Approach to refractory urinary incontinence
in children, with special emphasis on children
with intellectual and/or physical disability
Dr. Erik VAN LAECKE
Thesis submitted to obtain the degree of Doctor in the Medical Sciences 2009
Promotor: Prof. Dr. P. Hoebeke
Copromotor: Prof. Dr. J.Vande Walle
GHENT UNIVERSITY
Faculty of Medicine and Health Sciences
Paediatric Urology
Department of Urology
1
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Table of contents
List of abbreviations
5
Part 1
Introduction
8
Chapter 1
Normal development of lower urinary tract function
The lower urinary tract: anatomy, neuroanatomy and
neurophysiology.
10
Urinary incontinence in children
23
2.1. Terms and Definitions
23
2.2. Prevalence
25
2.3. Pathogenesis
2.3.1. Pathogenesis of urinary incontinence
2.3.1.1 Over active bladder
2.3.1.2 Dysfunctional voiding
2.3.1.3 Underactive detrusor
2.3.1.4 Voiding postponement
2.3.1.5 Giggle incontinence
2.3.1.6 Vesicovaginal reflux
2.3.1.7 Dysfunctional elimination syndrome
2.3.2. Pathophysiology of monosymptomatic enuresis
2.3.2.1 Increased nocturnal urine output – nocturnal polyuria
2.3.2.2 Reduced bladder capacity and/or detrusor overactivity
2.3.2.3 Sleep, arousal and CNS function
2.3.2.4 Genetic factors
2.3.3. Comorbidity
2.3.3.1 Constipation and faecal incontinence
2.3.3.2 Psychological and social disturbances
2.3.3.3 Attention Deficit Hyperactivity Disorder (ADHD)
2.3.3.4 Upper airway obstruction.
27
27
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30
31
31
32
32
33
34
34
35
36
37
38
38
38
38
39
Mental and Motor disabilities
40
3.1. Definitions
3.1.1. Mental retardation
3.1.1.1 DSM definition
3.1.1.2 AAMR definition
3.1.2. Motor disability
40
40
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40
41
Chapter 2
Chapter 3
2
Chapter 4
Chapter 5
3.2. Incidence and aetiology of developmental disabilities
41
3.3. Pathophysiology of urinary incontinence in
developmentally challenged children
3.3.1. Dysfunction of the lower urinary tract
3.3.2. Reduced bladder capacity
3.3.3. Mental development
3.3.4. Motor capacity
42
42
43
43
43
3.4. Comorbidity
3.4.1. Constipation and faecal incontinence
3.4.2. Attention Deficit Disorder (ADHD)
3.4.3. Sleep disorders
44
44
44
44
Evaluation of children with incontinence.
46
4.1. History taking
46
4.2. Physical examination
47
4.3. Laboratory tests
48
4.4. Non-invasive diagnostic techniques
4.4.1. Frequency/volume charts: bladder diary
4.4.2. Urinary flow
4.4.3. Ultrasound
48
48
49
50
4.5. Invasive diagnostic techniques
4.5.1. (Video)-Urodynamics (VUDE)
4.5.2. Cystoscopy
51
51
53
Therapeutical options
54
5.1. Treatment of urinary incontinence in children
5.1.1. Non pharmacological treatment
5.1.1.1 Urotherapy
5.1.1.2 Biofeedback
5.1.1.3 Neuromodulation
5.1.1.4 Alarm treatment
5.1.2. Pharmacological treatment
5.1.2.1 Antimuscarinic treatment
5.1.2.2 Botulinum toxin
5.1.2.3 Alpha blockers
54
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
4
5.2. Treatment of nocturnal enuresis in children
5.2.1. Non pharmacological treatment
5.2.1.1 Enuresis alarm
5.2.1.2 Acupuncture
5.2.2. Pharmacological treatment
5.2.2.1 Desmopressin
5.2.2.2 Antimuscarinic treatment
5.2.2.3 Tricyclic antidepressants
5.2.2.4 Inhibitors of prostaglandin synthesis
5.2.2.5 Combination therapy
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72
Objectives of this thesis and background of the research
performed at our centre.
73
Publications
77
Publication 1
78
Publication 2
84
Publication 3
90
Publication 4
95
Publication 5
99
Publication 6
103
General Discussion / Further research
111
General discussion
112
Further research
121
Part 4
Dutch Summary
123
Part 5
References
129
Chapter 6
Part 2
Part 3
Curriculum Vitae
149
Dankwoord
155
List of abbreviations
AAMR
American Association on
Mental Retardation
ACh
Acetyl choline
ADD
Attention deficit disorder
ADH
Antidiuretic hormone
ADHD
Attention deficit
hyperactivity disorder
ADHD-IA Attention deficit
hyperactivity disorderinattentive type
ATP Adenosine triphosphate
AUC
Area under the serum
concentration-time curve
AVP
Arginine vasopressine
BTX
Botulinum Toxin
BVWI
Bladder Volume/Bladder Wall
Thickness Index
Ca
calcium
cAMP
cyclic Adenosine
monophosphate
CGRP
Calcitonin-generelated
peptide
CIC
Clean intermittent
catheterisation
CMV
Cytomegalovirus
CNS
Central nervous system
dDAVP Desmopressin
DSM
Diagnostic and Statistical
Manual
EBC Expected bladder capacity
EEG
Electro-encephalography
EMG
Electro-myography
ER
Extended release
EUS
External urethral sphincter
FDA
Food and drugs
administration
ICCS
International children
continence society
ICS
International continence
society
IDO
Ideopathic detrusor
overactivity
IE
Internationale eenheden
IM
Intra muscular
IP
Inositol 1.4.5- triphosphate
IQ
Intelligence Quotient
IR
Immediate release
L
LUT
LUTS
Lumbar
Lower urinary tract
Lower urinary tract
symptoms
M
Muscarinic
MNE
Monosymptomatic nocturnal
enuresis
MRI
Magnetic resonance imaging
mRNA messenger Ribo nucleic acid
N
Nicotine
NANC
Nonadrenergic
noncholinergic
NE
Norepinephrine
NFU
Natural filling urodynamics
NGF
Nerve growth factor
NMNE
Non-monosymptomatic
nocturnal enuresis
NO
Nitric oxide
OAB
Overactive bladder
PACAP Pituitary adenylate cyclase
activating polypeptide
PAG
Periaqueductal gray area
Pdetmax maximum detrusor pressure
PET Positron emission
tomography
PMC
Pontine micturation centre
PSC
Pontine storage centre
P2X
purinoreceptor
S
Sacral
SAP
Synaptosomal-associated
protein
SP
Substance P
T
Thoracal
TENS
Transcutaneous electrical
nerve stimulation
TRP
Transient receptor potential
channels
U
Unit
US
United States
UTI
Urinary tract infection
(V)UDE (Video)- Urodynamics
VUR
Vesicoureteral reflux
WHO
World Health Organization
5
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Part 1
7
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Introduction
Urinary incontinence, during day, night or both is despite its high prevalence one
of the most distressing conditions in childhood. It is not only very unpractical and
embarrassing, but it also causes a high psychological distress to children and parents.
It is a very common problem in children. Urinary incontinence is the second most
common chronic health problem in childhood in our Western world, only preceded
by allergic conditions. The prevalence of daytime or combined daytime and nighttime
incontinence in seven-years-old children has been reported between 2-4 percent.
Often the children are believed to wet their pants and /or their beds because they are
too lazy or too occupied by their activities to go to the toilet in time, or because of stress
and psychological problems. Punishment is often their part.
Urinary incontinence in children is, even by medical professionals, believed to be a
benign disorder that either will resolve by puberty or is easily treatable with urotherapy
and anticholinergics, leading to neglect of the problem and often to lack of treatment.
Otherwise, in mentally and/or motor disabled children, it is often believed that urinary
incontinence is inevitable, and doesn’t need any treatment.
Reality is more complex. Recent literature demonstrates that urinary incontinence in
children is multifactorial in origin. Incontinence is classically divided into functional
abnormalities: over active bladder, dysfunctional voiding, and anatomical anomalies
such as ectopic ureter and vaginal reflux. These two conditions are widely overlapping.
Recent literature stresses the importance of behavioural factors such as voiding
postponement and co morbid factors such as constipation, ADD, ADHD, autism and
motor and mental disabilities which are all identified to play a role in the pathofysiology
of urinary incontinence. With a multifactorial origin there is no standard treatment
for urinary incontinence in childhood. Treatment should be tailored to each child
individually.
Modern treatment consists of urotherapy, pharmacotherapy, neuromodulation and
sometimes surgery. The exact role of each therapeutic modality has not been described
until today. Many times combined therapies are needed to achieve the ultimate goal
of treatment: dryness.
Knowledge of healthcare workers and compliance of patients and parents are essential
to obtain this goal.
8
Incontinence in children is challenging, and especially those children who do not
respond to standard treatment. With years of experience we have identified a large
group of children with refractory, often therapy resistant overactive bladder, and we have
been building our experience in the treatment of children who are developmentally
challenged.
We consider children to suffer refractory urinary incontinence when toilet training
is complicated because of developmental disabilities or when children with urinary
incontinence do show therapy resistance. The latter is the case when adequate standard
therapy for at least 18 months fails to be successful.
In this thesis we want to report our experience with these specific groups of children
and more specifically we want to answer the following questions:
1. What is the role of new pharmacological agents, Tolterodine, Solifenacin and
botulinum-A toxin in the treatment of overactive detrusor in children suffering
urinary incontinence?
2. What is the role of the daytime alarm in the treatment of children with persistent
urinary daytime incontinence?
3. What is the prevalence of urinary incontinence in developmentally challenged
children, and what are possible pathophysiological mechanisms to explain this?
4. From the new knowledge of pathophysiology of incontinence in developmentally
challenged children what is the role of adequate fluid intake in the treatment of
these children?
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
10
Chapter 1
Normal development of
lower urinary tract function.
The lower urinary tract: anatomy,
neuroanatomy and neurophysiology.
The bladder is a very unique organ of the human with a dual function of both storage
and emptying of urine. In order to accomplish this dual function a complex innervation
of voluntary and involuntary control of function is needed.
In the bladder two regions are distinguished based on their innervation and response
to pharmacological agents: the “ body “, which lies cranial to the level of the ureteric
orifices and the “ base ”, which is caudal to this level.
The detrusor consists of a meshwork of smooth muscle fibres arranged into a single
functioning unit with an ability to elicit nearly maximal active tension over a wide
range of length. This allows the bladder to fill with urine at low pressure (compliance).
The ability of the bladder to store urine is determined by the concomitant activity of
the detrusor muscle and the bladder outlet, consisting of the bladder neck, proximal
urethra and striated muscle of the pelvic floor.[1]
The bladder sphincter (external and internal) plays a major role in urinary continence
by closure of the bladder neck and proximal urethra. The anatomy of the external
urinary sphincter consists of a cylindrical structure, which is accentuated anteriorly and
thinned out or actually absent posteriorly. It has an inner layer of smooth muscle and
an outer layer of striated muscle, extending from the apex of the prostate to invest the
length of the membranous urethra in males. In the females this is less well developed
and extends from the bladder neck to the mid urethra. The internal sphincter has not
been well delineated anatomically. It has generally been accepted that it consists of
smooth muscle fibres continuing from the bladder base and trigone which traverse
inferiorly through the bladder neck to extend toward the proximal urethra. Its existence
has been better delineated on radiologic and urethral pressure measurement studies.
During micturation, the bladder base, bladder neck and proximal urethra can be shown
to contract simultaneously as a unit, producing a funnelling effect that opens up the
bladder outlet with initiation of voiding.
Detrusor muscle
Mucosa
Bladderneck
Ureter
Ureteral orifice
Urethra
External urethral
sphincter
Figure 1. The bladder and the lower urinary tract
Little is known about the natural course of development of maturation of the structure
as well as function of the sphincter mechanism. Literature suggests that immature
detrusor-sphincter coordination, manifested as detrusor hyper contractility and
interrupted voiding, commonly occurs in the first 1 to 2 years of life causing some
degree of functional bladder outflow obstruction.[2, 3]
The bladder and urethra function reciprocally. During bladder filling, “the urine storage
phase”, the detrusor remains quiescent, with little change in intravesical pressure. During
this phase, neural pathways that stimulate the bladder for micturation are quiescent,
and inhibitory pathways are active. The urethral outlet remains closed, with increasing
external urethral sphincter contractions. This progressive increase in external urethral
sphincter activity in response to increasing bladder volume is known as the “guarding
reflex”. When the bladder volume reaches a critical threshold, the external sphincter
relaxes, the detrusor contracts, the bladder neck opens, and elimination occurs.[4]
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Activation, coordination and integration of various parts of the bladder-sphincter
complex involves both the central somatic and autonomic nervous systems through
three sets of peripheral nerves: sacral parasympathetic (pelvic nerve), thoracolumbar
sympathetic (hypogastric nerves and sympathetic chain) and sacral somatic nerves
(primarily the pudendal nerve) [1]
The efferent parasympathetic pathway provides the major excitatory innervation of the
detrusor.[4]
Parasympathetic nerve fibres run in the pelvic nerve (S2-S4) to supply the pelvic and
vesical plexuses before entering the bladder. Parasympathetic ganglia are found within
these plexuses and in the bladder wall. Sympathetic nerves arise from segments T12 to
L2 of the spinal cord and go to the inferior mesenteric ganglion through the sympathetic
trunk. From the inferior mesenteric ganglion the nerve fibres pass to the pelvic plexus
and bladder through the hypogastric nerves. There is also a sympathetic innervation
originating from T10 to L2 supplying the detrusor and urethral sphincter. The somatic
nerve system (pudendal nerve) supplies the periurethral pelvic floor musculature. The
sensory and motor nerves carried by all three nerves innervate both the bladder and
urethral sphincter. They originate from parasympathetic ganglia located in the second,
third and fourth segments of the sacral spinal cord. Within the spinal cord, information
from bladder afferents is integrated with that from other viscera and somatic sources
and projected to the brain stem centres that coordinate the micturation cycle.
Bladder function in children is very different from adults. During the first 2 to 3 years of
life there is progressive development from an initially indiscriminate infantile voiding
pattern to a more socially conscious and voluntary or adult type of micturation. This is
achieved through an active learning process in which the child acquires the ability to
voluntary inhibit or initiate voiding at socially convenient times. This natural evolution
of bladder control entails an intact nervous system and depends on at least three main
events occurring in parallel: a progressive increase in bladder functional storage capacity,
maturation of voluntary control over the urethral striated muscle sphincter and pelvic
floor and development of direct volitional control over the bladder-sphincter unit by
which the child can voluntary initiate or inhibit the micturation reflex. This process can
also be influenced by an awareness of the accepted social norms in families during
toilet training. [5]
All nerves connected to the bladder are able to transport information from the organ
to the central nervous system (afferent impulses), which is mainly a sensory function,
and to transport information from the central nervous system to the organ (efferent
impulses), which is mainly a motor function.
Autonomic efferent fibres from the anterior portion of the pelvic plexus (the vesical
plexus) pass along the lateral and posterior ligaments to innervate the bladder. The
bladder wall is richly supplied with parasympathetic cholinergic nerve endings
12
and has abundant postganglionic cell bodies. Sparse sympathetic innervation of
the bladder has been proposed to mediate detrusor relaxation but probably lacks
functional significance. A separate nonadrenergic noncholinergic (NANC) component
of the autonomic nervous system participates in activating the detrusor, although the
neurotransmitter has not been identified. [6]
The male bladder neck receives abundant sympathetic innervation and expresses α1adrenergic receptors. The female bladder neck has little adrenergic innervation. Nitric
oxide synthase containing neurons have been identified in the detrusor, particularly at
the bladder neck, where they may facilitate relaxation during micturition. The trigonal
muscle is innervated by adrenergic and nitric oxide synthase-containing neurons. Like
the bladder neck, it relaxes during micturition.
The peripheral nervous system
The lower urinary tract is innervated by three sets of peripheral nerves involving the
parasympathetic, sympathetic and somatic nervous systems. Pelvic parasympathetic
nerves arise at the sacral level of the spinal cord, excite the bladder, and relax the
urethra. Lumbar sympathetic nerves inhibit the bladder body and excite the bladder
base and urethra. Pudendal nerves excite the external urethral sphincter. These nerves
contain afferent (sensory) as well as efferent axons.
Efferent nervous system
Parasympathetic pathways
Parasympathetic preganglionic neurons innervating the lower urinary tract are located
in the lateral part of the sacral intermediate gray matter in a region termed the sacral
parasympathetic nucleus. Parasympathetic preganglionic neurons send axons through
the ventral roots to peripheral ganglia, where they release the excitatory transmitter
acetylcholine.
Acetylcholine excitation of postsynaptic neurons is mediated by nicotinic receptors.
Postganglionic axons continue for a short distance in the pelvic nerve and terminate
in the detrusor layer, where they transmit ACh to the smooth muscle fibres, with
consequent contractions of the bladder. [4]
Radioligand studies have proven that the bladder body and base contain muscarinic
receptors.[7]
The major portion of neurohumoral stimulus for physiologic bladder contraction is
acetylcholine-induced stimulation of postganglionic parasympathetic muscarinic
cholinergic receptor sites in the bladder. In the bladder, mRNAs for all five of the
pharmacologically defined receptors, M1 to M5 have been demonstrated.[8] There is a
predominance of M2 and M3 receptors. M2 and M3 receptors can be found not only on
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
detrusor muscle cells, where M2 receptors predominate at least 3:1 over M3 receptors,
but also on other bladder structures, which may be of importance for detrusor activation.
Muscarinic receptors can be found on urothelial cells, on suburothelial nerves, and on
other suburothelial structures, such as interstitial cells.[9]
M3 receptors are believed to be the most important for contraction. M2 receptors have
been suggested to directly contribute to contraction of the bladder in certain disease
states, e.g. denervation, outlet obstruction.[10]
Muscarinic receptors are stimulated by acetylcholine. In the bladder this stimulation
provokes a bladder contraction by calcium entry through nifedipine-sensitive L-type
Ca ²+ channels in addition to increased polyphosphoinositide hydrolysis resulting in
inositol 1,4,5-triphosphate (IP 3) production and release of intracellular calcium stores,
and a rise in intravesical pressure. [11]
Acetylcholine is the principal excitatory transmitter at the parasympathetic-detrusor
cell synapse, but it is certainly not the only one. The purine, adenosine triphosphate
(ATP), is considered to be a parasympathetic cotransmitter responsible for atropine
resistant detrusor activation. The ATP effect appears to be mediated by stimulation of
one or more members of the P2X family of purinoceptors.
In addition to the parasympathetic stimulation of bladder smooth muscle, some
postsynaptic parasympathetic neurons exert a relaxation effect on urethral smooth
muscle, most likely via transmission of nitric oxide (NO), causing a relaxation of the
internal urethral sphincter during the elimination phase.[4]
Sympathetic pathways
Sympathetic outflow from the rostral lumbar spinal cord provides a noradrenergic
excitatory and inhibitory input to the bladder and the urethra. Activation of sympathetic
nerves induces relaxation of the bladder body and contraction of the bladder outlet and
urethra, which contribute to urine storage in the bladder. The peripheral sympathetic
pathways follow a complex route that passes through the sympathetic chain ganglia to
the inferior mesenteric ganglia and then through the hypogastric nerves to the pelvic
ganglia.
The preganglionic neurotransmitter is ACh, which acts via nicotinic receptors in the
postganglionic neurons. The postganglionic axons transmit norepinephrine (NE) at
their terminals.[4]
Alpha and beta adrenergic binding sites are found in human bladder and urethral
tissues. Beta receptors are predominantly found at the bladder dome, alpha receptors
at the base and outlet. It is believed that the adrenergic pathways facilitate bladder
storage by relaxing the detrusor and contracting the outlet.[12]
14
Alpha-adrenergic stimulation is not prominent in the normal bladder. Alpha-adrenergic
mechanisms are more important in urethral function. Substantial pharmacologic
and physiologic evidence indicates that urethral tone and intraurethral pressure are
influenced by α-adrenergic receptors.
Stimulation of β2- and β3-adrenergic receptors that exist in the human detrusor results
in the direct relaxation of the detrusor smooth muscle. In addition, β-adrenergicstimulated relaxation is mediated through the stimulation of adenylate cyclase and the
accumulation of cyclic AMP (cAMP). The relaxation induced by adrenergic stimulation
of the human detrusor is mediated mainly through β3 adrenoreceptor activation.
Somatic pathways
The external urethral sphincter motor neurons are located along the lateral border of
the ventral horn in sacral spinal cord segments S2-S4, commonly referred to as Onuf’s
nucleus. The pudendal nerve also supplies the pelvic floor muscles.[13]
The motor neuron axons release ACh which acts on nicotinic receptors in the striated
muscle, inducing muscle contraction to maintain closure of the external urethral
sphincter.[4]
Pelvic nerve
(parasympathetic)
ACh
+ M3
-ß3
Hypogastric nerve
(sympathetic)
NE
+α1
Pundendal nerve
(somatic)
ACh
+N
Figure 2. Innervation of the lower urinary tract
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Spinal cord
Inferior mesenteric
ganglion
Sympathic
Hypogastric nerve
T10-L2
Parasympathic
Pelvic nerve
NEACh+
S2-S4
Urethra
External
urethral
sphincter
Pelvic ganglion
Figure 3. Efferent pathways from the spinal cord to the bladder.
Spinal cord
Inferior mesenteric
ganglion
Sympathic
Hypogastric nerve
T10-L2
Parasympathic
Pelvic nerve
Bladder
NE+
S2-S4
NOSomatic
Pudendal nerve
ACh+
Pelvic ganglion
Figure 4. Efferent pathways from the spinal cord to the lower urinary tract.
16
Bladder
Urethra
External
urethral
sphincter
Afferent pathways
Afferent axons in the pelvic, hypogastric and pudendal nerves transmit information
from the lower urinary tract to the lumbosacral spinal cord. The primary afferent neurons
of the pelvic and pudendal nerves are contained in sacral dorsal root ganglia S2-S4,
while afferent innervation in the hypogastric nerves arises in the rostral thoracolumbar
dorsal root ganglia T10-L2. The central axons of the dorsal root ganglia neurons carry
the sensory information from the lower urinary tract to second-order neurons in the
spinal cord. Visceral afferent fibres of the pelvic and pudendal nerves enter the cord and
travel rostrocaudally within Lissauer’s tract.[4]
Afferent axons, identified primarily by neuropeptide immunoreactivity for calcitoningene-related peptide (CGRP), pituitary adenylate cyclase activating polypeptide
(PACAP), or substance P (SP), are distributed throughout the bladder wall.[14]
Pelvic nerve afferents, which monitor the volume of the bladder and the amplitude of
the bladder contraction, consist of myelinated (Aδ) and unmyelinated (C) axons. The
Aδ fibres are located at the smooth muscles and do sense bladder fullness. The C fibres
located at the mucosa are responsible for an adequate response to stretch (bladder
volume sensors) and nociception to overdistention and chemical irritants.
Glutamate is a neurotransmitter present in both the Aδ and C fibres. Substance P and
calcitonin gene-related peptide are additional neurotransmitters in the C fibres.[4]
Aδ fibre
Bladder
Glutamate
C fibre Glutamate
SP
CGRP
Spinal cord
Figure 5. Afferent fibres transmitting sensory information from
the lower urinary tract to the spinal cord.
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
18
Sensing bladder volume is of particular relevance during urine storage.
Fibre type
Location
Normal function
Aδ
Smooth muscle
Sense bladder fullness ( wall tension)
C fibres
Mucosa
Respond to stretch (bladder volume sensors)
C fibres
Mucosa
Muscle
Nociception to overdistension and chemicals
Silent afferent (mechanoinsensitive)
On the other hand, afferent discharges that occur during a bladder contraction have an
important reflex function and appear to reinforce the central drive that maintains the
detrusor contraction.
The different kind of receptors (pressure, pain, temperature, tension) are able to
intercept signals from the bladder and carry them to the central nervous system where
they can be perceived at the spinal cord level and generate reflexes, or be transported
to the central nervous system where they can become conscious stimuli, which can be
modified by behaviour.
The pathways responsible for the different sensations from the lower urinary tract are
reproduced in the next table
Pelvic afferent
pathway
Lumbar afferent
pathway
Pudendal afferent
pathway
Sensation of filling
yes
probably
no
Desire to void
yes
probably
no
possibly
possibly not
yes
Pain (bladder)
yes
yes
no
Pain (urethral)
probably
probably not
yes
Sensation
Strong desire to void
Multiple reflex pathways organized in the brain and spinal cord mediate coordination
between the urinary bladder and the urethra. The central pathways controlling lower
urinary tract function are organized as simple on-off switching circuits that maintain
a reciprocal relationship between the urinary bladder and the urethral outlet. Some
reflexes promote urine storage, whereas others facilitate voiding. It is also possible
that individual reflexes might be linked together in a serial manner to create complex
feedback mechanisms.
Historically the urothelium has been viewed as primarily a barrier. Currently it is becoming
clear that the urothelium is a responsive structure capable of detecting physiological
and chemical stimuli, and releasing a number of signalling molecules. As such it displays
a number of properties similar to those of nociceptive and mechanosensitive sensory
neurons and can use diverse signal-transduction mechanisms to detect physiological
stimuli. The urothelium expresses “sensor molecules” (receptors/ion channels) that have
been identified in afferent neurons, including receptors for bradykinin, neurotrophins,
purine (P2X and P2Y), norepinephrine (α and β), protease-activated receptors,
acetylcholine (nicotinic and muscarinic), amiloride/mechanosensitive Na+ channels
and a number of transient receptor potential channels (TRPV1, TRPV2, TRPV4, TRPM8).
In addition, urothelial cells can release neurotransmitters and signalling molecules
such as ATP, prostaglandins, nitric oxide, acetylcholine, NGF and SP, that influence the
excitability of afferent nerves.
Chemicals released from the urothelial cells may act directly on the afferent nerves or
indirectly via an action on suburothelial myofibroblast, also called interstitial cells or
Cajal like cells that lie in close proximity to afferent cells. Interstitial cells are extensively
linked by gap junctions and can release chemicals that in turn act on afferent nerves. [14]
Andersson et all. mentioned interstitial cells to have a pacemaking role in spontaneous
activity of the bladder.[11]
It is believed that urothelial cells and myofibroblasts can participate in sensory
mechanisms in the urinary tract by chemical coupling to the adjacent sensory nerves.[14]
The central nervous system
Neural control over the lower urinary tract occurs at different levels of the central
nervous system. Central nervous system control over lower urinary tract function is
very complex.
The main influences are inhibition of the micturition reflex, inhibition of spontaneous
detrusor reflex contractions, coordination of detrusor contraction and sphincter
relaxation. Understanding of the relationship between cerebral function and urologic
function has increased as a result of the insights gained from functional brain imaging.
Various studies indicate that the micturation reflex is normally mediated by a
spinobulbospinal reflex pathway passing through relay centres in the brain. The dorsal
pontine tegumentum has been firmly established as an essential control centre for
micturation in normal subjects, and has been described as the pontine micturition
centre.[15]
Brain imaging studies have implicated both the frontal cortex and the anterior
cingulated gyrus in control of micturation and have indicated that micturition is
controlled predominantly by the right side of the brain.[15]
19
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Positron emission tomography (PET) has shown increased activity in the periaqueductal
gray area (PAG), the hypothalamus, and the right pontine micturition centre during
micturition. Brain activity in other cortical areas and the cerebellar vermis also has been
noted to occur during micturition. Bladder storage activity is mediated by a sacralthoracolumbar reflex associated with a descending cortical control to allow one to
postpone bladder emptying. In PET scanning, increased bladder volumes correlate with
activity in the PAG, midline pons, mid cingulated cortex, and bilateral frontal cortex. An
increase in the desire to void was associated with a decrease in brain activity, possibly
because of cerebral attempts at suppressing the desire to void. Activity in the anterior
cingulated and insula areas also has been noted. In functional MRI studies, activity in
the parietal cortex, cerebellum, putamen, and supplementary motor area has been
associated with inhibition of micturition.
The areas of the brain that control voiding include parts of the midbrain, the PAG, the
cingulated cortex with connections to the insula, the hypothalamus, and the prefrontal
cortex. The frontal cortex may provide inhibition, and the cerebellum is active during
the storage phase and micturition. These findings can be interpreted as representing
a matrix of brain areas that control various aspects of urine storage and micturation,
including perceptions of fullness and desire to void that is influenced by environmental
cues.
Functional MRI (fMRI) studies illustrated that the supplementary motor area,
midcingulate cortex, insula, frontal operculum, and right prefrontal cortex were
consistently more active when the desire to void was enhanced without allowing urine
to pass (“attempted micturation”) than during a baseline task when bladder sensation
was suppressed. The right anterior insula and midbrain periaqueductal gray (PAG) were
more active at higher than at lower bladder volumes. Responses of the right thalamus
and several other right hemispherical regions were stronger in women than in men.
Using the psychophysiological interaction method illustrated that the midcingulate
cortex had stronger connectivity with the PAG and medial motor areas during
“attempted micturation” than during the baseline task, possibly reflecting monitoring of
urethral sphincter contractions. Conversely, the left and right insula showed decreased
connectivity with many other brain regions during “attempted micturation”, possibly
due to predominant processing of bladder-afferent input. Functional MRI study of brain
activity showed that intentional modulations of the desire to void change effective
connectivity of supraspinal regions involved in bladder control.[16]
The pontine micturation centre (PMC) and the pontine storage centre (PSC) which is
localised ventrolateral of the PMC, are the integrative centres, receiving and integrating
input from afferent spinal cord nerves and more rostral brain regions and controlling an
on/of switch for the lower urinary tract.
Neurons in the PSC project directly to the motoneurons in Onuf’s nucleus. Stimulation
of PSC neurons causes EUS contractions.
20
Neurons in the PMC project to the sacral parasympathetic nucleus. Stimulation of
PMC neurons results in bladder contraction and relaxation of the internal and external
urethral sphincter.
Glutamic acid, the major excitatory neurotransmitter, appears to function as the on
switch for the EUS. Suppression of glutamatergic transmission serves as the final signal
for EUS relaxation and bladder elimination. Several other supraspinal neurotransmitters
have mandatory roles in lower urinary tract function. Norepinephrine and serotonin
appear to have a positive neuromodulatory effect on EUS contraction. Dopamine and
γ-aminobutyric acid, a principal inhibitory neurotransmitter in the brain, contribute to
coordination of lower urinary tract function.[4]
Figure 6. Major reflex pathways
Pontine
micturation
centre
Hypogastric nerve
. contracts urethra
. relaxes bladder
Pontine
storage
centre
(-)
Sympathetic
(+)
(+)
-β3
+M3
Parasympathetic
Pelvic nerve
. contracts detrusor
. inhibits urethra
+α1
+N
Onuf’s nucleus
(-)
(+)
Pudendal nerve
■
■
■
Major reflex pathways from the pontine micturation centre to the lower tract
stimulating initiation and completion of micturation
Major reflex pathways to the lower urinary tract initiating and maintaining urine
storage
Major reflex pathways from the pontine micturation centre in the brainstem to the
lower urinary tract via the spinal cord regulating both micturation and urine storage
21
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Storage reflexes: Until the volume of urine in the bladder reaches a critical threshold for
voiding, the detrusor is quiet. During filling the bladder has a low and relatively constant
level of internal pressure. This is, to some extent, achieved passively because of 1) the
viscoelasticity of detrusor muscles and 2) the stimulatory parasympathetic pathway
that is quiescent. During the storage of urine, distension of the bladder produces lowlevel bladder afferent firing. Afferent firing in turn stimulates the sympathetic outflow
to the bladder outlet (base and urethra) and pudendal outflow to the external urethral
sphincter. The responses occur by spinal reflex pathways and represent “guarding
reflexes”, which promote continence. Sympathetic firing also inhibits detrusor muscle
and transmission in bladder ganglia.
Voiding reflexes: at the initiation of micturation, intense vesical afferent activity
activates the brainstem micturation centre, which inhibits the spinal guarding reflexes
(sympathetic and pudendal outflow to the urethra). The pontine micturation centre
also stimulates the parasympathetic outflow to the bladder and internal sphincter
smooth muscle. Maintenance of the voiding reflex is through ascending afferent input
from the spinal cord, which may pass through the periaqueductal gray matter before
reaching the pontine micturation centre.
Figure 7. The mechanism of storage and voiding reflexes
22
Chapter 2
2.1.
Urinary incontinence in children
Terms and Definitions
Until recently many definitions have been used to define urinary incontinence. This
inconsistent terminology is not only confusing but it also complicates interpretation
and comparison of scientific data.
Therefore we use the new Standardized ICCS Terminology in this thesis.[17]
According to the new ICCS terminology document urinary incontinence means
uncontrollable leakage of urine which can be continuous or intermittent.
Continuous incontinence is a phenomenon that is almost exclusively associated
with congenital malformations, i.e. ectopic ureter, or iatrogenic damage to the external
urethral sphincter. This term is applicable to children of all age since even infants have a
filling and emptying cycle of their bladder and are dry between voiding.
Intermittent incontinence is urine leakage in discrete amounts. It can occur during
the day and/or the night, and is applicable to children who are at least 5 years old.
Enuresis means intermittent incontinence while sleeping.
Enuresis can be subdivided into:
1. monosymptomatic enuresis: enuresis in a child without any other Lower Urinary
Tract (LUT) symptoms
2. nonmonosymptomatic enuresis: enuresis in a child with other LUT symptoms,
such as day-time incontinence, urgency, holding manoeuvres, etc.
According to the onset of enuresis it can be subdivided into:
1. primary enuresis: enuresis in a child who has previously been dry for less than 6
months
2. secondary enuresis: enuresis in a child who has previously been dry for at least 6
months
Urinary incontinence may be due to disturbances of the filling phase, the voiding
phase or a combination of both. In the new ICCS terminology these conditions are
termed LUT conditions or functional bladder disorders.
The classification of daytime LUT conditions is not that straightforward. There’s a
considerable overlap between conditions, borderline cases are common and the
pathogenetic rationale for the grouping of various symptom complexes into specific
conditions is often not fully evidence based. Furthermore, there is often an evolution
in time.
23
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
24
Therefore ICCS advises to assess and document 4 parameters in these patients:
1. incontinence
2. voiding frequency
3. voided volume
4. fluid intake
These conditions are applicable from the age at which bladder control is attained or 5 years.
In order to achieve greater pathogenic and clinical relevance this is often more
important than to subgroup children into the various recognized syndromes listed
below.
The daytime LUT conditions:
1. Overactive Bladder: the condition afflicting patients experiencing urgency
symptoms and Urge incontinence: incontinence in patients experiencing
urgency. The term “overactive bladder” replaces the former “bladder instability”.
2. Voiding postponement: incontinence in the presence of habitual holding
manoeuvres
3. Underactive bladder: term reserved for children with low voiding frequency
and a need to increase intra-abdominal pressure to initiate, maintain or complete
voiding, i.e. straining. Replaces the term “lazy bladder”.
4. Dysfunctional voiding: the urethral sphincter is contracted during voiding. The
term cannot be applied unless repeat uroflow measurements show curves with a
staccato pattern or unless verified by urodynamic investigation.
5. Obstruction: due to a mechanical or functional, static or phasic impediment to
urine outflow during voiding. It is characterized by increased detrusor pressure and
a decreased urine flow rate.
6. Stress incontinence: leakage of small amounts of urine at exertion or at increased
intra-abdominal pressure for various reasons. It is rare in neurologically normal
children.
7. Vaginal reflux: toilet trained prepubertal girls who experience incontinence
in moderate amounts, consistently occurring within 10 minutes after normal
voiding, experience vaginal reflux if no underlying mechanism other than vaginal
entrapment of urine is obvious.
8. Giggle incontinence: is a rare syndrome in which apparently complete voiding
occurs specifically during or immediately after laughing. Bladder function is normal
when the child is not laughing.
9. Extraordinary daytime urinary frequency: this term applies to children who
void often and with small volumes during the daytime only. Daytime voiding
frequency is at least once hourly and average voided volumes are less than 50%
of EBC, usually much smaller. Incontinence is not a usual or necessary ingredient
in the condition and nocturnal bladder behaviour is normal for the age of the
child. The term is applicable from the age of daytime bladder control or 3 years.
Decreased daytime voiding frequency: three or less voidings per day
Increased daytime voiding frequency: eight or more voidings per day
Expected bladder capacity for age (EBC): age related expected maximum voided
volume, calculated via the formula (30 + (age in years x 30)) ml, and used as a standard
for comparisons. This formula is useful up to age 12 yeas, after which age expected
bladder capacity has to be around 300 ml.
Voided volume: voided volume at micturation, as documented in a bladder diary.
Replaces the term “bladder capacity”
Maximum voided volume: the largest voided volume, as documented in a bladder
diary. Replaces the term “functional bladder capacity”. Maximum voided volume is
considered small if found to be less than 65% of EBC and large if greater than 150% of
EBC.
Residual urine is the amount of urine left in the bladder immediately after voiding.
Normal residual volume is 0ml, while 20ml or more on repeat measurements is
pathological.
Polyuria is defined as a 24-hour output of more than 2 l/m² body surface area. This is
applicable in children of all ages.
Nocturnal polyuria is defined as nocturnal urine output exceeding 130% of EBC for
age.
In children with enuresis nocturnal urine output can be determined by measuring the
netto weight of the diaper increased with the volume of the first morning void.
Also for video-urodynamic findings terminology has changed. Instead of “detrusor
instability” the term “detrusor overactivity” is now recommended to describe the
cystometric observation of involuntary detrusor contractions during the filling phase.
Detrusor-sphincter dyssynergia defines the cystometric observation of a detrusor
voiding contraction concurrent with an involuntary contraction of the urethra.
Detrusor underactivity is the cystometric observation of detrusor contractions of
reduced strength and/or duration
2.2.
Prevalence
It is very difficult to determine the exact prevalence of urinary incontinence in children,
based on literature, due to the fact that different studies have used different definitions
and criteria.
25
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
As most studies do not look for the type of daytime incontinence, i.e. filling or emptying
problems, only a general prevalence concerning daytime incontinence can be
estimated without going into pathophysiological details.
In normal, non-developmentally challenged children, daytime or combined daytime
and night-time incontinence, at least once a week, occurs in about 2-4 percent of
7-year old children and is more common in girls than in boys. [18, 19]
Overall prevalence varies from 1 to 20 percent. In general for 6-7 year old children it is
between 2 and 4 percent, and rapidly decreases during the following years.[19-29]
The prevalence of enuresis in 7-year old children varies between 5 and 10 percent. [28,
30-36]
This decreases to between1.2 and 4.7 percent at the age of 11 to 12 years. [28, 31, 33, 34, 36-40]
At the age of 16 to17 years a further decrease is seen to 0.5 -1.1%.[28, 41, 42] Children with
the severest form of bedwetting are likely to persist with the problem and to have the
more complex form (non-monosymptomatic) [43]
Daytime incontinence is more frequent in girls (female: male ratio 1.6), enuresis is more
frequent in boys (male: female ratio 1.6) [19, 30, 44]
Although spontaneous resolution of enuresis and urinary incontinence during daytime
has been documented in the previous studies, these problems may persist in some
cases.
Enuresis is found in 0.5% of the adults.[45] This means that 5% of the children suffering
enuresis are at risk for life-long problems if not treated adequately during childhood.
The spontaneous cure rate is estimated to be 14% annually between 5 and 9 years age
and 16% between 10 and 19 years.[46]
Swithinbank et al. found a prevalence of daywetting in 12.5% of the children at the age
of 10-11 years which decreased to 3% at the age of 15-16 years.[42] This means that the
prevalence of daytime incontinence diminishes by 1-2% per year.
In developmentally challenged children, i.e. mentally and/or motor disabled patients,
the incidence of urinary incontinence is higher than in the normal population.
In literature a wide variation of prevalence has been described, varying between 23%
and 86%. [18, 47-58] This is due to the fact that a lot of these studies were performed on
a small population and because the included patients were inadequately categorized
without taking into account the pathophysiology, age, mental and motor development
and type of incontinence. We described in our studies that between 39.6% and 47.4%
of the developmentally challenged children have achieved continence spontaneously.
[59]
No significant differences in continence pattern was found between those who
were mentally, motor and mentally and motor disabled.
26
Based on the publication of von Wendt L. et al. 7-year old children with mild mental
retardation differ relatively little from healthy children with respect to enuresis, i.e.
11.1% versus 9.8%. On the other hand the prevalence of daytime incontinence (16.7%)
is significantly higher in those children suffering mild mental retardation than in the
normal population (3.4%).[48]
The prevalence of urinary incontinence is directly related to the degree of mental
development. The more severe the mental retardation the higher the prevalence of
urinary incontinence. [48, 55, 60]
Not only intellectual capacity, but also the motor capacity is correlated with the
development of continence. The more immobile the higher the prevalence of urinary
incontinence.[49, 53]
Also in developmentally challenged children spontaneous cure of enuresis and
daytime urinary incontinence has been described, though less frequent than in the
normal population. The study of von Wendt et al. illustrates that only in the mild mental
retarded children an equal cure pattern for enuresis is found as in normal children. The
prevalence of daytime incontinence remains even in the mild mental retarded children
higher than in the normal population. The more severe the retardation the higher the
risk of persisting enuresis and urinary incontinence during the day.[48]
2.3.
Pathogenesis
2.3.1. Pathogenesis of urinary incontinence
Urinary incontinence in children may be caused by a congenital anatomical anomaly
such as exstrophia vesicae, epispadias or ectopic ureter, iatrogenic such as a trauma
to the sphincter or neurological such as myelomeningocoele. These causes are not
discussed in this thesis.
In the majority of incontinent children no obvious reason for this incontinence can be
given and they suffer so called “idiopathic” or “functional” incontinence. This functional
urinary incontinence may be caused by disturbances of the filling phase, the voiding
phase or a combination of both. [61]
2.3.1.1 Over active bladder
Detrusor overactivity is the most common cause of LUTS in children. In the study of
Ruarte et al. up to 57.4% of the incontinent children suffered overactive bladder.[62] It
appears to have a peak incidence between ages 5 to 7 years. [63]
Overactive bladder is not completely understood and it is thought to be a multifactorial
problem.
27
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
The higher cortical centres in the brain, pons, spinal cord, the peripherical autonomic
somatic and sensory afferent receptors in the lower urinary tract as well as anatomical
components of the lower urinary tract are involved in micturation. Overactivity of the
bladder can be caused by disturbance of one or more of these elements.
For many years it was thought that myogenic abnormalities were the primary cause
of overactive bladder. Nowadays new insights rather see this myogenic problems as a
consequence of a neurological or a anatomical obstructive pathology.[64]
Bladder control is believed to be under influence of the central nervous system. The
pontine region is considered to be responsible for detrusor sphincter coordination and
the cortical area is responsible for detrusor overactivity control.[65]
The prevailing theory is that overactive bladder is due to a delay in the acquisition of
cortical inhibition over uninhibited detrusor contractions in the course of achieving the
mature voiding pattern of adulthood. The site of maturational delay is thought to lie in
reticulospinal pathways of the spinal cord or it could be in the inhibitory centre in the
cerebral cortex.
Thus bladder maturation follows maturation of cortical inhibition processes.
In his paper Franco I. concludes that we probably have to move away from the
vesicocentric thinking towards a corticocentric mode of thinking to explain detrusor
overactivity. As such detrusor overactivity may be the results of a centrally located
dysfunction affecting bladder, bowel, sexual function and even mood and behaviour.[64,
66]
Functional MRI future studies will probably illuminate this enigma.[67]
The concept of delay of maturation of cortical control in ideopathic detrusor overactivity
(IDO) in children seems to be incorrect but more complex central nervous system
mechanisms could be at the base of this problem. Concepts of feed forward loops from
the generation of a high pressure system during voiding or filling are more frequently
described in animal experiments. Both the interplay of neural drive with motor control
and the dynamic nature of the growing bladder could be causative. This in contrast
to the adult population where detrusor overactivity is considered a chronic condition
whose origin is unrelated to functional use. There is no long-term data to determine
if childhood detrusor overactivity predicts detrusor overactivity during adulthood.[65]
Some rare longitudinal studies show a link between paediatric LUTS and adult LUTS,
where adults with a history of paediatric LUTS have a higher risk to develop LUTS in
adulthood.[68] Others have shown that adults with LUTS and a history of childhood LUTS
often have more severe symptoms.[69]
The term detrusor overactivity is used to describe the symptom complex of urgency,
with or without urge incontinence. This urge syndrome is characterized clinically by
frequent episodes of an urgent need to void, countered by contraction of the pelvic
28
floor muscles and holding manoeuvres, such as squatting and the “Vincent curtsey
sign”. The symptoms arise from detrusor overactivity during the filling phase. These
involuntary detrusor contractions are countered by voluntary contraction of the pelvic
floor muscles to postpone voiding and minimize wetting.
It is thought that active external sphincter contraction may cause a temporary reflex
relaxation in the detrusor, therefore, affording momentary relief from the effects of
uninhibited bladder contractions. Persistent isometric contractions of the detrusor
against the tightened sphincter or incomplete sphincter relaxation lead to detrusor
hypertrophy. This hypertrophy leads to a gradual decrease in maximum voided volume
and increased detrusor overactivity, creating a vicious cycle. [64]
Both the detrusor contraction and the increased activity of the pelvic floor muscles can
be registered urodynamically.
It has been postulated that such a strong bladder and pelvic floor muscles contractions
can damage the bladder mucosa. Some of these children may note suprapubic
or perineal pain. Hoebeke et al. described a cohort of patients suffering nighttime
pain syndromes based on pelvic floor spasms. Pelvic floor relaxation feedback was
successfully used in these patients. [70]
Mucosal damage due to decreased blood flow and relative hypoxia during the periods
of increased detrusor pressure during the involuntary overactive detrusor contractions
may lead to UTI’s. Up to 60% of the children with UTI’s suffer detrusor overactivity. [71]
During the contraction of the overactive detrusor the bladder neck is opened and urine
flows into the proximal urethra. Due to the “milk-back phenomenon” contaminated
urine flows back into the bladder during the contraction of the pelvic floor muscles.
This may cause UTI’s. [72-74]
Even in continent children with recurrent UTI’s and vesicoureteral reflux, over active
bladder should be considered. The factor incontinence is often masked by the
inadequate fluid intake in these patients.
Several authors have confirmed the relationship between detrusor overactivity and
vesicoureteral reflux. [2, 75, 76] Koff demonstrated that the treatment of detrusor overactivity
reduced the incidence of infection and increased the rate of reflux resolution.[77]
Constipation and faecal incontinence are often diagnosed in children with over active
bladder.[77, 78] Koff et al. demonstrated that constipation and bowel distension may lead
to deformation of the bladder, which in turn may lead to detrusor overactivity and thus
to urinary incontinence.[77] Söderstrom et al. in a cohort study of all schoolchildren in
the first and fourth grade, including 2222 students, demonstrated that children with
daytime incontinence often have faecal soiling and vice versa, whereas bedwetting
29
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
and faecal incontinence have little or no association.[29] The study from Mc Grath et al.
showed that, also in enuretic children, up to 36.1% were identified as constipated by the
clinician-based scoring method.[79] They should be classified as non monosymptomatic
nocturnal enuresis.
2.3.1.2 Dysfunctional voiding
Dysfunctional voiding refers to the inability of the urinary sphincter or pelvic floor
muscles to relax completely during voiding. There are no clear data on the possible
causes of dysfunctional voiding. There is no identified underlying neurologic
abnormality. In neurological conditions this same inability of the sphincter to relax
during voiding is well known and described as detrusor sphincter dyssynergia.
Without overt neuropathy, overtraining of the pelvic floor muscles may be at the origin of
dysfunctional voiding.[80] This overactivity of the pelvic floor muscles, with a subsequent
insufficient relaxation during voiding, may be caused by detrusor overactivity.[81]
Insufficient relaxation of the pelvic floor muscles may also be a learned condition. Too
strict toilet training programs, constipation, episodes of dysuria and sexual abuse have
been described as possible aetiology.
Poor toilet conditions and privacy issues have also been identified as possible causes.[82]
In some girls an anatomical anomaly of the external meatus may be the reason of
dysfunctional voiding. Anterior deflection of the urine stream causes a stimulation
of the clitoris with subsequent reflex activity of the bulbocavernosus muscle causing
intermittent voiding.[83]
Children suffering dysfunctional voiding usually present with urinary incontinence,
urinary tract infections and constipation.
During repeated uroflowmetries they demonstrate fluctuating or intermittent uroflow
patterns.
Bladder volume is usually larger than age-expected capacity. Residual urine is often
present. Detrusor overactivity may be seen but may also be absent.
Initially children with dysfunctional voiding often show signs of the “compensatory”
overactivity of the bladder along with poor emptying ability, such as: small bladder
capacity, increased detrusor thickness, decreased detrusor contractility, impaired
relaxation of the external urinary sphincter and pelvic floor muscles during voiding,
weak or interrupted urinary stream and large post-void residual urine. Secondary
vesicoureteral reflux, faecal incontinence or constipation may also occur.[84, 85]
30
On the long term, routine incomplete emptying of the bladder can progress to detrusor
over-distension associated with chronic urinary retention, the so called detrusor
underactivity.
This so called dysfunctional voiding cycle in which children evolve from overactive
bladder along dysfunctional voiding to underactive bladder has been documented but
is not applicable to all children with these problems. In a large study of our group on
urodynamics in children with functional voiding disorders we found that children with
dysfunctional voiding are younger than those with OAB, which is an argument against
this dysfunctional voiding cycle.[84]
As mentioned by Chiozza et al. urinary symptoms associated with dysfunctional voiding
range from urgency to complex incontinence patterns during day and night.[86]
Symptoms of dysfunctional voiding are significantly more common in children suffering
Attention Deficit Hyperactivity Disorder. [87, 88]
The incidence of vesicoureteral reflux is higher in children with dysfunctional voiding
than in children with normal voiding. Moreover it concerns more frequently high
degree vesicoureteral reflux.[84, 89]
Urinary tract infections and kidney damage are common sequels of dysfunctional
voiding.[90]
2.3.1.3 Underactive detrusor
Children with an underactive detrusor usually present with urinary incontinence and
urinary tract infections. They typically demonstrate low voiding frequency and an
inability to empty their bladder using the detrusor contraction alone. They often have
to use abdominal straining to empty their bladder. Voiding time is prolonged, with low
pressure and intermittent.
Urodynamic evaluation is the only way to diagnose this condition. On urodynamics
the bladder has a larger than normal capacity, a normal compliance and a reduced or
absent detrusor contraction during voiding. Abdominal straining is often necessary to
void.
2.3.1.4 Voiding postponement
Children postpone imminent micturation until overwhelmed by urgency, resulting in
urge incontinence.
Voiding postponement is characterized by the clinical symptom of wetting associated
with repetitive delay of micturation and low voiding frequency, which can be readily
diagnosed by history and flow charts.[91]
31
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Uroflowmetry is usually normal in voiding postponement. Lettgen found only 20%
of the patients with voiding postponement had a fluctuating voiding pattern. A
higher incidence of clinically relevant behavioural symptoms, especially attention
and delinquent problems, was found in the voiding postponers compared to patients
suffering OAB.[91]
2.3.1.5 Giggle incontinence
Giggle incontinence is characterised by a partial to complete bladder emptying
provoked by laughing. This may continue into the children’s teenage years, and
intermittently into adulthood. It occurs in girls and occasionally in boys and is generally
self-limiting.
The aetiology of giggle incontinence is not defined.
Urodynamic studies do not show any abnormalities, there is no anatomic dysfunction,
there are no neurologic anomalies, the upper tracts appear normal on ultrasound and
urinalysis is normal. [92, 93]
It is postulated that the giggle incontinence can be due to the fact that laughter
induces a generalized hypotonic state with urethral relaxation. However this effect has
not been demonstrated on either smooth or skeletal muscle.
Others have suggested that giggle incontinence is due to laughter triggering the
micturation reflex and overriding inhibitory mechanisms. One small study hinted at an
association with cataplexy.[94] The latter probably explains why methylphenidate was
found to be a viable treatment option for giggle incontinence.[94, 95]
2.3.1.6 Vesicovaginal reflux
Vesicovaginal reflux may be the cause of urinary leakage that occurs in girls a short
time after voiding to completion. In most cases the leakage is only a few millilitres. It is
a common cause of urinary leakage in schoolgirls. In their study performed on a group
of 169 girls referred to a specialist clinic because of daytime incontinence, Mattsson
et al. found that in more than 10% of these girls, vesicovaginal reflux was the causal
problem. [96]
Urine may become entrapped in the vagina due to labial adhesions, a funnel shaped
hymen, or an inappropriate position on the toilet.
Hoebeke et al. demonstrated that meatal anomalies may cause vaginal voiding but the
issue is still controversial.[83]
Obesity may be an associated risk factor.[65]
32
2.3.1.7 Dysfunctional elimination syndrome
The term dysfunctional elimination syndrome is used to describe dysfunctional
emptying of bowel and/or bladder with symptoms of detrusor over activity, constipation
and infrequent voiding.
Children with a dysfunctional elimination syndrome commonly complain of urinary
incontinence, non-monosymptomatic enuresis, recurrent urinary tract infections,
imperative urgency to void and exceptional urinary frequency. [97] Even idiopathic
urethritis in childhood has been related to dysfunctional elimination syndrome.[98]
On investigation they often have poor voiding efficiency, vesicoureteral reflux,
constipation, faecal incontinence, no regular bowel routine and infrequent toileting.
It is seen more frequently in girls. The incidence is unknown. [99]
The dysfunctional elimination syndrome is significantly associated with the presence of
vesicoureteral reflux and urinary tract infections. It has been reported that VUR is slower
to resolve and breakthrough UTI are significantly more common in children suffering
the dysfunctional elimination syndrome. [77, 100-104]
A study by Bower W.F. et al showed that childhood lower urinary tract dysfunction may
have a negative impact on bladder and bowel function in later life.[97]
The genitourinary tract and the gastrointestinal system are independent, sharing the
same embryologic origin, pelvic region and sacral innervation. Until recent the coexistence of voiding disturbances and bowel dysfunction was considered coincidental.
Now it is accepted that, in the absence of anatomical abnormality, they are interrelated. The common neural pathways, or the mutual passage through the pelvic
floor musculature, may provide a theoretical basis for this relationship, as may be the
acquisition of environmental and developmental learning. The latter can be influenced
by episodes of urinary tract infections, constipation, anal pain or trauma and poor toilet
facilities.[78, 82, 105]
Abnormal recruitment of the external anal sphincter during defecation or at call to
stool is considered causative, in that it elicits concomitant urethral sphincter and pelvic
floor co-contractions. Thus in both systems a functional obstruction to emptying is
generated. In the case of the urinary system, high pressure generated by the detrusor
muscle to overcome decrease in urethral diameter can stimulate detrusor hypertrophy,
detrusor overactivity, and lead to incompetence of vesicoureteric junctions. In the
early stages of defecation disorders, bowel emptying is incomplete, infrequent and
poorly executed. As the dysfunction progresses stool quality becomes abnormal, the
child develops distension of the rectum and descending colon, seems to lose normal
sensation and develops faecal retentive soiling. If constipation was not present as a
predisposing factor, it rapidly develops.[105]
33
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
2.3.2. Pathophysiology of monosymptomatic enuresis
Three mechanisms are recognized as pathogenetic factors in enuresis:
polyuria during sleep: due to a lack of arginine vasopressine (AVP) release or
response, or relative increased solute excretion during the night [106-108]
■■
reduced bladder capacity and/or detrusor overactivity [109]
■■
disturbed arousal mechanisms: inability to wake from sleep when the bladder is full
or empties too early [110-112]
It is the interaction of at least two of this factors that is responsible for enuresis
■■
2.3.2.1 Increased nocturnal urine output – nocturnal polyuria
Humans have a circadian rhythm of urine output resulting in a nocturnal reduction
in diuresis to approximately 50% of daytime levels and a corresponding increase of
urine osmolality during sleep.[113-115] Infants still have an immature circadian rhythm of
several vital functions including sleep and renal function (solute and water-excretion).
Vande Walle et al. illustrated that development of a proper circadian rhythm of the
renal function is a maturation effect. [116] The decrease in nocturnal diuresis is largely
attributed to nocturnal release of arginine vasopressine (AVP) that regulates free water
excretion. [117] Several authors questioned these findings, but a recent study by Rittig et
al. confirms the importance of a circadian rhythm of vasopressin. [106] This subtype of
patients is likely to be desmopressin responders, indirectly confirming the vasopressin
theory. Whether the low nocturnal vasopressin level is the primary defect or a secondary
compensatory phenomenon remains unclear.
In children this hormonal release causes an increased urine concentration and reduced
urine volume during sleep. This is why non-enuretic children sleep through the night
without wetting their bed.
The circadian rhythms in urine output are fully developed at the age of three and
remain unchanged at least until puberty.[117]
Two thirds of the children with mono-symptomatic enuresis have a lack of circadian
rhythm of vasopressin release, resulting in a high nocturnal diureses, exceeding the
bladder capacity.[107, 118, 119] A study by Devitt indicated that 18 percent of children have
normal levels of plasma vasopressin release but remain enuretic.[119]
A small group of mono-symptomatic enuretic children are only partially responding to
desmopressin.[120]
Our own findings demonstrated that, at least for the population with desmopressin
resistant nocturnal polyuria, pathogenesis might be more complex. We have
documented absent circadian rhythm of glomerular filtration [121], abnormal circadian
pattern in calciuria[122], abnormal circadian rhythm of renal tubular sodium handling
[122]
and increased osmotic excretion overnight to be causes of nocturnal polyuria.
34
Nocturnal polyuria due to disturbed osmotic and sodium excretion during the day
might be successfully treated with furosemide administered in the morning.[123]
Rittig et al. reported on the importance of a circadian rhythm of bloodpresssure. Several
vasoactive hormones, such as angiotensine II, aldosterone and natriuretic peptides
play a role in the regulation of solute excretion. All of these hormones have a circadian
rhythm.[124] Their role in the pathogenesis of nocturnal polyuria, in contrast to that of
prostaglandins, remains to be elucidated. The role of an abnormal circadian rhythm of
prostaglandins in persistent nocturnal polyuria was documented by Kamperis et al.[117]
Overall control of these physiological circadian rhythms is achieved through an internal
biological clock in the suprachiasmatic nucleus of the anterior hypothalamus.[125] In
addition, the supine position, reduction in activity, and the altered hemodynamic and
sympathetic system status during sleep also add to the complexity of the process. [126,
127]
Nocturnal urine output varies from night to night.[128] Long-term home recordings in
enuretic children demonstrated that nocturnal polyuria is only present on wet nights,
whereas the nocturnal urine production on dry nights is significantly lower or normal.
[129]
The nocturnal polyuria is higher in children with enuresis who respond best to
desmopressin (dDAVP).
By the time the child becomes adolescent, the circadian rhythm becomes less
prominent. In adolescents and adults with enuresis there is no diurnal rhythm of plasma
vasopressin concentration. The changes in nocturnal diureses occur from a decrease in
the urinary sodium excretion that is not due to differences in concentration of AVP but
due to lack of sensitivity to AVP with resultant increased urine output. [106, 130]
There may be a small sub-group of children with impaired renal sensitivity to vasopressin
or desmopressin.[107, 131]
2.3.2.2 Reduced bladder capacity and/or detrusor overactivity
An overactive detrusor was believed to be characteristic for non-monosymptomatic
enuresis. For a long time it was thought that bladder function was normal in
monosymptomatic enuretic children. Norgaard et al. challenged this theory. They
described detrusor overactivity during artificial nighttime bladder filling. [132] Watanabe
et al. discovered that 32 percent of the children suffering enuresis had detrusor
overactivity resulting in bedwetting on cystometry performed during sleep.
It was accepted that the bladder capacity of enuretic children was smaller than that of
dry children. Logically, a reduced maximum voided volume should be an important
cause of nocturnal enuresis. Review of the literature shows conflicting data. Some
studies confirmed this hypothesis [109, 133], others reported no differences in bladder
capacity in children with enuresis compared to age-matched dry children.[134]
35
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Most of the studies on bladder capacity and enuresis neglected circadian changes in
bladder reservoir function. Maximum voided volume varies between night and day
in normal children. Nighttime maximum voided volume is 1.6-2.1 times larger than
daytime maximum voided volume.[135]
C.K. Yeung et al. demonstrated that a reduction in nocturnal maximum bladder
capacity appears to be a common factor, probably the main cause of a mismatch
between nocturnal urine output and bladder storage capacity in patients with severe
bedwetting refractory to treatment. This reduction in nocturnal maximum bladder
capacity may occur only after sleep at night in association with the appearance of
detrusor overactivity in children with normal daytime urodynamics and maximum
voided volume, or may be a manifestation of occult voiding dysfunction or bladder
outlet obstruction that affects the bladder reservoir function both day and night. [136]
Troup et al. demonstrated that this difference in maximum voided volume in enuretic
children and dry children is functional and not anatomical.[137]
This reduced maximum voided volume, when smaller than 70% of the expected bladder
capacity for age, is likely to result in poor response to the treatment with dDAVP. [138]
Ultrasound studies of the bladder revealed an increase in bladder wall thickness in
children suffering enuresis. [139] According to the study of Sreedhar et al. increased
bladder wall thickness and reduced maximum voided volume predicted the response
to therapy in children with primary nocturnal enuresis.[140]
Bower et al. demonstrated that adults with refractory monosymptomatic nocturnal
enuresis showed significantly higher childhood scores of urgency, frequency, urge
incontinence, infrequent voiding and small voided volumes. [69] This suggest that in
adolescents and adults the bladder component plays an important role in enuresis as
these populations do not show the nocturnal polyuria problem seen more commonly
in younger children.
2.3.2.3 Sleep, arousal and CNS function
Nocturia and enuresis are due to the fact that the bladder fills to its capacity during
sleep and that there is a need to empty the filled bladder. Polyuria and/ or reduction of
the bladder capacity, due to detrusor overactivity, during sleep do not explain why the
enuretic child doesn’t wake up from the sensation of a full or contracting bladder. So
enuresis results from the child’s inability to wake up from sleep to empty the bladder
in a proper way.
Enuretic children are often reported to be deep sleepers, difficult to arouse at night.[112,
141]
36
Wolfish et al. found that enuretic children wet most frequently during the first two thirds
of the night, and that arousal attempts were less successful in children with enuresis
than in normal children.[110, 142]
Using EEG recordings during sleep, Watanbe et al. found that full bladder signals
were insufficient to wake children with enuresis completely, leaving them in a drowsy
condition while bedwetting.[143]
The observation by C.K. Yeung et al of detrusor overactivity appearing only after sleep
at night in some children with normal daytime urodynamics may also be related to
a deficiency of inhibitory signal processing in the brainstem that accounts for the
inability to inhibit both detrusor activities and micturation during sleep.[109] Theoretically
neurological impairment of a tiny brain area in the vicinity of the pontine micturation
centre, the posterior hypothalamus (responsible for secretion of antidiuretic hormone)
or the locus coeruleus which may be the cortical arousal centre could be the anatomical
location of most pathophysiological described mechanisms for nocturnal enuresis.[144]
According to these findings Yeung et al. questioned the classic deep sleep theory. They
found evidence of disturbed superficial sleep in children with enuresis. Children had
more light sleep associated with frequent cortical arousals but were unable to awaken.
Dhondt et al. found evidence of disrupted sleep architecture in children with refractory
nocturnal enuresis, with a high incidence of periodic limb movements during sleep at
night and increased cortical arousability leading to awakening. These results are also in
contrast with the classical accepted deep sleep theory.[145]
Other investigators observed a reduced prepulse inhibition of startle in enuretic
children, suggesting a dysfunction of the pedunculopontine tegmental nucleus might
be a reason for nocturnal enuresis.[146-148]
2.3.2.4 Genetic factors
Genetic studies illustrated that multiple genes may be involved in enuresis. Four gene
loci, 8, 12, 13 and 22 have been identified and the existence of others is presumed. [149]
This illustrates the locus heterogeneity.
Most commonly, nocturnal enuresis is inherited via an autosomal dominant mode of
transmission with high penetrance. No clear association between mode of inheritance
and specific phenotype was found. In fact, nocturnal enuresis as well as urinary
incontinence during day and night seems to have a comparable risk.[149, 150]
Loeys et al. confirmed a linkage of nocturnal enuresis to a region on chromosome
22q11, 13q13-14 and 12q. The results of this study support the hypothesis of genetic
and phenotypic heterogeneity of nocturnal enuresis mentioned by von Gontard et al.
[150-152]
37
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
According to von Gontard et al. certain syndromes of daywetting follow their own
genetic mechanisms. The association with the genetics of nocturnal enuresis is
unknown.[149]
2.3.3. Comorbidity
2.3.3.1 Constipation and faecal incontinence
The interrelation between GU and GI systems has been described before.
Constipation and faecal incontinence is common in children with urinary incontinence
and enuresis.[26, 79] The reported prevalence of constipation among enuretic children
ranges from 7.06% to 69.8%.[153, 154] Koff et al. demonstrated that constipation and bowel
distension may lead to deformation of the bladder, which in turn may lead to detrusor
overactivity and thus to urinary incontinence.[77] Söderstrom et al. demonstrated that
children with daytime incontinence often have faecal soiling and vice versa.[29]
2.3.3.2 Psychological and social disturbances
According to Jainson et al. children with daytime wetting have a higher risk of parentreported psychological problems than children who have no daytime wetting. The
reported rates of attention and activity problems (24.8%), oppositional behaviour
(10.9%), and conduct problems (11.8%) in daytime wetting children were around twice
the rates in children without daytime wetting.[155]
In a study by von Gontard et al. 40% of the children with enuresis had clinically
significant behavioural problems, according to the child behavioural checklist and
psychiatric diagnosis.[156]
Children with secondary nocturnal enuresis and voiding postponement carry the
highest risk for a mental disorder and those with urge incontinence and primary
monosymptomatic nocturnal enuresis the lowest. Internalizing disorders (such as
depressive and anxiety disorders) are less common than externalizing ones (such as
ADHD) In addition, subclinical emotional and behavioural symptoms are common.
These will often recede upon attaining dryness and self-esteem can increase.[157]
2.3.3.3 Attention Deficit Hyperactivity Disorder (ADHD)
There is ample evidence for a higher ADHD prevalence in children with enuresis than in
a comparison group without continence problems and up to 32% of the children with
ADHD show urinary problems.[87, 158-161]
Kodman-Jones et al. found an incidence of ADHD in daytime wetting children without
infection of 21% which is higher than the 3 to 5% found in the general population.[162, 163]
Baeyens et al. found that the prevalence of ADHD is significantly higher, up to 40%, in
children suffering nocturnal enuresis. Moreover, they found that the older the children,
38
the higher the prevalence of the inattentive subtype. According to organic parameters,
no difference was found between the enuresis group and the children with associated
diurnal symptoms, except for a slightly higher incidence of nocturnal polyuria in
children with an ADHD hyperactive/impulsive subtype. The data of this study indicate
that despite the high incidence of ADHD in enuretic children, ADHD is not associated
with a single phenotype of enuresis.[164]
Crimmins et al. found the treatment of urinary incontinence in children with ADHD
to be impaired, compared to those without ADHD. Moreover, treatment seems to be
directly affected by compliance and IQ.[165]
Further studies by Baeyens et al. indicated children with ADHD to be at risk for persistent
enuresis.[162, 166]
Startle eyeblink modification (SEM) research by Baeyens et al. showed a brainstem
inhibition deficit in children with enuresis. This could explain why these children
are unable to stay dry at night. Moreover, children with ADHD-IA fail to optimalize
sensory gating. In children with enuresis, this can result in an impairment of stimulus
identification leading to an inadequate or absent arousal effect. This additional
impairment might explain why the combination of enuresis with ADHD-IA is more
prevalent in older, therapy-resistant children.[167]
2.3.3.4 Upper airway obstruction.
Upper airway obstruction is a common problem in healthy children. Due to glossoptosis
and neuromotorical failure it is an even more common problem in disabled children
suffering cerebral palsy, Down syndrome and Prader-Willi syndrome. [168, 169]
Children with upper airway obstruction do have a higher incidence, up to 42%, of
nocturnal enuresis and upper airway obstruction is very common, up to 65.6%, in
children suffering nocturnal enuresis. [168-170] Several explanations, such as increased
bladder pressure due to increased respiratory efforts against obstructive airways,
decreased levels of antidiuretic hormone and increased levels of atrial natriuretic
peptide in patients with obstructive sleep apnoea have been mentioned in literature.
[170]
Complete resolution of nocturnal enuresis after adenotonsillectomy was found in 33%
to 63% of the patients. [170-172] Firoozi et al. even found an additional decrease in daytime
urinary frequency and episodes of incontinence. The mechanism of the latter remains
unclear. [170]
39
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Chapter 3
3.1.
Mental and Motor disabilities
Definitions
3.1.1. Mental retardation
Mental retardation is a state of functioning that begins in childhood and is characterized
by limitations in intelligence and adaptive skills. [173] Two definitions are commonly used.
One is published by the Diagnostic and Statistical Manual (DSM) IV and the other by the
American Association on Mental Retardation (AAMR).
3.1.1.1 DSM definition
DSM IV defines Mental Retardation by three co-existing criteria:
Significant sub-average intellectual functioning
■■
Adaptive functioning deficit or impairment
■■
Onset before 18 years of age
The severity of cognitive impairment is characterized by the extent of deviation of
the IQ below 100, the estimated mean for the population. The lower limit of normal is
considered to be two standard deviations below the mean or an IQ of 70. Gradations of
severity include IQs in the following ranges:
■■
Mild: from between 50 and 55 to approximately 70
■■
Moderate: from between 35 and 40 to between 50 and 55
■■
Severe: from between 20 and 25 to between 35 and 40
■■
Profound: from < 20 to 25
■■
Unspecified: not testable but presumed low
Adaptive skills are skills of daily living that are needed to live, work and play in the
community. They include communication, social and interpersonal skills, self-care,
home living, use of community resources, self-direction, functional academic skills
(reading, writing and basic mathematics), work, leisure, and health and safety. Adaptive
functioning is considered to be impaired when there is a deficit in at least two of these
areas compared to children of the same age and culture.[174]
■■
3.1.1.2 AAMR definition
The DSM IV definition has been expanded by the American Association of Mental
Retardation (AAMR) to reflect the personal functioning of a child within the context of
community environment, peers, and culture, and incorporates a description of supports
that are needed in the context of a child-community functional fit. According to AAMR
definition, “mental retardation is a disability characterized by significant limitations both
in intellectual functioning and in adaptive behaviour as expressed in conceptual, social,
and practical adaptive skills” with onset before 18 years of age. Limitation in intellectual
40
ability corresponds to an IQ less than 70 to 75. The AAMR describes the pattern and
intensity of supports as intermittent, limited, extensive, or pervasive.
A number of assumptions are essential to the application of the AAMR definition:
Limitations in function must be assessed relative to the child’s age, culture and
environment
■■
A valid assessment considers differences in language and culture, as well as those in
communication, motor, sensory, and behavioural factors
■■
Individuals often have strengths as well as limitations
■■
An important purpose of characterizing limitations is to identify supports that are
needed
■■
Providing appropriate individualized support over a sustained period usually will
improve the life functioning of a person with mental retardation.[173]
Children with mild or moderate mental retardation are educable or at least trainable,
whereas children suffering severe and profound mental retardation are considered to
be non-trainable.[175]
■■
Mental disorders affect approximately 30 to 70% of children with mental retardation,
which is up to 5 times more than non-retarded children.[176] Commonly associated
mental disorders are: autism and autistic spectrum disorder, Attention Deficit
Hyperactivity Disorder (ADHD), eating disorders, depression and anxiety.[177]
3.1.2. Motor disability
Motor disabilities are disabilities that affect a person’s ability to learn motor tasks (moving
and manipulating objects) such as walking, running, skipping, sitting, handwriting and
others. To be considered a disability, the problem must cause a person to have motor
coordination that is significantly below what would be expected for age, and the
problem must interfere with the activities of learning and daily living.
3.2.
Incidence and aetiology of developmental disabilities
Mental retardation is a common problem. Up to 10% of the school-aged children are
learning impaired and as many as 3% of the children in the US manifest some degree
of mental retardation. A study performed in Aberdeen, Scotland, showed that the
prevalence of mild mental retardation is about 1/77 and of severe mental retardation
is 1/300.[175] For the vast majority of individuals with mental retardation (45-63%) no
aetiology is identifiable.[178] More than 800 recognized syndromes are associated with
mental retardation, of which Trisomy 21 or Down Syndrome is certainly the best known.
Environmental factors, such as Foetal Alcohol Syndrome and peri- and postnatal
conditions, such as CMV, rubella and hypo-ischemic encephalopathy, may also be
responsible for mental retardation.[175]
41
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
The second most important cause of developmental disability is cerebral palsy.
Cerebral palsy is a non-progressive injury of the brain occurring in the perinatal period
that produces a neuromuscular disability or a specific symptom complex or cerebral
dysfunction.
The incidence of cerebral palsy is about 1.5 per 1000 births.[179]
Twenty percent of the mental retarded individuals suffer cerebral palsy, and 50% of the
cerebral palsy patients are mentally disabled. [175, 180]
3.3.
Pathophysiology of urinary incontinence in
developmentally challenged children
To develop continence several conditions, such as physical maturation of the bladder
and the neurological system, and a normal development of the mental and motor
capacity are required.
3.3.1. Dysfunction of the lower urinary tract
Several studies documented dysfunction of the lower urinary tract as an aetiological
factor of incontinence in children with a developmental disability.
Decter et al. performed an urodynamic evaluation in 57 patients suffering cerebral
palsy and urinary problems. Eighty-six percent of the patients were found to have a
“partial upper motor neuron lesion, 9.5% had a mixed upper and lower neuron lesion
and 1.5% showed an incomplete lower motor neuron lesion. Only 3% had a normal
urodynamic investigation.[54]
Other studies confirmed the high incidence of overactive detrusor in incontinent
developmentally disabled children.[55, 181]
In neurologically normal children (3-16 years old) the incidence of overactive detrusor
varies between 47% and 57%, which is significantly lower than the 74% up to 97%
found in developmentally challenged children.[55, 182-184]
Mayo et al. stated that in 50% of the children who suffered difficult voiding, this was due
to a failure of pelvic floor relaxation rather than to dysfunctional voiding.[47]
On the contrary Bross et al. showed an overactive detrusor and dysfunctional voiding
in 28 of the 29 patient that underwent an urodynamic investigation. Only 1 patient had
a normal urodynamic pattern.[184] Interestingly these pathological urodynamic findings
can be found in both symptomatic and asymptomatic patients, and as such are not
representative for the severity of complaints.[185]
42
The type of damage responsible for urinary incontinence in cerebral palsy patients
seems to be localized anatomically above the brainstem for those suffering detrusor
overactivity and coordinated sphincter. It was suggested that disturbed modulating
effects on autonomic function due to brain lesions in children with cerebral palsy
might account for overactive bladder. [186] Spinal cord damage might account for those
individuals with cerebral palsy suffering dysfunctional voiding. This lumbosacral cord
damage is probably due to severe anoxia.[54]
3.3.2. Reduced bladder capacity
Reduced bladder capacity is another major factor in the pathophysiology of urinary
incontinence in physically and intellectually disabled children. Several studies illustrated
that 75% up to 92% of these children have a too small bladder capacity.[47, 54, 55, 60, 187]
Both neurological involvement of bladder function leading to hyperreflexia of the
detrusor and low compliance, and restricted fluid intake because of swallowing
problems in some and nursing habits in most of these children could be at the origin
of this phenomenon.
3.3.3. Mental development
Mental development certainly plays a role in achieving continence. Children with mild
mental retardation seem to differ relatively little from healthy children with respect to
bowel control and nightwetting. Daywetting on the other hand is clearly more frequent
among mildly retarded children.[48] Only in moderately mentally retarded individuals
the development of urinary and bladder control differs clearly from healthy individuals.
[48, 60]
Reid et al. found that intellectual delay is not a barrier to successful management except
for patients with a severe degree of mental retardation.[55]
Understanding of bladder sensations and acting appropriately are essential skills to
obtain bladder control. In case of mental retardation this could be a problem.
3.3.4. Motor capacity
Motor capacity is another important aetiological factor. To become continent a person
should be able to go to an appropriate place to void (the toilet), to undress and
understand how to use the toilet facilities. This requires a degree of mobility, stability
and upper arm function.
Literature illustrates that the higher the degree of mobility the higher the incidence of
achieving continence.
Bross et al. concluded that urinary symptoms and pathological urodynamic findings
increase along with the degree of motor function impairment.[185]
43
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
According to Roijen et al. intellectual capacity and motor capacity (degree of spasticity)
do influence the development of urinary continence in cerebral palsy independently.
[49]
3.4.
Comorbidity
3.4.1. Constipation and faecal incontinence
Constipation is an important comorbidity in the process of incontinence in
developmentally challenged children. It is well known that there’s a correlation between
constipation and urinary incontinence, bladder overactivity, dysfunctional voiding and
recurrent urinary tract infections. [26, 188]
Children suffering intellectual and physical disabilities are more prone to constipation
and faecal incontinence than normal children. Böhmer et al. found an incidence of
70% for constipation in intellectually disabled children.[189] In cerebral palsy patients
constipation is significantly more present.[58] Up to 90% of the cerebral palsy children
are constipated and 47% suffer faecal incontinence, though most of them only to a
minor degree.[190]
3.4.2. Attention Deficit Disorder (ADHD)
ADHD and autism are more frequent in mentally disabled children.[177] There is a large
etiologic heterogeneity of ADHD among intellectual developmental disabilities.
[191]
As mentioned before there is a proven correlation between ADHD and urinary
incontinence.[87, 155, 157, 163]
3.4.3. Sleep disorders
Sleep is a complex neurological function. In children with brain damage, the autonomic
nervous system, which is involved in pineal melatonin secretion and sleep regulation,
might be affected.[192]
Sleep is also vulnerable to several other factors common in cerebral palsy. Muscle
spasms, decreased ability to change body position during sleep, epilepsy which is
known to disturb sleep physiology and predisposes to sleep disorders and glossoptosis
which can induce sleep-related breathing disturbances may be the cause of sleep
problems in these patients.[168, 193]
The incidence of sleep disorders in children from the general population varies between
10 % to more than 40%.
Children with intellectual disability have a higher risk of sleep disturbances. [194, 195]
Sleep disorders such as delayed insomnia, disrupted sleep, early awake or a combination
of these are frequently reported in cerebral palsy children. Newman et al. found that
44% of the patients presented at least one clinically significant sleep disorder. Epilepsy
44
and antiepileptic medication were the principal factors associated with the sleep
disturbance. Patients with total body involvement were significantly more affected.
Visual impairment or blindness and environmental factors were also associated with
disorders of initiation and maintainance of sleep. [168] Svedberg et al. found that 51%
of the children with cerebral palsy had a kind of sleep problem. These problems were
more often reported in non-walkers (72%) than in walkers (36%).[186]
As mentioned at 2.3.2.3. there might be a relation between sleep and nocturnal enuresis.
Further studies are needed to elucidate this relation in the group of intellectually and
physically disabled children.
45
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Chapter 4
Evaluation of children
with incontinence.
As urinary incontinence in children is often complex in nature, adequate treatment is
only possible based on a thorough diagnosis.
History taking and clinical examination are essential diagnostic factors. Monosymptomatic enuresis can be identified based on adequate history taking alone.
Laboratory tests do have a limited value in the work out of urinary incontinence.
Frequency/volume charts and a bladder diary are of utmost importance to determine
the degree of urinary and faecal incontinence, to evaluate the drinking and voiding
habits and to illustrate the characteristics of the bladder. Urinary flow and ultrasound
are non-invasive sources of additional information on bladder function and anatomy of
the urinary tract.
Invasive techniques like (video)-urodynamics and cystoscopy should be reserved for
selected cases of complex urinary incontinence.[196]
4.1.
History taking
History taking in children is always challenging. It is often very difficult for the
investigator to preserve the fragile balance between the anamnestic data from the
child and the hetero-anamnestic data from the parents. In case of developmentally
challenged children history taking is even more complicated. The children themselves
are often incapable to provide adequate anamnestic data. Generally, especially in
Belgium, intellectually and physically disabled children do stay during the week in well
specialized institutions. This means that the investigator not only has to get the heteroanamnestic data from the parents but also from the institution’s staff.
The use of a well structured questionnaire, adapted to the language and possibilities of
children, parents and caregivers is useful to gather reliable and comparable information.
This questionnaire should include items on enuresis, urinary incontinence, lower
urinary tract symptoms, and bowel function. It should also include questions relevant
to mental and motor development, familial disorders, the child’s psychosocial status
and its family situation, neurological and congenital anomalies, previous urinary tract
infections, relevant medication and surgery. In some cases it is even necessary to ask for
sexual functions and to rule out child abuse.
46
A voiding and drinking diary is essential to determine the child’s voiding frequency and
voided volumes and to evaluate the quantity and quality of fluid intake. A dry/wet diary
has to be kept up, and the same should be done for defecation registering defecation
frequency, stool consistency and soiling.
To help children, parents and caregivers in gathering adequate data the Belgian
Consensus Working Group of Enuresis composed a structured information booklet,
containing general information on enuresis, a clear and restricted questionnaire, a
voiding and drinking diary and a frequency volume chart.[197]
Some authors developed validated symptom score systems to identify and evaluate
lower urinary tract dysfunction, classify the severity and document the response
to treatment.[198-200] Some of these symptom score systems are rather general others
more specific. For example Tokgoz et al. developed a symptom scale specifically for
Dysfunctional Elimination Syndrome, providing objective assessment for diagnosis and
quantification of severity.[201]
The use of a standard symptom score system, which at present not exists, would
provide an accurate, objective and scientific based tool to grade the symptoms in
comparative research, diagnosis, treatment and follow-up of children with enuresis and
urinary incontinence.
4.2.
Physical examination
A physical examination should be performed in a child suffering enuresis, urinary and
faecal incontinence, LUT symptoms and recurrent UTI.
Theoretically physical examination should include the assessment of perineal sensation,
the perineal reflexes supplied by the sacral segments S1-S4 and anal sphincter tone
and control. Practically, as this is confronting for the child, this part of the physical
examination is restricted to those patients suspicious for neuropathy.
Special attention should be paid to signs of neuropathy such as: spine deformity,
abnormal gait, abnormal deep tendon reflexes, asymmetric atrophy of feet, high
plantar arches, hammer toes, and of occult spinal dysraphism, i.e. skin discoloration,
dimples, hairy tufts, subcutaneous lipoma, asymmetrical buttock, legs or feet and
oblique gluteal cleft.[202]
The abdomen should be palpated to asses a full bladder, full sigmoid or descending
colon and flank masses.
The external genital region has to be inspected for vaginitis and vulvitis, meatal web
and a hymen that covers nearly the complete vaginal introitus in girls and for penile
anomalies and meatal stenosis in boys.
47
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
In motor disabled children the locomotor system has to be evaluated according to
muscle power, mobility, stability and spasticity.
In mental retarded children the IQ and the functional autonomy has to be estimated.
In all children a detailed questioning of the parents’ observation of the child’s voiding
habits is important to elucidate the toilet position during micturation and defecation
and to describe the way they void or defecate. Proper support of the legs and a stable
position on the toilet are essential for adequate pelvic floor relaxation, and correction
of these factors may ameliorate or even eliminate LUT symptoms.[203]
4.3.
Laboratory tests
Urine analysis to exclude pyuria, proteinuria, glucosuria, hematuria, calciuria and
bacteriuria has to be done at the first office visit.
Pyuria, hematurie and bacteriuria occur commonly in children with urinary tract
infections. Hematuria and calciuria are indicative for urolithiasis. Urinary tract infections
and urolithiasis may be the cause of LUTS.
Proteinuria is a symptom of glomerular renal disease such as diabetes mellitus. Diabetes
mellitus also causes glucosuria. Polyuria can be due to renal insufficiency and diabetes
mellitus.
Hypercalciuria has been claimed to be related to nocturnal polyuria.[204]
Urinary culture should be reserved for those children with a history of previous urinary
tract infections.
Urine osmolality and electrolytes should be determined in case of monosymptomatic
enuresis with persistent therapy resistant polyuria.
4.4.
Non-invasive diagnostic techniques
4.4.1. Frequency/volume charts: bladder diary
The frequency/volume chart is a non invasive record of a child’s urine output over 24hour periods. The chart gives objective information on the number of voidings, the
distribution of day and night voids, along with the voided volumes and episodes of
urgency, urinary incontinence and enuresis.
To determine the exact amount of urine loss during the day one has to weigh the
sanitary napkins the patient should wear.
Ideally the chart should cover at least 3 complete days.
48
Bower et al. proved that the frequency/volume chart is a reliable non-invasive tool to
measure maximum voided volume and can be used as an outcome measure in children
with lower urinary tract symptoms if care is taken to minimise confounding factors and
sources of error during chart completion.[205]
In order to obtain more complete information it is better to ask for a bladder diary.
The ideal bladder diary indicates 24 hour fluid intake, urine output, and also defecation
frequency, soiling and faecal incontinence. In case of nocturnal enuresis and day-and
night urinary incontinence, duration of sleep, nocturia episodes and nocturnal diuresis
(net diaper weight + first morning voided volume) are also essential information.
This diary should be kept up for a fortnight.
Although the amount of urine voided by a non-supervised child during the day varies
considerably, mainly because of social circumstances, children with LUT symptoms
void smaller volumes than may be expected from traditional estimates. [205-207]
4.4.2. Urinary flow
The graphic registration of the urinary flow rate during voiding should be preformed in
all incontinent children except in that suffering monosymptomatic enuresis.
This non–invasive procedure should be repeated at least 2 times to allow adequate
evaluation of the flow pattern and rate. Mattsson et al. illustrated that at the first
micturation, more curves are irregular and flow rates are significantly lower than at the
second one. [208] Flow recordings with a voided volume of less than 50% of the estimated
bladder capacity for age are not consistent. Before micturation bladder volume can be
assessed with a bladder scan or an ultrasound. If the bladder isn’t yet full enough the
child should be asked to drink some more and to wait until the bladder is full enough.
Urinary flow may be described in terms of rate and pattern and may be continuous,
intermittent or fluctuating. The normal flow pattern is bell-shaped regardless of sex, age
and voided volume. [208] Approximately 1% of school children have a voiding that can
be labelled abnormal with flattened or intermittent flow curves. The remaining 99%
have a normal curve. A normal flow doesn’t exclude a voiding disturbance, nor does an
abnormal flow pattern automatically mean a bladder emptying disorder.[209, 210]
Some uroflow patterns are pathognomonic.
In overactive detrusor the voiding phase is essentially normal, but the detrusor
contraction during voiding can be extremely powerful. This may result in a “tower
shape “flow curve, with a quickly reached, very high maximum flow rate.
49
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
In dysfunctional voiding repeated uroflowmetries demonstrate fluctuating or
intermittent uroflow patterns.
Fluctuating (Staccato) voiding is characterized by a continuous flow with periodic
reductions in flow rate precipitated by bursts of pelvic floor activity. Voids are commonly
prolonged and incomplete.
Interrupted voiding is characterized by unsustained detrusor contractions resulting in
infrequent and incomplete voiding, with micturation in separate fractions.
In case of obstructive pathology, such as Moorman ring, mini urethral valves and meatal
stenosis, the flow curve is flattened and flow time is prolonged.
Some children feel uncomfortable when voiding in a strange environment. In those
children home uroflowmetry can be used successfully.[211]
Especially in developmentally challenged children uroflowmetry is often a problem.
Mentally disabled children are often too anxious to perform an uroflometry because
they can’t be properly explained what is going to happen to them. Motor disabled
children are often incapable to perform a non-disturbed void on the uroflow because
of their instable position on the flow chair. Therefore uroflowmetry in developmentally
challenged children should be performed in their own environment on their personal
adapted toilet chair.
4.4.3. Ultrasound
Ultrasound-imaging techniques are routinely used in children with urinary incontinence
to evaluate the upper and lower urinary tract.
In the upper urinary tract duplex systems, hydronephrosis and gross reflux nephropathy
can be readily detected.
In the lower urinary tract ureterocoeles, retrovesical dilated ureters and bladder wall
thickness can be evaluated. A bladder wall cross-section of more than 3-4 millimetres,
measured at 50% of the expected bladder capacity for age, is suspicious for detrusor
overactivity.[139, 212-214]
Sreedhar et al. described the Bladder Volume/Bladder Wall Thickness Index (BVWI),
which is calculated by measuring bladder volume (when the bladder is maximally full)
and bladder wall thickness (when bladder emptying is more than 90% of maximally full
bladder).[140] The bladder wall is defined to be thick with a BVWI of <70, normal with a
BVWI from 70- to 130 and thin when the BVWI is more than 130.
50
The results of the study show a high predictive value of this tool to distinguish between
children with enuresis and normal urodynamics and those with various bladder
dysfunctions.
Further study by the same group in children with recurrent urinary tract infection
confirmed the value of BVWI as a sensitive tool for diagnosing bladder dysfunction.
It can be used as a reliable guide for the appropriate choice of further urodynamic
studies.[215]
Ultrasound and bladder scan can also be used to measure the post-void residual
volume. Theoretically, except in small infants, the normal bladder empties completely
at every micturation.[216] To be conclusive measurement of post-void residual volume
should be done immediately after voiding. The finding of post void residual volume
requires confirmation before being considered significant. The absence of residual
urine doesn’t exclude bladder outlet obstruction or dysfunctional voiding.
The combination of ultrasound and uroflowmetry should be the standardised
procedure to obtain data on flow rate and pattern and post-void residual volume.
4.5.
Invasive diagnostic techniques
4.5.1. (Video)-Urodynamics (VUDE)
(Video)-Urodynamics remain an invasive examination in children. Therefore it should
only be considered if the outcome will influence the treatment.
It is of utmost importance that the children and the parents are carefully prepared
and given adequate information before the investigation is preformed. Transurethral
catheterisation, artificial bladder filling and voiding along a catheter are not evident.
Especially during the first procedure artefacts can be registered due to anxiety of the
child. Therefore it is important that the parents stay with their child and that the child is
distracted by reading a book, listening to some music or watching a movie during the
procedure. To get reliable information of a VUDE the procedure should be repeated at
least twice.[217]
VUDE should not be performed as a routine procedure in all patients suffering LUT
symptoms, enuresis or urinary incontinence.[218] In well selected cases, such as patients
with dysfunctional voiding in whom initial conventional management has failed, or
children suffering recurrent urinary tract infections, urodynamics reveal a high rate of
pathological findings.[84, 219]
To minimize the possible negative influence of the VUDE procedure on the bladder
behaviour it is important to use a strict VUDE protocol. For retrograde filling by a
catheter, the use of saline 0.9%, contrast medium or a mix of both at body temperature
is recommended. Especially in young infants bladder capacity and detrusor activity
51
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
seem to be influenced by the temperature of the filling fluid.[220] Slow fill cystometry (510% of the expected bladder capacity for age/minute, or < 10ml/min) is recommended
in children, as some cystometric parameters, notably changes in compliance and
detrusor overactivity, may be provoked by rapid bladder filling.
Important parameters to check for in children are: bladder sensation, although
difficult to evaluate in non toilet-trained children, maximum bladder capacity, bladder
compliance, detrusor activity, sphincter activity and pelvic floor activity during filling
and emptying phase and the flow pattern. The surplus value of video urodynamics is
certainly the fluoroscopic visualisation of the lower urinary tract, especially in cases of
anatomical obstruction and vesico-ureteral reflux.
Natural fill urodynamics are clearly more physiological than conventional (video)
urodynamics, but there are some practical drawbacks with this method. It is certainly
more invasive, as a suprapubic catheter has to be inserted under general anaesthesia.
Furthermore it is more time-consuming and more expensive than conventional (V)
UDE.
Yeung et al. found natural fill urodynamics to be superior to conventional (V)UDE for
assessing bladder function in children and infants. Their main arguments were: (1)
bladder function being investigated in near to natural conditions, (2) patients being
mostly unaffected by this procedure, and (3) the significant differences found between
NFU and conventional (V)UDE.[221]
The former and other studies in adults and children revealed that NFU is more sensitive
to detrusor overactivity. This increased overactivity seen on NFU is an indication of
problems including bladder wall distension (compliance). [221-226] Compliance is greater
and bladder capacity is lower for NFU.[221] Voiding pressure has been shown to be higher
during NFU than in conventional (V)UDE.[221, 227]
Detection and interpretation of compliance and leak point pressure are a problem in
NFU.[228] The study by Jorgensen et al. demonstrated a correlation between parameters
from NFU and parameters, such as leak point pressure and bladder compliance, from
conventional UDE.[225]
NFU provides more reliable data than conventional (V)UDE because it avoids anxiety
and other patient compliance problems.[222] On the other hand, due to its invasiveness,
it should be reserved for children who do not respond to treatment based on standard
(V)UDE findings, and for those suffering LUTS which are not reflected on conventional
(V)UDE.[225]
52
4.5.2. Cystoscopy
Cystoscopy is rather seldom indicated in children suffering LUT symptoms, enuresis
and urinary incontinence. Only in case of therapy resistant incontinence in boys with
an obstructive flow pattern, high detrusor pressure during micturation and an image
on VUDE suspicious for infra-vesical obstruction, a cystoscopy is indicated to rule out
and treat anatomical obstructions such as urethral valves, Moorman ring, syringocoele,
urethral stricture etc. It has to be mentioned that a voiding cystourethrography not
always shows these abnormalities.[229]
In girls meatal abnormalities causing an anterior deviation of the flow, causing vaginal
reflux and dysfunctional voiding have been described. A simple meatoplasty may solve
the problem.[83]
53
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Chapter 5
5.1.
Therapeutical options
Treatment of urinary incontinence in children
5.1.1. Non pharmacological treatment
5.1.1.1 Urotherapy
Anna Helena Hellstrom introduced the terms “urotherapy” and “urotherapist”. [230]
The term urotherapy is not strictly defined. Urotherapy means nonsurgical,
nonpharmacological treatment of lower urinary tract function. It can be defined as
a bladder re-education or rehabilitation program aiming at correcting of filling and
voiding function of the bladder-sphincter unit.[231] It is synonymous with the term LUT
rehabilitation frequently used in adults.[232]
To achieve the normalization of the micturation pattern and to prevent further
functional disturbances, a combination of patient education, cognitive, behavioural
and physical therapy methods is used.
Hoebeke et al. developed an outpatient training in which bladder regimens:
individual adapted voiding-drinking schedule and adequate toilet posture, pelvic floor
biofeedback and biofeedback uroflowmetry were combined. [233] Immediate success in
92% and a long-term effect of 82% was reported.
In girls suffering urinary incontinence due to vesicovaginal reflux correction of the toilet
position, treatment of the labial adhesions and meatal anomalies and diet may help to
resolve the problem.[83]
The Utrecht group reported on inpatient training, using a cognitive training program
that combines voiding and drinking charts, biofeedback uroflowmetry and wetting
alarm and reported a success rate of 80%.[234]
Bower et al. reported on a half-day urotherapy program consisting of teaching the child
about bladder function, bladder regimen, biofeedback uroflowmetry, and learning how
to relax the pelvic floor muscles. A success rate of 90% was mentioned. [235]
Similar success rates were described by other authors using either short course
urotherapy or more sophisticated computer games related urotherapy.[236, 237]
As mentioned by Hoebeke in his editorial on urotherapy in children, the major problem
with most of the urotherapy modalities is that there are no randomized controlled
trials on the effect of each treatment modality. Furthermore, most centres combine
treatments like voiding and drinking charts, instructions on toilet position, pelvic floor
54
biofeedback, and uroflow feedback, which makes it impossible to evaluate the effect
of each modality.[231] Despite this lack of randomized controlled data one can state that,
whatever the type, urotherapy works.
Even the term urotherapist is somewhat vague. Nurses, physiotherapists, psychologists
and even doctors can be urotherapists as long as they teach the child to correct the
malfunction leading to lower urinary tract symptoms.
5.1.1.2 Biofeedback
Biofeedback was first reported by Maizels et al.[238] It is a technique in which
physiological activity is monitored, amplified and conveyed to the patient as visual or
acoustical signals, thereby providing the patient with information about unconscious
physiological processes.
Biofeedback may consist of pelvic floor relaxation through proprioceptive exercises of
the pelvic floor by visualisation of the electromyografic registration of relaxation and
contraction of the pelvic floor:”relaxation biofeedback”, observation of the flowcurve
during voiding: “uroflow biofeedback”, or a combination of both. Schulman et al. found
that both types of biofeedback where equal successful in reducing daytime wetting
and urinary tract infections.[239]
Biofeedback may be utilized for the management of both filling phase (detrusor
overactivity) and voiding phase (dysfunctional voiding due to pelvic floor muscle
overactivity) disorders.
Biofeedback can help children to identify how to relax their pelvic floor muscles or
recognize involuntary detrusor contractions.
Commonly pelvic floor muscle relaxation is taught through the use of EMG biofeedback.
An anal plug or surface electrodes can be used to register the muscle activity.[233]
This can be extended with real-time uroflow. Interactive computer games are commonly
used to make biofeedback training more attractive to the children.[237, 240]
Kaye and Palmer compared animated and nonanimated biofeedback programs in
treating two identical groups of girls with documented dysfunctional voiding. They
found a similar cure rate using either method, but fewer sessions (3.6) were needed with
animated biofeedback as compared with 7.6 sessions with the nonanimated form.[241]
Combs et al. on the other hand found the same results in their nonanimated biofeedback
population as the previous group found in the animated form.[242] This suggests that
although the type of biofeedback equipment used may facilitate therapy for patients, it
is the experience of the therapist that may impact treatment response most.[243]
55
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Biofeedback can be used as a single treatment [238, 244], or combined with a comprehensive
rehabilitation program.[233, 234]
Klijn et al. reported successful treatment with home uroflowmetry biofeedback.[245]
The results of biofeedback are generally positive but overall may not be superior to
high quality standard urotherapy. Vasconcelos et al. found that the group receiving
adjunctive biofeedback did not achieve greater continence rates at the end of the
study, although more patients achieved earlier dryness. Furthermore the post void
residual volumes were significantly reduced in the biofeedback group compared to the
standard urotherapy group.[246]
Recently, Richardson et al. found that biofeedback techniques were successfully used
in the treatment of giggle incontinence. The children were taught to identify the
external sphincter muscles and to recruit them more rapidly and forcefully to decrease
incontinence. [247]
5.1.1.3 Neuromodulation
Neuromodulation has been used to treat a variety of lower urinary tract symptoms in
adults. The use of transcutaneous electrical nerve stimulation (TENS) of the S3 region
with surface electrodes made this technique also more applicable in children. [248]
Transcutaneous and percutaneous neuromodulation delivered over either the sacral
outflow or peroneal region of the ankle at a frequency between 10-25 Hz, has proven
(level of evidence is low) a useful adjunctive treatment in children with a lower urinary
tract symptoms.[249-252]
Recent studies indicate that sacral neuromodulation is effective in children with severe
dysfunctional elimination syndrome refractory to maximum medical treatment.[253-255]
Bower et al. illustrated that home application of TENS in children is successfully feasible
in children.[256]
The neuromodulation technique is based on the principle that electrical current directly
affects the central nervous system by artificially activating neural structures, facilitating
both neural plasticity and normative afferent and efferent activity of the lower urinary
tract.
Electrical stimulation of S3 activates the pelvic floor and modulates innervation of the
bladder, sphincter and pelvic floor, restoring the balance and coordination of sacral
reflexes. Changes in urodynamic parameters during stimulation have been reported
with TENS, suggesting that this therapy is useful for inhibiting detrusor contractions.[257]
56
The reported changes with neuromodulation include: significantly increased bladder
capacity, decreased severity of urgency, improved continence, and decreased frequency
of urinary tract infections. Significant improvement in urodynamic parameters of
bladder compliance, number of uninhibited contractions, and bladder volume at first
detrusor contraction have also been noted.[258]
These studies however were non prospective and uncontrolled and have low level of
evidence.
Hagstroem S. et al were the first to perform a prospective randomized placebo
controlled study on the effect of TENS for refractory daytime urinary urge incontinence
in children. In this rather small population, 27 patients, they found TENS to be superior
to placebo (sham treatment) for refractory daytime incontinence in children with
overactive bladder. The effect does not seem to be the result of improved bladder
capacity but might be related to improved sensory mechanisms.[259]
Intravesical stimulation can be used in underactive detrusor in which it can lead to
a potentially improvement of the detrusor contractility and enhancement of bladder
emptying.[260]
Recently reports on successful sacral nerve stimulation with implantable electrodes in
children have been published.[253-255] The authors consider this treatment in children
with severe dysfunctional elimination syndrome refractory to maximum medical
treatment.
In summary, there is an adjunctive role for the use of neuromodulation in children
with LUTS. However larger, controlled and randomized studies on neuromodulation in
children are necessary.
5.1.1.4 Alarm treatment
The use of alarm therapy has been well documented in children suffering enuresis, but
has rarely been used for the treatment of urinary incontinence during the day.
Halliday et al. reported of a randomized clinical trial comparing a contingent alarm
which sounded when the child was wetting, with a noncontingent alarm that sounded
at intermittent intervals to remind the child to void.[261] Therapy was considered to be
successful when the patients remained without daytime wetting for 6 consecutive
weeks. With the non-contingent alarm the success rate was 68% and 80% in the
contingent group, which was not significant different. Twenty three percent of those
who responded to treatment relapsed up to two years after completion of the trial.
Hvistendahl et al. found in contrast with a previous study from the same group that the
use of an alarm system during the night in enuretic children increased significantly the
maximal voided volume during the day. [262, 263]
57
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
In our retrospective study we reviewed the files of 63 children, treated with a daytime
alarm for therapy resistant urinary incontinence during the day. All patients had a
proven overactive detrusor. They were treated with the alarm for a fortnight. At a followup of 12 months 35% were successfully treated, 33% had a partial success and in 32%
treatment failed.[264]
Recently the use of a daytime alarm has been advocated as an effective option for
toilet training young healthy children. According to the authors it offers parents and
day-care providers clear guidelines and limits the time to complete toilet training in
many children.[265, 266]
5.1.2. Pharmacological treatment
5.1.2.1 Antimuscarinic treatment
Parasympathetic mediated, acetylcholine-induced stimulation of post-ganglionic
muscarinic receptors on detrusor smooth muscle is involved in both normal and
involuntary detrusor contraction. The latter causing bladder overactivity. Muscarinic
receptors are heterogeneous in nature and widely distributed throughout the body.
Five molecular distinct subtypes are known to be exist (M1-M5), and tissues may
contain a number of different subtypes. M2 and M3 receptors are the main muscarinic
receptors involved in bladder control. [267] The M2 receptor is the predominant subtype
in the bladder (80% of the total muscarinic receptor population), but mediation of
bladder contraction by the minor population of M3 is well reported.[268, 269]
Stimulation of M3 receptors by acetylcholine leads to phosphoinositol hydrolysis, and
ultimately to accumulation of intracellular calcium and smooth muscle contraction.
Activation of M2 receptors leads to inhibition of adenylate cyclase. This is thought
to cause smooth muscle contraction by indirect inhibition of sympathetically
(β-adrenoreceptor)-mediated augmentation of cyclic adenosine monophosphate
(cAMP) levels and bladder relaxation. During micturation, it has therefore been
suggested that activation of M3 receptors by acetylcholine evokes direct smooth
muscle contraction, while stimulation of M2 receptors reverses sympathetically
mediates smooth muscle relaxation. [267]
Anticholinergic agents are substances that block the neurotransmitter acetylcholine
in the central and peripheral nervous system. They are administered to reduce the
effects by acetylcholine on acetylcholine receptors in neurons through competitive
inhibition.
Antimuscarinic agents may not only interfere with the postjunctional effects of
acetylcholine on the detrusor, but also with acetylcholine release from parasympathetic
nerves. Presynaptic muscarinic receptors have been identified in various tissues,
including the bladder. Activation of these receptors facilitates (M1) or inhibits (M2/
M4) the release of acetylcholine, according to the frequency of nerve stimulation. It
is thought that activation of the presynaptic facilitating M1 receptor may serve as an
58
amplification mechanism during micturation, when intense parasympathetic activity
occurs. In contrast, the inhibitory M2/M4 receptors appear to be preferentially activated
at low frequencies of nerve stimulation.[267]
Antimuscarinic agents might block acetylcholine binding at more than one muscarinic
receptor subtype. Furthermore, receptor-selective agents might block muscarinic
receptors outside the bladder and cause adverse effects. Blockade of M3 receptors
in the salivary gland, lower bowel and ciliary smooth muscle are the most frequently
reported, associated with dry mouth, constipation and blurred vision.[270]
Currently, oxybutinin IR and oxybutinin ER are the only antimuscarinics approved
by the FDA for the treatment of overactive bladder symptoms in children. Therefore
oxybutinin is the most widely used pharmacological therapy in children with detrusor
overactivity. The recommended daily dose is 0.3 mg/kg body weight.
Dry mouth through reduced saliva production is the most commonly reported
adverse effect of antimuscarinic therapy. The incidence of dry mouth in patients taking
oxybutinin IR was 17-97%, oxybutinin ER 23-68% and transdermal oxybutinin 4-39%.
[270]
It doesn’t only cause discomfort for the patient but it also induces tooth decay.
[271]
Transdermal oxybutinin circumvents “first-pass” metabolism and results in lower
concentrations of the active metabolite N-desethyloxybutinin, a metabolite that has a
greater affinity than oxybutinin for muscarinic receptors in the parotid gland and might
contribute to dry mouth.[272]
Constipation is generally the second most common adverse effect. It is reported in
4-50% of the patients receiving oxybutinin IR and in 1-21% of those on transdermal
Oxybutinin.[270]
Constipation might cause or exacerbate urinary symptoms.
Abnormal vision was found in 3-24% of the patients taking oxybutinin IR and 18% of
those using transdermal oxybutinin.[270]
As oxybutinin crosses the blood brain barrier it may cause CNS effects, such as
psychological and personality changes.
Facial flushing, heat stroke, tachycardia, drowsiness and headache are other well known
adverse effects of antimuscarinic drugs. The frequent occurrence of side effects causes
up to 10% of the children using oxybutinin to stop treatment.[271] A study by Jonville et
al. reported that side effects with oxybutinin occur 4 times more frequently in children
than in adults.[273]
Oxybutinin ER utilizes a novel delivery system, which results in absorption in the
large intestine, thereby bypassing the first pass metabolism in the liver. This leads to a
59
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
decrease in the amount of active metabolite, which is produced in the liver, resulting
in a more favourable tolerability profile.[274] Another way to avoid the first pass effect
is intravesical therapy. As there is a need for catheterization it should be reserved for
the treatment of the neuropathic bladder.[275] Several studies illustrated that intravesical
administration of oxybutinin doesn’t decrease the adverse events, resulting in 25% of
the patients stopping therapy.[276, 277]
There are only a few studies, none randomized and double blinded, assessing the
efficacy of oxybutinin in detrusor overactivity in children.[278, 279] Some other data do
even suggest that oxybutinin is no more effective than non-pharmacologic therapy in
increasing bladder capacity in monosymptomatic enuretic children.[280]
In some countries the antimuscarinic agent with additional calcium channelmodulating properties, propiverine is approved for use in children. The recommended
daily dose is 0.8mg/kg body weight. Marschall-Kehrel et al. studied in a multicenter
placebo-controlled double-blind study the efficacy of propiverine for the treatment
of overactive bladder in children aged 5-10 years. The trial demonstrated significant
superiority of propiverine over placebo and good tolerability.[281] Madersbacher et al.
studied the effect of propiverine versus oxybutinin for treating neurogenic detrusor
overactivity in children and adolescents. They found propiverine to be at least as
effective as oxybutinin, but distinctly better tolerated. The overall clinical effectiveness
was found to be better for propiverine.[282]
Currently some new antimuscarinics have been introduced for the treatment of
detrusor overactivity in adults. Not one of them has been approved for use in children.
Tolterodine is a so called “bladder selective” antimuscarinic agent designed specifically
for use in detrusor overactivity. The chemical nature of tolterodine makes it less likely
to penetrate the blood brain barrier, which is supported by EEG studies.[283] The safety,
efficacy and dosing of tolterodine in the adult population have been extensively
studied in controlled clinical trials and reported.[284-287] These results demonstrated that
tolterodine at a dosage of 2mg twice daily has a favourable pharmacological profile
reflected by equal effectiveness but significantly fewer side-effects than oxybutinin.
As adverse effects are one of the main reasons to discontinue a treatment with
oxybutinin in children, new “bladder selective” antimuscarinic agents may become
important alternatives in future.
Goessl et al. published the first study of tolterodine in children. They reported tolterodine
to be equally effective and better tolerated than the standard drug oxybutinin chloride
in children with detrusor hyperreflexia .[288]
60
Christoph et al. studied a paediatric population treated with tolterodine because of
neurogenic detrusor overactive for five years. [289]The data of this study demonstrated
the efficacy and tolerability over a long follow-up period.
Munding et al. retrospectively reviewed their experience with 30 patients treated with
tolterodine at adult doses, for a primary diagnosis of dysfunctional voiding. Wetting
episode were cured in 33%, improved in 40% and failed to show improvement in 27%.
Side effects were reported in 13.3%. They concluded that tolterodine can be safely and
effectively used in children at an adult dose.[290]
The study by Bolduc et al. demonstrated that tolterodine is well tolerated by children.
In the group of patients who couldn’t tolerate oxybutinin, 78% were able to continue
tolterodine treatment with no significant side-effects.[291]
Hjalmas et al performed an open, unrandomized, dose-escalating study to determine the
safety, efficacy and pharmacokinetics of tolterodine in children with overactive bladder.
They found a dose-response for adverse events. There were more adverse events and
more severe events at 2mg than at the 0.5mg and 1mg dosages. Furthermore, adverse
events possibly related to the drug only became prevalent with the 2 mg dosage.
These results, coupled with the lack of differences in efficacy between 1 mg and 2 mg
dosages, and that the AUC of active moiety of the 1 mg dosage in children aged 5-10
years was comparable to the 2 mg dosage in adults, supported the use of 1mg twice
daily as the preferred dosage for children.[292]
Raes et al. preformed a retrospective analysis of efficacy and tolerability of tolterodine
in 256 children with video-urodynamically proven overactive bladder. [293] The results
suggested that tolterodine is well tolerated and offers effective treatment for urinary
symptoms due to overactive bladder. It is superior to non-selective antimuscarinic
drugs, with respect to adverse events, allowing more compliance and more effective
treatment.
Reinberg et al. compared therapeutic efficacy of extended release oxybutinin chloride,
and immediate release and long acting tolterodine in children with diurnal urinary
incontinence.[294] They found extended release oxybutinin and long acting tolterodine
being more effective than immediate release tolterodine in decreasing diurnal urinary
incontinence. Extended release oxybutinin chloride is more effective than either
immediate or long acting tolterodine for control of daytime urinary incontinence and
urinary frequency.
More recent studies in children with neurogenic detrusor overactivity reported that
tolterodine extended release and tolterodine instant release were as effective and well
tolerated. The instant release formulation was found to be more effective in terms of
urodynamic parameters. The extended release formulation is less expensive and has
61
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
the advantage of a single dose.[295, 296] Long-term treatment with extended release
tolterodine was found to be well tolerated by children.[297]
5.1.2.2 Botulinum toxin
Botulinum toxin (BTX) is a potent neurotoxin that inhibits acetylcholine release at
the presynaptic cholinergic junction, inducing muscle relaxation. It is produced by
Clostridium botulinum, a gram-positive anaerobic bacterium. Six additional strains
of botulinum producing neurotoxins have been identified.[298] Several subtypes of
botulinum toxin exist, identified as “A” through “G”.
A and B are commercially available. A as Dysport® (Ipsen) and Botox® (Allergan), B
as Myobloc® (Elan Pharmaceuticals). A has been FDA approved for the treatment of
strabismus, blepharospasm, disorders of the 7th nerve, cervical dystonia and moderate
to severe frown lines. B has been FDA approved for the treatment of cervical dystonia.
Up to now botulinum toxin has not been FDA approved for therapeutic use in urology.
In spite of this BTX-A toxin is used in adult urology to treat neurogenic detrusor
overactivity, chronic urinary retention, detrusor-sphincter dyssynergia, non-neurogenic
detrusor overactivity and chronic prostatic pain.[299]
In children BTX-A toxin has been mainly used to treat urinary incontinence in children
with a neurogenic bladder.
In vivo, type A appears to be the most potent subtype with the longest duration of
action as an injection.
Botulinum neurotoxin interferes with presynaptic release of acetylcholine from nerve
endings and interrupts neuromuscular transmission. It cleaves the synaptosomalassociated protein with a molecular weight of 25kD (SAP-25) [300] In addition, it exerts
a blocking action on the parasympathetic nervous system and may inhibit other
neurotransmitters, such as noradrenalin, dopamine, serotonin, g-amino-butyrate,
glycine and peptide methionine-enkephaline, glutamate, substance P, calcitonin generelated peptide or affect transmission of afferent neuronal impulses. [301]
There is increasing evidence that BTX has an antinociceptive effect separate from its
neuromuscular action, which may explain its efficacy in reducing urgency.[300, 302]
Recent research has focussed on the function of the myofibroblast cell in the
suburotheleum and its relation to the mechanism of action of botulinum toxin. [300, 303] It
is proposed that the myofibroblasts show functional similarity to the interstitial cells of
Cajal in the gastrointestinal tract, and may also be arranged within a plexus that acts as
a sensory organ in the suburothelium.[300, 304]
62
The effect is temporary and most of the recovery of neuromuscular function is due to
the recovery of the “mother” neuron and not from the sprout “touchdown”. Contrary to
reports on striated muscles, axonal sprouting within the detrusor is very limited after
BTX-injections, indicating pathophysiological different reactions to the toxin between
striated and smooth muscles. Eventually, regeneration of the original neuromuscular
junction takes place.[305] No changes in the ultrastructure of the detrusor have been
found after BTX-A injection.[306]
In the bladder, the action of BTX-A at presynaptic cholinergic junction induces detrusor
muscle relaxation, and potentially affects afferent sensory receptors in the urothelium.
[307]
Only a few studies documented the use of BTX in children. Investigators administered
doses varying between 5 and 12 U/kg body weight (similar to doses used in the I.M.
treatment of cerebral palsy) with a total dose of 50-360U Botox, reflecting a higher
dose/kg body weight than is used in adults.[300, 308-310] The number of injection sides was
20-50 which is similar to adult protocols. It is not known whether submucosal injection
or restricting the injection to the detrusor muscle is more efficacious.
Based on mounting evidence that BTX-A may also affect sensory nerves, investigators
have advocated injecting the trigone or the suburothelial space. No evidence of new or
worsening of pre-existing vesico-ureteric reflux was found following trigonal injections.
[311]
The maximum benefits are reached within 2-6 weeks of injection.[300, 301, 312]
The results last about 6-9 months and there is now evidence of its maintained efficacy
with repeated injections.[65, 301, 312, 313]
BTX-A treatments are well tolerated. Most studies reported no systemic adverse effects
after treatment with Botox. Urinary retention (5%) and the need for CIC in up to 16%
of patients with detrusor overactivity were reported.[301] Muscle weakness was not
reported in any of the studies in children.[312]
There is no study that assesses the impact of repeated injections on the bladder wall,
and on the risk of fibrosis and of bladder compliance alteration in time.[312]
BTX-A antibodies can develop after injection of BTX-A for urologic disorders. These
antibodies may cause therapy failure.[314] To minimise the small risk of BTX resistance,
most investigators currently recommend waiting at least 3 months between treatments,
avoiding the use of booster injections and using the smallest dose that achieves the
desired clinical effect.[315]
63
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Until now botulinum toxin A has been used mainly in the treatment of children with
neurogenic detrusor overactivity, mainly due to myelomeningocoele. Considerable
improvements in urinary continence, maximal cystometric capacity, Pdetmax, bladder
compliance and incidence of urinary tract infections were reported as well as resolution
of vesico-ureteral reflux. [300, 308, 309, 311, 312, 316-322]
In his review article, Xavier Gamé, illustrated the efficacy of BTX-A in children with
neurogenic detrusor overactivity. The mean reduction from baseline of urinary
incontinence score varied between 40 and 80%. Between 65% and 87% of patients
became completely continent, between CICs, after Botox treatment.[312]
According to the use of botulinum toxin A as a treatment of idiopathic detrusor
overactivity in children there’s only our own publication on 21 patients illustrating the
successful treatment in 70% of the patients.[310]
External urethral sphincter injections can be used to treat dysfunctional voiding in
children. Only 3 full studies and 1 case report have been published about this topic,
demonstrating improvement of the maximum flow-rate, post-void residual and leakpoint pressure. [300, 323-325]
5.1.2.3 Alpha blockers
In the genitourinary system, alpha-adrenergic receptors are predominantly located in
the bladder outlet and detrusor body, with their stimulation resulting in contraction of
the outlet and increased bladder tone.
Alpha-receptors have been found to modulate voiding function at the level of the
parasympathetic ganglia, resulting in decreased bladder compliance and increased
detrusor instability.
Central nervous system micturitional pathways are under alpha-adrenergic modulation
with alpha stimulation causing bladder contractions.
Alpha-adrenergic receptors are present in the bladder urothelium with stimulation
increasing the release of nitric oxide. Elevated intravesical nitric oxide concentrations
results in increased urinary frequency, urinary urgency, and sense of incomplete
bladder emptying.
Anatomic outlet obstructions and/or neurologic injury will result in alterations of the
supratrigonal alpha-adrenergic receptors in both receptor subtype and density. There
is also evidence that reorganization of the CNS alpha-adrenergic regulation of bladder
activity also occurs. These changes result in increased alpha-adrenergic responsiveness
to neural stimulation and directly correlate with a decrease in detrusor compliance and
increased detrusor instability.
64
Due to these findings, alpha blockers are no longer believed to relieve lower urinary
tract symptoms by an effect directed strictly at the bladder outlet. Alpha-blockers will
help relieve irritative bladder symptoms by its action on the receptors in the bladder
urothelium ( by decreasing sensation to void and feeling of incomplete bladder
emptying), parasympathetic ganglia ( by inhibiting detrusor contractility, improving
bladder compliance, increasing bladder capacity), and central nerve system ( by
inhibiting detrusor contractility, increased bladder capacity, delaying voiding intervals).
[326]
The use of alpha-adrenergic antagonists in paediatric urology is still in progress.
Austin et al. were the first to report the successful use of a selective alpha-1-blocker,
doxazosin, in the treatment of children with neuropathic and nonneuropathic voiding
difficulties and OAB.[327]
Kramer et al. performed a double-blind placebo controlled study to determine whether
the alpha-adrenergic antagonist doxazosin could be used as primary therapy in children
with voiding dysfunction. Compared to placebo, doxazosin did not demonstrate a
significant objective benefit. A significant subjective benefit, improvement of the
patient’s dysfunctional voiding symptom score and of the parent’s perception that the
children had improved urinary continence, was found.[328]
According to this results, alpha blockers are of little, if any use as primary therapeutic
agent in the treatment of voiding dysfunction.[326]
Yucel et al. illustrated with a randomized study that alpha antagonist therapy as
secondary therapy for recalcitrant voiding dysfunction is a viable alternative to
biofeedback techniques.[329] Cain et al. stated that it can be used as a replacement or in
addition to biofeedback.[330]
Donohoe et al. found alpha-adrenergic antagonists to be a clinically effective therapy
for primary bladder neck dysfunction in children.[331]
Selective alpha blocker therapy appears to be effective for improving bladder emptying
in children with an overactive bladder, wetting, recurrent infections and increased post
voiding residual urine. Several studies demonstrated symptomatic relief in more than
50% of the patients receiving a selective alpha-blocker. [332-334]
Doxazosin (starting dose 0.5mg/day, maximum at 4mg/day), tamsulosin (starting
dose 0.2mg/day, maximum at 0.8 mg/day) and terazosin (starting dose 0.5mg daily
increasing up to 5mg/day) are the three most common alpha antagonists used in
children at present. The safety and efficacy of tamsulosin and terazosin have not been
established in children. [326-329, 331, 335]
65
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Irrespective of the type of alpha-antagonist used, the medication is best tolerated if
given at night. This will reduce greatly the symptoms of hypotension and asthenia
(fatigue and muscle weakness) that can be noticed with morning ingestion of the
medication.[326, 334]
Major side effects (i.e. postural hypotension, syncope or palpitations) of alpha-blockers
have not been reported in children. Donohoe et al. found that 75% of their patients
receiving terazosin or doxazosin had mostly central nervous system side effects such as
mild degrees of headache, somnolence and nausea.[331] VanderBrink et al. studied the
effect of tamsulosin on systemic blood pressure. No patient experienced a clinically
significant alteration in systemic blood pressure. [334] At present it seems that selective
alpha-adrenergic blockers can be used safely in children.
5.2.
Treatment of nocturnal enuresis in children
5.2.1. Non pharmacological treatment
5.2.1.1 Enuresis alarm
Alarm therapy is the most effective treatment option of monosymptomatic nocturnal
enuresis. [113, 336] It is more effective than any other form of treatment, and lasting cure
rate appears to be twice as high.[337, 338]
A meta-analyses by Butler et al. showed success rates across all studies ranging from
30% to 87%. [339] The average success rate is nearly 68% with efficacy increasing with
the duration of therapy. Intervention with an alarm is associated with a nine time less
likelihood of relapse than antidiuretic therapy. Relapse rates in the 6 months following
treatment are between 15 and 30%. Meta-analysis showed a 43% lasting cure rate. [65,
337, 340]
Success rate is influenced by the type of enuresis, the treatment duration and the
success criteria adopted.
The exact mechanisms for alarm therapy are not known. The effects are not due to
classical conditioning as stimulus awakening occurs after and not before wetting.
Instead it is an operant type of behavioural approach, i.e. a learning program with
positive reinforcement that includes aversive elements.
Dryness is achieved either by waking up, leading to nocturia in 35% of the children or
by sleeping through the night with a full bladder in 65%.
Body worn alarms are as effective as bedside alarms[339]
The best results occur in optimal motivated children and parents. Lack of concern
shown by the child, lack of supervision, inconsistent use, technical failures, family stress,
abnormal scores on behaviour checklists, psychiatric disorders of the child, failure to
awaken in response to the alarm, unsatisfactory housing conditions and more than
one wetting episode per night are negative predictive factors of a successful treatment
66
with the alarm. The more frequent the wet nights a week the better the results of the
treatment and the lower the relapse rate.[341] Treatment shouldn’t be considered to be
ineffective before 6 to 8 weeks of treatment.[65]
Relapse after successful treatment occurs in 42% of the children.[339] Intensified
treatment, involving the consumption of large quantities of fluid during the evening to
provoke enuresis after primary success has been achieved, may reduce this risk.[336, 342]
Several studies showed that the nocturnal bladder capacity, but also the maximum
voided volume and the mean day-time voided volume in enuretic children with an
initially small bladder, increased significantly during alarm treatment. [262, 343, 344] This
possible explains why some children, after successful alarm treatment, are able to sleep
dry without nocturia. Normalization of the bladder capacity doesn’t lead to complete
dryness in all enuretic children.[345] A higher nocturnal urine production on nocturia
nights explains why some children have nocturia and others do not.[262]
Despite the fact that the enuresis alarm is clearly the most effective treatment option
in monosymptomatic nocturnal enuresis, it remains rather unpopular in patients
and physicians because of the demanding preconditions for successful treatment,
i.e. lengthy instructions, high compliance needed, close co-operation among family
members, and the slow onset of action of this treatment.[346, 347]
In an attempt to increase the success rate of the enuresis alarm, alarm therapy has been
combined with dry bed training and arousal training. The dry bed training incorporates
the enuresis alarm, cleanliness training and specific waking schedules.[348] Arousal
training entails reinforcing appropriate behaviour, i.e. waking and toileting, in response
to alarm triggering.[349]
High success rates and low drop out have been reported for both methods.[349-352]
Bollard et al. found that the enuresis alarm accounted for most of the success achieved
through dry bed training.[353]
Van Kampen et al. introduced the full-spectrum therapy for nocturnal enuresis. It
consists of enuresis alarm, bladder training, motivational therapy and pelvic floor muscle
training. The initial success rate was 87%. The relapse rate during the first year was 50%,
and after one year 16%. In a current study they showed that pelvic floor muscle exercise
has no beneficial effect in the treatment of children with enuresis.[354-356]
5.2.1.2 Acupuncture
Several studies illustrated the efficacy of acupuncture in the treatment of nocturnal
enuresis. Bower et al. performed a meta-analysis of 11 studies. All the trials were of
low methodological quality. The review provided tentative evidence for the efficacy
of acupuncture for the treatment of nocturnal enuresis. [357] The study by Serel et al.
67
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
concerned a fairly large population of 50 patients suffering primary persistent nocturnal
enuresis. Within 6 months 86% of the patients were completely dry, which is a rather
spectacular result.[358] This positive effect may be due to the increased nocturnal bladder
capacity. [359]
In line with traditional acupuncture, electro-acupuncture and laser-acupuncture
have been advocated for enuresis.[360-362] The study by Radmayr et al. , a prospective
randomized trial using laser acupuncture versus Desmopressin in the treatment
of nocturnal enuresis in children with a proven normal voiding pattern and a high
nighttime urine production, illustrated both treatments to be as efficacious.[361]
5.2.2. Pharmacological treatment
5.2.2.1 Desmopressin
Desmopressin acetate (dDAVP) is a synthetic analogue of arginine vasopressin (AVP).
AVP, also known as antidiuretic hormone (ADH), is produced in the hypothalamus
and released from the pituitary gland, principally in response to hyperosmolality or a
low effective circulating blood volume. Vasopressin receptors have been identified in
the kidney, liver, brain, pituitary gland, aortic smooth muscle and on platelets. These
receptors are divided into three subtypes: V1, V2 and V3. AVP acts on V2 receptors in the
collecting ducts and distal tubules to enhance water reabsorption. By virtue of its V1
receptor agonistic properties, AVP is also a potent vasoconstrictor.
Desmopressin (or dDAVP) is an analogue of vasopressin created by removing an
amino group from the cysteine molecule in position 1 and substituting D-arginine for
L-arginine at position 8. These structural modifications result in significant increase in
antidiuretic activity (2000-3000 times superior to that of AVP), extended half-life (1.5-3.5
hours) and markedly diminished vasopressor and smooth muscle activity. [65]
Since the late seventies dDAVP was found to be successful in the treatment of enuresis.
[363]
The use of dDAVP in the treatment of nocturnal enuresis increased markedly in most
parts of the world since Norgaard et al. demonstrated that a significant proportion of
children with monosymptomatic nocturnal enuresis lack the normal circadian rhythm
of AVP, producing large quantities of dilute urine at night.[118, 364] Subsequently the WHO
has supported dDAVP as the prime medication for use in enuresis therapy. Desmopressin
is the only pharmacological treatment given a level 1, grade A recommendation for use
in primary nocturnal enuresis by the ICI and ICCS.[365] In Europe and the United States
the drug has been approved for intranasal, sublingual and oral administration in the
treatment of enuresis.
Desmopressin is easy to administer and the clinical effects appear almost immediately.
The usual dose is 0.2-0.4mg orally, 120-240μg for the melt formulation or 20-40
68
micrograms intranasal at least one hour before bedtime, as the mean maximum
plasmaconcentration is reached within 1 hour of administration.[366]
The intranasal form is no longer recommended for nocturnal enuresis in many places
around the world, because of the increased risk for accidental overdosage and inherent
risk for water intoxication .[65]
It can be orally administrated as a tablet or as a melt formula. The latter consists of
a freeze-dried structure that disintegrates instantaneously into the saliva and then is
swallowed. [367]
The bioavailability of the melt formulation is approximately 60% greater than that
observed for the tablet formulation.
Lottmann et al. found a statistically significant preference for desmopressin melt in
children aged 5-11 years. Compared with the tablet, the Melt formulation requires
no intake of water and is associated with higher compliance. Meanwhile, it retains
similar levels of efficacy and safety at lower dosing levels than the tablet. Significantly,
desmopressin Melt was well accepted by all ages, and facilitates the early initiation of
treatment in children with primary nocturnal enuresis.[368]
The efficacy of desmopressin in the treatment of enuresis is well documented. Success
rate varying from 25 to 70% have been published. A Cochrane analysis confirmed
desmopressin rapidly reducing the number of wet nights per week, but there was
some evidence that this was not sustained after treatment was stopped.[369]
With long-term treatment, between 50-80% of patients showed a decrease of at least
50% in wet nights over 6-12 months and 40-70% became almost completely dry.[370, 371]
Cure rate in most studies was higher, up to 30%, than the annual spontaneous cure rate
of approximately 15%.[371-373]
The efficacy of desmopressin may not be maintained on discontinuing treatment.
Recurrence of symptoms after cessation of therapy varies between 50 and 95%.[374]
This is especially true after short-term treatment, while long-term treatment yields cure
rates up to 71%.[370, 375]
If desmopressin treatment is successful, a one-week interruption is recommended
every 3 months to see if the problem has been cured.[372]
Marschall-Kehrel et al. illustrated that structured desmopressin withdrawal improves
response and treatment outcome in children with monosymptomatic enuresis. They
compared abrupt termination and structural withdrawal, leaving the dose constant and
increasing daily treatment intervals to every second evening for 2 weeks, twice weekly
for 2 weeks and once weekly for 2 weeks. The abrupt termination group had a 51%
69
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
response whereas the structured withdrawal group had a 72% response. According to
the authors this might be due to the fact that structured withdrawal of desmopressin
stimulates maturation of the innate production of antidiuretic hormones. On the other
hand it also supports the idea that desmopressin might have more than one centre of
action, and also works in the central nervous system.[376]
Treatment with desmopressin is generally well tolerated, even during long term
treatment (≥ 1 year), and side effects are rare, provided that the patient does not
consume large amounts of liquids while taking the drug. Reported side effects are
generally described as mild and include headache, abdominal pain, nausea, nasal
congestion, rhinitis and epistaxis. Hyponatremia with convulsions or unconsciousness,
resulting from water retention due to the potent antidiuretic effect, is the single
most concerning potential adverse effect of desmopressin.[377] Two review studies,
investigating the risk of desmopressin-associated hyponatremia, showed that the
occurrence of water intoxication during desmopressin treatment is rare and that
most of these cases were secondary to excessive fluid intake or other conditions (e.g.
cystic fibrosis) contributing to this complication.[377, 378] Dehoorne et al. illustrated that a
prolonged desmopressin bioactivity may increase the risk of water intoxication. [379] The
incidence of mild asymptomatic hyponatremia is reported to be 1-10% in short term
trials and around 1% in long-term treatment trials.[371, 380, 381] The over-all incidence of
adverse effects in long-term clinical trials is low (0.8-5%).[370, 371]
The risk of hyponatremia can be minimised by starting the treatment at the lowest dose,
counselling the patients regarding evening fluid restriction (stop fluid intake one hour
before bedtime until the next morning) and potential warning signs of hyponatremia(
headache, nausea, vomiting, weight gain and in severe cases convulsions).
Studies showed that some patients do have a delayed , a partial or an absent response
to desmopressin.[370]
Clinical experience in partial responders showed that increasing the dose may lead to
higher response rates.[382]
Nocturnal bladder instability, increased nocturnal osmotic excretion, intermittent
inadequate desmopressin bioavailability, and a disorder in circadian rhythm of renal
glomerular and/or tubular functions have been mentioned as causal factors for
desmopressin resistant nocturnal enuresis. [120, 121, 383-386]
5.2.2.2 Antimuscarinic treatment
In those children who have nocturnal enuresis due to detrusor overactivity during
the night, and certainly in those with combined nocturnal enuresis and diurnal
incontinence, treatment with antimuscarinic drugs should be considered.[387-389]
70
Evidence however is low on the value of antimuscarinics in becoming dry. In a Cochrane
review no evidence was found that oxybutinin was more effective than placebo in the
treatment of nocturnal enuresis.[390]
5.2.2.3 Tricyclic antidepressants
Tricyclic drugs act on the central nervous system by blocking the synaptic alphareceptors’ re-uptake of noradrenalin and serotonin into the neurons, thus prolonging
their effects due to an accumulation and increased availability of neurotransmitter
substance at the postsynaptic membrane. Other pharmacological effects are an
anticholinergic effect in the central and peripheral nervous system, and a direct
decrease in smooth muscle contractile activity.[391]
Their usual clinical use is as antidepressants.
Imipramine also has a vasopressin independent antidiuretic effect due to increased
alpha-adrenergic stimulation in the proximal tubules with a secondary increased urea
and water reabsorption more distally in the nephron.[391]
Tricyclic antidepressants, such as imipramine, amitriptyline, nortriptyline and
clomipramine, as well as some drugs related to tricyclics ( viloxazine, desipramine,
mianserin and maprotiline) have been used in the treatment of nocturnal enuresis.
A Cochrane review of 58 randomized trials that included 3721 children concluded
that both imipramine and other tricyclic medications have been proved effective in
reducing bed-wetting.[392] Treatment with tricyclic agents, as compared with placebo,
reduced bed-wetting by about 1 wet night per week. About a fifth of the children
became dry. The lasting cure rate was only 17 percent, which restricts the use of these
drugs.[393]
However, owing to the unfavourable adverse event profile, which includes association
with mood changes and sleep disturbances, and the risk of death with an over dosage,
due to the potential cardiotoxic side effects, the ICCS recommends that imipramine be
used only when all therapies have failed.[393, 394]
Reboxitine, a novel selective norepinephrine reuptake inhibitor, with a minimal affinity
to the reuptake serotonin site, without an effect on the dopamine reuptake, and a
minimal affinity to the adrenergic (alpha 1) and muscarinic (M1) receptors, has been
effectively used as a non-cardiotoxic alternative to imipramine in the treatment of
nocturnal enuresis. [395-397]
5.2.2.4 Inhibitors of prostaglandin synthesis
In some patients nocturnal polyuria is due to an increase in nocturnal excretion of
sodium.[386, 398-401] High urinary prostaglandin E2 levels found in these children point
toward a role for increased prostaglandin synthesis in the pathogenesis of enuresis71
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
72
related polyuria. [386] In those cases prostaglandin synthesis inhibitors, such as diclofenac
and indomethacin, proved to be effective.[390, 402-404] Prostaglandin synthesis inhibitors
possess antinatriuretic, antidiuretic and bladder relaxing properties.[130, 405]
A Cochrane analysis showed indomethacin and diclofenac to be better than placebo.
Compared to desmopressin, indomethacin was less effective.[390]
Although no adverse effects were reported with the use of prostaglandin synthesis
inhibitors in children with enuresis, careful use of these drugs is necessary because of
their side effects such as gastrointestinal toxicity and acute renal failure
5.2.2.5 Combination therapy
The two most commonly combined therapies are the enuresis alarm and desmopressin.
It was found to be more effective than alarm treatment alone.[406]
Antimuscarinic drugs combined with desmopressin have been used successfully in
cases of limited response to desmopressin. [388, 407-409]
Chapter 6
Objectives of this thesis and
background of the research
performed at our centre.
The literature review in part 1 clearly demonstrates the complexity of urinary
incontinence and nocturnal enuresis.
A lot of children referred to a tertiary urinary incontinence centre suffer day and
night urinary incontinence. Even in children referred with so called refractory
monosymptomatic enuresis, thorough examination often reveals a combination of day
and night problems.[196]
This is even more the case in children with an intellectual and/or physical disability.
In our treatment philosophy we first deal with the daytime problem, and secondarily
focus on nocturnal enuresis.
Up till to date, in “normally developed” children suffering urinary incontinence,
the therapeutical approach consists of urotherapy whether or not combined with
biofeedback and/or antimuscarinics. The latter are still recommended as first choice
treatment of overactive bladder.
As illustrated in part 1 a lot of supplementary therapeutical options have been studied
in literature. Our own group illustrated the value of transcutaneous and percutaneous
nerve stimulation in the treatment of urinary incontinence.[249, 251]
This large variation of treatment modalities, often with low evidence, illustrates that a
real successful golden standard therapy for urinary incontinence doesn’t exist.
As mentioned antimuscarinics are of major importance in the treatment of overactive
bladder. At start of our research for this thesis, oxybutinin was the only antimuscarinic
drug, FDA approved to be used in children. The level of evidence of the studies with
oxybutinin is rather low.
One of the major concerns using oxybutinin is the numerous side effects reported in
literature. Moreover, the results of oxybutinin are often deceiving.
Because of these restrictions there is an ongoing search for more selective, more potent,
more effective and safer anti-muscarinics in adults. Unfortunately there is rather no
interest from industry for the urinary incontinent paediatric population. This prompted
us, tertiary paediatric incontinence centres, to use this “adult” medication off label in our
paediatric patients.
73
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Based on the promising results of the use of, a so called “bladder selective”, extensively
studied anti-muscarinic, tolterodine in adults and the sparse studies in children we
evaluated the efficacy and the tolerability of tolterodine in a non-selected paediatric
population.
The results of this retrospective analysis of efficacy and tolerability were promising.
Further studies considered tolterodine to be safe in children, but efficacy results were
rather disappointing. [297]
Tolterodine was certainly not the solution for all our patients. From our experience
with the use of tolterodine we found that some children are not treated sufficiently,
probably due to a faster metabolisation of drugs in children than in adults or because
of changed pharmacokinetics when tablets were broken.
Some remained refractory urinary incontinent despite adequate followed therapy.
Others failed because of low compliance.
Based on our experience with tolterodine we started to use off label another new
potent, selective anti-muscarinic, once daily oral agent: solifenacin succinate. We
reviewed the charts of children with therapy resistant overactive bladder treated with
solifenacin. The results of this retrospective study are very promising according to
efficacy and tolerability.
As mentioned before the use of antimuscarinics, even the more bladder selective, is
sometimes deceiving because of side effects and ineffectiveness. Therefore we started
to look for non-antimuscarinic alternatives.
Botulinum-A toxin had already been used successfully as treatment of neurogenic and
idiopathic detrusor overactivity in adults, and of neurogenic bladder in children.
The main advantage of a treatment with Botulinum-A toxin is that the results of a single
treatment last for about 6-9 months independent of the patients’ compliance. There are
three main disadvantages of the use of Botulinum-A toxin in children: 1. it is invasive
as complete anaesthesia is required, 2. the exact dose is still unknown and 3. the long
term safety has never been proven. Because of these disadvantages Botulinum-A toxin
can, in our opinion, only be used as a treatment of refractory, therapy resistant urinary
incontinence in children. Therefore we started a prospective, uncontrolled pilot study
to evaluate the tolerability and effectivity of Botulinum-A toxin in children with therapy
resistant overactive bladder. The results of this study illustrated Botulinum-A toxin to be
a valid alternative in the treatment of overactive detrusor in children.
In some cases of refractory, therapy resistant daytime incontinence, medication is
insufficient, not well tolerated or simply fails. In some patients parents do refuse the use
of further medication. Many of these children are no longer aware that incontinence
74
happens and wet pants are simply ignored. We wondered if a cognitive training with a
daytime alarm could increase their awareness and as such could offer a supplementary
solution in some of these cases. In a retrospective study we reviewed the files of 63
children suffering refractory daytime incontinence. We found a full response in 35%
of the patients and a partial response in another 35%, which is certainly encouraging
considering that all of them were “hard core day-wetters”.
Another group suffering refractory urinary incontinence, rarely studied, are the
intellectually and physically disabled children. Urinary incontinence is often thought to
be a minor, inevitable, untreatable and even unimportant part of their often complex
pathology.
The majority of studies in these children were performed on small, very heterogeneous
populations. Therefore results are often inconclusive.
We first set up a prospective pilot study to look for pathophysiologic factors, such as
dysfunctional voiding, reduced maximum voided volume and restricted fluid intake.
This study illustrated the importance of restricted fluid intake.
In a more recent study we prospectively evaluated the importance of adequate fluid
intake in the treatment of urinary incontinence in these children. It turned out to be a
very important factor.
In some of these children urotherapy alone will be insufficient to treat the urinary
incontinence. Overactive detrusor is also in this population an important causal factor.
Children with an intellectual and/or physical disability often show behavioural problems,
reduced concentration and hyperactivity. Also the incidence of constipation and faecal
incontinence is higher than in “normal” children. This means that these patients are
more prone to the side effects of anti-muscarinics, and that the advantages of the use
of more selective anti-muscarinics are even more important.
Even the use of Botulinum-A toxin and the daytime alarm might offer therapeutical
perspectives in this population. To our knowledge no studies on these topics have
been performed yet.
As mentioned many of our patients do not only suffer diurnal incontinence but also
have nocturnal enuresis. Once the daytime problem is nearly completely solved, our
attention has to be focussed on the nighttime problem.
Also enuresis is very complex in origin. This, sometimes underestimated, heterogeneity
is certainly one of the most important reasons for the large number of different
treatment options described in literature.
75
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
76
This thesis is part of a full research line on pathogenesis, pathophysiology and treatment
of urinary incontinence and nocturnal enuresis.
Our group performed studies on genetics [151], treatment of monosymptomatic
enuresis[17, 113, 367], and desmopressin resistant nocturnal polyuria. . [116, 120, 121, 123, 384]
We also studied the irrefutable importance of co morbidity factors, such as ADHD and
psychological disturbances, in nocturnal enuresis and urinary incontinence.[146, 161, 162, 164,
166, 167, 410-414]
Non-monosymptomatic nocturnal enuresis and urinary incontinence in children is less
evidence based documented in literature. Hoebeke et al. illustrated the importance of
bladder dysfunction in children with NMNE and urinary incontinence.[84]
Our group performed several studies on urotherapy [231] and especially pelvic floor
therapy in the treatment of dysfunctional voiding. [84, 233, 415-417]
Part 2 - Publications
77
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
78
Publication 1
Retrospective Analysis of Efficacy and Tolerability of Tolterodine in Children
with Overactive Bladder
A. Raes, P. Hoebeke, I. Segaert, E. Van Laecke, J. Dehoorne, J. Vande Walle
European Urology, 2004, Vol.45: 240-244
In this paper the efficacy and tolerability of tolterodine in children with an overactive
bladder is evaluated.
The results of this retrospective study suggest tolterodine to be a well tolerated and
effective treatment for urinary symptoms due to overactive bladder.
European
Urology
European Urology 45 (2004) 240–244
Retrospective Analysis of Efficacy and Tolerability of
Tolterodine in Children with Overactive Bladder
A. Raesa,*, P. Hoebekeb, I. Segaerta, E. Van Laeckeb, J. Dehoornea, J. Vande Wallea
a
Department of Paediatrics, Paediatric Uro-Nephrological Centre (PUNC), Ghent University Hospital, De Pintelaan185, B-9000 Ghent, Belgium
Department of Urology, Paediatric Uro-Nephrological Centre (PUNC), Ghent University Hospital, Ghent, Belgium
b
Accepted 17 October 2003
Published online 7 November 2003
Abstract
Objective: To evaluate the efficacy and tolerability of tolterodine in children with an overactive bladder, treated in a
single incontinence centre.
Materials and methods: A retrospective analysis of a database of a total of two hundred and fifty-six patients (175
boys and 81 girls, age range 3 years to 17 years, mean age 8.33 years) with urodynamically confirmed bladder
overactivity was performed. All children received tolterodine tartrate (dose range of 0.5–4 mg orally). In group I
(n ¼ 205) tolterodine tartrate replaced anticholinergic drugs (AC) (oxybutinin chloride or oxyphencyclimin
hydrochloride). A subgroup of patients switched because of intolerance due to serious adverse events (60.4%)
or because of lack of improvement in micturition variables (39.6%). In group II tolterodine was prescribed as initial
therapy (n ¼ 51). Tolerability was assessed by a standardised questionnaire on adverse events at every outdoor clinic
visit. Efficacy assessment was based on micturition diary variables, mean change of maximum bladder capacity and
number of incontinence episodes/24 h.
Results: The mean treatment time was 9.32 months with a range from 1.5 months to 23.4 months. The final dose was
0.1 mg/kg orally daily divided into two doses. In group I central nervous system disorders (81%) were the most
common adverse events, 26.2% showed flushing, 12.2% accommodation problems and 25.2% had gastrointestinal
complaints (constipation, encopresis, abdominal pain). Withdrawal of the non-selective antimuscarinic drug
resulted in total recovery from adverse events.
Introduction of tolterodine in group I and II caused no serious adverse events. Nine patients (3.5%) reported sideeffects and only two discontinued treatment. There were no reports of flushing, troubles of visual accommodation,
hyperpyrexia. In group I we observed a mean decrease in urgency by 38.7%, a mean increase in maximal bladder
capacity by 33.6% and the number of incontinence episodes decreased by 64.8%. In group II we observed equivalent
values with a significant ( p < 0:001) change in maximal bladder capacity (49.7%), incontinence episodes (64.8%)
and micturition episodes/24 h.
Conclusions: The results of this retrospective analysis suggest that tolterodine is well tolerated in children and offers
an effective treatment for urinary symptoms due to overactive bladder. Tolterodine is superior to non-selective
antimuscarinic drugs, with respect to adverse events, allowing more compliance and more effective treatment in
children.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Tolterodine; Overactive bladder; Antimuscarinic drugs; Children; Tolerability; Efficacy
1. Introduction
*
Corresponding author. Tel. þ32-9-240-64-62; Fax: þ32-9-240-38-75.
E-mail address: [email protected] (A. Raes).
Detrusor hyperactivity in childhood is a common
phenomenon and these children may suffer dayand nighttime wetting, urinary tract infections and
0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2003.10.009
79
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
80
A. Raes et al. / European Urology 45 (2004) 240–244
associated vesicoureteral reflux [1–3]. Treatment
options for children with symptoms of overactive
bladder range from simple behavioural measures such
as bladder training and biofeedback techniques through
medical treatment with drugs [5,6]. Among the drugs
used for the treatment of the overactive bladder,
antimuscarinic agents are still regarded as first-line
therapy. Since 1972 oxybutinin chloride (OC) is the
reference standard antimuscarinic drug [4]. This type
of drug is effective, but its use is limited by systemic
adverse events, in a significant proportion of children,
which may result in poor compliance or even discontinuation of treatment. Tolterodine is a potent antimuscarinic agent specifically developed for the treatment
of urinary incontinence and other symptoms related to
the overactive bladder. The safety, efficacy and dosing
of tolterodine in the adult population have been extensively studied in controlled clinical trials and reported
[7–11]. These results demonstrated that tolterodine at a
dosage of 2 mg twice daily has a favourable pharmacological profile reflected by equal effectiveness but
significantly fewer side-effects than OC. To date, only
three reports are published about the use of tolterodine
in children. Goessl et al. published the first study of
tolterodine in children with detrusor hyperreflexia and
demonstrated that the drug improved the bladder compliance in these children [13]. Munding et al. showed
that tolterodine may be efficacious in 30 children with
dysfunctional voiding to reduce wetting episodes without severe adverse effects [12]. Hjälmas published
pharmacokinetic data [14]. However the published data
are always on a limited number of selected patients,
with a short-term follow-up. Specific information
regarding the response to use of tolterodine in a
non-selected population of children with overactive
bladder remains sparse. The aim of our study was to
evaluate the efficacy and the tolerability of tolterodine
in a non-selected paediatric population through a retrospective analysis of the files. The ethical committee at
the University Hospital of Ghent approved this study.
241
ultrasound of the kidney, bladder and residual volume, uroflowmetry and micturition diary. If there is evidence for a small bladder,
without abnormal uroflow and/or residual urine, anticholinergics
are the treatment of choice, associated with bladder volume training
and instructions on drinking and voiding. Because tolterodine is
not yet registered in children, it is still not a first-choice therapy and
we do not prescribe the drug without documentation of the underlying bladder dysfunction. An overactive bladder had been confirmed by videocystomanometry in 237 patients. The other 19
children showed symptoms (urge, frequency) suggesting unstable
bladder and received anticholinergic treatment without urodynamic
investigation.
Before starting tolterodine, patients and parents were informed
that the drug was not registered for children in Belgium and that
international available data are limited. The patients were started on
a regimen of tolterodine in a dose range from 0.5 to 2 mg. In group
IA oxybutinin hydrochloride or oxyphencyclimin hydrochloride
was replaced by tolterodine due to adverse events and in group IB
tolterodine was introduced due to completely failing to respond to
treatment. In group II tolterodine was started as initial therapy when
a risk to develop side-effects was suspected. Most of these patients
had a clinical history of behavioural disorders (hyperactivity or
attention disorders). When only partial improvement was noted, the
dose of tolterodine was gradually increased to a total of 3 or 4 mg/
day. The children who received concurrent biofeedback training
continued with this therapy. Patients’ follow-up consisted of standardised evaluation at the outdoor clinic every six weeks, with
registration of the data on maximal bladder capacity, voiding chart
variables, a questionnaire on adverse events due to antimuscarinic
treatment and subjective symptoms. In addition, uroflowmetry was
performed at every visit, consequently followed by ultrasonographic assessment of residual volume and collection of these data
in the file. All adverse events regarding the intensity, seriousness
and therapeutic interventions were recorded.
Medical records are then used to collect data on their demographic data, primary diagnosis, previous treatments, compliance
with the medications, side-effects and voiding variables on the
tolterodine treatment. Efficacy assessment was based on micturition diaries collected by the patient at each visit. Efficacy was
measured by comparing the values at the end of the follow-up
period to baseline. Efficacy measures included the number of
micturitions/24 h, the number of incontinence episodes/24 h,
urgency and the mean change of maximum bladder capacity.
Efficacy was also evaluated through patients’ perception of their
bladder condition. Tolerability was assessed from adverse events
through an explicit questionnaire about adverse effects. Adverse
events were classified as mild, moderate or severe with respect to
therapeutic intervention. Appropriate parametric statistical methods were used for analysis, and significance was set at the 5% level.
2. Materials and methods
All the files of children treated with tolterodine at the University
Hospital of Ghent between November 1999 and August 2001 were
analysed. At least 6 weeks follow-up was required for inclusion.
Patients with a neuropathic bladder, anatomical abnormality of the
lower urinary tract and recurrent urinary tract infections were
excluded. 256 files were identified. All patients had evidence for
an overactive bladder. The majority presented with symptoms of
nocturnal enuresis associated with daytime wetting, frequency,
urgency and/or small bladder volume. At our institution all the
patients undergo a standardised initial evaluation, which includes a
complete clinical history, clinical examination, urine analysis,
3. Results
A total of 256 patients (175 boys and 81 girls; age
range of 3 years to 17 years; mean age 8.33 years) were
included for data analysis. The follow-up ranged from
6 weeks to 23.4 months with a mean of 9.32 months.
We excluded 3 files from further analysis due to
inadequate follow-up in 2, and subsequent anatomical
abnormality in 1.
Patients were divided in two groups.
A. Raes et al. / European Urology 45 (2004) 240–244
Group I consisted of 205 children (142 boys and 63
girls) between 4.1 years and 18.1 years of age (mean
age of 8.4 years), previously treated with an anticholinergic medication (oxybutinin hydrochloride or
oxyphencyclimin hydrochloride) but switched to
tolterodine because of significant adverse events
(subgroup A) or lack of improvement in micturiton
variables (subgroup B) during anticholinergic therapy.
All patients had previously been treated with anticholinergics for a minimum of 6 months. Hundred and
eight patients received concomitant biofeedback training, which was continued during this episode. In fortysix patients desmopressin (10–20 mg intranasal) was
associated.
Group II consisted of 51 children between 3.1 years
and 6.9 years (mean age 6.6) who had received no
anticholinergic medication before the initiation of
tolterodine treatment, but almost all children had a
clinical history of ADHD. Analysis of baseline demographics, disease characterization, micturition charts
and urodynamic variables revealed no significant differences between the two groups. The dose of tolterodine ranged from 0.5 mg to 4 mg, but the final dose
used was approximately 0.1 mg/kg orally, divided into
two gifts.
For both groups we observed a significant increase
( p < 0:001) in maximal bladder capacity. In group I
we found a mean change of 57 ml (33.6%) of maximal
bladder capacity from baseline value, without difference between the two subgroups. The second group
showed a greater increase in maximal bladder capacity
(mean of 73 ml (49.7%)) (Fig. 1).
Fig. 1. Mean change from baseline in maximal bladder capacity and
residual volume under treatment with tolterodine in group I ( ) and group
II ( ).
0
mean change from baseline (n)
242
-1
-2
micturitions
*
incontinence episodes
*
-3
urge
*
*
*
*
-4
-5
* p < 0,05
Fig. 2. Mean (� S.D.) change from baseline in number of micturitions,
incontinence episodes and urge/24 h during treatment with tolterodine in
group I ( ) and group II ( ).
There was a progressive decrease in the mean frequency of micturitions in both groups. The treatment
with tolterodine reduced the mean daily micturition
episodes with 0.3 (subgroup A) and 0.89 (subgroup B)
in group I. For the second group there was a significant
reduction ( p < 0:001) with a mean daily reduction of
1.1 micturition episodes (Fig. 2). In total 215 had
diurnal incontinence episodes at baseline. These
patients showed significant decrease from baseline in
both groups. The mean daily incontinence episodes
were reduced by 64.8% (n ¼ 2:3). In group I, 50% of
the patients reached diurnal continence and 27.4% had
a 50% reduction in wetting episodes, with no statistically difference between the subgroups. Those patients
who were completely continent with OC remained so
under tolterodine. In group II, 54% reached diurnal
continence and 24% had a 50% reduction in wetting
episodes. For the variable, urgency we observed a
reduction with 38.7% in the first group and of 28.9%
in the second group (Fig. 2).
Concerning the variable, residual urinary volume, we
observed a decrease of residual volume to normalisation
in 35 of 48 patients previously treated with antimuscarinic drugs. Serious adverse events during treatment
with tolterodine were not reported. During treatment
with oxybutinin and oxyphencyclimin hydrochloride
central nervous system disorders (81%) were the most
common adverse events (cognitive impairment, headache, behavioural abnormalities), 26.2% showed flushing, 12.2% had abnormal accommodation and 25.2%
had gastrointestinal complaints (constipation, soiling,
diarrhoea). Withdrawal of the non-selective antimuscarinic drug resulted in total recovery from adverse
events and introduction of tolterodine caused no
serious adverse events. Only 1 patient suffered from
behavioural disorder (aggressiveness) and 2 had mild
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
82
A. Raes et al. / European Urology 45 (2004) 240–244
gastrointestinal complaints. In the whole treatment
group we observed 3 patients with behavioural disorders (1 attack of fear, 1 trouble with concentration, 1
aggressiveness) and 6 with mild gastro-intestinal complaints (1 soiling, 2 diarrhoea and 3 mild complaints),
leading to treatment withdrawal in only two. There were
no reports of flushing, hyperpyrexia, abnormal accommodation, or dry mouth. Three patients withdraw the
tolterodine treatment due to the high price.
4. Discussion
Our data support that tolterodine might offer an
interesting and safe therapeutic alternative in children
with an overactive bladder. Antimuscarinic drugs are
generally regarded as the standard therapy for symptoms attributable to bladder overactivity. However their
utility is often limited by their adverse effects (dry
mouth, flushing, central nervous dysfunctions). Tolterodine, a new potent and selective antimuscarinic drug
was specifically developed for the treatment of detrusor
hyperactivity. Until now, controlled studies of tolterodine are only available for adults and tolterodine has
been shown to be equally effective and to result in
significantly fewer adverse effects than oxybutinin.
However paediatric experience with tolterodine is limited. Munding et al. reported that tolterodine in conjunction with behavioural modifications can improve
incontinence due to dysfunctional voiding to reduce
wetting episodes without severe adverse events in
children. Our data are the largest published for the
paediatric population until now. Despite limitations,
this study has several advantages. Limitations are not
only because it is a retrospective study, but also
because there is no control-group nor randomisation
and some patients have combined therapies. We are
aware of an ongoing large multi-centre prospective
double-blind randomised study with tolderodine
(extended release) in children. However high risk
patients (hyperkinetic children, patients with history
of severe side-effects on anticholinergic drugs, children with history of urinary tract infections, residual
urine and/or abnormal uroflow) might be excluded,
resulting in a highly selected population. Association
with other therapies such as bladder volume training,
psychological coaching, pelvic floor relaxation therapy
as treatment for uroflow abnormalities and/or residual
urine, and the introduction of DDAVP and/or alarm
therapy once daytime continence is achieved, is not
allowed in this prospective study. We, among others, do
believe that monotherapy results only in an extremely
poor success rate in this study population, resulting in
243
full day- and nighttime continence in only 10–25% at 1
year of therapy, with important negative psychological
effects on the child, and very high drop-out rates during
therapy.
Therefore we are convinced that there is definitely
need for data in a non-selected, probably high risk
population, but this kind of studies will probably never
be performed in a prospective randomised way. Such
data can only be obtained from retrospective data of
patients with compassionate use of this drug.
In our analysis we stratified results for children
previously treated with a non-selective antimuscarinic
drug (divided in a group who had prior adverse events
and a group without adequate improvement on therapy)
and children who had no prior therapy. Introduction of
tolterodine resulted in a significant difference of the
micturition variables in both groups. We observed a
marked increase in bladdercapacity and a significant
decrease in other micturition variables: number of
micturitions/24 h, number of incontinence episodes/
24 h, compared with baseline values for both groups
without statistical differences between the groups. In
only 4 children we observed a worsening of the incontinence. It could be argued that the high response in the
first group reflect a selection bias, as improvement on
previous anticholinergics failed due to reduction of the
dose or poor compliance. However comparing the
results from the patients previously treated with antimuscarinic drugs and those without prior therapy, we
were not able to detect a significant difference. Association with pelvic floor therapy could be an explanation for this observation. Therefore analysis of both
groups, for treatment with tolterodine alone and for
combination therapy of tolterodine and pelvic floor
therapy, was performed and data showed no significant
difference. The improvement was equally divided
between the two groups. Although this study is a
retrospective analysis, these results show that tolterodine has therapeutic efficacy in children with overactive bladder of different ages, comparable with other
anticholinergic drugs. This confirms the results of
Munding and Goessl and findings in adults, in whom
controlled studies tolterodine is an effective treatment
in patients with an overactive bladder and is equally
potent as the reference drug oxybutinin chloride.
Goessl et al. showed that one of 22 patients suffered
from a side-effect, transient flushing. In the study by
Munding et al. 4 of 24 children had mild side-effects.
Our study was designed to evaluate the tolerability of
tolterodine and to compare it with other antimuscarinic
drugs. The most frequent side-effects under treatment
with oxybutinin are central nervous disorders and
gastrointestinal complaints. In a total of 256 patients
244
A. Raes et al. / European Urology 45 (2004) 240–244
we observed only 9 patients with side-effects (3 behavioural disorders, 6 gastrointestinal complaints). None
of the children had dry mouth, flushing or abnormal
accommodation. The side-effects were not gender- or
age-related. From the 122 patients who had been
switched to tolterodine due to adverse events on previous treatment only 3 showed mild side-effects and
one discontinued due to inadequate improvement.
These results demonstrate an excellent tolerability of
tolterodine in children. Tolterodine is better tolerated
than oxybutinin, particularly with respect to the frequency and intensity of side-effects, behavioural disorders, accommodation abnormalities and other sideeffects. It is envisioned that the comparable efficacy
and significantly better tolerability would manifest
itself in improved quality of life for children treated
with tolterodine and allows more children to remain on
effective therapy than the current most commonly
prescribed agent for the treatment of the overactive
bladder [15].
5. Conclusions
These findings suggest that tolterodine offers a safe
and effective therapy for children with an overactive
bladder. Tolterodine enables children to continue treatment with a minimum of adverse effects, resulting in
improved compliance and more effective therapy than
the standard therapy. A tolterodine dose of 1–2 mg
twice daily combined favourable efficacy and tolerability in this retrospective analysis. Further evaluation
of this medication in controlled trials in children is
necessary to confirm both parameters.
References
[1] Bauer SB, Retik AB, Colocy AH, et al. The unstable bladder in
childhood. Urol Clin North Am 1980;7:312.
[2] Webster GD, Koefoot Jr RB, Sihelnik S. Urodynamic abnormalities
in neurologically normal children with mycturition dysfunction. J
Urol 1984;132:74.
[3] Koff SA, Lapides J, Piazza DH. Association of urinary tract infection
and reflux with inunhibited bladder contractions and voluntary
sphincteric obstruction. J Urol 1979;122:373.
[4] Diokno AC, Lapides J. Oxybutinin: a new drug with analgesic and
anticholinergic properties. J Urol 1972;108:307.
[5] Milroy E. Pharmacologic management of common urodynamic
problems. Urol Clin North Am 1979;6:265.
[6] Kass EJ, Diokno AC, Montealegre A. Enuresis: principles of
management and results of treatment. J Urol 1979;121:794.
[7] Appell RA. Clinical efficacy and safety of tolterodine in the
treatment of overactive bladder: a pooled analysis. Urology 1997;
50(Suppl 6A):90–6.
[8] Abrams P, Freeman R, Anderström A, Mattiasson A. Tolterodine, a
new antimuscarinic agent: as effective but better tolerated than oxybutinin in patients with an overactive bladder. Br J Urol 1998;81:801–10.
[9] Messelink AJ. Treatment of the overactive bladder with tolterodine,
a new muscarinic receptor antagonist. Br J Urol 1999;83(Suppl 2):
48–52.
[10] Nilvebrant L, Påhlman I, d’Argy R. Tissue distribution of tolterodine
and its metabolites: low penetration into the central nervous system.
Eur Urol 2000;37(Suppl 2):84 [Abstract 333].
[11] Chancellor MB. Tolterodine: selectivity for the bladder over effects
on visual accommodation. J Urol 2000;163:226.
[12] Munding M, Wesselis H, Thornberry B, Riben D. Use of tolterodine
in children with dysfunctional voiding: an initial report. J Urol 2001;
165:926–8.
[13] Goessl C, Sauter T, Michael T, et al. Efficacy and tolerability of
tolterodine in children with detrusor hyperreflexia. Urology 2000;55:
414.
[14] Hjälmas K, Hellström A-L, Mogren K, Läckgren G, Stenberg A.
Tthe overactive bladder in children: a potential future indication for
tolterodine. BJU Int 2001;87(6):569–74.
[15] Drutz H, Appell R, Gleason D, et al. Clinical efficacy and safety of
tolterodine compared with oxybutinin and placebo with overactive
bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:283.
83
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
84
Publication 2
Solifenacin for Therapy Resistant Overactive Bladder
Piet Hoebeke, Jan De Pooter, Karel De Caestecker, Ann Raes, Joke Dehoorne, Erik Van
Laecke, Johan Vande Walle
The Journal of Urology, October 2009, Vol.182: 2040-2044
Solifenacin, as a once daily oral agent, was used in therapy resistant children with
overactive bladder.
An uncontrolled, retrospective study was performed in 138 children suffering therapy
resistant overactive bladder.
The results according to efficacy and side effects are given in this paper
Solifenacin for Therapy Resistant Overactive Bladder
Piet Hoebeke,* Jan De Pooter, Karel De Caestecker, Ann Raes, Joke Dehoorne,
Erik Van Laecke and Johan Vande Walle
From the Division of Pediatric Urology, Department of Urology and Division of Pediatric Nephrology, Department of Pediatrics (AR, JD, JVW),
Ghent University Hospital, Ghent, Belgium
Abbreviations
and Acronyms
EN nocturnal enuresis
ID diurnal incontinence
OAB overactive bladder
Study received hospital ethical committee approval.
Supported by an Astellas educational grant.
* Correspondence: Department of Urology,
Ghent University Hospital, De Pintelaan 185, B 9000
Gent, Belgium (e-mail: [email protected]).
Purpose: With the availability of the once daily oral antimuscarinic agent solifenacin (5 mg), we started to use it for therapy resistant overactive bladder. We
evaluate side effects and efficacy.
Material and Methods: We reviewed the charts of children treated with solifenacin succinate between August 2005 and August 2008 for therapy resistant
OAB. Incontinence was compared at study entry and study end.
Results: During the study period 84 boys and 54 girls with a mean age of 9 years
2 months received solifenacin. Mean followup was 22.59 months. While on solifenacin, side effects were observed in 9 of 138 patients (6.5%). Efficacy evaluation
included only 99 patients after 3 months of therapy. Mean voided volume after
treatment was 253.5 ml, showing a significant 25% increase compared to the
mean value before therapy (50.5 vs 203.0 ml, p 0.01). Of the patients 84 (85%)
were considered responders, including 45 who were completely dry (full response)
and 39 who had fewer nocturnal enuresis or diurnal incontinence symptoms
(partial response). Of these 39 patients 17 became dry during the day, 1 became
dry during the night and 21 had more than a 50% decrease in nocturnal enuresis
and diurnal incontinence symptoms. In 15 patients the outcome was unchanged
or worse (no response).
Conclusion: In this group of children with OAB we noted favorable results with
solifenacin with few side effects. Despite the uncontrolled, retrospective study
design the effect is attributable to solifenacin intake.
Key Words: urinary bladder, overactive; anticholinergics; urinary
incontinence; nocturnal enuresis; drug resistance
2040
www.jurology.com
CHILDREN with idiopathic OAB are initially treated with urotherapy, a nonsurgical, nonpharmacological treatment
consisting of lower urinary tract rehabilitation using drinking and voiding
charts, lifestyle changes and some specific interventions such as physiotherapy,
neurostimulation and alarm therapy.1
When urotherapy fails, antimuscarinic
drugs can be used. Oxybutynin is the
only antimuscarinic drug licensed for use
in the pediatric age group. Tolterodine, a
newer antimuscarinic drug, has been
tested in children and was considered
safe but efficacy results were disappointing.2 Newer antimuscarinic drugs, such
as solifenacin, darifenacin and fesoterodine, have not been evaluated in children.
In nonresponding children some of these
treatments are off label options.
Solifenacin succinate, a once daily oral
antimuscarinic agent developed for OAB,
significantly decreased urgency episodes
in a pooled analysis of 4 pivotal trials in
more than 2,800 adults.3 The side effect
profile of this drug with a high affinity for
the M3 muscarinic receptor is much
more favorable than that of some unspe-
0022-5347/09/1824-2040/0
THE JOURNAL OF UROLOGY®
Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 2040-2044, October 2009
Printed in U.S.A.
DOI:10.1016/j.juro.2009.05.100
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
86
SOLIFENACIN FOR THERAPY RESISTANT OVERACTIVE BLADDER
cific antimuscarinics. Since we treat so many children
with OAB who do not respond to therapy and due to the
availability of solifenacin succinate (5 mg), we started to
use it in children. Because solifenacin is not licensed for
use in children this was off label use, for which parental
consent was obtained. The hospital ethical committee
approved this study. We retrospectively evaluated the
side effects and efficacy of solifenacin succinate in children with idiopathic OAB.
PATIENTS AND METHODS
We reviewed the charts of children treated with solifenacin succinate for therapy resistant OAB between August
2005 and August 2008. The Appendix shows the data that
were collected, entered into an Excel® database and subsequently analyzed. Preceding antimuscarinic therapy
was stopped 4 weeks before the start of solifenacin. All
patients were included in the side effect evaluation. For
efficacy evaluation only patients who received the drug for
at least 3 months were included. Patients with neurogenic bladder were excluded from this analysis. Efficacy
was measured based on incontinence during the day
and/or night, and by measuring voided volume. Incontinence and voided volume at study entry were compared to incontinence and voided volume at study end.
Treatment outcome definitions used were those proposed by the International Children’s Continence Society, including nonresponse— 0% to 49% decrease, partial response—50% to 89% decrease, response—90% or
greater decrease and full response—100% decrease in
incontinence or less than 1 incontinence incident
monthly.4 The paired Student t test was used for statistical analysis.
RESULTS
During the study period 84 boys and 54 girls with
a mean age of 9 years 2 months (range 4.50 to
16.59) were identified who received solifenacin.
Mean followup was 22.59 months. Mean therapy
duration was 6.61 months (range 0.40 to 27.93).
Patients were divided into 3 study groups by incontinence pattern, including group 1— 88 with
EN and ID, group 2—30 with ID without EN and
group 3—17 with monosymptomatic EN. Three
patients with neuropathic bladder were excluded
from the efficacy evaluation. No patients were dry
before starting solifenacin. Mean voided volume at
study entry in the whole study group was 201.4
ml. No patient had post-void residual urine after
voiding at study entry.
The main indication for study inclusion was
nonresponse to previous treatment. All patients
had been previously treated for OAB for more than
24 months. Treatment consisted of standard therapy,4,5 behavior therapy, bladder training, physiotherapy and medical therapy. All study patients
underwent videourodynamics in the period before
2041
the study. In all patients detrusor overactivity
was observed during filling. Six patients had recurrence after former successful anticholinergic
therapy and 16 changed to solifenacin because of
side effects on other anticholinergic therapy. The
solifenacin dose was 5 mg.
Side Effects
Of the patients 108 received another anticholinergic before starting solifenacin, of whom 42 (39%)
experienced side effects due to that therapy. On
solifenacin side effects were observed in 9 of 138
patients (6.5%), including behavior problems (hyperactivity) in 2, drowsiness in 1, insomnia in 1
and gastrointestinal problems in 5, that is constipation (3), gastrointestinal pain (1) and fecal impaction with hospitalization (1). Five of these 9
patients reported side effects during previous anticholinergic therapy. Except for fecal impaction
the side effects were considered mild. In 5 patients
solifenacin was discontinued because of adverse
effects. No patient had post-void residual urine
while on treatment.
Efficacy
Overall study group. Efficacy evaluation was performed in 99 of 138 patients. Of the patients 14 were
lost to followup, 17 could not be evaluated due to less
than 3 months of therapy, 5 stopped treatment because of adverse effects and 3 diagnosed with neuropathic bladder were excluded from efficacy evaluation.
Of the 84 patients (85%) considered responders, 45
were completely dry (full response) and 39 had fewer
symptoms of EN or ID (partial response). Of the 39
patients 17 became dry during the day, 1 became dry
during the night and 21 had more than a 50% decrease in ID and EN symptoms. In 12 patients the
outcome was unchanged and in 3 the outcome was
worse (no response) (fig. 1). Mean voided volume
after treatment was 253.5 ml, representing a significant 25% increase compared to the mean value before therapy (50.5 vs 203.0 ml, p 0.01, fig. 2). The
response was observed after 1 month at followup
visit 1. Most responders reported improvement after
1 week of treatment.
Group 1 (ID EN). Efficacy evaluation was performed in 63 of 88 patients. Eight patients were
lost to followup, 14 could not be evaluated due to
less than 3 months of therapy and 3 stopped therapy due to side effects. Of the patients 53 (84%)
were considered responders, of whom 24 became
completely dry (full response) and 29 had fewer
EN or ID symptoms (partial response). Of the 29
patients 17 became dry during the day, 1 became
dry during the night and 11 had more than a 50%
decrease in ID and EN symptoms. In 7 patients
the outcome was unchanged and in 3 the outcome
2042
SOLIFENACIN FOR THERAPY RESISTANT OVERACTIVE BLADDER
Figure 3. Efficacy in ID EN group. Nr, number
Figure 1. Efficacy in total study group
was worse (no response) (fig. 3). Mean voided volume after treatment was 233.6 ml, representing a
significant 21% increase compared to the mean
value before therapy (40.2 vs 193.4 ml, p 0.01,
fig. 2).
Group 2 (ID). Efficacy evaluation was performed in
21 of 30 patients. Five patients were lost to followup, 2 could not be evaluated due to less than 3
months of therapy and 2 stopped therapy due to
side effects. Of the patients 19 (90%) were considered responders, of whom 14 became completely
dry (full responder) and 5 had fewer EN or ID
symptoms (partial response). In 2 patients the
outcome was unchanged (no response) (fig. 4, A).
Mean voided volume after treatment was 297.1
ml, representing a significant 29% increase compared to the mean value before therapy (65.9 vs
231.2 ml, p 0.01, fig. 2).
Group 3 (EN). Efficacy evaluation was performed
in 15 of 17 patients. One patient was lost to followup and 1 could not be evaluated due to less
than 3 months of therapy. Of the patients 12 (80%)
were considered responders, of whom 7 became
completely dry (full response) and 5 had fewer EN
or ID symptoms (partial response). In 3 patients
the outcome was unchanged (no response) (fig. 4,
B). Mean voided volume after treatment was 283.3
ml, representing a 39% increase compared to the
mean value before therapy (79.8 vs 203.5 ml, p 0.01,
fig. 2).
Figure 2. Voided volume in ml in different groups. Blue bars
indicate pretreatment. Red bars indicate posttreatment.
Group comparison. We compared mean voided
volume in all study groups. The increase in voided
volume is expressed as the percent of voided vol-
87
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
SOLIFENACIN FOR THERAPY RESISTANT OVERACTIVE BLADDER
Figure 4. Efficacy in ID (A) and EN (B) groups. Nr, number
ume before therapy (table 1 and fig. 2). The EN
group had the highest increase (32%). We also
compared response rates in the different groups
(table 2).
DISCUSSION
OAB may lead to a disturbed detrusor filling
phase, characterized by urgency, frequency and at
times urge incontinence. Girls present with OAB
symptoms more often than boys. In addition to
urinary symptoms, children with OAB may also
have recurrent urinary tract infections and constipation.6 Antimuscarinic therapy remains a common OAB therapy. Its use is based on the concept
that parasympathetic mediated stimulation of
muscarinic receptors in the bladder causes detrusor overactivity, which is responsible for OAB
symptoms. Antimuscarinic agents increase bladder capacity and bladder compliance, and decrease
detrusor contractions in cases of neurogenic detrusor overactivity. Detrusor overactivity is believed
to have a role in many children with functional
incontinence, vesicoureteral reflux and urinary
tract infections.
Despite the frequent use of anticholinergic therapy the outcome of medical therapy for OAB in
children is unpredictable and inconsistent, and
few randomized studies have assessed drug safety
and efficacy. Currently the most widely used pharmacological therapy in children with detrusor
overactivity is oxybutynin. Historically oxybutynin has been limited by its adverse effect profile
with side effects such as dry mouth, constipation
and central nervous system effects. The incidence
of side effects seems to be dose related for oral and
intravesical administration. The central nervous
system effects are related to the ability of oxybutynin to cross the blood-brain barrier. Newer,
more selective anticholinergic drugs are currently
available for use in adults. Due to higher specific
receptor affinity (predominantly M3) these drugs
are associated with a lower side effect rate.
We retrospectively evaluated the effect of 5 mg
solifenacin succinate for OAB in children. Its side
effect profile is excellent. Children who received
previous anticholinergic treatment can be considered their own control group for side effect evaluation. While 39% of the children had side effects
on other anticholinergics only 6.5% had side effects on solifenacin. Five of the 9 patients with
side effects on solifenacin also had side effects on
Table 1. Voided volume
Table 2. Response rate
Voided vol (ml)
Pretreatment
Total group
ID EN
ID
EN
* p 0.01.
88
2043
203.0
193.4
231.2
203.5
Posttreatment
253.5
233.6
297.1
283.3
Difference*
50.5
40.2
65.9
79.8
% Response
% Increase
25
21
29
39
Total group
ID EN
EN
ID
No. Pts
Full
Partial
Overall
99
63
15
21
45
38
47
66
40
46
33
24
85
84
80
90
2044
SOLIFENACIN FOR THERAPY RESISTANT OVERACTIVE BLADDER
the previous anticholinergic therapy, which could
indicate that side effects were related to the patients. Some patients are likely to have higher
sensitivity to anticholinergic side effects than others. This is only clinical safety based on side effects. To our knowledge no pharmacokinetic or
dose finding studies have been performed so that
to date we can only report clinical safety and not
pharmacokinetic or pharmacodynamic profiles.
With the new safety regulations for drugs in children in the United States and Europe pharmacokinetic studies are needed before registration.
Solifenacin seems to be effective for OAB symptoms with an overall 85% response rate and a full
response in more than 50% of responders. Specifically the effect on daytime incontinence seems to
be more pronounced than the effect on nighttime
incontinence. Due to the significant increase in
voided volume this effect was to be expected. However, in our study the highest increase in voided
volume was seen in the EN group and the highest
response rate was seen in the ID group. The response in children with EN depends less on voided
volume since many of them need further alarm
treatment to become dry at night even when
voided volume is normalized.
The study limitation is its uncontrolled, retrospective design. Since this series was initially designed as a prospective, observational study of the
effects of an off label drug, it was decided at the
start of the study to have no control group. Due to
the off label availability of these new drugs this is
the only way to investigate their use in children.
CONCLUSIONS
In this group of children with OAB we report
favorable results with solifenacin. Despite the uncontrolled, retrospective study design the effect is
attributable to solifenacin intake. However, since
no pharmacokinetic or pharmacodynamic data
were obtained on this study group, we should be
careful when promoting this treatment. Only after
prospective, controlled studies with pharmacokinetic and pharmacodynamic data may the drug be
used. Until then off label application with informed consent is the only way to use it.
APPENDIX
Data From Charts
Patient identification
Birth date
Symptoms at entry
Treatment with other anticholinergics before (yes/no)
Duration of therapy with other anticholinergics (months)
Mean voided volume before therapy (ml)
Study group: ID EN, EN, ID
Date at start of solifenacin therapy
Age at start of solifenacin therapy
Duration of solifenacin therapy (months)
Voided volume after solifenacin therapy (ml)
Symptoms after solifenacin treatment
Completely dry (yes/no)
Adverse effects under solifenacin therapy (yes/no)
Kind of adverse effects
Adverse effects under other anticholinergic therapy (yes/no)
Kind of adverse effects
REFERENCES
1. Hellstrom AL: Urotherapy in children with dysfunctional bladder. Scand J Urol Nephrol, suppl., 1992;
141: 106.
3. Basra R and Kelleher C: A review of solifenacin in
the treatment of urinary incontinence. Ther Clin
Risk Manag 2008; 4: 117.
2. Nijman RJ, Borgstein NG, Ellsworth P et al:
Long-term tolerability of tolterodine extended
release in children 5–11 years of age: results
from a 12-month, open-label study. Eur Urol
2007; 52: 1511.
4. Neveus T, von Gontard A, Hoebeke P et al: The
standardization of terminology of lower urinary
tract function in children and adolescents: report
from the Standardisation Committee of the International Children’s Continence Society. J Urol
2006; 176: 314.
5. Vijverberg MA, Elzinga-Plomp A, Messer AP et al:
Bladder rehabilitation, the effect of a cognitive
training programme on urge incontinence. Eur Urol
1997; 31: 68.
6. Koff SA, Wagner TT and Jayanthi VR: The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol 1998;
160: 1019.
89
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
90
Publication 3
The Effect of Boltulinum-A Toxin in Incontinent Children with Therapy Resistant
Overactive Detrusor.
P. Hoebeke, K. De Caestecker, J. Vande Walle, J. Dehoorne, P. Verleyen, E. Van Laecke
The Journal of Urology, July 2006, Vol. 176: 328-331
In this paper the results of the first prospective study with botulinum-A toxin in a
paediatric population of therapy resistant children with a nonneurogenic overactive
bladder are illustrated.
Botulinum-A toxin injection in this population is a safe, excellent treatment adjunct,
leading to long-term results in 70% after 1 injection.
The Effect of Botulinum-A Toxin in Incontinent
Children With Therapy Resistant Overactive Detrusor
P. Hoebeke,* K. De Caestecker, J. Vande Walle, J. Dehoorne, A. Raes, P. Verleyen
and E. Van Laecke
From the Departments of Pediatric Urology and Pediatric Nephrology (JVW, JD, AR), Ghent University Hospital, Gent, Belgium
Purpose: We determined the effect of detrusor injection of botulinum-A toxin in a cohort of children with therapy resistant
nonneurogenic detrusor overactivity. This prospective study included therapy resistant children with overactive bladder.
Material and Methods: During the study period of 19 months 10 boys and 11 girls were included. All patients showed
decreased bladder capacity for age, urge and urge incontinence. Main treatment duration before inclusion was 45 months. A
dose of 100 U botulinum-A toxin (Botox®) was injected in the detrusor.
Results: Side effects were evaluated in all 21 included patients. The side effects reported were 10-day temporary urinary
retention in 1 girl and signs of vesicoureteral reflux with flank pain during voiding in 1 boy, which disappeared spontaneously
after 2 weeks. No further examinations were done since the boy refused. Two girls experienced 1 episode each of symptomatic
lower urinary tract infection. Eight girls and 7 boys with a minimum followup of 6 months represent the study group for
long-term evaluation. In this study group after 1 injection 9 patients showed full response (no more urge and dry during the
day) with a mean increase in bladder capacity from 167 to 271 ml (p 0.001). Three patients showed a partial response (50%
decrease in urge and incontinence) and 3 remained unchanged. Eight of the 9 full responders were still cured after 12 months,
while 1 of the initially successfully treated patients had relapse after 8 months. The 3 partial responders and the patient with
relapse underwent a second injection with a full response in the former full responder and in 1 partial responder.
Conclusions: Botulinum-A toxin injection in children with nonneurogenic overactive detrusor is an excellent treatment
adjunct, leading to long-term results in 70% after 1 injection.
Key Words: bladder; urinary incontinence; botulinum toxin type A; muscle, smooth; child
B
knowledge the first experience with botulinum-A toxin in a
pediatric population with nonneurogenic overactive bladder.
otulinum-A toxin is a potent neurotoxin that blocks
neuronal acetylcholine secretion by binding to presynaptic nerve endings. Intramuscular injection of
botulinum-A toxin blocks the neuromuscular junction at the
site of injection until new presynaptic nerve sprouts occur.
Initially used to treat striated muscle overactivity, increasing data in the literature are available on its effectiveness
for acetylcholine stimulated smooth muscle overactivity, as
in the lower urinary tract.
Botulinum-A toxin is used in adult urology to treat neurogenic detrusor overactivity, chronic urinary retention, detrusor-sphincter dyssynergia, nonneurogenic detrusor overactivity and chronic prostatic pain.1 Recent studies show
high short-term effectiveness for idiopathic detrusor overactivity in adults.2 In children it has been safely used to treat
strabismus, muscular hypertonia due to cerebral palsy and
neurogenic detrusor overactivity in those with myelomeningocele.3,4
Due to the high prevalence of overactive detrusor in the
pediatric population, the known effect on overactivity in
adults and safety in a pediatric population we designed a
prospective study. We report the results of what is to our
MATERIALS AND METHODS
A prospective protocol was designed for the use of botulinum-A toxin in children with urodynamically proven detrusor overactivity without overt neuropathy or uropathy. Urodynamics considered for inclusion had to be performed
within 2 months before inclusion. Methods conform to the
standards and recommendations for urodynamic studies of
the International Continence Society.5 Children who had
previously been treated without success were considered for
inclusion. Children with dysfunctional voiding or post-void
residual urine were excluded. The study was approved by
the ethics committee of the Ghent University Hospital. Subjects and their parents provided informed consent.
Treatment was done with the patient under general anesthesia. A dose of 100 U botulinum-A toxin (Botox®) was
diluted in 15 ml normal saline. Under cystoscopic guidance
the detrusor was injected at 15 sites with 1 ml injected per
site. A 3.7Fr Deflux® injection needle was used. Injection
was started above the superior edge of the trigone and a line
of 5 injections was given with each injection 1 cm apart. Two
more lines 1 cm cranial from the former line were injected
subsequently. The ventral bladder wall was avoided due to
its close relationship with the peritoneal cavity. After injection the bladder was emptied. After spontaneous voiding the
patient was sent home.
Study received approval from the ethics committee of Ghent University Hospital.
* Correspondence: Department of Pediatric Urology, Ghent University Hospital, De Pintelaan 185, B 9000 Gent, Belgium (e-mail:
[email protected]).
0022-5347/06/1761-0328/0
THE JOURNAL OF UROLOGY®
Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
328
Vol. 176, 328-331, July 2006
Printed in U.S.A.
DOI:10.1016/S0022-5347(06)00301-6
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
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BOTULINUM-A TOXIN IN INCONTINENT CHILDREN WITH OVERACTIVE DETRUSOR
The intent was to repeat urodynamics after injection.
However, we encountered strong patient and parent obstruction. Most patients had undergone urodynamics during
former treatments and just before study inclusion. Especially when the result was favorable, they refused followup
urodynamics. Therefore, we excluded this from the protocol
and considered a less invasive evaluation.
Patients were seen after 1 week for uroflowmetry and
post-void residual urine measurement. After 6 weeks patients were seen for clinical evaluation. A voiding diary was
supposed to be kept for a few days. Six and 12 months after
injection they were reevaluated. At each visit they were
questioned about side effects and the effects of treatment.
Outcome was measured by measuring bladder capacity
and documenting urge and urge incontinence in the voiding
diary. Nighttime continence was not used as an outcome
measure. We called the result a complete response when no
more daytime symptoms (urge and urge incontinence) were
observed. A 50% decrease in urge and urge incontinence was
called a partial response. No clinical improvement was
called failure. Functional bladder capacity was documented
and evaluated. However, it was not used as an outcome
measure.
RESULTS
During a study period of 19 months starting May 2003, 10
girls and 11 boys were included. Mean age at study inclusion
was 10.8 years (range 8 to 14). Based on voiding diaries all
patients showed decreased bladder capacity for age, urge
and urge incontinence before inclusion. All patients experienced nighttime incontinence. Constipation was seen in 7
patients.
The diagnosis was overactive bladder in all cases. None of
the patients showed dysfunctional voiding. The diagnosis
was confirmed by urodynamic study before treatment. None
of the patients showed post-void residual urine.
Main treatment duration before inclusion was 45 months.
Former treatment consisted of capacity training with antispasmodics or anticholinergics and urotherapy. All included
children had been treated without success at the voiding
school, which is 2-week in-hospital bladder training.
A dose of 100 U botulinum-A toxin (Botox®) was injected
in the detrusor with the patient under general anesthesia.
The side effects reported were 10-day temporary urinary
retention in 1 girl, temporary vesicoureteral reflux in 1 boy
and lower urinary tract infection in 2 girls. No other side
effects were seen.
Eight girls and 7 boys with a minimum followup of 6
months formed the study group for long-term evaluation.
After 1 injection 9 patients showed a full response (no more
urge and dry during the day) with a mean increase in bladder capacity from 167 to 271 ml (61%) (p 0.001). Three
patients showed a partial response (decreased urge and incontinence) and 3 remained unchanged. Eight of the 9 full
responders were still cured after 12 months. One patient
had relapse after 8 months.
The 3 partial responders and the patient with relapse
underwent a second injection with a full response in the
former full responder and in 1 partial responder. No further
response was observed in 2 partial responders.
On postoperative uroflowmetry no differences were seen
except voided volume in most patients. Three girls and 1 boy
329
had temporary dysfunctional characteristics on postoperative uroflowmetry. In 1 of these girls post-void ultrasound
showed significant residual urine (greater than 50% of capacity). Minimal post-void residual urine (less than 5% of
detrusor capacity) was seen in another 4 patients. After 6
weeks all patients voided to completion.
DISCUSSION
To our knowledge we report the first experience with botulinum-A toxin in a pediatric population with nonneurogenic
detrusor overactivity. The first difference in the current data
compared to results in the literature is the longer duration of
the effect. In studies in adults it has been shown that the
effect of botulinum-A toxin injection is temporary. In the
current study a long-term effect of more than 12 months was
seen in 8 of 15 patients. Former reports of use in children
with neurogenic bladder demonstrate an effect that lasted
10 months.1,3,4,6 Perhaps the fact that the treatment was
used for a disorder that is an expression of a maturation
delay of detrusor function rather than a structural anomaly
can account for this longer and better effect. Overactivity
inhibition can allow detrusor function to mature.
The dose of botulinum-A toxin used in the current study
was selected rather arbitrarily. Concerning the dose, no
clear guidelines are found in the literature. In children with
neuropathic overactive bladder higher doses are used. Riccabona et al used 10 U/kg body weight to a maximum of 360 U,4
while Schulte-Baukloh et al preferred 12.5 U/kg body weight
to a maximum of 300 U.3 Important and misleading for
determining the dose is the fact that the different brands of
botulinum-A toxin have different units. The 100 U used in
the current study are only applicable to Botox®.7
As long as the dose does not exceed 300 U, it is unlikely
that systemic weakness or paralysis would occur. Muscle
weakness has been described in urological procedures in
adults by some groups3,4 but to our knowledge it has never
been mentioned in the treatment of children to date. Temporary autonomic side effects have been described but they
mainly disappear after some weeks.6
In this study no systemic side effects were noted. It seems
to be important to keep the injected volume as low as possible because the risk of systemic absorption and generalized
weakness seems to be related more to the volume than to the
quantity of botulinum-A toxin.6,8
In the current study 1 serious side effect was seen in 1 girl
with a post-void residual urine volume of more than 50% of
functional bladder capacity. She needed intermittent catheterization for 10 days, after which voiding normalized.
It is even questionable if this retention was due only to
the autonomic side effect of botulinum-A toxin or rather the
result of a combination of detrusor-sphincter dyssynergia
and the botulinum-A toxin effect. In our study we found that
some children had a dysfunctional uroflow pattern some
weeks after injection, which later disappeared. One boy had
clinical vesicoureteral reflux with pain at the kidney site
during voiding. The patient refused voiding cystography, so
the diagnosis was not confirmed. The symptom disappeared
after 2 weeks. Furthermore, 2 girls had a lower urinary tract
infection after injection. These girls had normal uroflowmetry and emptied the bladder completely. Therefore, the
infections might have been unrelated to botulinum-A toxin
treatment.
330
BOTULINUM-A TOXIN IN INCONTINENT CHILDREN WITH OVERACTIVE DETRUSOR
After this pilot study, which proves safety and long-term
efficacy, some further studies are needed, especially in regard to the botulinum-A toxin dose. Possibly some children
may need multiple injection and, therefore, defining the dose
is important. With repeat injections it is known that resistance develops to the toxin in some patients. Humans may
form antibodies to botulinum-A neurotoxin or to associated
nontoxin proteins.6,9 It has been shown that shorter intervals between doses and higher doses contribute to the development of resistance.10 Therefore, it is recommended to
avoid booster injections, leave at least a 3-month interval
between 2 treatments and use the smallest clinically effective dose.11 The latter is probably the most challenging
factor because the dose used today in children is still determined rather empirically.
In our view the clinically effective dose is less influenced
by the body weight of the child than by bladder properties,
such as bladder mass and detrusor compliance. We postulate
that the thicker the bladder wall, as estimated on ultrasound, the more muscle mass and the higher the dose
needed to have a long lasting effect.
As in the treatment of neuropathic overactive bladder but
probably also in some children with nonneuropathic overactive bladder, several repeat injections are necessary. An
adequate method of determining the clinically effective dose
should be developed to avoid elimination of this valuable
treatment due to resistance.
In the current study it seems that a partial response was
a poor prognostic factor for repeating the injection. Three
partial responders underwent repeat injection but only 1
responded. One full responder who had relapse showed a
new full response after a second injection. Thus, probably a
full response after the first injection is a good prognostic
factor for further injection therapy. Repeat injections seem
to be as safe and effective as the first injection.12
Before botulinum-A toxin injection therapy can be used
as a primary therapy for overactive detrusor in childhood
further research is necessary. Most evidence could be gathered in a placebo controlled study. However, to our knowledge the industry shows no interest in the development of
such a protocol. Further clinical trials are needed to confirm
the results of this pilot study.
CONCLUSIONS
The use of botulinum-A toxin for nonneurogenic overactive
bladder in children who are resistant to common treatments
is a safe and effective treatment modality. Standardization
of this therapy, especially concerning the optimal clinical
effective dose, must be done if we want to keep this therapeutic tool effective in the long term.
REFERENCES
1.
Leippold, T., Reitz, A. and Schurch, B.: Botulinum-A toxin as a
new therapy option for voiding disorders: current state of
the art. Eur Urol, 44: 165, 2003
2. Flynn, M. K., Webster, G. D. and Amundsen, C. L.: The effect
of botulinum-A toxin on patients with severe urge urinary
incontinence. J Urol, 172: 2316, 2004
3. Schulte-Baukloh, H., Michael, T., Schobert, J., Stolze, T. and
Knispel, H. H.: Efficacy of botulinum-A toxin in children
with detrusor hyperreflexia due to myelomeningocele: preliminary results. Urology, 59: 325, 2002
4.
5.
6.
7.
8.
9.
10.
11.
12.
Riccabona, M., Koen, M., Schindler, M., Goedele, B., Pycha, A.,
Lusuardi, L. et al: Botulinum-A toxin injection into the
detrusor: a safe alternative in the treatment of children
with myelomeningocele with detrusor hyperreflexia. J Urol,
171: 845, 2004
Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P.,
Ulmsten, U. et al: The standardisation of terminology in
lower urinary tract function: report from the Standardisation Sub-Committee of the International Continence Society. Standardisation Sub-Committee of the International
Continence Society. Urology, 61: 37, 2003.
Smith, C. P. and Chancellor, M. B.: Emerging role of botulinum
toxin in the management of voiding dysfunction. J Urol,
171: 2128, 2004
Brin, M. F. and Blitzer, A.: Botulinum-A toxin: dangerous
terminology errors. J R Soc Med, 86: 493, 1993
Kim, H. S., Hwang, J. H., Jeong, S. T., Lee, Y. T., Lee, P. K.,
Suh, Y. L. et al: Effect of muscle activity and botulinum-A
toxin dilution volume on muscle paralysis. Dev Med Child
Neurol, 45: 200, 2003
Dolimbek, B. Z., Jankovic, J. and Atassi, M. Z.: Cross reaction
of tetanus and Botulinum neurotoxins A and B and the
boosting effect of botulinum neurotoxins A and B on primary anti-tetanus antibody response. Immunol Invest, 31:
247, 2002
Jankovic, J. and Schwartz, K.: Response and immunoresistance to botulinum-A toxin injections. Neurology, 45: 1743,
1995
Brin, M. F.: Botulinum-A toxin: chemistry, pharmacology, toxicity and immunology. Muscle Nerve Suppl, 6: S146, 1997
Grosse, J., Kramer, G. and Stohrer, M.: Success of repeat
detrusor injections of botulinum a toxin in patients with
severe neurogenic detrusor overactivity and incontinence.
Eur Urol, 47: 653, 2005
EDITORIAL COMMENT
The use of botulinum-A toxin was pioneered by Schurch et al
in 2000 by applying the toxin into the neurogenic overactive
detrusor and by that achieving increased bladder capacity
and decreased pressures.1 The first child to receive botulinum-A toxin for a neurourological condition was a 7-year-old
girl with upper tract dilatation.2 Since then, the overall use
in children with a urological condition has concentrated on
treating neurogenic overactive bladder.
In adults the indications for treatment with botulinum-A
toxin have now expanded to other urological conditions, eg
urinary incontinence and voiding disorders. Evidently this
trend will be reproduced in children. Therefore, it is important to bear in mind that overactive bladder in most children
is a dynamic condition, as opposed to the static overactive
bladder in adults. This fact should be taken into account
when considering this treatment.
At this point no major short-term or long-term adverse
effects have been described in children. Besides the generalized effect and antibody production, the primary risk is
that injection of the toxin may create irreversible long-term
side effects, eg ultrastructural and functional changes of the
detrusor. This would probably only be revealed after a
longer period of use. Reports of long-term followup with
repeat injections in the bladder of children through puberty
are nonexisting and a few short-term reports are based on
retrospective studies.
Schulte-Baukloh et al recently reported a study of repeat
injections of botulinum-A toxin in children with neurogenic
93
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
94
BOTULINUM-A TOXIN IN INCONTINENT CHILDREN WITH OVERACTIVE DETRUSOR
3
detrusor overactivity. As in similar studies, this study
shows increased capacity, decreased pressure and increased
bladder compliance. The current series is the first to explore
the effectiveness of injecting botulinum toxin into the detrusor in children with nonneurogenic overactive bladder. They
observed impressive results in a select, hard core group of
children with continuing incontinence after what modern
combined therapy could offer. The investigators injected a
standard dose of 100 U botulinum-A toxin into the detrusor.
This is interesting since the recommended dose in children
is 10 to 12 U/kg body weight (maximum 300 U). Since this is
not based on evidence but taken from the dose used in
pediatric neurology, this should be further evaluated.
Unfortunately, as in many other studies in children, intent to treat has replaced the randomized, controlled clinical
trial. Future studies including randomization, controls and
long-term followup are mandatory before this treatment for
331
nonneurological bladder dysfunction is taken into daily clinical use.
Bettina Jørgensen
Institute of Clinical Medicine
University of Aarhus
Aarhus, Denmark
1.
Schurch, B., Stohrer, M., Kramer, G., Schmid, D. M., Gaul, G.
and Hauri, D.: Botulinum toxin A for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative
to anticholinergic drugs. J Urol, 164: 692, 2000
2. Steinhardt, G. F., Naseer, S. and Cruz, O. A.: Botulinum toxin:
novel treatment for dramatic urethral dilation associated
with dysfunctional voiding. J Urol, 158: 190, 1997
3. Schulte-Baukloh, H., Knispel, H. H., Stolze, T., Weiss, C., Michael, T. and Miller, K.: Repeated botulinum-A toxin injections in treatment of children with neurogenic detrusor overactivity. Urology, 66: 865, 2005
Publication 4
The Daytime alarm: A useful Device for the Treatment
of Children with Daytime Incontinence
E. Van Laecke, S.Wille, J. Vande Walle, A. Raes, C. Renson, F. Peeren, P. Hoebeke
The Journal of Urology: July 2006, Vol.176: 325-327
In this paper we present the results of a daytime wetting alarm as treatment for therapy
resistant daytime incontinence in children with an overactive detrusor.
Complete cure was attained in 35% of patients, another third had a clear improvement
in their complaints and training failed in a third.
95
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
96
The Daytime Alarm: A Useful Device for the
Treatment of Children With Daytime Incontinence
E. Van Laecke,* S. Wille, J. Vande Walle, A. Raes, C. Renson, F. Peeren and P. Hoebeke
From the Departments of Pediatric Urology and Pediatric Nephrology (JVW, AR), Ghent University Hospital, Gent, Belgium
Purpose: We present the results of the use of a daytime wetting alarm as treatment for therapy resistant daytime wetting
in children with an overactive detrusor.
Material and Methods: In a retrospective study we reviewed the files of 63 children treated with a daytime alarm because
of persistent daytime wetting. Results were considered a complete success when the children were completely dry after
treatment, a partial success when there was greater than 50% improvement in daytime wetting and a failure when no change
was observed in daytime symptoms.
Results: During a study period of 25 months 63 children were treated with a daytime alarm at the department of pediatric
urology. The mean treatment period was 14 days. At a followup of 12 months treatment failed in 20 children (32%), 21 (33%)
had partial success and 22 (35%) were successfully treated.
Conclusions: In children with therapy resistant daytime wetting and an overactive detrusor the daytime alarm may be a
useful treatment tool. Complete cure of daytime incontinence can be attained in 35% of patients, almost a third have
improvement in their complaints and training fails in a third.
Key Words: urinary incontinence, bladder, awareness, treatment failure
O
constipation were excluded from study. The duration of therapy and concomitant treatments were noted.
The Charco® daytime alarm consists of an alarm device
with an auditory or a vibratory buzzer alarm. A wire connects a sensor strip fixed inside the underwear to the alarm
device. The alarm is carried around the waist, supported by
a waist belt.
During the 2-week home program the children wore the
alarm during the whole day. The alarm was activated the
moment that a drop of urine wet the sensor strip. The children
were taught by the physiotherapist to stop voiding and perform a withholding maneuver at the moment that the alarm
went off. They then went to the toilet and emptied the
bladder in a proper way.
Treatment was considered a complete success when the
child became dry while on treatment, a partial success when
there was greater than 50% improvement in daytime incontinence and a failure when no change was observed in daytime symptoms. The results of treatment were evaluated
immediately after training. They were reevaluated 6 weeks
later and finally 1 year after training was started.
veractive detrusor is a frequently observed problem
in children. Urge and urge incontinence are the typical symptoms. Treatment consists of providing insight into and knowledge of the problem, keeping voiding
diaries to increase this insight, bladder capacity training
and pharmacological treatment. Although good results are
reported with this treatment, some children are therapy
resistant.1 Awareness is an important part of this therapy
resistance. Many children are no longer aware that incontinence happens and wet pants are ignored. Especially when
attention is focused to a demanding activity, such as watching television or playing a computer game, incontinence
happens without awareness.
Therefore, it was postulated that increasing awareness
could improve the problems. To increase awareness treatment with daytime wetting alarms was started. Drawing the
attention of a child to bladder behavior by a daytime alarm
can contribute to a larger awareness of the bladder and
teach them to anticipate the incontinence problem by going
to the toilet on time. The results of this treatment were
reviewed retrospectively.
PATIENTS AND METHODS
RESULTS
The files of children treated with a daytime alarm for therapy resistant daytime wetting between June 1998 and August 2000 were retrospectively reviewed. The inclusion criterion for this retrospective study was persistent daytime
wetting with a frequency of 1 to 5 times daily. Children with
The files of 63 children with a minimal followup of 1 year
were reviewed. A total of 34 boys and 29 girls were identified. Mean age in the study group was 8 years (range 5 to
14). Of the children 15 (25.4%) experienced pure daytime
wetting, 2 boys (3.2%) had a history of posterior urethral
valves and daytime wetting, and 45 children (71.4%) experienced daytime and nighttime wetting. All children had a
proven diagnosis of overactive bladder on videourodynamic
examination. The previous failed treatment period was 21.6
* Correspondence: Paediatric Uro-Nephrologic Centre, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium (telephone: 32 9 240 22 76; FAX: 32 9 240 38 89; e-mail:
[email protected]).
0022-5347/06/1761-0325/0
THE JOURNAL OF UROLOGY®
Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
325
Vol. 176, 325-327, July 2006
Printed in U.S.A.
DOI:10.1016/S0022-5347(06)00303-X
326
ALARM TREATMENT FOR DAYTIME INCONTINENCE
months. Bladder capacity training failed in children while
on pharmacotherapy.
During the pre-alarm training period all children were
trained with a strict drinking and voiding schedule. A total
of 38 participants (60%) underwent pelvic floor therapy. All
children were initially treated with pharmacotherapy, including 5 (7.9%) with 1 anticholinergic (oxybutynin HCl), 30
(47.6%) subsequently with 2 anticholinergics (oxybutynin
HCl and oxyphencyclimin HCl) and 8 (12.7%) with 3 anticholinergics (oxybutynin HCl, oxyphencyclimin HCl and
tolterodine). Eight patients (12.7%) subsequently underwent treatment with 2 anticholinergics (oxybutynin HCl and
oxyphencyclimin HCl) and an -mimetic (imipramine). Nine
children (14.3%) were treated with a combination of anticholinergics (oxybutynin HCl in 4 and oxyphencyclimin HCl in
5) and an -mimetic (imipramine). Three children subsequently received treatment with oxybutynin HCl, oxyphencyclimin HCl and an -lytic (terazosin).
All children used the alarm for 2 weeks. According to the
anamnestic results of the children and the hetero-anamnestic results of the parents all children were highly motivated
and showed high compliance during the 2-week home program.
At the moment that the daytime alarm was started 15
children (23.8%) were on no concomitant treatment, 39
(50.8%) were being treated with anticholinergics (oxybutynin HCl and oxyphencyclimin HCl), 3 (4.8%) were on -mimetics (imipramine), 1 (1.6%) was on -lytics (terazosin) and
5 (7.9%) were on a combination of anticholinergics and -mimetics. Children remained on medication because they had
an initial positive if partial result, namely increased bladder
capacity, decreased urge and decreased wetting frequency.
This partial result was durable while on this therapy and it
clearly worsened when therapy was stopped. None of these
children became completely dry during the pre-alarm treatment period.
Results were evaluated separately in patients with and
without concomitant treatment. The table shows an evaluation of the results in the 15 children who were on no
concomitant therapy at the moment that the daytime alarm
was started.
Results in children with and without concomitant therapy when
alarm was started, and in entire study population
No concomitant therapy
After 2 wks of training
6 Wks after training
stopped
1 Yr after training
started
Concomitant therapy:
After 2 wks of training
6 Wks after training
stopped
1 Yr after training
started
Entire population:
After 2 wks of training
6 Wks after training
stopped
1 Yr after training
started
No.
Failure
(%)
No.
Success
(%)
No.
Partial Success
(%)
6 (40)
6 (40)
7 (47)
6 (40)
2 (13)
3 (20)
6 (40)
4 (27)
5 (33)
13 (27)
13 (27)
32 (66)
16 (33)
3 (6)
19 (39)
14 (29)
18 (38)
16 (33)
19 (30)
19 (30)
39 (62)
22 (35)
5 (8)
22 (35)
20 (32)
22 (35)
21 (33)
Immediately after the 2-week training period 7 children
(47%) had complete success, 2 (13%) had an incomplete
result and in 6 (40%) treatment failed. Reevaluation 6 weeks
after training was stopped showed that 6 children (40%)
remained successful and 1 who was initially successful had
a partial relapse. One year after therapy was started another 2 children, who were still successful after 6 weeks, had
a partial relapse. None of the children had a complete relapse. The 6 patients who were initially unsuccessful remained without a result after 1 year.
The table also shows the results in 48 children on concomitant treatment. The immediate complete success rate
after 2 weeks of training was 66%, 6% of children had a
partial result and 27% were unsuccessful. Six weeks after
training was stopped 50% of those who were initially dry had
a partial relapse. One year after therapy was started we
found that 1 girl who was completely dry after 6 weeks, and
1 boy and 2 girls who had an incomplete result after 6 weeks
had a complete relapse. Two girls who did not become dry
and 1 girl with an incomplete result at 6 weeks became
completely dry within a year after starting daytime alarm
training. After 1 year 18 patients (38%) were successful, 16
(33%) had a partial result and 14 (29%) remained without a
result.
Comparing results in children on pharmacological treatment at the moment that the daytime alarm was started
with results in those not on concomitant therapy showed
that the initial success rate was higher in the group on drug
therapy (66% vs 47%). Six weeks after the alarm was
stopped the success rate was decreased to 33% in the group
with concomitant treatment and to 40% in the group without
medication. Evaluation of the situation 1 year after starting
the daytime alarm showed that in the end a higher relapse
rate was found in the group without concomitant therapy
than in the group on concomitant medication. One year after
starting the alarm 27% of the children who had no concomitant therapy remained dry, in contrast to those with concomitant therapy, of whom up to 38% were successfully
trained to be dry.
Evaluation of the global study population showed that
the complete success rate immediately after the alarm training session was high, in that 62% of the children were
successfully trained, 8% had a partial result and about 30%
remained without a result (see table). Six weeks after training was stopped the complete success rate had decreased to
35%, 30% of the children remained unsuccessful and another 35% had partial success. Those who relapsed still had
a partial result. Evaluation 1 year after therapy was
started showed that study results remained almost unchanged. Of the children 35% were completely dry during
the day, 33% had partial success and 32% were without
any success.
Of the 29 girls 11 (38%) were completely successful 1 year
after therapy was started, 13 (45%) had a partial result and
5 (17%) remained untreated. Of the boys 11 (32%) were
completely successful, 8 (24%) had a partial result and up to
44% (15) had no result 1 year after starting alarm training.
According to the results in the global group we conclude
that in the long term (1 year) training failed in about a third
of the children, a third had an incomplete result and a third
seemed completely cured. Girls seemed to have a better
complete and partial training result than boys, although this
was not proved statistically.
97
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
98
ALARM TREATMENT FOR DAYTIME INCONTINENCE
DISCUSSION
Overactive detrusor is a frequent underlying condition in
children with daytime incontinence without underlying neuropathy or uropathy. In many of these children awareness of
the incontinence period is decreased or even absent. There
exists an adaptation to the feeling of wearing wet clothes or
neglect is a defense mechanism against the condition.
This lack of awareness seems to be an important factor in
the therapy resistance of some children. Indeed, before being
able to respond to an involuntarily event the patient must
recognize the signs that accompany the event. In cases of
overactive detrusor wetting occurs at the time of an overactive detrusor contraction. Relearning to recognize the feeling
of urge preceding urge incontinence enables the patient to
prevent wetting by going to the toilet on time or by central
inhibition of the overactive detrusor contraction. With this
in mind the daytime wetting alarm was introduced as a
treatment tool for daytime incontinence.
The daytime alarm is derived from the nighttime wetting
alarm. It consists of an alarm device with an auditory alarm
or a vibratory buzzer alarm. A wire connects a sensor strip
fixed inside the underwear to the alarm device. Although the
classic nighttime wetting alarm has been used successfully
to treat patients with persistent diurnal enuresis, it is preferable that the device has an adapted size and does not
interfere with the normal activities and normal behavior of
the child.2,3
It is important that the function and meaning of the
device be explained in detail to the child. At our department
this task is performed by a urotherapist. The child must
learn to react adequately to the alarm. After 1 drop the
alarm is activated. The child must try to stop the loss of
urine, go to the toilet and empty the bladder appropriately.
Many children with persistent diurnal incontinence demonstrate a lack of awareness or ignorance of bladder function. It is important to teach these patients to react adequately to bladder instability and prevent them from
wetting by going to the toilet on time or by central inhibition
of the overactive detrusor contraction. Vijverberg et al described a similar setting during an inpatient treatment program for persistent urge incontinence.4
In contrast to the belief that the daytime alarm alerts
patients to bladder behavior and enables them to stay dry,
Halliday et al stated that a noncontingent alarm that rings
unrelated to wetting events produces as good a response as
a contingent alarm.5 The results achieved in their study
with the contingent alarm were comparable to the results in
our study population. In our opinion, certainly in children
with difficult to treat, persistent daytime wetting, it is preferable and certainly more physiological to use a wetting
alarm that sounds when wetting occurs. It makes the children aware of bladder function, leading to better control and
better continence.
The success of this therapy is certainly influenced by
motivation and compliance with the training program by
participating children. Motivation and compliance during
the 2-week home program was high in this group. This is
because this was a highly select subpopulation of children
327
with multiple failed treatments in the past who looked forward to participating in this study with what was completely new therapy for them.
The good results found after 2 weeks of training are
certainly due to this fact. Although an inpatient daytime
alarm treatment with professional coaching by trained physiotherapists, nurses and psychologists may result in an increase in training compliance and success, this procedure
may be hardly acceptable because of psychological and economic reasons.
Decreases in patient motivation and attention in this
study population is certainly a reason for the high relapse
rate 6 weeks after training was completed. However, after 6
weeks the results seemed to be permanent since there was
almost no difference between results after 6 weeks and after
1 year. After a child has learned to cope with bladder dysfunction a positive, lasting continence result may be achieved.
Other factors, such as the natural resolution of wetting,
which are undoubtedly important for the outcome of treatment in the whole population of children with daytime wetting, were far less important in this highly select group of
children with persistent daytime wetting who showed no
progress while on common therapy during a mean of 21.6
months. As such, they do not really influence the results of our
study. Also, because overactive bladder in childhood is considered a maturation delay, it is postulated that this treatment
enhances the further maturation of detrusor function.
The results of this study are not stated in statistical data
because no reliable statistical analysis could be performed.
We were dealing with a heterogeneous group of patients
considering pathogenesis, age, sex, the number of previous
treatments and the duration of therapy.
CONCLUSIONS
The daytime alarm is certainly a useful device in children
with severe, often drug resistant daytime wetting. Complete
results were found in 35% of the patients and another 33%
showed an important improvement in their complaints. Outpatient use is preferable not only for psychological, but also
for economic reasons.
REFERENCES
1.
2.
3.
4.
5.
Curran, M. J., Kaefer, M., Peters, C., Logigian, E. and Bauer,
S. B.: The overactive bladder in childhood: long-term results
with conservative management. J Urol, 163: 574, 2000
Goel, K. M., Thomson, R. B., Gibb, E. M. and McAinsh, T. F.:
Evaluation of nine different types of enuresis alarms. Arch
Dis Child, 59: 748, 1984
Friman, P. C. and Volmer, D.: Successful use of the nocturnal
urine alarm for diurnal enuresis. J Appl Behav Anal, 28: 89,
1995
Vijverberg, M. A. W., Elzinga-Plomp, A., Messer, A. P., van
Gool, J. D. and de Jong, T. P. V. M.: Bladder rehabilitation:
the effect of a cognitive training programme on urge incontinence. Eur Urol, 31: 68, 1997
Halliday, S., Meadow, S. R. and Berg, I.: Successful management of daytime enuresis using alarm procedures: a randomly controlled trial. Arch Dis Child, 62: 132, 1987
Publication 5
Voiding Disorders in Severely Mentally and Motor Disabled Children
Erik Van Laecke, Luc Golinveaux, Luc Goossens, Ann Raes, Piet Hoebeke,
Johan Vande Walle
The Journal of Urology, December 2001, Vol. 166: 2404-2406
In this paper the voiding and continence pattern in severely mentally and motor
disabled children is presented.
A remarkably high incidence of urinary incontinence, 52.7% was found in the studied
population.
No correlation could be found between the uroflow pattern and the continence pattern.
Restricted fluid intake was correlated with an important bladder capacity deficit.
Continence seemed to be rather influenced by motor disability than by mental
development.
99
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
0022-5347/01/1666-2404/0
THE JOURNAL OF UROLOGY®
Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 166, 2404 –2406, December 2001
Printed in U.S.A.
VOIDING DISORDERS IN SEVERELY MENTALLY AND MOTOR
DISABLED CHILDREN
ERIK VAN LAECKE, LUC GOLINVEAUX, LUC GOOSSENS, ANN RAES, PIET HOEBEKE
J. VANDE WALLE
From the Departments of Paediatric Urology and Paediatric Nephrology, Ghent University Hospital, Ghent, and M.P.I. Ten Dries,
Landegem, Belgium
ABSTRACT
Purpose: We evaluated the voiding and continence patterns in severely mentally and motor
disabled children.
Materials and Methods: The hetero-anamnestic, uroflometer and morning urine concentration
profile results of 17 girls and 21 boys with severe mental and motor disability were evaluated in
a prospective study.
Results: Of the children 20 (52.7%) suffered daytime and/or nighttime wetting and 18 (47.4%)
were continent. Daytime and nighttime wetting occurred in 85.7% of children with tetraparesis
and in 66.6% of those with an IQ between 46 and 55, representing the highest incidence rates.
Bladder capacity was too small for age (mean deficit 145 ml.) in 92% of the children. Uroflowmetry demonstrated a dysfunctional pattern in 60.7% of patients. Dysfunctional voiding occurred
in 100% of children with coordination disorders and in 87.5% of those with an IQ between 46 and
55, representing the highest incidence rates. The morning urine concentration profiles showed an
osmolality of at least 1,021 mOsm./kg. in all cases.
Conclusions: Although we found a remarkably high incidence of dysfunctional voiding, no
correlation between the uroflow and continence patterns could be found. Restricted fluid intake,
due to swallowing problems and insufficient hydration, causes an important bladder capacity
deficit in most patients. Becoming continent is determined by motor disability, especially the
degree of mobility, rather than by mental development.
KEY WORDS: urination disorders; disabled, mentally; paresis; flowmetry
Daytime and nighttime wetting by severely mentally and
motor disabled children is too often considered an inevitable
fact, and literature on this underestimated problem is limited. Better insights into voiding and continence patterns of
these children can lead to better solutions or even treatment
of incontinence.
MATERIALS AND METHODS
The heteroanamnestic, uroflowmeter and morning urine
concentration profile results of 17 girls and 21 boys with a
mean age of 10.5 years (range 6 to 16) were evaluated in a
prospective study. The patients live in the same medical
pedagogical institution at which they are treated by classified medical and paramedical staff. All patients suffered
severe mental and spastic motor disability. IQ was 36 to 45
in 4 girls, 46 to 55 in 2 girls and 1 boy, 56 to 70 in 6 girls
and 10 boys, and 71 to 90 in 5 girls and 10 boys. Of the
patients 3 girls and 4 boys were quadriparetic, 8 girls and
6 boys were diparetic, and 1 girl and 5 boys were hemiparetic. Three girls and 1 boy had ataxia, 1 girl and 3 boys
had athetosis, 1 girl had severe coordination disorders and
2 boys had myopathy.
Hetero-anamnestic information about continence was
gathered from parents and institution staff. A gravimetric
uroflometer and adapted toilet chair were placed at the institution. All children performed 1 to 6 (mean 3) recordings,
the number of which for each patient was determined based
on local organizational possibilities of the paramedical staff.
Osmolality was measured by the same laboratory on a sample of morning urine from each child.
RESULTS
Based on the history of parents and staff members, 20
children (52.6%) had daytime and/or nighttime wetting, including 5 (13.2%) with nighttime wetting, 2 (5.3%) with daytime wetting and 13 (34.2%) with daytime and nighttime
wetting. The remaining 18 (47.4%) patients were continent.
The incidence of wetting according to motor disability is
shown in table 1. The highest incidences of daytime and
nighttime wetting were in children with myopathy (100%)
and tetraparesis (85.7%), while the lowest incidences occurred in those with coordination disorders (0%) and ataxia
(25%). The incidence of nighttime and daytime wetting according to mental development is also shown in table 1. The
highest incidence of nighttime wetting, 75%, was found in
children with an IQ of 36 to 45 (75%), and the highest incidence of daytime and nighttime wetting, 66.7%, was found in
the group with an IQ of 46 to 55 (66.7%).
Mean voiding frequency was 6 times a day (range 4 to 10).
Of the children 35 (92.1%) had a bladder capacity too small
for age compared with the estimated capacity formula.1
Mean bladder capacity deficit, determined as bladder capacity— estimated bladder capacity for age, was 145 ml. (range
23 to 345). Only 1 girl with diparesis had a normal bladder
capacity, and 1 boy with a hemiparesis and 1 girl with diparesis had a capacity too large (mean 189.5 ml.). The child
with a normal bladder capacity and the girl with a large
capacity had no incontinence problems, while the boy with a
large capacity had nighttime wetting infrequently.
Swallowing problems were severe in 1 tetraparetic girl,
and 1 girl and 1 boy with athetosis, and moderate in 2
tetraparetic boys, 1 diparetic girl and 1 girl with ataxia. The
remaining 31 (81.6%) children had no swallowing problems.
2404
100
AND
2405
VOIDING DISORDERS IN SEVERELY DISABLED CHILDREN
TABLE 1. The incidence of nighttime and daytime wetting according to motor disability and IQ
No. Continent (%)
Motor disability:
Tetraparesis
Myopathy
Diparesis
Hemiparesis
Athetosis
Ataxia
Coordination disorders
No. Nighttime Wetting (%)
No. Daytime Wetting (%)
1 (14.3)
10 (71.4)
3 (50)
3 (75)
1 (100)
Totals
IQ:
36–45
46–55
56–70
71–90
18 (47.4)
1 (25)
1 (33.3)
8 (50)
8 (53.3)
2 (14.3)
1 (16.7)
1 (25)
1 (25)
1 (16.7)
1 (25)
6 (85.7)
2 (100)
2 (14.3)
1 (16.7)
2 (50)
5 (13.2)
2 (5.3)
13 (34.2)
1 (6.3)
1 (6.7)
2 (50)
2 (66.7)
6 (37.5)
3 (20)
1
(25)
1 (6.3)
3 (20)
Mean bladder capacity deficit was 214.7 ml. in children with
severe swallowing problems, 207 ml. in those with moderate
problems and 127.6 ml. in children without swallowing problems. The children performed 112 uroflometer recordings
(mean 3 per patient, range from 1 to 6). Every uroflow recording was evaluated by the same investigator. The pattern
was normal on only 39 uroflow recordings (34.8%), dysfunctional, staccato or fractionated in 68 (60.7%), and purely
obstructive in 1 (0.9%). Four uroflow recordings (3.6%) were
pathognomonic for straining. The results of the uroflowmetry
according to the type of motor disability are listed in table 2.
The highest incidences of dysfunctional uroflowmetry were in
patients with dyscoordination disorders (100%) and ataxia
(78.6%), while the highest incidence of normal uroflowmetry
was in those with hemiparesis (47.6%). The uroflow patterns
according to mental development are also given in table 2.
The highest incidence of dysfunctional voiding was in the
group with an IQ of 46 to 55 (87.5%).
The correlation between the uroflow pattern and continence or incontinence pattern is shown in table 3. The pattern was considered normal if more than 50% of the recordings were normal, dysfunctional if more than 50% were
dysfunctional and mixed if 50% were normal and 50% dysfunctional. In table 4 the uroflow and continence patterns of
each patient are related to the mental and motor disability.
No statistical significance of the correlation among the continence pattern, voiding pattern and type of mental and
motor disability could be obtained due to the small study
population. The concentration profiles of the morning urine
showed an osmolality of 1,021 mOsm./kg. or more in all cases.
DISCUSSION
Severely mentally and motor disabled children often
present with symptoms of dysfunctional voiding. More than
TABLE 2. Results of the uroflow patterns according to motor
disability and IQ
% Normal
Motor disability:
Tetraparesis*
38.1
Diparesis
35.1
Hemiparesis
47.6
Ataxia
21.4
Coordination
disorders
Athetosis
27.3
Myopathy
40.0
IQ:
36–45
43.8
46–55
12.5
56–70
40.5
71–90†
30.4
* Pure obstruction in 4.8%.
† Pure obstruction in 2.2%.
% Dysfunctional
57.1
62.2
47.6
78.6
100
No. Daytime and Nighttime Wetting
(%)
% Straining
2.7
4.8
63.6
40.0
9.1
20.0
56.2
87.5
54.8
63.0
4.7
4.4
half of our population (52.6%) had daytime and/or nighttime
wetting, which is comparable to the incidence reported in the
literature (range 30% to 74%). McNeal et al studied 50 patients with cerebral palsy, of whom 36% had 1 or more
symptoms indicative of a neuropathic bladder.2 Decter et al
reported almost the same incidence (about 33%) of dysfunctional voiding symptoms in children with cerebral palsy.3
Vezina et al studied 17 children with spastic ataxia of whom
53% presented with urinary symptoms of urgency and urgent
incontinence.4 Also Houle et al found that nearly 50% of
children with cerebral palsy presented with dysfunctional
voiding symptoms.5 In contrast to the findings of Reid and
Borzyskowski, and according to the results of Brodak daytime and nighttime wetting was the most common presenting
symptom of our study population (65%) and not daytime
incontinence.6, 7
To our knowledge there have been no studies of the voiding
pattern of this population evaluated by uroflometry performed in their own environment, as all information in literature about bladder function has been based on videourodynamic investigations. Reid and Borzyskowski reported that
85% of their patients had an abnormal videourodynamic
study,6 and almost the same incidence (83%) was mentioned
by Decter et al.3 The most commonly diagnosed problems
were hyperreflexic detrusor contractions with reduced bladder capacity (87%)6 and detrusor hyperreflexia.3 Both reports
mentioned that detrusor-sphincter dyssynergia was found
rather infrequently in children with cerebral palsy.3, 6 Vezina
et al stated that 41% of their patients with spastic ataxia
showed a lack of detrusor inhibition on cystometric evaluation.4 In contrast to the aforementioned reports, they found a
higher incidence (37.5%) of abnormal electrical hyperactivity
of the external sphincter.
Of our children 25 (65.8%) had a disturbed uroflow pattern,
the most common of which was dysfunctional voiding, staccato or fractionated (84%). No correlation between the uroflow and continence patterns could be found. In fact the
incidence of daytime and/or nighttime wetting was higher in
patients with a normal (69.2%) than a disturbed (48%) uroflow pattern. No clear correlation could be found among continence pattern, uroflow pattern, mental development and
motor disability.
It is clear that mobility has an important role in continence. Nearly all children with tetraparesis and myopathy
had daytime and nighttime wetting. The more mobility, especially children with diparesis, ataxia and coordination disorders, the higher the incidence (71.4%, 75%, 100% respectively) of being continence. Mental development is less
correlated with the degree of continence. Although the fact
that 75% of children with an IQ of 36 to 45 and 66.6% of those
with an IQ of 46 to 55 were incontinent may make us believe
that mental capability has an important role in continence,
further evaluation showed that these children with inconti-
101
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
102
2406
VOIDING DISORDERS IN SEVERELY DISABLED CHILDREN
TABLE 3. Correlation between uroflow and continence or incontinence patterns
Uroflow Pattern
(No.)
No. Continent
(%)
No. Nighttime Wetting
(%)
No. Daytime Wetting
(%)
No. Daytime and Nighttime Wetting
(%)
Normal (13)
Dysfunctional (21)
Mixed (4)
4 (30.8)
11 (52.4)
2 (50)
1 (7.7)
4 (19)
1 (25)
1 (7.7)
1 (4.8)
7 (53.8)
5 (23.8)
1 (25)
17
6
2
Totals
13
TABLE 4. Relationship between uroflow and continence patterns of each patient, and mental and motor disability
Uroflow
Pattern
Continent (No.)
Normal
Hemiparesis IQ 56–70 (1),
hemiparesis IQ 71–90 (1),
diparesis IQ 56–70 (1), diparesis IQ 71–90 (2)
Dysfunctional
Tetraparesis IQ 71–90 (1),
hemiparesis IQ 56–70 (1),
diparesis IQ 56–70 (4), diparesis IQ 71–90 (2), ataxia IQ
36–45 (1), ataxia IQ 56–70
(1), coordination disorder IQ
46–55 (1)
Diparesis IQ 71–90 (1), ataxia
IQ 71–90 (1)
18
Mixed
Overall
Nighttime Wetting (No.)
Daytime Wetting (No.)
Hemiparesis IQ 56–70 (1)
Hemiparesis IQ 71–90 (1),
diparesis IQ 71–90 (1),
ataxia IQ 36–45 (1), athetosis IQ 71–90 (1)
Athetosis IQ 71–90 (1)
Diparesis IQ 56–70 (1)
5
nence also had a severe mobility problem. The children with
a low IQ but reasonable degree of mobility were continent.
On the other hand, nearly all children with a higher IQ but a
high degree of immobility were incontinent.
Bladder capacity deficit was found in nearly all children
(92.1%), and it was neither influenced by mental development or type of motor disability. In children with severe and
moderate swallowing problems the mean capacity deficit was
higher than in those without swallowing problems. The high
osmolality suggested that fluid intake was too low in all
children. Restricted fluid intake because of swallowing problems but certainly more often because of insufficient hydration of the patients due to their environment, was the main
cause of the bladder capacity deficit in most of those with
severe mental and motor disability. Probably an even higher
incidence of daytime and nighttime wetting would have been
found if all children had been sufficiently hydrated.
Eyman et al mentioned that toilet difficulties are predictive of poor survival.8 Especially in children with severe
mobility problems, achieving continence remains an important problem as toilet training often does not succeed. In
those children alternative options, such as clean intermittent
catheterization, must be considered.
CONCLUSIONS
Children with severe mental and motor disability often
suffer from bladder dysfunction and daytime and nighttime
wetting are the most frequent symptoms. The possibility to
become continent is determined by the motor disability
rather than mental development. The more mobile the higher
the incidence of continence. Although most children have
Nighttime and Daytime Wetting
(No.)
Tetraparesis IQ 36–45 (2), tetraparesis IQ 46–55 (1), tetraparesis
IQ 71–90 (1), diparesis IQ 56–70
(1), athetosis IQ 56–70 (1), myopathy IQ 56–70 (1)
Tetraparesis IQ 46–55 (1), tetraparesis IQ 56–70 (1), hemiparesis
IQ 56–70 (1), athetosis IQ 71–90
(1), myopathy IQ 56–70 (1)
Diparesis IQ 71–90 (1)
2
13
abnormal uroflowmetry no correlation could be found between the uroflow pattern and continence problem. A major
problem, in nearly all of these children is the often extreme
small bladder capacity. Insufficient fluid intake, because of
swallowing problems and insufficient hydration, remains the
main cause. Being continent is one of the factors determining
survival. Thus, achieving it by toilet training or alternative
options remains a priority in the treatment of patients with
severe mental and motor disability.
REFERENCES
1. Koff, S. A.: Estimating bladder capacity in children. Urology, 21:
248, 1983
2. McNeal, D. M., Hawtrey, C. E., Wolraich, M. L. et al: Symptomatic neurogenic bladder in cerebral-palsied population. Dev
Med Child Neurol, 25: 612, 1983
3. Decter, R. M., Bauer, S. B., Khoshbin, S. et al: Urodynamic
assessment of children with cerebral palsy. J Urol, part 2, 138:
1110, 1987
4. Vezina, J. G., Bouchard, J. P. and Bouchard, R.: Urodynamic
evaluation of patients with hereditary ataxias. Can J Neurol
Sci, 9: 127, 1982
5. Houle, A. M., Vernet, O., Jednak, R. et al: Bladder function
before and after selective dorsal rhizotomy in children with
cerebral palsy. J Urol, part 2, 160: 1088, 1998
6. Reid, C. J. and Borzyskowski, M.: Lower urinary tract dysfunction in cerebral palsy. Arch Dis Child, 68: 739, 1993
7. Brodak, P. P., Scherz, H. C., Packer, M. G. et al: Is urinary tract
screening necessary for patients with cerebral palsy. J Urol,
152: 1586, 1994
8. Eyman, R. K., Grossman, M. D., Chaney, R. H. et al: Survival of
profoundly disabled people with severe mental retardation.
Am J Dis Child, 147: 329, 1993
Publication 6
Adequate Fluid Intake, Urinary incontinence,
and Physical and/or Intellectual Disability
Erik Van Laecke, Ann Raes, Johan Vande Walle and Piet Hoebeke
The Journal of Urology, October 2009, Vol.182: 2079-2084
In this paper the value of adequate fluid intake as a part of urotherapy for urinary
incontinence in mentally and/or motor disabled children is illustrated.
103
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
104
Adequate Fluid Intake, Urinary Incontinence, and Physical and/or
Intellectual Disability
Erik Van Laecke,* Ann Raes, Johan Vande Walle and Piet Hoebeke
From the Departments of Paediatric Urology and Nephrology (AR, JVW), Ghent University Hospital, Gent, Belgium
Purpose: Urinary incontinence in physically and/or intellectually disabled children is a common problem. Literature on therapy is sparse. In these patients we
prospectively studied the effect of urotherapy, particularly adequate fluid intake.
Materials and Methods: In a prospective study 66 boys and 45 girls with a mean
age of 9.1 years were included, of whom 22 were motor disabled, 16 were mentally
disabled and 73 had mental and motor disability. All patients were put on a fluid
intake schedule of 1,500 ml/m2 body surface. Mean followup was 22.9 months (range
12 to 30). Patients were evaluated using a diary, uroflowmetry and bladder scan.
Results: Of the children 44 (39.6%) were dry at study inclusion, 41 (46.9%) had
daytime and nighttime urinary incontinence, 11 (9.9%) had daytime urinary
incontinence and 15 (13.5%) had nocturnal enuresis. Anticholinergics were
started in 18 children, of whom 11 became dry. The other children received only
an adequate fluid intake schedule. Eight patients (7.2%) withdrew from study. At
study end 69 children (67%) were completely dry during the day and night, 14
(13.6%) remained urinary incontinent during the day and night, 5 (4.9%) had
daytime urinary incontinence and 15 (14.6%) had nocturnal enuresis. Of the
children 73 (65.8%) drank at least 25% less than the physiologically necessary
quantity. Initially 62 children (55.9%) had a small age related expected maximum
voided volume, which decreased to 24 (21.6%) at end of study.
Conclusions: Adequate fluid intake is an important part of urotherapy for urinary incontinence in mentally and/or motor disabled children.
Study received University Hospital Ghent ethical committee approval.
* Correspondence: Department of Paediatric
Urology, Ghent University Hospital, De Pintelaan
185, B-9000, Belgium (telephone: 0032 9 332 2275;
FAX: 0032 9 332 3889; e-mail: erik.vanlaecke@
uzgent.be, [email protected]).
Key Words: urinary bladder, urinary incontinence, drinking behavior,
disabled children, questionnaires
URINARY incontinence in physically
and intellectually disabled children is
a common yet poorly investigated
problem. Far too often urinary incontinence is considered a normal, unavoidable and even minor problem in
this study population. We prospectively studied the prevalence of urinary
incontinence, looked for causal factors
and evaluated therapeutic options in a
group of intellectually and physically
disabled children. We determined the
efficacy of adequate fluid intake as part
of a treatment strategy.
0022-5347/09/1824-2079/0
THE JOURNAL OF UROLOGY®
Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
MATERIALS AND METHODS
Groups at 4 institutions for mentally and
motor disabled children participated in
the study. Children between 4 and 15
years old with a mental, motor or mental
and motor disability were included in
analysis, and those with proven neuropathic bladder were excluded. Approval of
the University Hospital Ghent ethical
committee was obtained. Informed consent was provided by all patient families
and informed assessment was obtained
from mentally capable children.
A questionnaire was used to collect
data on urinary continence problems, inVol. 182, 2079-2084, October 2009
Printed in U.S.A.
DOI:10.1016/j.juro.2009.05.125
www.jurology.com
2079
2080
ADEQUATE FLUID INTAKE, INCONTINENCE AND DISABILITY
cluding nocturnal enuresis, urinary incontinence during
the day, and during the day and night, stool problems,
constipation and fecal incontinence. This questionnaire
was completed by parents and institution staff. Maximum
voided volume, fluid intake quantity and urinary incontinence were recorded in a voiding and drinking diary.
Maximum voided volume was calculated from the voided
volumes recorded during a day. The children received no
extra water load. Mental status was evaluated by measuring IQ, mental age and verbal capacity. Motor disability
was scored based on mobility and postural stability. The
global handicap was evaluated as a degree of functional
autonomy.
All children underwent clinical examination done by 1
investigator. A uroflowmeter was installed at the institution. At least 3 recordings were made before and after
therapy, spread over several days. A personal adapted
toilet chair was used. Post-void residual urine was measured at least once with bladder scan. Clinical evaluation,
uroflowmetry and bladder scan were repeated regularly
during the entire 6-week study period. A bladder diary
was used to record maximum voided volume, fluid intake
quantity and incontinence.
After documenting maximum voided volume, fluid intake quantity and the degree of incontinence a personally
adapted fluid intake schedule was started. A mean fluid
intake of 1,500 ml/m2 body surface was recommended
equally divided during the day in 4 to 6 portions.1 Guidelines on fluid quality and quantity were given to parents
and caregivers. No specific voiding regimen was started.
Children indicated spontaneously when they wanted to
visit the toilet. No patients were placed on a timed voiding
regimen.
The toilet was adapted to the individual needs of the
children to optimize a stable toilet position and maximum
pelvic floor relaxation. The effect on maximum voided
volume and incontinence was evaluated. Medical treatment, anticholinergics and a wetting alarm were only
started after a minimum of 6 weeks of treatment with
adapted fluid intake. In select patients, including those
with urinary incontinence plus normal or disturbed uroflow and recurrent post-void residual urine, and those
with persistent urinary incontinence with no change in
maximum voided volume despite adequate therapy for
longer than 3 months, videourodynamics were performed
if parents provided consent. Results were analyzed using
the chi-square test with p 0.05 considered statistically
significant.
RESULTS
Included in the study were 45 girls and 66 boys with a
mean age of 9.1 years (range 4 to 15). Ten girls and 12
boys were only motor disabled, 9 girls and 7 boys were
only mentally disabled, and 26 girls and 47 boys were
intellectually and physically disabled. Table 1 lists
underlying pathological conditions. Of children with
mental retardation 45 (50.6%) were mildly, 32
(35.9%) were moderately, 9 (10.1%) were severely
and 3 (3.4%) were profoundly mentally retarded. Of
the 95 motor disabled children 48 (50.5%) had a
Table 1. Underlying pathological conditions
Condition
Unknown
Cerebral palsy
Duchenne’s disease
Encephalopathy
Prematurity
Microcephalia
Pierre Robin syndrome
Encephalitis
Dysmaturity
Posttraumatic
Langerhans’ syndrome
Metabolic disorder
Chromosome q13
Fragile X syndrome
Congenital glycosylation disorder-Jacken syndrome
Prader-Will syndrome
Myoclonic encephalopathy-myotonic dystrophy
Leigh syndrome
Sjögren-Larsson syndrome
Werdnig-Hoffman type II
Spinal muscular atrophy myotonic dystrophy
Charcot-marie-Tooth disease
No. Pts
12
68
5
4
3
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
certain degree of spasticity. The gender distribution
was 1.5 boys and 1 girl with mental retardation, and
1.6 boys and 1 girl with motor disability. Mean followup was 22.9 months (range 12 to 30). Eight patients (7.2%) withdrew from the study, including 1
who died, 2 who moved to an institution that did not
participate in the study and 5 at the time that strict
fluid intake was started.
Continence
At the time of study enrollment according to International Children’s Continence Society definitions2
39.6% of children were continent of urine, 36.9% had
daytime and nighttime urinary incontinence, 9.6%
had daytime urinary incontinence and 13.5% had
nocturnal enuresis. No significant difference was
noted among the 3 subgroups, ie mentally disabled,
motor disabled, and mentally and motor disabled
(p 0.05, table 2). At the end of the study period a
significant change in the continence pattern was
observed (p 0.001). Of the children 67% were completely continent and the incidence of urinary incontinence decreased from 46.9% at the study start to
18.4% at the end (table 3).
Fluid Intake
At the study start only 11 patients (9.9%) had a
normal fluid intake of 1,500 ml/m2 body surface
while 73 (65.8%) had an intake of less than 75% and
27 (24.3%) had an intake of less than 50% of the
expected normal fluid requirement. A significant difference in fluid intake was found between the group
with mental and motor disability, and the 2 other
groups (p 0.005). No significant difference was
105
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
106
ADEQUATE FLUID INTAKE, INCONTINENCE AND DISABILITY
2081
Table 2. Continence at study enrollment, fluid intake and continence patterns
Urinary Incontinence
Overall
No. pts (%)
No. motor disabled (%)
No. mentally disabled (%)
No. motor mentally disabled (%)
% Fluid intake change:
10 or Less
Greater than 25
Greater than 50
Continent
111
22
16
73
44
8
6
30
11
63
50
(39.6)
(36.4)
(37.5)
(41.1)
36.4
39.7
40.7
found between mentally and motor disabled patients
(p 0.05, table 4).
Swallowing Problems
Of the children 71 (64%) had no swallowing problems while 22 (19.8%) had moderate and 8 (7.2%)
had severe swallowing problems. In 2 children the
available information was inadequate. No significant difference was found in the fluid intake deficit
between children with vs without swallowing problems (p 0.05). Almost all children had a deficient
fluid intake. Of the patients with severe, moderate
and no swallowing problems 50%, 72.7% and 73.2%,
respectively, had an intake of less than 75% of the
expected normal fluid intake (see figure).
Maximum Voided Volume
A total of 12 children (10.8%) had an age related
expected maximum voided volume2,3 but 62 (55.9%)
had a maximum voided volume of less than 65% of
the age related expected maximum. Of those with a
normal maximum voided volume 83.3% were continent and 16.7% had nocturnal enuresis at study
enrollment. Of children with a maximum voided
volume of less than 65% of the age related expected
maximum only 35.5% were continent, 41.9% had
daytime and nighttime urinary incontinence, 9.7%
had daytime incontinence and 12.9% had nocturnal
enuresis, significantly different vs those with a normal maximum voided volume (p 0.01).
Increased Fluid Intake Influence
At the study start no significant difference was observed in the continence rate when correlated with
the degree of fluid intake (p 0.05, table 2). After
Day Night
41
6
6
29
(36.9)
(27.3)
(37.5)
(39.7)
36.4
38.4
40.7
Day
Nocturnal Enuresis
11 (9.9)
4 (18.2)
0
7 (9.6)
15 (13.5)
4 (18.2)
4 (25.0)
7 (9.6)
0.0
9.6
11.1
27.3
12.3
7.4
adequate fluid intake a 19.2% increase in continence
was observed in the group with normal drinking
(p 0.05). In the group with a fluid intake of less
than 75% of the expected intake a significant change
in the continence pattern was found with a 26.4%
increase in continence (p 0.01). Increased fluid intake resulted in a significant increase in continence
and maximum voided volume in those with an important decreased fluid intake at the study start
(table 5). Of the patients 58 (56.3%) gained more
than 25% of maximum voided volume and 45
(43.7%) gained more than 50%. An increase in maximum voided volume resulted in significant amelioration of continence (p 0.0001, table 5). No significant difference in the incidence of normalization of
maximum voided volume after treatment with adequate fluid intake was seen among the 3 subgroups,
including 53.4% in mentally and motor disabled,
43.8% in mentally disabled and 68.1% in motor disabled children (p 0.05).
Constipation/Fecal Incontinence
According to Rome III criteria4 fecal incontinence
and constipation were reported in 37 (33.3%) and 30
patients (27%), respectively. Only 5.4% of the children with fecal incontinence and 26.7% with constipation were continent of urine, significantly less
than the 56.8% without fecal incontinence and the
50.7% without constipation (p 0.001 and 0.05,
respectively).
Additional Therapy
At study enrollment 3 patients on anticholinergics
were continent, of whom 1 became incontinent again
during the study and 2 remained dry. In 18 children
Table 3. Continence pattern at study end
% Study Start/End (change)
Continence
Overall
Mentally disabled
Motor disabled
Mentally motor
disabled
39.6/67 (27.4)
37.5/66.7 (29.2)
36.4/70 (33.6)
41.1/66.2 (25.1)
Table 4. Fluid intake pattern
No. Fluid Intake (%)
Urinary Incontinence Nocturnal Enuresis
46.9/18.4 (28.5)
37.5/26.7 (10.8)
45.5/10 (35.5)
49.3/19.1 (30.2)
13.5/14.6
(1.1)
25/6.6 (18.4)
18.2/20
(1.8)
9.6/14.7
(5.1)
Overall
Mentally disabled
Motor disabled
Mentally motor disabled
Normal
Less Than 75% of Expected
10
4 (25)
5 (22.7)
1 (1.4)
73
7 (43.8)
13 (59.1)
53 (72.6)
ADEQUATE FLUID INTAKE, INCONTINENCE AND DISABILITY
2082
Degree of swallowing problem and fluid intake deficit. Blue bars
represent less than 10% change in fluid intake deficit. Red bars
indicate 25% or greater change in fluid intake deficit.
anticholinergics were started during the study due
to persistent urinary incontinence despite adequate
urotherapy, ie an individual fluid intake scheme, a
personally adapted toilet chair, and a voiding and
drinking diary. Of the patients 11 became continent on combined anticholinergics and continued
adequate fluid intake. In 2 severely mentally and
motor disabled children a daytime alarm was
started to make them more alert to the bladder.
Initially a positive reaction was noted but after 2
weeks the children did not want to cooperate further and even became angry with the device. This
therapy was cancelled. In another 2 patients with
only nocturnal enuresis a wetting alarm was
started successfully.
DISCUSSION
Although urinary incontinence is a common feature
in intellectually and physically disabled children, it
remains poorly documented. The literature is sparse
and mainly limited to prevalence and urodynamic
findings in children with cerebral palsy. Reports of
pathophysiology, prevention and treatment are rare
and often restricted to case reports.
We performed a prospective, uncontrolled study
in a population living in an institution for developmentally challenged children. The limitation of this
study is that it was uncontrolled and done in a
rather heterogeneous population according to the
underlying pathological condition.
According to prevalence a wide variation in incidence is reported (between 23% and 86%),5–15 most
likely because many studies were performed in a
small population and included patients were inadequately categorized according to underlying pathological condition, age, mental and motor development, and incontinence type.
In our study 39.6% of the population achieved
continence spontaneously. There were no significant
differences in the continence pattern among the 3
subgroups. Achieving continence is a multifactorial
process in which mental and motor development has
an important role. In the pathophysiology of nocturnal enuresis and daytime urinary incontinence detrusor overactivity with or without decreased voided
volume is often noted. Nocturnal polyuria and a
disturbed arousal mechanism are the other main
causative factors of nocturnal enuresis.16
According to the literature the prevalence of overactive detrusor in children with an intellectual
and/or physical disability may be as high as 97%.17
Insufficient fluid intake and decreased voided volume are major problems in developmentally challenged children. Our results are comparable with
those in the literature.13,14,18,19
Fluid intake is clearly influenced by pathological
condition severity. Patients with a mental and a
motor handicap have significantly lower fluid intake
than patients with a single disability, mainly because they depend more on caregivers for help with
normal daily activities such as eating, drinking and
visiting the toilet. Swallowing problems are often
thought to be a main reason why intellectually and
physically disabled children have insufficient fluid
intake. Our results do not sustain this theory. It
seems that regardless of swallowing problems most
of these children do not drink enough. We noted a
Table 5. Increased fluid intake and maximum voided volume vs continence pattern change
Change
% Fluid intake:
10 or Greater
25 or Greater
50 or Greater
% Max voided vol:
Greater than 25
Greater than 50
No. Pts
% Continence
% Day Night
Urinary Incontinence
% Day Urinary
Incontinence
% Nocturnal Enuresis
p Value
9
68
25
19.2
26.4
31.3
36.4
20.8
20.7
11.1
5.2
7.1
6.0
0.5
3.4
0.05
0.0001
0.0001
58
45
11.1
28.0
28.5
34.0
6.3
6.0
8
8
0.0001
0.0001
107
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
ADEQUATE FLUID INTAKE, INCONTINENCE AND DISABILITY
correlation between the severity of the swallowing
problem, and voided volume and the degree of continence. The more severe the swallowing problem,
the worse the therapeutic outcome.
A third of the patients had fecal incontinence and
27% had constipation. These data are somewhat
lower than expected from the literature,18,20,21 probably because many parents and caregivers do not
recognize these problems and only mentioned more
severe cases. As described by many groups,22–24 we
also found a strong correlation between fecal problems and urinary incontinence. Furthermore, a clear
correlation between urinary incontinence and constipation is documented in the literature. Adequate
fluid intake has a direct positive influence on urinary incontinence and is indirectly combined with a
healthy diet for constipation.
This study clearly proves that increasing the fluid
intake results in increased voided volume and significant amelioration of the continence pattern during the
day and during the night. Increased fluid intake during the day causes improvement in voided volume, and
a decrease in nocturnal diuresis and osmotic excretion
because of increased daytime osmotic excretion.25 Although adapting fluid intake to a normal level is often
time-consuming, it is probably one of the most important therapeutic factors for incontinence in physically
and intellectually disabled children. A standard drinking protocol according to fluid intake quantity (1,500
ml/m2 body surface), beverage quality and drinking
time schedule (4 to 6 times daily) is the cornerstone of
treatment and probably also of the prevention of urinary incontinence in developmentally challenged children. These children are often limited in their reaction
to stimuli, such as full bladder sensation. Increased
maximum voided volume and decreased nocturnal diuresis enable them to interpret and react more adequately to the desire to void, allowing them to reach
the toilet in time. This contributes to achieving continence.
In some patients adequate fluid intake, toilet adaptation and toilet position amelioration as urotherapy are insufficient to achieve continence. In
those cases when no contraindications exist, anticholinergics can be used successfully. Careful followup is needed, especially considering side effects
such as concentration and behavioral problems. A
wetting alarm during the day and night was used in
some cases but because of low participation its value
could not be determined. Further studies in larger
series are necessary.
Urinary incontinence in developmentally challenged children is a multifactorial problem. Adequate therapy starts with a thorough diagnosis. Optimal fluid intake together with other urotherapies,
such as toilet adaptation to achieve a stable toilet
position, keeping a voiding and drinking diary, and
constipation treatment, are the basics of therapy. In
cases of persistent incontinence additional diagnostic investigations such as uroflowmetry and videourodynamics may lead to extra information and a
change in therapy.
CONCLUSIONS
Developmentally challenged children are amenable to
continence rehabilitation. Although urinary incontinence is a common, multifactorial problem, treatment
is often not that complex. Adequate fluid intake has a
major role in the treatment strategy in urinary incontinent, developmentally challenged children. It has a
major impact on bladder capacity and constipation,
which are 2 important comorbidity factors of urinary
incontinence. Therapy starts with simple measures
such as environment adaptation, adequate fluid intake and a healthy diet. These measures are often
time-consuming and demanding but results often exceed expectations. Therapists must learn to adapt
their attitudes to children needs instead of trying to
adjust children attitudes to their needs.
REFERENCES
1. Cadnapaphornchai MA and Chantler C: Kidney
disease in children. In: Disease of Kidney and
Urinary Tract, 8th ed. Edited by RW Schrier.
Philadelphia: Lippincott Williams & Wilkins 2006;
vol 3, chapt 79, pp 2056 –2087.
4. Rasquin A, Di Lorenzo C, Forbes D et al: Childhood functional gastrointestinal disorders: child/
adolescent. Gastroenterology 2006. 130: 1527.
2. Nevéus T, van Gool A, Hoebeke P et al: The standardization of terminology of lower urinary tract
function in children and adolescents: report from the
Standardisation Committee of the International Children’s Continence Society. J Urol 2006; 176: 314.
6. Järvelin MR, Vikeväinen-Tervonen L, Moilanen I
et al: Enuresis in seven-year-old children. Acta
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3. Hjälmas K: Urodynamics in normal infants and
children. Scand J Urol Nephrol, suppl., 1988;
114: 20.
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5. Mayo ME: Lower urinary tact dysfunction in cerebral palsy. J Urol 1992; 147: 419.
7. von Wendt L, Similä S, Niskanen P et al: Development of bowel and bladder control in mentally
retarded. Devel Med Child Neurol 1990; 32: 515.
8. Roijen LE, Postema K, Limbeek J et al: Development
of bladder control in children and adolescents with
cerebral palsy. Devel Med Child Neurol 2001; 43:
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9. McNeal DM, Hawtrey CM, Wolraich ML et al:
Symptomatic neurogenic bladder in a cerebralpalsied population. Devel Med Child Neurol
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10. Pialoux B, Villoing P, Guillou M et al: À propos de
25 enfants infirmes moteurs d’origine cérébrale,
énurétiques ou incontinents. Ann Méd Phys 1981;
24: 77.
11. Brodak PP, Scherz HC, Packer MG et al: Is urinary
tract screening necessary for patients with cerebral palsy? J Urol 1994; 152: 1586.
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12. Van Laecke E, Golinveaux L, Goossens L et al:
Voiding disorders in severely mentally and motor
disabled children. J Urol 2001; 166: 2404.
13. Decter RM, Bauer SB, Khoshbin S et al: Urodynamic assessment of children with cerebral
palsy. J Urol 1987; 138: 1110.
dozo, P Abrams, S Khoury et al. Paris: Health
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17. Bross S, Pomer S, Döderlein L et al: Urodynamic
findings in patients with infantile cerebral palsy.
Akt Urol 2004; 35: 5.
21. Krogh K, Christiansen P and Laurberg S: Colorectal symptoms in patients with neurological diseases. Acta Neurol Scand 2001; 103: 335.
22. Chase JW, Homsy Y, Siggaard C et al: Functional
constipation in children. J Urol 2004; 171: 2641.
18. Singh BK, Masey H and Moron R: Levels of
continence in children with cerebral palsy. Paediatr Nurs 2006; 18: 23.
23. Loening-Baucke V: Prevalence rates for constipation and faecal and urinary incontinence. Arch Dis
Child 2007; 92: 486.
15. Bruschini H, Faria H, Garcez N et al: Development
of bladder control in mentally handicapped children. Int Braz J Urol 2003; 29: 455.
19. Gautheron V: Troubles mictionnels et maladie
neurologique à l’exclusion de la pathologie
médullaire évidente: les lésions cérébrales avec
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24. Loening-Baucke V: Urinary incontinence and urinary tract infection and their resolution with
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Pediatrics 1997; 100: 228.
16. Tekgul S, Nijman R, Hoebeke P et al: Diagnosis
and management of urinary incontinence in childhood. In: Incontinence, 4th ed. Edited by L Car-
20. Ozturk M, Oktem F, Kisioglu N et al: Bladder and
bowel control in children with cerebral palsy:
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109
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Part 3.
General Discussion
Further research
111
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
General discussion
Treatment of urinary incontinence in children remains challenging. Urinary incontinence
in children is a complex, multifactorial disease for which no golden standard therapy
exists.
Treatment of incontinence in children feels like completing a puzzle in which some
pieces are missing.
In this thesis some new “pieces” are presented.
For medical treatment of the overactive bladder, anti-muscarinic agents are still
regarded as first-line therapy. Oxybutinin chloride is the standard antimuscarinic drug.
[418]
This drug is effective, but its use is limited by systemic adverse events, in a significant
proportion of children, which may result in poor compliance or even discontinuation
of treatment.
Is tolterodine an effective and better tolerated alternative for oxybutinin in
the treatment of urinary incontinence due to overactive bladder in children?
(paper 1)
Tolterodine, a potent and selective anti-muscarinic drug was specifically developed for
the treatment of detrusor overactivity. At the moment of this study, controlled studies
of tolterodine were only available for adults. These studies showed tolterodine to be
equally effective and to result in significantly fewer adverse events than oxybutinin.
[284-286]
Despite limitations of this study, the fact that it is retrospective, non-controlled, and
non-randomized, our study has some advantages. The major advantage is the fact that
it includes a non-selected, general population of urinary incontinent children with an
overactive detrusor.
According to efficacy we found tolterodine to be very effective in the treatment of
symptoms, i.e. increase in maximum voided volume, and decrease in number of
micturations/24 hours and number of incontinence episodes / 24 hours, of overactive
detrusor in children. The effect was independent of previous treatment with a nonselective antimuscarinic, and was not significantly influenced by associated pelvic floor
therapy.
Results of our study illustrate that tolterodine is better tolerated than oxybutinin,
particularly with respect to the frequency and intensity of side-effects, behavioural
disorders, accommodation abnormalities and other side-effects.
112
Currently published studies do confirm our findings. Bolduc et al. found that in the
subgroup of patients who couldn’t tolerate oxybutinin, 77% were able to continue
tolterodine treatment with no significant side effects. [291] Christoph et al. performed
a study on long-term efficacy of tolterodine and patient compliance in children with
neurogenic detrusor overactivity.[289] They found that regular tolterodine application
significantly improved bladder volume, maximum detrusor pressure and detrusor
compliance. The 17% mild side effects they found was higher than the 3% we observed.
These mild side effects were well tolerated by the patients. Similar results were found
by Reddy et al.[296] Ellsworth et al. didn’t find a relationship between dose and adverse
events.[419]
The only double-blind, placebo-controlled studies of tolterodine ER in children
suffering urgency urinary incontinence by Nijman et al., confirmed that short-term (12
weeks) as well as long-term treatment (12 months) with tolterodine ER is well tolerated
in children. [297, 420]
Is there a place for Solifenacin in the treatment of therapy resistant overactive
bladder? (paper 2)
Solifenacin succinate is a specific antimuscarinic drug with a high affinity for the
M3 muscarinic receptor. The efficacy and long-term safety of this once daily oral
antimuscarinic agent developed for OAB in adults was illustrated in the review paper
of Basra et al.[421]
Since a lot of children with OAB do not or insufficiently answer to standard therapy, we
started to use solifenacin off label in a group of children with therapy resistant urinary
incontinence. In a retrospective study we reviewed the results of 138 children treated
with solifenacin. Due to the higher specific receptor affinity (predominantly M3) we
expected solifenacin to be associated with a lower side effect rate. Especially central
nervous system effects, which are related to the ability to cross the blood-brain barrier,
were expected to be less present. While 39% of the children had side effects on other
anticholinergics only 6.5% had side effects on solifenacin. Except for faecal impaction (1
patient) the side effects were considered mild. Only 2 patients had behaviour problems,
1 suffered drowsiness, 1 insomnia and 5 gastrointestinal problems. So the side effect
profile of solifenacin in children may be considered excellent despite the retrospective
design of the study. Remarkably 5 of the 9 patients with side effects on solifenacin
also had side effects on the previous anticholinergic therapy. This might suggest that
some patients are likely to have higher sensitivity to anticholinergic side effects than
others. The restriction of this study is that it only documents clinical safety based on
side effects. Further pharmacokinetic studies are needed to proof the safety of this drug
in children.
The overall efficacy was 85%. More than 50% of the responders were full responders,
and 46% were partial responders.
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Due to the significant increase (25%) in voided volume, the effect on daytime
incontinence seems to be more pronounced than the effect on nighttime incontinence.
The response in children with EN depends less on voided volume since many of them
need further alarm treatment to become dry at night even when voided volume is
normalized.
According to our findings, solifenacin seems to be a good if not superior alternative for
oxybutinin. As long as there are no prospective, controlled studies with pharmacokinetic
and pharmacodynamic data available, solifenacin can only be used off-label in children.
What about Botulinum-A toxin? Can it be used in the treatment of children
with therapy resistant overactive detrusor? (paper 3)
Botulinum-A toxin is a potent neurotoxin that has been successfully used in the
treatment of neurogenic detrusor overactivity and recently also in idiopathic detrusor
overactivity in adults. Until our study the urological application in children was
restricted to limited experience with the treatment of neurogenic detrusor overactivity
in patients with meningomyelocoele.
Due to the high prevalence of OAB in the paediatric population, which is often hard to
treat, we are looking for safe alternative treatment options. As Botulinum-A toxin was
safely and efficiently used to treat overactivity of the detrusor in adults and children
with neurogenic overactivity of the detrusor, we designed a prospective uncontrolled
pilot study to evaluate the safety and efficacy of Botulinum-A toxin in children with a
nonneurogenic overactive bladder.
Although the effect of a Botulinum-A toxin is temporary, we found it to last longer in our
population than in adults and children with neurogenic overactive detrusor. Perhaps
the fact that the treatment was used for a disorder that is an expression of a maturation
delay of detrusor function rather than a structural anomaly, can account for this longer
and better effect. Overactivity inhibition can allow detrusor control to mature.
In the long-term follow up group (≥ 6 months) 9 of the 15 patients showed a full
response, 3 a partial response and 3 remained unchanged.
The side effects reported were temporary urinary retention in 1 girl, temporary vesicoureteral reflux in a boy and lower urinary tract infection in 2 girls. No other side effects
were seen. On postoperative uroflow, 4 patients showed temporary dysfunctional
voiding characteristics. In 1 girl post-void ultrasound showed significant residual urine
and 4 other patients had minimal post-void residual urine. After 6 weeks all patients
voided spontaneously to completion.
114
Other side effects, such as systemic weakness or paralysis are unlikely to occur if the
dose does not exceed a maximum of 300 U. In this study no systemic side effects were
noted. It seems to be important to keep the injected volume as low as possible because
the risk of systemic absorption and generalized weakness seems to be related more to
the volume than to the quantity of Botulinum-A toxin.[422, 423]
According to the safety of this therapy, at this point no major short-term and longterm adverse effects have been described in children. The concern raised by Bettina
Jorgensen according to the risk that the toxin may create irreversible long-term side
effects, e.g. ultrastructural and functional changes of the detrusor, is questionable as
long as no long term studies have been performed.
The question about optimal dosage in children remains unanswered. We used a dose of
100 U Botulinum-A toxin. This dose, which was selected rather arbitrarily, is lower than
the dosages used by other authors in children with neuropathic overactive bladder.
Possibly some children may need multiple injections. It is known that repeat injections
may induce resistance to Botulinum-A toxin. It has been shown that shorter intervals
between doses and higher doses contribute to the development of resistance.
Therefore, it is recommended to avoid booster injections, leave at least a 3-month
interval between 2 treatments and use the smallest clinically effective dose.
In our view the clinically effective dose is less influenced by the body weight of the
child than by the bladder properties, such as bladder mass and detrusor compliance.
We postulate that the thicker the bladder wall, as estimated on ultrasound, the more
muscle mass and the higher the dose needed to have a long lasting effect.
Therefore it is of utmost importance to develop an adequate method of determining
the clinically effective dose, to avoid booster and quick repeat injections, which induce
resistance and inevitably will lead to elimination of this valuable treatment. Dose
response studies are absolutely needed in order to establish this issue.
In the current study it seems that partial response was a poor prognostic factor for
efficacy after repeat injection. Three partial responders underwent repeat injection but
only one responded. One full responder who had relapse showed a new full response
after a second injection. Thus, probably a full response after the first injection is a good
prognostic factor for further injection therapy. Repeat injections seem to be as safe and
effective as the first injection.
The results of our study are very promising, but it is clear that before Botulinum-A toxin
can be used as a primary therapy for overactive detrusor in childhood, further research
and placebo controlled studies are necessary.
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Does it make sense to use a daytime alarm as cognitive training in the
treatment of therapy resistant children with daytime incontinence? (paper 4)
In some children suffering therapy resistant urinary incontinence, lack of awareness
is an important part of the persistent problem. Many of these children are no longer
aware of incontinence and wet pants are ignored. Therefore, it was postulated that
increasing awareness, by drawing the attention of the child to bladder behaviour could
improve the problem by teaching them to go to toilet in time.
Indeed, before being able to respond to an involuntary event the patient must recognize
that signs that accompanies the event. In cases of overactive detrusor wetting occurs
at the time of an overactive detrusor contraction. Relearning to recognize the feeling of
urge proceeding urge incontinence enables the patients to prevent wetting by going
to the toilet on time or by central inhibition of the overactive detrusor contraction.
The daytime alarm method was first described by Vijverberg et al. in an inpatient setting.
Our patients were trained on an outpatient basis.
Halliday et al. stated that a noncontingent alarm produces as good response as a
contingent alarm. In our opinion, certainly in children with persistent, therapy resistant
urinary incontinence during the day, it is preferable and certainly more physiological
to use a contingent alarm. This is the only method to make these children aware of
bladder function, leading to adequate bladder control and better continence. Certainly
motivation and compliance are important factors in the success of this treatment
modality. This explains the good results after 2 weeks of training: 62% full response,
8% partial response and 30% failure. Decreases in patient motivation and attention are
certainly a reason for the high relapse rate 6 weeks after training was completed: 35%
full response, 35% partial response and 30% failure. Almost no difference was found
between the results after 6 weeks and after 1 year. This made us believe that once a
child has learned to cope with bladder dysfunction a positive, lasting continence result
may be achieved.
We believe that other factors, such as natural resolution of wetting, which are
undoubtedly important for the outcome of treatment in the whole population of
children with daytime incontinence, were far less important in this highly select group
of children with persistent daytime incontinence who showed no progress while on
common therapy during a mean of 21.6 months.
Also, because overactive bladder in childhood is considered a consequence of
maturation delay, it is postulated that this treatment enhances the further maturation
of detrusor function.
116
This theory is consolidated by the recent findings by Vermandel et al. who advocated
the use of a daytime alarm as an effective option for toilet training young healthy
children to limit the time to complete toilet training in many children.[265, 266]
Daytime alarm is certainly a useful device in children with therapy resistant urinary
incontinence during day. Outpatient use is preferable to inpatient treatment not only
for psychological, but also for economic reasons.
Urinary incontinence in physically and/or intellectually disabled children
is a common problem. What is the importance of dysfunctional voiding
in this population? Does restricted fluid intake play an important role in
incontinence? And if so does adequate fluid intake contribute to the treatment
of urinary incontinence in these patients? (paper 5 and 6)
Urinary incontinence in physically and intellectually disabled children is a common yet
poorly investigated problem. Far too often urinary incontinence is considered normal,
unavoidable and even a minor problem in this group of patients.
In our first prospective pilot study we found an incidence of 52.7%. In our more
current prospective study performed in 111 patients, 39.6% achieved continence
spontaneously, 36.9% had daytime and nighttime urinary incontinence, 9.6% had
daytime incontinence and 13.5% had nocturnal enuresis. No significant difference was
found among the 3 subgroups. Both studies showed that urinary incontinence during
day and night was the most common presenting symptom. The overall incidence of
urinary incontinence is clearly higher in the study group than in a normal paediatric
population.
To our knowledge there have been no studies of this population on the voiding
pattern evaluated by uroflowmetry performed in their own environment. In paper
5 we described the results of uroflowmetry. A disturbed uroflow pattern, the most
common of which was dysfunctional voiding, staccato or fractionated, was found in
65.8%. Remarkably, no correlation between the uroflow and continence patterns could
be found. In fact the incidence of daytime and/or nighttime incontinence was higher
in the patients with a normal uroflowmetry than in patients with a disturbed uroflow
pattern. No clear correlation could be found among continence pattern, uroflow
pattern, mental development and motor disability.
In paper 5 the influence of mobility and mental development on continence was
evaluated. The more mobile and the higher the IQ the higher the continence rate.
In this study population mobility seems to play a major role in achieving continence
compared to mental development. Children with a low IQ but reasonable degree
of mobility were continent, where as children with a higher IQ but a high degree of
immobility were incontinent.
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
118
In both studies about 90% of the children had an insufficient maximum voided volume.
This was neither influenced by motor development nor by type of motor disability.
In children with severe and moderate swallowing problems the mean maximum
voided volume deficit was higher than in those without swallowing problems.
In the pilot study (paper 5) the urinary osmolality was measured in all children. The
general too high osmolality suggested that fluid intake was to low in all children. In the
current study specific attention was paid to the fluid intake. Only 9.9% had a normal
fluid intake. According to our results fluid intake is clearly influenced by severity of the
underlying pathology. Patients with mental and a motor handicap have significantly
lower fluid intake than patients with a single disability, mainly because they depend
more on caregivers for help with normal daily activities such as eating, drinking and
visiting toilet.
Swallowing problems are often thought to be the main reason why intellectually
and physically disabled children have insufficient fluid intake. The results of paper 6
do not sustain this theory. It seems that regardless of swallowing problems most of
these children do not drink enough. We noted a correlation between the severity of
the swallowing problem, and voided volume and the degree of continence. The more
severe the swallowing problem, the worse the therapeutic outcome.
Inadequate fluid intake is mainly because of insufficient hydratation of the patient due
to their environment.
Increased fluid intake to a normal level of 1500ml/m² resulted in a significant increase
in continence and maximum voided volume in those with important decreased fluid
intake at start of study. Adequate fluid intake has a direct positive influence on urinary
incontinence, and is indirectly influencing urinary incontinence combined with a
healthy diet for constipation. This study clearly proves that increasing the fluid intake
results in increased voided volume and significant amelioration of the continence
pattern during the day and the night. An increase in continence of 27.4% was found.
Although adapting fluid intake to a normal level is often time-consuming, it is probably
one of the most important therapeutic factors for incontinence in physically and
intellectually disabled children. A standard drinking protocol according to fluid intake
quantity, beverage quality and drinking time schedule is the cornerstone of treatment
and probably also of the prevention of urinary incontinence in developmentally
challenged children. These children are often limited in their reaction to stimuli, such as
a full bladder sensation. Increased maximum voided volume and decreased nocturnal
diuresis enables them to interpret and react more adequately to the desire to void and
allows them to reach the toilet in time. This contributes to achieving continence. In
some patients adequate fluid intake, toilet adaptation and toilet position amelioration
are insufficient to achieve continence. In those cases when no contraindications exist,
anticholinergics can be used successfully.
Developmentally challenged children are amenable to continence rehabilitation.
Although urinary incontinence is a common, multifactorial problem, treatment is often
not that complex. Adequate fluid intake has a major role in this treatment strategy.
Consequences of these studies.
Based on the results of these studies we developed a therapeutical strategy in the
treatment of urinary incontinence in children.
In the normally developed children urotherapy still remains the basic intervention.
Urotherapy alone often fails in the treatment of urinary incontinence due to OAB. In
case of proven OAB and after exclusion of neurogenic bladder, obstructive uropathy
and underactive detrusor, antimuscarinics are started. The side effects of oxybutinin
are well explained to the parents and the existence of the alternatives tolterodine and
solifenacin is mentioned. As the safety of solifenacin in children has not been proven in
literature the use of the latter is restricted to children with a bodyweight of more than
25 kg.
The main disadvantage of tolterodin and solifenacin is the fact that they are expensive
and not reimbursed in contrast to oxybutinin. This is probably the main reason why
oxybutinin is still the first choice of a lot of parents. In case of important side effects or
inefficacy tolterodin or solifenacin are started with a clear preference for solifenacin due
to the promising results and the fact that it is a once daily dosage.
Neuromodulation can be started as mono-therapy or additional therapy in those
patients who prefer this treatment, in those who refuse medication, and in those whom
anti-muscarinics are insufficient or have to be stopped because of side effects.
If therapy fails because of lack of motivation and low compliance of parents and child,
additional psychotherapy and even an inpatient treatment in the voiding school is
offered.
In case of refractory urinary incontinence, and urodynamically proven bladder
overactivity and reduced bladder capacity, despite good patients’ compliance and
adequate followed therapy a treatment with Botulinum-A toxin is proposed.
The daytime alarm remains the ultimate treatment for the hard core daytime wetters.
In children with an intellectual and/or physical disability suffering urinary incontinence
adequate fluidintake is the major urotherapeutical step. A fluidintake of 1500ml/m²
119
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
120
bodysurface spread over the day should be achieved. A stable toilet position is also of
utmost importance.
If anti-muscarinics are necessary, tolterodin and solifenacin are preferably prescribed
because of their favourable spectrum of side effects.
We tried to use the daytime alarm in a few children without good result.
Until now we have no experience with the use of neuromodulation and Botulinum-A
toxin in these patients, and to our knowledge this has not been described in literature.
Further research
Considering the safety and effectiveness of new, more selective anti-muscarinics,
prospective, double blind controlled studies in children are needed. Pharmacokinetic
and pharmacodynamic and dose response relation should be investigated in order to
be able to use these drugs in the first line therapy of OAB.
The same is true for Botulinum-A toxin. Dose finding for this application is more
specifically important. These studies will be industry driven but from our academic
setting we should be involved in order to have good level of evidence after these
studies.
Urinary incontinence in developmentally challenged children remains a poorly
investigated problem. Most studies are in small, very heterogeneous populations.
Therefore multicentre prospective, large scale studies in well defined subgroups,
according to underlying causal pathology, are needed. The methodology developed
for this thesis and proven to be effective should be used to explore larger groups of
patients.
Finally some more basic research is needed into the pathophysiology of lower urinary
tract conditions in both healthy and disabled children. Natural fill urodynamic studies,
functional MRI and electrophysiological investigations should be planned in patients
next to basic research in animal models.
121
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Part 4. Dutch Summary
123
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
In deze thesis wordt de geactualiseerde aanpak van moeilijk te behandelen, vaak
therapieresistente urinaire incontinentie bij kinderen weergegeven.
Urinaire incontinentie bij kinderen is een complex probleem, dat door multipele
factoren beïnvloed wordt en waarvoor geen gouden standaard therapie bestaat.
In het eerste deel van deze thesis wordt de terminologie, de fysiopathologie, de
diagnostiek en de gangbare therapie van urinaire incontinentie en enuresis bij kinderen
belicht. De problematiek van urinaire incontinentie bij kinderen met een mentale en/of
motorische retardatie wordt daarbij apart benaderd.
Antispasmodica en anticholinergica behoren tot de eerstelijns therapie voor urinaire
incontinentie en enuresis veroorzaakt door een overactieve detrusor. Oxybutinine
chloride is in de pediatrische urologie nog steeds het standaard anticholinergicum. Dit
medicijn is zeer effectief, maar heeft het grote nadeel bij kinderen een behoorlijk aantal
systemische bijwerkingen te veroorzaken, die het gebruik ervan limiteren.
In artikel 1 en 2 wordt het gebruik van twee nieuwere, meer blaasspecifieke
anticholinergica, die nog niet geregistreerd zijn voor pediatrisch gebruik , bij kinderen
met urinaire incontinentie en/of enuresis bestudeerd.
In artikel 1 wordt retrospectief de effectiviteit en veiligheid van tolterodine bij
kinderen met een overactieve blaas nagegaan. In deze studie werden 256 kinderen
geïncludeerd. Uit deze studie bleek dat tolterodine zeer effectief was bij de behandeling
van symptomen van overactieve detrusor. Er werd een significante toename van
het maximum geplast volume, een afname van het aantal micties / 24 uur en een
vermindering van het aantal plasaccidenten per 24 uur waargenomen. Slechts bij 3%
van de kinderen werden milde bijwerkingen van de medicatie gezien, die slechts in 2
gevallen leidden tot stopzetten van de behandeling.
In het tweede artikel wordt op retrospectieve wijze het gebruik van solifenacine bij
kinderen met een therapie resistente overactiviteit van de blaas bestudeerd. Deze
niet-gecontroleerde, retrospectieve studie werd uitgevoerd op een populatie van
138 kinderen met therapie resistente overactieve blaas. Slechts 6.5% van de kinderen
hadden bijwerkingen op solifenacine. Behalve fecale impactie, gediagnosticeerd en
behandeld bij 1 kind, ging het om milde bijwerkingen. Opvallend was het feit dat 5 van
de 9 kinderen met bijwerkingen op solifenacine ook voordien al bijwerkingen hadden
op oxybutinine, wat er kan op wijzen dat sommige kinderen meer gevoelig zijn voor
anticholinerge bijwerkingen dan andere.
De medicatie leidde bij 50% van de kinderen tot volledige respons, 46% waren partiële
responders en bij 4% had de behandeling geen effect. Gezien de significante toename
van het geplast volume onder deze medicatie was het effect van solifenacine meer
uitgesproken bij kinderen met urinaire incontinentie dan bij kinderen met enuresis.
124
Gebaseerd op deze resultaten is solifenacine een waardig, misschien wel superieur
alternatief voor oxybutine. Verdere prospectieve, gecontroleerde studies met
farmacokinetische en farmacodynamische gegevens zijn noodzakelijk. Zolang kan
solifenacine enkel off-label gebruikt worden.
In het derde artikel wordt het gebruik van botuline-A toxine (Botox®) in de behandeling
van kinderen met therapie resistente overactieve detrusor beschreven.
In deze prospectieve studie werden 21 kinderen met therapie resistente niet-neurogene
detrusor overactiviteit geïncludeerd. Al deze kinderen hadden een te beperkte
blaascapaciteit volgens hun leeftijd en vertoonden aandrang en aandrangincontinentie.
Bij de groep die langer dan 6 maand na het injecteren van de Botox® gevolgd werd,
waren 9 van de 15 kinderen volkomen succesvol behandeld, 3 vertoonden een partieel
antwoord op de therapie en bij 3 werd geen verbetering van de klachten waargenomen.
Het gebruik van Botox® in de blaas bleek voor wat de korte termijn opvolging
betreft veilig te zijn. Slechts 1 meisje ontwikkelde een tijdelijke retentie, een jongen
vertoonde tijdelijk klachten van vesico-ureterale reflux. Vier kinderen hadden een
tijdelijk disfunctioneel uroflow patroon. Echografisch werd bij 1 meisje een significant
postmictioneel residu waargenomen en 4 kinderen hadden een minimaal residu. Na 6
weken plasten alle kinderen terug spontaan leeg. Systemische bijwerkingen werden in
deze studiepopulatie niet waargenomen.
Opvallend was het feit dat de patiënten met een partieel antwoord op de initiële
Botox® injectie het ook bij een tweede behandeling niet goed deden. Het patiëntje
dat een herval kende na een initieel succesvolle behandeling, was ook na een tweede
injectie terug volkomen droog.
Bij alle kinderen werden 100 IE geïnjecteerd in de detrusor. Het gaat daarbij om een
vrij arbitrair gekozen dosis, lager dan de dosis gebruikt bij kinderen met neurogeen
blaaslijden.
Er is dan ook absolute nood aan het bepalen van de minimaal effectieve dosis. Enkel op
die manier kunnen booster injecties en te snel herhalen van de behandeling, die leiden
tot resistentie en eliminatie van deze methode, vermeden worden.
De resultaten van deze studie laten het beste verhopen voor het gebruik van Botox®
in de behandeling van de overactieve blaas bij kinderen. Verder onderzoek en placebo
gecontroleerde studies zijn echter noodzakelijk.
In de vierde publicatie wordt het gebruik van de dagwekker bij kinderen met
broekplassen beschreven.
125
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
126
Bij sommige kinderen met therapie resistente urinaire incontinentie speelt een gebrek
aan bewustzijn van het probleem een belangrijke rol in het persisteren van de klacht.
Een contractie van de overactieve detrusor ligt aan de basis van de urinaire incontinentie
bij deze kinderen. Door middel van de dagwekker trachten we de kinderen beter het
aandranggevoel te leren interpreteren zodat zij daarop kunnen anticiperen door tijdig
naar het toilet te gaan.
Motivatie en medewerking spelen bij deze methode een belangrijke rol. Dit verklaart
de gunstige resultaten na 14 dagen therapie. Na 6 weken werd een duidelijke afname
gezien. Nadien blijven de resultaten nagenoeg onveranderd. Uiteindelijk werd na
een jaar een volledig succes gezien bij 35 % van deze kinderen, 35% vertoonde een
duidelijke verbetering en bij 30% faalde de methode. Gezien het hier om een therapie
resistente groep ging, kunnen deze resultaten als bevredigend beschouwd worden.
In artikel 5 en 6 wordt het probleem van urinaire incontinentie bij kinderen met een
mentale en/of motorische retardatie bestudeerd. In publicatie 5 worden de resultaten
van een piloot-studie uitgevoerd bij 38 kinderen weergegeven. Slechts 47.4% van deze
kinderen was continent. In artikel 6 worden de resultaten van een prospectieve studie
bij 111 kinderen beschreven. Slechts 39.6% van de kinderen waren continent bij het
begin van de studie.
De piloot-studie is de eerste studie waarin het plaspatroon wordt bestudeerd door
middel van een uroflow geplaatst in de leefwereld van de kinderen. Meer dan 65%
van de kinderen had een disfunctionele uroflow curve. Opvallend daarbij was dat
er geen correlatie kon aangetoond worden tussen het uroflowpatroon en het
continentiepatroon. Ook de invloed van de mobiliteit en de mentale ontwikkeling op
het verwerven van continentie werd nagegaan. Mobiliteit bleek bij deze populatie een
belangrijkere invloed te hebben dan mentale ontwikkeling.
Uit beide studies bleek dat meer dan 90% van de kinderen een te klein blaasvolume
hadden.
Uit de eerste studie bleek dat urinaire osmolaliteit bij de meeste kinderen te hoog
was. Dit liet vermoeden dat deze kinderen een te beperkte vochtinname hadden. In
de tweede studie werd de vochtinname van de kinderen in kaart gebracht. Minder
dan 10% van kinderen had een normale vochtinname. De vochtinname werd
duidelijk beïnvloed door de ernst van de ontwikkelingstoornis. Patiënten met een
gecombineerde motorische en mentale handicap deden het beduidend slechter.
Vaak wordt gedacht dat slikproblemen een belangrijke oorzaak zijn van de beperkte
vochtinname. De resultaten van studie 6 weerleggen dit ten dele. Onafhankelijk van de
graad van slikmoeilijkheden bleken de meeste kinderen te weinig te drinken. Wel was
er een correlatie tussen de ernst van de slikstoornis, en het blaasvolume en de graad
van continentie. Bovendien bleken kinderen met een ernstig slikprobleem moeilijker
te behandelen.
Aanpassen van de vochtinname tot een niveau van 1500 ml/m² resulteerde in een
significante toename van de continentie met 27,4%.
Deze studie toont duidelijk aan dat aanpassen van het drinkgedrag, ook al is dit vaak
erg tijdrovend, leidt tot een normaliseren van het geplast volume en tot een duidelijke
verbetering van de continentie.
Samen met enkele andere maatregelen, zoals aanpassen van het toilet aan de
noden van de patiënt, vormt aanpassen van het drankschema een hoeksteen van de
urotherapie bij incontinente kinderen met een ontwikkelingstoornis.
Uit deze studies blijkt dat urinaire incontinentie een complex probleem is waarvoor tot
op heden geen standaard therapie bestaat.
Gebaseerd op de resultaten van deze studies hebben wij onze therapeutische strategie
voor het behandelen van urinaire incontinentie bij kinderen aangepast.
Bij “normaal” ontwikkelde kinderen blijft urotherapie de basis behandeling. Wanneer
overactiviteit van de blaas de incontinentie veroorzaakt, is deze urotherapie als
monotherapie vaak ontoereikend. In die gevallen, en pas nadat neurogeen blaaslijden,
obstructieve uropathie en een onderactieve detrusor zijn uitgesloten, zal antimuscarine
medicatie gestart worden. Oxybutinine blijft daarbij tot vandaag het enige erkende,
terugbetaalde middel bij kinderen in België. De bijwerkingen van dit product en het
bestaan van alternatieve middelen zoals tolterodine en solifenacine worden uitvoerig
met de ouders besproken. Daar de veiligheid van solifenacine bij kinderen nog niet
bewezen is, wordt dit product enkel gebruik bij kinderen die meer dan 25 kilogram
wegen.
Daar tolterodine en solifenacine duur zijn, verkiezen de ouders vaak eerst een
behandeling met oxybutinine. Bij ernstige bijwerkingen of onvoldoende resultaat
met oxybutinine wordt tolterodine en solifenacine voorgesteld, met een voorkeur
voor solifenacine gezien de veelbelovende resultaten van onze studie en het feit dat
patiëntje maar één keer per dag medicatie dient in te nemen.
Neuromodulatie kan als monotherapie of als supplementaire behandeling gestart
worden bij die patiënten die deze therapie verkiezen, bij hen die medicatie weigeren en
bij diegene waar antimuscarine middelen onvoldoende werken of te veel bijwerkingen
veroorzaken.
Wanneer de therapie faalt door gebrekkige medewerking of motivatie van het kind
en/of de ouders wordt psychotherapie en soms zelfs een opname in de plasschool
voorgesteld.
127
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
128
Bij persisterende urinaire incontinentie, met urodynamisch bewezen overactiviteit van
de blaas en beperkte blaascapaciteit, ondanks een adequate therapie en therapietrouw,
heeft een intravesicale injectie met Botuline-A toxine zijn plaats.
De dag plaswekker wordt voorbehouden voor de zogenaamde“hard core”broekplassers.
Bij kinderen met een mentale en/of motorische handicap is optimalisatie van het
drinkgedrag en de vochtinname de eerste stap in de behandeling. Een vochtinname
van 1500ml/m² lichaamsoppervlak, gespreid in de dag, dient te worden nagestreefd.
Ook aandacht voor de toilethouding is bijzonder belangrijk.
Indien een behandeling met anti-muscarine medicatie noodzakelijk is, verdienen
tolterodine en solifenacine de voorkeur omwille van hun gunstiger bijwerking
spectrum.
De dag plaswekker werd enkele keren gebruikt zonder gunstig resultaat.
Tot op heden hebben we geen ervaring met Neuromodulatie en Botuline-A toxine bij
deze patiënten.
De zoektocht naar nieuwe, veiligere, meer adequate middelen om de urinaire
incontinentie, en dan zeker de resistente vormen ervan, te behandelen dient
onverminderd verder gezet te worden. Belangrijk daarbij is het feit dat kinderen geen
minivolwassenen zijn en dat studieresultaten bij volwassen vaak niet geëxtrapoleerd
kunnen worden naar de pediatrische populatie. Uitgebreid onderzoek naar de
farmakokinetiek en grote gerandomiseerde, gecontroleerde, dubbel blinde
prospectieve studies naar de farmokodynamiek van nieuwe geneesmiddelen zijn dan
ook uiterst noodzakelijk.
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Curriculum Vitae
149
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Erik Van Laecke
Born in Ghent on 22/04/65
Married with Inge Vanhoudt
Father of Hannes Van Laecke
Professional address:
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Dept. Paediatric Urology
Ghent University Hospital
De Pintelaan 185
B-9000 Ghent
Belgium
Tel: 0032 9 332 22 76
Email: [email protected]
Studies:
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Primary school:
Oefenschool K. Ledeganck, Ghent
Secondary school:
Koninklijk Atheneum III “Voskenslaan”, Ghent
Graduated on 30/06/1983
University: Faculty of medicine, Ghent University
Graduated on 03/07/1990 with honour
Supplementary certificates:
Electrocardiography
Radioprotection
Military Service:
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Lieutenant in the Medical Service of the Belgium Army
Urological Training:
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Surgeon in training from 01-09-91 until 31/08/1993 in the service of dr. M. Huyghe,
St. Camillusziekenhuis, Antwerp
Urologist in training from 01/09/93 until 30/9/97 in the department of urology of
Prof. dr. W. Oosterlinck at the Ghent University Hospital
Graduated as urologist on 28/10/1997
R.I.Z.I.V. number: 1-45686-08-450
Member of the European Board of Urology: 09/05/1998
Fellow of the European Academy of Paediatric Urology: 17/03/2006
Current position
Full staff member Paediatric Urology at the service of Urology of the Ghent University
Hospital, of Prof. dr. Piet Hoebeke since 01/01/1998
Fields of special interest:
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Paediatric Urological Laparoscopy
Voidingdysfunction in children with a mental and/or motor disability
Uro-lithiasis in children
Membership:
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ESPU
EAU
ICCS
Awards:
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Laureate of the “Professor Elautprijs” 1999 Belgium
Best Poster Presentation in the session « Pediatric voiding disorders – trauma and
tumours « van XV th Congress of the European Association of Urology, Brussels
2000, with the poster « Detrusor pressure is more harmful for renal function then
bacteriuria in patients with voiding dysfunction and vesico - ureteral reflux »
Courses:
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Training Endoscopic Surgery : Ethicon Endo - Surgery : 14 April 1992
1994 Course on Paediatric Urology, Robinson College, Cambridge : September 2223, 1994
1995 British Course of Paeditric Urology, Robinson College, Cambridge, September
27-28, 1995
ESPU Study Day : Perinatal Uro-Nephrology Symposium, Robinson College
Cambridge, September 29, 1995
1996 ESPU Course Paediatric Uro Endocrinology, Paris, September 27-28, 1996
1st Annual European Course in Urology, Rome, November 4-9, 1996
1997 Second Course on Paediatric Urodynamics, September 12-13, 1997, Utrecht
1999 ESPU Course Aarhus Denmark, September 16-18, 1999
2e ICCS - Course : Diagnostic and therapeutic approach to non-neuropathic bladder
sphincter dysfunction in children, Ghent, September 24-25, 2000
2001 Laparoscopic Paediatric Urology ESPU Practical Post-Congress Course ; April
29-30, 2001
2004 Laparoscopic Paediatric Urology ESPU Course; April 2004, Regensburg:
Germany
Co-ordination and organization of Voiding Camp Deinze, Belgium
Publications and abstracts:
A. Publications
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2.
3.
4.
Physiopathology of renal colic and the therapeutic consequences : E. Van Laecke, W.
Oosterlinck ; Acta Urologica Belgica 1994, 62, 2, 15-18
Colpopromontoriopexy : K. Everaert, E. Van Laecke, W.A. De Sy ; Acta urologica Belgica
1995, 63, 2, 47-50
Non Neurogenic Bladder Dysfunctions in Children : Bladder function and non-neurogenic
dysfunction in children : classification and terminology : P. Hoebeke, E. Van Laecke, A.
Raes, C. Renson, M. Theunis, J. Vande Walle ; Acta Urologica Belgica 1995, 63, 2, 93-98
Pathofysiologie van de nierkoliek en de therapeutische implicaties ervan : E. Van
Laecke,W. Oosterlinck, ; Tijdschrift voor Geneesk., 52, nr 19, 1996
151
Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
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One hundred consecutive cystoscopic examinations in children : Indications and Results :
P. Hoebeke, E. Van Laecke, A. Raes, J. Vande Walle ; Eur. Urol. 1996 ; 30 :112-118
The after-contraction in paediatric urodynamics : P. Hoebeke, J. Van Gool, E. Van Laecke,
J. Vande Walle, H. Plancke ; BJU Int. (1996), 78, 780-782
Trouble mictionenels révélateurs d’une valve de l’urètre posterieur : aspects cliniques : P.
Hoebeke, E. Van Laecke, A. Raes, J. Vande Walle ; Arch. Pédiatr. 1997 ; 4 (Suppl 1) : 10-13
Membrano-Bulbo-Urethral Junction Stenosis : posterior urethra obstruction due to
extreme caliber disproportion in the male urethra : P Hoebeke, E. Van Laecke, A. Raes, J.
Vande Walle, W. Oosterlinck ; Eur. Urol. 1997 ; 32 : 480-484
Current trends in the treatment of hypospadias : P. Hoebeke, E. Van Laecke, W. De Sy, W.
Oosterlinck ; Acta Urologica Belgica 1997, Vol. 65, no. 4 :17-24
The use of EMLA cream as an anaesthetic for minor urological surgery in children : P.
Hoebeke, P. Depauw, E. Van Laecke, W. Oosterlinck ; Acta Urologica Belgica 1997, Vol. 65,
no. 4 : 25-28
Persistent enuresis caused by nocturnal polyuria is a maturation defect of the nycthemeral
rhythm of diuresis : J. Vande Walle, P. Hoebeke, E. Van Laecke, D. Castillo, D. Miliçic, Che
Maraina Che Hussein, A. Raes ; BJU Int. 1998 May ; 81 Suppl. 3 : 40-5
Urodynamics in children : what and how to do it ? : P. Hoebeke, A. Raes, J. Vande Walle, E.
Van Laecke ; Acta Urologica Belgica 1998 May, 66 (2) : 23-30
Pelvic-floor therapy in girls with recurrent urinary tract infections and dysfunctional
voiding : H. De Paepe, P. Hoebeke, C. Renson, E. Van Laecke, A. Raes, E. Van Hoecke, J. Van
Daele, J. Vande Walle ; BJU Int. 1998 May ; 81 Suppl. 3 : 109-13
Assessment of lower urinary tract dysfunction in children with non-neurpathic bladder
sphincter dysfunction : P. Hoebeke, J. Vande Walle, K. Everaert, E. Van Laecke, JD. Van
Gool ; Eur. Urol. 1999 ; 35(1) : 57-69
Anomalies of the external urethral meatus in girls with non-neurogenic bladder sphincter
dysfunction : P. Hoebeke, E. Van Laecke, A. Raes,JD. Van Gool, J. Vande Walle ; BJU Int.
1999 Feb ;83(3) : 294-8
Pelvic-floor therapy and toilet training in young children with dysfunctional voiding and
obstipation : H. De Paepe, C. Renson, E. Van Laecke, A. Raes, J. Vande Walle, P. Hoebeke ;
BJU Int. 2000 ; 85 : 889-893
Urodynamic assessment of voiding dysfunction and dysfunctional voiding in girls
and women : K. Everaert, E. Van Laecke, M. De Muynck, H.Peeters, P. Hoebeke ; Int.
Urogynecol. J. Pelvic Floor Dysfunct. 2000 ;11(4) : 254-64
Bladder neck closure for treating pediatric incontinence :P. Hoebeke, P. De Kuyper, H.
Goeminne, E. Van Laecke, K. Everaert ; Eur. Urol. 2000 Oct ; 38(4) : 453-6
Impact of urinary tract infection and detrusor pressure on renal tubular function in
patients with vesicoureteral reflux : K. Everaert, E. Van Laecke, P. Dekuyper, P. Hoebeke, J.
Delanghe, W. Oosterlinck, J. Vande Walle; Eur. Urol. 23001 Mar;39(3): 337-42
One thousand video-urodynamisc studies in children with non-neurogenic bladder
sphincter dysfunction: P. Hoebeke, E. Van Laecke, C. Van Camp, A. Raes, J. Vande Walle;
BJU Int. 2001 Apr;87(6): 575-80
Voiding disorders in severely mentally and motor disabled children: E. Van Laecke, L.
Golinveaux, L. Goossens, A. Raes, P. Hoebeke, J. Vande Walle; J Urol. 2001 Dec;166(6): 2404-6
Transcutaneous neuromodulation for the urge syndrome in children: a pilot study: P.
Hoebeke, E. Van Laecke, K. Everaert, C. Renson, H. De Paepe, A. Raes, J. Vande Walle; J
Urol. 2001 Dec;166(6): 2416-9
A high easy-to-treat complication rate is the price for a continent stoma: J. De Ganck, K.
Everaert, E. Van Laecke, W. Oosterlinck, P. Hoebeke; BJU Int. 2002 Aug;90(3): 240-3
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The role of pelvic-floor therapy in the treatment of lower urinary tract dysfunctions in
children: H. De Paepe, C. Renson, P. Hoebeke, A. Raes, E. Van Laecke, J. Vande Walle;
Scand J Urol Nephrol. 2002;36(4): 260-7
“Batman excision” of ventral skin in hypospadias repair, clue to aesthetic repair ( point of
technique): P. Hoebeke, P.De Kuyper, E. Van Laecke; Eur Urol. 2002 Nov;42(5): 520-2
Retrospective analysis of efficacy and tolerability of tolteridine in children with overactive
bladder: A. Raes, P. Hoebeke, I. Segaert, E. Van Laecke, J. Dehoorne, J. Vande Walle; Eur
Urol. 2004 Feb;45(2): 240-4
Pelvic floor spasms in children: an unknown condition responding well to pelvic floor
therapy: Hoebeke P, Van Laecke E, Renson C, Raes A,Dehoorne J, Vermeiren P, Vande
Walle J; Eur Urol. 2004 Nov; 46(5):651-4
Familiale enuresis met nachtelijke polyurie: DDAVP resistentie door nasale obstructie:
Vande Walle J, Eeckhout P, Raes A, Van Laecke E; Tijdschrift voor Kindergeneeskunde 2005
Ventrale buikwanddefecten:presentatie en heelkundige benadering: Smets K, Kerremans
I, Van Laecke E, Hoebeke P; Percentiel 2005
De toenemende incidentie van hypospadie: Van Leeuwen E, Van Hemelrijck M, De Ronne
N, Van Laecke E, Tsjoen G, Hoebeke P; 2005: vol.61 nr. 11: 830-34
The daytime alarm: a useful device for the treatment of children with daytime
incontinence: Van Laecke E, Wille S, Vande Walle J, Raes A, Renson C, Peeren F, Hoebeke
P; J Urol. 2006 Jul; 176(1):325-7.
The effect of botulinum-A toxin in incontinent children with therapy resistant overactive
detrusor: Hoebeke P, De Caestecker K, Vande Walle J, Dehoorne J, Raes A, Verleyen P, Van
Laecke E;J. Urol. 2006 Jul; 176(1):328-30; discussion 330-1.
Is an anal plug useful in the treatment of fecal incontinence in children with spina bifida
or anal atresia? Van Winckel M, Van Biervliet S, Van Laecke E, Hoebeke P; J. Urol. 2006 Jul;
176(1):342-4
Desmopressin resistant nocturnal polyuria secondary to increased nocturnal osmotic
excretion: Dehoorne JL, Raes AM, Van Laecke E, Hoebeke P, Vande Walle JG;
J. Urol. 2006 Aug; 176(2):749-53
Desmopressin toxicity due to prolonged half-life in 18 patients with nocturnal enuresis
Dehoorne JL, Raes AM, Van Laecke E, Hoebeke P, Vande Walle JG; J. Urol. 2006 Aug;
176(2):754-7
Abnormal circadian rhythm of diuresis or nocturnal polyuria in a subgroup of children
with enuresis and hypercalciuria is related to increased sodium retention during daytime:
Raes A, Dehoorne J, Hoebeke P, Van Laecke E, Donckerwolcke R, Vande Walle J ; J. Urol.
2006 Sep;176(3):1147-51
Characteristics of a tertiary center enuresis population, with special emphasis on the
relation among nocturnal diuresis, functional bladder capacity and desmopressin
response: Dehoorne JL, Walle CV, Vansintjan P, Raes AM, De Guchtenaere AR, Van Laecke
E, Hoebeke P, Vande Walle JG; J. Urol. 2007 Mar; 177(3):1130-7
Partial response to intranasal desmopressin in children with monosymptomatic nocturnal
enuresis is related to persistent nocturnal polyuria on wet nights: Raes A, Dehoorne J,
Van Laecke E, Hoebeke P, Vande Walle C, Vansintjan P, Donckerwolcke R, Vande Walle J;
J. Urol. 2007 Sep; 178(3 Pt 1):1048-51
Achieving fecal continence in patients with spina bifida: a descriptive cohort study:
Vande Velde S, Van Biervliet S, Van Renterghem K, Van Laecke E, Hoebeke P, Van Winckel
M; J. Urol. 2007 Dec;178(6):2640-4
Desmopressin resistant nocturnal polyuria may benefit from furosemide therapy
administered in the morning: De Guchtenaere A, Vande Walle C, Van Sintjan P,
Donckerwolcke R, Raes A, Dehoorne J, Van Laecke E, Hoebeke P, Vande Walle J;
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41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
J. Urol. 2007 Dec;178(6):2635-9
Nocturnal polyuria is related to 24-hour diuresis and osmotic excretion in an enuresis
population referred to a tertiary center: Vande Walle J, Vande Walle C, Van Sintjan P, De
Guchtenaere A, Raes A, Donckerwolcke R, Van Laecke E, Mauel R, Dehoorne J, Van
Hoyweghen E, Hoebeke P; J. Urol. 2007 Dec; 178(6):2630-4
Nocturnal polyuria is related to absent circadian rhythm of glomerular filtration rate: De
Guchtenaere A, Vande Walle C, Van Sintjan P, Raes A, Donckerwolcke R, Van Laecke E,
Hoebeke P, Vande Walle J; J. Urol. 2007 Dec;178(6):2626-9
Pitfalls in studies of children with monosymptomatic nocturnal enuresis: Vande Walle J,
Van Laecke E; Pediatr Nephrol. 2008 Feb;23(2):173-8
Phalloplasty: a valuable treatment for males with penile insufficiency: Lumen N, Monstrey
S, Selvaggi G, Ceulemans P, De Cuypere G, Van Laecke E, Hoebeke P; Urology. 2008
Feb;71(2):272-6
Reconstructive surgery for severe penile inadequacy: phalloplasty with a free radical
forearm flap or a pedicled anterolateral thigh flap: Lumen N, Monstrey S, Ceulemans P,
Van Laecke E, Hoebeke P; Adv.Urol.2008:704343
Evidence of partial anti-enuretic response related to poor pharmacodynamic effects
of desmopressin nasal spray: De Guchtenaere A,Raes A,Vande Walle C, Hoebeke P, Van
Laecke E, Donckerwolcke R, Vande Walle J; J.Urol.2009 Jan; 181(1):302-9
Aandoeningen van de seksuele ontwikkeling: de actuele chirurgische aanpak: E. Van
Laecek, P. Hoebeke, Tijdschrift voor Genneskunde 2009 vol 65, nr 16: 750-53
Solifenacin for therapy resistant overactive bladder: Hoebeke P, De Pooter J, De Caestecker
K, Raes A, Dehoorne J, Van Laecke E, Vande Walle J; J. Urol. 2009 Oct; 182(4suppl):2040-4
Abnormal sleep architecture and refractory nocturnal enuresis: Dhondt K, Raes A, Hoebeke
P, Van Laecke E, Van Herzeele C, Vande Walle J; J. Urol.2009 Oct; 182(4suppl):1961-5
Adequate fluid intake, urinary incontinence, and physical and/or intellectual disability:
Van Laecke E, Raes A, Vande Walle J, Hoebeke P; J. Urol. 2009 Oct; 182(suppl4):2079-84
B. Books
1. Bedplassen, wat doe ik eraan? Hoofdstuk 8. De Technische onderzoeken; 99-105;
Lannoo/TERRA 1997
C. Publications
1.
2.
Ambulatory pelvic floor training in dysfunctional voiding: P. Hoebeke, C. Renson, H.
Vanden Broecke, M. Theunis, E. Van Laecke, J. Vande Walle; ICCS Monograph Series
N°.1: 3 rd international Children’s Continence Symposium 16 – 17 October 1995, Sydney,
Australia
New devices: E. Van Laecke; Syllabus of the second ICCS-Course: 96-99, September 2425, 2000, Ghent, Belgium
D. Abstracts
Author and co-author of several abstracts presented in international paediatric urology
meetings.
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Dankwoord
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Een thesis schrijven is als een berg beklimmen. Je begint eraan met het idee dat je weet
wat je te wachten staat, maar gaande weg wordt je geconfronteerd met de realiteit.
Bergpaden blijken steile rotswanden te zijn en sneeuwvelden blijken gletsjers met
aardig wat spleten.
Met geduld, heel wat inspanning en doorzetting weet je de top wel te bereiken, maar
onderweg wordt er toch behoorlijk wat afgezien en afgevloekt.
Dit is een klim die je niet allen kan waarmaken. Zonder goede gidsen en betrouwbare
touwgenoten was dit nooit gelukt.
Vooreest wil ik mijn beide gidsen bedanken.
Mijn promotor en diensthoofd, Prof. Dr. Piet Hoebeke. Piet, jij bent mijn grote, slimme
broer in de urologie. Je hebt mij niet alleen de kinderurologie bijgebracht, maar jij was
ook degene die mij op weg hebt gezet in het wetenschappelijk onderzoek. Ik weet dat
ik de laatste tijd regelmatig wat van je bijzonder schaarse tijd heb opgeëist. Bedankt dat
je toch nog de tijd vond om deze thesis te begeleiden en te corrigeren. Deze thesis is
het resultaat van een jarenlang voortreffelijke samenwerken. Ik ben ervan overtuigd dat
deze samenwerking ook in de toekomst nog heel wat perspectieven biedt.
Mijn copromotor Prof. Dr. Johan Vande Walle. Johan, jij bent een van de meest
fascinerende proffen die ik ken. Je enthousiasme, bereidwilligheid om te helpen en
onuitputtelijke bron van plannen en ideeën zijn voor mij een belangrijke bron van
inspiratie zowel bij het schrijven van deze thesis als in onze dagelijkse samenwerking
binnen het unieke PUNC team. Je al even legendarische verstrooidheid heeft mij af en
toe verdomd hard doen vloeken. Johan, je bent op zijn minst een uniek exemplaar te
noemen, en ik ben blij dat ik met jou mag samenwerken.
Mijn speciale dank wil ik betuigen aan een oude wijze gids, Prof. Dr. Wim Oosterlinck
Wim, jij hebt mij indertijd de kans gegeven om uroloog te worden. Jij was het ook die mij,
nog tijdens mijn opleiding de mogelijkheid gaf om mij in de kinderurologie, mijn grote
droom, extra te bekwamen. Jij was het die mij de kans gaf hier als stafmedewerker in
de kinderurologie verder mijn loopbaan uit te bouwen. Wim ik heb je altijd bewonderd
omwille van je vakkennis, maar zeker evenveel omwille van je menselijkheid. Ook
buiten de dienst heb ik je leren kennen als een bijzonder warm iemand. Ik ben dan ook
trots door jou opgeleid te zijn.
Hartelijke dank aan de leden van de examen- en leescommissie, Prof. Dr. G. Bogaert,
Prof. Dr. J.M. Nijman, Prof. Dr. K. Everaert, Prof. Dr. D. Matthys, Prof. Dr. W. Oosterlinck, Prof.
Dr. R. Van Coster en Prof. J. Vande Voorde voor het lezen en beoordelen van deze thesis.
Naast gidsen heeft men ook zijn touwgenoten.
156
Een aantal van deze artikels zouden er niet gekomen zijn zonder de enorme inzet en
bereidwillige medewerking van de artsen, opvoeders en verpleegkundigen van enkele
instellingen voor kinderen met een mentale en/of motorische handicap. Door met
jullie samen te werken is mijn interesse in deze patiëntjes nog intenser geworden. Jullie
aanstekelijk enthousiasme en inzet om deze kinderen een gewoon leven te laten leiden,
hebben mij een belangrijke ervaring rijker gemaakt. Ik wens dan ook alle medewerkers
van het MPI Ten Dries, het MPI De Triangel, het Dominiek Savio Instituut, het MPI SintLodewijk en De Zonnepoort te bedanken voor hun fantastische medewerking aan
deze studies.
De andere publicaties waren er waarschijnlijk niet gekomen zonder het PUNC team.
Dit multidisciplinair team binnen de kinderurologie – nefrologie maakt klinisch en
wetenschappelijk werken zo veel prettiger.
Wat is het geruststellend als je als “handige” uroloog te rade kan gaan bij een “verstandige
nefroloog”. Joke, Ann en Reiner het is fijn dat jullie zo verstandig zijn.
Dr. Raes. Beste Ann jij bent niet zomaar een fantastische collega voor mij. Jij bent mijn
maatje, mijn “grote“ vriendin. Bedankt dat ik af en toe mocht komen zagen over die
“verdomde” thesis.
Catherine, jij leerde mij alles over urotherapie en bekkenbodemkine. Bedankt voor je
ongebreidelde inzet en vriendschap.
Ook de andere leden van het PUNC team, psychologen, verpleegkundigen en kinesisten
wens ik te bedanken voor de fijne samenwerking.
Hoewel deze thesis zich zeer specifiek focust op een kinderurologisch onderwerp zou
zij zonder mijn collega’s van de urologie nooit verwezenlijkt geworden zijn.
Prof. Dr. Karel Everaert. Karel het is fijn om met jou samen te werken. Je hebt mij geleerd
dat werklust en genieten van het leven wel degelijk hand in hand kunnen gaan.
Nicolaas, Christel, Albert, Karel en Bart door jullie werk kreeg ik wat meer tijd om aan
deze thesis te schrijven. Ooit hoop ik hetzelfde voor jullie te kunnen doen.
Deze thesis werd vakkundig in boekvorm gegoten door Danny Vandekerchove en de
prachtige cover is afkomstig van het kunstzinnige brein en de speelse hand van Ellen
Cornelis. Mijn oprechte dank daarvoor.
Beste verpleegkundigen, collega’s en medewerkers van de polikliniek, de hospitalisatie
en het operatiekwartier, zonder jullie zou onze dienst nooit dezelfde uistraling en sfeer
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
hebben. Een sfeer waarbij iedereen regelmatig een extra tandje bij steekt zodat onze
overvolle werkschema’s toch nog gerealiseerd worden.
In het bijzonder wens ik Dirk te bedanken. Bij jou kan ik immers niet alleen terecht voor
organisatorische en ICT problemen maar ook voor een ontspannende babbel.
Dank ook aan zij die mij hebben opgeleid. Dr. P. Thibo, Dr. J.M. De Meyer, Dr. M. Huyghe,
Dr. Ph. Vanden Borre en Prof. Dr. Verbaeys, allemaal hebben jullie bijgedragen tot de arts
die ik nu ben. Bedankt.
Gelukkig bestaat er ook nog een leven buiten de geneeskunde. Veel te vaak heb ik de
laatste tijd tegen mijn vrienden moeten zeggen dat ik weer geen tijd had voor hen.
Maar beste makkers, er komen andere tijden. Ik kijk er al naar uit om stampend op onze
pedalen, trekkend aan de rotsen, hijgend bergop lopend of stuivend door kniediepe
sneeuw met jullie op pad te zijn.
Ludwig, Linda, Joke, Kaat en Luc jullie hebben ervoor gezorgd dat mijn levensdroom,
mijn miniboerderij bleef draaien wanneer ik er weer eens niet was. Ik en mijn beesten
danken u.
Mijn lieve ouders en broer. Jullie bezorgden mij een fantastische jeugd. Jullie warmte,
opvoeding en liefde hebben gemaakt dat ik kan zijn wie ik ben. Inzet, respect,
sportiviteit, zin voor avontuur en liefde voor de natuur werden mij met de paplepel
meegegeven. Jullie lieten mij voor arts studeren. Ik weet het mama, nachten heb je
geluisterd naar het opdreunen van mijn cursussen, omdat ik nu eenmaal beter luidop
dacht te studeren en daarvoor de nacht verkoos boven de dag. Onthutsender nog is
het feit dat jij van sommige van die cursussen meer hebt overgehouden dan ik. Pa jij
leerde mij wat doorzetten was als je weer eens een lichte tocht of training had bedacht
die dan toch weer net iets zwaarder bleek uit te vallen dan voorzien. Bart ik weet het.
Ge hebt afgezien met die broer van u, maar het heeft ons er toch niet van weerhouden
dikke vrienden te blijven.
Lieve Inge, bedankt om mij steeds weer bij te staan in dit af en toe onmogelijk lijkend
avontuur. Ondanks je drukke job weet jij steeds weer de energie te vinden om voor
Hannes en mij te zorgen als geen ander. Met zo’n basecamp moet de moeilijkste
expeditie slagen.
Liefste Hannes, mijn superdikke vriend. Eindelijk is “die” thesis klaar. Vanaf nu kunnen we
nog vaker kattenkwaad uithalen. Drie werf hoera!!!
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Approach to refractory urinary incontinence in children, with special emphasis on children with intellectual and/or physical disability.
Ontwerp cover : Ellen Cornelis
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