Overactive Bladder in Children

The symptoms of OAB are believed to be caused by detrusor overactivity during the filling phase, which causes urgency (see the image below).[2] These detrusor contractions are countered by voluntary contraction of the pelvic floor muscles in an attempt to postpone voiding and to minimize wetting. The voiding phase is essentially normal but may be associated with a powerful detrusor contraction during voiding. Childhood incontinence in girls has been noted to be a risk factor for urge symptoms and severe incontinence in adult women.[3]

The natural history of OAB is not well understood. Many believe that idiopathic OAB in children is the result of a maturation delay and that it resolves over time. This belief is in contrast to the theory behind OAB in adults, in whom the condition is believed to be chronic.

In children, OAB may arise from various etiologies, including neurogenic, anatomic, inflammatory, and idiopathic causes. Neurogenic etiologies include myelomeningocele, cerebral palsy, spinal cord injury, sacral agenesis, and imperforate anus. Twenty-two percent of children with a lumbosacral myelomeningocele have uninhibited bladder contractions.[4] In children with cerebral palsy, an unstable bladder is the most common urologic anomaly.

The most common anatomic abnormality associated with OAB is posterior urethral valves; 24% of males with this condition have OAB.[5] Inflammatory processes in the bladder wall (eg, urinary tract infections [UTIs]) may irritate receptors in the submucosa and detrusor muscle layers and may lead to OAB symptoms. Idiopathic OAB is thought to be secondary to delayed maturation of the reticulospinal pathways and inhibitory centers in the midbrain and cerebral cortex.

In a prospective multicenter study performed in 16 Korean medical school hospitals in 2006, the risk factors for OAB were evaluated. Enuresis, constipation, fecal incontinence, urinary tract infection, and delayed toilet training were considered risk factors associated with OAB.[6]

The prevalence of OAB in children is difficult to determine. To date, studies have focused primarily on daytime versus nighttime incontinence and have not attempted to differentiate the type of daytime incontinence. The prevalence of daytime urinary incontinence in children has been estimated to range from 10–17%.[7]

In a population survey of 1,192 individuals aged 1.5 to 27 years, diurnal accidents occurred in 13% of children aged 4 years, 7% of children aged 5 years, 10% of children aged 6 years, and 5% of children aged 7 years.[8]

Studies performed outside the United States have demonstrated that 2-4% of 7-year-old children have daytime or combined daytime and nighttime incontinence at least once per week and that it is more common in girls than in boys.[9]

In a population-based study of children aged 4-6 years in Australia, 19.2% had at least 1 daytime wetting episode in the preceding 6 months, with 16.5% having experienced more than 1 wetting episode and only 0.7% experiencing wetting on a daily basis.[10] Up to 50.7% of children with daytime wetting have been noted to have urgency, with 79% wetting themselves at least once in a 10-day period.[11]

Urge symptoms seem to peak in children aged 6-9 years and to diminish as they approach puberty, with an assumed spontaneous resolution rate for daytime wetting of 14% per year.[12, 13]

Hellstrom et al, assessing the prevalence of urinary incontinence in 7-year-old Swedish children, found that diurnal incontinence was more common in girls (6.7%) than in boys (3.8%).[14] Wetting every week was reported in 3.1% of girls and in 2.1% of boys. Most children with diurnal incontinence had other symptoms. Urgency was reported in 4.7% of girls and in 1.3% of boys.

The natural history of OAB in children is unknown. Similarly, data on the optimal duration of therapy limited are limited. OAB in children is not believed to be a chronic condition; however, little long-term information is available.

Curran et al, in a study of the long-term results of conservative treatment in children with idiopathic detrusor overactivity, reported that the average time to resolution of symptoms was 2.7 years. The authors noted that children with very small or large bladders were less likely to benefit from conservative management. Age and gender were not significant predictors of resolution, although symptom resolution was more likely in girls than in boys.[15]

Some of the consequences of OAB result from the child’s voluntary attempts to maintain continence during the involuntary detrusor contractions. These coping mechanisms, including forceful contractions of the external sphincter and squatting maneuvers to produce perineal compression, may lead to functional and morphologic changes in the bladder, which can increase the child’s risk of urinary tract infections (UTIs) and vesicoureteral reflux.

Frequent voluntary contractions of the pelvic floor muscles may also lead to postponement of defecation. Constipation and fecal soiling are often identified in children with OAB. Greater than 50% of children with lower urinary tract symptoms evaluated in a tertiary referral center fulfilled diagnostic criteria for functional defecation disorders.[16]

In addition, symptoms of pediatric OAB and urinary incontinence may lead to embarrassment in the child. The child may be inappropriately labeled as having a psychological problem. Children with OAB may refrain from social activities, in fear of wetting and of letting others know how frequently they void. Difficulties may develop between the child and the child’s peers, parents, or both.

Patient education is an important aid to management. Both the patients and their parents or caregivers must be educated on normal bladder and sphincter function.

The clinical presentation of overactive bladder (OAB) in children is similar to that in adults. The clinical features include urgency, urinary frequency, urinary urge incontinence, and nocturia or nocturnal enuresis. Many of the signs and symptoms of OAB are due to faulty perceptions of bladder signals and habitual nonphysiologic responses to these signals.[17]

A careful voiding and bowel history, as well as a review of fluid intake (including type of fluid), is important to note. In girls, voiding habits should be reviewed to ensure proper positioning during voiding to eliminate vaginal reflux voiding as a source of incontinence.

Children often exhibit various behaviors to prevent urinary leakage, including squatting behaviors and the Vincent curtsy sign.

Physical examination findings are usually normal in children who have idiopathic OAB. Some children with urinary incontinence have perineal excoriation.

A focused neurologic examination should be performed to rule out an underlying neurologic etiology. The examination includes an assessment of the following:

• Perineal sensation
• Perineal reflexes supplied by sacral segments S1-S4 (standing on toes, bulbocavernosus reflex)
• Anal sphincter tone
• Possible signs of occult lumbosacral neurospinal dysraphisms in the buttocks, legs, and feet 

The position and caliber of the urethral meatus should be inspected. The abdominal examination should include assessment for a distended bladder and a full sigmoid/descending colon (suggestive of constipation). The sacrum should be palpated to ensure that it is present and the presacral area inspected for dimples, abnormal gluteal clefts, hairy patches, and other signs of possible neurologic lesions.

Noninvasive diagnostic techniques are often used in the diagnostic evaluation of overactive bladder (OAB). Invasive testing is performed for selected indications, including the following:

• Straining or use of the Credé maneuver during voiding
• Weak or decreased urine stream
• Previous febrile urinary tract infection (UTI)
• Continuous dribbling incontinence
• Stress incontinence
• Prior history of vesicoureteral reflux
• Structural abnormalities on physical examination suggestive of an underlying neurologic etiology
• Suspected obstruction

Assessment of bowel function

Bowel habits should be evaluated in all children presenting with overactive bladder symptoms. The Rome III diagnostic criteria are often used to evaluate for constipation, but it is subjective and often relies on parent/guardian description of the child's stools.[19] Other commonly used methods are the Bristol stool form scale[20] and the Leech method to assess the level of stools within the intestine by plain radiography.[21, 22]

All children who present with OAB symptoms should undergo urinalysis. The primary aim is to rule out underlying UTI or glucosuria.

Ultrasonography of the kidneys and bladder is useful in assessing renal size, cortical thickness, hydronephrosis, and duplicated collecting systems and associated anomalies (ectopic ureters and ureteroceles). Ultrasonography of the bladder may be obtained before and after voiding to assess bladder emptying.

In addition, determination of bladder-wall thickness may be useful.[23, 24] A bladder wall cross-section of more than 3-4 mm measured at 50% of expected bladder capacity suggests underlying detrusor overactivity.

Magnetic resonance imaging (MRI) may be useful in some circumstances. MRI of the lumbosacral spine should be considered in children with neurologic abnormalities or a sacral dimple or other presacral abnormality.

Voiding cystourethrography (VCUG) is indicated in children with a history of a febrile UTI or recurrent UTIs, depending on age, to rule out vesicoureteral reflux. It may also be indicated in a child with an abnormal flow pattern to rule out bladder outlet obstruction (eg, from posterior urethral valves, stricture, or syringocele).

A spinning-top dilated proximal urethra revealed by VCUG during the voiding phase suggests detrusor-sphincter dysfunction.

A frequency/volume chart or bladder diary is helpful in the evaluation of pediatric OAB symptoms. Ideally, these charts should encompass a 3-day period. This will allow assessment of the child’s functional bladder capacity.

A frequency/volume chart is used to record the volumes voided and the time of each micturition, day and night, for at least 24 hours. A bladder diary is used to record the times of micturitions and voided volumes, incontinence episodes, pad usage, and other such information as fluid intake, the degree of urgency, and the degree of incontinence. A record of the bowel frequency and any fecal soiling is also helpful.

A uroflow study is also helpful in the assessment of OAB symptoms and is performed by having the child void into a specialized collection device. The uroflow study can be described in terms of flow rate (mL/sec) and flow pattern. The flow pattern may be continuous, intermittent (interrupted), or staccato (flow does not completely stop but fluctuates because of incomplete relaxation of the sphincter).

Obtain several uroflow studies to achieve consistency. Ninety-nine percent of school children have a bell-shaped flow curve, whereas the remaining 1% have an abnormal flow curve. Such abnormal flow curves include flattened or intermittent flow curves.

For a urinary flow rate to be useful, the voided volume should be at least 50% of the child’s functional bladder capacity. Before the study is initiated, a bladder scan may be helpful in determining the bladder volume.

Uroflow/electromyography study

A uroflow/electromyography (EMG) study involves the placement of perineal electrodes (often patch electrodes) and measurement of EMG activity before, during, and after voiding. Normally, sphincteric activity occurs during bladder filling but silences during voiding. Failure of relaxation or increased sphincteric activity during voiding may suggest a neurologic abnormality or dysfunctional voiding.

Postvoid residual volume determination is useful in ruling out dysfunctional voiding as a source of symptoms. In children, except in small infants, the bladder completely empties during each micturition.

An increased postvoid residual volume may be secondary to dysfunctional voiding. If the postvoid residual volume is initially increased, the study should be repeated because the results may not be accurate in an anxious child.

A urodynamic study is an invasive study that should be obtained only in select children with voiding dysfunction. Before this study is performed, the child and parents should be fully aware of what the study entails. If the child is very anxious during the study, the results may be affected, especially during the filling cycle (detrusor overactivity may be noted) or during voiding (incomplete pelvic floor muscle relaxation may be noted).

The urodynamic study has several components. The child is first asked to void just before the study is begun. A sterile urodynamic catheter is then placed via the urethra into the bladder, and the postvoid residual volume is recorded.

Cystometrography

Cystometrography (CMG), also known as filling cystometry, is the component of the urodynamic study that is used to assess the bladder during filling. CMG provides information on the pressure/volume relationship of the bladder during bladder filling.

The bladder should be filled with body-temperature 0.9% sterile saline at a rate of 5-10% of the child’s expected bladder capacity per minute to a maximum rate of 10 mL/min. Contrast material may also be used if fluoroscopic imaging is planned. The bladder capacity is measured during filling cystometry. The cystometric bladder capacity is the bladder volume at the end of the filling CMG, when the child is given permission to void.

The cystometric capacity is the volume voided together with any residual volume. The maximum cystometric capacity in patients with normal sensation is the bladder volume at which the patient feels that he or she can no longer delay voiding (strong desire to void).

The term bladder compliance refers to the relationship between the change in bladder volume and the change in detrusor pressure.

The International Continence Society recommends using the following 2 standard points for compliance calculations[1] :

1. The detrusor pressure at the start of bladder filling and the corresponding bladder volume (usually zero)
2. The detrusor pressure (and corresponding bladder volume) at cystometric capacity or immediately before the start of any detrusor contraction that causes significant leakage

Detrusor overactivity is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked (see in the image below).

Phasic detrusor overactivity is defined by a characteristic wave form and may not lead to urinary incontinence. Terminal detrusor overactivity is a single involuntary detrusor contraction occurring at cystometric capacity. It cannot be suppressed and results in incontinence, usually resulting in bladder emptying (voiding). Detrusor overactivity incontinence due to an involuntary detrusor contraction at any point during filling.

Pressure-flow studies

Pressure-flow studies may be obtained during the voiding phase of the urodynamic study. The pressure-flow study involves the plotting of the bladder pressure against the flow rate. This study may be useful when urinary obstruction is suspected.

Videourodynamic studies

Videourodynamic studies are urodynamic studies performed with fluoroscopic assistance. The addition of fluoroscopy allows for the detection of vesicoureteral reflux, a spinning-top urethra (often seen in girls with dysfunctional voiding), and other anatomic abnormalities.

Initial management of overactive bladder (OAB) involves a behavioral and cognitive approach. The child and caregiver must be educated on normal bladder and sphincter function. Dietary changes are helpful in some children, particularly those who drink caffeinated or acidic fluids and those with increased fluid intake.

Pharmacologic treatment is initiated if behavioral therapy fails or symptoms are severe. Surgical treatment may be considered if behavioral therapy and pharmacologic therapy fail.

As with adults, older children often institute various coping strategies, including defensive voiding, toilet mapping, and restriction of fluid intake. Thus, the management of OAB must consider not only the detrusor overactivity but also the responses to it.[25] The volume and types of fluids should be assessed and modifications made to encourage normal fluid intake as well as avoidance of potential bladder irritants and diuretics such as caffeine.

Constipation, if present, must be treated. Studies demonstrate improvement in OAB symptoms simply by treating constipation, if present, even without OAB therapy.[26, 27]

Urinary tract infections (UTIs) should be treated and, depending on the child’s age and whether the UTIs have been febrile or nonfebrile, investigated further with renal ultrasonography and voiding cystourethrography (VCUG). In children with recurrent UTIs, antibiotic prophylaxis may be helpful in decreasing the number of infections while voiding and bowel habits are being managed. Nitrofurantoin or trimethoprim-sulfamethoxazole, at one third to one half of the normal treatment dose administered once per day, is the typical choice for prophylaxis.

Voiding regimens are instituted in all children with OAB. Voiding is recommended every 2-3 hours while the child is awake. This often requires assistance from teachers to ensure that the child is complying with a voiding regimen at school.

In children who do not empty their bladder completely (increased postvoid residual volume), the practitioner should institute a double voiding regimen, whereby the child voids and then waits a minute or two and tries to void again, to improve bladder emptying.

Biofeedback-assisted therapy

In children who fail to improve with such voiding regimens, biofeedback-assisted therapy and pharmacologic therapy are the next treatment options.

Biofeedback is a technique in which physiologic activity is monitored, amplified, and conveyed to the patient as a visual or acoustic signal, providing the patient information about unconscious physiologic processes. It has been used for both filling-phase (detrusor overactivity) and voiding-phase (voiding dysfunction) abnormalities.

Biofeedback can help children identify and suppress involuntary detrusor contractions, as well as identify and relax their pelvic floor muscles. The limitation of biofeedback in the management of detrusor overactivity is the need for the placement of a catheter and the potential need for multiple sessions.

In children with associated pelvic floor dysfunction, biofeedback may be performed via the use of a uroflow with electromyography (EMG). The EMG activity can be identified on the monitor and followed as the child first locates and then learns to relax his or her pelvic floor muscles.

Few studies have evaluated urodynamic-based biofeedback in children with detrusor overactivity. The small numbers of patients and the variability in study design limit the value in drawing conclusions.

Kjolseth et al performed cystometrography-assisted biofeedback in 15 children aged 6-12 years with idiopathic detrusor overactivity. The children received 1-2 inpatient sessions, and follow-up sessions were determined by the severity of the child’s symptoms and the ease of learning for the child. A pronounced improvement was noted in 60% of children, and some improvement was noted in 13% of them. The children were monitored for up to 2 years after the end of therapy, and, in all children but one, the beneficial effects were maintained.[28]

If behavioral therapy fails or the child has severe symptoms, pharmacologic therapy is instituted. Although pharmacologic therapy is one of the mainstays in the treatment of adult OAB and the management of neurogenic detrusor overactivity, its role in the treatment of idiopathic OAB in children is less well defined.

Anticholinergics

The use of anticholinergic therapy in the management of OAB is predicated on the concept that parasympathetic-mediated stimulation of muscarinic receptors (M3 primarily) in the bladder leads to detrusor overactivity. Anticholinergic/antimuscarinic agents have been demonstrated to increase bladder capacity, to improve bladder compliance, and to decrease uninhibited detrusor contractions.

Anticholinergic agents are often used in children with OAB when behavioral therapy has failed or as an adjunct to behavioral therapy. Despite the frequent use of anticholinergic agents in children with OAB, few randomized studies have assessed the safety and efficacy of these drugs in this setting.

Oxybutynin

Currently, the most commonly used anticholinergic for the treatment of OAB in children is extended-release oxybutynin (Ditropan XL). This agent is a once-a-day formulation that is approved for use in children who can swallow a pill and who meet the drug’s age requirements.[29]

Historically, oxybutynin use has been limited by side effects, most notably dry mouth and constipation. In addition, the need for dosing 2 or 3 times daily may affect compliance. The extended-release preparation decreases such side effects. The risk of side effects appears to be dose-related. Both oral oxybutynin and intravesical oxybutynin may have side effects involving the central nervous system (CNS) and cognitive function.[30, 31]  However, such reports have not been documented with extended-release oxybutynin.

Extended-release oxybutynin is delivered via the osmotic release oral system (OROS). The tablet cannot be crushed, cracked, or chewed and must be swallowed whole. Oxybutynin is metabolized by the cytochrome P-450 (CYP-450) enzyme systems, particularly the CYP3A in the liver and gut wall. The pharmacokinetics of extended-release oxybutynin were evaluated in 19 children aged 5-15 years with neuropathic detrusor overactivity and were found to be consistent with those reported for adults.

The contraindications to the use of extended-release oxybutynin in children are the same as those in the adult population (ie, urinary retention, severe decreased gastrointestinal motility conditions, uncontrolled narrow angle glaucoma). Caution should be used in treating patients with severe hepatic impairment and those on potent CYP3A4 inhibitors.

A 24-week open-label trial that studied the safety and efficacy of extended-release oxybutynin in 60 children aged 6-15 years with neuropathic detrusor overactivity demonstrated that this agent, in doses ranging from 5 to 20 mg, yielded an increase from baseline in mean urine volume per catheterization and an increase from baseline in the mean percentage of catheterizations without a leaking episode.48 Urodynamic results were found to be consistent with clinical results.

The recommended initial starting dose of extended-release oxybutynin in children aged 6 years or older is 5 mg/d. The dosage may be increased in 5-mg increments up to a maximum of 20 mg/d to achieve a balance of efficacy and tolerability.

Adverse effects of extended-release oxybutynin are those commonly encountered with anticholinergic agents, including dry mouth, constipation, facial flushing, central nervous system effects (headache, dizziness, somnolence), and blurred vision. The incidence of side effects with extended-release oxybutynin is significantly lower than with other oxybutynin formulations, particularly with respect to dry mouth and constipation.

Tolterodine

Tolterodine (Detrol), a nonselective antimuscarinic agent with a favorable tolerability profile compared with that of oxybutynin, has been studied in children. Tolterodine is metabolized in the liver, and the active metabolite has a therapeutic effect that is similar to that of oxybutynin. Because tolterodine is metabolized by the liver, care should be taken with agents that affect CYP2d6 and CYP3A4 activity, and practitioners should adjust dosage in patients with severe liver disease. Tolterodine is contraindicated in patients with urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, or documented hypersensitivity to the drug or its ingredients.

Safety and efficacy studies performed in European children on oral tolterodine doses ranging from 0.5 to 2.0 mg twice daily for 14 days demonstrated a 21% mean decrease from baseline in micturition frequency and a 44% mean decrease from baseline in the number of incontinence episodes among children who received the 1-mg dose.[32]

The efficacy of tolterodine in children has not been determined. The results of 2 pediatric phase III, placebo-controlled, double-blind, 12-week studies demonstrated aggressive, abnormal, and hyperactive behavior and attention disorder in 2.9% of children treated with Detrol LA compared with 0.9% treated with placebo. The most common adverse events were dry mouth, constipation, headache, vertigo/dizziness, and abdominal pain. Patients also reported abnormal vision (accommodation abnormalities), an expected side effect of an antimuscarinic agent.

Imipramine

Imipramine has been studied for the treatment of refractory daytime incontinence in children. One hundred and three patients (55 males and 48 females) were included in the study. Of those children with complete follow-up (n = 83), 44 (53%) experienced complete treatment response. Side effects were reported by 11 out of 83 (13.3%) patients. A side effects were nearly twice as common (26.1%) among the 23 children with a partial response to treatment.[33]

Trospium chloride

Trospium chloride (Sanctura), another agent used in adults, has been studied in a small series of children, with dosages ranging from 10 to 25 mg/d, divided into 2 doses daily; overall, 32% of the subjects had an excellent response to the drug, 42% a good response, and 8% a fair response.[34]  Detrusor overactivity resolved completely in 35%. Trospium is currently approved for use in the United States for adults in a dose of 20 mg orally twice daily. No dosing guidelines or safety and efficacy information are available regarding its use in children.

Solifenacin

Solifenacin (Vesicare), an agent commonly used in adults, was studied in small series of children. A prospective open-label study evaluated its efficacy in children with OAB refractory to oxybutynin or tolterodine. An adjusted-dose regimen of 1.25-10 mg of solifenacin was used in 45 children with OAB and 27 children with neurogenic bladder. Mean urodynamic capacity improved, uninhibited contractions decreased, and continence improved in all patients. Fifteen patients had mild adverse effects, 3 had moderate adverse effects, and 4 withdrew because of intolerable adverse effects.[35]

A long-term extension of that study, with recruitment of additional patients, was conducted in children with neurogenic (n=53) and non-neurogenic (n=191) OAB in whom intensive optimized oxybutynin or tolterodine treatment and behavioral therapies produced only partial clinical and urodynamic responses or significant side effects. Minimum follow-up was 5 months and mean duration of treatment was 21 months.[36]

Urodynamic capacity improved from 145+/- 76 mL to 339 +/- 152 mL and the amplitude of uninhibited bladder contractions decreased from 66 +/- 26 to 20 +/- 20 cm H2O (P < 0.0001). The overall success rate was 94% for non-neurogenic OAB and 79% for neurogenic OAB; 23 patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 175 patients, mild by 46, moderate by 9, and 14 withdrew due to side effects. Ten patients developed post void residuals of 20 mL or greater.[36]  

Hoebeke et al reviewed the charts of children treated with 5 mg of solifenacin for resistant OAB from August 2005 to August 2008 to evaluate the effect on incontinence. One hundred thirty-nine children received solifenacin. Adverse effects were reported in 6.5%. A 25% increase in mean voided volume was noted, and 84 (85%) were considered to be responders, with 45 completely dry and 39 with fewer nocturnal enuresis episodes or diurnal incontinence symptoms. In 25, the outcome was unchanged or worse (nonresponder).[37]

In an open-label study of 34 children with newly diagnosed OAB, treatment with a 5-mg fixed dose of solifenacin resulted in a decrease of the mean voiding frequency during daytime from 9.4 ± 3.0 to 6.5 ± 2.3 times after 12 weeks (P < 0.001). The urgency and urgency urinary incontinence significantly improved and complete resolution of urgency occurred in 38.9% of patients. Drug-induced adverse effects were reported in 7 patients (20.6%) but were mild and included dry mouth, constipation, fatigue and sleepiness.[38]

A phase III randomized double-blind, placebo-controlled clinical trial (n=189) evaluated the efficacy and safety of once-daily oral solifenacin suspension in overactive bladder patients age 5 to 11 years (children) and age 12 to 18 years (adolescents). After a 4-week urotherapy run-in, patients were randomized to 12 weeks of solifenacin or placebo along with urotherapy. Solifenacin was started at a dose of 5 mg and titrated to an optimum dose at 3-week intervals over 9 weeks, resulting in at least 3 weeks at optimum dosing before the end of treatment (EoT).[39]

In children, solifenacin was superior to placebo in the following ways:

• Change from baseline to EoT for maximum voided volume – Solifenacin - placebo difference 12 mL (95% CI 0.2-24.0; P=0.046)
• Daytime maximum voided volume/micturition (DMaxVV) – Difference in adjusted mean change from baseline for solifenacin - placebo 31.9 mL (95% CI 4.3-39.5; P=0.024)
• Micturition frequency adjusted for total baseline total volume voided (P=0.0028)

In solifenacin-treated children, the most common treatment-related adverse events were constipation, prolonged QT interval (5.5%), and dry mouth (2.7%). In placebo-treated children, they were constipation and prolonged QT interval (both 2.7%). Two serious adverse events (frontal lobe epilepsy and pyelonephritis) were reported in 2 solifenacin-treated children and 3 serious adverse events (lymphadenitis, hypertension, and tachycardia) were noted in placebo-treated children.[39]

Fesoterodine

Fesoterodine was evaluated for pharmacokinetics and tolerability in a dose-escalation study in children with overactive bladder, and it was demonstrated that oral administration of fesoterodine in pediatric patients (>25 kg) with idiopathic OAB or neurogenic detrusor overactivity produced steady-state plasma 5-hydroxy-methyltolterodine exposures similar to those in adults. The doses given were well tolerated.[40]

Mirabegron

Mirabegron is a beta 3 adrenoreceptor agonist that facilitates relaxation of the bladder. The FDA approved mirabegron in March 2021 for neurogenic detrusor overactivity (NDO) in children aged 3 years and older. Approval was based on a phase 3, 52-week, open-label, multicenter trial in which bladder capacity improved from baseline and detrusor contractions decreased from baseline.[41]  Of the 86 patients enrolled, 71 completed treatment through week 24 and 70 completed 52 weeks of treatment. A total of 68 patients (43 patients aged 3 to less than 12 years and 25 patients aged 12 to 17 years) had valid urodynamic measurements for evaluation of efficacy.

In a prospective pilot study in 58 pediatric patients (median age 10.1 years), mirabegron appeared to be a safe and effective alternative for children with idiopathic OAB who had experienced no symptom improvement with behavioral and medical therapies and/or had significant side effects with at least two different antimuscarinic agents. After a median 11.5 months of treatment, median bladder capacity improved from 150 to 200 mL (P < 0.001). Continence improved in 52 of the 58 patients, with 13 being completely dry. Eight patients reported mild to moderate side effects.[42]

Botulinum toxin

Botulinum toxin is currently being used to treat pediatric detrusor overactivity, particularly cases with a neurogenic cause. In children, a total of 50-100 IU, on average, is injected in 30-40 bladder sites. The results last 6-9 months.[43]  Although the initial results in children seem promising, researchers need to perform additional studies on this treatment approach.

Botulinum toxin interacts with the protein complex necessary for the release of acetylcholine and other transmitters from the presynaptic nerve endings and prevents the release of the transmitters from the presynaptic vesicles. This effect results in decreased muscle contractility and atrophy at the injection site. 

The use of botulinum toxin in children is limited by the need for preinjection anesthesia and the need for repeat injections. Few data are available regarding the dose, concentration, site or sites, number of injections, long-term efficacy, and side effects in both adult and pediatric patients with OAB. In adults, generalized weakness and development of resistance to the toxin has been reported. Other adverse effects reported in adults include urinary tract infection, dysuria, and urinary retention.[44, 45]

Although neuromodulation is used more commonly in adults, this treatment approach has been used in children in whom behavioral and pharmacologic therapy fails. The exact mechanism by which neuromodulation affects detrusor overactivity is not fully understood. Sacral nerve stimulation may induce reflex-mediated inhibitory effects on the detrusor through afferent and/or efferent stimulation of the sacral nerves. In addition, stimulation of the somatic fibers of the nerves may activate the pelvic floor muscles, causing further detrusor inhibition.[46]

The procedure requires surgery; thus, many parents are reluctant to proceed. In addition, the current version of the device is relatively large for a child, so this procedure may be more attractive to parents when a smaller device becomes available.

Transcutaneous stimulation has been used in children. This involves placement of surface electrodes to stimulate the sacral root (S3). Several stimulation frequencies have been used, and stimulation of 2 Hz seems to be sufficient. Researchers have not yet determined the optimal length of each stimulation during a treatment session nor how many sessions the treatment should continue.[47, 48, 49]

Surgical procedures such as bladder augmentation or autoaugmentation are rarely needed in children with idiopathic OAB but may be indicated in children with neurogenic OAB refractory to medical therapy.

Behavioral therapy is an important component in the management of OAB, and clinicians should ensure that such regimens are being followed for maximal response.

Although the urodynamic effects of anticholinergic agents occur within 24 hours of dosing, the clinical effects tend to take longer. The authors recommend that an individual remain on an anticholinergic agent for at least 2-4 weeks before determining whether the medication is effective. Furthermore, in individuals who note some response to therapy, improvement may increase throughout the first month of therapy. Thus, the effectiveness of the medication should be evaluated.

In children who respond to anticholinergic therapy, the child should remain on therapy for 3-6 months before attempting to wean off the therapy. If the weaning fails, the child should return to the dose that kept his or her symptoms controlled for an additional 3-6 months before attempting another trial of weaning.

In children who are refractory to behavioral therapy and anticholinergic therapy, further evaluation is indicated. Urodynamic studies are helpful to evaluate bladder and sphincteric function in these children. In addition, children who do not respond to therapy should be reassessed to rule out an underlying neurologic etiology.[50]

Although pharmacologic therapy is one of the mainstays in the treatment of adult overactive bladder (OAB) and the management of neurogenic detrusor overactivity, its role in the treatment of idiopathic OAB in children is less well defined.

Anticholinergic agents are often used in children with OAB when behavioral therapy has failed or as an adjunct to behavioral therapy. The most commonly used anticholinergics in children are oxybutynin (78%) and tolterodine (17%).[51]

Immediate-release (IR) oxybutynin tablets and syrup and tolterodine are approved by the US Food & Drug Administration (FDA) for children age 5 years and older, and extended-release (ER) oxybutynin tablets are FDA-approved for children age 6 years and older since they must be ingested whole. No other antimuscarinics have been FDA-approved for use in children under 18 years of age and no antimuscarinic drugs have been approved for children under 5 years of age.[52]  

Mirabegron, a beta3 agonist, gained FDA approval for NDO in children aged 3 years and older.[41]  

Trospium chloride (Sanctura), an agent used in adults, has been used in a small series of children, with doses varying from 10-25 mg/d, divided bid. Other anticholinergic agents used in adult patients with OAB include solifenacin (Vesicare) and darifenacin (Enablex).

Class Summary

Anticholinergic agents inhibit the binding of acetylcholine to the cholinergic receptor, thereby suppressing involuntary bladder contraction of any etiology. In addition, they increase the volume of the first involuntary bladder contraction, decrease the amplitude of the involuntary bladder contraction, and may increase bladder capacity.

Oxybutynin (Ditropan, Ditropan XL, Oxytrol, Gelnique)

Oxybutynin inhibits the action of acetylcholine on smooth muscle and has a direct antispasmodic effect on smooth muscles, increasing bladder capacity and decreasing uninhibited contractions.

Class Summary

Beta-3 adrenergic receptor agonists causes relaxation of the detrusor smooth muscle of the urinary bladder and increases bladder capacity. 

Mirabegron (Myrbetriq)

Indicated for neurogenic detrusor overactivity (NDO) in children aged 3 years and older.