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Evaluation and Targeted Therapy of Voiding Dysfunction in Children
Accepted Manuscript Title: Evaluation and Targeted Therapy of Voiding Dysfunction in Children Author: Lane S. Palmer PII: DOI: Reference:
S0090-4295(16)00121-7 http://dx.doi.org/doi: 10.1016/j.urology.2016.02.002 URL 19614
To appear in:
Urology
Received date: Accepted date:
1-12-2015 2-2-2016
Please cite this article as: Lane S. Palmer, Evaluation and Targeted Therapy of Voiding Dysfunction in Children, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Evaluation and Targeted Therapy of Voiding Dysfunction in Children Lane S. Palmer, MD, FACS Division of Pediatric Urology, Cohen Children’s Medical Center of New York, Hofstra North Shore-LIJ School of Medicine, Long Island, New York and Pediatric Urology Associates, PC, Long Island, New York Correspondence: 1999 Marcus Avenue, M18, Lake Success, NY 11042; [email protected]. Phone: 516-466-6953. Fax: 516-466-5608 No Funding Abstract Significant strides have been made over the past two decades in more precisely evaluating and managing children with voiding complaints. A thorough history should offer insight into the possible causes for the presenting complaints and this is supplemented by physical examination, urine studies and select imaging. Uroflowmetry and external sphincter electromyography with measurement of post-void residual urine should allow for accurate diagnosis using categories offered by the International Children’s Continence Society. This ability to make an accurate diagnosis should naturally lead to the use of treatment options (urotherapy, pharmacotherapy, biofeedback, and neuromodulation) that specifically target the responsible cause of the complaints rather than simply their symptoms. The management of lower urinary tract voiding disorders in children has undergone a marked evolution over the past 25 years. In an acknowledged simplification (but not far from the truth) prior urologic evaluation of these children sought to stratify incontinence as nocturnal or diurnal, and associated with infections and then treated with timed voiding, desmopressin for nocturnal enuresis and anticholinergic agents for daytime incontinence or urinary frequency/urgency. Today, there is a significantly greater understanding of the factors associated with bladder dysfunction and the relationship that exists with constipation; thus, the evaluation of bladder-bowel dysfunction (BBD) is much more extensive, and the armamentarium of management strategies includes a structured non-invasive educational approach known as urotherapy, a roster of pharmacologic agents acting at various points of the lower urinary tract, biofeedback or pelvic floor rehabilitation and neuromodulation which allow a management approach that targets the specific cause.
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PATIENT EVALUATION History. An accurate history, taken of the child and confirmed by the caretaker, should aim to establish the primary cause of the child’s voiding complaints and to identify confounding or comorbid conditions. The areas of inquiry are listed in Table 1. The voiding history should be investigative (the interval of voiding is more helpful than simply the number of daily voids) about the storage and emptying aspects of the bladder: urgency, incontinence (urge, “not aware”, locations where this happens, frequency of events), initiation and continuous nature of the stream and sense of post-void urgency. Any prior treatment efforts should be discussed and reasons behind their failures understood. An evacuation assessing frequency of stools, nature of the stools using a reliable scale (Bristol), and episodes of encopresis is imperative. Diaries to register the time, amount and nature of fluid and food intake as well voiding and bowel movements are also helpful to corroborate or better understand the complaints. Physical Examination. A good general physical examination should take place along but more scrutiny of the genitalia. Ear anomalies may infer a renal abnormality. The abdomen should be palpated for masses, a full bladder, and stool. The back should be inspected for signs of occult spinal dysraphism (café au lait spots, abnormal creases, dimples, hair tufts, evidence of prior surgery) which may then be followed by additional history regarding neurologic symptoms and an MR of the spine. The penis should be evaluated for prior surgery (child uninformed about prior hypospadias surgery), meatal stenosis, and palpable urethral abnormality (stricture, diverticulum). The introitus should be inspected for the presence of labial adhesions, recessed urethra, pooled urine, infection, and signs of sexual abuse. Urine Studies. A urine analysis screens for glucosuria, proteinuria, diabetes insipidus, and infection. A spot calcium/creatinine assesses for hypercalciuria in the presence of urgency, frequency, and hematuria. Imaging. Ultrasound offers screens for anatomic abnormalities of the kidneys (hydronephrosis, duplication anomalies) and bladder (ureterocele, diverticulum, hydroureter) as well as for masses, evidence of bladder outlet obstruction (bladder wall thickening) and the presence of stool; measurement of a post void residual (PVR) is vital (see below). The measurement of bladder wall thickening varies with the degree of bladder fullness and thus, has not been standardized. KUB assists in assessing constipation and the integrity of the bony spine (sacral agenesis, spina bifida oculta, etc). The indications for VCUG lay in abnormal renal or bladder ultrasound findings, a history of infections or in recalcitrant cases where an anatomic abnormality is sought (posterior urethral valves, bladder diverticulum). MR of the spine aids in the diagnosis of a tethered cord or other spinal cord abnormality. Urodynamics. A non-invasive uroflow- external sphincter electromyography (EMG) allows for the best assessment of voiding dynamics in the majority of cases while complete urodynamics, including cystometrogram, assists in cases refractory to therapy 2
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or concern for a neurogenic cause. Proper lead placement and adequate bladder filling reduces artifact of this study and allows excellent direct assessment of bladder emptying as contributed by the detrusor and external sphincter mechanisms and an indirect assessment of the internal sphincter mechanism. The 5 flow curve patterns described by the ICCS1: Bell, Tower, Staccato, Interrupted, and plateau, offer insight into detrusor function, but two important corollaries should be made, (1) EMG assessment must be part of the evaluation to best determine the relationship between the bladder’s ability to generate such curves and the external sphincter/pelvic floor’s ability to provide an unencumbered outlet. (2) An immediate PVR volume must be assessed for accuracy. The literature is replete with studies reporting absolute PVR values or PVR related to age-expected bladder capacity; however, the former fails to account for age differences and the latter assumes patients had full bladders at the time of the study. Uroflows are best performed with bladders at about 50% of expected capacity otherwise artifactual uroflow patterns such as Tower may occur. PVR should be related to the volume in the bladder at the time of the void: measured PVR/bladder volume prior to void x 100. The prevoid volume is known by either sonogram (used to confirm adequate bladder filling) or the sum of the voided volume and PVR Classification. The International Children’s Continence Society (ICCS) has provided a standardization classification system1 that has been modified several times since first proposed in 1998.2 The most recent categories are listed in Table 2. The limitations of any classification system stem from the overlap of symptoms that exist among the categories and agreement upon the evaluation needed to label the condition in any specific case. However, this categorization schema very effectively provides a framework for this complex constellation of disorders.
MANAGEMENT Management should target the identifiable cause(s) of the child’s condition and not symptomatic relief, unless a cause is not identifiable. (Figure 1) This approach requires a thorough investigative history and exclusion of etiologies by physical examination, urine studies and imaging. Co-morbidities, should be sought after and addressed first. Medications with side effects that may affect urine production, or cause urinary frequency and associated urgency, or urinary retention should be noted and alternatives discussed with the prescriber. Subsequent management of voiding dysfunction is then initiated. Urotherapy. The combination of education, behavior modification and cataloging voiding patterns, termed standard urotherapy, should be the first management effort made and may involve input from various professionals. Education regarding basic anatomy and physiology is aimed at clarifying lower urinary tract function for the child 3
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and family. Behavior modification should be guided towards factors identified during the evaluation and may include dietary advice, fluid intake guidelines, proper hygiene, timed voiding, aversion of holding postures, and bowel management. Timed voiding schema must be memorable and convenient to help ensure compliance. Allen et al found 45% of patients with daytime incontinence responded simply to compliance with a timed voiding schedule3 and Hagestroem et al noted significantly higher success with the addition of a timer watch in a prospective randomized trial.4 Constipation and Bowel Management. While the neuroanatomic relationships between bladder and bowel function and dysfunction are beyond the scope of this report, the mechanical and microbiological effects of stool on the bladder impacts its ability to store and empty pose an increased risk of incontinence 5, UTI and vesicoureteral reflux.6 Constipation has been related to incomplete bladder emptying7 and is more common among children with idiopathic OAB than controls8 and dysfunctional voiding.9 While rectal distension may not equate with constipation, a rectum diameter >30 cm, imaged on pelvic sonogram,10,11has significant but unpredictable effects on bladder capacity, sensation and overactivity in nearly 70% of children with LUTS.12 Bowel management should be instituted before evaluating bladder function via uroflow-EMG to eliminate any confounding effect. The tenets of bowel management is to first empty the colon and then maintain soft, regular and complete bowel movements. The use of increased fiber, ample fluid intake, and supplemented with osmotic and/or stimulant cathartic agents work towards achieving this goal. Polyethylene glycol (PEG) has supplanted lactulose, senna, mineral oil, and other agents for both complete evacuation (enemas may be used instead) or for maintenance therapy. A Cochrane review determined that PEG preparations may be superior to placebo, lactulose and milk of magnesia for treatment of constipation in children.13 Parents should be counselled that bowel management may require a prolonged period of time and that relapses of constipation may occur. The Bristol scale aids in gauging the efficacy of the bowel regimen Reassessment. Urotherapy and aggressive bowel management should satisfactorily treat many of the conditions itemized by the ICCS. Timed voiding or intermittent catheterization (Voiding Postponement, Underactive Bladder), postural and wiping technique changes when sitting to void (Vaginal Reflux), and symptomatic relief with anticholinergic agents (Extraordinary Daytime Urinary Frequency). The ICCS recognizes BBD as a general term and isolating the bladder dysfunction by properly treating the bowel dysfunction should allow for a more targeting approach to the detrusor and continence mechanisms. Stress incontinence is included in this classification system but requires formal urodynamic evaluation to make the diagnosis. Methylphenidate, acting centrally14, and biofeedback, to strengthen external sphincter tone and recruitment for situational control15, are effective for Giggle Incontinence. The 4
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remaining 4 conditions have considerable overlap by history but can be discriminated by properly performed uroflow-EMG and PVR measurement. Bladder outlet obstruction includes stricture disease which can only be assessed cystoscopically or radiographically and will come to the forefront based on history or a refractory response to treatment of the other two causes, internal and external sphincter mechanism overactivity. The remainder of this discussion will focus on managing the detrusor for OAB, the external sphincter mechanism for dysfunctional voiding, and the internal sphincter mechanism for primary bladder neck dysfunction.
Detrusor (OAB) OAB is defined as urinary urgency usually accompanied by frequency and nocturia in the absence of infection or other pathology.1 Pharmacotherapy is the mainstay of treatment aimed at stabilizing the overactive bladder with the aim of increasing urine storage by reducing the threshold to bladder contraction, reduce the vigor of the contractions, and to increase bladder capacity. First line treatment continues to be pharmacotherapy using anticholinergic agents followed by either intra-detrusor injection of botulinum-A toxin or the use of neuromodulation Anticholinergics. The use of anticholinergic agents dates back over 50 years with propantheline16 which was replaced by oxybutynin which had fewer side effects. While the liquid and tablet form of immediate release oxybutynin offers flexibility in dosing and tapering, the inconvenience of administration and greater side effects led to the sustained released oxybutynin and its use for OAB in children. The subsequent agents were more selective for subtypes of muscarinic receptors and all sustained release except for hyoscamine and tolterodine which also came as sustained release formulation. While none of the agents are FDA approved for non-neurogenic bladder dysfunction in children, series of off-label use for oxybutynin17, tolterodine18, tropsium19, darifenacin20, solifenacin21, fesoterodine22, all demonstrate efficacy in pediatric OAB. Double therapy has been advocated in resistant cases to a particular agent. 23 Botulinum-A toxin. Intradetrusor injection of botulinum-A offers promising results for refractory cases of OAB. Hoebeke et al24, first reported on 21 such patients with decreased age-related bladder capacity, urgency and urge incontinence injected with 100 U botulinum-A toxin. After at least 6 month follow-up, 9/15 patients showed full response after 1 injection with a mean increase in bladder capacity from 167 to 271 ml (p <0.001); 8 remained dry after 12 months. A second injection yielded a full response in 2 of 4 patients (3 partial responders and a relapse patient). One girl had self-limited urinary retention. Marte25 noted progressive improvement with time and repeated number of injections in 21 patients using 12.5 IU/kg diluted in saline at 20 detrusor sites. By 18 months, a full response was seen in 85% of patients. No severe systemic complications or urinary retention was noted. Lahdes-Vasama26 compared preoperative and postoperative (3 months) urodynamics in 13 patients after injection of 50-100 IU 5
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over 15-20 detrusor sites without side effects and found a significant increase in bladder capacity and decrease in the number of patients with uninhibited detrusor contractions. Using higher doses in 27 children (400-500 IU), Blackburn27 noted improvement in frequency (10 patients), nocturia (7) and resolution of urgency (10) and urge incontinence (12); the impact on incontinence was independent of dose or functional bladder capacity. The complications included UTI (7), urinary retention (1) and bladder pain (1). Neuromodulation: The target of neuomodulation is to block the afferent limb of the sacral reflex arc leading to detrusor contraction inhibition. Cutaneous and percutaneous approaches via peripheral nerves have been used; cutaneous stimulation has been applied to the parasacral area, and implantable device used at the posterior S3 foramen. All techniques have been used successfully and safely in children with OAB. Parasacral transcutaneous electrical neurostimulation (TENS) for refractory OAB has been used successfully. In the earliest reports, Bower et al28, noted improved continence in 73% after at least 1 month while Malm-Buatsi et al29, noted cure or significant improvement in 13%, and 60%, respectively and marked improvement in urinary frequency in 75% after several months of treatment. A post-TENS parabolic uroflow curve was associated (p<0.05) with those who became dry or improved. In a longer term study, Lordelo30 noted success in 73% among 30 patients followed at least 2 years and a 10% recurrence rate. TENS has been shown offer greater success over OAB symptoms than PTNS31 and similar success to oxybutynin but without the side effects.32 A more direct approach to the sacral arc is through tibial nerve stimulation. Hoebeke 33 prospectively performed percutaneous tibial nerve stimulation (PTNS) in children with OAB and reported resolution or improvement of urgency in 25% and 36% respectively while incontinence resolved in 17% or improved in 53%. The uroflowmetry curve normalized in 43% and the mean bladder capacity increased 51%. DeGennaro et al 34, noted that 8 of 10 children with OAB demonstrated symptomatic improvement and incontinence was cured in 5 of 9; urodynamics showed bladder capacity normalization in 62.5% and absence of unstable contractions in those who became continent. Interestingly, Capitanucci, et al35, found greater success when PTNS was used in dysfunctional voiders versus those with OAB. The use of transcutaneous units (TENS) offers a less invasive form of PTNS with optimistic results. Patidar et al36, conducted a prospective sham-controlled study in 40 children in which 2/3 patients reported cure and 23.8% reported significant improvement of OAB symptoms and 71.4% reported cured incontinence. Side effects are limited to local skin reactions. The experience with implantable sacral neuromodulators for refractory OAB is limited but favorable. In a series of 18 children followed 28.8 months (mean), Groen 37 noted an initial response rate of 78% (full-50%, partial-28%) with significant reduction in incontinent events and frequency of catheterizations. At study’s end, 40% had a full 6
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response and 33% had a partial response. Reinberg et al38, who have the largest experience, report in their most recent series of 105 consecutive patients followed for 2.7 years (median), that despite the 56% reoperative risk (mainly device malfunction; explantation in 35% mainly for complete symptom resolution), 94% experienced improvement of at least 1 symptom. Resolution or improvement was noted for urinary incontinence (41%, 88%), constipation (40%, 79%), frequency and/or urgency (28%, 67%), and nocturnal enuresis (28%, 66%). The potential side effects of these devices include pain and local skin reactions/infections as well as mechanical failure.
External sphincter (dysfunctional voiding) Biofeedback. Dysfunctional voiding, with Hinman-Allen syndrome as its extreme, refers to external sphincter activity during micturition. This condition was felt to be a learned behavior with few management options: hypnosis, timed voiding, urethral dilation, and anticholinergic agents. Maizels39 introduced biofeedback, the modulation of a bodily function in response to an auditory or visual representation of that function, in 1979 using urodynamic equipment and successfully retrained 2 of 3 patients. Prior to the introduction of animated computer games in 199940, biofeedback was slow to acceptance as it depended on differences in EMG tracing or their translated sounds coming from patches placed in the area of the external urinary sphincter. Currently, EMG activity is translated into an animated sequence that can be controlled by the patient as he/she contracts or relaxes the external urinary sphincter. Upon isolating the sphincter, the patient uses the games to learn to modulate the sphincter and then repeat this modulation when voiding. As biofeedback is a teaching modality, proper patient selection is critical for success. Children and families must be motivated and committed to the process and home practice. Personnel should be encouraging and be capable educators. Most importantly, patients must be dysfunctional voiders; i.e., an external urinary sphincter does not relax appropriately during voiding on EMG-Flow-PVR study. Among 42 children (5-11 years old), McKenna40 reported improvement in nocturnal enuresis (90%), diurnal enuresis (89%), constipation (100%) and encopresis (100%). Kaye and Palmer41 found equal success for voiding symptoms between non-animated and animated biofeedback but in significantly fewer sessions in the animated biofeedback group. While some of this symptomatic improvement is attributable to education and bowel management, improvement in uroflow tracings in both series, and the related improvement in PVR and urodynamic behavior speak to the efficacy of this modality. In an analysis of 27 series, DeSantis42 reported a pooled improvement in UTI (83%), daytime incontinence (80%), and improvement in constipation (18%-100%), frequency (67%-100%), urgency (71%-88%) and vesicoureteral reflux (21%-100%). The detrimental relationship of bladder and bowel dysfunction (BBD) and reflux has been well documented and includes increased risk of recurrent pyelonephritis, and inferior surgical success rates.43 Palmer et al noted that in patients with dysfunctional 7
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voiding and reflux, biofeedback expedited the resolution of reflux or lowered the grade of reflux in 71% and fostered a bladder environment that allowed successful ureteral reimplantation in the others.44 Similar results were noted by Khen-Dunlop45 and Kibar46. Biofeedback is labor intensive and efforts to simplify or compress the education have been assessed. Sener et al47, compared results from two centers using different methods: four sessions vs 6-10 (mean 7) sessions and found no difference in normalization of uroflows-EMGs, and reflux resolution between the two centers. Hoebeke et al48, presented a voiding school where children were reeducated on voiding and drinking and used individualized voiding diaries, pelvic floor biofeedback training, uroflowmetry, alarm therapy, cognitive therapy and psychological support. A positive effect was noted in 92% of children and only 26% remained incontinent. In a follow up report, these authors reinforced the need for longer term follow-up as significant relapse rates were noted at 2 years for pelvic floor tone and incontinence490 While biofeedback is commonly applied to teach children to properly modulate their external sphincter during voiding, biofeedback has been helpful in treating giggle incontinence. Richardson and Palmer found biofeedback to be curative (67%) or helpful (33%) for girls with giggle incontinence who failed other approaches where patients heighten external urinary sphincter awareness and muscle recruitment in anticipation or early during an incontinence episode.15 Botulinum-A toxin. Contraction of the striated muscle of the external sphincter mechanism controlled by acetylcholine can be blocked through the injection of botulinum-A toxin which prevents fusion of neurosecretory vesicles with the surface of the synaptic plasma membrane. Clinically, in cases of external sphincter contraction that are refractory to treatment, including biofeedback, injection of botulinum-A toxin holds considerable promise since Steinhardt50 reported the first successful case in a 7year-old girl. Several subsequent series corroborated botulinum-A toxin’s benefit in refractory cases using higher doses and reporting reliable durability and infrequent complications. Radojicic51 injected transperineally (50-100 IU) and restarted behavioral and biofeedback therapy 15 days later. By 6 months, PVR was significantly reduced and 17/20 patients reestablished normal or improved voiding curves; transient incontinence in 1 patient was the sole complication. Mokhless et al52, prospectively injected 50-100 IU cystoscopically at the 3, 6 and 9 o'clock positions in 10 children with repeated monthly according to the response and found the PVR decreased by 89%, detrusor leak point pressure decreased significantly, and a marked increase in maximum urine flow occurred. In the only long-term study (20-71 months), Vricella et al53, reported on 12 children of which 8 (67%) had significantly improved PVR and mean maximum flow rate. A second injection was needed (mean, 15 months) in 50%. Neuropsychiatric problems were present in 3 of 4 non-responders.
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Internal sphincter (primary bladder neck dysfunction). Proper urinary continence involves both external striated sphincter, under voluntary control via the pudendal nerve, and internal sphincter mechanism of the bladder neck and proximal urethra under sympathetic control, via alpha adrenergic receptors. Alphaadrenergic receptor inhibition decreases outlet resistance via smooth muscle relaxation which should result in improved bladder emptying and decreased voiding symptoms. The early experience using non-selective alpha blockers was limited by the associated side-effect of hypotension and dizziness which were reduced with the development of “selective” alpha blockers targeting α-1 receptors. Austin54 administered non-selective doxazosin (0.5-1.0 mg) to 17 children with poor bladder emptying and noted symptoms and/or emptying improvement in 82%. PVR declined in 10 patients and maximum flow rate increased in 3. Mild postural hypotension (1 child), resolved with dose reduction. Cain55 used doxazosin in 55 children with urinary incontinence, urgency and urinary tract infection and an increased PVR. After 6 weeks, there was an 88% reduction in PVR (p <0.0001); doxazocin was stopped in 2 patients due to side effects. Combs et al,56 described the EMG lagtime as the duration between absence of EMG activity (indicating an open external sphincter) and the beginning of the uroflow (inferring the opening of the bladder neck). While there are several limitations to the methodology (including the “control group” of symptomatic patients) of this and subsequent studies, it did offer a better definition of primary bladder neck dysfunction. More importantly, alpha blockers were used to specifically treat the increased bladder neck tone, targeted therapy, and found symptomatic and urodynamic improvement. In 2 follow up studies, terazosin, doxazosin or tamsulosin was prescribed for 26 and 51 such patients, respectively and consistently found significant increases in uroflow rates and decreases in both EMG lag time and PVR; all patients reported significant symptomatic improvement and no major adverse side effects.57,58 Using an alternative assessment of bladder neck dysfunction, VanderBrink et al, prescribed tamsulosin to 23 children with plateau type low flow rate uroflows in the presence of an appropriately relaxed floor for a mean of 7 months and a follow up of 20 months and found significant reduction in incontinence episodes and PVR and increase in flow rates and normalization of flow patterns; there was no decrease in mean blood pressures.59 Conclusion. The future of the scope of understanding and managing voiding disorders in children is bright as we build on the recent rapid and expansive increase in knowledge. New pharmacological agents will become available to specifically treat the bladder and sphincter mechanisms and perhaps the central nervous system. A greater experience with biofeedback, neuromodulation and other treatment modalities will provide physicians with greater management options for these children with inconvenient and sometimes socially devastating voiding conditions. Nonetheless, providing a treatment that targets the underlying cause of the child’s voiding disorder, rather than simply symptomatic relief, should always be the goal. 9
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14. Berry AK, Zderic S, Carr M. Methylphenidate for giggle incontinence. J Urol. 2009 Oct;182(4 Suppl):2028-32 15. Richardson I, Palmer LS. Successful treatment for giggle incontinence with biofeedback. J Urol. 2009 Oct;182(4 Suppl):2062-6. 16. Williams H, Jeffs R, Mckendry J, et al. A study of enuresis, using propantheline bromide (pro-banthine), including a note on urological investigation of urinary incontinence. Can Med Assoc J. 1960 Jun 25;82:1312-7. 17. Youdim K, Kogan BA. Preliminary study of the safety and efficacy of extendedrelease oxybutynin in children. Urology. 2002 Mar;59(3):428-32. 18. Reinberg Y, Crocker J, Wolpert J, et al. Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence. J Urol. 2003 Jan;169(1):317-9. 19. Lopez Pereira P, Miguelez C, Caffarati J, et al. Trospium chloride for the treatment of detrusor instability in children. J Urol. 2003 Nov;170(5):1978-81. 20. Nijman RJ. Role of antimuscarinics in the treatment of nonneurogenic daytime urinary incontinence in children. Urology. 2004 Mar;63(3 Suppl 1):45-50. 21. Nadeau G, Schröder A, Moore K, et al. Long-term use of solifenacin in pediatric patients with overactive bladder: Extension of a prospective open-label study. Can Urol Assoc J. 2014 Mar;8(3-4):118-23. doi: 10.5489/cuaj.1356. 22. Malhotra B, El-Tahtawy A, Wang EQ, et al. Dose-escalating study of the pharmacokinetics and tolerability of fesoterodine in children with overactive bladder. J Pediatr Urol. 2012 Aug;8(4):336-42. 23. Bolduc S, Moore K, Lebel S, et al. Double anticholinergic therapy for refractory overactive bladder. J Urol. 2009 Oct;182(4 Suppl):2033-8 24. Hoebeke P, De Caestecker K, Vande Walle J, et al. The effect of botulinum-A toxin in incontinent children with therapy resistant overactive detrusor. J Urol. 2006 Jul;176(1):328-30. 25. Marte A, Borrelli M, Sabatino MD, et al. Effectiveness of botulinum-A toxin for the treatment of refractory overactive bladder in children. Eur J Pediatr Surg. 2010 May;20(3):153-7 26. Lahdes-Vasama TT, Anttila A, Wahl E, et al. Urodynamic assessment of children treated with botulinum toxin A injections for urge incontinence: a pilot study. Scand J Urol Nephrol. 2011 Dec;45(6):397-400.
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27. Blackburn SC, Jones C, Bedoya S, et al. Intravesical botulinum type-A toxin (Dysport®) in the treatment of idiopathic detrusor overactivity in children. J Pediatr Urol. 2013 Dec;9(6 Pt A):750-3. 28. Bower WF, Moore KH, Adams RD. A pilot study of the home application of transcutaneous neuromodulation in children with urgency or urge incontinence. J Urol. 2001 Dec;166(6):2420-2. 29. Malm-Buatsi E, Nepple KG, Boyt MA, et al. Efficacy of transcutaneous electrical nerve stimulation in children with overactive bladder refractory to pharmacotherapy. Urology. 2007 Nov;70(5):980-3. 30. Lordêlo P, Soares PV, Maciel I, et al. Prospective study of transcutaneous parasacral electrical stimulation for overactive bladder in children: long-term results. J Urol. 2009 Dec;182(6):2900-4. 31. Barroso U Jr, Viterbo W, Bittencourt et al. Posterior tibial nerve stimulation vs parasacral transcutaneous neuromodulation for overactive bladder in children. J Urol. 2013 Aug;190(2):673-7. 32. Quintiliano F, Veiga ML, Moraes M, et al. Transcutaneous parasacral electrical stimulation vs oxybutynin for the treatment of overactive bladder in children: a randomized clinical trial. J Urol. 2015 May;193(5 Suppl):1749-53 33. Hoebeke P, Renson C, Petillon L, et al. Percutaneous electrical nerve stimulation in children with therapy resistant nonneuropathic bladder sphincter dysfunction: a pilot study. J Urol. 2002 Dec;168(6):2605-7; discussion 2607-8. 34. De Gennaro M, Capitanucci ML, Mastracci P, et al. Percutaneous tibial nerve neuromodulation is well tolerated in children and effective for treating refractory vesical dysfunction. J Urol. 2004 May;171(5):1911-3. 35. Capitanucci ML, Camanni D, Demelas F, et al. Long-term efficacy of percutaneous tibial nerve stimulation for different types of lower urinary tract dysfunction in children. J Urol. 2009 Oct;182(4 Suppl):2056-61 36. Patidar N, Mittal V, Kumar M, et al. Transcutaneous posterior tibial nerve stimulation in pediatric overactive bladder: A preliminary report. J Pediatr Urol. 2015 Jul 29. [Epub ahead of print] 37. Groen LA, Hoebeke P, Loret N, et al. Sacral neuromodulation with an implantable pulse generator in children with lower urinary tract symptoms: 15year experience. J Urol. 2012 Oct;188(4):1313-7 38. Dwyer ME, Vandersteen DR, Hollatz P, et al. Sacral neuromodulation for the dysfunctional elimination syndrome: a 10-year single-center experience with 105 consecutive children. Urology. 2014 Oct;84(4):911-7. 12
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39. Maizels M, King LR, Firlit CF. Urodynamic biofeedback: a new approach to treat vesical sphincter dyssynergia. J Urol. 1979 Aug;122(2):205-9. 40. McKenna PH, Herndon CD, Connery S, et al. Pelvic floor muscle retraining for pediatric voiding dysfunction using interactive computer games. J Urol. 1999 Sep;162(3 Pt 2):1056-62; 41. Kaye JD, Palmer LS. Animated biofeedback yields more rapid results than nonanimated biofeedback in the treatment of dysfunctional voiding in girls. J Urol. 2008 Jul;180(1):300-5 42. Desantis DJ, Leonard MP, Preston MA, et al. Effectiveness of biofeedback for dysfunctional elimination syndrome in pediatrics: a systematic review. J Pediatr Urol. 2011 Jun;7(3):342-8 43. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998 Sep;160(3 Pt 2):1019-22. 44. Palmer LS, Franco I, Rotario P, et al. Biofeedback therapy expedites the resolution of reflux in older children. J Urol. 2002 Oct;168(4 Pt 2):1699-702; 45. Khen-Dunlop N, Van Egroo A, Bouteiller C, et al. Biofeedback therapy in the treatment of bladder overactivity, vesico-ureteral reflux and urinary tract infection. J Pediatr Urol. 2006 Oct;2(5):424-9. 46. Kibar Y, Ors O, Demir E, et al. Results of biofeedback treatment on reflux resolution rates in children with dysfunctional voiding and vesicoureteral reflux. Urology. 2007 Sep;70(3):563-6 47. Sener NC, Altunkol A, Unal U, et al. Can a four-session biofeedback regimen be used effectively for treating children with dysfunctional voiding? Int Urol Nephrol. 2015 Jan;47(1):5-9. 48. Hoebeke P, Renson C, De Schryver M, et al. Prospective evaluation of clinical voiding reeducation or voiding school for lower urinary tract conditions in children. J Urol. 2011 Aug;186(2):648-54. 49. Van den Broeck C, Roman de Mettelinge T, Deschepper E, et al. Prospective evaluation of the long-term effects of clinical voiding reeducation or voiding school for lower urinary tract conditions in children. J Pediatr Urol. 2015 Jul 30. [Epub ahead of print] 50. Steinhardt GF, Naseer S, Cruz OA. Botulinum-A toxin: novel treatment for dramatic urethral dilatation associated with dysfunctional voiding. J Urol. 1997 Jul;158(1):190-1 13
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51. Radojicic ZI, Perovic SV, Milic NM.Is it reasonable to treat refractory voiding dysfunction in children with botulinum-A toxin? J Urol. 2006 Jul;176(1):332-6. 52. Mokhless I, Gaafar S, Fouda K, et al. Botulinum A toxin urethral sphincter injection in children with nonneurogenic neurogenic bladder. J Urol. 2006 Oct;176(4 Pt 2):1767-70. 53. Vricella GJ, Campigotto M, Coplen DE, et al. Long-term efficacy and durability of botulinum-A toxin for refractory dysfunctional voiding in children. J Urol. 2014 May;191(5 Suppl):1586-91 54. Austin PF, Homsy YL, Masel JL, et al. alpha-Adrenergic blockade in children with neuropathic and nonneuropathic voiding dysfunction. J Urol. 1999 Sep;162(3 Pt 2):1064-7. 55. Cain MP, Wu SD, Austin PF, et al. Alpha blocker therapy for children with dysfunctional voiding and urinary retention. J Urol. 2003 Oct;170(4 Pt 2):1514-5. 56. Combs AJ, Grafstein N, Horowitz M, et al. . Primary bladder neck dysfunction in children and adolescents I: pelvic floor electromyography lag time--a new noninvasive method to screen for and monitor therapeutic response. J Urol. 2005 Jan;173(1):207-10 57. Donohoe JM, Combs AJ, Glassberg KI. Primary bladder neck dysfunction in children and adolescents II: results of treatment with alpha-adrenergic antagonists. J Urol. 2005 Jan;173(1):212-6. 58. Van Batavia JP, Combs AJ, Horowitz M, et al. Primary bladder neck dysfunction in children and adolescents III: results of long-term alpha-blocker therapy. J Urol. 2010 Feb;183(2):724-30 59. Vanderbrink BA, Gitlin J, Toro S, et al. Effect of tamsulosin on systemic blood pressure and nonneurogenic dysfunctional voiding in children. J Urol. 2009 Feb;181(2):817-22.
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Figure Legends
Figure 1. Schematic flow chart for targeted management of voiding dysfunction in children. Table 1: Important Points of History in Evaluating the Child with Voiding Dysfunction Pregnancy - Prenatal abnormalities • Medical History • Urologic • UTIs • Posterior urethral valves • Reflux • Ureterocele • Non-Urologic • Diabetes • Trauma • Renal disease • Psychiatric diagnoses • ADHD • OCD • Mania • Depression • Sleep apnea • Neurological diseases • Spinal dysraphism • Surgical History • Hypospadias repair • Anti-Reflux procedure/surgery • Ureterocele incision • TUR valves • Spinal Surgery • Abdominal Surgery (ex. Tumor excision, augmentation, Mitrofanoff) • Pelvic Surgery (ex. rectal pull through, bladder neck surgery) • Developmental Milestones • Family History of Voiding Dysfunction • Enuresis • Interstitial cystitis • Childhood incontinence • Urethral dilation • Psychosocial History (ex. Recent deaths, family strife, school stress) • Medications • Lithium • ADHD Meds 15
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•
• Antidepressants • Tricyclics (anticholinergic) • Diuretics • Antihistamines Wetting History • Toilet training (timing of daytime, nighttime, and stool; persistence of continence) • Voiding patterns/habits • Voiding frequency and intervals • Urgency + incontinence • Incontinence (daytime and nighttime episodes and intervals, giggle or stress, awareness, need for protective pad, associated with urge to void ) • Fluid intake/thirst • Bowel habits (frequency, consistency, associated rectal or abdominal pain, Bristol scale) • Posturing (ex. Vincent’s curtsy, leg-crossing, squatting, dancing and wiggling when need to void)
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Table 2: International Children’s Continence Society Classification of Lower Urinary Tract Dysfunction1 1. Bladder and Bowel Dysfunction (BBD) 2. Overactive Bladder (OAB) 3. Voiding Postponement 4. Underactive Bladder 5. Dysfunctional Voiding 6. Bladder Outlet Obstruction 7. Stress Incontinence 8. Vaginal Reflux 9. Giggle Incontinence 10. Extraordinary Daytime Urinary Frequency 11. Bladder Neck Dysfunction
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S0090-4295(16)00121-7 http://dx.doi.org/doi: 10.1016/j.urology.2016.02.002 URL 19614
To appear in:
Urology
Received date: Accepted date:
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Please cite this article as: Lane S. Palmer, Evaluation and Targeted Therapy of Voiding Dysfunction in Children, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Evaluation and Targeted Therapy of Voiding Dysfunction in Children Lane S. Palmer, MD, FACS Division of Pediatric Urology, Cohen Children’s Medical Center of New York, Hofstra North Shore-LIJ School of Medicine, Long Island, New York and Pediatric Urology Associates, PC, Long Island, New York Correspondence: 1999 Marcus Avenue, M18, Lake Success, NY 11042; [email protected]. Phone: 516-466-6953. Fax: 516-466-5608 No Funding Abstract Significant strides have been made over the past two decades in more precisely evaluating and managing children with voiding complaints. A thorough history should offer insight into the possible causes for the presenting complaints and this is supplemented by physical examination, urine studies and select imaging. Uroflowmetry and external sphincter electromyography with measurement of post-void residual urine should allow for accurate diagnosis using categories offered by the International Children’s Continence Society. This ability to make an accurate diagnosis should naturally lead to the use of treatment options (urotherapy, pharmacotherapy, biofeedback, and neuromodulation) that specifically target the responsible cause of the complaints rather than simply their symptoms. The management of lower urinary tract voiding disorders in children has undergone a marked evolution over the past 25 years. In an acknowledged simplification (but not far from the truth) prior urologic evaluation of these children sought to stratify incontinence as nocturnal or diurnal, and associated with infections and then treated with timed voiding, desmopressin for nocturnal enuresis and anticholinergic agents for daytime incontinence or urinary frequency/urgency. Today, there is a significantly greater understanding of the factors associated with bladder dysfunction and the relationship that exists with constipation; thus, the evaluation of bladder-bowel dysfunction (BBD) is much more extensive, and the armamentarium of management strategies includes a structured non-invasive educational approach known as urotherapy, a roster of pharmacologic agents acting at various points of the lower urinary tract, biofeedback or pelvic floor rehabilitation and neuromodulation which allow a management approach that targets the specific cause.
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PATIENT EVALUATION History. An accurate history, taken of the child and confirmed by the caretaker, should aim to establish the primary cause of the child’s voiding complaints and to identify confounding or comorbid conditions. The areas of inquiry are listed in Table 1. The voiding history should be investigative (the interval of voiding is more helpful than simply the number of daily voids) about the storage and emptying aspects of the bladder: urgency, incontinence (urge, “not aware”, locations where this happens, frequency of events), initiation and continuous nature of the stream and sense of post-void urgency. Any prior treatment efforts should be discussed and reasons behind their failures understood. An evacuation assessing frequency of stools, nature of the stools using a reliable scale (Bristol), and episodes of encopresis is imperative. Diaries to register the time, amount and nature of fluid and food intake as well voiding and bowel movements are also helpful to corroborate or better understand the complaints. Physical Examination. A good general physical examination should take place along but more scrutiny of the genitalia. Ear anomalies may infer a renal abnormality. The abdomen should be palpated for masses, a full bladder, and stool. The back should be inspected for signs of occult spinal dysraphism (café au lait spots, abnormal creases, dimples, hair tufts, evidence of prior surgery) which may then be followed by additional history regarding neurologic symptoms and an MR of the spine. The penis should be evaluated for prior surgery (child uninformed about prior hypospadias surgery), meatal stenosis, and palpable urethral abnormality (stricture, diverticulum). The introitus should be inspected for the presence of labial adhesions, recessed urethra, pooled urine, infection, and signs of sexual abuse. Urine Studies. A urine analysis screens for glucosuria, proteinuria, diabetes insipidus, and infection. A spot calcium/creatinine assesses for hypercalciuria in the presence of urgency, frequency, and hematuria. Imaging. Ultrasound offers screens for anatomic abnormalities of the kidneys (hydronephrosis, duplication anomalies) and bladder (ureterocele, diverticulum, hydroureter) as well as for masses, evidence of bladder outlet obstruction (bladder wall thickening) and the presence of stool; measurement of a post void residual (PVR) is vital (see below). The measurement of bladder wall thickening varies with the degree of bladder fullness and thus, has not been standardized. KUB assists in assessing constipation and the integrity of the bony spine (sacral agenesis, spina bifida oculta, etc). The indications for VCUG lay in abnormal renal or bladder ultrasound findings, a history of infections or in recalcitrant cases where an anatomic abnormality is sought (posterior urethral valves, bladder diverticulum). MR of the spine aids in the diagnosis of a tethered cord or other spinal cord abnormality. Urodynamics. A non-invasive uroflow- external sphincter electromyography (EMG) allows for the best assessment of voiding dynamics in the majority of cases while complete urodynamics, including cystometrogram, assists in cases refractory to therapy 2
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or concern for a neurogenic cause. Proper lead placement and adequate bladder filling reduces artifact of this study and allows excellent direct assessment of bladder emptying as contributed by the detrusor and external sphincter mechanisms and an indirect assessment of the internal sphincter mechanism. The 5 flow curve patterns described by the ICCS1: Bell, Tower, Staccato, Interrupted, and plateau, offer insight into detrusor function, but two important corollaries should be made, (1) EMG assessment must be part of the evaluation to best determine the relationship between the bladder’s ability to generate such curves and the external sphincter/pelvic floor’s ability to provide an unencumbered outlet. (2) An immediate PVR volume must be assessed for accuracy. The literature is replete with studies reporting absolute PVR values or PVR related to age-expected bladder capacity; however, the former fails to account for age differences and the latter assumes patients had full bladders at the time of the study. Uroflows are best performed with bladders at about 50% of expected capacity otherwise artifactual uroflow patterns such as Tower may occur. PVR should be related to the volume in the bladder at the time of the void: measured PVR/bladder volume prior to void x 100. The prevoid volume is known by either sonogram (used to confirm adequate bladder filling) or the sum of the voided volume and PVR Classification. The International Children’s Continence Society (ICCS) has provided a standardization classification system1 that has been modified several times since first proposed in 1998.2 The most recent categories are listed in Table 2. The limitations of any classification system stem from the overlap of symptoms that exist among the categories and agreement upon the evaluation needed to label the condition in any specific case. However, this categorization schema very effectively provides a framework for this complex constellation of disorders.
MANAGEMENT Management should target the identifiable cause(s) of the child’s condition and not symptomatic relief, unless a cause is not identifiable. (Figure 1) This approach requires a thorough investigative history and exclusion of etiologies by physical examination, urine studies and imaging. Co-morbidities, should be sought after and addressed first. Medications with side effects that may affect urine production, or cause urinary frequency and associated urgency, or urinary retention should be noted and alternatives discussed with the prescriber. Subsequent management of voiding dysfunction is then initiated. Urotherapy. The combination of education, behavior modification and cataloging voiding patterns, termed standard urotherapy, should be the first management effort made and may involve input from various professionals. Education regarding basic anatomy and physiology is aimed at clarifying lower urinary tract function for the child 3
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and family. Behavior modification should be guided towards factors identified during the evaluation and may include dietary advice, fluid intake guidelines, proper hygiene, timed voiding, aversion of holding postures, and bowel management. Timed voiding schema must be memorable and convenient to help ensure compliance. Allen et al found 45% of patients with daytime incontinence responded simply to compliance with a timed voiding schedule3 and Hagestroem et al noted significantly higher success with the addition of a timer watch in a prospective randomized trial.4 Constipation and Bowel Management. While the neuroanatomic relationships between bladder and bowel function and dysfunction are beyond the scope of this report, the mechanical and microbiological effects of stool on the bladder impacts its ability to store and empty pose an increased risk of incontinence 5, UTI and vesicoureteral reflux.6 Constipation has been related to incomplete bladder emptying7 and is more common among children with idiopathic OAB than controls8 and dysfunctional voiding.9 While rectal distension may not equate with constipation, a rectum diameter >30 cm, imaged on pelvic sonogram,10,11has significant but unpredictable effects on bladder capacity, sensation and overactivity in nearly 70% of children with LUTS.12 Bowel management should be instituted before evaluating bladder function via uroflow-EMG to eliminate any confounding effect. The tenets of bowel management is to first empty the colon and then maintain soft, regular and complete bowel movements. The use of increased fiber, ample fluid intake, and supplemented with osmotic and/or stimulant cathartic agents work towards achieving this goal. Polyethylene glycol (PEG) has supplanted lactulose, senna, mineral oil, and other agents for both complete evacuation (enemas may be used instead) or for maintenance therapy. A Cochrane review determined that PEG preparations may be superior to placebo, lactulose and milk of magnesia for treatment of constipation in children.13 Parents should be counselled that bowel management may require a prolonged period of time and that relapses of constipation may occur. The Bristol scale aids in gauging the efficacy of the bowel regimen Reassessment. Urotherapy and aggressive bowel management should satisfactorily treat many of the conditions itemized by the ICCS. Timed voiding or intermittent catheterization (Voiding Postponement, Underactive Bladder), postural and wiping technique changes when sitting to void (Vaginal Reflux), and symptomatic relief with anticholinergic agents (Extraordinary Daytime Urinary Frequency). The ICCS recognizes BBD as a general term and isolating the bladder dysfunction by properly treating the bowel dysfunction should allow for a more targeting approach to the detrusor and continence mechanisms. Stress incontinence is included in this classification system but requires formal urodynamic evaluation to make the diagnosis. Methylphenidate, acting centrally14, and biofeedback, to strengthen external sphincter tone and recruitment for situational control15, are effective for Giggle Incontinence. The 4
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remaining 4 conditions have considerable overlap by history but can be discriminated by properly performed uroflow-EMG and PVR measurement. Bladder outlet obstruction includes stricture disease which can only be assessed cystoscopically or radiographically and will come to the forefront based on history or a refractory response to treatment of the other two causes, internal and external sphincter mechanism overactivity. The remainder of this discussion will focus on managing the detrusor for OAB, the external sphincter mechanism for dysfunctional voiding, and the internal sphincter mechanism for primary bladder neck dysfunction.
Detrusor (OAB) OAB is defined as urinary urgency usually accompanied by frequency and nocturia in the absence of infection or other pathology.1 Pharmacotherapy is the mainstay of treatment aimed at stabilizing the overactive bladder with the aim of increasing urine storage by reducing the threshold to bladder contraction, reduce the vigor of the contractions, and to increase bladder capacity. First line treatment continues to be pharmacotherapy using anticholinergic agents followed by either intra-detrusor injection of botulinum-A toxin or the use of neuromodulation Anticholinergics. The use of anticholinergic agents dates back over 50 years with propantheline16 which was replaced by oxybutynin which had fewer side effects. While the liquid and tablet form of immediate release oxybutynin offers flexibility in dosing and tapering, the inconvenience of administration and greater side effects led to the sustained released oxybutynin and its use for OAB in children. The subsequent agents were more selective for subtypes of muscarinic receptors and all sustained release except for hyoscamine and tolterodine which also came as sustained release formulation. While none of the agents are FDA approved for non-neurogenic bladder dysfunction in children, series of off-label use for oxybutynin17, tolterodine18, tropsium19, darifenacin20, solifenacin21, fesoterodine22, all demonstrate efficacy in pediatric OAB. Double therapy has been advocated in resistant cases to a particular agent. 23 Botulinum-A toxin. Intradetrusor injection of botulinum-A offers promising results for refractory cases of OAB. Hoebeke et al24, first reported on 21 such patients with decreased age-related bladder capacity, urgency and urge incontinence injected with 100 U botulinum-A toxin. After at least 6 month follow-up, 9/15 patients showed full response after 1 injection with a mean increase in bladder capacity from 167 to 271 ml (p <0.001); 8 remained dry after 12 months. A second injection yielded a full response in 2 of 4 patients (3 partial responders and a relapse patient). One girl had self-limited urinary retention. Marte25 noted progressive improvement with time and repeated number of injections in 21 patients using 12.5 IU/kg diluted in saline at 20 detrusor sites. By 18 months, a full response was seen in 85% of patients. No severe systemic complications or urinary retention was noted. Lahdes-Vasama26 compared preoperative and postoperative (3 months) urodynamics in 13 patients after injection of 50-100 IU 5
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over 15-20 detrusor sites without side effects and found a significant increase in bladder capacity and decrease in the number of patients with uninhibited detrusor contractions. Using higher doses in 27 children (400-500 IU), Blackburn27 noted improvement in frequency (10 patients), nocturia (7) and resolution of urgency (10) and urge incontinence (12); the impact on incontinence was independent of dose or functional bladder capacity. The complications included UTI (7), urinary retention (1) and bladder pain (1). Neuromodulation: The target of neuomodulation is to block the afferent limb of the sacral reflex arc leading to detrusor contraction inhibition. Cutaneous and percutaneous approaches via peripheral nerves have been used; cutaneous stimulation has been applied to the parasacral area, and implantable device used at the posterior S3 foramen. All techniques have been used successfully and safely in children with OAB. Parasacral transcutaneous electrical neurostimulation (TENS) for refractory OAB has been used successfully. In the earliest reports, Bower et al28, noted improved continence in 73% after at least 1 month while Malm-Buatsi et al29, noted cure or significant improvement in 13%, and 60%, respectively and marked improvement in urinary frequency in 75% after several months of treatment. A post-TENS parabolic uroflow curve was associated (p<0.05) with those who became dry or improved. In a longer term study, Lordelo30 noted success in 73% among 30 patients followed at least 2 years and a 10% recurrence rate. TENS has been shown offer greater success over OAB symptoms than PTNS31 and similar success to oxybutynin but without the side effects.32 A more direct approach to the sacral arc is through tibial nerve stimulation. Hoebeke 33 prospectively performed percutaneous tibial nerve stimulation (PTNS) in children with OAB and reported resolution or improvement of urgency in 25% and 36% respectively while incontinence resolved in 17% or improved in 53%. The uroflowmetry curve normalized in 43% and the mean bladder capacity increased 51%. DeGennaro et al 34, noted that 8 of 10 children with OAB demonstrated symptomatic improvement and incontinence was cured in 5 of 9; urodynamics showed bladder capacity normalization in 62.5% and absence of unstable contractions in those who became continent. Interestingly, Capitanucci, et al35, found greater success when PTNS was used in dysfunctional voiders versus those with OAB. The use of transcutaneous units (TENS) offers a less invasive form of PTNS with optimistic results. Patidar et al36, conducted a prospective sham-controlled study in 40 children in which 2/3 patients reported cure and 23.8% reported significant improvement of OAB symptoms and 71.4% reported cured incontinence. Side effects are limited to local skin reactions. The experience with implantable sacral neuromodulators for refractory OAB is limited but favorable. In a series of 18 children followed 28.8 months (mean), Groen 37 noted an initial response rate of 78% (full-50%, partial-28%) with significant reduction in incontinent events and frequency of catheterizations. At study’s end, 40% had a full 6
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response and 33% had a partial response. Reinberg et al38, who have the largest experience, report in their most recent series of 105 consecutive patients followed for 2.7 years (median), that despite the 56% reoperative risk (mainly device malfunction; explantation in 35% mainly for complete symptom resolution), 94% experienced improvement of at least 1 symptom. Resolution or improvement was noted for urinary incontinence (41%, 88%), constipation (40%, 79%), frequency and/or urgency (28%, 67%), and nocturnal enuresis (28%, 66%). The potential side effects of these devices include pain and local skin reactions/infections as well as mechanical failure.
External sphincter (dysfunctional voiding) Biofeedback. Dysfunctional voiding, with Hinman-Allen syndrome as its extreme, refers to external sphincter activity during micturition. This condition was felt to be a learned behavior with few management options: hypnosis, timed voiding, urethral dilation, and anticholinergic agents. Maizels39 introduced biofeedback, the modulation of a bodily function in response to an auditory or visual representation of that function, in 1979 using urodynamic equipment and successfully retrained 2 of 3 patients. Prior to the introduction of animated computer games in 199940, biofeedback was slow to acceptance as it depended on differences in EMG tracing or their translated sounds coming from patches placed in the area of the external urinary sphincter. Currently, EMG activity is translated into an animated sequence that can be controlled by the patient as he/she contracts or relaxes the external urinary sphincter. Upon isolating the sphincter, the patient uses the games to learn to modulate the sphincter and then repeat this modulation when voiding. As biofeedback is a teaching modality, proper patient selection is critical for success. Children and families must be motivated and committed to the process and home practice. Personnel should be encouraging and be capable educators. Most importantly, patients must be dysfunctional voiders; i.e., an external urinary sphincter does not relax appropriately during voiding on EMG-Flow-PVR study. Among 42 children (5-11 years old), McKenna40 reported improvement in nocturnal enuresis (90%), diurnal enuresis (89%), constipation (100%) and encopresis (100%). Kaye and Palmer41 found equal success for voiding symptoms between non-animated and animated biofeedback but in significantly fewer sessions in the animated biofeedback group. While some of this symptomatic improvement is attributable to education and bowel management, improvement in uroflow tracings in both series, and the related improvement in PVR and urodynamic behavior speak to the efficacy of this modality. In an analysis of 27 series, DeSantis42 reported a pooled improvement in UTI (83%), daytime incontinence (80%), and improvement in constipation (18%-100%), frequency (67%-100%), urgency (71%-88%) and vesicoureteral reflux (21%-100%). The detrimental relationship of bladder and bowel dysfunction (BBD) and reflux has been well documented and includes increased risk of recurrent pyelonephritis, and inferior surgical success rates.43 Palmer et al noted that in patients with dysfunctional 7
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voiding and reflux, biofeedback expedited the resolution of reflux or lowered the grade of reflux in 71% and fostered a bladder environment that allowed successful ureteral reimplantation in the others.44 Similar results were noted by Khen-Dunlop45 and Kibar46. Biofeedback is labor intensive and efforts to simplify or compress the education have been assessed. Sener et al47, compared results from two centers using different methods: four sessions vs 6-10 (mean 7) sessions and found no difference in normalization of uroflows-EMGs, and reflux resolution between the two centers. Hoebeke et al48, presented a voiding school where children were reeducated on voiding and drinking and used individualized voiding diaries, pelvic floor biofeedback training, uroflowmetry, alarm therapy, cognitive therapy and psychological support. A positive effect was noted in 92% of children and only 26% remained incontinent. In a follow up report, these authors reinforced the need for longer term follow-up as significant relapse rates were noted at 2 years for pelvic floor tone and incontinence490 While biofeedback is commonly applied to teach children to properly modulate their external sphincter during voiding, biofeedback has been helpful in treating giggle incontinence. Richardson and Palmer found biofeedback to be curative (67%) or helpful (33%) for girls with giggle incontinence who failed other approaches where patients heighten external urinary sphincter awareness and muscle recruitment in anticipation or early during an incontinence episode.15 Botulinum-A toxin. Contraction of the striated muscle of the external sphincter mechanism controlled by acetylcholine can be blocked through the injection of botulinum-A toxin which prevents fusion of neurosecretory vesicles with the surface of the synaptic plasma membrane. Clinically, in cases of external sphincter contraction that are refractory to treatment, including biofeedback, injection of botulinum-A toxin holds considerable promise since Steinhardt50 reported the first successful case in a 7year-old girl. Several subsequent series corroborated botulinum-A toxin’s benefit in refractory cases using higher doses and reporting reliable durability and infrequent complications. Radojicic51 injected transperineally (50-100 IU) and restarted behavioral and biofeedback therapy 15 days later. By 6 months, PVR was significantly reduced and 17/20 patients reestablished normal or improved voiding curves; transient incontinence in 1 patient was the sole complication. Mokhless et al52, prospectively injected 50-100 IU cystoscopically at the 3, 6 and 9 o'clock positions in 10 children with repeated monthly according to the response and found the PVR decreased by 89%, detrusor leak point pressure decreased significantly, and a marked increase in maximum urine flow occurred. In the only long-term study (20-71 months), Vricella et al53, reported on 12 children of which 8 (67%) had significantly improved PVR and mean maximum flow rate. A second injection was needed (mean, 15 months) in 50%. Neuropsychiatric problems were present in 3 of 4 non-responders.
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Internal sphincter (primary bladder neck dysfunction). Proper urinary continence involves both external striated sphincter, under voluntary control via the pudendal nerve, and internal sphincter mechanism of the bladder neck and proximal urethra under sympathetic control, via alpha adrenergic receptors. Alphaadrenergic receptor inhibition decreases outlet resistance via smooth muscle relaxation which should result in improved bladder emptying and decreased voiding symptoms. The early experience using non-selective alpha blockers was limited by the associated side-effect of hypotension and dizziness which were reduced with the development of “selective” alpha blockers targeting α-1 receptors. Austin54 administered non-selective doxazosin (0.5-1.0 mg) to 17 children with poor bladder emptying and noted symptoms and/or emptying improvement in 82%. PVR declined in 10 patients and maximum flow rate increased in 3. Mild postural hypotension (1 child), resolved with dose reduction. Cain55 used doxazosin in 55 children with urinary incontinence, urgency and urinary tract infection and an increased PVR. After 6 weeks, there was an 88% reduction in PVR (p <0.0001); doxazocin was stopped in 2 patients due to side effects. Combs et al,56 described the EMG lagtime as the duration between absence of EMG activity (indicating an open external sphincter) and the beginning of the uroflow (inferring the opening of the bladder neck). While there are several limitations to the methodology (including the “control group” of symptomatic patients) of this and subsequent studies, it did offer a better definition of primary bladder neck dysfunction. More importantly, alpha blockers were used to specifically treat the increased bladder neck tone, targeted therapy, and found symptomatic and urodynamic improvement. In 2 follow up studies, terazosin, doxazosin or tamsulosin was prescribed for 26 and 51 such patients, respectively and consistently found significant increases in uroflow rates and decreases in both EMG lag time and PVR; all patients reported significant symptomatic improvement and no major adverse side effects.57,58 Using an alternative assessment of bladder neck dysfunction, VanderBrink et al, prescribed tamsulosin to 23 children with plateau type low flow rate uroflows in the presence of an appropriately relaxed floor for a mean of 7 months and a follow up of 20 months and found significant reduction in incontinence episodes and PVR and increase in flow rates and normalization of flow patterns; there was no decrease in mean blood pressures.59 Conclusion. The future of the scope of understanding and managing voiding disorders in children is bright as we build on the recent rapid and expansive increase in knowledge. New pharmacological agents will become available to specifically treat the bladder and sphincter mechanisms and perhaps the central nervous system. A greater experience with biofeedback, neuromodulation and other treatment modalities will provide physicians with greater management options for these children with inconvenient and sometimes socially devastating voiding conditions. Nonetheless, providing a treatment that targets the underlying cause of the child’s voiding disorder, rather than simply symptomatic relief, should always be the goal. 9
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References 1. Austin PF, Bauer SB, Bower W, et al. The standardization of terminology of lower urinary tract function in children and adolescents: Update report from the standardization committee of the International Children's Continence Society. Neurourol Urodyn. 2015 Mar 14. doi: 10.1002/nau.22751. [Epub ahead of print] 2. Norgaard JP, van Gool JD, Hjalmas K, et al. Standardization and definitions in lower urinary tract dysfunction in children. International Children’s Continence Society. Br J Urol 1998;81:1. 3. Allen HA, Austin JC, Boyt MA, et al. Initial trial of timed voiding is warranted for all children with daytime incontinence. Urology. 2007 May;69(5):962-5. 4. Hagstroem S, Rittig S, Kamperis K, et al. Timer watch assisted urotherapy in children: a randomized controlled trial. J Urol. 2010 Oct;184(4):1482-8 5. O'Regan S, Yazbeck S, Hamberger B, et al.. Constipation a commonly unrecognized cause of enuresis. Am J Dis Child. 1986 Mar;140(3):260-1. 6. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998 Sep;160(3 Pt 2):1019-22. 7. Chang SJ, Hsieh CH, Yang SS. Constipation is associated with incomplete bladder emptying in healthy children. Neurourol Urodyn. 2012 Jan;31(1):105-8 8. Veiga ML, Lordêlo P, Farias T, et al. Constipation in children with isolated overactive bladders. J Pediatr Urol. 2013 Dec;9(6 Pt A):945-9. 9. Combs AJ, Van Batavia JP, Chan J, et al. Dysfunctional elimination syndromes-how closely linked are constipation and encopresis with specific lower urinary tract conditions? J Urol. 2013 Sep;190(3):1015-20. 10. Joensson IM, Siggaard C, Rittig S, et al. Transabdominal ultrasound of rectum as a diagnostic tool in childhood constipation. J Urol. 2008 May;179(5):1997-2002. 11. Klijn AJ, Asselman M, Vijverberg MA, et al. The diameter of the rectum on ultrasonography as a diagnostic tool for constipation in children with dysfunctional voiding. J Urol. 2004 Nov;172(5 Pt 1):1986-8. 12. Burgers R, Liem O, Canon S, et al. Effect of rectal distention on lower urinary tract function in children. J Urol. 2010 Oct;184(4 Suppl):1680-5. 13. Gordon M, Naidoo K, Akobeng AK, et al. Cochrane Review: Osmotic and stimulant laxatives for the management of childhood constipation (Review). Evid Based Child Health. 2013 Jan;8(1):57-109. 10
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14. Berry AK, Zderic S, Carr M. Methylphenidate for giggle incontinence. J Urol. 2009 Oct;182(4 Suppl):2028-32 15. Richardson I, Palmer LS. Successful treatment for giggle incontinence with biofeedback. J Urol. 2009 Oct;182(4 Suppl):2062-6. 16. Williams H, Jeffs R, Mckendry J, et al. A study of enuresis, using propantheline bromide (pro-banthine), including a note on urological investigation of urinary incontinence. Can Med Assoc J. 1960 Jun 25;82:1312-7. 17. Youdim K, Kogan BA. Preliminary study of the safety and efficacy of extendedrelease oxybutynin in children. Urology. 2002 Mar;59(3):428-32. 18. Reinberg Y, Crocker J, Wolpert J, et al. Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence. J Urol. 2003 Jan;169(1):317-9. 19. Lopez Pereira P, Miguelez C, Caffarati J, et al. Trospium chloride for the treatment of detrusor instability in children. J Urol. 2003 Nov;170(5):1978-81. 20. Nijman RJ. Role of antimuscarinics in the treatment of nonneurogenic daytime urinary incontinence in children. Urology. 2004 Mar;63(3 Suppl 1):45-50. 21. Nadeau G, Schröder A, Moore K, et al. Long-term use of solifenacin in pediatric patients with overactive bladder: Extension of a prospective open-label study. Can Urol Assoc J. 2014 Mar;8(3-4):118-23. doi: 10.5489/cuaj.1356. 22. Malhotra B, El-Tahtawy A, Wang EQ, et al. Dose-escalating study of the pharmacokinetics and tolerability of fesoterodine in children with overactive bladder. J Pediatr Urol. 2012 Aug;8(4):336-42. 23. Bolduc S, Moore K, Lebel S, et al. Double anticholinergic therapy for refractory overactive bladder. J Urol. 2009 Oct;182(4 Suppl):2033-8 24. Hoebeke P, De Caestecker K, Vande Walle J, et al. The effect of botulinum-A toxin in incontinent children with therapy resistant overactive detrusor. J Urol. 2006 Jul;176(1):328-30. 25. Marte A, Borrelli M, Sabatino MD, et al. Effectiveness of botulinum-A toxin for the treatment of refractory overactive bladder in children. Eur J Pediatr Surg. 2010 May;20(3):153-7 26. Lahdes-Vasama TT, Anttila A, Wahl E, et al. Urodynamic assessment of children treated with botulinum toxin A injections for urge incontinence: a pilot study. Scand J Urol Nephrol. 2011 Dec;45(6):397-400.
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27. Blackburn SC, Jones C, Bedoya S, et al. Intravesical botulinum type-A toxin (Dysport®) in the treatment of idiopathic detrusor overactivity in children. J Pediatr Urol. 2013 Dec;9(6 Pt A):750-3. 28. Bower WF, Moore KH, Adams RD. A pilot study of the home application of transcutaneous neuromodulation in children with urgency or urge incontinence. J Urol. 2001 Dec;166(6):2420-2. 29. Malm-Buatsi E, Nepple KG, Boyt MA, et al. Efficacy of transcutaneous electrical nerve stimulation in children with overactive bladder refractory to pharmacotherapy. Urology. 2007 Nov;70(5):980-3. 30. Lordêlo P, Soares PV, Maciel I, et al. Prospective study of transcutaneous parasacral electrical stimulation for overactive bladder in children: long-term results. J Urol. 2009 Dec;182(6):2900-4. 31. Barroso U Jr, Viterbo W, Bittencourt et al. Posterior tibial nerve stimulation vs parasacral transcutaneous neuromodulation for overactive bladder in children. J Urol. 2013 Aug;190(2):673-7. 32. Quintiliano F, Veiga ML, Moraes M, et al. Transcutaneous parasacral electrical stimulation vs oxybutynin for the treatment of overactive bladder in children: a randomized clinical trial. J Urol. 2015 May;193(5 Suppl):1749-53 33. Hoebeke P, Renson C, Petillon L, et al. Percutaneous electrical nerve stimulation in children with therapy resistant nonneuropathic bladder sphincter dysfunction: a pilot study. J Urol. 2002 Dec;168(6):2605-7; discussion 2607-8. 34. De Gennaro M, Capitanucci ML, Mastracci P, et al. Percutaneous tibial nerve neuromodulation is well tolerated in children and effective for treating refractory vesical dysfunction. J Urol. 2004 May;171(5):1911-3. 35. Capitanucci ML, Camanni D, Demelas F, et al. Long-term efficacy of percutaneous tibial nerve stimulation for different types of lower urinary tract dysfunction in children. J Urol. 2009 Oct;182(4 Suppl):2056-61 36. Patidar N, Mittal V, Kumar M, et al. Transcutaneous posterior tibial nerve stimulation in pediatric overactive bladder: A preliminary report. J Pediatr Urol. 2015 Jul 29. [Epub ahead of print] 37. Groen LA, Hoebeke P, Loret N, et al. Sacral neuromodulation with an implantable pulse generator in children with lower urinary tract symptoms: 15year experience. J Urol. 2012 Oct;188(4):1313-7 38. Dwyer ME, Vandersteen DR, Hollatz P, et al. Sacral neuromodulation for the dysfunctional elimination syndrome: a 10-year single-center experience with 105 consecutive children. Urology. 2014 Oct;84(4):911-7. 12
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39. Maizels M, King LR, Firlit CF. Urodynamic biofeedback: a new approach to treat vesical sphincter dyssynergia. J Urol. 1979 Aug;122(2):205-9. 40. McKenna PH, Herndon CD, Connery S, et al. Pelvic floor muscle retraining for pediatric voiding dysfunction using interactive computer games. J Urol. 1999 Sep;162(3 Pt 2):1056-62; 41. Kaye JD, Palmer LS. Animated biofeedback yields more rapid results than nonanimated biofeedback in the treatment of dysfunctional voiding in girls. J Urol. 2008 Jul;180(1):300-5 42. Desantis DJ, Leonard MP, Preston MA, et al. Effectiveness of biofeedback for dysfunctional elimination syndrome in pediatrics: a systematic review. J Pediatr Urol. 2011 Jun;7(3):342-8 43. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998 Sep;160(3 Pt 2):1019-22. 44. Palmer LS, Franco I, Rotario P, et al. Biofeedback therapy expedites the resolution of reflux in older children. J Urol. 2002 Oct;168(4 Pt 2):1699-702; 45. Khen-Dunlop N, Van Egroo A, Bouteiller C, et al. Biofeedback therapy in the treatment of bladder overactivity, vesico-ureteral reflux and urinary tract infection. J Pediatr Urol. 2006 Oct;2(5):424-9. 46. Kibar Y, Ors O, Demir E, et al. Results of biofeedback treatment on reflux resolution rates in children with dysfunctional voiding and vesicoureteral reflux. Urology. 2007 Sep;70(3):563-6 47. Sener NC, Altunkol A, Unal U, et al. Can a four-session biofeedback regimen be used effectively for treating children with dysfunctional voiding? Int Urol Nephrol. 2015 Jan;47(1):5-9. 48. Hoebeke P, Renson C, De Schryver M, et al. Prospective evaluation of clinical voiding reeducation or voiding school for lower urinary tract conditions in children. J Urol. 2011 Aug;186(2):648-54. 49. Van den Broeck C, Roman de Mettelinge T, Deschepper E, et al. Prospective evaluation of the long-term effects of clinical voiding reeducation or voiding school for lower urinary tract conditions in children. J Pediatr Urol. 2015 Jul 30. [Epub ahead of print] 50. Steinhardt GF, Naseer S, Cruz OA. Botulinum-A toxin: novel treatment for dramatic urethral dilatation associated with dysfunctional voiding. J Urol. 1997 Jul;158(1):190-1 13
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51. Radojicic ZI, Perovic SV, Milic NM.Is it reasonable to treat refractory voiding dysfunction in children with botulinum-A toxin? J Urol. 2006 Jul;176(1):332-6. 52. Mokhless I, Gaafar S, Fouda K, et al. Botulinum A toxin urethral sphincter injection in children with nonneurogenic neurogenic bladder. J Urol. 2006 Oct;176(4 Pt 2):1767-70. 53. Vricella GJ, Campigotto M, Coplen DE, et al. Long-term efficacy and durability of botulinum-A toxin for refractory dysfunctional voiding in children. J Urol. 2014 May;191(5 Suppl):1586-91 54. Austin PF, Homsy YL, Masel JL, et al. alpha-Adrenergic blockade in children with neuropathic and nonneuropathic voiding dysfunction. J Urol. 1999 Sep;162(3 Pt 2):1064-7. 55. Cain MP, Wu SD, Austin PF, et al. Alpha blocker therapy for children with dysfunctional voiding and urinary retention. J Urol. 2003 Oct;170(4 Pt 2):1514-5. 56. Combs AJ, Grafstein N, Horowitz M, et al. . Primary bladder neck dysfunction in children and adolescents I: pelvic floor electromyography lag time--a new noninvasive method to screen for and monitor therapeutic response. J Urol. 2005 Jan;173(1):207-10 57. Donohoe JM, Combs AJ, Glassberg KI. Primary bladder neck dysfunction in children and adolescents II: results of treatment with alpha-adrenergic antagonists. J Urol. 2005 Jan;173(1):212-6. 58. Van Batavia JP, Combs AJ, Horowitz M, et al. Primary bladder neck dysfunction in children and adolescents III: results of long-term alpha-blocker therapy. J Urol. 2010 Feb;183(2):724-30 59. Vanderbrink BA, Gitlin J, Toro S, et al. Effect of tamsulosin on systemic blood pressure and nonneurogenic dysfunctional voiding in children. J Urol. 2009 Feb;181(2):817-22.
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Figure Legends
Figure 1. Schematic flow chart for targeted management of voiding dysfunction in children. Table 1: Important Points of History in Evaluating the Child with Voiding Dysfunction Pregnancy - Prenatal abnormalities • Medical History • Urologic • UTIs • Posterior urethral valves • Reflux • Ureterocele • Non-Urologic • Diabetes • Trauma • Renal disease • Psychiatric diagnoses • ADHD • OCD • Mania • Depression • Sleep apnea • Neurological diseases • Spinal dysraphism • Surgical History • Hypospadias repair • Anti-Reflux procedure/surgery • Ureterocele incision • TUR valves • Spinal Surgery • Abdominal Surgery (ex. Tumor excision, augmentation, Mitrofanoff) • Pelvic Surgery (ex. rectal pull through, bladder neck surgery) • Developmental Milestones • Family History of Voiding Dysfunction • Enuresis • Interstitial cystitis • Childhood incontinence • Urethral dilation • Psychosocial History (ex. Recent deaths, family strife, school stress) • Medications • Lithium • ADHD Meds 15
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•
• Antidepressants • Tricyclics (anticholinergic) • Diuretics • Antihistamines Wetting History • Toilet training (timing of daytime, nighttime, and stool; persistence of continence) • Voiding patterns/habits • Voiding frequency and intervals • Urgency + incontinence • Incontinence (daytime and nighttime episodes and intervals, giggle or stress, awareness, need for protective pad, associated with urge to void ) • Fluid intake/thirst • Bowel habits (frequency, consistency, associated rectal or abdominal pain, Bristol scale) • Posturing (ex. Vincent’s curtsy, leg-crossing, squatting, dancing and wiggling when need to void)
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Table 2: International Children’s Continence Society Classification of Lower Urinary Tract Dysfunction1 1. Bladder and Bowel Dysfunction (BBD) 2. Overactive Bladder (OAB) 3. Voiding Postponement 4. Underactive Bladder 5. Dysfunctional Voiding 6. Bladder Outlet Obstruction 7. Stress Incontinence 8. Vaginal Reflux 9. Giggle Incontinence 10. Extraordinary Daytime Urinary Frequency 11. Bladder Neck Dysfunction
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