pain
Definition, classification
Pain is an unpleasant sensory and emotional experience associated or
not with the presence of tissue damage or described in such a way that such a
lesion can be identified. (IAS P 1994).
The pain is caused by stimulation of free nerve endings called
nociceptors. It is estimated that in the human body there are about 200 per
cm2 of skin.
200
There is no uniform classification, thus variations related to the
duration and pathophysiology are accepted. Depending on the duration of the
pain can be acute and chronic. In terms of pathophysiological the pain can be
nociceptive or neuropathic. Acute pain is less than one month duration and
chronic exceeds 3-6 months. Neuropathic pain is triggered and maintained
by a lesion of the central or peripheral nervous system. In some cases the
nociceptive and neuropathic pain can coexist. Examples are pain in
malignancies, of carpal tunnel syndrome or lumbar radiculopathy.
Nociceptive pain is the result of nociceptors involvement in
inflammatory or non-inflammatory reversible process. The pain is localized
at the disease process or place of injury (fractures, burns, abrasions,
swelling). The pain can become chronic especially in the case of
osteoarthritis.
Pathophysiology
Neuropathic pain is due to primary lesions or dysfunctions of the
nervous system with its localization structures involved namely: nerves,
roots, bone, brain. The perception of painful sensation may be the same at
the injury site. This usually becomes chronic pain which requires the
installation of elements like bone marrow, thalamic and cortical
neuroplasticity phenomenon that favors the onset and maintenance of pain.
Involvement of the nervous system in a pathological process leading
to the presence of positive symptoms (irritation) and negative (deficit).
Positive symptoms are spontaneous pain, allodynia, hiperalgesia, dysesthesia
and paresthesia. The main negative symptoms are hypoesthesia, anesthesia,
hypoalgesia, analgesia (definitions are illustrated in Table 1).
The pathophysiology of neuropathic pain requires the involvement of
both the peripheral sensory neurons and those who enter the CNS structures
like spinal cord, thalamic, cortical. The main mechanisms are peripheral
neurons hyperexcitability, loss of inhibitory control and central
hypersensitivity. Functional desynchronization of these mechanisms leads to
abnormal discharge which will be reflected at the cortical pain sensation
area. In thier way up the impulses triggered by nociceptive or neuropathic
pain mechanisms suffer "processing" by spinal cord and thalamus so
controlateral parietal cortical level pain is perceived with a certain intensity.
The hemisphere on the same side of the lesion exerts an inhibitory effect on
the spinal posterior horn of the same side making a significant downward
modulation. Downward modulation loss is one of the causes of pain
perception.
Persistent injuries or disorders of the nervous system leading to
increased afferents to the posterior horn where it appears that central
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sensitization results in chronic pain and perception of variants irritative or
deficient type changes.
Pozitive symptoms Negative Symptoms

Spontaneous pain painful Hypoesthesia low sensibility to
sensation felt without an obvious stimulation, except special senses
stimuli (eg. Touch, pain)
Allodynia pain due to a stimulus Anesthesia total loss of sensation
that normaly causes pain (eg. Touch, (expecially tactile one)
movement, cold, heat)
Hyperalgesia increased answer to Hypoalgesia painful diminished
normal painful stimulus (eg. Cold, response to a normal painful stimulus
hot, sting)
Dysesthesia abnormal unpleasant Analgesia absence of pain as a
sensation, spontaneous or provoked response to a stimulus that normally
(eg. Sensation of stinging) would be painful
Paresthesia abnormal sensation,
spontaneous or provoked (eg.
Tingling, vibration)
Table 1 Pozitive and negative symptoms in abnormal sensation
At acortical level the pain gets an emotional value that depends on

the previous experience of the subject, emotional context, presence of a
degree of depression or anxiety and cultural level. In case of brain
pathologies associated with pain a number of mechanisms are involved
including spontaneity (loss feedback in the posterior horn), denervation,
hypersensitivity, decreased GABA-mediated inhibition, negative
neuroplasticity phenomena. Spinothalamic tract involvement leads to
changes in thalamic neurons discharge and pain perception changes.
Peripheral neuropathies hyperalgesia

Pain accompanies both peripheral neuropathy and a number of CNS
disorders. In peripheral disease feeling pain has variations from nerve to
nerve, from person to person, there are even differences between sexes. Pain
accompanies peripheral neuropathies when dealing with thin fibers but also
damage is in the thicker fibers but a sufficient number of thin fibers is
needed.
Aching in peripheral neuropathy is caused by impulses from free
nerve endings in tissues (nociceptors) which are under irritative or
destructive pathophysiological mechanism. Pain is transmitted through small
myelinated A delta fibers but also by unmyelinated C. A delta fibers
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stimulation leads to a sharp pain perception but well located. C fiber
nociceptors associated stimulation leads to the perception of delayed pain
and diffuse burning sensation.
As intracellular mechanisms involved are the intimate sodium
channels of unmyelinated axons of nociceptors, which are in the growth
phase of the activity (up regulation) resulting in final ectopic activity in the
presence of C fibers leading to the first neuron sensory awareness (peripheral
sensitization). Increased activity of the first sensitive neuron generates a
cascade of events that causes secondary changes in the posterior horn, after
which it senzitising the second and third neuron. Peripheral and central
sensitization results in altered sodium channel function, increased activity of
glutamate at the N methyl D aspartate (NMDA) receptor and decreased
activity of GABA receptors (gamma aminobutyric acid).
The most popular peripheral neuropathy accompanied by pain are
presented in table no 2.
Periferal nervous impairment in diabetes

Diabetic neuropathy
Symetrical painful polyneuropathy
Asymmetrical painful polyradiculoplexopathy
Nervous trunk mononeuropathy
Lumbarsacral and brachial plexopathy

Asymmetrical painful polyradiculoplexopathy
Toxic neuropathies
Arsenic, thalium
Alcohol
Vincristie, cysplatine
Amyloid neuropathies: primary and familial

Paraneoplasic sensitive neuropathy
Sjogren syndrome
Distal symmetrical polyneuropathy HIV related
Uremic neuropathy
Fabry disease
Hereditary autonomous sensitive neuropathy
Cryptogenic small fibers neuropathy
Tabel 2. Peripheral diabetic neuropathies
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CNS hyperalgesic pathology
Pain accompanies a series of CNS disorders including stroke, MS,

spinal cord pathology, Parkinson's disease. Any involvement by ischemic or
hemorrhagic vascular processes affecting the spinotalamocortical tract may
cause pain. Thus medullary vascular syndromes, bulbar, pontine, midbrain,
thalamic, cortical and subcortical white matter may be accompanied by pain.
The brainstem nuclei through the cranial nerves and sensory thalamus
have additional vulnerability. It seems that among the mechanisms
generating stroke pain include hyperexcitability and loss of central
inhibition.
Through the affected structures is the thalamus which generates a
special kind of pain with an emotional tone: exacerbating at stress or with
conflict situations. The involvement of the geniculo-thalamic arterial pedicle
determines the highest percentage in the accompanying pain syndrome.
In the neuropathic pain due to medullary lesions there is a central and
segmental component. The central component involves among other changes
astrocytal activation, the presence of chemokines, hyperexcitability of the
spinal posterior horn and loss of GABA inhibition. Pain is perceived as
allodynia or hyperalgesia.
Inclusion of the sensory root in the pathologic process generates the
segmental pain. Pain is a regular in MS patients. Demyelination promotes
contact between sensory fibers still intact through so-called EFAP. Most
popular neuropathic pain syndromes which are common in MS patients are
the Lhermitte's sign and trigeminal neuralgia. Lhermitte sign is obtained by
flexion of the cervical spine that triggers a downward sensation compared by
patients with an electric discharge. "Downloading" can reach up lumbar
regions.
Painful phantom limb syndrome is characterized by the perception of
painful sensations localized in the segment already amputated. The
phenomenon is most intense when in the case of surgery one part of the
breast, penis, testicles, eyes, tongue and teeth is amputated. At the same
patients stump pain syndrome and phantom limb (stump pain) can coexist.
Perception of pain in amputated territory is supported by some changes
including increased excitability in the posterior horn, decreased inhibitory
processes, reorganization of thalamic relays and cortical representation. A
series of structural changes are produced that may be associated with
degenerative processes characteristic of neuropathic pain in general.
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Treatament
Antiepileptics Antidepressan Opioids Other classes of drugs

ts
Gabapentin Amytriptiline Oxicodon Memantine
1200-3600 25-150 mg/day 10-120
mg/zi mg/zi
Pregabalin Venlafaxine Slow Tetrahidrocannabinol
150-600 mg/zi 150-225 mg/zi releasing (cannabis smoking,
morphine tetrahidrocannabinol,
15-300 spray oromucoas 2.7mg,
mg/zi delta-9-
tetrahidrocannabinol/2.5
mg cannabidiol)
Carbamazepi Imipramine Metadone Capsaicine (patch)
ne 200-1200 150 mg/zi 15 mg/zi
mg/zi
Oxcarbazepin Duloxetine Tramadol Lidocain (patch)
e 300-1800 60-120 mg/zi 200-400
mg/zi mg/zi
Lamotrigine Clomipramine Levorfan
200-400 mg/zi 25-100 mg/zi ol
2,7-8,9
mg/zi
Topiramat , Desipramine
Valproate, 65-73 mg/zi
Levetiracetam
Nortriptiline
25-150 mg/zi
Table 3. Pharmacological management of chronic pain
Headache
Vascular headache
In the arterial and venous walls are a large number of motor receptors
for various pathological processes that are triggering vascular pain.
Intracerebral aneurysms may indicate the presence of perceived pain
especially when they reach a critical size or rupture, triggering subarachnoid
hemorrhage. Arterial venous malformations may generate a complex clinical
picture that include symptomatic migraine syndrome, seizures and focal
neurological deficits.
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Both, aneurysms and arterial venous malformations, if evolution is to
subarachnoid hemorrhage, will generate a heinous headache associated with
rupture in the subarachnoid space or invasion of the brain parenchyma.
Sometimes the clinical picture is dramatic, with generalizing
headache, pain descending towards the cervical and dorsal regions, loss of
consciousness, vomiting.
The presence of blood in the subarachnoid space can cause disruption
of CSF resorption, leading to a variation of hydrocephalus.
The evolution of bleeding from inside the brain into the subarachnoid
space or inside the ventricles depends on the blood pressure and the
resistance of the brain parenchyma. Sometimes both versions can coexist
with reserved vital prognosis. Headache may signal a hemorrhagic
transformation, infarction and cerebral edema which may increase pain
syndrome.
Cervico-cephalic arterial wall pathology (carotid and vertebral) can
cause headaches. The eventuality is carotid and vertebral artery and
dissection. Dissection occurs when there are pathological processes that
enhance but weaken the medial thickness and enhance the adhesion to
endothelium. The presence of other factors such as hypertension or neck
trauma can make this event possible accompanied by pain usually located
right of the affected side.
Also inflammatory phenomena of the arterial walls (vasculitis) can
generate headaches. One of the best known is giant cell arteritis. The
inflammatory process happens in the endothelium and media, sometimes
extending to the adventitia. Inside the walls of the arteries can be identified
by biopsy the so-called mononuclear cells. The inflammatory process
interests the ophthalmic arteries, superficial temporal, carotid, vertebral,
coronary arteriay, the branches that are distributed to the upper limb inducing
claudication, transient ischemia and thrombosis. The main investigation are:
sedimentation rate (up to 80-85% / minute), temporal artery biopsy,
increased C-reactive protein level, possibly MRI angiography.
Evocative clinical signs include headache, highlighting the superficial
temporal artery route, pain on palpation of the arteries, amaurosis fugax type
crisis. Treatment consists of administration of prednisone 40-60 mg/day for
one month followed by lower doses 10% of the administered weekly. There
may be situations where the patient relapsed and preventive treatment is
recommended 75-10 mg for several years.
Traumatic headache
Head and neck injuries resulting in bleeding or hematoma generate
pain as it happens in the chronic subdural hematoma. Headaches may be
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associated with nausea, (dizziness) neuropsychological disorders that persist
and induce a genuine subjective persistent posttraumatic syndrome.
Treatment will include NSAIDs, antidepressants, antiepileptics, non-opioid
analgesics.
Non vasculitic inflammatory phenomena can cause pain by invasion
of the meninges, brain tissue and vascular structures.
Meningitis and meningo encephalitis feature a symptomatic triad,
which include headache, neck stiffness and fever. Other localized
inflammatory processes in the sinuses (maxillary, frontal, ethmoid,
sphenoid), mastoid, pericranial tissue can cause pain with evocative location.
Brain replacing processes can cause headache by constitution and
influencing growth of the ventricular CSF circulation. Headache becomes
more intense as the replacing brain process increases, leading to intracranial
hypertension. Headache often arise the patient from sleep, and vomiting, by
lowering the liquid volume improves the headache.
Pain in the front and temporal side of the head is characteristic for
supratentorial brain replacing processes space and the occipital one for
formations located in the posterior fossa.
Disorders of CSF flow

CSF is composed by the secretion of the extracellular choroid plexus
and the one from the brain circulation. Mainly secreted by the choroid plexus
is has a movement toward the subarachnoid space through the holes of
Magendie and Luschka, moving downward toward the spinal canal and to
the hemispheric areas where it is absorbed into the circulation of venous
sinuses by the small grains of Pacchioni.
Headache is the most common symptom associated with CSF
pressure change. Disturbances that occur in its production, circulation or
discharge may increase or decrease CSF intracranial pressure. CSF pressure
direction changes can influence the headache features. Thus in intracranial
hypotension the orthostatic headache occurs and in intracranial hypertension
the installation of the headache depends on both the increased pressure and
the local activation of pain-sensitive structures.
Normal intracranial pressure is between 70 and 200 mm water.
Intracranial hypotension symptoms occur when water pressure drops below
50 mm. In terms of etiologic hypotension it can be classified in spontaneous
intracranial hypotension when there is evidence of CSF leakage or systemic
disorders and symptomatic when it is secondary to CSF leak. The most
common cause of intracranial hypotension is lumbar puncture for diagnostic
purposes or for anesthesia. Head or spinal injuries, craniotomy, spinal
surgery are other situations that may occur with loss of CSF and intracranial
207
hypotension. Intracranial hypotension syndrome can appear also due to
systemic diseases such as severe dehydration, uremia, meningo encephalitis,
septicemia, hiperpnea, infusions of hypertonic solutions.
Almost all patients in whom CSF pressure drop occurs show
headache. This is emphasized in standing and supine positions. It may have
location in frontal or occipital part of the head or it can be broadcast. It has a
severe character, sometimes resistance to painkillers. Headache is aggravated
by sudden head movements and jugular vein compression. Other symptoms
that occur are anorexia, nausea, vomiting, vertigo and tinnitus.
Increased intracranial pressure may be caused by accelerating the
formation of CSF, poor absorption, increased intracranial venous pressure,
obstruction of CSF circulation, increase brain mass or volume due to
neoformation or cerebral edema (vasogenic/cytotoxic/interstitial), subdural
hematoma or combination of the above. According to the doctrine of Monro
any increase in brain volume increases intracranial pressure resulting in
compression of the skull which walls are rigid and inextensible. Clinically
the suffering induced by the brain compression is characterized by headache,
vomiting and papilla edema. There is not always a correlation between the
presence of headache and degree of increase intracranial pressure.
Associated with hypertension

Headache may be secondary to disorders that are associated with
elevated blood pressure. In these situations the sudden high values of the
blood pressure is more important than the absolute value. One of the diseases
that manifest as sudden increases in blood pressure is pheochromocytoma.
Between 51 and 80% of patients with pheochromocytoma declare this
headache. It has a paroxysmal character, pulsed or continuous sometimes
more frequently and is located in the frontal or occipital part. It is usually
accompanied by palpitations, anxiety, sweating and facial pallor. It installs
when blood pressure rises suddenly and in 70% of cases improve or
disappear within an hour from the normalized blood pressure.
Migraine
Definition
Migraine is the second most frequent type of headache. According to
the International Headache Society classification it is a primary headache
(meaning that the headache itself is a disease and not secondary to another
pathology).
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It is a chronic disorder punctuated by disabling recurrent attacks of
head pain accompanied by other neurologic and systemic dysfunctions.
Although in its most typical form the clinical characteristics of migraine are
easily recognized, there are situations when the type of headache (and the
therapeutical approach) are not that easily discerned. The IHS has provided
diagnostic criteria that help differentiate and properly diagnose migraine.
Etiology and pathogeny

There is no clear etiology of migraine, although there is probably a
strong genetic component. In some patients there is a documented ion
channel abnormality. Migraine is more prevalent in women (women/men =
3-4/1)(possibly accounted for by the hormonal differences) (in children the
boys/girls rate is close to 1). White seem to be more affected than black and
asian (at least in american populations). Migraine is more common in people
from low socioeconomic groups and low education.
The highest incidence of migraine attacks is in the 35 to 45 years age
range.
Pathogenesis of migraine has been largely studied and more
mechanisms seem to be involved in its developpment: the spreading
depression, neurogenic inflammation, peripheral sensitization and central
pain facilitation.
The aura has been correlated with the wave of cortical spreading
depression (CSD), a front of neuronal and glial excitation followed by
depolarization (depression) that advances at a rate of 2-3 mm/minute and
lasts for about 1 minute. It is associated with marked decrease in membrane
resistance, increase in extracellular K+ and intracellular Na+ and Ca2+ levels
and also of the level of neurotransmitters. The exact mechanism that triggers
CSD is not known. It develops in different brain areas, including the cerebral
cortex, hippocampus, cerebellum, and it can be experimentally triggered by
electrical or chemical stimulation.
The headache probably results from activation of meningeal and
vascular pain receptors (the so called "trigemino-vascular system").
Stimulation of the cranial vessels, such as the superior sagital synus, is
painful in humans. Activation of the trigeminal receptors leads to increased
release of P substance, calcitonin gene related peptide and to modulation of
blood vessel activity (leading to abnormal wall permeability, activation of
platelets and other cells and abnormal blood flow).
The trigemino-vascular reflex triggers the secretion of serotonine
and histamine. Serotonin induces contraction of the cerebral vessels, together
with increased capilary permeability. Plasma kinins penetrate the vessel wall
and change the treshold for pain in the periarterial structures. This is similar
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to inflammatory processes sterile neurogenic inflamation is an important
component of the migraine and it is thought to be responsible for the
sensitization of the peripheral nerve structures. As vasodilation follows, the
typical pain is generated.
Trigeminal sensory information is conveyed in the caudal brainstem
and high cervical spinal cord, and then, through the quintotalamic tract to the
thalamus, mostly in the ventroposteromedial thalamus and the intralaminar
thalamus. Brainstem activation represents a fundamental part of migraine.
Abnormal neural excitation in the diencephalon (especially in the thalamic
regions representing the trigeminal area) has also an important role in the
pathogenesis of migraine.
Clinical picture
According to the IHS the diagnostic criteria for migraine include
recurrence (at least 5 attacks) duration (headache must last between 4 and 72
hours in adults if not treated or unsuccessfull treatment), special characters
regarding location and character (unilateral, pulsating, moderate to severe
intensity, aggravated by physical activity, even those related to habitual
activity), and association with other symptoms (nausea and/or vomiting,
and/or abnormal sensitivity to light and noise. In children below 14 years of
age the duration of the attack may be shorter (2-48h); the patient has to fulfill
at least 3 of the special characters.
Unilateral headache (hemicranial) with temporal and parietal
localization characterizes 2/3 of the patients, and affects most of the times
(but not always) the same part of the head. It can be bilateral or migrate from
one side to the other during the same attack. The pain is usually described as
pulsating and throbbing. Accompanying symptoms include nausea (90% of
patients), anorexia (60% of patients), intolerance to sound, light or odors
patients are usually in a bad mood and search for a quiet dark room to rest.
Sleep usually calms the pain.
A classic migraine attack has a prodromal phase (preceding the actual
pain with hours or days), the aura (immediately preceding the headache), the
headache itself and the postdrome (the patient is tired, irritable, with residual
neurological symptoms, scalp tenderness or mood changes).
During the headache phase other vegetative symptoms may occur
conjunctive injection, pallor, elevated blood pressure.
The attacks can appear at a variable pace from a few a year to a few
a week. Precipitating factors include menstruation or different substances (eg
chocolate, aspartame, fermented cheese).
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Classification
Classification of migraine (Table 1) takes into account the presence
or absence of an aura. Common migraine (migraine without aura) is the most
frequent form (80%). Aura is a complex of focal neurological symptoms that
immediately precedes the attack or accompanies it. It can involve motor,
sensory or visual phenomena. It develops relatively fast (a few minutes) and
lasts for less than 1 hour. Migraine with aura is the second most frequent
form. Other features taken into account for classification are associated
features sight disturbances or other neurological problems.
Migraine types (IHS classification, 2004)

1. Migraine without aura
2. Migraine with aura
3. Childhood periodic syndromes that are commonly
precursors of migraine (cyclical vomiting, abdominal
migraine, benign paroxysmal vertigo of childhood)
4. Retinal migraine
5. Complications of migraine (chronic migraine, status
migrainosus, persistent aura without infarction,
migrainous infarction, migraine-triggered seizures)
6. Probable migraine
Table 4. Classification of migraine
Complicated migraine associates additional neurological

manifestations to the headache. Status migrainosus is defined as an attack of
migraine that lasts for more than 72 hours despite correct treatment.
Ophtalmoplegic migraine is very rare form that associates headache to
paresis of one or more oculomotor nerves. Retinal migraine associates visual
impairment that may mimic amaurosis fugax (scintillating scotoma appear
10-20 minutes before the headache, and migrate from the center of the visual
field outward, until they "fall out", leaving a transient blurriness of vision).
Hemiplegic migraine (migraine accompagnee) is characterized by the
association of transient hemiparesis (or other type of focal neurological
deficit), that precede the headache and usually last for hours (at most 1-2
days usually, but sometimes longer). Familial hemiplegic migraine is rarely
followed by a permanent motor deficit. In alternating migraine of childhood
attacks of hemiparesis on alternating sides of the body associate with
psychomotor retardation, movement disorders. Basilar migraine associates
dysfunction of the structures in the posterior fossa, with posterior headache.
Association of typical headache makes easy the differential
diagnosis.
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A clear clinical picture does not require further evaluation, unless
attacks change in frequency or character, or they begin after 40 years of age.
If one suspects a secondary headache, or other neurological
abnormalities are found, MRI evaluation of the brain (eventually with
angiographic reconstruction) are recommended. Routine blood tests
including electrolytes and thyroid function might be necessary.
Differential diagnosis includes other causes of headache tumors,
cervical pathology, temporomandibular artropathy, trigeminal neuralgia,
intracerebral aneurysms, glaucoma, sinusitis, transient ischemic attacks,
other abdominal pathology in abdominal migraine.
Treatment
Migraine treatment focuses on two objectives: acute treatment aims
to end/alleviate the attack, and the preventive treatment aims to prevent (or at
least lower the frequency) of the attacks. Depending on the characteristics of
the disease in a patient (mainly intensity and frequency of the attacks) the
physician may choose to use one or both the therapeuthical approaches.
Acute treatment may be specific and nonspecific.
The specific drugs used in migraine are the triptans and ergot
derivates they act on specific pathophysiologic mechanisms in migraine
and aren't useful in other types of pain. Non specific treatment includes
nonsteroidal antiinflamatory drugs (NSAIDS), analgesics, antiemetics,
steroids and other drugs that may be used to control associated pathology
(table 2).
While analgetics are used for mild and moderate attacks, triptans are
used for moderate to severe attacks and dihydroergotamine mesylate must be
reserved to severe attacks that do not respond to triptans. Acute treatment
must be administered before or as soon as possible after the attack has begun
(the earlier the more effective). Early intervention prevents escalation and
may increase efficacy.
Triptans are a relativelly homogenous group in regard of efficacy,
safety and pharmacology. The fastest effect appears with subcutaneous
Sumatriptane (as well as the best efficacy), while orally administered drugs
take 30-60 minutes to act. Intranasal dosing is also faster than the oral way.
Recurrence rates (15-40% of attacks) seem to be higher in faster and
more efficient drugs, while drugs that offer a better protection against
recurrence tend to have a slower but more prolonged action. Triptans are
aggressive vasoactive drugs, so caution is needed in patients with known or
suspected cardiovascular pathology.
Preventive treatment aims at a reduction of the frequency, duration
and severity of the attacks, and also to improve the efficacy and
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responsiveness to acute treatment. It is recommended whenever the attacks
significantly disrupt the lifestyle of the patient, when the incidence of attacks
is above 2/month, if there is a low reactivity or if there are contraindications
for the acute treatment, or in special situations, as complicated migraine or
migrainous infarction. Medication is to be started with low doses and
increased slowly until either therapeuthical efficacy is met (a reduction of at
least 50% in attack frequency over 3 months), either maximal dosage is
reached or adverse effects appear.
Drug class Drugs Indication

NSAIDs Acetylsalicilic acid (ASA); Ibuprofen;
Naproxene; Diclofenac; Paracetamol Headache
Combinations ASA+Paracetamol+Caffeine; ASA-lysine- acute
Metoclopramid treatment
Triptans Sumatriptane, Naratriptane, Rizatriptane, (level A)
Frovatriptane
Antiemetics Metoclopramide, Domperidone Nausea, vomiting
(level B)
Beta blockers Metoprolol; Propranolol;
Timolol; Nadolol
Calcium Flunarizine Prevention of attacs
channel (level A)
blockers
Antiepileptics Topiramate, Valproic acid
Antidepressants Amitriptyline, Venlafaxyne Prevention of attacs
(level B)
Others Gabapentine, Lysinopril, Prevention of attacs
Candesartan, Riboflavine, (level C)
Magnesium, Petasites hybridus
extract, ergot alcaloids
Table 5. Drugs used in acute and prevention treatment of migraine attacks
Drugs that have proven efficacy in migraine attack prevention are

some beta blockers, topiramate, amitriptyline, divalproex. Other drugs are
probably effective (gabapentin, venlafaxine, MIG-99), while others have
only third line indication, with limited or conflicting evidence supporting
their use.
Acute self admininstered medication overuse can lead to medication
overuse headache (chronic daily headache), and even dependence for
sedatives. A diary for migraine attacks and medication should be used to
ensure a proper efficacy evaluation.
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Rescue medication is necessary when initial acute medication has not
given enough relief from an attack. ASA 1000 mg i.v. or Sumatriptane 6 mg
s.c. can be used. In status migrainosus prednisone or dexamethasone are
used. Other drugs used in severe attacks are dihydroergotamyne 2mg
(intranasal or intrarectal), i.v. metamizole (with risk of severe arterial
hypotension and alergic reactions).
Cluster headache
Cluster headache (CH) is characterized by recurrent, severe
headaches. Attacks are usually grouped in "clusters" that appear periodically
(most often during spring and autumn). Painful periods last between 1 week
to 1 year. Spontaneous remission separates clusters of painful attacks
(usually over 1 month). In 10-15% of cases there is no remission between the
clusters of attacks. Most of the times disease starts in the last part of the
second life decade.
The precise etiology for CH has not yet been established, but
different mechanisms have been proposed (neurogenic inflammation,
vegetative dysfunction, circadian rhythm alteration). In rare families it has
been shown to have an autosomal dominant transmission.
The painful attacks are relatively short (30-90 minutes). Usually there
are 1-2 attacks/day. The pain is severe, unilateral, located in the orbital,
supraorbital and/or temporal region. It is described as burning, stabbing,
boring or squeezing. The intensity of the pain rises quickly during an attack.
At least one of the accompanying autonomic symptoms should appear:
lacrimation, conjunctival injection, nasal congestion and rhinorrhea,
swelling around the eye, miosis, palpebral ptosis or edema, typically
confined to the side of the head with the pain.
Accompanying psychological and cognitive symptoms can appear -
inability to organize thoughts and plans, physical exhaustion, confusion,
agitation, aggressiveness, depression and anxiety. People with CH may dread
facing another headache and may develop generalized anxiety disorders,
panic disorder, serious depressive disorders, social withdrawal and isolation.
The attacks awaken the patient and tend to happen around the same
time every day.
Acute treatment includes fast acting triptans (subcutaneous or
intranasal Sumatriptan), oxygen, eventually ergot derivates (DHE). During
attacks, triggers such as alcohol, nitroglycerine and naps during the day
should be avoided.
As in migraine, preventive treatment can lower the number of attacks.
Calcium channel blockers (Verapamil) have proven efficient (first line).
Corticosteroids can be useful. Other drugs that may be helpful in prevention
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of the attacks are topiramate, melatonin, lithium. Local interventions
(ranging from capsaicin, local anesthetics to surgical intervention) can be
tried if the medical approach fails.
Tension Headache
Tension headache is the most frequent of the primary headaches.
Although it can alter life quality, it is usually benign, without major
pathological associations. It can appear at any age, although it tend to be
more present in young adults.
Etiology is thought to involve abnormal central pain processing, with
increased sensitivity for pain (due to abnormal serotonin, monoamin or nitric
oxide signaling pathways). Abnormal contraction of the muscles around the
head and neck (sustained contraction) is probably another mechanism
involved in pain generation.
Various precipitating factors may cause/favour tension-type
headaches in susceptible individuals: stress: usually occurs in the afternoon
after long stressful work hours or after an exam, fatigue, sleep deprivation,
hunger, eyestrain, abnormal/uncomfortable position of the neck/head.
Tension headache can be classified in episodic and chronic. Episodic
headache can be frequent (more than 1 but less than 15 days/month) or
infrequent (less than 1 day/month). Chronic tension type headache appears in
more than 15 days/month.
Typical attacks last usually for 4-6 hours (30 minutes to 7 days). Pain
is usually mild to moderate, with a pressing/ constricting quality (non-
pulsating), dull. No vegetative symptoms (vomiting, nausea, conjunctival
injection) should be present. The pain is usually bilateral.
NSAIDs and usual analgesics are usually efficient as acute treatment.
Drug overuse and self medication can lead to medication overuse headache.
If attacks are frequent and disturbing, Amitriptyline is the first
choice drug for long time prevention. Other antidepressants, as well as beta
blockers and antiepileptics can be useful. Physical therapy, manual therapy
(spinal manipulation, myofascial trigger point treatment, chiropractice) and
biofeedback are thought to be helpful, although there is no clear evidence to
support their efficacy.
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patient with headache. Semin Neurol. 30:131-144 2010
4. International Headache Society Classification
Subcommittee:International classification of headache disorders,
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5. Ju Y.-E.S., Schwedt T.J.: Abrupt-onset severe headaches. Semin
Neurol. 30:192-200 2010
6. KAZEMI H, SPECKMANN E-J, GORJI A. Familial Hemiplegic
Migraine and Spreading Depression. Iranian Journal of Child
Neurology 2014;8(3):6-11.
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disorders. Semin Neurol. 30:107-119 2010
9. Ropper AH, Adams and Victor's Principles of Neurology, Eighth
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neuroimaging procedures in non-acute headache: guidelines and
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11. Smetana G.W., Shmerling R.H.: Does this patient have temporal
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12. Zimmermann M.: Pathobiology of neuropathic pain. Eur J
Pharmacol. 429:23-37 2001
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Chapter XII.
Cerebrovascular diseases
General data Cervical arteries disection

Cerebral infarction Cerebral tromboflebitis
Cerebellar infaction Procoagulability state in stroke
Transient ischemic attack Intracranial hemorrhages
Carotid TIAs Treatment in stroke
Embolic stroke Antiaggregant and anticoagulant
Lacunar infarction therapy in neurological disease
General data
Stroke is the third leading cause of death worldwide and is preceded
by heart disease and cancer mortality. Disabling stroke is so extreme that
30% of patients need help for daily activities, 20% went have the gait
influenced and need help to move, and 16% remain institutionalized.
Worldwide in 2010, roughly 10% of the 52 769 700 deaths were due
to stroke. Latest data show that although stroke mortality rates and mortality-
to-incidence ratios have decreased in the past two decades, the global burden
of stroke in terms of the absolute number of people affected every year,
stroke survivors and related deaths, are great and increasing, with most of the
burden in low-income and middle-income countries. If these trends in stroke
incidence, mortality, by 2030 there will be almost 12 million stroke deaths.
Stroke was traditionally thought of as a disease of elderly people;
however, recent data show that the proportion of stroke burden is greater
overall in individuals younger than 75 years than in those who are older.
Although in the past two decades there was a trend towards occurrence of
incident stroke later in life, probably because of an ageing population, the
proportion of young people (aged <20 years) and young and middle-aged
adults (2064 years) affected by stroke increased. However, more than 83
000 children and youths aged 20 years and younger are affected by stroke
annually In view of the worldwide epidemic of diabetes and increasing
217
prevalence of other cardiovascular risk factors in young adults the shift in
stroke burden towards younger populations is likely to continue globally
unless effective preventive strategies are urgently implemented.
It is also important to recognize that silent stroke and diffuse white
matter disease are aspects of cerebrovascular disease with major effects on
risk of cognitive impairment and dementia contributing to mortality in the
aging population. Increased application of advanced neuroimaging such as
magnetic resonance imaging might improve the diagnosis of milder, less
fatal strokes over time
Strokes can be ischemic and hemorrhagic. The ischemic one is the
most frequent one and can be 80% of the total. To produce an ischemic
stroke there must exist a series of pathological changes. These include an
existing atheromatosis of the cerebral arterial system, at least one embolic
source, inflammatory changes of the arterial wall (vasculitis), blood diseases
which can induce states of pro coagulation, the impossibility of venous
drainage in certain territories, thrombophlebitis.
Hemorrhagic strokes occur in case of existence of an arteriovenous
malformations, aneurysms, hypercoagulable states, anticoagulant treatment
or hypertension.
The incidence of stroke increases significantly with age and
accumulation of risk factors. Age, sex, race, family history and genetic
factors are modifiable risk factors. Hypertension, heart disease embolic,
diabetes, dyslipidemia, smoking, alcohol consumption, obesity, use of
contraceptives are modifiable risk factors either by treatment or through
lifestyle changes. The main modifiable risk factor is hypertension, from
which suffer at least 25% of the population and for which there is an
effective therapy.
Stroke is the third leading cause of death worldwide and is precedeed
by heart disease and cancer mortality. Disabling stroke is so extreme that
30% of patients need help for daily activities, 20% went have the gait
influenced and need help to move, and 16% remain institutionalized.
Pathological characteristics depend on the etiology of the ischemic
stroke (thrombotic, embolic, hemodynamic), the size of vascular pedicle
interested and the possibilities of alternate system of collaterals. Therefore it
can be described syndromes of large artery (internal carotid), post polygonal
artery (anterior cerebral, middle and posterior) or arteries dependent on the
vertebra basilar trunk (cerebellar arteries). Added to these are the small
penetrating arteries induced pathology (lacunar infarcts) and developed
thrombophlebitis in certain venous brain structures.
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Cerebral infarction
Cerebral infarction is defined as zone of brain tissue necrosis due
either to a thromboembolic occlusive mechanism, or a hemodynamic one.
An important role is atributed to atherosclerosis developed in the cerebral
arterial and anastomotic systems. Stenosis due to development of an
atherosclerotic plaques favors the formation of a mural thrombus wich may
grow out from the vessel wall into the lumen being bend in the direction of
the flow of blood; the thrombus may undergo resorption through
fibrinolysis, or may fragmantate and migrate to other arterial territories.
Cerebral embolism is another cause of cerebral infarction.
The most common source of emboli is heart disease, the carotid
system being prevalently affected. The hemodynamic mechanisms due either
to narrow or multi level stenosis usualy result in jonctional infarcts with a
marginal low blood flow. Another hemodynamic mechanisms is the
syndrome of intracerebral and extracranial hemodeterminism. Intracerebral
hemodeterminism is due to the presence of some arteriovenous
malformations or vascularized tumors. One of the most common phenomena
of extracranial determinism is the subclavian steal syndrome resulting from
stenosis or oclusion of subclavian artery proximal to the origin of vertebral
artery. Under these circumstances the flow of the blood in the vertebral
artery is reversed, and the upper extremity steals blood from the
vertebrobasilar system.
Around the area of necrosis appears a dim area, characterized by a
decrease in cerebral blood flow, wich blocks the synaptic activity with the
preservation of cell and ionic gradient integrity. This area of ischemic dim is
irreversible.
Infarction of brain area results from oxygen and glucose deprivation.
Lack of oxygen alters the oxidative metabolism of glucose determining an
increase in lactate level and appearance of acidosis. Acidoses breaks
blood brain barrier aggravating the celullar dysfunction especially by the
penetration of natrium ion into the cel land exteriorization of potassium ion.
Water migrates toward the intracellular space, and thus a cytotoxic
intracellular edema results. Associated to this edema is an extarcellular
edema resulting from the transfer of water and macromolecules from the
vascular sector to the extracelular one.
When either by reirrigation or thrombus mobilization the
hemorrhagic transformation of the infarct occurs , the cerebral edema
expands.
Depending on the compensatory hemodynamic mechanisms and
location of some thrombi or emboli, cerebral infarcts are: junctional,
territorial, terminal, proximal, and central.
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Junctional infarct is due to a decreased blood flow in the border zone
of two arterial territories. Territorial infarct affects the entire volume of
cerebral tissue irrigated by the occluded artery. Terminal infarction is sited in
the distal territories of the thrombosed artery. Proximal infarct is located in
the territory proximal to the origin of the thrombossed artery. Central infarct
is sited in the center of the theritory of distribution of an artery while the
proximal and distal areas receive enough blood through anastomoses.
Infarctions within the carotid artery territory are more common than
those in the vertebrobasilar system. Several territories , such as the origin of
the trunks in the aortic arch , origin of internal carotid artery, carotid siphon,
and terminal part of the common carotid artery, prove to be more vulnerable
to atheroma plaques formation, wich in their turn favor cerebral thrombosis
and infarction. Several occlusive syndromes within the territory of the
common carotid artery internal carotid artery, anterior, middle and posterior
cerebral artery may develop.
The occlusive syndrome of the common carotid artery may be of
proximal or distal type. The proximal occlusive syndrome is clinically
manifest by controlateral pyramidal syndrome, and diminished or absent
pulsation of some collateral arteries. A controlateral pyramidal syndrome
may be accompanied by visual field disturbances, loss of sensibility, mental
confusion, seizures, and speech disturbances when damage is to the
dominant hemisphere.
The distal occlusive syndrome determines hemiplegia on the opposite
side and absence of pulsation at the superficial temporal artery.
Thrombosis of the internal carotid artery may occur both proximally (
extracranial) or distally( intracranial). With proximal location, in the
presence of some functional or rapid circulatory adaptation abnormalities,
controlateral hemiplegia, lateral homonymous hemianopia, and aphasia may
occur. Complete and suden thrombosis may be fatal.
Intracranial occlusion occurs before or beyond the origin of
ophthalmic artery. Failure of ophthalmic artery to irrigate the eyeballs
determines a optic-pyramidal syndrome consisting in ipsilateral blindness
and controlateral hemiplegia. Thrombosis of the terminal part of internal
carotid artery causes an extensive hemispheric infarct characterized by
contralateral hemiplegia, coma, sign of brainstem involvement.
The anterior cerebral artery supplies a superficial and deep territory .
Infarction in the superficial territory results in hemiplegia predominant in
leg, hypesthesia with the same topography, mutism followed by aphasia, as
well as other signs characteristic to frontal lobe sindrome (grasp reflex,
unilateral left apraxia, behaviour disorders). Infarction in the deep territory
results in a brachial-facial hemiparesis asociated with a soft palate and
tongue defict and dysarthria. In some cases a single anterior cerebral artery
220
may totally or partially supply the contralateral teritorry. Oclusion of such
an artery may cause paraplegia, akinetic mutism, urinary incontinence, and
bilateral gasp reflex.
Infarcts in the sylvian territory may be superficial and deep; the
complete sylvian infarction is also described. Deep infarction may cover the
entire cotical- subcortical territory of distribution, or may be partial and
located either anteriorly or posteriorly. Complete superficial sylvian infarct
results in hemiplegia with predominantly facial- brachial deficit,
hemihypesthesia, astereognosis, lateral homonymous hemianopsia,
anosognozia or hemianosognozia (damage to the minor hemisphere), total or
Brocas aphasia with ideomotor apraxia( damage to the major hemisphere).
Anterior infarcts causes hemiplegia and contralateral sensory deficits (with
facial brachial predominance), paralysis of eye conjugate movements to the
opposite side, predominantly motor aphasia (verbal hemisphere).
Infarcts in the posterior territory result in lateral homonymous
hemianopsia on the opposite side, sensory aphasia, ideomotor aoraxia,
constructional apraxia, alexia, agraphia, acalculia, digital agnosia (lesion
affects the dominant hemisphere). Posterior infarction of non-verbal
hemisphere results in anosognozia, hemiasomatognozia, left space agnosia,
constructional and dressing apraxia. Infarction in the deep sylvian territory
determines contralateral hemiplegia (capsular) with lateralhomonymous
hemianopsia and expressive aphasia with dysartric element (damage of the
verbal hemisphere). Complete sylvian infarct is severe, progressing to death
by temporal lobe herniation. Contralateral hemiplegia, hemianestesia, lateral
homonymous hemianopia, deviation of the eyes on the same side , comatose
state are present.
Infarction of the posterior cerebral artery may be of complete,
superficial and deep type. Complete infarction causes damage to the
posterior and inner parts of cerebral hemispheres, high territory of cerebral
peduncles, thalamus, hypothalamus (posterior or inferior), corpus Luysii,
optic radiations, posterior partb of corpus callosum and pineal gland. Thus, a
hemiplegia with hemianopia, hemianesthesia, cerrebelar disturbances, and
sensory aphasia will develop.
Superficial infarct may be unilateral or bilateral. The unilateral one is
characterized by lateral homonymous hemianopia (mainly in upper quadrant)
wich may be accompanied by alexia and visual agnosia. With a bilateral
superficial infarct, cortical blindness or bilateral hemianopia ensue. Infarcte
in the deep territory of the posterior cerebral artery may result in peduncular,
thalamic, and subthalamic syndromes, Weber syndrome, Claude syndrome,
Benedict syndrome, Parinaud syndrome, or Foville syndrome are the most
common peduncular syndromes. Thalamic syndromes follow occlusion of
the talamoperforant, talamogeniculate branches, and posterior choroidal
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arteries. The most common effect of a talamoperforant infarct is a
confusional syndrome associated with ocular motor distrubances,
contralateral hemiparesis, hemihypestesia, hemiataxia and choreoathetosis.
When there is a single pedicle (talamoperforant), a bilateral infarction
characterized by disorders of consciousness, amnesia, paralysis of vertical,
oblique deviation of the eyes, internuclear ophthalmoplegia, lid drop, and
myosis do result.
With a thalamogeniculate infarction there is a transitory hemiparesis,
accompanied by superficial hemianesthesia, hemiataxia, astereognosis, and
contralateral choreoathetotic movements.
Infarction in the posterior choroidal territory results I upper or lower
quadranopia, and few cases in hemiparesis with hemihypestesia.
Ischemia in the subtalamic territory causes a hemiparesis, with
hemianesthesia, choreoathetotic movements, cerebellar hemisyndrome (all of
them contralatreal) and lateral homonymous hemianopia.
The main guidelines of a therapeutic strategy in case of acut
ecerebrakl infarction are:
1. Emergency support therapy and treatments of complications:
- protection of the airways and ventilation assistance;
- a moderate treatment of the arterial hypertension;
- treatment of fever sources;
- control of hypo or hyperglycemia after stoke;
- treatment of cerebral edema and raise of intracranial pressure;
- treatment of epileptic seizures.
2. General and early maintenance therapy:
- prevention of subacute complications;
- start the chronic therapy top revent stoke recurence;
- start of effort to recuperate the neurologic functions;
- prevention of deep venous thrombosis;
3. Immediate therapy with antithrombotic drugs and antiplatelet
aggregants.
4. Thrombolytic therapy.
5. Isovolemic hemidilution.
6. Cytoprotective therapy ( steroids, barbiturics and Ca- chanel blocking
drugs.).
7. Surgical interventions ( carotid endarterectomy and angioplasty).
Cerebellar infarction
The cerebellums vascularization is provided by three circumferential
cerebellar arteries:
- Posterior inferior cerebellar artery (PICA);
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- Anterior inferior cerebellar artery (AICA);
- Superior cerebellar artery (SCA).
The cerebellar stroke is usually caused by PICA or vertebral arterys
occlusion.
The onset can be either acute or subacute, manifested by posterior
headache, intense vertigo, vomiting, cerebellar ataxy, dizarthria and
nistagmus. It may also manifest by peripheral facial palsy and even comatose
state.
From clinical perspective, there are two forms described: a severe
form with manifestations described above, and a benign form, manifesting
more likely by vertigo.
PICA gives collaterals to the arteries supplying the dorsal medullary
territory, to the
lobulus semilunaris inferior, the lobulus gracilis, the lobulus biventer, the
tonsilla cerebella and also at vermian level, to the clivus, the tuber, the
pyramis, the uvula and the nodulus.
An infarction located in PICAs territory will manifest by Wallenberg
syndrome. This, depending on the size of the stroke and the interested nerve
tracts, can be followed by clinical manifestations such sensory deficits of
ipsilateral face and the contralateral trunk and extremities, ataxy, nistagmus,
nausea, vertigo or dysphagia.
AICA provides vascularization for the ponto-cerebellar territory,
irrigating the lateral territory of the lower part of the pons, the middle
cerebellar peduncle, the flocculus and the neighbouring lobules of
cerebellum. In cases when PICA is hypoplastic, AICA provides irrigation for
the territory usually irrigated by the lateral branch of PICA. A stroke located
in AICAs territory will clinically manifest by: tinnitus, vertigo and
dysarthria.
SCA irrigates the brainstem region situated on the dorsal tegumentum
and the tectum of the upper segment of the pons. It also supplies the upper
cerebellar region: lobulus semilunaris superior, lobulus anterior and lobulus
simplex. At vermian level, vascularization goes to the lobulus centralis, the
culmen and clivus (thus the dentate nucleus).
More clinical signs can be observed in SCA infarction. The clinical
picture in this situation may consist of: ipsilaterally Horner syndrome,
hemiataxy, intentional tremor, disarthria, vertigo, controlateral sensitive
deficits, nausea or headache.
Vertigo, vomiting, ataxy and nistagmus are clinical signs that can be
encountered in all the three localisations. Headache tends to be much more
present in PICA involvement, as well as Horner syndrome, wich may also
inconstantly occus in AICA stroke.
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Transient ischemic attack (TIA)
A recent definition of TIA (2002) states that this is a brief episode of

neurological dysfunction causing focal ischemia or retinal symptoms that can
last up to one hour without identifying an acute infarction. The diagnosis is
important because it can announce a future stroke or major cause for deficits
or even death.
TIA incidence increases in relation to age and risk factors.
Approximately 75% of the TIAs occur in the carotid teritory. The variant
"amaurosis fugax" can be found in approximately 18% of patients. The study
Minnesota C. Rochester found an incidence of 68 cases per 100,000
population of TIAs. This incidence increases with age so that in the interval
between 75 and 84 years may reach up to 584 cases per 100,000 inhabitants.
The risk factors that may favor the occurrence of TIA include
hypertension, smoking, diabetes, atrial fibrillation, aortic arch and cervico-
cephalic arteries atheromatosis, myocardial infarction. The risk of fatal or
disabling stroke at 90 days after TIA is 10-20%.
The brain is not able to make deposits of glucose and oxygen and
therefore requires a rhythmic supply. TIA can be produced by the presence
of atheroma localized inseide the cerebral arteries or by embolic mechanism
involving the penetrating arteries. In addition to changes in the arterial walls
made by atheromatosis and hyalinosis also a number of blood diseases that
can cause cerebral circulation disorders have been identified.
The first place in the order of incidence is taken by the mechanisms
leading to the emergence and development of atheromatosis. The lumen
narrowing is associated with increased platelet aggregation and can lead to a
TIA. W also have to consider the time of diagnosis and the possibility of a
arterial dissection.
The TIA determinism involves causes like arterial pathology, blood
diseases, embolic mechanisms, genetic diseasee are listed in the table above.
The difficulty lies in the rapid diagnosis and installation and
disappearance of clinical signs. The rapid onset of deficits, presence of signs
of dysfunction (motor, sensory, visual, speech disorder) and their rapid
disappearance in 60% of cases in less than an hour, are the characteristics of
a TIA. Clinical signs are characteristic of carotid or vertebrobasilar
localization.
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Causes of TIAs
Arterial causes: Blood diseases:
- Aortic and cervico-cephalic - sickle cell anemia
atheromatosis - thrombocytosis, polycythemia,
- Arterial dissection - hyperviscosity
- Temporal arteritis and other - antiphospholipid antibody
vasculities syndrome
- Moya-Moya disease - hypercoagulable states
- CADASIL
- MELAS
Causes of embolic stroke: Genetic diseases:
- Arterio-arterial - Fabry disease
- Presence of foramen ovale - homocysteinemia
- Atrial myxoma Other causes:
- Non bacterial thrombotic - hypoperfusion
endocarditis bacterial - amphetamine or cocaine
Table 1. Causes of TIAs
Carotid TIAs
Transient monocular visual loss is due to carotid TIA. The existence

of a transient episode of monocular loss of vision for 1-10 minutes or aphasia
accompanied by dysarthria is suggestive of a TIA.
There are also so-called "spectacular shrinking deficit" due to an
embolus reaching the distal internal carotid artery or the proximal middle
cerebral artery. The patient presents with sensory motor deficit, hemianopsia,
aphasia or neglect of the left space, signs that disappear after 3-4 hours due
to thrombus migration and its lysis.
A TIA due to involvement of the vertebral arteries is accompanied by
vertigo, normalization, diplopia and headache. A TIA charcterised by vertigo
elements can evolve into a stroke in the coming weeks.
If basilar artery is involved the patient may experience signs of
bilateral motor fluctuating damage. The involvement of the posterior cerebral
artery territory may cause visual phenomena such as "graying" or
"darkening" localized in unilateral vision or flashing lights in red or white.
TIA due to the involvement of small penetrating vessels can be
repetitive with a longer duration than in large vessels. In most cases the TIA
in penetrating vessels is followed by a ischemic stroke in short time. It
describes the so-called "capsular warning syndrome," which is due to
transient ischemia of the internal capsule produced by involving of the small
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penetrating arteries. The same syndrome can be produced in rare situations
by large artery pathology.
In a few cases the patient may be investigated before or during the
production of TIA. In most cases the practical investigations are done after
12-48 hours. Investigations should include an examination of large vessels
(doppler cervico-cephalic), echocardiography, CTscan or MRI and
angiography. There are helpful: glucose, urea, creatinine, lipids and
colesterole.
As for differential diagnosis you have removed any partial seizures,
migraine crisis, cardiac arrhythmia, cerebral venous thrombosis or even the
existence of an subdural hematoma or brain tumors. It is also necessary to
exclude a hypoglycemic crisis or hyponatremia. A neuronal layrinth
infection can mimic a TIA in the vertebrobasilar territory.
The treatment is done after exclusion of cardiac emboli generating
pathology. Patients will be treated with antiplatelet agents (aspirin,
clopidogrel, aspirin combined with dipyridamole). Patients with cardiac
disease (most frecevnt AF) will receive anticoagulants. If there is a 70-90%
carotid or vertebral stenosis in the extracranial segments, patients will
undergo intervention such as endarterectomy or stenting. Angioplasty and
stenting are charged for carotid stenosis. The main risk factors are identified,
in order to be delayed, with means like hypotensive medication,
normolipidemic or hypoglycaemic.
A TIA is to be interpreted as a sign requiring emergency rapid
assessment and correction of therapy. It is a real telegram that may announce
an ischemic stroke at a short interval.
The embolic stroke
The heart remains the main source of emboli reaching the general
circulation including the brain. New data support that the aortic arch to the
left subclavian artery detachment and the great cervico-cephalic vessels can
become sources of arterio-arterial emboli. In these cases accidental
embolization caused by vascular interventions or exploratory techniques are
added. Embolic mechanism is responsible for about 20-25% of ischemic
stroke. The incidence appears to be increasing under the age of 45 years.
Emboli can form cavities in relation with atrial or ventricular valvular
pathology. Atriums can form emboli on the existence of arrhythmias such as
atrial fibrillation and flutter. The persistence of foramen ovale and atrial
septal aneurysm are fulfilling the conditions to achieve the so-called
"paradoxical embolism". The existence or development of an atrial septal
aneurysm formation creates the favorable condition for hemodynamic
226
emboli. Here you can form and develop a benign tumor formation - atrial
myxoma. This tumor is friable and is possible to detach fragments and
embolization. Carotid sinus syndrome or "sick sinus syndrome" creates the
necessary formation and release of embolized fragments.
Rheumatic valvular stenosis pathology, bacterial endocarditis and
prosthetic nonbacterian or metal (mitral) valvs are risks for the formation and
release of emboli into circulation. The ventricular cavities can cause emboli
in the conditions of a recent myocardial infarction, hypertrophic or dilated
cardiomyopathies, the existence of akinetic areas, or Chagas disease.
Surgical interventions on the heart, aorta and the great vessels can
generate embolic particles to the cephalic extremity. In rare cases
angiography and aortography investigations type can cause cerebral
embolism.
Clinical signs are characterized by sudden installing and when
spontaneous recanalization happens by spectacular improvements.
Embolization may interest both the carotid and vertebral basilar teritory. In
patients undergoing cardio-embolic stroke there should be a disease that
causes the formation of emboli (ex. AF, recent MI etc.) or atheromatosis
with possible complication in the aorta and great vessels, which goes to the
brain. Particles can embolize cortico-subcortical and achieve both infarction
and damage in the deep penetrating arteries teritory. This kind of embolism
depends on the size and distribution and the path that the emboli goes.
Infarction occurs most often in the middle cerebral artery territory and less in
the pre or post cerebral arteries.
The investigations will focus on identifying the source of emboli and
the cerebral infarcted territory. It usually starts by CTscan or MRI, diffusion
weighted MRI can specify exactly the lesions of different ages which
signifies a repetitive mechanism.
Ultrasound examination can provide data on etiology. Trans-
oesophageal echocardiography or transthoracic and clarify the pathology of
cardiac emboli generation. EKG or tracking longer intervals (Holter) can
explain the pathogenesis of cerebral infarction.
Communication from the right - left with persistent foramen ovale may be
diagnosed using ultrasonography associated with the intravenous injection of
a ultrasonic contrast.
The treatment consists in recent embolization intravenous
thrombolysis with tPA administered within 3 hours. Intra-arterial
thrombolysis may be considered if the patient presents within the first 3-6
hours and unlikely to achieve recanalization by intravenous tPA. Clot
extraction using Merci device is an alternative to be considered in relation to
its benefit and risk.
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Heparin Anticoagulation starting and continuing oral medicine is the
main medication.
Anticoagulation therapy should be individualized to prevent bleeding or
hemorrhage transformation. Take into account the infarct location, its size,
presence of comorbidities and risk factors. Immediate anticoagulation is
recommended for patients with relapsed stroke, the presence of intracavitary
thrombus, multiple DWI infarcted areas or repeated presence of indications
for the presence of microemboli.
Antithrombotic and thrombolytic therapy is contraindicated in
patients with embolic stroke starting from endocarditis. Atrial myxoma and
papillary fibroelastoma must be operated on, the presence of atrial
fibrillation require long-term anticoagulation therapy, as the existence of a
metal valve. In the bio-prosthetic valves the beginning of anticoagulation is
changed after 3 months on antiaggregation. Persistence of foramen ovale
leads to the need of antiagregation.
Lacunar cerebral infarction
The infarcted territory appears as a small cavity located deep in the

brain parenchyma and is due to the occlusion of a penetrating artery. The
territories that are most vulnerable are ones of the lenticulostriate thalamic
and pontine perforating arteries. Other territories may be interested
especially the ones irigated unequally by small diameter penetrating arteries.
This type of stroke is quite common in medical practice, representing
between 14 and 24% of all ischemic strokes. There is a definite causal link
with hypertension, so that at least 50% of those who do lacunar infarctions
have high blood pressure. Most cases with lacunar infarcts are associated
with diabetes and smoking. Heart disease can generate this kind of stroke.
The infarction is occurring as a result of changes in the penetrating
arteries which decrease their diameter. Age and the presence of other risk
factors may lead to morphological changes in the penetrating arteries and
therefore develop microatheromas and lipohialinosis. Lipohialinosis affects
the penetrating arteries with a diameter of 40-200 nm, which develop
changes due to reshuffling of the fibrinoid necrosis and so in the cortical wall
structure appear collagen fibers which have a tendency to sclerosis. The
microatheroamas can measure between 200-300 nm leading to local
thrombosis, followed by the emergence of infarcted areas somewhat larger 5
mm diameter. The first lacunar infarctions caused by lipohialinosis may go
unnoticed by the patient in the absence of clinical evidence. Lacunar
infarction caused by the presence of microaneurysms produce clinical signs
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that bring the patient to the doctor. It is not excluded a version of
microembolization that can generate the same kind of stroke.
There have been incriminated a number of arterial microemboli who
were detached from the atherom plaque on the aortic arch, or large arteries
with cerebral destination. The clinical picture consists of motor dysfunction,
sensory ataxia.
Pure hemiparesis is the most common variant, and the patient has
facial nerve paresis of central type and limb defects more or less expressed.
The pyramidal tract may be affected in the posterior part of internal capsule,
the corona radiata, pons or midbrain. This type of defect may occur in
approximately 50% of patients. Sensorimotor deficit may be due to
infarction located deep in the posterior part of internal capsule, consisting of
hemihipoesthesia. The deficit is the result of purely sensory thalamic cortical
infarction. In some patients this may be a transitory deficit.
Ataxic hemiparesis may be the result of lacunar infarction located in
the pons or internal capsule, where the clinical picture consists of facial
paralysis, dysarthria, dysphagia and unstable hand (hand clumsiness) and the
lesion is located in the internal capsule. In patients who have lacunar
infarctions, after the acute episode and in time, a frequent occurrence of a
cognitive decline. Recurrence of lacunar stroke speeds the installation of a
cognitive deficit.
Imagery investigations provide conclusive data about lacunar
infarctions. The most common method is the CTscan which can provide
diagnostic errors in the first 48 hours, especially if the infarction is less than
10 mm in diameter. MRI examination is more accurate, especially in the
acute phase, providing important information about the infarcted area, even
if it is small.
Early treatment with aspirin reduces the risk of relapse but may
increase the risk of hemorrhagic transformation.
Thrombolysis with rtPA practiced inside the therapeutic window
improves the clinical picture of patients with ischemic stroke. Secondary
prevention is done with antiplatelet (aspirin, clopidogrel,
aspirin+dipyridamole) and correction of the pathological risk factors
(perindorpil, indapamide, statins).
Disection of cervico-cerebral arteries
Stroke caused by arterial dissections are relatively rare (2.6 cases per
100,000 inhabitants), affecting especially the carotid arteries; approximately
25% of patients under 45 years can have this kind of accident.
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The main etiology is related to neck injuries or to a medical cause,
namely cervical manipulation. There may be a predisposition linked to a
certain thickness of the medial and impaired tissue and elastic artery wall.
Dissection, especially the spontaneous version can be found in
patients with Marfan syndrome, Ehlers-Danlos disease or fibromuscular
dysplasia. It creates a new space between the intima and media where the
blood enters, developing an intramural hematoma, which increases the local
diameter creates a stenosis of the artery lumen. Some fragments of
endothelium may be emboli, which are released into the bloodstream,
causing stroke. There is also the possibility of penetration of blood between
media and adventitia, creating a pseudoaneurysm or rupture of the artery.
The clinical picture is achieved by compression of neighboring
structures and neurological deficits. Facial nerve, Claude-Bernard Horner
syndrome, cranial nerve palsies may be some of the evocative signs.
Carotid artery dissection is accompanied by ipsilateral headache that
also goes to the face, neck, jaw region. To these are added the involvement
of nerves IX-XII, abnormal taste and unilateral Claude Bernard Horner
syndrome.
Signs of cerebral infarction may consist of transitional variants such
as amaurosis fugax or defects characteristic to a carotid ischemic syndrome.
Vertebral artery dissection occurs near the V3 segment located near
the C1 and C2 vertebrae and may be related to a flexion or extension which
is quite limited in this segment. Initially, the patient experiences
laterocervical pain, followed by an interval of hours or days of installing a
characteristic pathology of ischemia inside the brainstem or cerebellum.
Ultrasound is one of the most used methods, both in B mode
(identifying changes in lumen) and the Doppler variant highlighting the
blood flow velocities. The MRI or CT or angiography of the head and neck
may be carried because these techniques provide more complete data about
changes at the site of the dissection. Conventional angiography can be used
and it may reveal the false lumen and changes in the blood circulation.
In the first 3 hours of dissection the treatment can be intra-arterial or
arteriovenous thrombolysis. After overcoming the initial therapeutic window
heparin anticoagulation is recommended in patients with extracranial
dissection. Carotid or vertebral dissections are located intracranial and
anticoagulant therapy should be avoided because sometimes it causes
subarachnoid hemorrhage.
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Cerebral thrombophlebitis
Sinus venous thrombosis determine either as initial signs ischemic
strokes due to the impossibility of drainage or intracranial hypertension.
The incidence of this disease varies from 0.67 cases per 100,000
population per year in children (Canadian study) and 7 cases per 100,000
inpatients (Saudi Arabia) and causes a mortality of about 8%, but cerebral
thrombophlebitis and developments may have very favorable, with a good
functional prognosis.
Cerebral thrombophlebitis is especially common in women than men
with a 3/1 ratio. Pathology is especially common in young adults, calculating
an average age of about 37 years. In women it is demonstrated a relationship
with hormonal factors, especially for pregnancy and contraceptive use. It is
also related to disease pathology system that enhances the appearance and
local factors, among which are distinguished infections and trauma.
Systemic diseases may be of hormonal, coagulation disorders, excess
blood components of inflammatory, malignant or due to dehydration. Among
local causes include the infection of the mastoid cell, sinusitis, meningitis,
brain abscess and head trauma, tumors, some explorations or neurosurgical
intervention.
There are also so-called risk factors including deficiency of protein S,
factor C and antithrombin III, the procoagulant factor V Leiden mutation of
prothrombin gene. Localized infections such as otitis media, mastoiditis,
sinusitis and systemic venous thrombosis may favour the formation of the
process.
The clinical picture is variable, being in relation to the onset or
location. Venous sinuses thrombosis causes clinical signs of intracranial
hypertension due to disturbance of cerebrospinal fluid resorption. Patient
experiences headache, disturbance of consciousness, visual or cognitive
disorders and seizures. Initial symptoms are acute, then subacute or chronic.
If the sinus thrombosis is accompanied by the involvement of cortical
veins, then bleeding can appear. Other signs may be present such as
hemiplegia, sensory disturbance, aphasia, visual neglect phenomena and
seizures. Seizures may occur in patients with sinus thrombosis, without
having a stroke.
CT scanning is able to identify the areas of the venous infarction. The
delta sign of the thrombus set up by a triangular area with contrast may be
found. Although it provides important information the CT scan is not enough
so that with angiography especially for venous thrombi is performed. Also it
proved to be useful the MRI venography with the sinus thrombosis
hyperintense in T1 and T2. Cerebral angiography with special tracking of the
venous thrombus is sometimes the most effective exploration.
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Anticoagulation in the early acute phase is the key therapy to success.
It starts with heparin followed by oral anticoagulants to continue for at least
6 months and may be extended if coagulability disorders persist. If
thrombotic phenomenon extends and signs of intracranial hypertension
appear then a decompressive craniectomy will be useful.
Procoagulability state in stroke

Abnormal blood composition may change in relation to some
diseases. One of the causes of ischemic stroke is the hyperviscosity. This
occurs when the patient has sickle cell anemia, thrombocytosis or
polycythemia vera. Changes in blood are relatively easy to identify and the
treatment with hydroxyurea, antiplatelet, antithrombotic agents and marrow
transplantation may maintain the limits nearly normal and the number of
cells involved in the pathology not to progress.
Polycythemia vera is responsive to aspirin for prevention of stroke.
Thrombocythemia can be controlled using the "plateletpheresis",
hydroxyurea and interferon recombinanted. Prothrombotic states are often
genetically transmitted. The best known are the deficiency of antithrombin
(AT), protein C and S deficiency is transmitted autosomal dominant. AT and
the occurrence of clinical signs of venous or arterial thrombosis is
characteristic and is precipitated by pregnancy, surgery, infection or the use
of contraceptives. AT deficiency does not respond to heparin, but to oral
anticoagulants (warfarin).
Protein C is activated when a blood clot forms on the surface of
endothelial cells and plays an important role in the inhibition of coagulation
in plasma. Protein S is a cofactor to the activated protein C (APC Activated
protein C), as carried out with the APC and protein S anticoagulant and even
fibrinolytic activity. APC deficiency can be induced of certain liver disease,
vitamin K absorption disorders, infections, sepsis, neoplastic disease,
disseminated intravascular coagulation. APC resistance may be due to
genetic mutation of the factor V Leiden.
Homocysteinemia has been identified as an independent risk factor
for ischemic stroke. Elevated homocysteine serum accelerates clotting
through the damaged endothelium leading to vascular occlusion. Elevated
plasma homocysteine is enhanced by lack of vitamin B12, folate, kidney
disease and even some long term treatment with anticonvulsants.
The antiphospholipid antibodies can induce primary and secondary
type of antiphospholipid syndrome. Primary APLS is characterized by the
presence of clinical signs of migraine, repetitive miscarriages, mild
thrombocytopenia, VDRL tests false positive, arterial and venous
232
thromboses including brain, which may progress to encephalopathy and
seizures. Secondary APLS is associated with lupus erythematosus, immune
complex disease, malignancies, adverse effects of some medications. In these
patients there is a high titer of lupus anticoagulant antibodies and
anticardiolipinic antibodies. Prevention of stroke recurrence can be done
with Warfarin. Complex treatment may be associated with additional
immunosuppression with aspirin.
Thrombocytopenic purpura is characterized by hemolytic anemia,
coagulopathy, thrombocytopenia and cerebral ischemic pathology, including
stroke. The pathological changes affect mainly the small arteries in the brain
and kidneys. You can highlight microthrombus (platelet aggregates), intimal
hyperplasia, subintimal fibrin deposits. The clinical picture consists of
fluctuating encephalopathy associated with seizures. Treatment includes
corticosteroids, plasma exchanges, aggregation, splenectomy.
Pro-coagulant factors
Venous and arterial thrombosis, as well as embolic complications are
influenced either by excessive activation of the coagulation process, or as a
result of anticoagulant mechanisms inhibition.
Among thrombosis physiopathology, the major factors involved are
included in the Virchow triad:
- Lesions in the vascular wall;
- Blood flow anomalies;
- Blood composition modifications.
The screening for such pathological events includes investigation of S
and C proteins,
Factor V Leiden mutation, antithrombin III, Homocysteine or Lupus
anticoagulant.
Protein Cs functions as an anticoagulant, circulating through plasma
and preventing thrombosis by inactivating factors V and VIII. It also
functions as profibrinolitic agent. When activated by thrombin, it can reduce
pro-coagulant plasma activity.
The heterozygous deficit of protein C is associated with pulmonary
embolism and deep venous thrombosis, especially in young patients (there is
also a homozygous deficit that manifests right after birth, leading to
potentially fatally complications).
The deficit is not only hereditary, but also can be achieved in patients
with hepatic pathology, hypertension, diabetes mellitus insulin-dependent,
disseminated intravascular coagulation, malign neoplasm or after oral
anticoagulant treatment.
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The Protein S helps in the inactivation of factors Va and VIIIa. It has
a fibrinolitic effect of activated Protein C.
The Protein S deficit leads to recurrent venous thrombosis in young
patients, that may become or may not become complicated with pulmonary
embolism.
The deficit can also be a personal acquisition by the use of oral
contraceptive drugs, in hepatic affectation, diabetic neuropathy, cerebral
venous thrombosis, during pregnancy or in autoimmune pathology.
Resistance to activated Protein C is defined as the impossibility of
activated protein C to anticoagulate plasma. This phenomenon is related to
factor V mutation, this being the main cause that leads to venous thrombosis.
In the rare cases of coexistence with factor V mutation, it can be
encountered during pregnancy, substitution hormonal therapies, use of oral
contraceptive drugs, lupus anticoagulant or elevated factor VIII
Factor V Leiden is derived from a chromosomal mutation (1q23),
which codifies factor V synthesis, thus leading to the modification of APC
binding site. The factor V resulted is taking more time to inactivate,
persisting for a longer period of time in circulation and also generating more
thrombin. All these events lead to a hypercoagulability state of the organism.
The mutation exists in patients with pulmonary embolism, deep
venous thrombosis, cerebral sinuses thrombosis, hepatic veins thrombosis or
occlusion of the central retinal vein. The homozygous condition carries a
higher risk for such events compared to general population.
The risk increases in case of associating other genetic mutations such
as MTHFR or hyperhomocysteinemia, and also during pregnancy or use of
oral contraceptive drugs.
There is also a predisposition for myocardial infarction, independent
risk from the traditional coronary risk factors.
Hyperhomocysteinemia occurs whenever anomalies in its
metabolization exist, most often being manifest by early atherosclerosis,
mental retardation and arterial thromboembolism. Other causes are the
vitamin B6 deficiency, lupus, chronic renal pathologies, Methotrexat or L-
Dopa treatments.
It usually associates with cardiovascular diseases, venous thrombosis
or pregnancy complications.
It can be also found in case of MTHFR gene presence (homozygous
state), as cofactor enzyme in remetylation of homocysteine to methionin.
Antithrombin III is the natural anticoagulant that inhibits reactions
from the coagulation fall (factors Xa, IXa, IIa, XIIa, VIIa and tissue factor
5). Combined with heparin it realizes a both performant and essential
mechanism in the coagulation process. The deficit is also associated to a high
risk of thromboembolism.
234
The presence of lupus anticoagulant is also associated to thrombotic
risk, by deep thrombosis and pulmonary embolism. There are also cases of
spontaneous abortions associated to the presence of lupus anticoagulants.
Intracranial hemorrhages
This type of hemorrhage is due to some preexisting conditions which
favor blood extravasation. primary intracerebral hemorrhage (hypertensive)
is the result of arterial wall rupture on the background of hypertension.
Hemorrhage is also favored by segmentary lipohyanolisis or presence of a
false Charcot-Bouchard aneurysm. Other causes of intracranial hemorrhage
are : ruptured aneurysm, rupture of arterious-venous malformations, skull
trauma, blood diseases (leukemia, thrombocytopenic purpura, hemophilia,
liver disorders, complications of anticoagulant therapy, presence of
hyperfibrinolysis, intratumoral hemorrhage, arterial amyloidosis, cavernous
angiomas etc).
Cerebral hemorrhage
According to localization, cerebral hemorrhage may be classified into
four types: extradural, subdural, intracerebral and subarachnoid.
The most common cause of extradural and subdural hemorrhage is
trauma, the collection of blood being limited and forming hematomas. Of the
many causes nontraumatic intracranial hemorrhage the commonest are:
rupture of the arteries, ruptured aneurysm, bleeding from arteriovenous
malformations, idiopathic purpura, hypertensive encephalopathy, brainstem
compression.
Cerebral hemorrhage has arterial hypertension among its main
causes. Under the influence of hypertension a lipohyalin degeneration of the
arterial walls occurs, atherosclerosis develops and progresses more rapidly,
and microaneurysms are formed. All these changes contribute to a decreased
resistance favoring hemorrhage. The most common sites for hypertensive
hemorrhage are: the vicinity of internal capsule, cerebellum, pons and
cerebral lobes.
Often, cerebral hemorrhage may begin during periods of physical or
intellectual exertion. The most common picture is that associating putaminal
hemorrhage with involvement of the adjacent internal capsule. It has some
characteristic features: deviation of the head and eyes to the lesion side,
contralateral flaccid hemiplegia, comatose state, sphincteric incontinence or
retention. Gradually the picture worsens and hyperthermia, bradycardia,
235
stertorous or Cheyene-Stokes respirations are added. There is also inequality
of pupils and the eyes are in diverging strabismus. When painful stimuli are
applied to the paralysed limbs, the motor reactions are absent both as a result
of the motor deficit and of hemianesthesia due to the interruption of sensory
pathways.
Putaminal hemorrhage may determine the inundation of a lateral
ventricle or blood may exteriorize, the hemorrhage becoming
cerebromeningeal. Within the hemorrhagic focus there is a red thrombus
which destroys and compresses the cerebral tissue. Later on a cerebral edema
appears, thus aggravating the cerebral disturbance. If the patient survives, the
blood will be absorbed and replaced either by a neuroglial scar, or by a
cavity containing a yellowish serous collection.
Ventricular inundation is characterized by deep coma, bilateral
pyramidal signs, hyperthermia, nuchal rigidity, important autonomic
disturbances.
Pontine hemorrhage has the following distinctive features: peripheral
facial paralysis on the side of the lesion, deviation of the eyes and head to the
paralysed limb and myosis, most commonly bilateral. Terminal hyperpyrexia
is another sign characteristic to pontine hemorrhage.
In cerebellar hemorrhage there are repeated vomiting, inability to sit,
stand or walk, vertigo, occipital headache, dysarthria, dysphagia, paresis of
conjugate lateral gaze to the side of hemorrhage or forced deviation of the
eyes to the opposite side. In the more advanced stages, signs of lesion
expansion towards the brainstem or brainstem compression appear: Babinski
sign, coma.
Lobar hemorrhage is due to hypertension, malformations,
vascularized tumors or some angiopathies. Their clinical manifestations vary
according to thei location: occipital hematomas present with hemianopsia,
temporal hematomas with aphasia and delirium, sensorimotor and visual
field deficits are produced by parietal foci and motor deficits by frontal
hematomas. Brainstem compression determines the occurrence of a
comatose state.
Prognosis. Hemorrhage with ventricular inundation are fatal within a
few hours. Hemorrhages accompanied by bilateral palsies of the limbs and
cerebellar hemorrhages associated with an over 7-day comatose state are
often fatal. Hemorrhage with unilateral lesions partially remmiting with time
have a better prognosis.
Treatment. Ideally, the treatment aims at the evacuation of blood
content and control of bleeding. Surgical evacuation of the hemorrhage and
halt of bleeding has proved beneficial in some cases. Unfortunately, given
the age of patients, the site and complexity of arterial malformation and the
236
status of circulatory system, neurosurgery is not practicable in too many
cases.
Mannitol and other osmotic compounds lower the intracranial
pressure. The return of blood pressure to normal levels is essential in the
treatment of these cerebral syndromes.
Subarachnoid hemorrhages
Subarachnoid hemorrhages are due to rupture of some arterial
structures or vascular malformations followed by discharge of blood into the
subarachnoid space. Most commonly, subarachnoid hemorrhage is due to a
ruptured aneurysm, bleeding of some cerebral angiomas or hypertension-
induced extravasation of a cerebral hemorrhage.
Meningeal hemorrhages resulting from the rupture of some vascular
intracerebral formations and followed by discharge of blood into the
subarachnoid spaces are probably caused by hypertensive angiopathy,
amyloid angiopathy, Moya-Moya disease, primitive and secondary angiitis,
cranial trauma, intracerebral trauma, cerebral metastases, blood disorders and
anticoagulant treatment.
In the etiology of subarachnoid hemorrhage the arterial aneurysm,
arteriovenous malformations, cerebral atherosclerosis and the alteration of
arterial walls under the influence of hypertension are implicated to a great
extent.
Most commonly the aneurysm is located on the internal carotid site,
at the origin of the posterior communicating artery, on the middle cerebral
artery, at the bifurcation of the vertebrobasilar system, and at the bifurcation
of the internal carotid artery.
Familial aneurysms, accompanying hereditary diseases and
hypertension-induced aneurysms have been also described. Ussualy, when
reaching the critical size these aneurysms rupture.
The arteriovenous malformations are congenital and consist of a
tangle of abnormal arteries and veins with superficial but also deep location.
Their rupture may cause both a hematoma and subarachnoid or
cerebromeningeal hemorrhage.
Atherosclerotic aneurysms, as well as those developing under the
influence of hypertension are chiefly located at the bifurcation of arteries.
Clinical signs: sometimes the clinical signs are suggestive for
aneurysms or arteriovenous malformation the rupture of which may
determine meningeal hemorrhage. With large aneurysms located on that
portion of the internal carotid artery that lies within the cavernous sinus, the
third, fourth and sixth nerves may be involved, and hypoesthesia in the
territory of the ophthalmic division of the fifth nerve may be present. Giant
237
aneurysms in the vertebrobasilar territory causes hydrocephalus by the
blockage of the CSF pathways. Sometimes the rupture of a giant aneurysm is
preceded by a transient ischemic attack by the mobilization of some platelet
emboli from the aneurismal pouch. A loud bruit and epileptic seizures are
almost patognomonic of arteriovenous malformation.
Rupture of an aneurysm may be preceded by minor leakage from the
aneurysm with atypical periorbital, hemifacial or hemicranial headache
accompanied by nausea and vomiting as the chief sign.
The onset is sudden, often following physical exercise, sexual
intercourse, cough, defecation, stress. the clinical signs consist in: headache,
signs of meningeal irritation, alteration of consciousness and sometimes
focal neurological signs. The discharge of blood into the subarachnoid
spaces causes the filling of the interhemispheric cisterns and intracranial
hypertension which aggravates the clinical condition of the patient. signs of
meningeal irritation are also present: nuchal rigidity (stiffness of the neck),
flexion at the hip and knee in response to forward flexion of the neck
(Brudzinski sign) and inability to completely extend legs (Kerning signs). To
these signs fever, vegetative disturbances, transient collapse, psychomotor
agitation, epileptic seizures, confusional state are added.
Laboratory findings. Usually an axial CT scan will detect blood
within the subarachnoid space. The visualization of some hyperdense areas
in the basal cisterns or interhemispheric fissure confirms the pericerebral
diffusion of blood. The CT scan may also identify the arteriovenous
malformations, giant aneurysms ot hemorrhages from cerebral tumors.
Lumbar puncture is performed only when a CT scan is not available.
Usually the CSF is bloody and deep xanthochromia is found after
centrifugation.
Carotid and vertebral angiography is the most reliable means of
demonstrating the site of vascular malformations and ruptures. Based on the
result of this investigation the indication for neurosurgical treatment is made.
Examination of the fund I may reveal hemorrhages, edema or
papilledema, sometimes varying with the time elapsed since the onset of
hemorrhage.
The complications consist of recurrences, arterial spasm and
hydrocephalus. Recurrences occur in a great number of patients within 7 to
14 days after the original bleeding, and are probably due to naturally
occurring mechanisms of clot formation and lysis. Few patients survive a
reccurence.
Arterial spasm may appear after 3 to 10 days following bleeding,
aggravating by ischemia the general condition and indicating some focal
deficits. The patient becomes comatose, hemiplegia and other focal deficits
do occur.
238
The blockage of CSF circulation via the blood in the cerebral cisterns
and the limitation of its resorption by arachnoid villi causes a hydrocephalus,
usually relieved only by neurosurgery.
Treatment is medical and surgical. For bringing the arterial blood
pressure to normal calcium channel blockers, beta blockers, conversion
enzyme inhibitors are used. Coughing, constipation and all form of exertion
are avoided.
Cerebral edema will be prevented with mannitol, glycerol, diuretics.
The vasospasm reacts favorably to calcium channel blockers. The surgical
treatment aims at evacuating the aneurysm or malformations and avoiding
the internal hydrocephalus by creating CSF flow shunts.
Treatment in stroke
The first 3-4.5 hours from the onset of the stroke are important
because this range is considered the "therapeutic window" when
thrombolysis may be applied. Intention to direct the patient to such a
therapeutic option is to be announced during prehospital transport so that on
arrival in the specialized cerebrovascular emergencies care centers
everything to be prepared. Typically, the onset of a stroke is accompanied by
increased blood pressure and lowering it is the first intention. Blood pressure
should be reduced if it exceeds 180 mmHg systolic and 120 mmHg diastolic.
Preparing the patient for CT or MRI examination in order to distinguish
between ischemic and hemorrhagic stroke is the next step. Once at the
hospital and the CT or MRI examination is done then to the patient will be
applied the first general measures, namely bed rest, monitoring vital signs,
blood pressure, heart rate, respiratory rate, diuresis, fever. It is also
recommended to monitor the intake of fluids and to maintain the electrolyte
and caloric balance. Pulmonary thromboembolism prophylaxis measures
and anti decubitus lesions should be done. The steps begin with passive
motion, and proper therapy should be initiated for associated diseases such as
hypertension, diabetes, heart failure, atrial fibrillation.
Treatment includes counteract of pathogenic cerebral edema,
anticoagulation, antiplatelet, nootropics and the medication to stimulate
neuroplasticity. Cerebral edema is controlled with mannitol, glycerol,
Furosemide. Anticoagulation is done with warfarin or Acenocumarol or the
new generation of anticoagulants. Anticoagulation acts as secondary
prevention also in case of an embolic stroke. Antiplatelet therapy (aspirin,
clopidogrel, Triflusal, ticlopidine, dipyridamole) has a certain gastric
aggressiveness that is why it should be given together with gastric
protectives.
239
The major advantages brought by the new generation of
anticoagulants consist in its predictable effect without the need to monitor
the INR or other coagulation test, fewer drug interactions or power, duration
of action (half-life in plasma) and a good efficiency/safety raport.
The new anticoagulants available on European area are: dabigatran
(Pradaxa) a direct thrombin inhibitor, rivaroxaban (Xarelto) and apixaban
(Eliquis) both of the inhibition mechanism coagulation factor X directly.
Dabigatran and apixaban are superior to warfarin in preventing stroke and
systemic embolic events in case of non-valvular atrial fibrillation.
Rivaroxaban is currently only approved for the treatment and prevention of
DVT and TEP and their recurrence. Apixaban and rivaroxaban may be
administered to patients with renal problems but with a creatinine clearance
of at least 15-30 mL/min. Before introducing the treatment with the novel
anticoagulants the patient renal and hepatic function should be evaluted.
Subsequently, renal function should be evaluated periodically.
The nootropic substances used (optional) are versions of piracetam.
Neuroplasticity is stimulated with following repeated cycles but spaced in
time with Cerebrolysin infusion or injection.
Thrombolytic therapy may be intravenous or intra-arterial done with
rtPA. If it fulfills the criteria of administration then arterial recanalization of
the thrombosed segment is done. In case of symptomatic carotid stenosis
stenting or endarterectomy can be recommended.
Antiaggregant and anticoagulant therapy in neurological diseases
Platelet antiaggregant therapy, mainly represented by acetylsalicylic

acid, is useful for the inhibition of platelet adhesion and aggregation, which
are implicated in intra-arterial thrombogenesis. Platelet activation usually
occurs after a vascular injury or as a result of endothelial dysfunctions
(caused by hypertension, elevated LDL, diabetes or smoking). By interaction
with von Willebrand factor and collagen, the platelets adhere to the vascular
wall and become activated. Once activated, the platelets shift form and
release substances from the cytoplasmatic granules (ADP and serotonin),
COX-1 also being stimulated. Thromboxan A2 and ADP activate specific
receptors, that will determine conformational modifications of GP IIb/IIIa
inside the platelet membrane, thus the glycoprotein gains affinity for
fibrinogen. This is the moment when fibrinogen bridges are interconnected,
resulting the thrombus that can either block a bleeding process, or blocks the
blood flow, causing stroke.
240
Acetylsalicylic acid inhibates COX-1 and by this, thromboxan A2
synthesis, 75-100 mg daily of antiaggregant being sufficient, nevertheless
carrying a risk for gastro-intestinal manifestations or asthmatic crisis.
Oral anticoagulants are structurally related to vitamin K, 4-
Hydroxycoumarins acting as antivitamin K. By carboxylation, vitamin K is
transformed in vitamin K-epoxid. Hydroxicumarin interferes with vitamin K
regeneration, resulting an active vitamin K deficit. Cumarinics are well
absorbed after oral administration, their action lasting variably. Coagulation
factors synthesis depends on the ratio of intrahepatocitary cumarine
concentration and vitamin K. The proper dose for an adequate anticoagulant
effect must be individually determined for each patient. Monitoring the
therapy is performed by INR control (international normalized ratio), which
replaced another classic analysis, the Quick time.
The ischaemic stroke is the most frequent neurological pathology in
which we discuss about antiaggregant/anticoagulant treatment.
In an ischaemic stroke, it is known that antiaggregant therapy reduces
vascular events. Secondary prevention is a very important part of the
treatment and is based on some basic recommendations according to actual
guidelines:
- Aspirin is used in many cases for both primary and secondary prevention.
- Clopidogrel is less efficient than Aspirin, but may be useful for patients
with elevated risk for stroke.
- Dipiridamol has similar results with Aspirin.
- Triflusal reduces stroke recurrence similar to Aspirin, but with less
secondary effects;
- Clopidogrel + Aspirin not preferably;
- Oral anticoagulation reduces stroke recurrence in patients with non-
valvulary fibrillation.
- In patients with fibrillation and coronary stable illness aspirin should not
be associated to oral anticoagulation.
Recommendations dealing with antiaggregant/ anticoagulant therapy
as a specific treatment in stroke suggest that Aspirin (160-325 mg loading
dose) should be administered within 48 hours from the onset of stroke. In
case there is thrombolytic therapy scheduled, Aspirin and other
antithrombotic treatments should not be started within the first 24 hours.
As a main conclusion, according to guidelines, Aspirin administration
is sure and efficient when started 48 h after the onset of stroke. Clopidogrel,
dipiridamol or associations of other antiaggregant didnt show benefit so far
in this stage. Anticoagulation strategies in 24 to 48 hours from onset reveal
no major benefit whatsoever.
Antithrombotic therapy recommendations
241
Antiaggregant Anticoagulant
Aspirin or Triflusalum; Oral anticoagulation for patients
with atrial fibrillation (INR: 2.0-
Aspirin + Clopidogrel 3.0);
only for patients with
Ischaemic unstable angina, Anticoagulation for patients with
Stroke miocardic infarction non- cardio-embolic stroke not related
Secondary Q or recent stents; to fibrillation;
prevention
issues Aspirin + Dipiridamol if Anticoagulation for non-
anticoagulation is not cardioembolic stroke in case of:
indicated. aortic ateroma, basilar artery
fusiform aneurysms, cervical
artery dissection.
Table 2. Antithrombotic therapy recommandations
Cerebral hemorrhage may occur in patients following anticoagulant
treatment, an increase of the INR above 3.5 - 4.5 being very dangerous. The
increase of INR is also related to the hematomas expansion and to the
general prognosis. The risk of hemorrhage doubles every 0.5 above 4.5 INR.
For patients that require anticoagulant treatment after cerebral
hemorrhage, unfractionated heparin in venous perfusion is much safer than
oral anticoagulants.
Thrombophilia can be documented in patients younger than 40 years
with cerebral ischemia. The following conditions should benefit from
anticoagulant therapy after a cerebral ischemic event:
- Activated protein C (APC) resistance (factor V Leiden)
- Antithrombin III deficiency
- Plasminogen deficiency/inhibition
- Protein C deficiency
- Protein S deficiency
- Dysfibrinogenemia
Thrombophilia can be also treated with low-dose subcutaneous
unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).
In the case of different thrombophilias combined, permanent
anticoagulation is a desirable therapeutic solution.
Patients with Venous Sinus Thrombosis benefit from oral
anticoagulation after heparin treatment with benefic results. It may also be
benefic in patients with recurrent thrombotic events, by switching from
warfarin to unfractionated heparin or low-molecular weight heparin, or even
adding antiaggregant, in order to maintain a better INR control.
Antiphospholipid Antibodies Thrombosis is a condition in which there
is a certain therapeutic challenge consisting in realizing secondary
242
prevention of stroke. Both Aspirin and Warfarin show similar benefits.
Therefore, patients with ischemic stroke and a single positive
antiphospholipid antibody can be treated either with aspirin (325 mg/day) or
warfarin. In this case, Aspirin is preferred because of its ease of use and lack
of need for laboratory monitoring.
On the other hand, patients with ischemic stroke due to cerebral
arterial thrombosis and a positive antiphospholipid antibody, associating
history of venous thrombosis without anticoagulant treatment when the
stroke occured should be treated with moderate-intensity warfarin.
1. Adams and Victors Principles of Neurology, Ropper HA, Brown
RH Editors, Eighth Edition, McGraw Hill, Medical Publishing
Division, 2005;
2. Amarenco P, Hauw JJ, Anatomy of the cerebellar arteries, Rev
Neurol (Paris). 1989;145(4):267-76;
2012;
6. Jensen MB, St Louis EK, Management of acute cerebellar stroke,
Arch Neurol. 2005 Apr;62(4):537-44;
7. Lee RM, Adams SR, Kim D, Wallenberg Syndrome, Clinical
Vignette, Proceedings of UCLA Healthcare, 2012, Vol 16;
12. Popoviciu L, A gian B, Bazele semiologice ale practicii
neurologice i neurochirurgicale, Edit. Medical, Bucure ti,
1991;
13. tefanache F, Popescu CD, Neurologie clinic, UMF Ia i, 1997;
243
244
Chapter XIII.
Multiple sclerosis
Definition Classification of MS according to the

Age of onset and prognosis clinical evolution
Pathogeny CIS, RRMS, SPMS, PPMS, PRMS,
Clinical picture other demyelinating diseases
Diagnosis. Investigations Treatment
Differential diagnosis Treatment of relapse
Imunommodulatory treatment
Symptomatic treatment
Definition
Multiple sclerosis is an inflammatory disease of the central nervous
system, characterized by myelin sheet damage, gliosis and axonal lesions.
All of these processes contribute to a polimorphic (heterogenous) clinical
picture.
Epidemiology and geographical distribution

MS is the most frequent neurological disease of the young adult, with
a prevalence of 30-80/100000 persons in Europe, higher in the northern
countries.
The disease is characterized by a latitude gradient, being more
common above the 45th parallel. High prevalence (60/100000 or above) is
encountered in Europe, south of Canada, north of the USA, New Zealand
and south of Australia. Orkney Islands hold a record prevalence of
300/100000 inhabitants. The disease is rare in Japan, blacks and american
indians.
Age of onset and prognosis

The average onset age is usually in the third decade of life (29-32
years). The disease is more common in women, with a cumulative rate of
1.77 to 1. The peak incidence age is 5 years earlier in women than in men,
245
and the onset of the disease is earlier, in the second decade of life. In
approximately 5% of the patients the disease begins before the age of 18.
Average death age in MS patients is 58.1 years, while the average age
for death of all causes is around 70. Life expectancy in MS is about 82% of
that in the general population.
Pathogeny
Multiple sclerosys is part of the group of diseases characterised by
initial myelin pathology and secondary involvement of axonal structure and
of neuronal bodies.
Diseases due to abnormal myelin can be classified in dysmyelinating
diseases (implying abnormal synthesys of myelin) and demyelinating (due to
a pathological process that damages myelin and/or the olygodendrocytes).
Demyelinating diseases can be caused by autoimmune, toxic, infectious,
toxic-metabolic and vascular processes (Table 1)
Autoimmune Infectious Toxic Vascula Hereditary

r
Acute Progressive Carbon Binswan Adrenoleukodystr
disseminated multifocal monoxi ger ophy,
encephalomyelit leukoencephalo de, disease Metachromatic
is (ADEM), pathy (PML) Alcohol leukodystrophy
Acute , B12
hemorrhagic vitamin
leukoencephalo deficien
pathy, Multiple cy
sclerosis
Table 1. Dysmyelinating diseases
At first the disease is dominated by inflammatory phenomena,

followed by degeneration that ultimately lead to neuronal and axonal loss.
Although MS is considered to be primarily a white matter disease, pathologic
inflammatory and degenerative phenomena affect both the gray and white
matter.
Inflammation is involved in the pathogeny of the initial clinical
events that associate with relapses. Blood brain barrier (BBB) disruption is
critical to the autoimmune process. MRI enhancement translates BBB
increased permeability for the contrast media.
Trans BBB migration of blood cells (lymphocytes, macrophages and
occasionally plasmocytes) triggers the aggression on myelin and then on
axons and cellular bodies. The electro physiological consequence is
conduction block, the basic process behind clinical signs.
246
The inflammatory phase is characterized by relapses and the typical
MRI changes. During the late (degenerative) phase axonal loss and cerebral
atrophy are the typical phenomena.
Demyelinating plaques are the pathological hallmark of MS, and can
be active, chronic active and chronic silent. Classification takes into account
time evolution, imflammation and degeneration. An acute lesion is
characterised by inflammatory phenomena, myelinolysis, immune cell
infiltrate (T lymphocytes, monocytes, macrophages) and parenchimal edema.
Apoptosis of olygodendrocytes can be found in the vicinity of blood vessels
(especially venules). Demyelinating lesions are often located in the
periventricular regions, near the corpus callosum, in the cervical spinal cord
and in the brainstem.
Myelin distruction, hypocellularity and glial scars are found in cronic
lesions. Active microglia, macrophages, antimyelin antibodies and activated
complement are found in the periphery of cronic active lesions, while no
inflammation is found in relation to cronic silent lesions.
Although normal appearing white matter (NAWM) shows no
pathological markers on conventional MRI techniques, use of special and
more advanced MRI approaches has shown myelin abnormalities and
diminished axonal density within the appearantly normal areas.
Gray matter is also impaired in MS. All basal ganglia, the cortex,
cerebellum, and the spinal cord can be involved. Gray matter lesions
correlate with cognitive impairment, and appear more important in PPMS si
SPMS.
Disruption of the normal function of the myelinated fibers in the CNS
is caused initially by myelin sheaths damage. In the first phase a 'conduction
block' does not allow the passage of nerve impulses. The electrophysiologic
conduction block occurs during the inflammatory phase, corresponding to
the clinical relapse.
Brain volume measurements are not used in routine clinical practice,
but brain volume loss in MS is clinically relevant, robust and could offer an
in vivo measure of neurodegeneration. Overall, brain atrophy (pathological
loss of tissue) represents the net effect of tissue damage in MS. The
mechanism involves axonal loss within white matter lesions including the
amount of tissue lost within the lesions themselves, and Wallerian
degeneration in pathways related to the lesions.
Clinical picture
Depending on the location of demyelinating plaques a characteristic
clinical picture will be found. An isolated neurologic event may be the first
sign of a complex disease with variable evolution.
247
The clinical isolated syndrome may be an acute or subacute
neurologic event restricted to dysfunction of the central nervous system. The
most characteristic clinical settings are optic neuritis, Lhermitte sign,
"useless hand syndrome", double vision (diplopia, usually in the context of
an internucleary palsy), transverse myelitis or brainstem syndromes.
A relapse is a neurologic disorder compatible with MS that lasts at
least 24 h, followed by complete or partial remission of the dysfunction.
New abnormalities or an exacerbation of previously existing
disorders can be taken into account. It is considered that an interval of at
least 30 days must separate such neurologic events for them to be considered
distinct relapses. Spontaneous remission occurs over variable time frames,
usually between a few days and 6 months.
Relapses associate with new or enlarging lesions (although MRI
identification of the acute lesion is not always possible).
Pseudo-relapses must be differentiated, and may be taken into
account whenever neurological dysfunction appears in the context of fever,
infections, physical activity or metabolic dysfunction.
Clinical picture in MS may include:
- Sensory symptoms ( numbness , pain , Lhermitte's sign , feeling hot
and cold, often asymmetrical and more severe distally; unstable hand;
- Motor manifestations (pyramidal motor deficit as paraparesys,
hemiparesys, quadriparesys, monoparesys, spasticity, spinal cord
lesions, Brown-Sequard sybdrome);
- Optic neuritis;
- Cerebellar signs (ataxia, tremor, cerebellar dysarthria);
- Brainstem syndromes (oculomotor palsies, trigeminal damage, facial
palsy, nystagmus, swallowing disturbances, etc;
- Bladder abnormalities, sexual dysfunction
- Cognitive dysfunction.
Diagnosis
The diagnosis of MS is based on a combination of clinical signs
and laboratory findings (oligoclonal bands in the CSF, MRI, evoked
potentials). The core features of the diagnostic are proving the existence of
dissemination in time (DIT) and dissemination in space (DIS).
The criteria proposed by McDonald in 2005 are still in use (with
the 2010 revision). The latest revision increases the sensitivity of the criteria
in diagnosing early stages of MS, and allow treatment to be introduced
sooner (Table 2).
248
Table 2. The revised McDonald criteria for the diagnosis of MS
(Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple
sclerosis: 2010 Revisions to the McDonald criteria. Annals of Neurology
2011;69(2):292-302)
MRI remains the most important laboratory contribution both

during the initial diagnosis and for monitoring the progress of the disease and
the impact of therapy. The method can identify silent lesions (without a
clinical correspondent), but also the severity of cerebral atrophy.
Location of the demyelinating lesions, their number and
enhancement status are important in diagnosing MS, follow up and
249
evaluation of therapeutic impact. Simple plaques (usually with 1-2 cm
diameter) can confluate into larger demyelinated areas.
FLAIR sequences have shown that cortical lesions are present in
MS patients. Conventional MRI sequences (T1, T2, Flair) identify MRI
demyelinating lesions that have a particular topography . They are placed
near the ventricles (paraventricularily), are oval in shape and are placed
tangentially to the surface of the ventricle. In the corpus callosum they take
the form of digital extensions, perpendicular to the corpus callosum in sagital
sections, being known as "Dawson's fingers". Over time, the lesions may
confluate. Exploring in T1 the so-called "black holes" are seen (lesions are
hypointense in T1 and hyperintense (bright white) in T2 and Flair). Black
holes correspond to lesions where axonal loss is important.
The administration of gadolinium based contrast media may reveal
blood-brain barrier abnormal permeability. "Active" lesions take up the
contrast substance for several weeks (contrast uptake is associated with new
or recent lesions). Active lesions are hyperintense in all sequences, and their
aspect changes from fully enhancing lesions to peripheral incomplete ring-
shaped enhancement. Coexistence of active and inactive lesions or
appearance of new lesions on seriate MRI evaluations can be used to prove
dissemination in time.
Special techniques as magnetisation transfer ratio, diffusion tensor
imaging and MR spectroscopy can be used and offer supplementary
information. Computer programs calculate "brain parenchyma fraction" and
evaluate brain atrophy.
Accidental finding of a MS compatible MRI aspect is called
radiological isolated syndrome it is a high risk situation for MS, hence the
need for careful clinical monitoring and MRI seriate evaluation.
The presence of oligoclonal bands in the CSF is no longer needed
for the diagnosis or relapsing remitting MS (although it increases the
certitude and can be of help), but is necessary to prove the existence of
progressive forms of the disease.
Abnormal evoked potentials (mostly the visual evoked potentials,
but also auditory evoked potentials and somatosensory evoked potentials)
could play an important role in diagnosing MS. In visual evoked potentials
the P100 wave has increased latency (>120 ms) and a relatively well
preserved shape in chronic optic pathway lesions. In acute optic neuritis VEP
amplitudes are largely diminished. VEP abnormalities can be transient, but
most of the times increased latencies allow for a retrospective optic neuritis
diagnosis. VEP abnormalities are very important if MRI findings do not
clearly support a typical clinical picture. Uni- and multimodal EP
abnormalities can support both DIS and DIT if correctly interpreted.
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Optical coherence tomography (OCT) is an imaging technique based
on low-coherence interferometry, typically employing near-infrared light. It
can be used to obtain high-resolution images of retina, providing a
straightforward assessment of axonal integrity and neurodegeneration in
multiple sclerosis.
Classification of MS according to the clinical evolution

The classification is based on two elements: presence of relapses
and evolution. The accepted MS types are relapsing-remitting, secondary
progressive, primary progressive, progressive relapsing. Acute fulminant MS
is characterized by a highly aggressive onset. Assigning a patient to one of
the courses of evolution of the disease is important in establishing the
appropriate treatment approach and the prognosis.
Clinically isolated syndrome

It is the first clinical episode, marking the clinical onset of the
disease. It lasts at least 24 h, and it is caused by inflammatory and
demyelinating aggresion in the CNS. Usually it is the event that triggers
investigations that would eventually lead to a CIS/MS diagnosis. In
approximativelly 50% of the CIS patients white matter lesions are seen on
MRI. It is a high risk condition for later development of a definite MS, and
early treatment delays or prevents this transition.
Depending on the clinical involvement CIS can be
monosymptomatic (with signs/symptoms from a single CNS functional
system) or polysymptomatic (with signs/symptoms proving impairment in
multiple sites in the CNS).
Frequent clinical presentations in CIS patients include:
- Optic neuritis - Double vision
- Myelitis - Dysarthria
- Internuclear - Hemiparesys
ophtalmoplegia - Seizures
- Paraparesys - Lhermittes sign
- Sensory symptoms
Relapsing remitting multiple sclerosis (RRMS)

Is characterized by relapses and by stable clinical picture between
them. Remission after a relapse can be complete, incomplete (partial), or
completely absent (no clinical recovery).
Worsening of the neurological status (the relapse) may last from a
few days to 4-8 weeks. The new symptoms typically disappear (the
remission) especially at the beginning of the disease, but dysfunction can
become permanent.
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RRMS is the most frequent type of disease. In time it has the
potential to evolve to secondary progressive MS. Weakness, sensory
abnormalities, double vision, incoordination, vestibular syndrome or optic
neuritis are possible clinical presentations of a relapse. Optic neuritis
associates sight loss (ranging from minor visual acuity impairment to
complete anopsia) with retroorbitary pain.
Secondary progressive MS (SPMS)

This MS type is usually characterized by slow continous progression,
following an initial RR type of evolution. Progression can be interrupted or
not by relapses, and if this happens, the remission process is usually
incomplete and lengthy. Occasionally the disease may plateau for variable
amounts of time.
It arises from RRMS after an average 10 years of disease. It is
considered that while RRMS is characterized by inflammation and
demyelination, the crossing towards SPMS signals a dramatic change in
pathogenic mechanism, with axonal loss prevailing in the latter stages of the
disease.
Primary progressive MS (PPMS)

This type of disease is characterized by slow progression from the
very beginning. Occasionally the disease may plateau or even temporarily
improve. The onset is later than in the other types (around 40 years of age),
and incidence is fairly equal for the 2 sexes. This type accounts for
approximately 10% of the MS cases. No relapses are recorded, as the clinical
picture gradually worsens. Higher disability states are attained faster than in
RRMS. Asymmetric motor signs (paraparesys) are often part of the clinical
picture at diagnosis.
Progressive relapsing multiple sclerosis (PRMS)

Even if there is continous progression from the onset, relapses are
present. Relapses may or may not completely recover. An estimated 5% of
the MS patients are assigned to this type.
Acute fulminant MS is characterized by a very severe onset, that may
be followed by a high number of relapses that lead to fast accumulation of
disability.
Other demyelinating diseases

Transverse myelitis is a demyelinating inflammatory disease that is
secondary to an infection in approximately 50% of cases. Evolution is
usually fast, with signs of complete/almost complete spinal cord section
252
(motor impairment, sensory dysfunction, sfincterian problems). CSF analysis
reveals pleiocytosis without oligoclinal bands.
Neuromyelitis Optica (Devic Disease) is a demyelinating pathology
that associates optic neuritis and myelopathy. The myelopathy evolves more
aggressively than in typical MS, with less potential for improvement under
corticosteroid and rehabilitation therapy. In most cases myelopathy and the
optic neuropathy appear in separate moments in time (similar to relapses),
but there are cases of simultaneous optic neuropatis and myelopathy. Anti
aquaporin-4 antibodies are found in approximately 70% of the patients, and
are useful in the differential diagnosis with MS.
Tumefactive MS (Acute Tumor-like MS) is a clinical entity
characterized by the presence of a large tumor-like acute lesion, that can
cause mass-effect, leading to variable symptoms (neglect syndrome,
confusion or motor deficit such as hemiparesys).
Corticosteroids are efficient and represent a good therapeutic
approach. As lymphomas or gliomas also respond to steroids, MRI
documented reduction in the lesions size after corticoids can not be used as
diagnostic criteria. In these cases biopsy can help provide an accurate
diagnosis. Demyelinating episodes tend to reoccur, either as a new pseudo-
tumoral lesion, or as a typical type of MS.
Differential diagnosis is important when a progressive or relapsing
neurological picture is present, accompanied by suggestive MRI lesions.
Anamnesys, familial hystory and the onset type are important. An
extended differential diagnosis, including clinical and MRI features, should
include several inflammatory, infectious or inherited diseases (Table 3).
Systemic Lupus Erithematosus (SLE)

Although a pure neurological clinical onset of the disease is rare, a
variable clinical picture can occur, with possible hemiplegia, sensory
syndromes, cerebellar syndromes, brainstem dysfunction, spinal cord
impairment (myelits), optic neuritis, generalized/focal seizures, coreic
movements, cognitive impairment, psychotic episodes. The patient has to
fulfill the ARA criteria, with multiorgan lesions and positive laboratory
markers (ANA, anti ADNdc Abs).
Aquired
diseases and
Inflammatory Infectious Genetic
malformation
s
253
B12
Granulomatou
Lyme Metachromatic deficiency
s angiitis
Human T-cell leukodystrophy Arnold-
Systemic
lyphotropic virus Adrenomyeloleukodystrop Chiari
lupus
type 1 (HTLV 1) hy malformation
erythematosus
HIV Spinocerebellar disorders Medullary
Sjogren
Neurosyphilis CADASIL (Cerebral compresions
disease
Progressive Autosomal-Dominant Arterio-
Behcet
multifocal Arteriopathy with venous
disease
leukoencephalopat Subcortical Infarcts and malformation
Polyarteritis
hy (PML) Leukoencephalopathy) s
nodosa
Table 3 Differential diagnosis of MS
Behet disease
Demyelinating brain lesions have variable locations, with focal
neurological signs. Perioral and genital ulcerations, uveitis, articular and
cutaneous signs suggest the presence of this disease. Laboratory tests show
the inflammatory syndrome, and lymphocytic pleocytosis is found in the
CSF.
Sjgren syndrome
The characteristic clinical feature is the sicca syndrome, associating
xerostomia and keratoconjunctivitis. Dry skin, kidney, liver or pancreatic
abnormalities are possible. Neurologic impairment is directed primarily
towards the peripheral nervous system, with axonal sensory motor
neuropathy, but diffuse demyelinating lesions can also be found in the CNS.
Ancillary tests that support the diagnosis are the Schirmer test (to evaluate
tear secretion), salivary glands biopsy, presence of the SSA/Anti Ro and
SSB/Anti La antibodies. Sjgren syndrome can be associated to SLE,
rheumatoid arthritis and systemic sclerosis.
Polyarteritis nodosa (PAN)

PAN is a vasculitis of medium and small-sized arteries. It is a
multisystem autoimmune disease. In polyarteritis nodosa, small aneurysms
are strung like the beads of a rosary, therefore making "rosary sign" an
important diagnostic feature of the vasculitis. Arteries from skin, kidney,
digestive tract, heart, eyes and nervous system are involved.
Clinical picture include fever, transpiration, weight loss, muscle and joint
pain. Neurologic signs relate to the peripheral neuropathy present in 50-70%
of the patients (paresthesia, dysesthesia in the hand and feet). Demyelinating
254
lesions appear in the CNS 2 to 3 years after the onset, and cause cognitive
dysfunction, seizures or other focal deficits.
HTLV-1
HTLV-1 infection causes myelopathy that appears as progressive
spasticity affecting the lower limbs, in association with sphincter
dysfunction, low back pain and proprioceptive sensation impairment, only
seldom affecting upper limbs, the cerebellum and the cranial nerves. Chronic
inflammation of the white matter, gray matter and meninges, demyelination,
small vessel proliferation and astrocytic glyosis are among the pathogenic
findings. It is more frequent in Japan, Caribbean Islands, south America and
Africa.
High titer of anti HTLV-1 antibodies in the blood and the CSF
confirms the diagnosis.
Human immunodefficience virus (HIV) and AIDS

Neurological signs in HIV infection are variable, and may include
almost any type of disorder, from peripheral neuropathy to multifocal
leukoencephalitys. Multisystemic disseminated inflammatory changes are
behind focal signs. Neurologic abnormalities may be the first signs of HIV
infection.
Serologic identification of the virus confirms the diagnosis.
Neurosyphilis
The possible clinical picture is diverse, but there are a few specific
traits as is tabetic neuropathy (isolated loss of proprioceptive sensation).
Neurological impairment appears late in the disease, as a few years usually
separates them from the primary infection. Positive serology for syphilis
confirms the diagnosis.
Progressive Multifocal Leukoencephalopathy (PML)

PML is due to CNS infection with the JC virus. It is an opportunistic
infection favoured among others by HIV infection or Natalizumab treatment.
Clinical symptoms include aphasia, apraxia, cortical blindness.
If the patient is treated with Natalizumab, the treatment has to be
halted, and an evaluation protocol including MRI and laboratory tests
(research of viral DNA in CSF by PCR) is mandatory. If clinical and MRI
signs are highly suggestive but PCR is negative brain biopsy may be taken
into consideration. Plasma exchange helps clear out Natalizumab (but also
antiviral antibodies, by this helping reduce the risk of IRIS (Immune
Reconstitution Inflammatory Syndrome). Treatment is done with high dose
steroids.
255
EDSS (Expanded Disability Status Scale)
The functional deficit generated by the disease can be quantified by
the EDSS scale. It is composed of 8 subscales (visual function, brainstem
function, motor function, cerebellar function, sensory function, bowel and
bladder, cerebral and other). Individual functional deficits and walking are
taken into account when establishing the final score. Disability increases
with the score from 0 (normal neurological status) to 10 (death due to MS)
(Fig. 1).
After a positive diagnosis of MS and of the disease type has been
established, one must evaluate disability using the EDSS scale (Kurtzke
Expanded Disability Status Scale), an important criteria to establish the
appropriate treatment.
Fig.1 Important milestones of the EDSS scale
Treatment has to be initiated as early as the CIS phase (EDSS 0.5-

1.0). DMTs have proven efficacy below an EDSS score of 5.5. Walking
impairment starts at an EDSS of 4. At an EDSS score of 7 the patient is
restricted to wheelchair for ambulation. EDSS values of 8 or 9 mean that the
patient is immobilized in bed.
Treatment
MS treatment covers at least 4 specific areas: disease modifying
therapy, treatment of relapse, symptomatic treatment, and rehabilitation.
256
Treatment of relapse
Corticosteroid therapy used to treat relapses leads to the
disappearance or improvement of the clinical feature (or symptom) that
constitutes the relapse. It does so by cumulating the effect of several
mechanisms: diminishment or remission of inflammatory processes, favoring
of the intracellular and extracellular rebalancing on an electrophysiological
level.
In the initial period of the disease the effect is more favorable, but in
the degenerative phase of MS axonal and neuronal loss are significant, and
the resulting clinical impairment is often disabling and progressive, with
poor response to corticosteroids.
Intravenous infusion is preferred for corticosteroids, but in special
conditions they can be administered orally, in sufficient dosage to induce a
similar effect and no supplementary adverse events compared to the i.v.
route of administration. The current approach states that the decision to treat
a relapse must be taken according to its severity and impact on current
activities or profession. Mild relapses (as examples a mild vestibular
syndrome or discrete sensory disturbances) can be treated solely with
symptomatic drugs.
The following substances are currently used in MS relapses:
- Methylprednisolone (high dose): 1000 qd, iv infusion, for 3-5 days;
equivalent doses of oral methyl prednisolone can be used;
- Dexamethasone 8-12 mg tid, iv infusion, for 3-7 days, followed by
oral tapering;
- Prednisone 60-80 mg qd po for 7 days, with tapering (dose
decreased with 10 mg every 4 days, for a month).
In severe relapses that have not responded to maximal steroid doses
plasma exchange might be used.
Disease modifying therapy

Current therapeutic options allow an active intervention even from
the first disease manifestation (CIS). Treatment is more efficient if started
early, within the therapeutic window.
Depending on the therapeutic impact of a specific treatment in a patient,
changes between active substances are possible, so that a stable clinical
evolution and stagnating MRI aspects (or at least with minimal activity
marks) is attained.
RRMS patients show the most benefit from disease modifying
therapies (DMT). All available drugs are efficient for this type of disease,
while SPMS patients benefit only interferon 1b and 1a sc.
Cyclophosphamide has an indication for SPMS patients with rapid
progression.
257
PPMS is hard to treat, as none of the current drugs has proven efficacy.
Immunosuppressant agents and long time corticotherapy can be tried.
Early treatment is important for a favorable long term prognosis. CIS
patients can be treated (depending on local regulations) with DMT (beta
interferons and glatirameracetate have proven efficacy in CIS), with a
subsequent diminishment of the conversion rate to definite MS. High risk
CIS (more than 6 lesions on MRI or presence of atrophy or black holes,
important or persistent neurological deficit after the first attack) have a high
probability to transform into definite MS and need to be treated.
For RRMS 4 lines of treatment exist and can be used depending on
the disease activity and reaction to previously tried medication.
Treatment is initiated with first line drugs: IFN , glatiramer acetate,
dimethyl fumarate and teriflunomide (table 4).
Betainterferons have been used since 1993 (with Betaferon). Flu-like
syndrome is common to all preparations and can be prevented with the use of
a NSAID (acetaminophen). Although liver dysfunction is usually mild, there
have been rare cases of severe hepatitis. Neutralizing antibodies can be a
problem, as up to 35% of Betaferon users and 5-10% of Avonex users might
develop them.
Glatirameracetate is a combination of 4 amino acids in special
concentrations. It acts in a different manner than the interferons, so that if
adverse events or unsatisfactory therapeutic response appears, therapy can be
switched from one type to the other.
All immune modulator MS therapy has to be interrupted before
pregnancy, because the effect of the drugs on the baby is either not known or
theratogenic (as is teriflunomide).
Dimethyl fumarate is a relatively new drug for MS. It is an orally
administered drug, and in special situations it can be continued during
pregnancy. Another new oral drug is teriflunomide, with similar efficacy
compared to classic medication. In case of adverse events, accelerated
removal of the drug from the organism can be facilitated with colestiramine
or activated charcoal.
If the response is suboptimal (with signs of disease activity either
clinically or at MRI), a second line therapy must be used (table 5). Second
line DMTs in MS have a higher efficacy than those in the first line, but also
increased risk for more severe adverse events. Depending on local
guidelines, second line drugs can also be used as first intention drugs in
special situations. Available high efficacy high risk drugs are Fingolimod,
Natalizumab and Alemtuzumab.
258
Drug/substance Adverse events Special attention and precaution
Injection site Transient immediate reaction (skin
Glatiramer
reactions, rash, thoracic pain, palpitations,
acetate
lipoatrophy; anxiety, dyspnoea, laryngeal
(Copaxone)
Vasodilatation, constriction and/or urticaria)
20 mg sc qd, or
rash, dyspnoea, Lypoatrophy and tegument
40 mg sc 3
thoracic necrosis
times/week
constriction Possible impact on immune system
Interferon beta 1a
Flu-like syndrome;
(Avonex,) Depression, suicide , psychosis ;
30 mcg im once injection site
Liver function impairment;
weekly reactions; liver
Allergic / anaphylactic reactions;
enzyme increase;
Interferon beta 1a Heart failure ; Seizures ;
(Rebif) reduced number of
Decreased blood cells (all series) ;
22 or 44 mcg sc 3 WBC Other autoimmune diseases
times/week
Flu-like syndrome; Liver function impairment;
Interferon beta 1b injection site
Allergic / anaphylactic reactions;
(Betaferon,
reactions; liver
Depression, suicide , psychosis ;
Extavia)
0,25 mcg every enzyme increase; Heart failure ; Injection site
other day reduced number of necrosis, low leukocyte numbers,
WBC Flu-like syndrome, Seizures
Transient Lymphopenia;
Dimethil fumarate tegumentary Rare opportunistic infections
(Tecfidera) erythema, digestive (PML) (in patients that have been
240 mg po bid tract symptoms, administered fumarate for
pruritus, rash psoriasis
Liver toxicity, known
theratogenicity; decreased
neutrophils, lymphocytes,
Liver enzyme platelets; infection risk, including
increase, alopecia, tuberculosis; potential increased
Teriflunomide diarrhea, upper risk for cancer; peripheral
(Aubagio)
respiratory neuropathy; acute kidney failure;
7mg or 14 mg po
qd infections, nausea, hyper potassemia; increased
paresthesia clearance for uric acid; interstitial
pneumopathy, Stevens-Johnson
syndrome; toxic epidermal
necrolysis; increased blood
pressure
Table 4. First line DMT used in MS
259
Natalizumab (Tysabri) is a monoclonal antibody against lymphocytic
4 integrins. It is useful in RRMS after first line therapy has failed to provide
an adequate control, but also (depending on local legislation) for aggressive
onset MS. The risk for a major complication (progressive multifocal
encephalitis due to opportunistic JC virus) is relatively small (around 1/1000)
and can be stratified upon existing/non existing anti-JC AB, existing/non
existing previous immunosuppressive therapy and treatment duration.
Highest risk ratio is close to 1%, but respecting treatment rules keeps it under
1/1000 patients. Careful monitoring and wise treatment choice are critical, as
PML remains a severe complication. Use of immunosuppressants as add-on
to first line therapy compromises further use of natalizumab.
Fingolimod (Gilenya) is indicated for patients with intense disease
activity (despite treatment but also as first line therapy). It has
immunosuppressant effects, so that switch to natalizumab in case of lack of
efficacy is controversial. First dose is administered with special precautions
due to cardiac adverse events.
Special attention and

Drug/substance Adverse events
precaution
Bradyarithmia and/or
atrioventricular block after first
dose administration; infections
Headache; upper respiratory risk; macular edema; reversible
tract infection; diarrhea; posterior encephalopathy
back pain; increased liver syndrome (PRES); decreased
Fingolimod enzymes; cough; functional lung parameters
(Gilenya) bradycardia (upon first (FEV1); liver toxicity; arterial
0,5 mg po qd dose); macular edema; hypertension;
bronchitis /pneumonia (8% Drug must be interrupted at
vs. 4% in placebo treated least 2 months before
patients) conception (theratogenic risk)
Lymphopenia lasts for 2
months after the treatment was
interrupted
Headache, fatigue, urinary
Progressive multifocal
Natalizumab tract infection, lower
encephalopathy (PML)
(Tysabri) respiratory tract infection,
Liver damage; herpes simplex
300 mg iv arthralgia, urticaria (hives),
encephalitis and meningitis;
infusion, monthly gastroenteritis, vaginitis,
allergic reactions
depression
Table 5. Second line DMT in MS
260
Alemtuzumab is a highly promising monoclonal antibody (against
CD52) that is already used in chronic lymphocytic leukemia. It has been
approved in MS therapy.
If second line therapy fails to provide desired therapeutic efficacy,
third line drugs may be used: mitoxantrone (table 6) and cladribine.
Mitoxantrone reduces relapses and clinical disability in RRMS,
PRMS and SPMS. It is an immunosuppressant drug. Cardiac monitoring
(ejection fraction) and hematological monitoring are mandatory.
Cladribine is a synthetic anti-cancer drug. As an oral therapy it had
been approved in some countries for MS treatment (not in EU and USA) but
finally dropped due to insufficient risk versus benefit evidence.
Special attention and

Drug/substance Adverse events
precaution
Temporary bluish color of
urine and sclera; nausea;
Mitoxantrone alopecia; menstrual
(Novantrone) abnormalities (up to Severe tissue lesions in case of
12 mg/m2 iv amenorrhea and extra vascular effusion
infusion, every 3 infertility), infections Cardiac toxicity
months up to a (stomatitis, urinary and Acute myeloid leukemia
maximum respiratory infections); Bone marrow suppression
cumulated dose of Cardiac toxicity
140 mg/m2 (arrhythmia, ECG
abnormalities, heart
failure)
Table 6. Third line DMT in MS
For special situations, and if all of proven therapies have failed,

fourth line therapy can be used.
Complete lymphoid irradiation or complete body irradiation followed
by bone marrow transplant might decrease the clinical progression and MRI
activity of MS lesions. It carries increased risk for infectious complications.
To be efficient it needs to be used during the inflammatory stage of the
disease (RRMS).
Symptomatic treatment and rehabilitation

The aim of symptomatic treatment and rehabilitation is an
improvement of the quality of life and of a better social integration of the MS
patients, without interfering with the long time evolution of the disease.
Limitation of complications of the disease, diminishment of handicap and of
the dependence is achieved by a better use of the existing physical and
psychological resources of the patient. Symptomatic treatment needs to be
261
adjusted accordingly to the stage and individual characteristics of the
disease, and responds to each patient's specific needs.
Physical therapy and occupational therapy are paralleled by measures
against incontinence, bowel dynamics, control of chronic fatigue, spasticity,
sexual disorders, as well as cognitive intervention and treatment of
depression (table 7).
Gait disorder can be successfully approached with Fampyra
(fampridine) 10 mg bid. It is a potassium channel blocker and by reducing
the ionic influx through these channels prolongs repolarization and supports
action potential in demyelinated axons. An improvement in motor function
(gait) is obtained. Kidney function, sensitization reactions and heart rhythm
must be monitored.
Fatigue Spasticity Bladder Sexual Bowel Pain

dysfunction dysfunction dysfunction
Amantadine; Baclofen Anti- Erectile Slow transit: Carbamezepi
Modafinil; (Lioresal) cholinergic dysfunction: Laxatives, ne
Fluoxetine ; drugs: Phenoxy- purgation, (Tegretol),
(Prozac) Tizanidine Oxybutinine, benzamin, metocloprami Fenitoin
(treats HCl Tolretodine, Papaverine, d, (Dilantin),
depression); (Zanaflex); Flavoxone, Alprostadil Neostigmine, Pregabalin
4- Diazepam Trospium (prostagladin Sodium (Lyrica),
amynopiridin; (Valium); e E1), docusate. Gabapentin
Fampridine Clonazepa Alfa- Sildenafil (Neurontin)
SR m blockers: Incontinence:
(Fampyra, (Klonopin) Fenoxy- Perineal Anticholinerg
Dalfampridine ; benzamine, dysesthesia: ics
); Dantrolene Prazosine, Amitriptiline
Methylphenid sodium Doxazosine ,
ate (Dantrium + Carbamazepi

); Desmopressi ne
Clonidine ne (for
(Catapres incontinence
); and nicturia)
Botulinum
toxinum
Table 7. Symptomatic treatment in MS
Pharmacological intervention in MS is still limited, partly because of

lack of evidence of efficacy for some of the drugs.
262
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264
Chapter XIV.
Infectious Diseases of the
Nervous System
_____________________________________________________________
General data Fungal infections of the Nervous

CNS affectation in bacterial System
infections Nervous System involvement in
- Syphilitic encephalitis protozoar, helminths and prion
Bacterial neuropathies infection:
CNS affectation in viral infections - Protozoars
- Rabic encephalopathy - Helminths
Viral neuropathies - Prions
Neurological complications of HIV
infection
General data
Nervous system infections can be caused by: bacteria, viruses, fungs,
protozoares, parasites and prions. There are also aseptic meningitis and
encephalitis to be mentioned.
The neurological complications of infections generate a great variety
on clinical pictures, involving both the CNS and the PNS. It is very
important to establish an accurate etiology, because treating at the right
moment with the right drug can stop the evolution of the disease, ameliorate
and even totally cure.
Of great importance in the diagnosis process is also the considering
of the geographical areal of the pathogneic agents, the modalities of
transmission and the risk of various structures of the nervous system to be
predilectly affected.
265
Neuroinfections are part of differential diagnosis algoritms, being
identifyble by detecting specific markers in blood, CSF or different
secretions.
At CNS level infections cause meningitis, encephalitis (with
predominantly interest of either substantia nigra or the white matter, as well
as the existence of panencephalitic entities), myelitis and tromboflebitis.
The PNS can also be victim of infectious aggressions, by generating
distal symmetrically polyneuropathies (Lyme disease, C virus hepatitis,
HIV), demyelinating neuropathies (diphtheria, HIV), mononevritis multiplex
(CMV, HIV, leprae, Lyme disease, motor mononeuropathies, poliomyelitis,
West Nile virus also check the diseases of the PMN).
Infectious neuropathies can be divided into two major neropathies:
bacterian and viral. Beside this, protosoares must also be mentioned among
the infectious pathology of the NS (eg. Trypanosoma cruzi).
Among the radiculopathic pathology, the etiology consists in: CMV,
Herpes simplex type 2, Lyme disease, sifilis (tabes dorsalis). The cranial
nerves can also be agressed through varicella zoster. A special attention
should be directed towards HIV, which can lead to all sorts of either central
or pheripheral neuropathies.
Bacterian infections can disseminate to the nervous system by several
ways, out of which the hematogen way is most often incriminated, as it
facilitates transportation from other infectious levels (pulmonary, sinusal,
mastoidian, tegumentary and other).
Traumatisms can as well facilitate the infection of bone and
meningeal structures, finally leading to NS infection. Contaminated aliments
may also represent a way of contracting a NS infection (eg. Listeria
Monocytogenes).
CNS affectation in bacterial infections

The course of infection is dependent on the first impact of the
pathogen agent with the organism. In this process, the integrity of the natural
protective barriers against agressions is most important. This is why, after
mucous-cutaneous barriers have been overpassed, most pathogens multiply
until they reach a sufficient agressity level (directly dependent on a
weakened immune system), afterwards, through the blood flow the infection
disseminates either to the CNS or to the peripheral nerves.
Once the Blood Brain Barrier (BBB) is penetrated by pathogens, they
can easily reach the parenchyma or the CSF by different strategies (eg.
Neisseria meningitides preffers endocytosis, while Haemophilus influenzae
realizes intracellular invasion).
266
The defense mechanisms of the CNS are limited. An inflammatory
reaction occurs (triggered by the presence of germs inside CSF spaces).
Complement fractions, cytokines, chemokines and adhesion molecules are
released, leukocytes and macrophages migrate towards the infection sites,
microglias and astrocytes are activated and so, the permeability of the
vascular endothelial increases, leading to intensification of liquids and
proteines transfer inside the parechyma, and therefore, edema appears. The
edema will lead to an increase of the intracranial pressure, which along with
vasculitis and blood pressure fluctuations can cause ischaemic, metabolic or
hypoxic lesions.
A great variey of bacterias can determine meningitis, brain abscess,
cranial epidural abscess and also spinal epidural abscess, as shown in the
table below.
Cranial Spinal
Meningitis Brain Abscess Epidural Epidural
Abscess Abscess
S. pneumoniae S. pneumoniae Staphylococcus Staphylococcus
N. meningitides N. meningitides aureus aureus
L. Haemophilus
monocytogenes influenzae Aerobes Gram negative
Staphylococcus Listeria bacilii
spp. monocytogenes Anaerobs
E.coli Group B Streptococcus
Klebsiella streptococcus: Gram negative spp.
Enterobacter Streptococcus organisms
P. aeruginosa agalactiae
Haemophilius Enterobacteriaceae:
influenzae Klebsiella, E. coli
M. tuberculosis
Treponema
pallidum
Borrelia spp.
Leptospira spp.
Table 1. Ethiology of menigitis
The clinical pictures may vary between meningeal, encephalitis or

myelitis syndromes.
Meningitis is characterised by fever and meningism (neck stiffness,
photophobia and headache), and can be clinically documented by the Kernig
sign (inability to straighten the leg when the hip is flexed to 90 degrees) and
267
the Brudzinski sign (hips and knees flex involuntary when the neck is
flexed).
The encephalitic syndrome may add seizures to the clinical signs
already described, it can affect cranial nerves (III, IV, VI, VII) and also
cauze aphasia, hemiparesis, behavioural disturbances and pain in the
extremities.
Pain is also a common sign of myelitis, leading to paraparesis and
paresthesias.
Syphilis
Syphilis (caused by Treponema pallidum) is a sexually transmitted
disease, caused by having unprotected sexual intercourse with multiple
partners. Among manifestations that become at certain point visible during
the evolution of the disease are the tegumentary rash, lymphatic
adenopathies, uveitis and meningitis.
The first manifestation of the disease, the acute one, is characterised
by the presence of genital lesions (genital sores). If this first infection is not
observed, diagnosed and treated, the secondary period of the infection will
be characterised by the absence of lesions and the innaparent progresivity of
the disease.
During secondary syphilis, the nervous system becomes invaded,
without any noticeble modifications at the CSF exam. The most important
neurosyphilis manifestations are: acute syphilitic meningitis, stroke and
neuropsychiatric disturbances. Tabes dorsalis is a rare enthity.
There are 2 formes of meningitis that can be found: acute and
chronic. The acute form manifests through fever and neck stiffness, while the
chronic one associates cranial nerves paralysis.
Stroke cand be either wide or limited, according to the size of the
blood vessel implicated. Among large calibre vessels, the carotidian territory
and the medial cerebral artery are the most frequent implicated in ischaemic
events. Ischaemic complications may also characterize the spinal cord, by an
initial spinal shock followed by spastic paraparesis.
Syphilis can induce encephalopathies that are accompanied by
comitial crisis and combination of delirium-dementia. The pupilary sign
Argyll-Robertson ("light-near dissociation" - a pupil that is small and
constricts poorly to direct light but briskly when a target within reading
distance is viewed) is inconstant.
After many years or even decades, the installation of the tertiary
syphilis, induces tabes dorsalis and general progressive paralysis. Tabes
dorsalis is represented by sensitive ataxy of limbs, pain and sphinterian
disorders.
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A diagnosis can be established by CSF analysis (mild increase of
mononucleous cells) and positive VDRL.
The treatment with intravenous penicillin for 10-14 days is sufficient
and efficient.
Bacterial neuropathies
The main bacterial infectious agents involved in neuropathies are:
Borrelia burgdorferi, Clostridium botulinum, Corynebacterium diphteriae
and Mycobacterium leprae.
Corynebacterium diphtheriae
Diphtheria is caused by Corynebacterium diphtheriae, an is
characterised by the presence of pharingeal pseudomembranes.
The exotoxin has a great afinity for the PNS, which is involved 3
weeks after the infection. The gravity of the infection depends on the
pharyngeal, laryngeal and respiratory muscles paralysis.
Other signs of nervous system involvemnt are: dysphonia,
acommodation paralysis and polyneuropathy. The disease sometimes has a
biphasic evolution, meaning that bulbar suffering can be added to the clinical
picture once with affection of the limbs.
The disease is rare. The treatment is based on administration of
antitoxin.
Borrelia burgdorferi
The spirochete responsible for Lyme disease is transmitted through
the bite of infected ticks. This usually happens during activities in nature
(forests, parks), the microorganism afterwards locating itself in different
tissues causing various clinical manifestations, initially affecting the
teguments, followed by joint and nervous system affectation. The disease can
easily be diagnosed right after the bite, by observing the specific
tegumentary lesion called Bulls eye rash.
During the acute infection, a multifocal radiculopathy can occur, also
involving the cranial nerve VII. The chronic phase is rather characterized in
the early stage by a distal sensory polyneuropathy. Clinical manifestations
from the onset of the disease include: fatigability, fever, headaches, arthragia
and myalgia. Lymphocitary meningitis with mild neck stiffness and
cerebellar ataxy may install as well.
The symptomatology can diminish during the following weeks, even
while in the absence of a diagnosis or a treatment, the patient, unawarely
evolving towards the Lyme encephalopathy (neuroborreliosis).
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Detection of specific antibodie in the CSF is useful for the
paraclinical diagnosis, completed by PCR and ELISA analysis in later stages
of evolution. EMG may be useul by detecting the nervous affectation, either
proximal or distal. Cerebral MRI can reveal white matter lesions, a
differential diagnosis with Multiple Sclerosis being frequently required.
Doxycycline 100 mg twice daily is useful in treatment, with
favorable effects in ameliorating the symptomatology after 14-21 days of
treatment, for the acute phase of the disease. In the chronic satage,
Ceftriaxone is recommended, 2g/day or Penicillin G 24 million U/day, 14
days.
Both the diagnosis and treatment, if established at the right time can
stop the evolution of the disease and prevent neurological complications.
Any person known to have been bitten by a tick should be treated as soon as
possible.
Clostridium botulinum
Botulism is caused by the toxine synthethised by Clostridium
botulinum. In this disease, the release of acetylcholoine is blocked at
neurojunction level. Most often incriminated antigenic type is BTX A.
The contamination ways are represented by the ingestion of the toxin
through contaminated aliments, by absorbtion of the toxin in the circulatory
torrent, either through inhaling (the pure toxin) or injuries (also through
intestinal colonization), sometimes accomapenied by vegetative forms.
The initial symptoms in case of ingestion of contaminated aliments
appear in 12 up to 38 hours and are represented by: ptosis, visual
disturbances, strabismus (especially by VI nerve palsy), diplopy, mydriasis,
facial palsy, dyzarthria and hoarseness. The evolution is characterized by the
loss of cephalic postural maintaining ability, descendent motor deficit
(pharingian, upper limbs, accessory respiratory muscles, diaphragmus, the
lower part of the body), abolition of the deglutition reflex and abolition of
osteotendinous reflexes, or autonomus difunctions (severe constipation).
A descendent symmetrical flaccid paralysis can also be observed,
accompanied by significant bulbar paralysis, but sensitivity is normal.
Nerve conduction studies reveal the presinaptic neuromusculat
transmission block, with reduced motor potentials (but increased amplitude
in repetitive stimulation). The EMG exam records fibrillation potentials.
The treatment is represented by the administration of antitoxine until
the symptomatology is ameliorated and Guanidine for ameliorating the
motor deficit.
Knowing the fact that the toxin is inactivated by heat and water
chlorination, the prophilaxy can be efficiently done by proper cooking of
aliments and avoiding the consume of water from doubtful sources.
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Mycobacterium leprae
The mononeuropathy multiplex caused by M. leprae is affecting
mainly the peripheral nerves in cooler regions of the body, causing
deformities that carry a lot of stigma.
The disease can be tuberculoid, lepromatous or borderline type.
General symptoms in leprae are: the thickening of the skin,
hyperesthesia and anhidrosis, accompanied by sensory loss that spares the
anterior midline of the trunk, the axilla and the scalp.
It affects the cranial nerves V and VII, the median, ulnar and peroneal
nerves.
The diseases evolution may lead to claw hand deformity, footdrop
and the inability of closing the eyelids.
CNS involvement in viral infections

The clinical aspects in viral infections are similar to the bacterial
ones; however, there are some differences in the way diagnosing a viral
infection, in this particular case, an IRM would be preffered rather than a
CT. The CSF is also a criteria to consider when differentiating a viral from a
bacterian etiology: in a bacterial meningitis the CSF is cloudy, while in a
viral one it is clear. Also, the serum procalcitonin is elevated in the bacterial
forms, while in the viral cases of CNS infection it is normal.
Acute Meningitis Acute Encephalitis

Enteroviruses (Coxackie, Echo) Herpes simplex 1
Herpes simplex 2 Varicella Zoster Virus
Varicella Zoster Virus West-Nile Virus
Arboviruses Epstein-Barr
HIV Rabies
Epstein-Barr CMV
Enteroviruses
Table 2. Differential between meningitis and encephalitis
Clinical features of viral meningitis include symptoms such as: fever,

neck stiffness, headaches, photophobia, nausea, anorexia and myalgias.
Encephalitis usually occurs simultaneously with meningitis as
meningoencephalitis, manifesting as: fever, headache, neck stiffness, altered
mental functions with disorientation and behavioural disturbances. This
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clinical manifestations can evolve into aphasia and even complex partial
seizures.
Rabic encephalopaty
This form of encephalopathy is a neurological complication of the

infection with the rabies virus (Lyssa virus).
The disease is transmitted from a donor to a receiver by biting,
scratching or licking, some wild or even domestic aniamals being able to
transmit the disease to persons (especially by bite).
The animals able to transmit the infection are: dogs, wolves, cats,
foxes, bats and other. The period in which the animal becomes fully
competent in transmitting the disease is characterized by an increase of
agressivity, an abnormal behaviour compared to the other members of the
same species.
The bite wound evolves towards cicatrization, being accompanied by
muscle fibres contractions. The incubation period can last up to 30-40 days;
meanwhile the virus migrates towards the CNS following the axonal way.
It is important for a proper diagnosis, to demonstrate that the animal
that bit was infected.
The symptoms vary from paresthesias, fever and headache, during
the first days, to hydrophobia, respiratory muscle spasm, agitation and in the
final stages, paralysis and death (if untreated).
Vaccination (administration of antirabies immunoglobulin) and a
proper igienization of the bite plague is an efficient treatment.
Viral neuropathies
There are many viruses that can affect both the CNS and the PNS,
either as their predominantly characteristic, or as a complication of other
pathologies. The oropharynx is the site of primay replication, along with the
gastrointestinal tract, the respiratory pathways and regional lymphatic nodes.
The viruses multiply locally, inside the vascular endothelium or at lymph
nodes level, afterwards they invade the nervous system using the
hematological way or along peripheral nerves. Another invasion startegy is
attaching to the presynaptic membrane and following the retrograde
axoplasmatic flux. Particullarly the trigeminal and the ophtalmic nerves can
be veritable pathways for infection dissemination towards the CNS.
The most frequent viral neuropathies have as etiological agents the
viruses herpes simplex and zoster, hepatitis B and C, HIV and the rabies
virus. Hepatitis C virus can lead to a sensorymotor, polyneuropathy,
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mononeuropathy or multiplex mononeuropathy (in association with
cryoglobulinemia).
Herpex simplex
The neuropathic pain in herpes simplex infection (HSV-1 or HSV-2)
is actually about a reactivation of the dormant virus, most often inside the
trigeminal or lombosacrat ganglions. When the organisms defence
mechanisms are overwhelmed, the infection spreads following the nerve
tracts, leading to clinical manifestations such as painful rashes around the
mouth or located at the genital organs.
If in case of HSV-1 encephalitis is the most important complication,
in case of HSV-2 infection characteristic is the radiculopathy manifestations,
the virus also being able to cause myelitis in immunosupressed patients. The
main clinical manifestations include: fever, headache and neck stiffness.
Neuropathic manifestations can be encountered in both forms of infections.
Clically, vesicular lesions can be observed at the tegumentary surface
(zosteriform eruption), HSV-1 being responsible for lesions above the neck.
HSV-2 is more likely to cause cutaneous lesions below belly, the recurrent
episodes of pain being most often attributed to this particular type of virus.
PCR is useful for identifying the virus.
Herpes zoster
After the primary infection caused by the varicella-zoster virus
(varicella), it remains dormant in the sensitive nerve roots, immune
mechanisms acting towards stopping the replication. However, in
immunosupression conditions, the virus can be reactivated, situation in
which it will migrate by the sesory fibers to the tegument.
The pain that starts to manifest is followed in 3-4 days by the
cutaneous rash, thus the inflammatory syndrome involves the nerve roots,
and manifests by a decrease of muscle strength. The infection can manifest
through oculomotory affectation, facial palsy (Ramsey Hunt syndrome),
thoraco-lombary zoster and loss of sensitiveness at this level. The pain can
decrese after a week, but it might also continue to manifest as the
postherpetic neuralgia.
Exist i variante atipice, cum ar fi zoster multiplex, n care erup ia
poate apare in mai multe dermatoame, mai ales la pacienti
imunocompromisi; sau reactivarea infec iei fr erup ia caracteristic, dar
cu durere la nivelul dermatomului afectat. Tot la imunocompromi i poate
aprea i mielita.
273
There is also knowledge about atypical versions of the infection, such
as zoster multiplex, in which the eruption can involve more dermatomes,
especially in immunocompromised patients. There might also be a
reactivation of the infection without the characteristic rash, but with pain in
the affected dermatome. Myelitis may also occur in immunocompromised
patients.
The treatment is based on the administration of Aciclovir or
Famciclovir, completed by the cure of the neuralgia: Nortriptilin or
Gabapentin, as well as topical administration of Lidocain.
Fungal infections of the nervous system

Fungal infections are rare, this the main reason why such a diagnosis
is usually difficult to establish. In this catgory belong: candidiasis,
aspergilosis, cryptococcosis, coccidiomycosis, mucormycosis and
histoplasmosis.
The pathogen agents can be present without causing clinical
manifestations, especially after antibiotic treatment. They are often
encountered in diabetes patients, or those who have suffered a transpantation
or received a long term chemotherapy treatment. These infections can be also
present in new-born and patients with congenital numerary deficiences.
The diseases that may appear are: meningitis and encephalitis, but
also clinical manifestations associating other organs sufferings, involvement
of the sinuses, nazal cavities or the cavernous sinus.
The positive diagnosis is based on cerebral imagistics, CSF exam,
and investigation of other organs where infectious processes with the same
etiology might occur.
Nervous System involvement in protozoar, helminths and

prion infection
Protozoars are intracellulary parasites that can invade the brain and
other organs, triggering or maintaining a subacute persistent evolution. The
most common infectious entithies in this category are malaria and
toxoplasmosis.
Malaria is most often present in tropical regions and is transmitted by
the Anopheles mosquito. It generates a high percentage of mortality by
invading the brain (cerebral malaria).
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Toxoplasmosis is world-wide spreaded by contaminated hands,
contaminated aliments and water. It can also be contracted durin the
intrauterine life or as an oportunistic cerebral infection in HIV patients.
Helminths include cestodes, nematodes and trematodes.

Their pathogenic cycle includes two or more hosts, their infectious
mechanisms interfering with the immune system of the host.
They are predilect for the CNS, which is accesed by hematogenous
pathway or by ectopic migration of a larva. This is the way
Neurocysticercosis and Echinococcosis occur.
Prions are proteic infectious particles that cause spongious

transmissible encephalopathy, which proves to be an irreversible and fatal
form of degeneration of the nervous system. The most known clincal
enthities are the Creutzfeld-Jacob (CJ) disease and the fatal insomnia,
diseases that can be either sporadic or familial. CJ can be contracted by
direct contact with the prion, or iatrogenic, following invasive medical
techniques.
The most important symptomes belong to the cognitive field, and can
occur by cognitive impairment with evolution towards dementia. The clinical
picture also adds behavioural disturbances, cortical cecity, ataxy, involuntary
movements or piramidal signs.
There is no treatment available, except profilaxy measures for
avoiding iatrogenic CJ. Death usually occurs after approximately 2 years.
Neurological complications of HIV infection

HIV is part of the Retroviridae family, Lentiviruses subfamily, AIDS
(acquired immune deficiency syndrome) being nowadays a very actual
research subject for both neurobiology and fiziopathology, also presenting a
great interes in the neuroinfectious clinical activity.
The interest for what at that time was a new infectious pathology,
started to manifest among the scientific community over three decades ago.
What we know today about HIV is that it leads to a semnificative cell
mediated immune depression: lymphopenia, affect of the CD4/CD8 ratio as a
result of a low level of CD4, an affectation of macrophages and also a
disorder of the lymphoprolipherative answer to the action of numerous
antigens. The result of all these reactions is the clinical vulnerability to
aggressive agents, either from the internal or external environment, also from
opportunistic infections, in conclusion, a deficitary ability of the organism to
fight against infections.
275
The two pathogenic forms of the virus for humans are the HIV-1
(most often met across the American continent) and HIV-2 (frequent in
countries from Western Africa and in Asia). The main HIV transmission
ways are widely known: unprotected sexual intercourse, blood or use of
syringes in common for drugs administration. There is also a iatrogenic
possibility from use of medical instruments unsufficiently sterilized, cases of
infection being known in people that contracted HIV, HVC or HVB in the
years before the use of single-use medical materials.
Both the CNS, as well as the PNS, are along with other organs and
systems, at risk in case of HIV infection. Neurological involvement can be
found present in approximately one third of the infected patients;
nevertheless, necropsy of deceased AIDS patients suggests infection of the
nervous system in almost all patients.
The main targets of HIV in neurological pathology are: the brain, the
spinal cord, the meninges, the peripheral nerves and also the nerve roots, the
AIDS patient risking a large amount of complications localized at any of
these levels.
The neurologic complications of HIV

The neurologic complications of HIV infected patients can be divided
into two cathegories:
1. Direct effects of HIV infection;
2. Secondary effects manifested throughout opportunistic infections
and neoplasms.
The direct effects of HIV infection

Is represented by cognitive impairment and dementia
(HIV encephalopathy), aseptic meningitis, myelopathies and peripheral
neuropathies. The involvement of the PNS manifests through acute
inflammatory demyelinating polyneuropathy (Guillian-Barr) or through
chronic inflammatory demyelinating polyneuropathy (CIDP). There are also
manifestations such as mononevritis multiplex, symmetrical distal
polyneuropathy and different forms of myopathies.
1.a. Dementia and the cognitive impairment appear late during the
diseases evolution, and are reffered to as HIV-associated neurocognitive
impairment (HNCI), with its most severe form: the AIDS dementia complex
(ADS). In children with AIDS, dementia is unfortunately much more
frequent than in adults, with a noticeable stagnation in the encephalus
development, especially in the first months after birth.
The first symptoms that appear consist of attention deficit, short
memory losses, personality disorders, mild speaking difficulties and a
general state of apathy. From the motor perspective, there is a frequent poor
276
coordination of the limbs movements, ataxia, saccadic eye movements,
exaggerated osteotendinous reflexes, Babinski sign, and even paraplegia and
bladder dysfuntions, all concuring for a clinical picture suggestive for both
cerebral and spinal involvement.
The evolution is usually fast progressive once dementia is installed,
especially in absence of a treatment, life expectancy in this case being
situated at 6 months. In case of a specific AIDS treatment, dementia has a
lower incidence, of approximately 1% of the patients, compared to 60% of
untreated patients with at least a mild form of cognitive impairment.
CSF analysis is suggestive for lymphocitary unspecific pleiocytosis.
MRI can provide informations about diffuse, confluent, periventricular
lesions, in T2 seqences.
1.b. Aseptic meningitis is a complication that is present in any moment of

the disease-s evolution, with clinical manifestations consisting in headache,
fever, nausea, anorexy and photophobia. It can interest the cranial nerves
VII, V and VIII.
A differential diagnosis with a viral meningitis is almost impossible
to perform, the CSF exam suggestion lymphocitary pleocytosis and elevated
protein levels, glucose remaining normal. The evolution towards healing
takes 2-4 weeks, even if, there are cases of patients who develop a chronic
persistence of these clinical signs.
1.c. Myelopathies, peripheral neuropathies and myopathies are frequent

evolutive complications.
Myelopathy can be found in 20% of the patients with AIDS, and in
90% of the cases it is associated with dementia. The vacuolar mylopathy is
the most frequent form, caractherised by postural disturbances, ataxy and
spasticity, bladder dysfunctions, exaggerated osteotendinous reflexes and
Babinski sign.
From morphopathological perspective, the myelin stealth presents
spongiform anomalies with vacuolization, thus the name of the condition.
The treatment is symptomatic, associated to the antiretroviral therapy.
HIV infection can be accompanied by peripheral neuropathy,
frequently distal, symmetrical, with axonal affectation. It manifests through
sensory deficit and disesthesias (HIV was isolated from peripheral nerves
and ganglions). Other peripheral manifestations are multiplex
mononeuropathy, especially related to a vasculitis, and also cauda equine
syndrome, related to the presence of CMV. Guillian-Barr and CIDP types
of demyelinating inflammatory neuropathies have also been described.
Laboratory findings show pleiocytosis and elevated proteins in the
CSF. Pheripheral nerve biopsy may also contribute to a diagnosis, the
277
perivascular infiltrate being suggestive for an autoimmune pathology. Nerve
conduction studies and EMG are also useful in appreciating the prolonged
distal latencies, the F wave modifications and the decrease of motor
conduction velocities.
A differential diagnosis must take into consideration diabetes
mellitus, B12 deficiency and possible effect of some drugs (Metronidazol or
Dapsone).
There is talk about a possible screening for HIV among patients with
demyelinating polyneuropathies, however, such initiative would be most
likely to be applied in certain groups of patients in geographical regions
exposed to risk.
Such polyneuropathies usually evolve favorable, either as a result of
plasmapheresis, or after no therpy at all. Glucocorticoids should be avoided
because of immunosupression, however, they might be useful in some cases
of refractory CIDP. Symptomatic treatment can include in some cases:
Gabapentin, Carbamazepin sau usual analgesics. To all these, antiretroviral
treatment should be continued.
Myopathies may occur in any stage of the disease, manifesting by
decrease of force on proximal level and rarelt rhabdomyolisis (subacute
syndrome), with inconstant response to corticotherapy. Asymptomatic
increases of CK levels sometimes occur after physical exercise.
Important muscle loss can be observed after long treatment with
Zidovudine, the hallmark morphopathological abnormality in this case being
the presence of red ragged fibers.
Secondary effects
Oportunistic infections with nervous involvement are toxoplasmosis,
cryptococcosis, progressive multifocal leucoencephalopahy, syphilitic
infections, infections with CMV and Mycobacterium tuberculosis. Infectious
complications can even lead to a dementia.
Toxoplasmosis is determined by the Toxoplasma gondii protozoar,
becoming manifest when CD4 level falls beneath 100 cells/mm3, sometimes
contracting the disease takes place in intrauterine life. The main transmission
path is the fecal-oral one, the infection remaining latent for a long period of
time.
Signs and symptoms can be connected to a lesion with focalization on
the parenchyma: headache, hemiparesis, hemianopsy, aphasia and ataxy.
There are also symtomes that can be attributed to a subacute encephalitis:
fever, headache, confusional syndrome, behavioural disturbances and
attention deficit.
The diagnosis is established by detecting IgG antibodies or CSF
analysis: high level of proteins and lymphocitary pleiocytosis, nevertheless, a
278
lumbar puncture is not indicated in the presence of space-occupying lesions
that realize mass effect. Cerebral IRM can reveal multiple lesions in various
locations.
The treatment is based on pyrimethamine and sulfadizine for 6
weeks, followed by a period of using lower doses of the same drugs. Folinic
acid can be added for balancing the toxicity of pyrimethamine. Primary
profilaxy can be achieved by using trimethoprim-sulfamethoxazol as well as
general recommendations: avoiding consuming meat insufficient cooked or
contact with materials possible contaminated with cat fecals.
Cryptococcosis is the most encountered fungal infections during the
evolutive course of AIDS, as well as the most common cause of meningitis
in this pathology.
C. neoformans is responsible for subacute meningoencephalitis
during a significant decrease of CD4 (<100/uL), and is frequently contracted
in Africa (approximately 20% of the patients), the prostate in this case, acts
as a reservoir for the latent microorganism.
The symptoms are: fever, nausea, vomiting, headache and meningeal
signs and also cranial nerves involvement. CSF exam may suggest a mild
increase of the leucocytes and proteins number, and a slight decrease of the
glucose level, but can whatsoever be useful for detecting the pathogen. MRI
can reveal hiperintense lesions in T2 sequences.
The treatment is based on the administration of Amphotericin B and
Flucytosine the first 2 weeks, followed by progressively decreasing doses the
following 2-3 months.
Progressive multifocal leucoencephalopathy (PML) is caused by
the JC virus, and is a late manifestation of the disease, due to the reactivation
of the virus.
The MRI exam shows lesions that are viewed as demyelinating
regions inT2, in the white matter subcortically, in the cerebral hemispheres,
cerebellum or the brainstem. It clinically manifests with multifocal
neurologic deficits, seizures, ataxy, hemiparesis, aphasia or sensory deficits.
The virus can be identified in the CSF.
There is no specific treatment, except going on with the highly active
antiretroviral therapy (HAART), 50% of the patients presenting at some
point a neurological amelioration.
Neurosiphilis also has a high incidence among AIDS patients, the
diagnosis in this case depending on serologic tests.
Tuberculosis may occur in drug consumers already HIV infected,
carrying the risk of developing tuberculous meningitis. The treatment is the
same as in case of TB non-HIV patients.
CMV infection can be found in 1/3 of the AIDS patients,
manifesting through an encephalopathy form that leads to confusional
279
episodes, delirum, ophtalmoplegia, nistagmus, facial palsy and ptosis, and
even polyradiculonevritis-like manifestations.
MRI exam is useful for determining the periventricular affectation
and also at the meningel level, the treatment consisting in antiviral agents
(eg. Ganciclovir).
Lymphoma is the neoplasm very often encountered during HIV
infections, a CNS affectation also being possible in 20% of the patients with
the systemic type of disease.
The clinical signs are represented by focal deficits, headache or
seizures, cranial nerve involvement, and determined by limited 3-5 cm
lesions in the white matter, visible in CT or MRI exams.
A treatment is difficult to establish in HIV patients as in these cases
the disease is already in advanced stages. A palliative radiotherapic approach
may offer a slight amelioration, however maintaining a bad prognosis.
Neurological complications in HIV patients are frequent
manifestations (20-40%) and are related to the primary infection, as well as
many other opportunistic factors.
Headache and mental status changes are problems that appear
relatively early, suggesting a CNS affectation. Other signs consist of
attention deficits, memory losses and also concentration difficulties.
Observing such clinical manifestations in an HIV patient is a favourable
moment for a proper diagnosis and an appropriate therapeutic approach.
HAART (highly active antiretroviral therapy) has been playing an
important role throughout the last years in a decline of complications for
HIV infected patients. Reasearch is also directed towards HIV-1 (HAND -
HIV-1-associated neurocognitive disorder). Meanwhile, the secondary
effects of antiretroviral therapy are also discussed, with the main purpose of
allocating more interest and resources towards HAND prevention and
treatment.
All these therapeutic strategies and also a palliative treatment at the
right moment may result in a decrease of morbidity in this disease so serious
but at the same time so complex.
280
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281
Chapter XIV.
Muscular pathology
Orest Bolbocean
General data
Progressive muscular dystrophy Metabolic myopathies
a. Duchenne muscular dystrophy Periodic kalemic paralyses
b. Becker-Kiener muscular Dermatomyositis and polymiositis
dystrophy Endocrine and metabolic
myopathies
c. Scapular and pelvic muscular
Toxic myopathies
dystrophy Myotonia
d. Facio - scapular humeral Myasthenia gravis
dystrophy
Congenital myopathies
General data
Muscle tissue accounts for 40% of the weight of adult human body,
being responsible for performinig the movement ordered by the nervous
system. The nervous system is compartimented structurally and
metabolically, fact explaining its partial and selective vulnerability. The
muscle is made up of fibers of variable lengths, originating from a single
cell.This cell is multinucleated, and represents an indivisible anatomic and
physiologic unit. It has a sarcolema, sacoplasm and nuclei. The sarcoplasm
contains myofibrils, mitocondria, Golgi complex and endoplasmic reticulum.
In turn, the myofibrils are composed of myofilaments made up of contractile
proteins, actin and myosin, which produce the striation characteristic to
scheletal muscles. Intracellulary, glycogen, myoglobin, stored fat, various
proteins and enzymes are also found. The muscle fiber is surrounded by
endomysium; the group of muscle fibres is wraped by perimysium and the
muscle is covered by epimysium.
The muscular system depends on innervation. Each muscle fiber
receives a nerve twig from a motor neuron in die anterior horns of spinal
cord or motor nucleus of a cranial nerve. The junction between nerve and
muscle is done at the motor end plate, which has acetylcholine as a mediator.
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The substrate of acetylcholine action and its time-limited action is realized
by the specialized receptors and acetylcholinesterase.
The motor unit responsible for all voluntary and reflex contraction is
formed by the group or muscle fibers innervated by the same motor neuron.
The variations in length of the striated muscle are transmitted to the nervous
system by some specialized sensory terminations which surround the
intrafusal stiated muscle fibers. Striated muscles have a motor and sensory
innervations. They also have receptors such as the muscle spindles, Golgi
tendon organs, and nonspecific receptors. Muscle spindle contains "nuclear
bag" and "nuclear chain" fibers controlled by the gamma motor neuron in the
anterior horn. The muscle spindle may be considered the sensing element of
a reflex system that registers differences in length between itself and the
main muscle mass and acts to reduce this difference; thus, the first to
contract for a movement ordered by the nervous system are the intrafusal
striated muscles innervated by the gamma motor neuron. The changes in
length or diameter determine the stimulation of annulospiral and flower-
spray endings which will inform the nervous system determining the
cessation of the ordered contraction. At the level of the neuromuscular
junction there are the Golgi tendon organs, which are placed in series; these
send information to the nervous system about the beginning, amplitude and
termination of contraction. The muscle also contains free nerve endings,
which conduct the sensation of pain, and sympathetic fibers, which innervate
to blood vessels.
Neurogenous atrophy is characterized by the decrease in size of the
denervated motor units. The neighboring, but unaffected motor units show
hypertrophied fibers.
Segmental necrosis with degeneration of muscle fiber and myophagism
is characteristic to infectious polymyositis, progressive muscular dystrophy
and paroxysmal myohemoglobinuria.
The structural changes consist in sarcoplasmatic masses with
agglutinated nuclei (characteristic to progressive muscular dystrophies),
complexes of glycogen granules (glycogenoses), rods (nemaline myopathy)
and other cytoplasmic bodies. The changes in the number and size of muscle
fibers are characteristic to growth disorders, congenital myopathies,
immobilization atrophy, and to cachectic individuals. Hypertrophy occurs
when some motor units are much employed.
Pareses and paralyses are the result of lesions in the corticospinal
pathways and peripheral motor neurons. A progressive diminution of
strength following repeated contractions and progressive fatigability are the
most common features of myasthenia.
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The inability of muscles to relax rapidly associated with prolonged
contraction are specific for myotonia. Also characteristic to this disease is the
aggravation of the deficit when cold.
The increase in muscle strength at repeated contractions is met in the
myasthenic syndrome of Eaton and Lambert. Muscle contractions are also
found in tetanus, tetanies, muscle cramps by neurogenic irritation, and
muscle phosphorylase deficiency in McArdle glycogenosis. Changes in
muscle volumeand consistency are caused by hypertrophies, pseudotrophies,
atrophies and denervations.
The classification of primitive muscle diseases is:
I. Hereditary:
A. Muscular dystrophies, myotonic dystrophy
B. Congenital myopathies
C. Metabolic myopathies
D. Congenital myotonia and paramyotonia
E. Hypokalemic and hyperkalemic periodic paralysis
II. Inflammatory:
A. Myopathies in collagen diseases
B. Myopathies in sarcoidosis
C. Myopathy in the infections with protozoa, viruses, parasites
D. Polymyositis and dermatomyositis
III. Endocrine and Metabolic:
A. Endocrine with hypo and hyperfunctions
B. Metabolic
IV. Toxic (alcohol, opiates, pentazocine, etc)
V. Tumors and muscular masses: metastases, infections, sarcoidosis,
myositis ossificans, muscle ruptures and hemorrhages.
I.A. Progressive muscular dystrophy

Neurological muscle diseases are chronic diseases characterized by
muscle atrophy with special topography, hereditary, familial. They usually
begin in the childhood, occurring in women due to X-linked autosomal
transmission. Pathophysiological muscle fibers produce replacement with
tissue or fat, process affecting the proximal limb muscles, belts. The
muscular atrophies are symmetrical, unlike neuropathies which are
asymmetrical. There may be appearent pseudohypertrophies with increased
volume of muscle, adipose tissue and secondary growth replacing necrotic
muscle fibers. The patient has no twitching or sensory disturbance and
contraction is diminished or abolished, this change occurring early.
The electromyographic changes that are seen is a myogenic pattern
with low motor unit potential duration and low amplitude and polyphasic
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wave. Tendon retractions are obvious with Achilles tendon contracture of the
crural triceps leading to vicious attitudes and positions.
Myogenic muscular disease etiology may be due to the damage to the
muscle (myopathies), which in turn can be primary (muscular dystrophy) and
secondary to inflammation (myositis, dermatomyositis and polymyositis).
Another etiology may be neurogenic when the muscle disease is due to
peripheral motor neuron lesions.
a) Duchenne muscular dystrophy:

It is the most common muscular dystrophy with a 1 in 3500
newborns alive only in males. It is transmitted recessive sex-linked X on
chromosome p 21 gene encoding dystrophin, the protein that exists within
the cells in the muscle fibers and stabilizes the sarcolemma. In 2/3 cases, the
cause is DNA depletion and in 1/3 of the cases mutations at this level. In
evolution occurs with deficit in muscle fiber necrosis and in sarcolemma
stability.
Onset is between 2-5 years after the onset of walking, with muscle
weakness, hard starting, "swinging" walking, tendency to fall; lifting from
the ground using his upper limbs in the so-called "climbing himself" sign. In
the evolution pseudohypertrophy of the calves appear and Achilles tendon
retraction, with walking and standing on tiptoe and external support on the
plant. Evolution is initial slow, progressive, from 7 to 10 years there is a
relative stabilization, after 10 years the development is increasing
progressively and the disease becomes disabling approximately around 12
years old (immobilized in wheelchairs), emphasizing rapid evolution and
complications, which ultimately lead to death.
On examination, the muscle strength is reduced in the belts area
(breech, shoulder, axial), paravertebral muscles, the patient acquiring vicious
positions with increased lumbar lordosis and dorsal kyphoscoliosis, which
can lead to complications of respiratory mechanics. From the psychological
point of view, intelligence is affected with mental retardation in 20% of
cases.
Among laboratory examinations, biological analyzes observe
elevated creatine kinase (released in the process of necrosis),
electromyographic examination detects a myogenic pattern and muscle
biopsy highlightes the indiscriminate fibrillary degeneration, fibrosis, fibrous
tissue, fat (usually in the calf), with identification of dystrophin by
immunohistochemistry techniques even from birth.
There is no specific treatment, but improvement was observed with
corticosteroids (prednisone 0.75 mg / kg / day) which prolongs the life with
2-3 years and all immobilization period up to 2-3 years. The orthopedic
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practice of supportive care (for lordosis, kyphoscoliosis), assisted ventilation
when it is required (respiratory complications) and integration in special
centers. Recent research focuses on genetic engineering, the replacement of
missing DNA segment, myofibroblasts transplant from father or male
relatives. Before conception, mothers should be reconciled, to receive
genetic counseling and prenatal diagnostic benefit.
b) Becker-Kiener muscular dystrophy:

It is a benign variant of Duchenne dystrophy, more rare, transmitted
X recessive with the defective allele located on the same gene as in
Duchenne dystrophy; lack of dystrophin synthesis is according to the
intensity of genetic deficiency and it affects only males. Clinical
manifestations range from asymptomatic to severe evolution, severe to fatal.
The onset is at the age of 5-25 years old, with considerable backlog
of at least 20 years (patients can pass the age of 50 years). Intellectual
retardation and cardiac changes are absent. It is a communicable disease to
the grandchildren through the daughters as a vector.
c) Scapular and pelvic muscular dystrophy:

It appears in 1 case of 16 000 new born alive and is a recessive
autosomal disease, but there are a number of sporadic cases too.
The onset is in the second or third decade or later in the decade,
affecting shoulder girdle muscles first, then pelvic. The severity and rate of
progression is variable, being more serious with motor deficit in 20 years
after onset. Clinical disease is similar to Duchenne, but differ in slow
progression. Cardiac and skeletal involvement is rare, and the intelligence is
normal.
d) Facio - scapular humeral dystrophy (Dejerine):

It is an autosomal dominant disease with defect on 4q35. The onset is
as a teenager in the muscles of the face. During sleep the eyelid orbicularis
does not close the eye and can not perform gestures mimic muscles
(whistling). In evolution the shoulder girdle is affected with motor deficit,
arm muscles (biceps, triceps). Slowly progressive muscular atrophy in the in
muscles on the face, shoulder girdle muscles (pectoral muscles, trapezius)
muscles of the arm.
Evolution can be benign, slowly progressive over the years or
malignant, when a worsening occurs at 30-40 years old and in 2-3 years the
patient becomes disabled by affecting the pelvic girdle muscles and legs.
Clinical forms are the infantile-onset form which starts at 1-2 years old and
the scapular-peroneal form with muscle atrophy in the scapular region and
the peroneal are of the lower leg.
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Laboratory diagnosis of muscular dystrophy is based on serum
biochemical examination (enzymes) which show an increased aldolase, CPK,
LDH, GOT, with a maximum in the early phase when the patient is clinically
fine, examination of urine with increased creatin. Muscle biopsy shows
fibrillar elements, atrophy, a phenomenon of fragmentation (splitting) of the
muscle cell necrosis and hyaline interstitial reaction. On electromyography
the average duration of motor unit potentials decreases below 80%, the
maximum amplitude of the motor unit potential decreases by at least 30%
and increase the incidence of polyphasic potentials. At the
electroneurographic examination galvanic and faradic hypoexcitability are
seen.
The pathogenesis for dystrophies include the vascular theory with
oxidative changes occurring in the catecholamine metabolism, the
neurogenic theory when there is a change in the primary neurons inside the
anterior spinal horns and the myogenic theory of structural proteins with
molecular lesions of the muscle membrane.
The differential diagnosis can be made with degenerative diseases,
spinal atrophies, polyneuropathies and polyradiculoneuritis, collagenosis and
polymyositis.
I.B. Congenital myopathies

Congenital myopathies are characterized by the presence of some
abnormalities in the muscle structure.
Usually, these affections do not progress, but induce dysfunction such
as: hypotonia, kyphoscoliosis, pes cavus, excavated sternum. To this group
of diseases belong: central core myopathy, nemaline myopathy,
centronuclear or myotubular myopathy, and congenital myopathy with fiber-
type disproportion.
Central core myopathy has an autosomal dominant but also sporadic
type of inheritance. It is characterized by hypotonia and a delay in motor
development. Usually, the disease is diagnosed at adult age, when hypotonia
with dislocation of the hips, scoliosis, pes cavus, and excavated sternum are
present. Facial and limb muscles are also involved. The diagnosis is made by
muscle biopsy which reveals in the central portion of each muscle fiber a
disorganization of myofibrils and lack of mitochondria.
Nemaline myopathy is transmitted as an autosomal dominant,
recessive or sporadic trait. The face is elongated, and the palate high.
Kyphoscoliosis, pes cavus or excavated sternum may also be found. The
diagnosis rests on the demonstration of the morphological change of Z band,
which has the aspect of bacilli-like rods.
Centronuclear or myotubular myopathy. The pattern of inheritance
is not constant, X-linked recessive, autosomal dominant, and autosomal
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recessive patterns having all been described. Hypotonia becomes manifest
soon after birth, and may cause death. The disease may or may not be
progressive. The diagnosisis based on muscle biopsy which reveals central
nucleation, most of the centrally placed nuclei being surrounded by a clear
zone.
Congenital myopathy with fiber - type disproportion causes
hypotonia, muscle weakness, delays in motor development, skeletal
deformities. Muscle biopsy reveals an increased proportion of type I fibers
and sometimes a hypertrophy of type II fibers.
I.C. Metabolic myopathies

The striated muscles have two energy sources, namely glucose and
fatty acids. A disturbed metabolism of glucose and fatty acids will determine
clinical manifestations and muscular changes of atrophic or dystrophic type.
Thus, there are two main groups of diseases: glycogen storage disease and
lipid storage diseases. These groups of diseases are genetically transmitted.
Glycogen storage diseases are induced by a single or multiple
enzymatic deficiencies, disturbing the glycogen metabolism. The muscle
does no longer receive and process the energy source required for
contraction and trophicity. As a result, the muscle deficits are accompanied
by cramps and pains. Glycogen can accumulate in the motor neurons of the
spinal and cerebral trunks. Glycogenoses may shorten the child's or adult's
life and are often accompanied by hepatomegaly and cardiomegaly.
The disorders of lipid metabolism are due to deficiencies in carnitine,
carnitine palmityltransferase, myoadenylate deaminase, and appearance of
abnormal mitochondria.
Among the symptoms are: motor deficits, progressive
ophthalmoplegia, rhabdomyolytic episodes, liver, kidney and heart disorders.
I.D. Periodic kalemic paralyses

Potassium ion is very important for the muscle contraction ordered by
the peripheral motor neuron. The paralyses induced by changes in potassium
ion concentrations causes reversible motor deficits, either confined to some
muscle groups, or generalized.
Episodic paralyses may be associated with other disturbances of
potassium metabolism, such as aldosteronism, 17 alpha-hydroxylase
deficiency, barium poisoning, or abuse of thyroid hormone.
Kalemic paralyses may be divided into: hypokalemic paralyses
(paroxysmal myoplegia), hyperkalemic paralyses (adynamia episodica
hereditaria), and normokalemic paralyses.
Hypokalemic periodic paralysis. Its usual pattern of inheritance is
autosomal dominant, but recessive inheritance is also known to occur. Males
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are more commonly affected, developing more severe forms of disease. The
onset is in adolescence, rarely after 25 years of age. The paretic attack
evolves over 3 to 4 hours or more and is more frequent after meals rich in
carbohydrates and sodium salts. The paralyses are located in the lumbar
muscles, proximal muscles of limbs, sometimes in the distal, oculomotor,
respiratory muscles, as well as in those innervated by the nerves of medulla
oblongata.
The paralyses are accompanied by marked hypotonia of the involved
muscle groups. Tendon and idiomuscular reflexes are absent. Within few
hours or days, as the attack subsides, the paralyses disappear first in the
muscles that were last to be involved. This is not a neuronal or end-plate
dysfunction, but a transient disturbance of muscle contractility. During the
attack, serum potassium level decreases as low as 1.8 meq/1 due to the
increase of blood flow toward the striated muscles. Presumably, the
potassium ion migrates into the muscle fiber making the muscle cell
membrane electrically inexcitable. It seems that a decrease in insulin level
may also induce hypokalemia.
In some atypical cases, following pareses at the limb girdle level, a
progressive proximal myopathy develops. For stating the diagnosis,
determination of serum potassium level, electrocardiogram, electromyogram
and, sometimes, muscle biopsy are needed.
The potassium ion level is low (less than 3 mEq per liter).
Electrocardiogram changes are specific for hypokalemia.
Electromyography is not suggestive; however, it reveals a muscular
disorder; muscle biopsy may demonstrate the presence of round or oval
vacuoles.
Treatment. Administration of 0.2 to 0.4 millimols/kg body weight of
KC1 orally, and in case there is no improvement, 15 to 30 minutes later the
dose is given again. If the patient is vomiting, 0.1 millimols/kg of KC1 is
administered intravenously, and if required is repeated after 5 to 10 minutes.
If potassium perfusions are required, the agent of choice is mannitol.
For preventing the paretic attack, 120-1000 mg/day of acetazolamide may be
given, but its long term administration may result in renal calculi.
Spironolactone and triamterene (25-100 mg/day) may be also helpful in
preventing the attacks.
Hyperkalemic periodic paralysis (adynamia episodica hereditaria) is
transmitted as an autosomal dominant defect, sporadic cases being also
described.
The attacks last less, and the muscle deficits are less extended. The
paralyses occur when-the patient is resting, and at day time.
The deficits begin in the shoulders, forearms, muscles innervated by
the cranial and respiratory nerves. The pontine muscle groups are slightly
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painful. Serum potassium is modestly elevated or even normal. The
administration of potassium precipitates the attack. These episodic paralyses
are caused by abnormalities of muscle cell membranes. In some cases, an
increased permeability of the muscle membrane for sodium, or a decreased
activity of sodium-potassium pump, involved in the spontaneous
depolarization, have been noted.
The treatment of attacks consists in the oral administration of glucose
or other carbohydrates. Acetazolamide, which has a kaliopenic effect, is
useful in preventing the hyperkalemic paralyses.
Normokalemic periodic paralysis is transmitted as an autosomal
dominant trait, and may be precipitated by potassium salts in excess. The
motor deficits are more ample, and the paralyses last longer as compared to
the hyperkalemic form. In some cases, acetazolamide and 9 alpha
fluorohydrocortisone may prevent the attacks.
General remarks on kalemic paralyses. The nocturnal onset is more
characteristic to hypokalemic paralyses. Some patients with hyperkalemic
paralysis show an increased sensitivity to cold, and myotonic elements. In
the normokalemic paralysis, the paretic attacks are more severe and last
longer.
II. Dermatomyositis and polymiositis

The morphopathologic changes involve the muscles, skin and
connective tissue. When the muscular system is solely affected, the disease is
termed polymyositis. The extension of the lesions to the skin is termed
dermatomyositis.
The etiology of these diseases is not fully known. There are several
theories on their causation, among which one suggesting a viral infection of
the skeletal muscles and another one an autoimmune disorder. The
identification by electron- microscopy of some virus-like particles in the
muscle tissue, and the myositic reactions in some viral disease support the
viral infection theory. Arguments pleading for an immune-allergic etiology
are the experimental myopathic reactions following the injection of sterile
muscle extracts together with Freund's adjuvant, and the induction of muscle
fibers necrosis by the activation of T cells and macrophages. Another
argument would be the possible depositions of immunoglobulins on the
intramuscular blood vessels.
The classifications of polymyositis and dermatomyositis were subject
to numerous changes. These two diseases are now classified into the
following groups:
Group I: Primary idiopathic polymyositis
Group II: Primary idiopathic dermatomyositis
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Group III: Polymyositis or dermatomyositis associated with neoplasia
Group IV: Childhood dermatomyositis or polymyositis associated with
vasculitis
Group V: Polymyositis or dermatomyositis associated with collagen
vascular disease
Primary idiopathic polymyositis

The motor deficit is insidiously progressive, affecting the proximal
limb muscles and shoulder girdle muscles. The progression is over several
weeks to several years. Early symptoms are dysphagia, inability to walk,
weakness of flexor muscles of the neck, in some cases the motor deficit may
be more restricted, mainly affecting the neck, shoulder and quadriceps
muscles. The muscles of the limb extremities and trunk may be also
involved. Besides the motor deficit, muscle atrophies, contractures,
induration of some muscular masses, and diminished tendon reflexes are also
present. The involvement of the striated muscles of the pharynx and upper
esophagus causes dysphonia and dysphagia, and ocular motoricity
disturbances occur when the ocular muscles are affected. The polymyositic
process may also induce some minor ECG changes, such as arrhythmias or
even necrosis of myocardial fibers.
Primary idiopathic dermatomyositis

The skin manifestations may precede, accompany or follow the muscle
involvement. The skin changes consist in a localized or diffuse erythema,
maculopapular eruptions, squamous and exfoliative dermatites. The most
common signs of skin involvement are: the heliotrope rash on the face,
periorbital and peribuccal edema, periarticular lesions and ulcerations. The
presence of Raynaud syndrome is another clinical finding suggesting
dermatomyositis. The proximal and pharyngeal muscles are most commonly
involved.
The blood test will reveal the presence of an inflammatory process
with elevated erythrocyte sedimentation rate. The serum levels of creatine
kinase (CK), aldolase, lactic acid dehydrogenase, TGO, TCP, and gamma
globulins are elevated.
Electromyographically, a myogenic tracing with fibrillation potentials
and myotonic discharges at rest are seen. Muscle biopsy reveals atrophies of
muscle fibers with the presence of necrosis, degeneration and regeneration of
muscle fibers. A perivascular inflammatory cell infiltrate (lymphocytes,
plasma cells, polynuclears) is characteristic for polymyositis.
Polymyositis may be easily misdiagnosed as trichinosis, and only
sensitivity to intradermal Trichina antigen differentiate them. Differential
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diagnosis also includes polyradiculoneuritis, especially in the case of the
pseudomyopathic clinical forms or those with proximal muscles
involvement.
Treatment
Corticoid therapy is effective in most cases. Prednisone, administered
at a dose of 1 to 2 mg/kg body weight per day, may cause improvement
within 1 to 4 weeks. The treatment needs be continued for 3 months, with a
reduction in the daily dose of 5 mg every 4 weeks. Azathioprine, at a dose of
150 - 300mg/ per day, cyclophosphamide and methotrexate may be also
beneficial.
III. Endocrine and metabolic myopathies

Several endocrine disorders and metabolic disturbances may induce
muscular affections. The muscular pathology is due to alterations in hormone
secretion or in circulating metabolites. The thyroid and corticoadrenal
disorders induce quite severe myopathies as compared to the dysfunctions in
the other glands.
In hyperthyroidism, the onset of myopathy is heralded by muscular
asthenia. The muscle deficit is located proximally in the limbs, or in the area
innervated by the spinal nerves. Muscle contractures, dysphonia and
dysphagia together with muscle asthenia are the clinical signs of
hyperthyroid myopathy.
Hypothyroid myopathy - among its specific symptoms are: muscle
cramps and hypertrophies, presence of myotonic and asthenic elements. In
the Kocher-Debre-Semelaigne syndrome of children, it is associated with
muscle hypertrophy and cretinism.
Hyperparathyroid myopathy is characterized by decreased muscle
strength, especially in the quadriceps. The patient also presents amyotrophies
and muscle pains. The tendon reflexes are present. The muscular syndrome
is associated with osteomalacia.
Hypoparathyroid myopathy. The neuro-muscular manifestations are
usually of tetany-type with tendon hyporeflexia or areflexia. Chvostek's sign
is present.
The most characteristic muscle disorder in the pathogenesis of
corticoadrenal glands is corticosteroid myopathy. The muscle deficit is
located in the pelvic girdle. Amyotrophies have the same topography, are
unpainful and symmetrical. Corticosteroid myopathy is often iatrogenic.
Therapy with prednisone or ACTH in multiple sclerosis, polyradiculoneuritis
and polymyositis may cause this type of myopathy.
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Acromegaly may be initially associated with muscle hypertrophy, and
later on with muscle atrophy. The proximal muscle groups of the limbs are
involved.
Other metabolic disturbances occurring during chronic respiratory
disorders, hepatic and renal dysfunctions, hypercalcemia and hypocalcemia
are often associated with decreases in muscle strength inducing myopathies,
often mild.
IV. Toxic myopathies

Toxic myopathies are produced by the administration of some drugs
and chemicals. They are classified into focal and generalized myopathies.
Focal myopathies occur as a result of the injection of some drugs in the
deltoid, triceps, quadriceps, gluteus maximus muscles. Of the drugs injected
intramuscularly, pentazocine and meperidine frequently cause focal
myopathy. The generalized toxic myopathies, with prevalently proximal
muscle deficit, occur during the long-term treatment with emetine, D-
penicillamine, procainamide, chloroquine, colchicine, glucocorticoids,
propranolol, alcohol, barbiturates, cocaine.
In some instances the toxic effect may cause rhabdomyolysis and
myoglobinuria, which are induced by: alcohol, azathioprine, heroin,
amphetamine, clofibrate, cocaine, barbiturates.
MYOTONIA
Myotonies are subdivided into:
- myotonic dystrophy
- congenital myotonies (Thomsen)
- congenital paramyotonies
Myotonic dystrophy (Steinert)

The disease is characterized by an autosomal dominant pattern of
inheritance affecting the muscles and other tissues. It is also known under the
name of Steinert disease or atrophic myotony. The child bom by a myotonic
mother presents transient myotonic phenomena. The phenomenon of
myotonia consists in a prolonged muscle contraction and delayed relaxation,
and it seems to be due to the repetitive discharges of muscle fibers. It is
believed that sarcolemma is "irritable", and muscle contraction lasts longer
than a prolonged voluntary contraction. Prolonged contraction also occurs in
other hereditary diseases, such as kalemic episodic paralysis.
The myotonic behavior of muscle cell seems to be related to the
abnormal decrease in membrane permeability for chloride ion. It has been
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shown that the muscle membrane potential in myotonia congenita has a
greatly increased resting membrane resistance which is attributed to a
decrease in membrane chloride permeability. Since an increase in the
external potassium concentration further reduces permeability to chloride it
will aggravate myotonia whereas increase in the internal potassium will
prevent the repetitive spike discharges. The effect of procainamide and
phnytoin lies on their stabilization of the muscle membrane. The disease has
an incidence of 1 case per 10,000 inhabitants, and is not usually manifest
until the second or third decade of life. The clinical picture is dominated by
the myotonic and dystrophic syndromes.
Myotonic syndrome consists in prolonged contraction and a long
delay in relaxation. By repetition, the relaxation may become normal,
especially in the distal muscles of the limbs. Myotonia in some muscles or
muscle groups can be demonstrated by percussion.
The pseudocontracture (myostatic contracture) is persistent and
relaxation delayed. Myostatic contraction persists even after motor nerve
section or muscle curarization, fact supporting the hypothesis of a muscle
fiber pathology.
Dystrophic syndrome affects both the muscles and other organs. The
atrophies of the small muscles of the hand seem to be onset manifestations
which later on extend to the other segments of the limbs. With time, a
marked amyotrophy of the distal extremities of the lower legs develops. At
the cephalic extremity, eyelid ptosis, wrinkled forehead, atrophy of the
stenomastoids, tongue, pharyngeal and laryngeal weakness are common.
To these muscular phenomena, early frontal baldness, cataract,
testicular or ovarian atrophy are added. The complete clinical picture also
includes impaired intelligence, hypersomnia, cardiac, respiratory and
gastrointestinal abnormalities.
The disease is transmitted through a mutant gene located on the short
arm of chromosome 19. which is linked to the gene for producing
apolipoprotein CII, peptidase D, and the third component of the complement.
The diagnosis is based on the clinical picture, EMG and muscle biopsy
changes. At galvanic stimulation the muscle remains contracted even after
the current is interrupted. The phenomenon is more easily demonstrated in
the thenar muscles. The EMG shows typical myotonic discharges made up of
short potentials, variable in amplitude, with a frequency of 30-40 per second,
and lasting for several seconds.
Biopsy reveals atrophy of type 1 muscle fibers and the presence in
some muscle fibres and the presence of some muscle fibres of sarcoplasmic
masses and chains of central nuclei. In the atrophied muscles ring fibers are
described.
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Most commonly, phenytoin is the drug of choice, although other drugs,
such as quinine and procainamide, have favorable effects, but may influence
the cardiac conduction.
Congenital myotonic dystrophy manifests in the new horns of
myotonic mothers. Focal, bulbar disturbances, respiratory failure are present,
phenomena which disappear short after.
Congenital myotonia (Thomsen disease)

Is inherited as an autosomal dominant or autosomal recessive trait. The
muscles with myotonic behavior are hypertrophied, giving the patient an
athletic appearance.
The histological examination reveals an enlargement of muscle fibers
due to increased numbers of myofibrils. The treatment with quinine,
procainamide, phenytoin, acetazoiamide may be beneficial.
Congenital paramyotonia is transmitted as an autosomal dominant trait.
The myotonic phenomenon is worsened by exposure to cold. The specific
manifestations are seen after ice cream ingestion, immersion into cold water,
or lowering of external temperature.
MYASTENIA GRAVIS
Myasthenia gravis is a disease characterized by the occurrence of a
motor deficit on exertion and relieved by rest, more or less corrected by
inhibiting medication (which degrades acetylcholine and blocks the activity
of cholinesterase reaching the synaptic cleft). The events are given by
reduced number of receptors for acetylcholine on the postsynaptic membrane
caused by an autoimmune process against these receptors.
The pathophysiology consists in the secretion of acetylcholine from
presynaptic button, which is stored in vesicles. Action potential occurs in
opening the channels for Ca, when it enters the cellule and occurs the release
of acetylcholine in the synaptic cleft. In myasthenia gravis acetylcholine
effect on the postsynaptic membrane will be decreased, thereby decreasing
contractile effect and recruitment of increasingly smaller muscle fiber
contraction.
As etiology there is suggested a genetic susceptibility that those who
do have certain HLA genotypes disease, plus thymic pathology. This is
represented by thymic tumor (10-15% of cases) of thymic hyperplasia or
limfoepiteliom type (75% of cases), in which the containing thymic islands
germ centers although the thymus appears normal macroscopically. In
thymus the selection of T lymphocytes occurs with own thymic antigens
selection and not trigger are not attacked, except autoimmune diseases. There
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mioide thymus cells (pseudomuscular) that express the surface receptors for
acethylcholine, which is why in myasthenia the rupture occurs with
recruitment of immune tolerance LT helper that will stimulate the production
of antireceptor for acetylcholine antibodies. Relative tumor malignancy is
being given to the possibility of extending local and invasion of mediastinal
vascular structures, especially in severe forms of myasthenia with late
appearance without any sex prevalent.
Clinically, the disease prevalence is 1/10,000, the ratio B/F was 2/1.
Muscle disorders in spikes, which can occur at any age (maximum incidence
at 15-20 years). The onset may be apparent in the context of infection,
poisoning, trauma producing patient decompensation. There is motor deficit
but the patient does not appear to stand during and after an effort or repeated
activity; it is progressive and can cause total paralysis. There may be
permanent motor deficit in certain territories which improves with rest and
worsens with the effort. There is variable distribution of motor deficit from
time to time; it is of muscle-type distribution rather than nervous. For
example in the eyelid muscles ptosis occurs, in the pharyngeal muscles
swallowing and phonation abnormalities occur, patients can not work with
arms raised. The most commonly affected areas are the extrinsic ocular
muscles (20%), diplopia and ptosis leading to asymmetrical facial muscles,
resulting in inability of blowing or whistling, expressionless face and
masticatory muscles, fonatory and swallowing, neck muscles that can
produce head tilting and muscles from the proximal limb producing motor
deficit. Neurological physical examination include normal reflexes without
sensitive disorders.
Classification (Osserman):
I. Occular myasthenia: benign form, poor drug-response
II. Myasthenia with slow progression and without respiratory
involvement; activity restriction are imposed to the patient.
Unfavorable prognosis.
III. Generalized myasthenia with rapid progression and respiratory crises.
High mortality.
IV. Generalized myasthenia with respiratory crises and acular onset or
generalized but without respiratory crises. Uncertain prognosis
Laboratory findings are:

1) Electroneurographic (repetitive nerve stimulation) (3 stimuli / second)
a) Highlights the myasthenic decrement (decrease by > 10% amplitude
of the compound muscle action potential (CMAP) in the 4th or 5th
stimulation) - marker of muscle fatigue
296
b) Still low amplitude followed by a slight recovery but returns to
baseline
2) Needle EMG (detection) highlights the electrical activity of the muscle at
rest and during contractions
a) Changes can be found even at the onset of the disease, before the
clinical picture is complete
b) Allows differential diagnosis with other neuromuscular diseases
(amyotrophic lateral sclerosis, polymyositis)
3) Pharmacological tests
a) Transmission defect at the neuromuscular junction = myasthenic
block which may be of presynaptic (releasing acetylcholine
deficiency) or postsynaptic cause (MG)
b) Differentiation is achieved by pharmacological tests on the
myasthenic block
c) The administration of anticholinesterases substances reduce the block
if postsynaptic and presynaptic remains unchanged
4) MRI can detect tumors or thymic hyperplasia
5) CT can evidentiate thymic hyperplasia or tumors
6) Immunologic testing antibodies against AchR and anti MUSK
antibodys.
Evolution and complications

The evolution of MG is fluctuating and capricious.
The myasthenic crisis is respiratory failure from myasthenic
weakness, manifested by emphasizing the myasthenic deficit, respiratory
disorders, hypoventilation and ineffective cough. An identifiable
precipitating event such as infection, aspiration, surgery or medication
change precedes most of episodes of crisis.
The medical management of the myasthenic crisis consists of
hospitalizing the patient as soon as possible in the intensive care unit and
stopping the anticholinesterasic medication. If the patient needs respiratory
assistance then endotracheal intubation should be practiced with assisted
breathing, and then you can proceed to diagnose the type of crisis. The
edrophonium test can be done if the patient does not have apnea and if there
is an improvement, then the dose of anticholinesterases can be increased. If it
is not too clear if the patient is improving the any medication will be stopped
for 72 h. The main treatment of the myasthenic crisis is plasmapheresis and
IV Ig. Corticosteroids may actually worsen or prolong the crisis by
increasing the intensity of the motor deficit and increasing the risk of
infection.
The cholinergic crisis consists of respiratory failure from
anticholinesterases overdose and is more common before the introduction of
297
immunosuppressive therapy. It is manifested by respiratory problems,
bronchial hypersecretion, shaking and salivary hypersecretion. The
management consists of transfering the patient in a intensive care unit for
respiratory assistance and performing the edrophonium test. If the patients
symptoms get worse then it is a cholinergic crisis and we need to stop the
anticholinergic medication and start Atropine 0,25mg iv or im. Atropine will
not improve the muscle strength and ability to breath in someone with
cholinergic crisis. Such a patient will require mechanical ventilation support
via endotracheal intubation until the crisis resolves on its own. The
respiratory compromise from the cholinergic crisis unfortunately has no
pharmacologic solution or therapy.
Treatment
1. treatment of neuromuscular blockade with:
a. anticholinesterases - Miostin, Mestinon
b. plasmapheresis to remove the antireceptor antibodies from the
blood; used in critical situations when the patient is
particularly fatigued, with respiratory disorders
c. iv Ig that block the antireceptor antibodies; they are used
together with corticosteroids and plasmapheresis mainly in
patients with respiratory signs
2. immunosuppressants - corticosteroids 1 mg / kg to 2 days,
especially for the ocular form, preoperative or if the patient
does not respond to thymectomy
- azathioprine (Imuran) -> 2.5 mg/kg/day
- cyclophosphamide 2mg/day;
- cyclosporine 4-5 mg/kg/day (adverse efects:
renal toxicity, high blood pressure).
3. surgical thymectomy is practiced in patients with generalised
myastenia or in those in which the corticosteriod treatment did not
show any improvement (the surgical intervention improves about
80% of operated patients)
The (Eaton-Lambert) myasthenic syndrome occurs in patients with

neoplasms. Most frequently, the paraneoplastic syndrome accompanies a
lung cancer. The syndrome is caused by an autoantibody directed against
calcium channels on the motor nerve terminals, impairing the release of
acetylcholine.
298
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299
Abbreviations
ACA anterior cerebral artery CBF cerebral blood flow
AD - Alzheimers disease CH cluster headache
AD autosomal dominant CIDP - chronic inflammatory
ADEM acute disseminated demyelinating polyneuropathy
encephalomyelitis CIS clinical isolated syndrome
AED antiepileptic drug CK creatin kinase
AICA anterior inferior cerebellar CMV cytomegalovirus
artery CNS central nervous system
AIDS - acquired immune COMT catecol-O-methyl-
deficiency syndrome transpherase
ALS amyotrophic lateral CR continuous release
sclerosis CSD cortical spreading
ALT - Alanine transaminase depression
APC- activated protein C CSF cerebrospinal fluid
APLS antiphospholipid CT computed tomography
syndrome DBS deep brain stimulation
AR autosomal recessive DIS dissemination in space
ARAS ascending reticular DIT dissemination in time
activating system DLB dementia with Lewy
ASA acetyl salicylic acid Bodies
AST aspartate aminotransferase DMT disease modifying therapy
AT antithrombin DNA deoxyribonucleic acid
ATP - adenosine triphosphate EB eye ball
BAL British Anti-Lewisite ECG - electrocardiography
(dimercaprol) EDSS expanded disability
BBB blood brain barrier status scale
BDNF - brain-derived EDTA
neurotrophic factor Ethylenediaminetetraacetic acid
BP blood pressure EDX - electrodiagnostic medicine
BTX botulinum toxin EEG - electroencephalography
CADASIL Cerebral autosomal ELISA enzyme-linked
dominant arteriopathy with immunosorbent assay
subcortical infarcts EMG electromyography
andleukoencephalopathy ENT ear nose throat
CBC complete blood count EP evoked potentials
CBD cortico-basal degeneration
300
FTDP fronto-temporal dementia MCA medial cerebral artery
with parkinsonism MCS motor conduction study
GABA gamma aminobutyric MG myasthenia gravis
acid MRI magnetic resonance
GBS Guillan Barre syndrome imaging
GCS Glasgow coma scale MS multiple sclresosis
GGT gamma-glutamyl MSA multiple system atrophy
transferase MTHFR
GP general practitioner methylenetetrahydrofolate
GPi globus pallidus internal reductase
segment NAWM normal appearing white
HCV hepatitis C virus matter
HD Huntingtons disease NCS nerve conduction study
HIV human immunodeficiency NMDA N methyl D aspartate
virus NSAID - nonsteroidal anti-
HSMN hereditary sensory motor inflammatory drug
neuropathy OCT optical coherence
HSN hereditary sensory tomography
neuropathy PALS primary amyotrophic
HSV herpes simplex virus lateral sclerosis
HTLV human T-lymphotropic PAN - polyarteritis nodosa
virus PCR polymerase chain reaction
HVB hepatitis b virus PD Parkinson disease
ICH intracranian hemorrhage PET - positron emission
IHS International headache tomography
society PICA posterior inferior
ILAE International league cerebellar artery
against epilepsy PML - progressive multifocal
INR international normalized leukoencephalopathy
ratio PNP polyneuropathy
IRIS immune reconstitution PNS peripheral nervous sysytem
inflammatory syndrome PP - pellagra preventer (vitamin
IVIG intravenous B3, niacin)
immunoglobulin PPMS primary progressive
JC - John Cunningham virus multiple sclerosis
LCIG - Levodopa/carbidopa PRMS progressive relapsing
intestinal gel multiple sclerosis
LDH lactic dehydrogenase PSP progressive supranuclear
LMN lower motor neuron palsy
LMWH low-molecular-weight REM rapid eye movements
heparin RNA ribonucleic acid
MAO monoaminoxidase
301
RRMS recurrent remissive SPMS secondary progressive
multiple sclerosis multiple sclerosis
SBD sleep breathing disorders SSRI selective serotonin
SCA spino-cerebellar atrophies reuptake inhibitors
SCS sensitive conduction study STN subthalamic nucleus
SEP sensitive evoked potentials TB tuberculosis
SLE systemic lupus TBI traumatic brain injury
erithematosus TIA transient ischemic attack
SMA spinal muscular atrophy TMS - transcranial magnetic
SNRI serotonin-norepinephrine stimulation
reuptake inhibitors UFH unfractionated heparin
SOD super oxide dismutase UMN upper motor neuron
SPECT single positron emission VaD vascular dementia
computed tomography VEP visual evoked potentials
WNV West Nile virus
302
Index
A
abducens nerve 121, 128
absences 187,188
acethylcholine 296
achromatopsia 175
acidosis 17, 101, 218
acromegaly 293
action potential 23, 262,295,
acute anterior poliomyelitis 30, 87
AIDS 177, 255, 275-279
akinetic mutism 95, 107, 168, 220
alcoholic polyneuropathy 67
algodystrophy 48
Alzheimer disease 179, 180
amantadine 140, 262
amaurosis fugax 205, 210, 223, 229
ampicillin 65
amyloid angiopathy 182, 236
amyotrophic lateral sclerosis 29, 34, 294
amyotrophic neuralgia 43
analgesia 200, 201
anesthesia 44, 51, 201, 206
angiography 84, 230, 237
angiomas 136, 234
annulospiral 283
anosodiaphoria 173
anosognosia 172
anterior cerebral artery 219
anterior horn 27, 91, 282,
anterior spinal artery 84, 85
anterior spinal cord artery syndrome 75
anticholinergic drugs 180, 262
aphasia 170, 172, 177, 179, 181, 219, 230
apraxia 220, 255,
arterial aneurysm 236
ascending
reticular activating system 98
asomatognosia 172, 173
association areas 169, 174, 175
303
astereognosis 220
astrocytoma 15, 82
atherosclerotic 15, 218
aneurysm 101,118, 124, 225, 234
atonic seizures 188
auditory evoked potentials 106, 250,
autoimmune disease 17, 254, 258, 295
autonomic disturbances 55, 100, 235
Avellis syndrome 93
axillary nerve paralysis 44
axillary nerve 44
axon 20, 22, 139,
axonal degeneration 55, 139, 154
azathioprine 64, 293, 298
B
Babinski sign 28, 277
Babinski Nageotte syndrome
Balint syndrome 117
bacterial meningitis 271,
basal ganglia 12, 142, 145, 155, 176, 246
basal meningitis 36, 131
basilar invagination 77
Benedikt syndrome 96, 120
benserazide 152
Biermer anemia 80,
bipolar neuron 20
blood disorders 236
blood-brain barrier 21, 102, 249
blood pressure 57, 109, 113, 186, 205, 227, 235, 237, 298, 267,
bradycardia 62
brain abscess 267
brain tumors 15, 100, 225,
brain 274, 276
brainstem 89-98, 111, 116, 120, 132, 235, 247, 253
Brown Sequard syndrome 74,75
bulbar paralysis 270
C
calcarine scissure 174
calcarine fissure 174
capsular warning syndrome 224
carbamazepine 59, 195, 204
carbidopa 152, 154
304
carotid artery 118
cauda equine syndrome 79, 277
caudate nucleus 159
causalgia 47
cavernous sinus 118, 120, 124, 236
cell body 19, 22, 54
central core myopathy 287
central infarct 219
centronuclear myopathy 287
cephalosporins 65
cerebellar cortex 139
cerebellar hemorrhage 137, 235
cerebellar tumors 92, 139
cerebellar syndromes 137, 253
cerebellum 133, 137, 139, 142, 157, 208, 222, 229, 234, 246
cerebral aneurysm 204, 211
cerebral angioma 236
cerebral atherosclerosis 236
cerebral blood flow 101, 218
cerebral edema 105, 118, 205, 221, 234
cerebral hemisphere 12, 106, 166, 220, 279
cerebral hemorrhage 234
cerebral infarct 218, 227
cerebral metastases 236
cerebral thrombophlebitis 230
ceruloplasmin 155, 157
cervical ribs 43
changes in pupillary diameter 116
Charcot Marie Tooth disease 55
chemical synapse 22
chorda tympani 128, 129
choreoathetotic movements 221
choroid plexuses 22, 206
chromosome 55, 56, 137, 158, 285, 294
chronic spinal cord ischemia 86
Claude syndrome 96,120, 220
Claude-Bernard-Horner syndrome 93, 95, 97
clawfoot 50
clawhand 46
clonazepam 127, 191, 261
cluster headache 213
coma 100, 101, 106,
305
combined sclerosis 80
common carotid artery 219
common migraine 210
common peroneal nerve 49, 50
complete nuclear palsy 117
complete superficial sylvian infarct 220
complete transaction 79, 80
computer tomography 41, 83
congenital myopathy 287, 288
congenital myotonia 284, 295
congenital myotonic dystrophy 295
congenital paramyotonia 295
consciousness 99, 230, 221
constructional apraxia 173, 220
conus medullaris syndrome 79
convergent strabismus 118, 121
cornea 125, 130, 131, 156, 155
cortical veins 230
corticobasal degeneration 142
corticoid therapy 292
corticonuclear 27, 94, 108, 132
corticosteroid myopathy 292
cranial nerve palsies 229
crocodile tears syndrome 131
crural monoplegia 81
CSF abnormalities 17
CSF fistula 14
cyanosis 50, 55, 109
cyclophosphamide 64, 292
cytoplasm 19, 240, 283
cytotoxic intracellular edema 218
D
D-penicillamine 293
decerebrate rigidity 105
decorticate rigidity 105
deep radial nerve 44
deep sleep 45
degenerative disorders 77, 176
delirium 16, 100, 146, 235
dementia 165, 182, 275-278,
dentate nuclei 137, 139,157, 222
deposition of copper 154
306
descending reticular system 114
Devic disease 252
diabetic polyneuropathy 58, 59
Diazepam 38, 191, 195
diencephalic syndrome 105
diphteric polyneuropathy 66
diplopia 116, 224, 226
disseminated encephalomyelitis 245
distal occlusive syndrome 219
disturbances of equilibrium 58, 171
diuretics 237
dopaminergic agonists 150-153
dopamine 150-155, 160
Doppler ultrasonography 43, 225, 229
drop attacks 83, 114
dysembryoplastic theory 77
dyskinesia 149-154
dysmetria 96, 134, 138,
dystonic form 155
dystrophic syndrome 294
E
edrophonium 297
electroencephalogram 185
electroencephalography 191
electromyography 36, 287, 289
emboli 225, 229, 233, 236, 238, 245
emboliform nuclei 133
emotional lability 28, 138
encephalitis 16, 32, 108, 206, 259-273
ependymoma 15, 82
epidural hematoma 81, 82
epidural hemorrhage 84
epidural metastases 82
epilepsy 17, 100, 185-196, 296
essential trigeminal neuralgia 125, 127
ethosuximide 195
expressive aphasia 220
extramedullary arteriovenous malformations 83
extramedullary hemorrhage 84, 86
extrapyramidal 12, 110, 120, 123, 125, 128, 137, 180
F
facial hemispasm 131,132
307
facial nerve 128, 129, 132
facial paralysis 130, 132
fasciculations 29-35, 53, 63, 78, 92
fastigial nucleus 133
feedback 20, 142, 201, 214
femoral (anterior crural) nerve paralysis 47
fissure of Rolando 166
focal neurological deficits 204
focal signs 254
forced grimacing 155
Foville syndrome 94, 122, 220
fractures 14,40-50, 78-82
Frank cavitation 156
Friedreich ataxia 75
Friedreich disease 137
frontal baldness 294
frontal lobe 115, 167-169, 180
frontal lobe syndrome 219
fungal infections 274
G
GABA 23, 102, 201-203
gait disturbances 78
gait disturbances 48, 182, 217, 261,
gasserian ganglion 124
gastric intrinsic factor 80
generalized seizures 186-188
genetic code 20
geniculate ganglion 128
genu recurvatum 48
Gerstmann syndrome 173
Glasgow coma scale 105
glioma 15, 252
globose nuclei 133
glossopharyngeal neuralgia 110
glucose 59, 61, 101, 138, 159, 195, 218, 239, 288, 290
glutamate 21, 38
glycerol 237, 238
glycogen storage disease 288
glycogenoses 288
Golgi apparatus 20
Golgi tendon organs 283
granuloma 87
308
grasp reflex 219
gray matter 13, 19, 21, 73, 246, 254
H
haloperidol 160, 161
headache phase 209
headache 204-215
hemangioblastoma 136
hematomyelia 77, 82, 86
hemianopsia 220, 224, 235
hemicord syndrome (Brown Sequard) 86
hemiplegic migraine 210
hemodynamic mechanism 218
hemorrhage 233-240
hemorrhagic focus 234
hepatic manifestation 156
hepatic transplantation 157
hepatolenticular degeneration 155-156
hereditary spastic paraplegia 29
herpes simplex encephalitis 260
HIV 16, 62-65, 70, 145, 280
Hoffman 28, 33
horizontal diplopia 116
Huntington chorea 158
hydatid cyst 83
hydrocephalus 17, 78, 205, 236, 237
hyperalgesia 201, 203
hyperesthesia 82, 136
hyperkalemic periodic paralysis 284, 289
hyperplasia 147, 195, 231, 295, 297
hypersomnia 99-113, 294
hypertensive encephalopathy 102, 194
hypertrophic neuropathy 55
hyperventilation 102
hypesthesia 219
hypokalemic periodic paralysis 288
hypoparathyroid myopathy 292
hypotension 70, 110, 147, 206
hypothalamus 91, 102, 170
hypothyroidism 17, 102, 177
hypotonia 29, 30, 33, 42, 50, 73, 80, 87, 106, 135, 287
hypothyroid myopathy 292
I
309
ideomotor 173, 220
iliopsoas muscle 48
immunosuppression 64, 231
incontinence 28, 261,
infectious diseases 54, 58, 73, 80, 107, 168
infectious lesions 53
interferon 64, 258
internal capsule 224, 234, 228
internuclear ophtalmoplegia 118
intracranial hypertension 15, 16, 101, 136, 237
intramedullary arteriovenous malformations 84
J
Jackson syndrome 94
jamais vu 171, 190
joints 36
junctional infarct 219
K
kalemic paralysis 290
Kayser-Fleischer ring 155
Kerning sign 237
Kestenbaum syndrome 122
kidney 54, 59, 60,63, 156, 194
kyphoscoliosis 138, 287
L
Lhermitte sign 203
lacrimal glands 129,
lactate level 218
lacunar infarcts 182, 217, 227
lamotrigine 195, 204
lateral cord 42,44, 68, 75
lateral syndrome 93
lateral ventricle 157, 159,
left hemisphere 167,169, 172
lenticular degeneration 155-157
leprous polyneuropathy 66
lethargy 99
leukomyelitis 87
levodopa 140, 150, 154
limbic system 107
lipid metabolism 288
lipofuscin 20
liver 54, 60, 62, 67, 69, 155-157
310
lobar hemorrhage 235
locked in syndrome 108
loss of pain 59, 77, 82
lower motor neuron 29, 31, 34, 81,142
lower plexus 42, 43
lower primary trunk 41
M
microglia 21, 22, 35, 246, 267
Madopar 152
magnetic resonance 37, 41, 83,84, 86, 217
mandibular nerve 124
mannitol 235, 237, 238, 289
maxillary nerve 124
McArdle glycogenosis 284
McDonald criteria 248
medial longitudinal fasciculus 115, 117
median nerve 41, 42, 46, 47
median nerve paralysis 46
medulloblastoma 135, 136,
melanin 135
memory alteration 158
meningeal hemorrhage 84, 236
meningeal signs 279
meningioma 15, 81
meningitis 14, 63, 69, 87, 101, 131, 206, 260-279
mental disturbances 61
metabolic and endocrine disease 17
metals 20
methotrexate 64, 67, 292
microtubules 19
middle cerebral artery 19, 174, 226, 236, 240
middle plexus 42, 43
middle trunk 41, 42
migraine 182, 207-213, 225, 231
Monro foramen 17
motor deficits 16, 45, 46, 50, 52, 83, 87, 235, 288
motor nuclei 27, 30, 35, 79, 115
motor signs 45, 46, 50, 188, 190, 251
MRI 36, 250-257, 280, 297
multiple sclerosis 17, 124, 137, 244, 251
muscle spindles 283,
muscle tone 99, 111, 113, 114, 135, 146
311
muscular rigidity 148, 155
musculocutaneous nerve paralysis 44
myasthenia gravis 17, 23, 295
mycobacterium tuberculosis 16, 278
myelitis 31, 86-88, 250, 267, 274
myotonic dystrophy 293
myotonic syndrome 294
N
Negro sign 129
neoplasm 42, 135, 232, 276, 280, 298
nerve fibers 15, 22, 97
nerve impulse 81
neuralgia 43, 48, 110, 124, 273,
neuroglia 235
neuron 19, 27, 29, 34
neuronal death 21, 159, 179, 191
neuropraxia 45
neurotransmitter 22, 23, 102, 179, 208
hydrocephalus 17, 78, 103, 205, 237
normokalemic periodic paralysis 290
neurotropic viruses 120
O
obturator nerve paralysis 49
occipital lobe 173, 115, 133, 166, 170
oculomotor nerve 115,119, 121, 210
olfactory hallucination 171
oligodendrocytes 22, 25
oligodendroglioma 15, 82
ophthalmic artery 219
ophthalmic nerve 124
ophtalmoplegia 118, 120, 250, 280
ophtalmoplegic migraine 210
opportunistic infection 16, 258, 275
optic neuritis 69, 247-253
optic radiation 169, 220
orbital apex syndrome 120
ovarian atrophy 294
P
pain 199-214, 229, 247, 251, 254, 268, 273
Papez circuit 170,
paralysis of abduction 118
paraplegia 29, 30, 73, 76, 81, 86, 94, 138, 168
312
parasitic infections 87
paresthesia 43, 53, 67, 70, 80, 148, 172, 190, 201, 254, 258, 268
parietal lobe 171, 173
Parinaud syndrome 96, 122, 220
partial palsy 117
partial seizures 118, 189, 192, 215, 272
peduncular hallucinosis 99, 114
pellagra 177
penicillin 88, 269
penicillin G 270
pergolide 150
periodic hypersomnia 99
peroneal nerve 49, 50, 56
PET 193
phenobarbital 68, 137, 195
phenytoin 140, 195, 295
physical therapy 24, 150, 154, 214, 261
piribedil 150
plasmapheresis 57, 63, 64, 278, 297
platelet emboli 236
platybasia 77, 78
platysma muscle 129
poliomyelitis virus 31, 87
poliomyelitis 31, 87, 266
polyneuropathy 18, 53-70, 110, 202, 276
polyopia 175
pontine hemorrhage 108, 235
porphyric polyneuropathy 60
postcentral gyrus 171, 172
posterior cerebral artery 219
posterior choroidal arteries 221
posterior columns 76, 81
posterior fossa 133, 206
postsynaptic membrane 22, 295
postural reflex 143
posture 96, 105, 138, 168, 189
potassium ion 218, 288, 289
prednisone 64, 88, 132, 205, 213, 292
prefrontal area 165, 168
premotor area 27, 168
presynaptic membrane 22, 23, 272
primary auditory area 169
313
primary motor area 24, 167
primidone 68
prodromal phase 209
prosopagnosia 173, 175, 181
protoplasmic astrocytes 21
proximal infarct 219
proximal occlusive syndrome 219
pseudosclerosis form 155
pseudounipolar neuron 20
psychiatric disorders 16, 68, 70, 99, 114
ptosis 53, 66, 116-119, 123, 213, 270, 280, 294, 296
putamen 149, 159
putaminal hemorrhage 234
pyramidal decussation syndrome 93
pyramidal syndrome 82, 94, 219
R
rachidian epidural hematoma 82
radial nerve paralysis 44
radial nerve 45
radiographs of the spine 41
recent memory 179
reciprocal innervation 20
reciprocal synapse 23
red nucleus syndrome 96
Refsum disease 55, 56
rehabilitation 256, 261,
retention 54, 87, 234
reticular nuclei 98
reticular 90, 97, 133,
ribosomes 20, 159
right hemisphere 167,
S
Schmidt syndrome 94
Schwann cells 22, 55
sciatic nerve paralysis 49
scoliosis 76,
secondary generalized 188
secondary auditory area 169
secondary syphilis 268
seizures 111, 132, 136, 158, 185-195, 210, 221, 230, 237, 254, 258, 268, 279
selective vulnerability 16, 282
sensory dissociation 78
314
sensory evoked potential 68, 139, 249
sensory polyneuropathy 58, 65, 67, 269
sensory seizures 172
serial synapses 23
short term memory 170
simultanagnosia 173, 175
Sinemet 152
somatognosia 172, 173
somatosensory evoked potential
somnolence139, 249
Souques sign 130
speech 24, 28, 126, 134-138, 150, 166-170, 175, 177, 180, 219
spikes 192, 296
spinal cord ischemia 83, 85, 86
spinal hemiplegia 117
spinal nerve roots 40, 41
spiral groove 44,45
standing 207, 285
state of consciousness 188
stenosis 110, 218, 225-229
steppage gait 50
stiffman syndrome 114
subacute combined degeneration 80, 81
subclavian steal syndrome 218
subdural empyema 16
subdural hematoma 205, 207, 225
subdural hemorrhage 225, 234
substantia nigra 20, 35, 110, 143, 151, 266
superficial territory 219
suppurative myelitis 87
supranuclear palsy 142, 145
supranuclear pathway 115
supratentorial lesion 103
Sydenham chorea 160
sylvian aqueduct 17
sylvian territory 220
synapse 22, 185, 124
synaptic cleft 295
synaptic transmission 22-24
syphilis 268
syphilitic meningitis 87, 268
syphilitic myelitis 87, 88
315
syringobulbia 77, 124
syringomyelia 38, 77, 78,
syringomyelobulbia 38
T
tabes dorsalis 16, 75, 87, 266, 268
temperature senses 77, 78
temporal lobe 115, 169, 171, 180, 190, 198,
tendon reflexes 41, 291, 292
tendon retractions 285
terminal hyperpyrexia 235
terminal infarction 219
territorial infarct 219
tertiary syphilis 268
testicular atrophy 32
tetraplegia 29, 30, 52, 62, 66, 79
thalamus 35, 98, 111, 129, 209, 220
third ventricle 17, 157
thoracic outlet syndrome 43
thrombophlebitis 14,16, 80, 109, 217, 230
thrombus 218, 224, 227, 230, 234, 240,
thymectomy 298
thymic hyperplasia 297, 295
thymic tumor 295
tibial nerve 40, 50
topographic agnosia 173
transient ischemic attack 223, 236
transsynaptic degeneration 21
transverse myelitis 87
trauma 14, 230, 205
treatment of migraine attack 212
tremor 22, 143, 145, 155, 222, 247,
Treponema pallidum 16, 267, 268
trichinosis 291
triethylene tetramine hydrochloride 157
trigeminal nerve 59, 62, 67, 124, 196
trigger zone 126
trismus 125
trochlear nerve 92, 118,
tubercle 89, 96, 97
tuberculostatics 88
tuberculous meningitis 88, 279
tuberculous myelitis 87,88
316
U
ulnar nerve paralysis 45
unipolar neuron 20
upper motor neuron 27, 82, 142,
upper plexus 42
upper trunk 41, 42
urinary copper 157
excretion 155, 156
V
vasa nervorum 15, 58
vascular diseases 15, 83, 216
vascular malformation 85, 187, 235
vasculitis 66, 267, 276
VDRL 36, 231, 269
vermis 133, 135
ventricular inundation 235
verbal agnosia 170
vermis syndrome 135
vertebral angiography 237
vertebral dislocations 78, 79
vertebrobasilar territory 101
viral encephalitis 177
visual evoked potential 249
visual hallucination 100
visual illusion 175
vomiting 31, 236, 279, 289
W
walking 29, 160, 255, 285,
Wallenberg syndrome 92, 222
Weber syndrome 95
Wernicke aphasia 170
Werdnig-Hoffman 33
West Nile virus 32
Wilson disease 155
wristdrop 45
317

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Gr. T. Popa Publisher, U.M.F.

Prof. SIMU MIHAELA ADRIANA, M.D., Ph.D.

Front cover: Marius ATANASIU

Gr. T. Popa Publisher

Typeset by Tipografia Universitii de Medicin i Farmacie

ETIOLOGY OF THE NERVOUS SYSTEM PATHOLOGY. ...........................................14

CRISTIAN DINU POPESCU

NEUROANATOMY DATA ...................................................................................20

CRISTIAN DINU POPESCU

DISEASES OF THE MOTOR NEURONS.................................................................28

CRISTIAN DINU POPESCU

PERIPHERAL PARALYSIS OF THE LIMBS..............................................................41

SPINAL CORD PATHOLOGY ...............................................................................73

CRISTIAN DINU POPESCU, CRISTINA GROSU

PATHOLOGY OF BRAINSTEM. CRANIAL NERVES. CEREBELLUM. FRIEDREICH

DANIEL ALEXA, DRAGOS POPESCU

MOVEMENT DISORDERS ................................................................................ 143

CEREBRAL LOBES. HIGHER CEREBRAL FUNCTIONS. DEMENTIA......................... 166

EMILIAN-BOGDAN IGNAT, DANIELA MATEI

EPILEPSY ........................................................................................................ 186

PAINFUL SYNDROMES: NEUROPATHIC PAIN, HEADACHE................................. 200

CRISTIAN DINU POPESCU, EMILIAN-BOGDAN IGNAT

CEREBROVASCULAR DISEASES ........................................................................ 217

CRISTIAN DINU POPESCU

MULTIPLE SCLEROSIS ..................................................................................... 245

CRISTIAN DINU POPESCU

INFECTIOUS DISEASES OF THE NERVOUS SYSTEM............................................ 265

CRISTIAN DINU POPESCU

MUSCULAR PATHOLOGY ................................................................................ 282

INDEX ............................................................................................................ 303

The first course of neurology for students studying in English at "Gr.

Congenital diseases Infectious

The nervous system can be affected by several mechanisms, with its

II. Degenerative diseases

IV. Vascular diseases

VI. Infectious diseases

VII. Autoimmune and inflammatory diseases

VIII. Metabolic and Endocrine Diseases

IX. CSF circulation disorders

Glial tissue and the blood-brain barrier

Diseases of the Motor Neurons

Upper motor neuron syndrome Lower motor neuron disease

Upper motor neuron syndrome

The upper motor neuron (UMN) is located in the primary motor

Upper motor neuron disease

Primary Amyotrophic Lateral Sclerosis (PALS)

Hereditary Spastic Paraplegia

Lower Motor Neuron Syndrome

Lower motor neuron disease

West Nile virus infection

Spinal Muscular Atrophies (SMAs)

Diseases of both upper and lower motor neurons

Criteria for the clinical diagnosis of ALS

Definite clinical UMN and LMN in at least 3 regions (bulbar + 2

Probable clinical UMN and LMN in 2 regions, with UMN signs

Familial ALS, Unexplained UMN or LMN signs in at least 1

Frequent Symptomatic treatment

Peripheral Paralysis of the

Pheripheral Paralysis of Upper Limbs Paralysis of the Lower Limbs

- Brachial Plexus Paralysis - Femoral (Anterior Crural)

PHERIPHERAL PARALYSES OF UPPER LIMBS

BRACHIAL PLEXUS PARALYSIS

Cord Nerves Function

Axillary (circumflex) nerve paralyisis.