CHAPTER I

INTRODUCTION

1.1. Definition of Primary Nocturnal Enuresis

Based on Diagnostic and Statistical Manual of Mental Disorder, fourth
edition (DSM-IV), enuresis is diagnosed based on repeated voiding of urine in
one’s clothes or bed, either intentionally or unintentionally, at least twice per week
for three consecutive months. The person must be at least five years old, and a
medical condition or substance cannot better account for the behavior.1

There are categories of enuresis, primary enuresis is diagnosed when

continence has not been established for six month or longer and secondary
enuresis is the return of enuresis in child who had been continent for more than
six months, nocturnal enuresis occurs during sleep only and diural enuresis
occurs when the child is awake. Monosymptomatic or uncomplicated enuresis
refers to nocturnal enuresis where the there are no identified urinary tract
problems.
Primary nocturnal enuresis (PNE) is currently defined as involuntary voiding
of urine during sleep at least twice per week in children over 5 years. 3 This
diagnosis requires exclusion of congenital or acquired defects of the central
nervous system (CNS) and the absence of diuretic substances effect.3

1.2. Epidemiology Aspect of Primary Nocturnal Enuresis

Epidemiological studies in western countries have reported the prevalence of
PNE (Primary Nocturnal Enuresis) to be 13–19% in boys and 9–16% in girls
above five years of age.3 At the age of 16 years, 1–2% of boys and girls continue
to be affected by PNE.3 Representative study of children in the United States
found a 4.45% prevalence rate among children ages 8 to 11. 1 The rates were
significantly higher in boys (6.21%) than girls (2.51%).1 Lower rates were found
in the 11 year old children compared with 8 year olds. Higher rates were found in
Black youth. Additionally, the study found only 36% of children with enuresis had
received health care service for the condition.1 The prevalence of bedwetting (≥ 2
nights per week) in one large British study was 8% at 9.5 years. 4 Primary

1
Nocturnal Enuresis affect up to 20 % of young children ( <5 years old ) and nearly
2 % of all young adult.2 Incidence rate of enuresis in ADHD patient is higher than
healthy children.2

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 CHAPTER II
CONTENT

2.1. Psychological Aspect

Primary Nocturnal Enuresis persisting into adult life can be a very
distressing symptom with significant implications for self-esteem and for
developing relationships. Similar in children, PNE must be treated actively as it
can result in low self-esteem, secondary psychological problems, and low school
performance.3 Primary Nocturnal Enuresis can cause significant psychological
stress and later in life potentially cause more serious complication.2
Social stigma regarding enuresis may result in parental displeasure, teasing
from siblings or peers, and lower self-esteem. Parent also feel the emotional, time
and finacial burdens of enuresis. For example, washing bed sheet is time
consuming, training pants and diapers are expensive, and higher rates of stress and
depression are found in parents who have children with enuresis.1

2.2 Biological Aspect

There are numerous biological factor that correlated to Primary Nocturnal
Enuresis, including deficient arginine vasopresin (AVP) secretion, sleep awareness
disorder and bladder dysfunction.2 Low nocturnal release of vasopressin may lead
to increase of urinary volume and decreased osmolality; bladder abnormalities
(small functional volume/ detrusor hyperactivity; and inability to achieve adequate
arousal during sleep to experience bladder fullness.5 The suggestion of behavioral
condition such as attention deficit hyperactivity disorder (ADHD) that can
increase the risk of children to have persisten Primary Nocturnal Enuresis is fined
in current research.2
Primary Nocturnal Enuresis childeren have similar IQ level with age-
macthed healthy children but significantly there is intelligence abnormality like
different memory and attention level in primary noctural enuresis children. 2 These
studies indicate that multiple brain region and circuits might be associated with
the symptoms of enuresis and conigtive diaorder in PNE children. 2 Result of

3
studies in this jurnal found that cerebello-talamo-frontal circuit abnormalities are
likely to be involved in the onset and progression of attention impairment in PNE
children.2
Primary Nocturnal Enuresis can be caused by nocturnal polyuria, inability
to wake up, and a constitutionally small bladder. The treatment was directed
toward reducing the symptoms of PNE because the exact pathophysiological
mechanisms involved are unclear.

Genetic play a role in enuresis. Children have a significant increased in

risk when one parent experienced enuresis as a child and higher risk if both
parents have the disorder. Recent studies have identified several chromosomal
location thats that may be resposible for the transmission of enuresis, and sleep
patern and developmental delays have been explored for possible link with
enuresis as well.1

2.3 Treatment Options of Primary Nocturnal Enuresis

Ellington and Mc Guinness (2012) stated some treatment options for PNE:

1. Nonpharmacological Treatment

Behavioral interventions are considered first line treatment for enuresis for
example reward system for dry night, walking the child at night to void, retention
control training (RCT) to enlarge bladder capacity and fluid restriction.1

Psychotheraphy is helpful only when a psychological problem is a contributing

factor.1

Of all behavioral interventions, the urine alarms has the strongest evidence
base. The urine alarm is a moisture sensitive system that is clipped on underwear
or placed under a bed sheet. The bell sounds when it is exposed to urine and
wakes the child. In time, repeated awakenings at start of nocturia result in an
avoidance response to the aversive stimulus.1

2. Pharmacological Treatment
a. Imipramine.
Mechanism of action are anticholinergic effects and lighthening of sleep. The
recommended dosage is 1.0 to 2.5 mg/kg, given 1 hour before bedtime. Onset

4
 of action is within hours, so can be used sporadically. After 3 to 6 month of
treatment, a gradual titration off imipramine is suggested. Studies have shown
effectiveness in 20% to 60% of participants, but the relaps rate after
discontinuation is as high as 50%. Potential adverse effect include drowsiness,
gastrointestinal upset, mood change, and sleep disturbance.1
b. Desmopressin
This antidiuretic agent is a synthesis from of vasopressin, which reduces night
time urine production. Starting dosages are 0.2 mg (tablet) or 10 mcg (spray)
every night and dosage can be increased weekly up to 0.6 mg 0r 10 mcg.
Duration of action is 10 to 12 hours and it can be used sporadically. A slow
step down discontinuation is suggested at 3 to 6 month intervals.
Effectiveness is achived in 10% to 70% of patients, but relaps rate after
discontinuation is 50% 80%. There is small risk for hyponatremia or seizure
related to water intoxication.
c. Oxybutin
Oxybutil may decrease enuresis through its antimuscarinic properties and
relaxant effect on urinary smooth muscle. Some evidence shows that adding
oxybutin to desmpressin may improve result. Common side effect includes
dry mouth, blurred vision, headache, nausea, dizziness, gatrointestinal upset,
and tachycardia.1

On the other hand, Yu B et al (2013) came up with a solution of antidiuretic.

He stated that for treatment Primary Nocturnal Enuresis, antidiuretic is notably
have been shown to enhance short term memory. Imprivement is obeserved when
antidiuretic hormone analog 1-desamino-8-D-arginin vasopresin (DDAVP) is
administered.2

Koumi et al (2013) brought up acupuncture as a main management of

PNE. The term “acupuncture” is originally derived from Latin which refers to
piercing with a sharp instrument. The acupuncture practitioners use a concept of
12 primary meridians (energy channels) along which are distributed into 360
acupuncture points. Each point is located in an area of low electrical resistance.
The objective is to induce a smoother blood flow and natural energy flow, which
in Chinese culture is called Qi or Chi. The stimulation of those points might
include manual pressure, penetration of the skin, heating, the application of laser,

5
electrotherapy, or moxibustion is thought to induce homeostatic changes. The sites
which are used to treat bladder dysfunction appear to coincide with innervation by
spinal sacral segments S2 through S4. More recently, high concentrations of
neuroendocrine transmitters and hormones have been identified at acupuncture
points. Furthermore, needling or mechanical stimulation of acupuncture points
induces release and spread of neurotransmitter substances. Based on this study,
final response of PNE to acupuncture therapy was a good result which the
percentage of cured patients showed a significant number and no side effects were
reported. It also appeared to be effective both in terms of the percentage of dry
nights at the end of treatment and the stability of results. Furthermore, larger and
controlled trials are needed to confirm these results and to explain the therapeutic
mechanism of acupuncture.3

Darcie A (2012) on the other hand, emphasize the importance of “Bed alarm
therapy” for PNE. The bed alarm is believed to address the difficulty children may
have in waking in response to bladder sensations; however, many children who
are successful using the alarm may remain dry without waking. It is the only treat-
ment that has been shown to treat bedwetting with long-lasting effect. A
systematic review found that after 10–20 weeks, 66% of children maintained 14
consecutive dry nights compared with only 4% of children with no treatment
(rela- tive risk [RR] for failure 0.38, 95% confidence interval [CI] 0.33–0.45).14
The effect lasts even after the bed alarm is stopped. Success with the bed alarm
depends on active involvement of the parents. If children do not wake with the
noise or vibration, it is important for their parents to wake them. This can cause
stress within the family and may not be practical if children share rooms. The bed
alarm can be a very effective treatment in motivated families for children who are
dis- tressed by the bedwetting.4

Patel V (2012) stated the significant need for behavioural therapies on

PNE:

6
 -
“Bell and pad” method->since 1930->success rate 80-90% Moisture
sensitive blanket during enuretic episode sounds Bell and arouses the child
-
Noninvasive ultrasound device that detect baldder size and gives feedback
when bladder volume reaches critical size
-
Bladder training
-
Fluid restrictions at bedtime5

Patrina (2013) mentioned some important points on the treatment of PNE.

She stated that the choice of treatment depends on the frequency and severity of
the enuresis, the child’s age and motivation, the parent or carer’s ability to cope,
supportive treatment, and whether short term dryness is a priority.6

-
Conservative measures
Conservative non-surgical, non-pharmacological treatment for lower urinary tract
dysfunction is encouraged for all children. This includes providing support and
education about the condition and advice about voiding and avoiding caffeine
based drinks, encouraging adequate fluid intake, and managing constipation.
Correct voiding posture is for the child to undress adequately and sit securely on
the toilet, with buttock and foot support, in a comfortable hip abduction position
for girls. Children should void every two to three hours during the day and avoid
holding on when they feel the urge to urinate.6
-
Simple behavioural therapies
Families often try simple behavioural therapies - such as fluid restriction, rewards,
and taking the child to the toilet at night—as first attempts to manage the problem.
Avoid ineffective and even potentially harmful strategies, such as fluid restriction,
retention control training (encouraging the child not to void for as long as possible
to expand bladder capacity), and unnecessary drugs. Rewarding agreed behaviour
(such as drinking adequately, voiding before sleep, and engaging in management)
may be more effective than rewarding dry nights, which are out of the child’s
conscious control. Although simple behavioural therapies are superior to no active
treatment, they are inferior to confirmed effective treatments.6

-
Anticholinergic drugs

7
Anticholinergic drugs have a potential role, mainly in non-monosymptomatic
nocturnal enuresis. They are thought to act by treating the underlying overactive
bladder, thereby increasing the storage capacity of the bladder. Although
anticholinergic monotherapy is ineffective, it can improve treatment response
when combined with other established treatments, such as imipramine,
desmopressin, or enuresis alarms, particularly in treatment resistant cases.6
Reza M (2014) researched sertraline as a pharmacotherapy modality for PNE,
if the main modalities (Desmopressin, oxibutynin,imipramine) fails. From march
2009 to april 2011 the study was conducted, 25 patients were recommended to
take one oral tablet of sertraline (50mg) every morning after meal for 3 months.
After 6 weeks of therapy , a significant reduction in the mean number of wet
nights was found. 18 patients achieve primary efficacy outcome, 6 patients had
partial response, 4 patients presented with a relapse after 6 months of follow up.
No drug-emergent adverse events were observed. The known side effects of
sertraline include sleep disturbance, headache, tremors, agitation, and
gastrointestinal upset. This report supports the previous evidence suggesting a
serotonergic mechanism in enuresis, which may be at least partially independent
of the serotonergic mechanism of mood disorder. Nevertheless, deterioration in
some responders with time raises important question about the long term efficacy
of this therapy and the need for further maintenance sessions.7

Ahmed et al (2013) stated that the combination of both desmopressin and

enuresis alarm are very effective in treating PNE. Alarm therapy is an effective
treatment strategy for primary nocturnal enuresis owing to its efficacy,low relapse
rates, and absenceof side effects. It is presumed to cure primary nocturnal enuresis
by increasing nocturnal bladder reservoir function or as a result of conditioning
effects on arousal. Another option in the treatment of primary nocturnal enuresis is
desmopressin medical therapy. It was originally introduced for the treatment of
central diabetes insipidus. Desmopressin oral melt is the preferable formulation
overtablet and requires no water intake and is associated withhigh compliance
among children aged 5 to 11 years. Moreover, desmopressin is a safe drug with
few side effectsand low risks even when used for many years. In conclusion,
desmopressin, enuresis alarm, and combined therapy areeffective in the treatment

8
of nocturnal enuresis. Desmopressin produces an immediate effect but
relapseswere common. The enuresis alarm results in gradual effects that persist to
post-treatment. Combined therapyshowed better immediate response rates.8

Thomas et al (2012) stated the importance of practical measures. These

practical measures include advising individuals to limit fluid intake during the
evening, avoid caffeine and alcohol, and empty their bladder before going to
sleep. He also mentioned amitriptyline, desmopressin, ephedrine and
anticholinergics such as oxybutynin and trihexyphenidyl as a modality therapy for
PNE.9

Johan et al (2012) treatment options for PNE are similar to Ahmed et al

(2013). He suggests desmopressin and bed alarm therapy, or the combination of
both as a management of PNE.10

There are some solutions for patients that fails in treating their PNE with
main modalities (Desmopressin, imipramine, anticholinergics), for example Reza
M (2014) already proved that sertraline can be one of the options through his
research. On the other hand, Dudley R, Linda C (2012) promoted Antimuscarinic
agents as a modality option for PNE. They also have researched its work. The
clinical effectiveness of antimuscarinic agents was first questioned in a systematic
review o f32 randomised controlled trials including 6800 participants. 10
Cureorimprovementafter treatment were all significantly in favour of
antimuscarinic drugs (relativerisk 1.41 (95% confidence interval 1.29 to 1.54),
P<0.0001), although the differences from place bowere small and of questionable
clinical significance. Asubsequent Cochrane review of 61 randomised controlled
trials including 11 956 patients was supportive of these findings, with a
significantly greater cure or improvement rate in the antimuscarinic group
compared with placebo.11

CHAPTER III

SUMMARY

9
3.1. Primary nocturnal enuresis (PNE) is currently defined as involuntary voiding
of urine during sleep at least twice per week in children over 5 years.
3.2. Boys is more dominant to affected PNE than girl. Lower rates were found in
the 11 year old children compared with 8 year olds
3.3. Primary Nocturnal Enuresis can cause significant psychological stress and
later in life potentially cause more serious complication
3.4. There are numerous biological factor that correlated to Primary Nocturnal
Enuresis
3.5. Based on the journals, there are many option treatment for PNE and
imipramine, desmopressin and anticholinergic are concluded to be the first
line treatment for PNE.

REFERENCES

10
1. Ellington, E.E., and McGuinness, T.M. 2012. Mental Health Consideration in
Pediatric Enuresis. Journal of Psychosocial Nursing and Mental Heatlh
Service, 50(4), 40-45.

2. Yu B, Sun H, Ma H, Peng M, Kong E, et al. 2013. Abberant Whole-Brain

Functional Connectivity and Intelligence Structure in Children with Primary
Nocturnal Enuresis. PLoS ONE 8(1)
3. Koumi MA, Ahmed SA, Salama AM, et al. 2013. Acupuncture Efficacy in the
Treatment of Persistent Primary Nocturnal Enuresis. Arab Journal of
Nephrology and Transplantation.; 6(3):173-6.
4. Darcie A. 2012. Nocturnal Enuresis. Canadian Medical Journal Association
5. Patel Vishal, Golwakar Rujuta, Beniwal Sumit, et al. 2012 Elimination
disorders: Enuresis. Medical Journal of Dr. D. Y. Patil University; 8:14-17
6. Patrina H Y, Aniruddh V D, Alexander VG. 2013. Management of nocturnal
enuresis. The BMJ
7. Reza M, Ali S. 2014. Treatment of Monosymptomatic Nocturnal Enuresis:
Sertraline for Non-Responders to Desmopressin. Iranian Journal of Medical
Sciences
8. Ahmed et al. 2013. Efficacy of an Enuresis Alarm, Desmopressin, and
Combination Therapy in the Treatment of Saudi Children With Primary
Monosymptomatic Nocturnal Enuresis. Korean J Urol; 54:783-790
9. Thomas et al. 2012. Nocturnal Enuresis with Antipsychotic Medication. The
British Journal of Psychiatry
10. Johan et al. 2012. Practical Consensus Guideline for the Management of
Enuresis. Springer
11. Dudley Robinson, Linda Cardozo. 2012. Antimuscarinic drugs to treat
overactive bladder. Departement of Urogynaecology King’s College Hospital

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 APPENDIX
ORIGINAL ARTICLES

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