What is behaviour therapy?

Behaviour therapy (BT) is based on the principles of Applied Behavioural Analysis (ABA)
and focuses on reducing challenging behaviours and teaching new skills. It has many
applications, including reducing aggressive behaviour, improving language skills, enhancing
social behaviours, reducing self-injurious behaviours and toileting. BT focuses on observable
behaviours rather than attitudes or beliefs; results are measurable and designed to be
maintained over time.

ABA is an evidence-based approach that is considered to be effective in helping children with

Autism Spectrum Disorder (ASD). One common misconception is that BT can only be used
to treat ASD; while the therapy is useful for treating this disorder, it has much broader
applications.

The method works to understand the causes or functions of challenging behaviours that
interfere with daily life and identify more appropriate behaviours as replacements. For
instance, if a child screams and bites when given work in class, a behaviour therapist might
teach the child to use a picture symbol or communicate that they need a break. This will
reduce the need to engage in the challenging behaviour (biting and screaming) and increase
functional communication.

Behaviour therapists (BTs) draw on different techniques from the field to increase or decrease
behaviours. Decreasing a challenging behaviour can also involve teaching the caregivers how
to respond effectively when the behaviour occurs. Increasing a skill involves finding ways to
prompt that behaviour, motivating the child to repeat it and rewarding its occurrence.

The therapist works toward broad goals like social skills or communication, and tracks
progress by breaking that goal down, and looking at very specific indicators, such as how
often a child makes eye contact, makes a request or takes turnswhatever measure is
appropriate for the goal.

Who can benefit from BT?

Children with Autism Spectrum Disorder or intellectual disabilities (sometimes referred to as

Global Developmental Delay) often benefit from BT. Children with specific behaviour
disorders like Attention Deficit Hyperactivity Disorder (ADHD) or Oppositional Defiant
Disorder are also good candidates for BT.

As well as helping children with specific behaviour issues, BT can build foundational skills
that enable future learning. For example, imitation is a fundamental social behaviour that is
useful for everything from knowing when to clap at a party to figuring out where to line up to
take the bus. Using BT to enhance these foundational skills can have a lifelong impact.

What role can parents play?

The behaviour therapist can help parents design routines (e.g., morning, bedtime), as well as
teach strategies to enhance or reduce behaviours. Morneau Shepells Childrens Support
Solutions team will guide parents on how they can best support their child. Parents should ask
any questions that are on their mind.
How does Morneau Shepell use behaviour therapy?

There are two primary areas of support provided at Morneau Shepells Childrens Support
Solutions: behaviour consultation both of which design treatment programs based on the
principles of ABA. We support early intervention programs (called Intensive Behaviour
Intervention, IBI, in Ontario) which are best practice for children with Autism Spectrum
Disorder; but can also provide support for children with other diagnosis like Down
Syndrome. We also provide behaviour management support for children of all abilities which
include programs like toilet training, morning routines and more.

How our early intervention work Intensive Behaviour Intervention (IBI)

works

In IBI therapy, children typically work with behaviour therapists for anywhere from 20 to 40
hours per week towards individualized goals. It is ideal for a child to begin IBI therapy as
early as possible, typically around the age of 3. Many children who start IBI therapy have a
diagnosis of Autism, but a diagnosis is not required to start therapy.

The first step in IBI is conducting an assessment that typically uses one of two tools; the
Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) or the
Assessment of Basic Language and Learning Skills (ABLLS). The assessment generally
takes from six to ten hours and provides detailed insight into a childs strengths and needs.
Then the supervising therapist develops a treatment program to target teaching and
developing the skills identified by the assessment. In IBI the program is always building on a
childs successes to help them get to their next best step. Every 6 months the same assessment
will be administered (it may be supplemented by other assessments) to determine the
progress the child has made and confirm this therapeutic approach is the best way to support
that individual child and if its necessary to bring in any additional team members.

Government of Ontario funded IBI services and the Direct Funding Option
(DFO)

Parents typically pay for IBI therapy through private-pay, charitable, or government
funding.

In Ontario, children with a diagnosis of Autism may qualify for government funding for IBI.
Eligibility is determined by the regional program in your area. If your child qualifies for
funding, we are happy to support this program. We work with clinical psycholgists that are
approved in the local regional program to supervise government funded IBI programs. We
offer flexibility in terms of the hours and treatment location (home, clinic, school) for your
child. We are also able to support integrating disciplines including speech-language
pathology, occupational therapy, physiotherapy and more.

Behaviour Consultation

In behaviour consultation, a behaviour therapist assesses the family and childs needs, and
may conduct a functional behaviour assessment. The BT will then provide strategies and may
model the use of these strategies for parents to implement at home and in the community to
help their child.
How are behaviour therapists trained and certified?

Therapists typically have an undergraduate degree in psychology, sociology, education or life

sciences, as well as a more specialized certificate in autism or behavioural science. There are
also many professionals at Morneau Shepells Childrens Support Solutions who have or are
working toward a masters degree.

The main certifications of a behaviour consultant are:

BCBA Board Certified Behaviour Analyst

BCaBA Board Certified Assistant Behaviour Analyst

RBT Registered Behaviour Technician

 Dysfunctional Voiding and Other Daytime Wetting Disorders

Mike OBrien
Dept of Urology.
Royal Childrens Hospital
Melbourne,
Australia

Many are familiar with the often quoted statement of Thomas Watson, Chairman of IBM who
in 1943 stated that I think there is a world market for maybe five computers. Less well
known but equally inaccurate is Bloomfields declaration in 1956 that Owing to the
relatively small number of affected children it is unprofitable to make a more detailed study
of day wetting.

Daytime wetting disorders are largely the result of how a child is built - anatomical
abnormalities, how they are wired - neurological abnormalities or how they use what they
have. It is this latter group of functional voiding disorders that this chapter will focus on.
 According to the International Childrens
Continence Society Dysfunctional Voiding is a
specific subtype of daytime voiding abnormality
(1). It is the result of regular inappropriate
contraction of the urethral sphincter during
micturition. As such it is not strictly speaking a
daytime wetting disorder, though it may be
associated with urinary incontinence. The ICCS
defined daytime lower urinary tract conditions
may be divided into abnormalities of either of
the two primary bladder functions, storage or
elimination (see Table 1). There is however
considerable overlap between these conditions
and grouping patients into one category is even
more complex than with enuresis. Patients may
have symptoms of more than one sub-type (e.g.
overactive bladder and dysfunctional voiding) or
may evolve from one category to another.
Children may display symptoms from more than
one sub-type either synchronously (e.g.
overactive bladder and dysfunctional voiding) or metachronously, progressing from
predominantly one sub-type to another (e.g. overactive bladder thru voiding postponement to
under-active bladder.

Until the publication in 1998 and the subsequent revision in 2006 of standardized
terminology for lower urinary tract dysfunction there was sufficient variability in the
definition of incontinence in children to preclude meaningful comparison and evaluation.
Various authors placed differing levels of emphasis on the severity, frequency or duration of
the incontinence episodes. Cultural diversity, research methodology and response rates to
population questionnaires have further confounded prevalence rates. What is evident from
these studies is 1) a geographical variation (probably the result of a lower threshold for
reporting, coupled with better documentation); 2) a slightly higher prevalence among girls,
especially as they get older; and 3) a reduction in prevalence with increasing age (see Table
2).

In order to have an understanding of the pathophysiology of voiding dysfunction it is first

necessary to understand the complexities that underlie lower urinary tract function.

Genetics/Etiology
As discussed in the chapter on Nocturnal Enuresis some genetic predisposition to enuresis
has been demonstrated. By contrast the genetics and heritability of daytime urinary
incontinence have not been extensively studied. This is explained in part by the diversity of
etiologies and the heterogeneous nature of the patient population. However evidence
continues to emerge illustrating the multi-factorial etiology of voiding dysfunction. The
Avon Longitudinal Study of Parents and Children (ALSPAC), which is an on-going
population study following, prospectively, a birth cohort of almost 14,000. In a report on
8,230 children the prevalence of daytime urinary incontinence was 7.8%, of which 6.8% had
infrequent (< 2 episodes/week) wetting and 1% wet twice a week of more frequently (1). The
odds ratio of a child with a maternal history of daytime incontinence herself as a child
developing infrequent urinary incontinence was 2.64 and 5.47 if the father had suffered from
daytime urinary incontinence. The odds ratios were even greater in children with severe
enuresis reaching 3.28 with a maternal history and 10.1 if the father had a history of
childhood enuresis. Further complicating efforts to identify genetic associations is the
heterogeneous nature of the various sub-types of daytime urinary incontinence e.g.
dysfunctional voiding, urge syndrome, giggle incontinence, polakiuria etc. That voiding
dysfunction may have a congenital or inherited predisposition is supported by the finding of a
loss of function mutation in the heparanase 2 gene in patients with Urofacial (Ochoa)
Syndrome(2). Originally described by Elejalde in 1979 but called after Dr. Bernardo Ochoa
who contributed 36 patents with non-neuropathic neuropathic bladder and inversion of
facial features or a characteristic facial grimace when smiling
(http://omim.org/entry/236730). Affected patients often present prenatally or in early
childhood (before the age of toilet-training) suggesting a congenital rather than an acquired
pathogenesis.

Physiology

Normal bladder functions of urine storage without leakage and volitional emptying are the
result of complex interactions between the bladder, the somatic, autonomic and central
nervous systems. The seemingly simple and unique ability of the bladder to accommodate
increasing volumes of urine at low pressures is the result of rather complex interactions
between the smooth muscle cells and extracellular matrix of the bladder wall(3). The
extracellular matrix rather than merely being a scaffold for the cells of the bladder wall is
continually being remodeled in reaction to stresses and strains placed upon it in a process
referred to as dynamic reciprocity. As well as collagens, elastins, laminins and integrins the
extracellular matrix is awash with bioactive substances such as Matrix Metalloproteases and a
host of growth factors from VEGF to EGF and TGF(4). The amount of collagen in the
bladder wall is considerable with more than a third of the dry bladder weight being collagen.
Though some of the collagen can be found with the muscle bundles the majority of collagen
in the bladder wall is located outside of the muscle bundles. The ability of the bladder to hold
reasonable quantities of urine at a low pressure is a reflection of its compliance. The
compliance of the bladder has both active (muscle) and passive (collagen etc) components. It
has been demonstrated that the inner mucosal layer of the bladder has the capacity to expand
with little or no resistance due at least in part to the presence and composition of collagen
contained within. The outer detrusor layer serves to limit this distention in an active manner
(5). The result is a distensible bladder that usually stores urine at a pressure of less than 10-
15cm H20 until the bladder reaches its capacity. There is a correlation between bladder
compliance and the amounts of Collagen types I and III. Outlet obstruction is associated with
 increased deposition of collagen type III which in turn induces muscle hypertrophy resulting
in bladder wall thickening and reduced compliance (3).

A detailed discussion of bladder neurophysiology is beyond the scope of this chapter. In its
simplest form the bladder has three sources of neurological input (6).

1. Parasympathetic efferent nerves, which promote bladder emptying by

inducing detrusor muscle contraction, and bladder outlet relaxation, exit
the spinal canal between S2 and S4 and travel to the bladder in the Pelvic
nerve.

2. Sympathetic efferent nerves, which inhibit detrusor contraction and

stimulate urethral smooth muscle contraction to promote continence, exit
the thoracolumbar spinal cord between T10 and L2 and travel to the
bladder in the Hypogastric nerve.

3. Somatic efferent nerves, whose cell bodies are located in Onufs nucleus
along the lateral border of the ventral grey matter of the spinal cord, exit
at S2 to S4 and travel to the external urethral sphincter in the Pudendal
nerve.

There are two principal types of afferent fibre within the bladder and are principally found in
a sub-urothelial plexus.

o Myelinated Ad fibers which respond to bladder distention.

o Unmyelinated C fibers, largely inactive in normal bladders but

become activated in pathological conditions such as inflammation
etc.

Higher, supra-spinal neurological control is mediated by the Pontine Micturition

Centre(PMC) or Barringtons Nucleus which co-ordinates detrusor contraction and
sphincter relaxation in response to bladder sensory input ascending thru the peri-
aqueductal grey matter, thalamus and hypothalamus. Conscious voiding control
originates in the Anterior Cingulate Gyrus and is also coordinated via the PMC.

Acting via a spinal reflex pathway bladder filling detected by Ad fiber initiates
sympathetic activation of the muscles of the bladder neck and proximal urethra via a-
adrenergic receptors and relaxation of the detrusor muscle via b-adrenergic receptors.
It also triggers somatic activation of the external urethral sphincter. Voiding is
initiated in the cerebral cortex and begins with relaxation of the external urethral
sphincter together with inhibition of sympathetic activity and para-sympatheticly
induced detrusor contraction.

The primary neurotransmitter involved in micturition control is Acetylcholine which

acts on two different receptors - nicotinic and muscarinic. Nicotinic receptors have
little if any role in control of micturition. There are five muscarinic receptor subtypes,
M1 to M5, of which subtypes M2 and M3 are the most prevalent in the bladder. M2
receptors (70%) are predominant but it is M3 that are largely responsible for detrusor
contraction.

All of these structures are present at birth but in common with most volitional
neuromuscular functions in human neonates are not functionally developed at birth.
The rate of acquisition of urine control has been determined by a number of studies
but the most recent and relevant is by Sillen et al who in a series of publications has
prospectively studied the continence rates in children from birth of preterm infants to
6 years old (7-9). They found that in a western culture where toilet training is driven
by the sensory awareness of the child that perception of bladder fullness was reported
by 31%, 79% and 100% of children aged 2, 3 and 4 years respectively. The median
age of attaining daytime dryness was 3.5 years and all but one child was dry by night
within 10 months of being dry day. There is evidence that earlier initiation of toilet
training is associated with earlier completion but it does take longer (10).

Further evidence of the relative immaturity of the control of micturition at birth is

reflected in incomplete bladder emptying/interrupted voiding due to presumed
detrusor-sphincter dysco-ordination. They noted interrupted voiding in fetuses based
on repeated antenatal ultrasonography, 58% of preterm infants, 33% of term infants,
25% of 1 year olds and 3% of children prior to toilet-training. This dysco-ordination
has been demonstrated urodynamically by this group and others (11).

That this age of achieving dryness is driven primarily by societo-cultural norms is

supported by the increasing age at which it is attained and by the significantly earlier
age of dryness in different cultures for example the Digo people of East Africa whose
infants are dry by day and night by the age of 5-6 months (12). Similarly early age at
toilet training has been demonstrated in Vietnamese children (13). This cultural
difference is not due to inherited or genetic differences in maturation of the central
nervous system as the technique has been successfully applied to an italian infant
(14). We also capitalize on this ability to impose learned cortical control on lower
urinary tract function in older children when we apply biofeedback training methods
to treat children with continence issues.

Pathophysiology

To try and define the pathophysiology or etiology of pediatric dysfunctional voiding

or other daytime wetting disorders is difficult given the varied nature of presentation
and classification. According to the ICCS incontinence, the uncontrollable leakage of
urine can be either continuous or intermittent (1). Continuous incontinence is almost
always due to an anatomical abnormality and will not be discussed further in this
chapter. Strictly speaking the term intermittent incontinence, the day or nighttime loss
of discrete amounts of urine, is not applied until after the age of 5 years however if the
child has previously been dry for a period of 6 months or more investigation and
intervention does not need to be delayed. Nighttime intermittent incontinence is
addressed in the chapter on nocturnal enuresis. There is a great deal of overlap
between the daytime presentation of incontinence with occasional progression from
one to another. For clarity and to facilitate comparison of published articles/series the
ICCS strongly advocates greater emphasis on the accurate description of patient
symptomatology using their prescribed terminology rather than attempting to pigeon-
hole patients into specific sub-groups. That said there are some specific groups that
can be reasonably accurately defined:

Pollakiuria or Extraordinary daytime urinary frequency.

This term refers to children who present with frequent small volume voids during the
daytime. The ICCS definition mandates that they void at least hourly, however most
case void much more frequently that that (1,15). A unique pathognomic feature is the
absence of any nocturnal polyuria. The pathogenesis is not understood. Dietary
intake of bladder irritants, psychosocial or emotional stress and even climatic factors
have all been implicated.

The absence of any clear precipitating of provoking factors is indicated by the paucity
of successful treatment modalities. The cornerstone of treatment is reassurance that
the condition is self limiting, lasting from a few days to rarely a few years but on
average 6 months and recurrence is rare. For the 50% who have an identified
psychosocial or emotional stress counseling to address the underlying stressful event
and the natural history of the condition is all that is needed. Clearly management
should include the exclusion of known dietary triggers such as caffeinated soft drinks,
acidic fruit juices, drinks with a high oxalate of calcium content. There is no ideal
drug therapy but treating with anticholinergics such as Oxybutynin has some
empirical merit for refractory or prolonged cases. For some Pelvic Floor Biofeedback
has been successful but remains to be tested in a randomized trial to distinguish
benefit from spontaneous resolution.

Giggle Incontinence or Enuresis Risoria

Giggle incontinence is again a very specific condition where a patient, usually female,
otherwise lacking any lower urinary tract symptoms suffers complete bladder
emptying during or immediately after laughing. The ICCS places importance on
distinguishing genuine isolated giggle incontinence from laughter provoked detrusor
overactivity (this latter patient group have on close investigation other lower urinary
tract dysfunction) (1). The frequently large volume of the incontinent episode
provoked by laughter is the defining feature for which no cause has as yet been
identified.

Analogies and comparison with cataplexy have been made. Cataplexy is a crucial
component of the Narcolepsy, a disorder characterized by excessive daytime
sleepiness, abnormal REM sleep, hypnagogic hallucinations cataplexy and sleep
paralysis (16). Cataplexy is associated with a sudden loss of striated muscle tone
which may be limited to facial or limb muscles but may be more extensive. It is
usually triggered by positive emotions such as laughter - hence people who fall down
laughing! There is a strong family history in narcolepsy sufferers with an inherited
predisposition. 85-95% of sufferers carry the HLA DQB1*0602 allele. Narcolepsy
has been shown to be associated with the loss of hypocretin ( a wakefulness-
associated neurotransmitter present in CSF) from the hypothalamus. How this relates
to cataplexy or to giggle incontinence is yet to be elucidated.

Given the similarities with cataplexy Sher and Reinberg hypothesized a similar
pathogenesis and applied methylphenidate (Ritalin, previously used for
narcolepsy/cataplexy) to refractory children with giggle incontinence to varying
success in all (17). This success has subsequently been repeated with a larger series
of patients
For patients in whom the Ritalin failed or was not tolerated treatment focuses on
behavioral modifications such as frequent bladder emptying, avoidance of situations
known to provoke laughter (how depressing!!) and a hope that they will grow out of it
which is not likely. Pelvic floor biofeedback therapy has been proven to be of some
benefit.

Vaginal Voiding

This really is a form of psuedo-incontinence rather than true incontinence as the urine
that leaks immediately post-micturition, upon resuming an upright posture is urine
that during micturition has entered the vagina. It may be associated with labial
adhesions in the younger child, possibly by causing recurring vulvovaginitis
contributing to the persisting adhesions and ongoing vaginal voiding. It more
typically presents in older girls who tend to be overweight and is attributed to poor
voiding posture with internal rotation of the hips and closure of the perineal area.
Sitting backwards on the toilet (facing the cistern) is both diagnostic and therapeutic.
In the authors experience compliance with this treatment strategy is short-lived as it
usually requires complete removal of underwear from one leg. It does however
confirm the diagnosis and emphasizes to the patient the curative nature of correct
posture.

Stress Incontinence

Genuine stress incontinence (of the kind seen in post-partum women) is exceptionally
rare in neurologically and anatomically normal children. Episodes of urinary
incontinence may be seen to be precipitated by exercise in adolescent female athletes.
Urinary incontinence, associated with coughing has been reported in 19-49% of girls
increasing to 30-69% of adult women with cystic fibrosis (18).

Overactive Bladder, Urge Syndrome, Urgency-Frequency Syndrome

According to the International Childrens Continence Society the subjective hallmark
of overactive bladder is urgency (the sudden and unexpected experience of an
immediate need to void) associated with which may be urinary incontinence and
increased voiding frequency (1). It is probably the most common cause of urinary
incontinence in children and has been known by a number of previous synonyms
including hyperactive bladder, detrusor overactivity or irritable bladder. It has been
estimated that 5 to 7 million American children, 6 years and older are affected with
urinary incontinence, with a peak incidence between the ages of 5 and 7 years (19).
For too long overactive bladder was viewed as either the result of a delay in
maturation of micturition control or a regression to a childhood pattern, hence the
synonym of persistent infantile bladder. Despite affecting over 34 million individuals
in the USA and an estimated annual cost of $12.6 billion, the pathogenesis of OAB is
still not completely understood (20). In adult patients overactive bladder has been
associated with a number of differing etiologies - 1) neurogenic (e.g. Spina Bifida,
Spinal Cord Injury); 2) myogenic (e.g. obstruction, benign prostatic hyperplasia; 3)
inflammatory (e.g. interstitial cystitis, infection); 4) idiopathic (21). Whilst children
may also be subject to these same predisposing factors the majority (and the focus of
this chapter) will have idiopathic detrusor overactivity or IDO.

Urgency has been described as the cornerstone symptom of overactive bladder (22)
and in fact is the only symptom that the patient must have to diagnose overactive
bladder. Given the pivotal role of urgency in diagnosing overactive bladder it is
imperative that we be able to objectively appreciate, assess and quantify its presence
and severity. Implicit in the definition of urgency is the understanding that it can be
distinguished from normal bladder sensation of a need to void as the bladder reaches
capacity. For some patients however urgency is a continuous or chronic sensation of a
need to void to avert urinary incontinence rather than a feeling of sudden onset. Not
all episodes of urgency result in incontinence or micturition, in approximately 50% of
cases the patient cant suppress the urge. Distinguishing significant urgency from
normal is further complicated by the discovery on enquiry of an urgent need to void
(<15mins) in 10% of women (22).

How one assesses urgency is also the subject of much investigation and debate. The
simplest tool is to ask. However in asking we are exposed to a number of
confounding biases including but not limited to recall bias, previous opinion bias and
my own personal favorite obsequiousness bias (where responses are altered by
respondents in the direction they perceive desired by the investigator) (23). Brubaker,
to demonstrate the complexity of assessing urgency as a symptom, makes an excellent
analogy to hunger. The sensory perception of hunger is heightened by asking about it
or in an environment where the subject is exposed to the sights, sounds and smells of
foods. Similar neurophysiological mechanisms may be at play in the urgency
associated with running water, washing hands or the key in the front door. To
circumvent this investigator prompting, a number of researchers have developed
patient activated input devices to record and grade severity of urgency (without
prompting) during and correlated with urodynamic studies (24,25). Others have
developed and validated an urge scale to measure urgency (26). There are still other
subjective (Indevus Urgency Severity Scale (IUSS); Urgency Perception Score
(UPS)) and objective (warning time - the interval between first sensation of urgency
and voiding; voiding diaries) scoring systems, with the objective measures having
greater reliability, repeatability and less susceptibility to confusion between urge and
normal filling sensations (27).

Urgency may be centrally or peripherally mediated. That urgency may be centrally

mediated is supported by the latch-key urgency described above. Furthermore the
presence of urgency in patients without demonstrable rise in detrusor pressure and the
reduction in urgency at initiation of micturition, when the detrusor pressure is still
increasing, support a supra-vesical source. Whether latch-key urgency is the result
of a centrally-mediated release from cortical suppression of a spinal voiding reflex or
represents some form of Pavlovian conditioning is not known (28). Almost all (75-
100%) of patients with supra-pontine lesions and 25% of those with Parkinsons
disease have detrusor over-activity (29). Functional magnetic resonance imaging
(fMRI) has greatly enhanced our understanding of cortical activity during the storage
phase of bladder function. In normal healthy subjects afferent signals from the
bladder and urethra are received in the peri-aqueductal grey matter (PAG) and are
relayed via the thalamus to the insula, to register the sensation of bladder filling. This
activity is monitored by the anterior cingulate gyrus (ACG) which effectively
coordinates the response to these signals in addition to motor and emotional input,
including input from the pre-frontal cortex where a decision to void or not arises
ultimately resulting in a decision to either relax or maintain inhibition of the voiding
reflex (30). Individuals with urgency and urge incontinence demonstrate altered brain
responses to bladder filling both at low and high bladder volumes and in response to
detrusor overactivity. They tend to demonstrate weak responses at low levels of
bladder filling, exaggerated (perhaps learned) responses at large bladder volumes and
again weak or deactivated pre-frontal cortical activity during detrusor overactivity
perhaps explaining the involuntary nature of urge incontinence and the often observed
apparent lack of awareness.

Peripheral neurological disorders are also associated with detrusor overactivity as

seen in patients with Multiple Sclerosis which is usually associated with spinal
involvement and also seen in patients with spinal cord injury (29). The complex
interaction between the peripheral nerves and micturition is evidenced in the
successful suppression of detrusor overactivity by sacral nerve root stimulation, dorsal
penile nerve root stimulation and posterior tibial nerve stimulation with
transcutaneous electrical stimulation (31). Regardless of whether the loss of
neurological inhibition is the result of a central or peripheral neurological disorder,
both probably result in increased afferent activity from sensitization of the normally
silent C fibers. This is sometimes referred to as the neurogenic hypothesis on the
origin of lower urinary tract symptoms (32). Alternative, but not necessarily
exclusionary hypotheses are the myogenic and urothelial hypotheses.

The myogenic hypothesis proposes that a deregulation of normal detrusor smooth

muscle excitability and communication results in uninhibited bladder contractions.
Contrary to popular belief we know that the normal bladder is not an inert elastic
container that simply accommodates increasing urine volumes during the storage
phase of the micturition cycle. We have known for over 120 years that the bladder
during filling demonstrates autonomous or non-rhythmic contractions that do not
result in micturition (33). The theory behind these micromotions or micro-
contractions was that they both facilitated local stretching or micro-stretching of the
bladder wall and triggered afferent sensory signals to the higher cortical regions
(34). These localized contractions have been demonstrated in animal models and in-
vitro with human detrusor tissue and have been shown to be a feature of the smooth
muscle cell (related to Ca++ influx) rather than triggered by neurological input i.e.
they still happen in the presence of neurotoxins (35). How these naturally occurring
and seemingly essential micro-contractions relate to larger more generalized or
widespread detrusor contractions seen in detrusor overactivity is still being
established especially as the ability of an electrical impulse to spread from detrusor
myocyte to myocyte is diminished relative to other smooth muscles. There are fewer
gap junctions between adjacent detrusor smooth muscle cells than seen in cardiac
smooth muscle. However this increased resistance or reduced conductivity seen in
the detrusor is associated with an enhanced local excitability which may be relevant to
that pathophysiology of detrusor overactivity (35).

The urothelial hypothesis highlights that the urothelium is much more than a water-
proof barrier, in fact it is possibly the most complex structure in the bladder. The
epithelium itself has a number of unique properties that enable it to fulfill its role.
The spherical shape of the bladder provides the minimum of surface area to volume of
urine during the storage phase. The innermost layer of cells, adjacent to the lumen,
so-called umbrella cells or facet cells have the capacity to infold their epithelial
surface to provide a mechanism for stretching with increasing bladder volumes (36).
It is relatively impermeable to passive transport of molecules, whether this is due to
the tight junctions between the umbrella cells or the glycosamino-glycan layer of
Uroplakins that sit on top of the epithelium has not been determined. Because the
urothelium is not absolutely impermeable it has also has some active transport
mechanisms to ensure urothelial cellular homeostasis (37). The urothelium has an
inherent inertness which serves to protect and preserve its impermeability.

As well as its barrier function the urothelium expresses a number of sensory receptors
more typically found on peripheral nerves. These include TRPV1 (transient receptor
potential cation channel subfamily vanilloid member 1). TRPV1 expression has been
shown to be increased in both Idiopathic Detrusor Overactivity and Neurogenic
Detrusor Overactivity. Increased expression of purinergic receptor subtypes (P2X and
P2Y) has also been documented in IDO and NDO and are thought to be responding in
an autocrine or paracrine manner to ATP released from the urothelium. Cannabinoid
receptors (CB1) have also been found in urothelium, as have both alpha and beta
adrenoreceptors which when stimulated have been shown to release ATP and NO. All
five muscarinic receptor subtypes have been identified in urothelium with M3 widely
distributed, M1 localizing to the basal cell layer and M2 to the umbrella cells (32).
The urothelium secretes an equally wide range of bioactive substances such as ATP,
NO, ACh, CGRP. ATP is released in response to stretch, muscarinic and adrenergic
receptor stimulation and stimulation of TRPV1. By acting on the nerves and
interstitial cells in the sub-urothelial area ATP is thought to signal bladder fullness,
possibly activating micturition. NO triggered by the same stimuli appears to have an
inhibitory action on the bladder. This is suggested by the inhibition of detrusor
overactivity in animals treated with NO donors and the induction of overactivity when
subjected to NO scavengers. Urothelial cells have also been shown to release ACh in
response to mechanical or chemical stimulation. No specific role has yet been found
for CGRP in the bladder.

Beneath the urothelium is the equally functionally important sub-urothelial layer

which contains connective tissue, nerves and blood vessels. Whilst the most sensitive
nerve endings in the bladder are located in the detrusor muscle and transmit via the
myelinated A delta neurons. The nerve endings of the unmyelinated C-fibres on the
other hand terminate in the urothelium and lamina propria. Under normal
circumstances C-fibres are thought to only be activated by bladder distention greater
than that which activates A delta fibres. It is thought that C-fibre activation becomes
relevant in pathological conditions and therefore may be more relevant to the
sensation of urgency (38). Many of the nerves in the lamina propria express receptors
for Substance P and CGRP as well as TRPV1 and P2X receptors. That C-fibres can be
stimulated by urothelial derived neurotransmitters implicates the urothelium directly
in the generation of urgency. Furthermore the lamina propria contains interstitial cells
that form a functional syncytium that may help to propagate a depolarization wave or
localized detrusor contraction in response to urothelial derived neurotransmitters.
Detrusor overactivity has been linked to increased Gap junction expression in lamina
propria interstitial cells possibly having a role in the genesis of DO thru enhanced
conductivity. Some of these interstitial cells have recently been shown to have
properties similar to the gut derived Interstitial Cells of Cajal and therefore capable of
spontaneous activation. This has led to further comparisons with the gastrointestinal
neuro-enteric system suggesting that the nerves and interstitial cells of the urothelium
may be arranged into functional rather than anatomical myovesical plexuses
analogous to the myoenteric plexus of the GI tract (39). Clearly the urothelium is an
active participant rather than an innocent bystander (40).

As we have seen here and in the chapter on enuresis our understanding of the
complexity of the neurological and vesical contributions to bladder function have
grown exponentially in recent decades. No longer can we view the bladder as a
muscular bag over which we exercise volitional control. Rather the bladder is a
complex sensory organ capable of responding to a variety of differing stimuli. Where
previously it was thought that conscious bladder sensation arose in a consistent and
predictable manner starting with first sensation of bladder filling, first desire to
void and strong desire to void (41), we now know that the Central nervous system is
constantly being inundated with sensory information, that could be described as
afferent noise (42). Afferent sensory information from the bladder is continually
arriving in the CNS and which impulses reach consciousness and trigger micturition
remains to be elucidated. The constant streaming of bladder sensations, though not
conscious, are able to be accessed at will to provide a snapshot of the current state of
bladder filling. This necessity to ignore some afferent output from the bladder, in
order to focus on other daytime activities, may explain some of the features associated
with voiding dysfunction such as impaired sensation of the need to or often of the act
of voiding.

Dysfunctional Voiding, Dysfunctional Eliminations Syndrome, Nonneurogenic

Neurogenic Bladder

Dysfunctional voiding, as defined by the ICCS (1), is a term that can only be applied
with either uroflowmetric or urodynamic evidence of inappropriate sphincteric
contraction during micturition resulting in a staccato urinary stream. It is the
equivalent of detrusor-sphincter dyssynergia seen in patients with overt neuropathy
and results from a loss of normal coordination between the detrusor and external
sphincter. As it is a symptom of the voiding phase it can co-exist with storage phase
symptoms such as overactive bladder. In fact dysfunctional voiding is often
considered to have arisen as a response to urge incontinence where heightened pelvic
floor tone develops to prevent incontinence and ultimately the loss of adequate
relaxation during micturition. This often leads to incomplete bladder emptying, high
post-void residuals and recurrent urinary tract infections which then cause bladder
inflammation and urgency thus creating a vicious cycle. An alternative hypothesis is
that dysfunctional voiding is due to psychosocial (as seen in girls with a history of
sexual abuse) or centrally mediated phenomenon (as seen in children with Ochoa
Syndrome or ADHD) (43). Further confusion arises from the alpha-adrenergic
activity of the centrally acting agents used to treat ADHD which may therefore
precipitate or aggravate dysfunctional voiding.

The most extreme end of the dysfunctional spectrum is Hinman-Allen Syndrome or

Non-neurogenic Neurogenic Bladder (44). Originally described by Beer in 1915 as
chronic urinary retention in children, type 2C or due to spasticity of the sphincter
without neurologic signs but presumed due to disease of the sacral cord (45). That
Hinman-Allen Syndrome represents the end-stage of an acquired voiding dysfunction
has been called in to doubt by publications that have identified patients as young as 5
months, well before the age of toilet training or the acquisition of volitional bladder
control (46). Jayanthi and others have reported cases diagnosed post-natally but with
antenatal features of severe hydronephrosis suggesting a congenital or pre-natal
etiology (47). However we do no from video-urodynamic studies carried out in
asymptomatic, control infants that dyscoordinated and high pressure voiding is a
normal phenomenon. As with detrusor overactivity our emerging understanding of
the varied pathogenesis of dysfunctional voiding would suggest that there are
differing sub-types that may respond better to differing treatment strategies whether
that be hypnotherapy a-la Hinman for late onset ? psychogenic/? sexual abuse
patients, early vesicostomy for suspected but unconfirmed antenatal cases or
Biofeedback +/- alpha-blockers for those who present in childhood. One of the
defining features of Hinman-Allen Syndrome is the associated renal impairment, the
origin of which is again probably multifactorial and related to high intra-vesical
pressures, reduced bladder compliance, recurrent urinary tract infections and vesico-
ureteric reflux.

The association between dysfunctional voiding and vesico-ureteric reflux is well

documented having been first recognized by Lapides in 1970. Of the children
enrolled in the International Reflux Study 18% had dysfunctional voiding with a
lower prevalence among those with spontaneous resolution of their reflux (43). The
relationship between VUR and dysfunctional voiding is a complex one of cause and
effect. That VUR may arise as a result of bladder dysfunction is supported by the
reflux seen to develop in patients with anatomical outlet obstruction such as Posterior
Urethral Valves and in Neurogenic Destrusor Overactivity or Detrusor Sphincter
Dyssynergia seen in patients with Spina Bifida. There are numerous studies
documenting 38-75% prevalence rates of dysfunctional voiding in children with
vesico-ureteric reflux (48). Successful treatment of dysfunctional voiding with
biofeedback or anticholinergic medication has been associated with resolution of
VUR in 37-63% of patients with a downgrading of the grade of VUR in a further 16-
29%. In a recent review of the literature Sillen was unable to convincingly show
evidence of a significant positive effect on the resolution of VUR following treatment
of dysfunctional voiding.

The relationship between bowel and bladder dysfunction has been discussed
elsewhere, the association is so well documented that Koff coined the term
Dysfunctional Elimination Syndrome. In fact Koff found that bowel dysfunction
(constipation) had an equal if not more significant impact on the spontaneous
resolution of VUR (49). Dysfunctional elimination syndrome is more common in girls
(50) with a peal incidence between 5-12 years of age (51). Though there is an
association a clear causal relation has not been demonstrated.

Diagnosis
Patients are usually referred to a Pediatric Urologist either because of recurrent
urinary tract infections or intractable urinary incontinence - >99% (52). They have
usually been receiving treatment from their family practitioner and/or Pediatrician
(who may or may not have an interest in incontinence) for a few years prior to
eventual referral. The referring doctor is usually requesting urodynamic investigation
to confirm or exclude an occult neurogenic bladder. The patient/parents, on the other
hand, are usually expecting a miracle cure whether that be surgical or not. This ever
increasing reliance on diagnostic tests and investigations belies the importance of a
detailed and targeted history and physical examination. In my experience the initial
clinical consultation is often fraught with parental and patient angst because of the
need to start again with a comprehensive history etc. Initial questioning should focus
on defining the nature of the problem to identify anatomical causes of incontinence
and occult neuropathy. Having excluded these structural causes of incontinence
questioning should them aim to identify the subtype of voiding dysfunction.

When taking a history it is important to have a good understanding of the patients

voiding habits. How often does he/she void? Three times a day or less is by definition
a decreased daytime frequency or infrequent voider whereas 8 times or more
represents increased frequency (1). How urgently do they need to void once they feel
the need? In other words can they hold on if they have to e.g. when in the car, at the
movies, during class etc.? When they void do they do so with a continuous stream
with ease or is the stream intermittent or associated with straining? Are there any
difficulties initiating voiding or is there a sensation of incomplete emptying? Are they
incontinent of urine? If so to what extent e.g. damp undies at the end of the day or
frequent change of clothing during the day? Are they continuously incontinent
(suggestive of an anatomical abnormality such as an ectopic ureter or epispadias) or is
it episodic and if so when does it happen and what if anything provokes it? Does it
only occur immediately after voiding in an overweight teenage girl, suggestive of
vaginal voiding or reflux that then leaks out when she resumes an erect posture?
Does it only occur towards the end of the day in a girl who avoids urinating in
school? Is it only provoked by laughter suggestive of giggle incontinence? Are they
aware of these episodes before they occur, as they occur or only afterwards? Are they
also incontinent or urine during the night? How long has it been happening? Have
they ever been dry for a period of 6 months or more - this distinguishes primary from
secondary incontinence? Do they have any pain associated with micturition? Do they
practice any voiding postponement maneuvers (usually the parents are more reliable
witnesses of this) e.g. the pee-pee dance, boys grasping their penis, girls
demonstrating Vincents curtsy (squatting down on their heel to avert urinary
incontinence, often likened to putting the cork in the bottle but more likely to work
via a spinal reflex suppressing detrusor contraction) (53). For smaller girls it is
important to establish if they can sit on the toilet with their feet supported, use a step
or balance? To where do they take down their underwear, knees or ankles? For older
girls when voiding outside the home do they sit or try to hover above the dirty toilet
seat? Will they use the school toilets?
How often do they open their bowels? What is the nature of their stool? The Bristol
Stool Form Scale is a very useful visual aid, though most girls deny looking at their
own stool! Do they pass stool easily or with discomfort and straining? Is there any
faecal soiling of their underwear, and if so to what extent - a small skid mark or
enough to require removal prior to washing? What is the nature of their fluid intake -
volume, frequency and nature of fluid consumed? Certain fluids such as soft drinks,
dark cordials, teas, coffee etc are more likely to provoke or aggravate storage
symptoms. Children who wet consciously and subconsciously reduce their fluid
intake in order to minimize the likelihood. The nature of their dietary fibre intake as
it relates to their bowel habit is important in those children with constipation.

History

Micturition habits Frequency of micturition, urgency, postponement,

nature of urinary stream, voiding posture

Defaecation habits Frequency, consistency, straining, soiling

Dietary habits Fluid and fibre intake

Past Medical History Incorporating ante-natal, peri-natal and post-natal

events including developmental milestones, academic
achievement, previous urinary tract infections, age at
initiation and attainment of toilet-training

Family History Voiding dysfunction, enuresis, vesico-ureteric reflux

Social History Major life events such as arrival of new sibling,

parental separation, new home etc.

Table 3 - Salient points in patient history

When enquiring into their past medical history it is important to ascertain any history
of urinary tract infection and to scrutinize this closely to understand the underlying
symptoms that provoked investigation and the nature and precise detail of specimen
acquisition, analysis an interpretation. It is important to distinguish between a culture
proven UTI and balanitis in boys or vulvovaginitis in girls. Any co-morbidities
especially of the genitourinary tract or neuro-developmental may be relevant.
Children with ADHD have significantly higher rates of incontinence and other
symptoms of urinary and bowel dysfunction than the normal population (54).

Physical examination is usually unhelpful but none the less essential. It is aimed at
detecting or excluding anatomical abnormalities. Examination begins with the lower
abdomen looking for a palpable and/or expressible bladder, palpable stool suggestive
of constipation and palpation of the symphysis pubis. It then extends down to the
genitalia looking for labial adhesions, a bifid clitoris and a uro-genital sinus in girls
and meatal stenosis or pathological phimosis in boys. Skin excoriation or
discoloration from urinary incontinence and faecal or urinary staining of their
underpants may also be seen. The examination extends posteriorly to the lower back
and sacral region looking for signs of sacral agenesis or stigmata of occult spinal
dysraphism such as a vascular malformation, a cutaneous hairy patch, a sacral sinus or
asymmetrical buttock creases. A brief neurological examination is an essential part of
the physical examination and begins when the patient walks into the examination
room by assessing their gait. Gross lower limb tone and sensation, asymmetrical calf
wasting, unilateral loss of normal plantar arches, perineal/peri-anal sensation and ano-
cutaneous reflex constitute the minimum neurological examination required.

Investigations

The initial investigation should be urinalysis and urine culture to exclude a urinary
tract infection. Further baseline investigations may include a plain abdominal film
often referred to as a KUB. This is probably better referred to as a BUCKS film - B =
bladder, U = ureter, C = colon, K = Kidney and S = spine, the additional benefit being
information about the bowels and the spine for dysraphism. An ultrasound of the
renal tract with assessment of pre- and post-void bladder volumes will provide
information about the upper urinary tract such as the presence of a Duplex kidney in a
girl which may be associated with an ectopic ureter. At the bladder level, bladder wall
thickening or large post-void residuals are suggestive of dysfunctional voiding. In a
large series of over 1,000 unselected patients with dysfunctional voiding ultrasound
was normal in 97% (52). The exact role of imaging in the investigation has yet to be
determined and must be decided on an individual patient basis (55). The routine use
of other radiological imaging is generally reserved for patients who present with a
history of recurrent febrile urinary tract infections (52).

Perhaps the most crucial initial investigation is a detailed elimination diary. Diaries
have been shown to be the most cost effective of all initial investigations (56). They
found diaries to have 88% sensitivity and 83% specificity for the detection of detrusor
overactivity. The ICCS recommendation is that a detailed bladder diary be used for
initial investigation and that a less exhaustive frequency-volume chart be used for
follow-up. We prefer elimination diary as it also incorporates a record of bowel
function. A great deal has been written about bladder diaries - over 1463 published
studies make reference to or investigated the role of urinary diaries, varying from
Micturition Charts that simply record the times of micturition, to
Frequency/Volume Charts that included voided volumes to Bladder Diaries that
additionally captured information about incontinence episodes, urgency and fluid
intake (57). Despite this flurry of publication there is still no validated diary format.
The optimal duration of a bladder diary has yet (and probably will never be) to be
determined. Diary durations ranging from 1 -14 days have been used. Diaries that
are too short in duration have a problem with reliability whereas those that are too
long have a problem with compliance either at commencement (diary despair) or
near completion (diary fatigue). Durations of 4 days have been shown to be as
reliable as 7-day diaries and currently most authors recommend a minimum of 3 days,
ideally 4 but 5 if the number of incontinence episodes is important (58). Compliance
with data entry and diary completion is significantly enhanced if an electronic diary
rather than a paper one is used. In a study of adults with chronic pain required to
make diary entires ideally within 30mins and at worst within 90mins, patient self-
reported compliance with paper diary entry was 90-95% whereas actual compliance
was 11-20% which compares unfavorably with 95% actual compliance with an
electronic diary (59). Forty percent of patients completing a paper diary were found
to have at least 1 day of hoarding (where the data for for that was entered
retrospectively which renders them far more susceptible to recall bias than electronic
diaries. Different diary parameters require different diary durations to achieve
reliability (60). One must also be aware of the placebo effect associated with the
completion of a
bladder diary and
the inevitable bias
that would
introduce if the
diary was for an
extended period.

A variety of
symptom scoring
systems have
been developed to
help both with
patient evaluation
both at the time of
initial diagnosis and also to monitor progress both clinically and in the context of drug
trials (61-65).

It is important that a bladder diary have some form of validated assessment of urgency
(such as the Urgency Severity Score or the Urgency Perception Score) (66) - see Table
4. When providing patients with a diary for completion, a detailed explanation must
be provided to patients to ensure adequate completion and to minimize social
desirability and obsequiousness biases. The bladder diary has been shown by Abrams
and Klevmark to be capable of suggesting a clinical diagnosis (see Table 5).
 Type of Voiding Pattern Description of Clinical
Application
Type 1 normal volumes, normal frequency normal patients

Type 2 normal volumes, increased frequency polyuria, suggestive of increased fluid intake

Type 3a reduced fixed volumes, day and night suggestive of intravesical pathology e.e
interstitial cystitis

Type 3b reduced variable volumes, day and indicative of detrusor overactivity

night

Type 4 normal early morning, reduced and possibly psychosomatic; suggestive of

variable day volumes compensatory increased frequency to avert
incontinence

Type 5 nocturnal polyuria idiopathic; enuresis; cardiac failure

Table 5 - Modified Klevmark Classification (Scand J Urol Nephrol

1996, 179, 47-53)
The next level of investigation involves objective assessment of urine flow thru the
use of uroflowmetry either in isolation or combined with pelvic floor
electromyography. Simple uroflowmetry alone is useful as a screening tool where
(when combined with ultrasonographic assessment of post-void residual) when
repeated can document a normal flow rate. Assessment of post void residual needs to
be made as soon as possible after voiding to reduce the possibility of pseudo-residuals
and residuals consistently greater than 20mls are to be considered pathological.
Whilst the uroflow apparatus provides detailed analysis of urine flow such as Qmax -
maximum flow rate, Qave - average flow rate, Vt - voiding time, tQmax - time to
maximum flow rate - these are merely mathematical numerical descriptors of the
shape of the urine flow curve and are as such subject to error and misinterpretation.
Most clinicians place greater emphasis on the shape of the flow curve. There is
marked inter- and intra-observer agreement on the shape of a normal curve but less so
in abnormal curves (67), even when the observers are pediatric urologists (68).
However given that the primary purpose of uroflowmetry is to distinguish those
patients who would benefit from more invasive urodynamic assessment from those
who would undergo unnecessary investigation, it remains a valuable screening tool.

It is a tool that has been greatly enhanced thru the addition of pelvic floor
electromyography (69). The addition of EMG allows simultaneous assessment of
pelvic floor muscle activity with assessment of urine flow. Pelvic floor EMG is most
accurately recorded thru the use of specifically designed barbed needle electrodes,
however these are not particularly appealing to adult let alone pediatric patients. It is
much more common then to use surface patch electrodes which though less targeted
achieve the same end. Glassberg et al. have used combined uroflow/EMG to stratify
children with a variety of lower urinary tract symptoms into one of 4 urodynamically
defined groups (70).

o Dysfunctional Voiding - active pelvic floor EMG during voiding, with

or without detrusor overactivity.

o Idiopathic Detrusor Overactivity Disorder - detrusor overactivity on

urodynamics, with quiet pelvic floor EMG during micturition

o Detrusor Underutilization Disorder - willful infrequent but otherwise

normal voiding

o Primary Bladder Neck Dysfunction

The same group found that similar classification could be achieved thru the use of
uroflow/EMG. They introduced the concept of EMG lag time - the interval between
the start of pelvic floor relaxation and the start of urine flow, between 2-6 seconds in
normal children.

o Dysfunctional Voiding - active pelvic floor EMG during voiding with

or without staccato flow

2a) Idiopathic Detrusor Overactivity Disorder A - a quiet pelvic floor during voiding
and a shortened lag time (<2secs.)
2b) Idiopathic Detrusor Overactivity Disorder B - a quiet pelvic floor with a normal
lag time

o Detrusor Underutilization Disorder - volitionally deferred voiding

with expanded bladder capacity but a quiet pelvic floor

o Primary bladder neck dysfunction - prolonged lag time (>6secs.)

and a depressed, right shifted flow curve with a quiet pelvic floor
during voiding

Whilst the terminology they use is not strictly in accord with ICCS recommendations
they demonstrate the usefulness of Urolflow/EMG for diagnosing and directing
treatment of children with lower urinary tract symptoms.

The place of more formal video-urodynamics is still the subject of debate with some
arguing that it has a role and others arguing it is an unnecessary and extravagant
expense. Glassberg refers to the later group as impressionists as they base their
clinical diagnosis and treatment plan on the key aspects of the history they deem
relevant. This is often augmented with some non-invasive investigation. The other
extreme they refer to as purists believe all patients require formal video-urodynamics
for an accurate diagnosis. This accuracy comes at an increased cost (69). The reality
is that the majority of patients are appropriately managed with a less invasive
approach. In a large series of 3,500 children with non-neurogenic bladder
dysfunction, 1,000 were selected for video-urodynamics based on a history of UTI, a
small bladder capacity not responding to urotherapy, repeated dysfunctional
uroflowmetry, ultrasononographic abnormalities and resistance to treatment (71).
They found normal urodynamic studies in 6%, urge syndrome (58%), dysfunctional
voiding (31%) and lazy bladder (4%). What they did not show in that paper was the
impact of urodynamics of patient management or outcome. Others have also reported
a high diagnostic yield from urodynamics in children with non-neurogenic bladder
dysfunction reporting normal (37%), storage phase abnormalities, predominantly DO
(42%) and voiding phase abnormalities in 21% (72). That said the vast majority of
reports do not advocate routine urodynamics but rather they advocate they be used for
those patients who are failing to respond to therapy (52,73,74).

Non-operative Management

While the treatment of voiding dysfunction should be matched and tailored to the
particular sub-type of lower urinary tract dysfunction that the patient is afflicted with,
there are some initial therapeutic interventions that are applicable to all. These
measures have collectively termed - Urotherapy. Initially termed compound
therapy in Scandinavia in the 1980s it included behavioral, cognitive and physical
therapies including some biofeedback. Nowadays the term urotherapy encompasses
patient and family education, fluid management, optimal bowel management, and
possibly pelvic floor muscle re-education/biofeedback and neuromodulation,
essentially the non-surgical and non-pharmacological measures. Once a clinical
diagnosis has been made the initial and possibly most important step is to educate the
patient and their parents about the nature of the condition essentially demystifying
their problem and removing any culture of blame. Therapy starts with behavioral
modifications based on history, clinical examination, the elimination diary and
uroflowmetry with PVR measurement. For girls initial advice should focus on
voiding posture. It is important to ensure that young girls are able to sit with their feet
supported (either on the floor or a step). All girls should sit with their hips abducted
opening up the pelvic floor to optimize urine flow and avoid vaginal voiding. For
those with a history of urinary tract infection appropriate post micturition perineal
hygiene should be taught. For those with perineal irritation or vulvovaginitis
additional advice re the substitution of synthetic underwear (e.g. polyester) with more
breathable fabrics such as cotton. There is a suspicion that some foods/drinks may
cause perineal irritation similar to those that are implicated in interstitial cystitis.
These include citrus juices, chocolate, carbonated soft drinks, spicy foods, tomato and
vinegar to name a few (75).

A frequent recommendation is the exclusion of caffeinated drinks based on in-vitro

evidence of direct detrusor stimulation by caffeine and urodynamically demonstrated
detrusor overactivity. Following initial ingestion of caffeine in healthy volunteers
there is a demonstrable diuresis to which subjects seem to become resistant with on-
going administration (76). Whether patients with bladder dysfunction develop the
same tolerance has not been investigated. Swithinbank et al found no benefit from
dietary exclusion of caffeine containing drinks on incontinence rates in adult women
with stress or urge incontinence (77). A number of epidemiological studies looking at
over 16,000 adult patients in total, found no correlation between self-reported caffeine
intake and symptoms of incontinence. In the largest prospective study yet looking at
the relationship between caffeine intake and urinary incontinence involving over
21,000 patients no obvious correlation between caffeine intake and progression of
urinary incontinence could be detected (78). That same group reporting on over
65,000 adults found that high caffeine intake but not low levels were associated with
incontinence (79). Despite this there are studies reporting a reduction in incontinence
episodes in symptomatic adults following a reduction in caffeine intake (80). Hence a
restriction or elimination of caffeinated drinks remains a widespread recommendation.

There is some evidence in adult patients with obesity and urinary incontinence of a
reduction in episodes of incontinence equivalent to that seen with some behavioral or
pharmacological therapies. Obese women, with a BMI of 25-45Kg/m2, who lost
between 5-10% body weight had at least a 50% reduction in frequency of
incontinence episodes (81).

The elimination diary will identify those children who are infrequent voiders and may
benefit from a timed voiding regimen to encourage them to void a minimum of 5
times per day and ideally 7. For young children a parent can remind them out of
school and they can use the school schedule to remember during the school day.
Unfortunately many parents report that these reminders to void often result in conflict
with the patient who does not feel the need to void and will do so once they finish
the activity they are currently involved in. For these a Star Chart reward system
(similar to that used when toilet training) may help to reduce this conflict and engage
the patient. For those children who are sufficiently motivated and wish to take
ownership of their problem a vibrating watch such as the Malem Vibralite or Wobl
watch can be set to vibrate silently at the appropriate time so their peers remain
unaware. Regular timed voiding is also a cornerstone in the management of children
with detrusor overactivity where it can be used to re-establish good voiding patterns
by establishing a minimum frequency of micturition e.g. 7 times per day, and in
addition encouraging them to void at all other times when they feel the need to. The
addition of a programmable watch has been shown to make a significant additional
contribution to the management of children with daytime urge incontinence.
Compared to a control group receiving standard Urotherapy the addition of a
programmable watch to remind the patient to void 7 times a day led to a significant
reduction of wet days in 60% which translated into 60% being continent at a median
of 6 months compared to 30% of those who were not using a watch (82). Micturition
postponement is to be avoided at all times as, rather than encouraging increased
bladder capacity as hoped, it reinforces subconscious suppression of bladder
sensation. There was a period in the late 70s and 80s when bladder training was
advocated by Frewen and others where patients were encouraged to postpone
micturition to prolong intervals between voids. He reported that bladder training
resulted in 87% subjective and 53% objective improvement in abnormal urinary
symptoms, most interestingly the first to improve was nocturia (83). However there
was a high relapse rate (84). His assertions that the deleterious effects on bladder
function of frequent and urgent voiding can become an addictive habit that will
then spread to their children thru a process of mimicry would not have any credibility
with our increasing understanding of bladder function (85).

The ideal initial inter-void interval can be based on the elimination diary and
gradually increased, in 15 min increments, at fortnightly intervals in response to
successful dry periods. For those patients with dysfunctional voiding (thickened
bladder wall, high post-void residuals, recurrent UTIs, abnormal uroflowmetry)
double or triple voiding (based on ultrasonography) may be necessary to ensure
sufficient bladder emptying, thus minimizing recurrent UTIs which of course
contribute to detrusor overactivity, frequency, urgency and incomplete emptying
thereby perpetuating the cycle.

The complex interactions between bowel and bladder function underpin the
importance of appropriate and adequate bowel management as an initial step in the
treatment of patients with lower urinary tract symptoms. Though a clinical association
between bowel and bladder dysfunction has been identified since 1952, it was not
until 1998 that their association was cemented in the term dysfunctional elimination
syndrome (49). Loening-Baucke looking at 234 consecutive patients with functional
constipation and encopresis noted a history of daytime urinary incontinence (29%),
nocturnal enuresis (34%) and UTIs (11%). Successful relief of constipation in 52%
was associated with resolution of daytime urinary incontinence in 89%, of nocturnal
enuresis in 63% and a complete cessation of UTIs (86). A cornerstone of initial
therapy is to focus on achieving a normal bowel habit. Ideally a good bowel habit is
based on adequate and appropriate dietary fibre and fluid intake. The American
Academy of Pediatrics has recommended that the daily fiber intake of children over 2
years old should be between age in years + 5gm/day to age +8 gm/day (87). That said
in a randomized trial of dietary fiber supplements from Spain patients with chronic
constipation had a daily fiber intake in excess of age + 5gm/day proving that there is
more to the management of constipation that merely increasing fiber intake (88).
Another routine recommendation is to increase fluid intake (with the intention of both
improving stool consistency, by binding to the increased fiber, and improving urine
output. There is however no evidence of a change in stool consistency in response to
increased fluid intake whether that fluid be hypo-, iso- or hypertonic. All it seems to
affect is the urine output, as the majority of fluid is absorbed high up in the GI tract
(89). Other, frequently used non-pharmacologic measures to address constipation
include exercise, pre-biotics, probiotics, behavioral therapy (counseling etc) have also
not been shown in clinical trails to have any actual benefit over placebo in either
adults or children (90,91). However most of the trials that have been carried out have
been underpowered and have focussed on a single aspect of therapy rather than
combination. Intuitively additional fibre and fluid should have a complimentary
effect that either alone. Failure of constipation to resolve with these measures should
be followed up with aggressive administration of laxatives. Once an effective
regimen has been identified, and there is no evidence for the efficacy of one particular
laxative over another, laxative treatment must be maintained for months and
gradually weaned. Up to 20% of patients will be cured by these steps alone

The response to these behavioral modifications and the clinical diagnosis will
determine the next therapeutic intervention to be offered. Whereas the above
behavioral modifications can be readily incorporated in the patients daily life their
success is determined by patient motivation and attrition and relapse rates are high.
The highest success rates come from those programs that educate and empower
patients and provide intensive support and on-going back-up (92). Weiner et al
reported improvement of symptoms in 74% at one year, maintained in 59% at 5 years
with simple urotherapy. of those patients 77% would recommend this treatment to
others (93). Whether the better approach is to introduce each measure individually or
use a combined approach from the start remains to be elucidated.

Pelvic Floor Muscle Therapy/Biofeedback

Kegel, over 60 years ago, is credited with the introduction of pelvic floor muscle
therapy to treat urinary incontinence in adult females with stress urinary incontinence
in whom he reported success in 64 patients with the aid of his Perineometer (94).
Whereas Kegel applied these principles to adult women with post-partum
incontinence it was Maizels who first applied the principle of Biofeedback to children
(95). Two thirds of adults who have benefitted from pelvic floor muscle training and
have continued to practice the exercises have been found to have sustained
improvement 10 years later (96). In the pediatric population pelvic floor muscle
rehabilitation has been utilized with good success to increase floor muscle awareness
in children with dysfunctional voiding, recurrent urinary tract infections with poor
bladder emptying and vesico-ureteric reflux. What is not clear from the literature is
whether education alone, Kegels exercises or biofeedback therapy provide the best
outcome. Biofeedback therapy provides real-time monitoring of a particular
physiologic function in either an audible or visual manner to enable learned control of
that function. Modern day biofeedback for lower urinary tract dysfunction is usually
based on either uroflowmetry or pelvic floor muscle electromyography. There is a
paucity of published randomized trials evaluating pelvic floor muscle therapy or
Biofeedback. What has been published prohibits meaningful meta-analysis as
different, often incompletely defined, treatment strategies have been used to treat a
heterogeneous group of conditions. With a mean of 2.8 behavioral therapy sessions
(range 1- 7) administered by a trained psychologist they reported improvement in
daytime urinary control in 72.7% at 12 months that was sustained in 59.6% at 5
years.

Wiener et al reported short and medium term outcomes following what they describe
as simple behavioral therapy for children with daytime urinary incontinence (93).
Reporting on 48 responding participants from an original cohort of 74, with a median
follow-up of 5 years. This was neither a randomized nor a blinded study with some
patients receiving counseling, some anti-cholinergics and some both. That said their
conclusion that more intensive/invasive Biofeedback therapy may not be necessary in
a large proportion of patients has some merit. In line with this thinking many centers
have reported their management algorithm of escalating intervention.

For those in whom an escalation to Biofeedback is necessary there is an ever

increasing number of treatment options. Uroflowmetry-based biofeedback aims to
promote a bell-shaped urine flow curve by providing a real-time on-screen visual
display during voiding. Whilst uroflow-based treatment has been shown to achieve
similar results to EMG-based therapy in fewer sessions, it is a very labour-intensive
therapy and sessional duration must be prolonged by the need to re-fill the bladder
after each void, individual sessions taking 6 hours as compared with 45-90mins for
EMG-based treatment (97). EMG-based biofeedback which initially used auditory or
linear computer traces have evolved into interactive computer games. These were
initially introduced by McKenna in 1999 who reported success rates approaching
100% (98). This high level of success has been repeated by others such as Schulman
who reported 80-100% resolution of daytime wetting and 67-94% normalization of
uroflow curves (97); DePaepe et al reported 83% resolution of recurrent UTIs
secondary to dysfunctional voiding with weekly EMG based biofeedback, with some
requiring as many as 24 sessions(99); Porena et al reported complete resolution of
dysfunctional voiding in all 43 children (occurred more quickly in girls) and 87%
resolution of associated recurrent UTIs at 2 year follow-up which reduced to 80% at 4
years (100). The application of EMG-based biofeedback has been extended to patients
with detrusor overactivity with reports of 66% success in patients with refractory DO
(101) thought to be acting at least in part thru enhanced suppression of detrusor
contraction secondary to pelvic floor contraction (102). It has also been shown to
have a positive impact on vesico-ureteric reflux often seen to be associated with
dysfunctional voiding with complete resolution in 63% and a down-grade in severity
in a further 29% (103). Biofeedback therapy continues to evolve with continued
experimentation of new techniques such as intra-vesical biofeedback to increase
bladder capacity (104).

What remains to be determined are questions around ideal patient selection, treatment
location and duration. In line with an increasingly minimalist approach to patient
investigation and management some units are providing home based biofeedback with
reasonable success (105). There have been a number of studies that have attempted to
quantify the additional benefit of biofeedback over standard urotherapy without much
success (97,106). This may be because of poor patient selection and a lack of
heterogeneity in the study population. What is clear is that the addition of computer-
based animation shortens the duration of treatment necessary to achieve the same
effect (107,108). All of the work published in this area points to two areas of absolute
importance to a successful outcome, firstly, a motivated and compliant patient and
secondly an enthusiastic, trained and dedicated urotherapist (whether that be a nurse,
physiotherapist or doctor is not important).

Pharmacotherapy

When considering pharmacological intervention for patient with dysfunctional

voiding and other daytime wetting disorders therapeutic agents can used to target
either the bladder itself (detrusor muscle) or the bladder neck/proximal urethra. For
either target one can choose agents intended to stimulate or suppress.

Stimulants or Agonists

Direct bladder stimulation, for patients with under-active detrusor/lazy bladder, with
agents such as Bethanechol or Carbachol that act directly on the muscarinic receptor
to stimulate it or Distigmine, an acetylcholinesterase inhibitor that acts by preventing
the breakdown of acetylcholine at the neuromuscular junction has largely been
abandoned due to lack of proven benefit (109,110). Bethanechol which was used a lot
for GI motility disorders, is enjoying something of a resurgence as a detrusor pro-
kinetic for the prevention of post-hysterectomy urinary retention (111).

The list or active neurotransmitters in the bladder neck and urethra and therefore
potential targets for pharmacotherapy is ever expanding including a) Adrenergic alpha
(- contraction) of which there are 4 different subtypes present and beta (- relaxation)
receptors, 2 sub=types present; b) Cholinergic muscarinic (M2 and M3) receptors; c)
Nonadrenergic Noncholinergic (NANC) pathways including Nitric Oxide, ATP,
Carbon Monoxide, VIP, Neuropeptide Y, Tachykinins, Prostanoids, Endothelins, 5-
Hydroxytryptamine, Rho-kinase to mention but a few!! For a more detailed
discussion on these pathways the reader is directed to the Canda and Schwinn papers
(112,113). Many of these pathways/potential targets have only recently been
described and as such therapeutic agents have yet to be developed.

There is ample evidence that Alpha-adrenergic activity contributes significantly to

urethral tone. Ephedrine and Phenylpropanolamine both directly stimulate alpha and
beta receptors and cause local release of noradrenaline and thereby increase urethral
tone. Unfortunately they are not urethral specific and are associated with high blood
pressure, palpitations, headaches and tremors thereby limiting their clinical use.
There has been some success with their use in adult post-menopausal women with
stress incontinence when used in combination with oestrogen therapy (114).
Imipramine is a tricyclic antidepressant that inhibits noradrenaline re-uptake,
increasing urethral tone and raising urethral closing pressure. It also has some anti-
cholinergic properties (discussed in the chapter on nocturnal enuresis) and possibly a
central effect related to its inhibition of serotonin re-uptake (115). Duloxetine is also a
noradrenaline and 5-HT re-uptake inhibitor has also been shown to be better than
placebo for women suffering from stress urinary incontinence (116).

Clenbutarol, a beta-receptor agonist, has been shown to have benefit in adult women
with urinary incontinence, through an unknown mechanism but possibly by acting
directly on urethral striated. A bladder selective beta-agonist may aid in the treatment
of detrusor overactivity and avoid the cardio-vascular side-effects (Tachycardia,
hypotension) of non-selective ones. Mirabegron is just such a selective beta3-
adrenoreceptor agonist that has already been approved and trialled in Japan is well
tolerated, effective and associated with minimal side effects (117).

Inhibitors or Antagonists

Inhibitors or antagonists may be used to treat inappropriate bladder contractions as in

detrusor overactivity or to further reduce outlet resistance and improve bladder
emptying efficiency as in dysfunctional voiding.

Anti-muscarinics
The most common class of drugs used to treat detrusor overactivity are the anti-
muscarinic family of drugs, believed to act by blocking the muscarinic receptors on
the detrusor muscle, preventing stimulation by Acetylcholine. Given that they work
primarily to reduce symptoms of urgency and to increase functional bladder capacity
there exact mechanism of action is uncertain. There are 5 muscarinic receptor
subtypes (M1 - M5). In human detrusor M2 receptors account for 2/3 and M3 the
remainder. M3 are responsible for detrusor contraction in the normal bladder. M2
receptors in the bladder seem to function to oppose sympathetically induced bladder
relaxation. M4 receptors are pre-synaptic and though to inhibit neurotransmitter
release, whereas M1 are thought to facilitate ACh release. Muscarinic receptors are
also found on urothelial cells. Anti-muscarinic drugs exert their effect during the
storage phase of bladder function, during which there is no parasympathetic activity.
There must be some other source of acetylcholine, possibly the urothelium, that is
contributing to detrusor muscle tone (118). This would in part explain the association
of detrusor overactivity and urinary tract infection or bladder inflammation.

Propanthline Bromide is a quaternary ammonium compound that is a non-selective

muscarinic receptor antagonist. It has a low (5-10% bioavailability and has to be
taken four times a day (119). In a number of comparative studies in both adults and
children with idiopathic detrusor overactivity it has been shown to be no better than
oxybutynin t.d.s. or in some cases placebo.
Trospium Chloride is another quaternary ammonium compound with non-selective
anti-muscarinic and possibly ganglion blocking activity. It has been shown to have
similar effect to oxybutynin, with fewer side effects, in patients with neurogenic
detrusor overactivity . Interestingly it has been found to have better long term
compliance than many of its rivals, perhaps related to its twice daily administration
and better side effect profile (120).

Emepronium bromide is a similar non-selective anti-muscarinic quaternary

ammonium administered 4 times a day with some proven benefit in adult women but
no studies in children. Emepronium bromide has been withdrawn because of
oesophageal ulceration, however Emepronium carrageenate may still be available.

Oxybutynin is a tertiary amine that has anti-muscarinic, direct muscle relaxant and
local anaesthetic (only relevant if administered intra-vesically) effects. It is a chiral
compound with R- and S- enantiomers. The majority of its impact on detrusor
overactivity is related to its anti-muscarinic properties. It is the first anticholinergic to
have been approved for use in detrusor overactivity, having been approved by the US
FDA in 1975. In-vitro it is 500 times more potent as an anti-muscarinic agent than as
a direct muscle relaxant. It seems to have a higher affinity for M1 and M3 receptors,
having 10-fold greater affinity for M3 over M2 (121). The immediate release
formulation has a bio-availability of about 6%, but with a marked, up to 8-fold,
variability between subjects (122). Oxybutynin is metabolized in the liver by
Cytochrome P450 isoenzyme 3A into an active metabolite N-desethyl-oxybutynin
which results in higher concentrations than the parent compound and may be largely
responsible for the therapeutic effect. N-desethyl-oxybutynin also appears to have
higher affinity for the parotid gland, implicating it in the major side effect of dry
mouth. That said studies have failed to show a correlation between volume of saliva
production and the sensation of dry mouth (123). The relatively small size of both
oxybutynin and its primary metabolite coupled with its fat solubility mean it crosses
the blood/brain barrier easily and contributes to its CNS side effect profile. Plasma
concentrations of oxybutynin have a half-life of 2 hours (124) but given the
therapeutic effect of its primary metabolite administration bd or tds is generally
recommended. The initial dose of oxybutynin is somewhat subjective given
variability in patient population. For children less than 5 years old a dose of
immediate release formulation 0.2mg/kg/dose tds or 1mg/year of age bd to a max of
5mg bd. For those between 5 and 10 years of age 5mg bd and for those > 10years old
10mg bd of immediate release or 10mg of extended release once daily. In general we
start with a lower dose (to avoid side effects) and dose increase, following a failure to
achieve the desired effect, at an interval of 1-2 months (122).

Oxybutynin is available in a number of formulations including immediate release,

extended release and transdermal. The immediate release formulation remains the
gold-standard against which newer drugs and formulations are compared. To improve
compliance thru less frequent dosing and reduce side effects by limiting peak levels a
once daily extended release or slow release formulation was developed (125). The
extended release formulation makes use of an osmotic release system (OROS). This
consists of a 2 layer core the outer containing oxybutynin chloride and the inner
osmotic agents. Once in the GI tract water ingress creates a suspension of the
oxybutynin that is slowly expelled thru a small hole in the capsule membrane by
expansion of the osmotic agents (126). It is released throughout the GI tract but
primarily in the colon which minimizes its first pass metabolism resulting in a higher
bioavailability of oxybutynin and reduced levels of N-desethyl-oxybutynin.
Transdermal oxybutynin evolved again from a desire to avoid or minimize first pass
metabolism and is possible because of its lipophilicity. The system consists of a
polyester strip that is removed to apply to the skin. An outer protective layer and an
adhesive layer that contains both the oxybutynin and triacetin to enhance skin
permeation. It is applied twice weekly, reaches a steady state by the second
application and results in minimal fluctuations in plasma concentrations of
oxybutynin during the 96-hour wear period. Patch construction is capable of
delivering 1mg/day/cm2 and currently the patch exists in only one size that delivers
3.9mg/day. It can however be cut with similar certainty of dose.

Immediate release oxybutynin has been demonstrated to reduce urinary frequency by

about 50% and urge incontinence by 70% when compared to placebo (124). The
extended release formulation has the same efficacy as the immediate release but is
better tolerated with up to 57% reduction in side effects (127). The OBJECT
(overactive bladder: judging effective control and treatment) trial found extended
release oxybutynin to be more effective than immediate release tolterodine with
similar side effects. The OPERA (Overactive bladder: performance of extended
release agents) trial found similar reductions in urge incontinence with both extended
release oxybutynin and long-acting tolterodine (128). Oxybutynin had a greater
impact on frequency of micturition but was associated with a higher incidence of dry
mouth. Transdermal oxybutynin is associated with fewer complaints of dry mouth
than extended release preparations.

Tolterodine is another tertiary amine, anti-muscarinic that though not selective for any
specific muscarinic receptor, has enhanced selectivity for bladder over salivary
glands. It has similar affinity for muscarinic receptors as oxybutynin and also
undergoes significant first pass metabolism in the liver again to an active metabolite
5-hydroxymethyl tolterodine. 7% of caucasians do not metabolize tolterodine. It has
quite marked bioavailability ranging from 10-70% that is enhanced by taking with
food. As discussed above it comes in both immediate release and extended release
formats which contains the active agent in soluble microspheres (129).

The efficacy of tolterodine has been discussed above. Unlike the OPERA trial the
ACET (Anti-muscarinic clinical effectiveness trial) found 4mg Tolterodine extended
release to have better efficacy and tolerability than extended release oxybutynin (130).
Fesoterodine is an inactive tertiary amine that is metabolized to 5-hydroxymethyl
tolterodine, the same metabolite as tolterodine. It has been demonstrated to haver
greater efficacy than tolterodine but with higher rates of dry mouth and
discontinuation because of adverse events (131).
Solifenacin is a tertiary amine with M3 selectivity. it has 90% bioavailability after
oral administration. It has been shown to be as effective as oxybutynin but with fewer
side effects. It was also found to have enhanced efficacy compared to tolterodine
(132). It has been used with moderate success in the treatment of therapy resistant
detrusor overactivity in children(133). Of the 108 patients in the study, 42% had had
complications related to their previous anti-cholinergic therapy with only 9 (6.5%)
experiencing side-effects on Solifenacin. Of the patients eligible for assessment 85%
were improved on Solifenacin, of whom 54% had a complete response and 46% a
partial response.
Darifenacin is an engineered tertiary amine and selective M3 antagonist (121). It has
been shown to be better than placebo for urinary symptoms but to still cause
significant dry mouth. That said it has demonstrated long-term tolerability in an open
label study of adults with >40% of patients claiming >90% reduction in incontinence
episodes at 2 years (134). One of the major advantages of Darifenacin and
Solifenacin is the once daily administration.
Propiverine, used primarily in children with nocturnal enuresis has been shown to
have both anti-cholinergic and calcium-channel antagonistic properties (119). Again
it has been shown to have similar efficacy compared to oxybutynin but with fewer
side effects, experienced in 20% and primarily related to its anti-cholinergic
properties. Theoretically calcium channel blockers by preventing calcium in-flux
could thereby inhibit detrusor contraction none of the studies thus far looking at
Nifedepine or Verapamil have proven effective.
Flavoxate is a drug with uncertain mechanism of action but known calcium-channel
antagonistic properties, that also inhibits phosphodiesterase. It has similar efficacy
when compared with oxybutynin, with fewer side effects.
Capsaicin and Resiniferatoxin are from a family of drugs called vanilloids. Capsaicin
is the ingredient in chili peppers that elicits the burning sensation by selectively
activating sensory neurons, It acts by stimulating Transient Receptor Potential cation
channels of the vanilloid sub-family (TRPV-1). It acts by initially stimulating and
later blocking or desensitizing the sensory nerves possible thru depletion of
neuropeptide stores, in particular of unmyelinated C-fibres. Capsaicin has used
efficaciously in patients with neurogenic detrusor overactivity and found to last from
2-7 months after a single administration, in those for whom it worked. The most
significant side-effect is intense bladder discomfort that is best managed by either
administration under GA or prior intravesical administration of lignocaine (119).
Resiniferatoxin is derived from Euphorbia, a cactus-like plant, that similarly acts on
TRPV-1 but with 1000-fold potency compared to Capsaicin, but with only 100-fold
the inflammatory effect. It appears to have less excitatory effect (prior to subsequent
desensitization) than Capsaicin and hence may be a better alternative. While
Resiniferatoxin has been used for patients with neurogenic detrusor overactivity there
have been no reports of its use in children that this author could find and there has
been only one report of its use in patients with idiopathic detrusor overactivity. In a
nonrandomized study of adult patients with IDO that failed to respond to anti-
cholinergic medication, were treated with out-patient intra-vesical instillation of
Resiniferatoxin on a weekly basis, preceded by intra-vesical lignocaine, for 4 weeks
with 50% response rates (135).

Choice of Anti-cholinergic
Kessler in a large meta-analysis of anticholinergic therapy looking at 69 trials and
>26,000 patients found that with the exception of immediate release oxybutynin all
other anti-cholinergics have very similar side effect profiles (136). Cost and
availability are important considerations when choosing an anticholinergic with little
published data on either. Hashim and Abrams in 2004 found a cost differential, in the
UK, between Oxybutynin immediate release and Tolterodine (either formulation) of 6
-fold (137). Here in Australia Oxybutynin extended release, Tolterodine LA,
Fesoterodine and Trospium are all not available, thereby influencing selection.

Botulinum Toxin
Botulinum toxin is one of the most potent neurotoxin known, produced by
Clostridium Botulinum, that comes in 7 sero-types (A-G) of which 2 (A & B) have
been used clinically (138). It binds to peripheral nerves, preventing the release of
acetylcholine, by cleaving SNARE (soluble N-ethylmaleimide sensitive factor
attachment receptor) proteins (BTX-A cleaves synaptosome-associated protein
(SNAP-25); BTX-B cleaves vesicle associated membrane protein (VAMP)). This
prevents vesicle migration to and fusion with the pre-synaptic membrane. It is
important to understand that different preparations of BTX-A (Onabotulinum Toxin -
Botox & Abobotulinum Toxin - Dysport) have dramatically different potencies.
Similarly BTX-B exists if different preparations (Myobloc & Neurobloc).
BTX-A was first used in 1998 to treat neurogenic detrusor overactivity and urinary
incontinence in adults with spinal cord injury (139). Seventeen of 21 were improved 6
week slater and this was maintained in 16 at 36 weeks. A systematic literature review
by Karsenty et al identified 18 articles investigating the safety and efficacy of Botox
in adults with NDO, with most studies reporting 40-80% continence rates following
injection (140). Its use in patients with NDO has been associated with a dramatic
reduction in the need for bladder augmentation (141). The effect happens with 7-30
days and lasts from 6-9months. It has been shown to improve quality if life in
patients with both IDO and NDO (142).
Intravesical Botox in children with NDO has been reported to achieve continence in
65-87% (143). The optimal dose of onabotulinum toxin A for detrusor overactivity
has gradually been reduced from a maximum of 300IU to 100IU without loss of
efficacy (144). In fact reducing the dose injected to 100IU results in a significant
reduction in complications related to Botox such as urinary tract infection, acute
urinary retention and need for intermittent catheterization. The intra-vesical use of
100units of Botox in children with non-neurogenic detrusor overactivity, resistant to
anti-cholinergic therapy yielded a complete response in 60%, a partial response in
20% and no response in 20% after 6 months, at the expense of temporary urinary
retention in 5% and UTI in 10% (145).
The first use of botulinum toxin in a child was by Steinhardt in 1997 where it was
used to treat dramatic urethral dilatation in a girl with dysfunctional voiding (146).
Since then there have been a number of reports if its use in children with
dysfunctional voiding. Franco et al retrospectively reported on 16 patients with EMG
proven dysfunctional voiding and urinary incontinence that had failed all previous
therapies including Biofeedback and alpha-blocker therapy (147). They reported 75%
dryness and 20% improved after a single injection, with a significant reduction in
post-void residuals but interestingly no change in uroflowmetry. A similar
improvement, without affecting uroflowmetry, was demonstrated by Petronijevic and
seen to last 6 months (148).

Alpha-Blockers
Stimulation of the large concentration of alpha receptors found in the region of the
bladder neck and urethra results in increased outlet resistance (149). Cain et al
reported on 55 consecutive children with urinary incontinence and inadequate bladder
emptying treated with Doxazosin at a dose of 0.5-2mg/day (150) in addition to other
standard therapy. They found an 88% reduction in post-void residual urine volumes,
improvement in urinary incontinence in 83% and a reduction in urgency in 70%.

Future Directions for Pharmacotherapy

Our increased understanding of neurophysiology of bladder contraction is revealing

new and potentially novel targets for the treatment of lower urinary tract dysfunction
including connexin 43 and c-kit (involved in cell coupling or signal translation);
cannabinoid and beta-3 receptors antagonists and phosphodiesterase inhibitors (151).

Neuromodulation

For that minority of patients whose symptoms persist despite urotherapy, biofeedback
and pharmacotherapy the next level of intervention is some form of electrical
neuromodulation. It is difficult to find a clear definition of neuromodulation but
essentially it is a therapy that aims to bring about a therapeutic modulation of neural
activity thru stimulation of the central peripheral or autonomic nervous systems. Its
origins have been traced to the first century AD where Scribonius Largus described
the application of live Torpedo fish to treat gout. The use of electricity as a
therapeutic agent enjoyed a large resurgence during the late 19th and early 20th
centuries but it has really been it the last 2-3 decades, in conjunction with our
enhanced understanding of neurophysiology that significant progress has been made
in this area. Neuromodulatory techniques have been successfully applied to patients
with neuropathic pain, anorexia, epilepsy, depression, OCD and now also with
bladder dysfunction. A number or techniques have been used to treat detrusor
overactivity including Transcutaneous Electrical Neural Stimulation (TENS),
Posterior Tibial Nerve Stimulation (PTNS), implantable sacral nerve root stimulation
(Interstim). The exact mechanism of action of neuromodulation is not known but is
thought to act thru stimulation of both bladder afferents and efferents. Detrusor
overactivity may have in part its origins in the emergence of new reflex arcs involving
C-fibers within the bladder wall. It is thought that by directly stimulating these nerves
that sacral neuromodulation may interfere with these reflex contractions. PTNS is
thought to act in a similar way but at either the sacral cord or supra-spinal level, so too
Pudendal nerve, dorsal penile nerve and endo-anal stimulation (152).

TENS treatment in children with detrusor overactivity, who failed anticholinergic

therapy has been associated with an initial response in 76% and cure at 1 year in 56%
(153). Response rates of 13-73% have been reported in children with daytime urinary
incontinence (154-156). Up to a quarter of patients failed to demonstrate any
response to TENS therapy (157). It is noteworthy that in an elegant randomized and
blinded (not easy to do!) study by Lordelo et al that up to a third of sham treated
patients reported a significant improvement in symptoms of overactive bladder,
though none reported cure (158). Given that TENS therapy is associated with
discomfort at the skin level patient compliance is a concern with drop-out or non
compliance rates of 11-22% reported. Malm-Buatsi et al reported incomplete
adherence to treatment regimen because of discomfort in 11%, and complete
abandonment in 5.5%. Hoebeke reported 22% lack of success because of a lack of
motivation and therefore presumed non-compliance. Once treatment is stopped
relapse rates of 10-25% have been reported (153,158). Advances in technology and
electro-physiology have led to the development of a new generation of TENS
machine that utilizes interfering electrical currents to minimize skin discomfort to
improve compliance (159,160). TENS therapy has the additional advantage of being
able to be administered at home.

Posterior Tibial Nerve Stimulation on the other hand cannot be administered at home
as this more invasive therapy involves the insertion of a percutaneous needle electrode
near the medial malleolus of the ankle. of the 75 children enrolled in 3 different trials
of PTNS symptomatic improvement was reported in 78-84% (161-163). Up to a third
of patients discontinue therapy, of which 10% do so because of a fear of the needle
(161).

Interstim is a surgically implanted system designed to deliver sacral neuromodulation

that was approved by the FDA for the treatment of urge incontinence in 1997 and for
the treatment of urinary retention since 1999. If a percutaneously inserted temporary
needle electrode (at the S3 foramen) connected to an external pulse generator is
proven to be successful the system is converted to a fully implanted pulse generator.
Since 1997 over 100,000 units have been installed worldwide, mainly in adult
patients. Interstim was reported to have an initial success rate in 84% of 19 patients,
with complete resolution of urinary incontinence in 16% and improvement (defined as
greater than 50% reduction in symptoms) in 68% (164). Those who improved went
from a mean of 1.45 episodes of incontinence per day to 0.64. This group of
researchers continued to follow some of this group of patients and also to add new
patients. With improved patient selection (largely based on patient motivation) they
reported 88% improvement in urinary incontinence (75% complete resolution, 12.5%
partial resolution (165). They also reported improvement in other areas such as
urinary urgency (69%) and constipation (71%). They openly acknowledge the
nonrandomized nature of this study of a technique applied to a very heterogenous
cohort of patients. Whilst only 5 (25%) of patients were rendered symptom free, only
6 (30%) of patients were able to stop all adjuvant pharmacotherapy and 4 (20%) of
patients required surgery for complication of the device they have shown that
Interstim therapy can be utilized in carefully selected children with refractory
incontinence with modest hope of success.

Functional magnetic stimulation (FMS) using a device capable of generating low

frequency pulsating electromagnetic fields e.g. Pulsegen or NeoControl. In the only
published trial to compare FMS with electrical neuromodulation (FES) Yamanishi et
al reported increases in both maximum cystometric capacity and bladder volume at
first desire to void (166). They found a significantly greater increase (114+/124mls)
in the FMS group than in the FES group (32+/-57mls), though the pre-treatment mean
volume in the FMS group was small than that in the FES group. FMS completely
abolished detrusor overactivity in 3 of 15 patients, whereas FES did not achieve this
in any patient. In a placebo controlled trail of FMS But did not report any cures but
did find a 56% reduction in urinary incontinence symptoms in the control group
compared with 26% in the placebo group (167).

Operative Management

Surgical intervention for dysfunctional voiding is usually reserved for those

intractable patients who have failed all of the aforementioned therapeutic
interventions. Fortunately this is an ever reducing percentage of the overall
population but it does represent those that are the most difficult and despairing to
treat. Clearly there will have been some operative intervention by the urologist before
this watershed point for instance cystoscopy may have been undertaken for diagnostic
reasons, to insert a supra-pubic catheter for video-urodynamics or for Botox injection.
Neurosurgical involvement may have been sought to insert the tined electrode for
Interstim therapy. Beyond this the nature of the surgical intervention will be tailored
to particular subtype of voiding dysfunction.

Patients with detrusor under-activity, recurrent UTIs secondary to dysfunctional

voiding with large post-void residuals and those with non-neurogeneic neurogenic
bladder may require surgical intervention to facilitate bladder emptying. Clean
intermittent catheterization was originally described by Lapides in 1972 (168).
Interestingly he described clean catheterization to help prevent recurrent urinary tract
infection in patients with neuropathic bladders but not by reducing post-void residuals
themselves which he thought were of doubtful importance in the genesis of urinary
infection. Rather he believed that raised intra-vesical pressure compromised intra-
mural blood flow and thereby impaired host immune defenses. The advantage of the
clean approach is the simpler preparation and a recent Cochrane review was unable
to find any evidence of difference in frequency of UTI when comparing sterile with
clean catheterization. In one of the largest reports on the use of CIC in
neurologically normal children with voiding dysfunction Pohl et al published 70%
tolerability or compliance with CI in children with sensate urethrae (169). With a
mean age of 4.5 (1.5-9) years, 15 of these children learned CIC within 2 days, 4
refused to learn after the initial visit and the remaining 4 took 2 weeks to learn (of
whom 3 stopped soon after).

For the 30% or so of children in whom the need to improve bladder emptying has
been identified but who cannot/will not perform CIC per urethra an alternative route
may need to found. Originally described by Mitrofanoff in 1980 to facilitate bladder
emptying in patients who were simultaneously undergoing bladder neck closure
(16/23) or subsequently underwent bladder neck closure (a further 5 patients) in
patients with neuropathic bladders (170). With 20 year follow-up they reported 47%
stomal complications of either stenosis or leakage and intestinal complications
(volvulus or adhesions) in 5(22%) patients. This technique has been applied to
children with sensate urethrae (171-173). The actual technique of Mitrofanoff
formation is discussed elsewhere.

For patients with detrusor over-activity once all of the non-operative therapies have
been exhausted surgical intervention aims to increase functional bladder capacity and
reduce the maximal detrusor pressure which currently involves some form of bladder
augmentation either in the form of augmentation cystoplasty or auto-augmentation.
Auto-augmentation, originally described in 1989 by Cartwright and Snow but its not a
procedure that produces as large an increase in bladder capacity as ileo-cystoplasty
and does not last as long (174). Other techniques such as trans-trigonal phenol
injection and detrusor transection have been abandoned because of a lack of
consistent efficacy and/or longevity. Detailed discussion of the operative techniques
is covered elsewhere in this book. Augmentation cystoplasty utilizes either sigmoid
or ileum, with a preference for the latter as it results in better compliance and
produces less mucus. It must be remembered that following augmentation a high
proportion of patients 33-50% may require intermittent catheterization. Augmentation
cystoplasty remains an intervention of last choice (175). It has been reported in adults
with non-neurogenic neurogenic bladder to produce a 93% continence rate.
Furthermore it has been shown, after 3 years, to be as cost effective as sacral
neuromodulation of Botox injection. Augmentation cystoplasty has been shown to be
associated with improvements in quality of life despite recurrent UTIs in a third, a
need for prophylactic antibiotics in 15%, and a need to perform CIC in 85% (176).
That said Mundy has reported continence rates of 93% in patients undergoing
augmentation for idiopathic detrusor overactivity (177). They reported CIC rates of
only 6% in this population of patients.

Prognosis

Whilst there are lots of publications detailing the short term outcome for children with
voiding dysfunction there are very few that report the medium to long-term
outcomes. Those studies by their nature have tended to be cross-sectional rather than
longitudinal. The ALSPAC project which followed on a birth cohort of 13,793
children followed for 9.5 years reported that daytime urinary incontinence, which was
more common in girls declined in prevalence from 15.5% at 4.5 years of age to 4.9%
at 9.5 years of age (178). They also found that the prevalence of more frequent
wetting (>2 episodes per week) also reduced from 1.9% to 0.5% over the same time
period. There was a stronger association with urgency in this group who also were
more likely to receive treatment and more likely to remain wet over time. The same
group 12 years earlier reported on urinary symptom progression during adolescence
of over 1,000 school children. Similarly they found urinary incontinence to be more
prevalent in girls and to decline with age in both sexes (179). Daytime urinary
incontinence fell from 16.6% of 11-12 year old girls to 4.7% of 15-16 year olds. In
boys it fell from 7.2% to 0.98%. The apparent increase in prevalence from 4.9% at
9.5 years to 16.6% at 11-12 years is largely explicable for different definitions of
incontinence. Of the 25 girls and 4 boys who were wet at 15-16 years, 10 of the girls
and 3 of the boys had new onset incontinence, not present when they were aged 11-
12. Schulman et al reported 45% cure (dry, off all meds) after minimum of 6 month
follow-up in a cohort of 222 children with daytime wetting (180). A further 37% were
improved (>50% reduction in symptoms) but possibly still on medication. The same
group subsequently published on a subset of these patients with 6.5 years of follow-
up reporting 91% complete resolution of daytime wetting with a median of 2.9 years
to dryness (181). Interestingly despite the comprehensive treatment received (which
included antibiotics, anti-cholinergics, biofeedback and psychological counseling)
parents felt that maturation was the single most important factor in symptom
resolution. In summary the resolution rates for daytime urinary incontinence is about
0.2% per year of life from 7 - 17 years of age.

Of course a small percentage do not resolve and in some cases their condition
deteriorates. This has been described by some as a dysfunctional voiding sequence
which is often considered to start with detrusor overactivity, which by inducing
urethral sphincter overactivity develops into dysfunctional voiding and ultimately
ends in an under-active detrusor (43). If that progression exists then it should be
evident in age differences between the different sub-types of voiding dysfunction.
 Hoebeke et al reported 1,000 video-urodynamic performed on a selected subset of
over 3,500 patients presenting for investigation of incontinence over a four year
period (71). Of the studies 6.2% were normal, 58% detrusor overactivity, 32%
dysfunctional voiding and 4% detrusor under-activity or lazy bladder. There was no
evidence of a dysfunctional voiding sequence form the ages of these sub-types. It
seems that children who are incontinent of urine have different primary pathologies.

Long-term Outcomes

There have been a number of studies (e.g. NOBLE, EPIC, EpiLUTS) quantify the
prevalence and progression of urinary incontinence in adulthood (182,183).
Wennberg et al followed a randomly selected group of women from Gothenburg,
Sweden over 16 years (184). They found an increased prevalence of urinary
incontinence (see Table 6), frequency, nocturia and overactive bladder to increase
over time. Over the intervening 16 years 21% of women who werent wetting initially
developed urinary incontinence. A similar sized portion (34%) of those who wet
initially became dry during that same period. The overall prevalence of overactive
bladder increased from 17 to 26% during the 16 year period. All of this increase was
in those women with incontinence as the prevalence rate for OAB dry (i.e. urgency
without incontinence) was 11% initially and 10% 16 years later whereas that for OAB
wet increased from 6% initially to 16% later with a similar increase seen in all age
groups. Many others have reported similar progression and regression of overactive
bladder symptoms in the adult population over time emphasizing the dynamic nature
of LUT dysfunction (185).

It has long been suspected that there is a

Age at entry 1991 2007 correlation between childhood voiding
20-34 6% 23%
dysfunction and adult lower urinary tract
35-49 19% 28% symptoms. Currently there are no
longitudinal studies that have followed
50-64 20% 32% children all the way thru to adulthood. Most
studies rely on adult recall of childhood
>65 18% 32% symptoms. The known association between
adult urinary incontinence and paediatric
Table 6 - Prevalence of Urinary nocturnal enuresis has been discussed
elsewhere in the chapter on nocturnal
Incontinence
enuresis. Minassian et al reporting a case
control study of adult women referred to a uro-gynaecology clinic with urinary incontinence
was unable to demonstrate an increased likelihood of childhood dysfunctional voiding (186).
They found that 42% of the control group of asymptomatic adult women also had a history of
childhood LUTS. However when they combined both groups for sub-group analysis they
found a a significant correlation between symptomatic women and childhood LUTS
concluding that prospectively following symptomatic children into adulthood may be the
only way to
answer the question properly. Fitzgerald et al questioned 2109 randomly selected women,
aged between 40 - 69 finding that women who reported childhood daytime urinary frequency
were twice as likely to report urinary urgency as adults (187). Furthermore women with a
childhood history of urinary incontinence were 2.6 times more likely to suffer from urinary
incontinence as an adult. These findings are supported by those of Bower et al who found
that adult women attending a uro-gynaecology clinic with symptoms of LUT dysfunction
who found that a history or urgency in childhood was associated with a 2.3 fold increased
risk of developing dysfunctional elimination syndrome in adulthood (188).

Summary

In conclusion the ideal management of patients with voiding dysfunction begins with
a detailed and targeted history and physical examination. This is supplemented with
appropriate but not excessive investigation. Treatment begins with education and
urotherapy in all patients, before careful selection of adjuvant therapies. Central to
happy parents and patients is realistic expectations. Lack of realistic expectations
(and particularly a belief in the efficacy of that treatment) contributes to the drop out
rate for medication compliance seen in adults and also in children (120,189). Too
often these children present to the urologist at the end of their treatment journey and
come expecting a surgical cure or fix. We can see that none of the therapies
discussed above has 100% success rate and as one moves onto more aggressive
treatments the success rates lessen. As is true of the management of nocturnal
enuresis it is likely that greater success will arise from combination therapy rather
than any isolated individual approach (190).

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