Problems With Urinary Control
Symptoms Of Voiding Problems
- Loss of Urinary Control (Enuresis)
- Frequent Urination
- Squatting/Squeezing To Prevent Urination
- Tendency towards Constipation
- Recurrent Urinary Tract Infections
What Causes Incontinence(Enuresis)
Enuresis is probably caused by many factors.
Most children with enuresis have a developmental delay in their ability to hold
urine. Not all children develop this ability at the same rate, and gaining
bladder control may take longer in some children. Children who have only night
wetting and have never had urinary tract infections rarely have structural
abnormalities of the urinary tract to account for wetting. Recent studies
suggest that these children produce more urine at night than other children.
Some children will have wetting problems during the day and night. They may
even have been perfectly dry for some period after toilet training. This is
usually very different from night wetting. Reasons to explain this are urinary
tract infections, structural abnormalities of the urinary tract or problems
with bathroom habits. (Such problems include: holding urine and bowel
movements, infrequent or very frequent urination, insufficient time spent on
the commode to empty bladder or eliminate stool, and painful bowel movements
with straining). Many children with severe problems will be incontinent of
stools.
Physician Evaluation
The initial evaluation should include a
thorough history and physical evaluation, a urine analysis, and a urine culture
to screen for infection.
Further evaluation may be necessary to help
determine the reason for your child’s wetting. Frequently, the only test
that may be done is a sonogram of the abdomen. The sonogram is a safe,
non-evasive test to screen children for abnormalities in the urinary tract.
X-rays are not usually indicated unless there is a history of urinary
infections or an abnormality is discovered on the sonogram. Cystoscopy is
rarely indicated and urethral stretching(dilatation) is not helpful.
How Common Is Enuresis?
15% of all 5 year olds, 5% of all 10 year
olds, and 1% of all 15 year old children occasionally wet themselves. This,
therefore, represents a common childhood problem.
Is There A Cure For Enuresis?
Yes.
For children who wet themselves at night and
void normally during the day, patience and understanding are most important. A
common sense approach includes: Voiding just before bedtime and encouraging
success with a positive reinforcement (reward) program. Punishment should
always be avoided. Treatment options that have proven to be effective include
the enuretic conditioning alarm and DDAVP nasal
spray.
Children with daytime urinary symptoms often
respond to medication (bladder muscle relaxants). Many of these children have a
tendency toward constipation and this should be treated vigorously with high
fiber diets, stool softeners, laxatives and even enemas if necessary.
Timed-Voiding by the clock every 3-4 hours during the day helps encourage
regular bladder emptying. Occasionally, for severe problems, bladder emptying
may be improved by intermittent catheterization or behavior modification.
Children with anatomic abnormalities will
usually show improvement once the cause is addressed. Treatment may include
surgery. Children with neurologic dysfunction (spina bifida, spinal cord
injury) often require a combination of medication, intermittent catheterization
and surgery.
The Role of
Constipation in Overactive bladder and
recurrent UTI’s
There is a close
association between constipation or fecal retention with overactive bladder.
The mainstay in management of overactive bladder is the correction of
constipation and fecal retention. An understanding of normal defecation is
essential in understanding problems associated with overactive bladder. The
stimulus for defecation is initiated primarily by rectal distention. There are
no other receptors in the rectum other than stretch receptors. The rectum
normally distends when peristaltic activity propels feces from the sigmoid
colon to the rectum stimulating sensory receptors in the rectal wall. These
sensations when picked up are sent to the brain and processed as a sense of
distention. Distention of the rectum causes involuntary temporary contraction
of the striated external sphincter and puborectalis muscles. Voluntarily
maintaining this contraction will cause the rectum to adapt to the increased
volume and the sense of fecal urgency will subsequently disappear until the
arrival of another fecal bolus. This mechanism lends itself very easily for children
to develop large distended rectums over a period of time and fecal hoarding and
chronic pelvic floor hypertonicity. In a study by Miyacato et al, [i] the
researchers found that rectal distention leads to decreased amplitude and
shortened duration of bladder contraction and finally can almost abolish
bladder activity. These effects can be reversed by injection of strychnine and
Bicuculline intrathecally. This restores the amplitudes of bladder contractions
to control levels. It is postulated that an inhibitory recto-vesicle reflex
exists in the lumbosacral cord of rats. The afferent limb is in the
spinobulbospinal micturition reflex pathway may be additionally and redundantly
inhibited by glycinergic and gabanergic mechanism, while the efferent limb may
be synergistically inhibited by these mechanism. 43 These findings may explain why
we see such a high predominance of hoarding of urine in patients who have
chronic problems with constipation and rectal distention. Distention in the
rectal wall will generate impulses that are transmitted distally through its
walls via the myenteric plexus activating the rectal sphincteric relaxation
reflex causing smooth muscle relaxation in the internal anal sphincter. The
degree of relaxation is in proportion to the fecal volume and the speed at
which the rectum is distended. An increase of intraabdominal pressure lowers
the pelvic floor thereby increasing intrarectal pressure. Relaxation of the
external sphincter allows the fecal bolus to be expelled. In many children who
have intermittent fecal soiling or fecal marks on their underwear the
involuntary relaxation of the internal sphincter will allow stool to present
itself at the anus thereby soiling their underwear. When they sense the stool
at the anal verge they clamp down on the external sphincter and the stool is
pushed back in. Maintenance of this chronic rectal sphincter tone will lead to
a sustained pelvic floor hypertonicity that may persist during voiding. This
may contribute to detrusor hyperplasia commonly seen in children with
constipation. In agreement with these theories we have noted in our biofeedback
patients that we can easily predict if the child has been compliant with their
bowel program. Children who normally do well with their biofeedback sessions at
times will come in unable to relax their sphincter. In these cases the common
answer is that they have been off their bowel program underscoring the
association between the two.
There are some theories
that the increased fecal mass that is stored in the rectum and sigmoid may
exert some type of pressure on the bladder wall. This increase in volume in the
pelvis will therefore reduce functional bladder capacity. The example of a
gravid uterus compressing the bladder and leading to urinary urgency in pregnant
woman has been used by some authors to describe the possible effects of stool
in the pelvis leading to bladder instability. 8 It is possible that
stretch receptors within the bladder wall can be stimulated by the extrinsic
fecal mass thereby triggering detrusor contractions of various amplitudes thus
sustaining a vicious cycle of continued contractions. It is also possible that
colonic contractions may be triggering bladder contractions via shared neural
pathways in the pelvis or spinal cord as evidenced by the findings in patients
with imperforate anus.[ii] Recently, Pezzone et al. reported that acute
colitis triggers bladder hyperactivity in rats, providing experimental evidence
for crosstalk between different pelvic viscera. [iii] [iv] We noticed this in our patients
with colitis, when there is an acute flair up of the colitis there generally
will be an increase in voiding symptoms.
When the colitis is controlled the symptoms cease. Patients can exhibit dyssynergic voiding as
well as urgency/ frequency in these situations.
We have also found that many cases of young boys presenting with chronic
erections and girls complaining of chronic vaginal or perineal pain have been
corrected with a good bowel program. These
cross talk mechanisms support the findings noted in the imperforate anus
patients, in patients with colitis and even in normal children who get a sudden
urge to void associated with gaseous distention or a colonic contraction that
at times is imperceptible to them. This
cross talk mechanism underscores the importance of a bowel management program
in the treatment of OAB.
Treatment of
constipation and fecal retention
Correlation of
constipation with bladder problems was brought to light in a landmark study in
1997 by Loening-Bauke [v]
of 234 constipated children. Twenty nine percent had daytime urinary
incontinence, 34% had nighttime incontinence and 11 % had UTl's. After one year
when constipation was relieved in 52% of the patients, all patients who had
their constipation completely corrected ceased to have urinary tract infections
and 80% of the patients had their daytime urinary incontinence corrected. Sixty
three percent of the nighttime incontinence was also corrected. It is
interesting to note that children who have had problems with chronic
constipation can accommodate a rectal balloon with up to a 120 mls before they
feel a sensation to defecate. Normal children will only accommodate a balloon
with a volume of 20 cc's before they have a sudden urge to defecate. [vi] This
indicates that many of these children will have retention of stool in their
rectal vaults thereby confirmation by parents that they have bowel movements
everyday is usually not adequate reason to assume that these children are not
constipated. Constipation can be readily diagnosed in a uniform manner and
patient progress can be followed by using the
Tegaserod is a 5-HT4
agonist which causes increased motility of the gut.[ix]
[x] [xi] Studies
have indicated that the colon is the largest repository of 5-HT within the body
and patients with irritable bowel syndrome with chronic constipation have low
levels of serotonin in the gut. Treatment of their constipation with tegaserod may have a dual beneficial effect. Correction of
the constipation and emptying of the colon leads to elimination of strong
peristaltic waves that could prevent strong sudden bladder contractions that
lead to urge incontinence. Besides the aforementioned reestablishment of a
normal serotonin homeostasis in the colon possible crossover into the central
nervous system may help correct detrusor hyperactivity that may be centrally
mediated. We know that Onuf’s
nucleus is rich in 5-HT receptors and this site also modulates bowel
function. Our experience in children who
have had refractory overactive bladder with squatting and sudden urge
incontinence who had been on numerous types of bowel programs and were not
responding well to all forms of treatment have responded to the treatment of
their constipation with tegaserod.
The prevailing thoughts on pediatric Overactive
bladder:
Overactive bladder is not
completely understood and the feeling is that it most certainly is a
multifactorial problem. In some instances anatomic abnormalities can lead to
overactive bladder (these will not be discussed in this review) while in other
cases, functional voiding problems may be the source of the overactive bladder.
In other instances neurologic lesions may lead to the development of overactive
bladder.
The prevailing theory in children is that
overactive bladder is believed to be due to a delay in the acquisition of
cortical inhibition over uninhibited detrusor contractions in the course of
achieving a mature voiding pattern of adulthood. The site of maturational delay
is thought to lie in reticulospinal pathways of the spinal cord or it could be
in the inhibitory center within the cerebral cortex. We do know that cortical
control is normally established between three to five years of age. Delay in
the fine-tuning of bladder sphincter coordination during voiding will cause
uninhibited detrusor contractions to be met with voluntary external urethral
sphincter contractions, the control of which is thought to be acquired at an
earlier age. [xii]
An increase in intravesicle pressure can manifest itself in an array of
symptoms that include urgency, urge incontinence and nocturnal enuresis.
Overactive bladder triggers bladder overactivity
usually in the early filling phase causing the pelvic floor to respond by
voluntary contraction. This voluntary contraction will lead to classic holding
maneuvers such as leg crossing, penile grabbing and squatting. It is thought
that active external sphincter contraction may possibly cause a temporary
reflex relaxation in the detrusor and therefore affording momentary relief from
the effects of uninhibited bladder contractions. Persistent isometric
contractions of the detrusor against the tightened sphincter or incomplete
relaxation of the sphincter leads the bladder muscle to hypertrophy and this
increased hypertrophy will lead to a gradual decrease in functional bladder
capacity and increased instability of the bladder, thereby creating a vicious
cycle where the overactive bladder is
worsened. The concomitant increased pelvic floor activity may be associated
with increased autonomic stimulation of the perineal organs and musculature.
This increased activity may be associated with sexual dysfunction in adults.[xiii]
[xiv] [xv] [xvi] [xvii]
There is compelling
evidence now that high pressure voiding does occur in utero in the fetus and.
Sillen, C.K. Young and
others [xviii]
[xix]
[xx] [xxi] [xxii]
[xxiii]
[xxiv]
[xxv]have
made us aware that abnormal high pressure voiding does occur in utero may be
the cause of renal damage in reflux (water hammer effect). This abnormal
voiding may and persist in some cases.
The probable lack of outright detrusor abnormalities in these bladders
would thereby lead us to believe that the problem is more likely to originate
from a neurologic source. It is
Mitchell’s [xxvi]contentions
that the lack of proper bladder cycling in the exstrophic bladder is the
primary cause why these bladders fail to function properly even after they have
been closed. A similar example exists
with boys with posterior urethral valves, in this group even long after the
valves had been ablated and bladder muscle has thinned out there is persistence
of abnormal voiding patterns. These
situations are analogous to the child with a TE fistula or a tracheostomy who
is not fed early in life and will generally fail to develop normal swallowing
patterns and requires intensive retraining.
In all of these cases there appears to be a link between repetitive
normal muscle activity and the development of normal voiding and swallowing
mechanisms. This form of muscle memory
is most likely imprinted in the brain during development and is crucial to the
proper functioning of the voiding reflexes during development and postnatally.
A finding that confirms a
central process and a genetic mode of transmission for a voiding dysfunction is
the Ochoa urofacial (syndrome).[xxvii]
In many ways the Ochoa syndrome is similar to Hinman (non-neurogenic neurogenic
bladder) syndrome. The Ochoa syndrome was first described by Bernard Ochoa of
Pathophysiology of
Overactive Bladder
Symptoms of hyperreflexia
may have many potential causes and contributing factors. Urination involves the
use of higher cortical centers in the brain, pons, spinal cord, peripheral autonomic
somatic and sensory afferent receptors in the lower urinary tract and the
anatomical components in the lower urinary tract itself. Any disorder of these
structures may contribute to symptoms of overactive bladder. The normal bladder
functions like a compliant balloon filling gradually. In the compliant bladder
as it fills the pressure remains low, this decreased pressure is lower than the
typical urethral resistance. With normal urination urethral resistance
decreases and contraction of the detrusor empties the bladder. Detrusor
overactivity usually is associated with involuntary contractions of the
detrusor. Overactivity of the detrusor either from neuropathic causes can
result in urgency or urge incontinence depending on the response of the sphincter.
Overactive bladder may also have a myogenic origin. The prevailing theory for
many years has been that myogenic abnormalities are a primary cause of
overactive bladder. The treatment of these problems rests primarily around the
use of anticholinergics that target muscarinic receptors. It would seem
simplistic to think that there would be a primary myogenic problem that affects
the bladder without some form of myogenic processes that would be affecting
other smooth muscles. It would make more sense to implicate a process that
causes detrusor hyperplasia either due to neurologic causes or outlet
obstruction as the source of these myogenic problems. Eventual correction of
these problems should be the mainstay of treatment. This approach would
eventually treat the underlying problem and eradicate the symptoms instead of
just concentrating on the symptoms as we have for many years.
There are a variety of
efferent and afferent neural pathway reflexes, central, and peripheral
neurotransmitters that are involved in urinary storage and bladder emptying.
Their relationships as of yet are not completely understood. With the use of
functional MRl's (magnetic resonance imaging)and PET (positron emission
tomography) scans we are starting now to see and understand better the role
that these central neurotransmitters may play. Serotonergic activity
facilitates urine storage by enhancing the sympathetic reflex pathway
inhibiting the parasympathetic voiding pathway. Dopaminergic pathways may exert
both inhibitory and facilitory effects on voiding. Dopamine Dl receptors appear
to have a role in suppressing bladder activity whereas dopamine D2 receptors
appears to facilitate voiding. Other neurotransmitters such as a-Aminobutyric
acid and Enkephalin inhibit voiding in animals. acetylcholine which interacts
with muscarinic receptors at the detrusor is the predominant peripheral
neurotransmitter responsible for bladder contraction. Pathologic states can
alter sensitivity to muscarinic stimulation, for example bladder outflow
obstruction appears to enhance responses to acetylcholine similar to
denervation supersensitivity. Normally only a small proportion of bladder
contractions are resistant to atropine probably as a result of the interaction
of ATP with purinergic receptors, however ATP may play a more prominent role in
bladder contractions in patients with overactive bladder.[xxix]
(Figure !) Anatomical correlates of
detrusor overactivity have been described. Bladders of patients with detrusor
overactivity appear to have abnormal gap junction between smooth muscle cells.
Such further correlates need further studying. Increasing attention has been
paid to the lower sensory afferent nerves in normal voiding and overactive
bladder.25 During bladder filling
afferent activity of the bladder and urethra reaches the spinal cord
predominantly by the means of the pelvic nerve. Sensory input during bladder
filling results in an increase in the sympathetic tone. Norepinephrine (NA)
release from the hypogastric nerve stimulates Beta 3 adrenergic receptors in
the bladder to cause the smooth muscle to relax, as well as the alpha
adrenoreceptors in the smooth muscle of the bladder neck and proximal urethra
to contract. Acetylcholine released by somatic pudendal nerve and the sacral
nerve fibers elicits a contraction of the striated urethral sphincter and
pelvic floor. Glutamate is thought to be the primary descending
neurotransmitter for the storage reflex. Glutamate is released in the ventral
horn of the sacral spinal cord (Onuf’s nucleus). In Onuf’s nucleus axons projecting from
the CNS synapse with the pudendal nerve.
The release of glutamate activates the pudendal nerve and leads to
contraction of the rhabdosphincter. It
should be noted that Onuf’s nucleus is densely populated with 5-HT and NA
terminals and contains a high density of 5-HT and NA receptors. 5-HT and NA
play a modulatory role in that they enhance the
contraction of the rhabdosphincter but are not able to induce a contraction of
the rhabdosphincter on their own.[xxx]
(Figure 2a and 2b) Once micturition starts glutamate is no longer released and
pudendal nerve activity ceases. Myelinated A Delta sensory fibers
respond to passive distention and active contraction of the detrusor muscle.
Unmyelinated C sensory fibers have a higher mechanical threshold and respond to
a variety of neurotransmitters. C fibers are relatively inactive during normal
voiding but may have a critical role in symptoms of overactive bladder in
patients with neurologic and other disorders. Several types of receptors have
been identified in afferent nerves including vanilloid receptors which are
activated by capsaicin and possibly by endogenous anadamide; purinergic
receptors (P2X) which are
activated by ATP; Neurokinin receptors, which respond to substance P and
neurokinin A; receptors for nerve growth factor. Other substances including
nitric oxide, Calcitonin gene-related protein and brain derived neurotrophic
factor may also have an important role in modulating the sensory afferents in
the human detrusor. 25 Better understanding of the complex
interplay between these various neurotransmitters may yield new and more
specific targets for drug treatment for overactive bladder. A full discussion
of the role of all the neurotransmitters involved in the urination process is
beyond the scope of this review. An excellent review of these neurotransmitters
and their functions is available in an article by Yoshimura and Chancellor.[xxxi]
Neural Pathways
The micturition center in
the spinal cord is primarily located in three sacral spinal cord segments S2-4
with S3 being the most important. This is anatomically located at vertebral
levels T2 through L1. The grey matter in the spinal cord is divided into a
series of zones. The parasympathetic preganglionic motor neurons lie within an
intermediolateral grey column. The cells extend in a vertical plane along the
border between the white and grey matters and in a horizontal plane at the base
of the dorsal horn at lamina 7 and lamina 5 in the dog. The former serves as
the center for bladder control and the latter more medial gray matter of
parasympathetic cells serving as rectal control. Somatic nerve fibers originate
from the nucleus of Onuf in the mid ventral spinal grey matter. Innervations to
most striated muscles of the pelvic floor including those of the periurethral
and anal sphincters originate within the nucleus of Onuf. Activity travels up
the spinal cord via the spinothalamic tracts. Exteroceptive signals carried up
the spinothalamic tracts include sensations of pain, temperature and touch
generated in the urothelium. Proprioceptive sensory impulses initiated in the
bladder muscles and the periurethral striated muscle travel in the posterior
columns. Proprioceptive axons enter the dorsal portion of the grey matter
otherwise known as a periaqueductal gray area (PGA) and turn to travel
rostrally to synapse in the pontine mesencephalic reticular formation.
Exteroceptive sensory impulses travel in the spinothalamic tracts and synapse
in the thalamus and the sensorimotor cortex.[xxxii]
In humans, stimulation of
the hypogastric plexus originating from spinal levels T-10 through L-2 result
in relaxation of detrusor muscle and contraction of the intrinsic sphincter
thereby inhibiting micturition. Stimulation of passive sympathetic nerves
originating from spinal level S-2 through S-4 has an opposite effect. In
children, a common procedure that is performed to cause the urge to urinate to
cease, is the squeezing of the glans penis.[xxxiii] Clitoral compression can cause similar
effects in girls. Studies have shown that this causes cessation of intravesical
pressure on urodynamics during the filling phase. Pudendal nerve reflex has
been proposed as the mechanism of bladder inhibition with this maneuver.
Squatting on the heel in girls and what appears to be masturbatory behavior in
boys in girls could actually be a mechanism used by some children to suppress
bladder contractions. Pudendal nerve stimulation stimulates the sympathetic
system that suppresses bladder activity via the beta-adrenergic system with
spinal interneurons that release inhibitory neurotransmitters such as in enkephalin, glycerin and alpha aminobutyric acid.
There is a close
relationship between OAB and bowel problems.
It is possible that stretch receptors within the bladder wall can be
stimulated by the extrinsic fecal mass thereby triggering detrusor contractions
of various amplitudes thus sustaining a vicious cycle of continued
contractions. It is also possible that colonic contractions may be triggering
bladder contractions via shared neural pathways in the pelvis or spinal cord as
evidenced by the findings in patients with imperforate anus.[xxxiv] Recently, Pezzone et al. reported that
acute colitis triggers bladder hyperactivity in rats, providing experimental
evidence for crosstalk between different pelvic viscera. [xxxv]
[xxxvi] We noticed this in our patients
with colitis, when there is an acute flair up of the colitis there generally
will be an increase in voiding symptoms.
When the colitis is controlled the symptoms cease. Patients can exhibit dyssynergic voiding as
well as urgency/ frequency in these situations.
We have also found that many cases of young boys presenting with chronic
erections and girls complaining of chronic vaginal or perineal pain have been
corrected with a good bowel program.
These cross talk mechanisms support the findings noted in the
imperforate anus patients, in patients with colitis and even in normal children
who get a sudden urge to void associated with gaseous distention or a colonic
contraction that at times is imperceptible to them. This cross talk mechanism underscores the
importance of a bowel management program in the treatment of OAB.
The role of serotonin
(5-HT) and norepinephrine (NA) in the nervous system is far ranging. 5-HT predominates in the enteric nervous
system while NA predominates in the sympathetic autonomic nervous system. Neurons expressing 5-HT and NA are
concentrated in a few distinct nuclei in the brainstem (i.e. medulla and pons)
but these axons traverse large distances from the prefrontal cortex to the
caudal spinal cord. These neurons are
involved in the fight or flight reflex through facilitating motor activity and
inhibiting pain perception. They play a
major role in the regulation of mood, pain perception, attention, temperature,
gastrointestinal motility, sleep, sexual function and micturition process.26
These neurotransmitter pathways appear to be gaining increasing importance in
the management of voiding dysfunctions in both children and adults. Their ability to modulate critical functions
appears to be the central role that these pathways play. Most of the voiding dysfunctions that we see
appear to be a problem of poor modulation of reflexes that are an all or none
responses. It is not surprising that
agents that affect 5-HT and NA homeostasis have effects that are far ranging
from treatment of depression to LUTS, erectile and ejaculatory dysfunction.
It was initially thought that the sacral neuromodulation was mainly effective in the pelvic floor muscles by inducing muscle hypertrophy. The change in histochemical properties was supposed to lead to improved pelvic floor efficiency. Because neuromodulation takes place below the threshold for direct motor responses, this theory is not convincing. Today it is well accepted that the effects of sacral root modulation occur at the spinal and supraspinal level by the inhibition of spinal tract neurons involved in the micturition reflex and interneurons involved in spinal segmental reflexes in postganglionic neurons. Furthermore, there may be inhibition with primary afferent pathway and indirect suppression of guarding reflexes by turning off bladder input to internal sphincter sympathetic or external urethral sphincter interneurons. Also, in urinary retention we obtain effects believed by some groups to be the result of changed pelvic floor behavior directly or as part of a returning brain stem on/off switch mechanism.[xxxvii]
Functional MRI and PET
scanning studies indicate that bladder fullness is associated with increased
activity in the anterior midbrain.[xxxviii] [xxxix]
[xl]
[xli]
Signals from here were seen to travel to the substantia nigra. This is a
source of ascending dopaminergic neurons to the striatum which is reciprocally
connected to the brainstem micturition centers. Anterior midbrain was also seen
connecting to the pons and medulla (micturition center) with increased
activity. A third site of increased activity was noted in the cortical centers,
primarily in the anterior and posterior cingulate gyrus. The anterior gyrus is
associated with executive activity while the posterior gyrus is associated with
evaluative activities. An example of a typical evaluative activity would be the
decision that is made to empty the bladder even though it is not completely
full. This cognitive functioning would prevent a sudden urge to have to go to
the bathroom. Patients who have increased activity in the micturition centers
and midbrain with urgency typically do not have increased activity in the
cortical centers primarily the cingulate gyrus. In a group of patients who had
urge syndrome with spinal stimulators once the stimulators were turned on an
increase in activity in the cingulate gyrus areas was noted. The cingulate gyrus
is associated with contextual representations or better known as behavior
control. Inability to activate this cingulate gyrus and suppress autonomic
activities leads to hyperreflexia.
Inactivity in the
cingulate gyrus may be a good explanation for overactive bladder seen in familial settings. This decreased
activity in the cingulate gyrus and frontal lobes may also explain the high
association of voiding dysfunction in patients with behavioral, learning and
psychiatric disorders. Disorders such Asperger's syndrome, Tourrette's
syndrome, bipolar disease, depression, obsessive compulsive disorder, panic
disorders, anxiety disorders, ADD and ADHD all are associated with decreased
activity in the frontal lobes.[xlii]
It is well known that there is an increased incidence of urinary incontinence
in children who have ADD/ADHD.[xliii]
[xliv]
lt is also recognized that in children who have
problems with incontinence the incidence of behavioral and psychiatric
disorders is three times greater than in the general population.[xlv] [xlvi]
[xlvii]An
association exists between increased urinary incontinence and obesity[xlviii]. There is also an increased association with
stool incontinence and constipation in patients with obesity. [xlix]
Recent studies indicate that there is an increased incidence of obsessive-compulsive
behavior in chronically obese male and female patients, as well as increased
incidence of depression in chronically obese males.[l]
This association between obesity incontinence and constipation may all be
linked to a possible problem with disinhibition in the frontal lobe that can
explain all three phenomena.
Drug therapy of OAB
Many
classes of drugs have been studied or proposed for the treatment of symptoms of
overactive bladder in adults but only 2 antimuscarinics have formally achieved approval
for use in children. Several pitfalls limit the quality of clinical studies,
heterogeneity of the patients and there symptoms and the fact that many
patients can have more than one confounding problem. The clinical trials
performed in children have generally utilized patients with neurogenic voiding
problems and have not concentrated on the non neurogenic patients. All
anticholinergic drugs can have bothersome side effects. Although dry mouth is
the most common, constipation, gastroesophageal reflux, blurry vision, urinary
retention, and cognitive side effects can also occur these symptoms are
generally less bothersome in children. The potential for adverse cognitive
effects and delirium due to antimuscarinic drugs can occur in children it is
generally limited to overdosing situations. In adult trials quantitative
electroencephalographic data suggest that oxybutynin has more central nervous
system effects than trospium or tolterodine. [li]
Long-acting anticholinergic agents and newer, more selective antimuscarinic
agents should be tested for clinically important cognitive side effects.
Oxybutynin is a nonselective antimuscarinic agent that relaxes bladder muscles
and has local anesthetic activity. Recent data suggests that antimuscarinics
may be functioning more at the sensory
limb of the reflex arc in neurologically intact patients than at the motor
side.[lii] It is available in immediate and
extended-release forms, as well as in a transdermal patch. Immediate-release
oxybutynin appears to be efficacious for the treatment of neurogenic and
non-neurogenic overactivity of the detrusor muscle with urge incontinence. The
efficacy of immediate-release oxybutynin has been limited by antimuscarinic
side effects; dry mouth, of the parent drug and its active metabolite (N-desethyloxybutynin)
Generic immediate-release oxybutynin is relatively inexpensive and may be
useful for patients whose symptoms are best managed by a short-acting drug
(e.g., symptoms that are bothersome only when the patient is away from home or
at night). A once-daily controlled-release formulation of oxybutynin appears to
have the same beneficial effects as immediate-release oxybutynin, with fewer
side effects — a benefit ascribed to the more constant levels of the
parent drug and, possibly, a lower rate of conversion to the active metabolite
in the stomach and small intestine.[liii]
A transdermal oxybutynin patch is also available that is as efficacious as
immediate release oxybutynin but with half the incidence of dry mouth. [liv],[lv]
In one placebo-controlled trial, the patch caused local skin erythema in more
than half the subjects (3 percent of cases were severe) and was associated with
pruritus in up to 17 percent. 50 Oxybutynin has been instilled
intravesicularly through a catheter to treat severe overactivity of the
detrusor muscle in patients with neurogenic bladders with minimal side effects
but it’s use is of limited value in children with non neurogenic
problems.
Tolterodine
is a muscarinic antagonist that is available in short-acting (twice-daily) and
long-acting (once-daily) preparations. Side effects are similar to those of
short-acting oxybutynin, with dry mouth in 20 to 25 percent of patients, and
the rates of discontinuation due to side effects are similar to those for
placebo (5 to 6 percent). Randomized, controlled trials indicate that propiverine and trospium are effective for the treatment of
urge incontinence and have fewer side effects than short-acting oxybutynin.[lvi] [lvii]
[lviii]
[lix] Tropsium is currently available in the
We
have found Imipramine, a tricyclic antidepressant
with both anticholinergic and alpha adrenergic effects and, possibly, a central
effect on voiding reflexes to be effective in controlling urge incontinence in
some children who were refractory to antimuscarinic therapy. Imipramine can
cause postural hypotension and cardiac-conduction abnormalities and thus must
be used carefully. Amitriptyline another tricyclic
has been used more frequently for the management of interstitial cystitis and
OAB in adults and it’s use in children is limited. SSRI’s and SNRI’s have been
useful in older patients with OAB especially when there is evidence of anxiety
disorders of clinical significance. We
have found that management of the anxiety problems at the central level or in
combination with antimuscarinics is more effective than with antimuscarinics
along.
Alpha
blockers are playing a larger role in the management of OAB in our practice
over time. Aside from the role that they play in the management of bladder neck
dysfunction and urinary retention we have found them to be useful in
ameliorating the symptoms of urgency and urge incontinence in some
children. In many cases terazosin is our
first line drug for urgency and frequency due to its non selective properties
and the potential to cross the blood brain barrier. More selective alpha
blockers such as tamusolin and alfuzosin are better suited for management of bladder neck
dysfunction that can lead to detrusor hypertrophy and instability. Because non selective alpha blockers can
cause postural hypotension, they require a gradual titration of the dose and
must be used carefully. In patients
where there is a family history of easily fainting or postural hypotension dose
titration is essential even with the selective alpha blockers. For the most part children tolerate alpha
blockade well and we have used terazosin in children as young as 2 years old
for bladder neck dysfunction associated with high grade vesicoureteral reflux.
Further research is needed to determine the optimal use of alpha-blockers and
anticholinergic drugs — alone, together, or combined with behavioral
therapy — as a treatment for overactive bladder. Although currently
available beta-agonists have not been shown to be useful for overactive
bladder, more selective b3-agonists may have therapeutic value.
Drugs
that act by means of potassium-channel transporters to hyperpolarize smooth
muscle and decrease spontaneous bladder contractions may be useful for
suppressing involuntary bladder contractions without interfering with normal
voiding.[lx]
However, first-generation agents in this class have had effects on vascular
smooth muscle and can cause hypotension.
Drugs that act on sensory
afferent pathways are also being developed and hold promise when used either
alone or in combination with other drugs. Vanilloids
such as capsaicin and resiniferatoxin activate nociceptive sensory nerve fibers through an ion channel,
known as vanilloid receptor subtype. This receptor is a nonselective cation channel that is activated by heat and protons,
suggesting that it functions as a transducer of painful thermal stimuli and
acidity in vivo. Vanilloid receptors are located predominantly on C-fiber
bladder afferents and activating the receptors initially excites and
subsequently desensitizes C-fibers. 27 Resiniferatoxin
appears to be more potent and less irritating than capsaicin and may be more
useful clinically. Other drugs that block receptors on sensory afferents, such
as neurokinin-receptor antagonists might not cause urinary retention, which can
occur with antimuscarinic agents.
The
role of phosphodiesterase inhibitors in OAB is something that needs further
exploration and only time will tell if it may also play a useful role. [lxi]
[lxii]
Botulinum A toxin
Botulinum A toxin is the
most potent biological toxin known. The toxin acts at the neuromuscular
junction at the external sphincter to block vesicle transport of acetylcholine
in essence producing chemical denervation. Clinical effects begin within 5-7
days and are reversible because of terminal resprouting occurs within six
months. The clinical success of Botulinum A toxin is supported by laboratory
research showing marked decreases in the release of labeled norepinephrine and
acetylcholine in Botulinum A toxin injected rat bladders and urethras. While
therapeutic effects of inhibiting acetylcholine release is obvious, blocking
norepinephrine release may provide clinical benefit by inhibiting sympathetic
transmission in smooth muscle dyssynergia. This is why some of the patients who
we have treated who have combined internal and external dyssynergia have
responded well to Botulinum A toxin injections. [lxiii]
Botulinum A toxin has also
been used to inject the bladder to reduce detrusor hyperactivity. Studies in
adult spinal cord injury patients and children with spina bifida have indicated
success with multiple injections occurring throughout the floor of the bladder.
Botulinum A toxin injections of the detrusor have been performed for
nonneurogenic OAB in symptomatic adults with some success. One of the drawbacks of this treatment is the
need for retreatment since the probable underlying cause is not in the bladder but elsewhere. Hoebeke et al [lxiv]
published their experience in 15 children indicating that durable (greater than
12 months relief of symptoms could be achieved in over 50% of the patients with
a single injection. Only 3 patients did not respond while patients that had
partial responses appeared to respond to a second injection. These findings are encouraging and could help
further the treatment of OAB in children where the etiology is not due to
sphincter dyssynergia.
On the other hand the use of
Botulinum A toxin injections for sphincter dyssynergia could possibly be very
beneficial in that elimination of the dyssynergic voiding pattern could
possibly help eliminate detrusor hypertrophy that is commonly associated with
detrusor overactivity. Botulinum A toxin
injection produces a reversible chemical sphincterotomy which avoids a major
surgical procedure with its attendant risks. Botulinum A toxin has been used to
treat spinal cord injury patients with detrusor sphincter dyssynergia in adults
and children with spina bifida. It’s use to treat nonneurogenic DSD has
been described by Steinhardt [lxv]
in a neurologically normal child in 1997 and by Maizels
et al [lxvi]
in a series of 20 females with “lazy bladder” and external
sphincter spasticity who were treated with Botulinum A toxin on a prospective
basis. Even though this study appears to
have been flawed for many reasons it further strengthened the foundation for the
use of Botulinum A toxin injections in neurologically normal children. More recently a larger series of 20
patients presented by Radojicic et al[lxvii]
indicates that the treatment of detrusor sphincter dyssynergia is clearly
helped by the use of Botulinum A toxin injections in neurologically normal
children. We have had exceptionally
good results in children in whom we used Botulinum A toxin to treat external
sphincter dyssynergia of non neurogenic origin. [lxviii]
We injected 12 patients with Botulinum A toxin with 300 units in and around the
external sphincter, all 12 patients responded well to the injections with no
adverse effects. Only one patient had to be reinjected more then once. One
patient was on intermittent catheterization unable to empty her bladder,
leaving a post void residual of 250 cc at a time. This child is completely dry,
has no accidents and voids to completion a year and a half post injection.
Another child had been offered augmentation cystoplasty to manage his
intractable wetting and severe DSD
leading to chronic epididymitis.
In the limited studies that we have available to date Botulinum A toxin
represents a viable option for treating detrusor sphincter dyssynergia. Correction of the DSD has led to resolution
of the associated OAB symptoms.
BIOFEEDBACK
THERAPY
Biofeedback therapy has
been used in urology for many years. The use of Kegel exercises was introduced
to help patients with stress urinary incontinence. Subsequently in the mid 90's
biofeedback was introduced for managing children who had chronic wetting
problems as well as an inability to empty the bladder completely. We started
performing biofeedback therapy in 1997 and our program has been extremely
successful.[lxix]
Many children who failed the initial treatment with management of their
constipation and exhibited signs of external sphincter dyssynergia would
undergo biofeedback therapy. A uroflow study with concomitant abdominal and
perineal EMG would be performed. This study would then indicate the presence of
external sphincter dyssynergia by increased activity in the perineal sphincter
EMG probe. If there was no increase in activity in the perineal sphincter probe
and there was abdominal straining then the presence of internal sphincter
dyssynergia would be suggested by the study. If there was internal and external
sphincter dyssynergia present, treatment would consist of the use of
Alpha-blockers as well as biofeedback. Each session lasts approximately 45
minutes with a trained nurse performing the biofeedback therapy. Initial
biofeedback therapy included the simple relaxation and contraction exercises
while the patient monitored oscilloscopic activity of the perineum. The
technology has evolved such that we now use a computerized system with a game
like interactive setting where the child attempts to move an icon of their
choice i.e. dolphin, car or bird within the predetermined ranges that have been
set. This has facilitated the training process and lowered the age that
children can be treated. Preliminary data from our use of this program
indicates a reduction in the number of biofeedback sessions required for
children to master pelvic floor relaxation. Biofeedback therapy is limited by
the ability of the child to cooperate with the healthcare provider running the
session. Children younger than five years of age typically are incapable of
doing biofeedback on a regular basis. Occasionally some children younger than
five can be taught to relax their pelvic floor muscles appropriately with
biofeedback. Children with significant learning disabilities, behavior problems
and other neurologic problems are not candidates for biofeedback. Biofeedback
therapy is useful in the management of overactive bladder primarily by reducing
the outlet resistance during voiding which leads to detrusor hypertrophy
thereby leading to detrusor instability.
Urethral
Overdistention.
Management of overactive
bladder and bladder instability by the use of urethral dilation is something
that has been going on for many years in adult urologic practices. Numerous
women with urethral syndrome had their urethras dilated monthly for years on
end. Many of these women have classic symptoms of overactive bladder, pelvic
discomfort and dysuria. This mechanism of overdilation probably works in a very
similar fashion to the use of Botulinum A toxin at the level of the external
sphincter. This temporary sphincterotomy occurs either by overdistention and or
tearing of the sphincter muscles. Central neural processes may lead to
resetting of receptors in the spinal cord and possibly in the brain which may
lead to decreased activity of the sphincter. This decrease in sphincter
activity will lead to improved bladder emptying due to reduced outlet
resistance thereby allowing the detrusor muscle in the bladder to not work as
hard. This decrease in detrusor activity will in turn be translated to possible
reduction in overactivity at the bladder level.
Spinal cord
simulation
Spinal cord stimulation is
something that has been used with increasing regularity in adult patients.
Selective stimulation of the sacral nerves and the pudendal nerves has led to a
significant improvement in overactive bladder
in patients who have had stimulators implanted. The role of spinal
stimulation in children is yet to be well defined. Only one study by Reinberg et al indicates some usefulness in children with
voiding dysfunctions. [lxx]
Peripheral Nerve Stimulation.
Electrical tibial nerve
stimulation (PTNS) is based on the traditional Chinese practice of using
acupuncture points over the common peroneal posterior tibial nerves to inhibit
bladder activity.[lxxi]
Transcutaneous posterior tibial nerve stimulation has been evaluated in
clinical trials with variable results. The technique involved using a 34-gauge
stainless steel needle, which is inserted approximately 5 cm cephalad to the
medial malleolus just posterior to the margin of the tibia. A stick-on
electrode is placed on the medial surface of the calcaneus. More substantial
data is necessary, but present reports in adults indicate it is beneficial.
Limited reports of its use in children have indicated efficacy as well. In one
study by Hoebeke et al., [lxxii] they showed that 17 out of 28
children who had been refractory to medical treatment had a resolution or
improvement in their symptoms. In 16 out of 19 patients who had abnormal
frequency, showed marked improvement. An overall for the group, mean bladder
capacity increased significantly. This study indicates a role for an
improvement in overactive bladder in
children with peripheral nerve stimulation. The exact mechanism for this
modality is unclear. What we can extrapolate from the recent findings with the
sacral modulation is that PTNS may function in a similar fashion to sacral
modulation having an effect on the brain.
Prepared by Dr I Franco.
