Find best premium and Free Joomla templates at GetJoomlaTemplatesFree.com

Neuropathic Bladder in Childhood

Junaid Ashraf, Anna Radford

Department of Paediatric Urology, Leeds General Infirmary, Leeds, United Kingdom

 

Correspondence:

Junaid Ashraf

Department of Paediatric Urology

Leeds General Infirmary

Leeds, LS1, 3EX, United Kingdom

E- mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Phone: 0113 392 6228

 

Abstract

AimThe aim of this article to give a concise summary of the assessment and management of neuropathic bladders as per the current literature in the paediatric age group.

Keywords: neuropathic bladder, assessment, investigation, conservative treatment, surgical management

 

Introduction

Normally a bladder should be able to fill to a certain capacity as per age while maintaining low bladder pressures, a sensation to void when bladder is full and stay under voluntary control and ultimately empty at the end of voiding without significant residual urine volumes [1]. Neuropathic bladder is a dysfunction of urinary bladder due to disease of central or peripheral nervous system in control of micturition [1]. Neuropathic bladder in children is almost always due to spinal cord anomalies both congenital and acquired [1] . The most common cause of bladder dysfunction in children is the abnormal development of spinal canal and spinal cord termed neural tube defects (NTD) [1]. Aims of management should be directed towards preserving renal function, preventing progressive bladder damage and decreasing the frequency and impact of urinary tract infections [22]. By taking a holistic approach it can also be possible to optimize continence and associated social issues.

Aetiology

Neuropathic bladder dysfunction may complicate a variety of neurological conditions (Table 1). The aetiology of congenital abnormalities, such as spina bifida and related NTD is still debated but genetic and environmental factors appear to play a major pathophysiological role. Multiple physical factors are implicated include; irradiation [2] , hyperthermia [3], drugs including thalidomide, folate antagonists, anti-epileptics like valproate and carbamazepine [4], hypervitaminosis A, substance abuse like alcohol, chemical agents e.g., organic mercury, lead [5]. Certain maternal infections like rubella [6], cytomegalovirus [7] as well as maternal metabolic conditions including gestational diabetes mellitus with obesity [8]. The most well known cause being nutritional particularly folate deficiency, possibly due to polymorphisms in folate metabolising enzymes and enhanced likelihood of meiotic non disjunction, particulary in trisomy 21 [9]. Dietary supplementation with folic acid in the peri conceptual period can reduce the incidence of NTD by approximately 50% [10].

Table 1:  Causes of Neuropathic bladder in childhood

CONGENITAL

ACQUIRED

1.

Myelomeningocele

1.

Trauma to Spinal Cord

2.

Spinal bifida Occulta (lumbosacral lipoma,intraspinal cysts, tethered cord, Diastematomyelia)

2.

Vascular - Ischaemia and Thrombosis of Spinal Cord (due to prematurity, cardiac/aortic surgery)

3.

Sacral anomalies and Caudal Regression

3.

Tumors (Sacrococcygeal teratoma, Neuroblastoma, bladder and prostate Rhabdomyosarcoma)

4.

Transverse Myelitis

5.

Functional-Non-neurogenic Neuropathic bladder (Hinman-Allen Syndrome), Disturbed voiding patterns, toilet phobias or refusal, Idiopathic

Epidemiology

The incidence of spina bifida is 2-3/1000 live births [10] . There is female predominance which is more marked in anencephaly. There is also geographical variation with increased incidence in Ireland, Scotland, Wales and decreased incidence in Japan. Similarly the incidence in African Americans is 0.1-0.4 per 1000 births vs. 1 in 1000 live births in while population. A family with one child with NTD has a 2-5% chance of each subsequent sibling suffering from same condition [10].

Pathophysiology

The aim of treatment of neuropathic bladder is to try as much as possible to replicate normal bladder functions including (a) filling and storage of urine at a low bladder pressure (b) maximum emptying of bladder to reduce urine stasis related problems particularly infection and (c) voiding/emptying of bladder at regular intervals.

Classification of Neuropathic bladder:

Bladder dysfunction can be classified very simply in relation to its normal function and to the function of the sphincteric complex [14].

A. Failure to Store Urine: a) Detrusor: Poor compliance, involuntary contractions, small capacity bladder and sensory abnormalities. b) Inadequate bladder outlet resistance: Physiological, anatomical or psychological.

B. Failure to empty voluntarily and completely: a) Weak Detrusor: neurogenic, myogenic, psychological and Idiopathic. b) Increased Bladder outlet resistance: Neurogenic, anatomical, physiological (sphincter dyssynergia),psychological.

Patterns of Neuropathic Bladder:

There are three basic patterns of neuropathic bladders seen by urodynamic evaluation [1].

1. Contractile bladder / Supra sacral Cord Lesions: The innervations of the detrusor and external urethral sphincter are intact and conus reflexes are positive. Voiding occurs by detrusor hyperreflexia almost always associated with detrusor-sphincter dyssynergia. This is also called dynamic sphincteric obstruction. Intravesical pressures are invariably high and may lead to secondary upper renal tract complications

2. Acontractile bladder /Sacral Cord Lesions: The innervations of both detrusor and external sphincter is destroyed, conus reflexes are absent along with negative Detrusor contractility but some degree of sphincteric incompetence is always present. Voiding occurs either by overflow dribbling or by raising intra-abdominal pressure. There is a fixed urethral resistance of varying severity in different patients but constant in any individual patient. Degree of detrusor non-compliance is common.

3. Intermediate bladder Dysfunction: This bladder comprises of a combination of anomalies including various degrees of detrusor non-compliance, detrusor hyper reflexia and sphincteric incontinence. In NTD, the patterns of bladder dysfunction are 25% contractile, 15% acontractile and 60% intermediate [4].

Secondary upper renal tract complications

Around 20% of children with NTD are affected by upper renal tract complications by 2 years of age [4]. Approximately 50% of boys are at risk of upper tract complications by puberty. Risk in girls is slightly less than that.

Factors responsible for these complications include urine Infection which is extremely common mostly resulting from bladder dysfunction [15]. Vesicoureteric reflux (VUR) will affect 40% of children with neuropathic bladder, by the age of five [16]. VUR could be primary or more often secondary in which case the treatment is aimed to correct the underlying bladder abnormal function.

Neuropathic bladders and non neuropathic neuropathic bladders can either be seen as “safe”, whereby the pressure experienced within them is low, usually due to an ineffective sphincter, resulting in 60% of adolescents being incontinent [16] or “at risk”. In the latter group bladder outflow obstruction either in the form of detrusor-sphincter dyssynergia or static sphincteric obstruction is associated with increased intra vesical pressure. In an attempt to compensate for this the bladder will distend, lose compliance, be at risk of infection, become scarred and form diverticuli in order to increase capacity and thereby reduce pressure. When these countermeasures fail the system the detrusor becomes overactive and there is loss of compliance placing the upper tracts at risk of damage. The resulting pathology is known as end stage bladder disease.

As previously mentioned a number of diseases of the urinary bladder culminated in end stage bladder disease characterised by small contracted bladders that create high pressure systems with consequences for kidney function [17]. These conditions, have a poorly defined pathological pathway. Urothelium cells isolated from neuropathic bladders have been shown to have a compromised proliferative and differentiated phenotype in vitro [18], but as the urothelium is not implicated in the primary pathogenesis the reasons for this are unknown.

Patient Assessment

History

Detailed history is invaluable in workup of these patients and should include antenatal history and complications, birth and development [19]. It is important to establish both day and night time voiding symptoms which can be divided into: a) Storage symptoms including urgency, urge incontinence, frequency and dysuria. b) Obstructive symptoms including urinary retention, hesitancy, staccato voiding (starting and starting), straining to void and feeling of incomplete bladder emptying.

Examination

Physical examination should include examination of abdomen (palpable faeces/bladder), back (hair tuft, nevus, dimple over lumbosacral spine, asymmetrical gluteal crease), genitalia and lower extremities (reflexes, muscles mass, strength, gait, perineal sensation, tone, gross and fine movement) [19]. Neurological assessment is done to demonstrate presence or absence of conus reflexes and existence of any sacral sensory or motor sparing. Positive conus reflexes are associated with sphincteric competence and is therefore associated with excellent prognosis.

It is worth mentioning here that in a neonate if the bladder is expressible or conus reflexes are negative or if there is no sensory sparing then a neuropathic bladder is almost certainly present.

Investigations

Blood Tests are usually not needed unless clinically indicated. If a child with known neuropathic bladder presents with symptoms of upper urine tract infection, then it's reasonable to perform routine tests including full blood count, urea and creatinine along with urine examination, microscopy and culture [19].

Spine X Ray

X-Ray of the spine (Fig. 1) is a quick way to identify the segment of the spine involved [23]. Abdominal X rays may also be required to assess faecal loading/constipation.

Figure 1: X ray of lumbosacral spine showing the pedicles of the sacral vertebrae are widely spaced consistent with the diagnosis of spina bifida. There is an associated moderate generalised faecal loading of the colon.

10.4 4 1

Ultrasound

Ultrasound (Fig. 2) is non- invasive, quick, and radiation-free. It has become the standard technique to look for upper tract dilatation and post-micturation bladder residual volume [23].

Figure 2: Ultrasound of a neuropathic bladder showing the thickened bladder wall with trabeculations and echoes are identified within the bladder, consistent with debris secondary to poor bladder emptying. There is bilateral dilated ureters seen behind the bladder as well suggestive of high intravesical pressures.

10.4 4 2

Micturating Cystourethrogram (MCUG)

Micturating Cystourethrogram (Fig. 3 and 4) is done to understand bladder anatomy, look for presence of vesicoureteric reflux, bladder wall anatomy including trabeculations, diverticulae formation, bladder outflow obstruction [23].

Figure 3: Micturating cystourethrogram in a Neuropathic bladder. The examination was performed via an indwelling Foleys catheter showing bladder with elongated configuration, irregular outline with diverticulae and is thick walled with trabeculations. There is grade 4 vesico-ureteric reflux the right side, a secondary Vesicoureteric reflux representing high Intravesical pressures.

10.4 4 3

Figure 4: Micturating cystourethrogram study done on an Augmented bladder. Contrast outlined the irregular augmented bladder without evidence of contrast leak. Augmentation has significantly increased bladder capacity, the native small volume bladder can be seen below with Augmented segment on top.

10.4 4 4

Dimercapto succinic acid (DMSA) Scan

Other imaging like scans like DMSA scan (Fig. 5) may be needed if there are dilated upper tracts/vesico ureteric reflux seen on the ultrasounds particularly if there is a history of recurrent urine infections to assess kidney scarring and assess baseline differential function of the kidneys [20,23].

Figure 5: Renal DMSA. Left kidney is generally small and central photopenia represent the mild collecting system dilatation (can be correlated with similar findings on ultrasound scan).There is far greater central photopenia due to collecting system dilatation on the right side, The split renal function calculated lies outside the normal range (Calculated differential : left kidney 16% and right kidney 84%).

10.4 4 5

Urodynamics

Urodynamics is indispensable in elucidating the various patterns of bladder dysfunction associated with neuropathic bladder [21]. This helps to understand bladder anatomy and physiology and help plan further management. Video-urodynamics (a combination of filling cystometry and pressure flow study) is the gold standard for urodynamic investigation in patients with neurogenic lower urinary tract dysfunction [21, 23].

Treatment

Treatment needs to be individualized and initial steps after diagnosis should include identification of potential risks to renal function, optimise voiding patterns and management of associated bowel dysfunction [19]. To increase urine storage, gentle stretching of the bladder by increased oral fluids should be encouraged.

Medical

Pharmacological treatment must be provided alongside urotherapy and biofeedback and adequate constipation treatment has been assured [22].

Anticholinergics

Anticholinergics (like Oxybutynin, Tolterodine & Solifenacin) inhibit the binding of acetylcholine to the muscarinic receptors in the detrusor, thereby suppressing involuntary bladder contractions. This results in an increase in bladder volume voided and a decrease in micturition frequency, sensation of urgency, and number of urge incontinence episodes [23].

Oxybutynin inhibits the action of acetylcholine on smooth muscle and has a direct antispasmodic effect on smooth muscles. This, in turn, increases bladder capacity and decreases uninhibited contractions. Oxybutynin is relatively M3, M1 bladder receptor specific [43].

Tolterodine is a nonspecific competitive muscarinic receptor antagonist for OAB. However, it differs from other anticholinergic types in that it has selectivity for urinary bladder over salivary glands. Tolterodine exhibits a high specificity for muscarinic receptors [43].

Solifenacin is a tertiary amine approved by the FDA for OAB in adults since 2005. It has excellent bioavailability, a long half-life and potentially a superior side-effect profile due to subtype receptor selectivity for the bladder [23,44]. It was shown that the combination of two different anticholinergics might be a well tolerated and successful option in children with overactive refractory to monotherapy, as well as administration of a receptor-selective antimuscarinic such as solifenacin [23, 42]. The role of alpha-blockers such as doxazosin in the treatment of neuropathic bladder in children remains controversial [24].

Clean Intermittent Catheterisation

To improve bladder emptying double voiding and timed bladder voiding is needed of course when they are toilet trained. Clean intermittent catheterisation (CIC) may be needed if bladder emptying is poor. Clean intermittent catheterisation along with an anti-cholinergic is the standard therapy for a neuropathic bladder [6, 23]. Ideally CIC needs to be instituted early to prevent both renal damage as well as secondary bladder wall changes that helps to improve long term outcomes.

Antibiotics

Urine infection needs either short course of antibiotics or low dose prophylactic antibiotic to prevent infections, although in the era of antibiotic guardianship to prevent infection there is increasing evidence to suggest that prophylaxis should be used only in selected cases [27].

Surgical Options

There are various surgical options which are only considered following thorough bladder assessment, informed consent with child and family [28].

1. Suprapubic catheter or Vesicostomy Button

This is generally a short term emergency measure or a bridging option to a major surgical intervention to buy time and acclimatizes child and parents with use of catheters for bladder drainage [38]. When intermittent urethral catheterization cannot be established, Mitrofanoff continent urinary diversion (described later) seems to be a major surgery for patients and their parents. In addition, for some patients, intermittent bladder emptying may be required for a transitory period. For all these reasons, there is a place for a reversible vesicostomy with a minimally invasive procedure. Button vesicostomy seems to be a good alternative [38] definitely as a short term measure to empty bladders regularly and reduce intra vesical pressures.

2. Botulinum Toxin

Both detrusor hyper-reflexia and detrusor noncompliance can be managed with injection of botulinum toxin but the affect usually lasts for around 6 months [29]. It also carries the risk of needed bladder catheterisation acutely or exacerbating incontinence. It can also be injected into the sphincters to decrease outflow resistance.

4. Catheterising Conduits

Appendicovesicostomy (Mitrofanoff Procedure) is done for those who are either unable to catheterise urethra for anatomical reasons or because of presence of sensate urethra. This procedure creates a channel between the bladder and the wall of the abdomen to allow intermittent self-catheterisation i.e., drainage of the bladder. The Mitrofanoff is preferentially made from the appendix (or small bowel) which is mobilised on its blood supply or a piece of bowel. One end is tunnelled into the wall of the bladder to create a valve that acts as a continent mechanism, the other end is passed through an opening in the abdominal wall to form a small stoma through which a catheter can pass to empty the bladder 4-6 times a day.

The Mitrofanoff is often situated on the right hand side of the lower abdomen, just below the underwear line or for cosmetic appearances another possible site is the umbilicus [39].

5. Augmentation Cystoplasty

Enterocystoplasty remains the principal means of bladder augmentation since is available widely. The overall aim is reduction in urinary tract infections (UTIs), improved continence and important reduced bladder pressures and subsequent damage to the upper urinary tracts. Various visceral segments have been used in bladder augmentation including ileum [23], sigmoid colon and stomach. Complications include; mucus production [30] causing blockage of catheter, stenosis, infections, metabolic changes [31], spontaneous perforation [32], malignancy [33], bowel problems like diarrhoea, dysuria and hematuria particularly with gastrocystoplasty [28].

Other Augmentation options include autoaugmentation, autoaugmentation with demucosalised enterocystoplasty [34, 35], detrusorectomy [35], augmentation with tissue engineered neobladder and ureterocystoplasty [28]. One group has reported using synthetic and natural biomaterial scaffolds in the form of polyglycolic acid (PGA) and small intestinal submucosa (SIS) in auto-augmentation in rabbits only [36].

6. Sphincter Incompetence

Surgical options include bladder neck repair and urethral sling procedures which are usually done in conjunction with bladder augmentation procedures if there is minimal outlet resistance. Some common techniques include Young Dees, Kropp and Pippi Salle procedure, bladder neck suspension, urethral sling procedures, periurethral bulking agents and artificial urinary sphincter [28, 37].

7. Urinary Diversion

Ileal conduit or continent bladder replacement surgical procedures are done with a pouch of colon. These are associated with long term complication with dilatation and infection as well as metabolic complications and neoplasia therefore usually carried out as salvage procedures [37, 41].

Bowel Management

Spinal cord lesions has the similar effects on rectum and anal sphincters leading to faecal incontinence either due to constipation, overflow incontinence, sphincteric competence or combination of these factors. Initial treatment includes appropriate diet, laxatives, regular colonic emptying by manual evacuations, purgatives, suppositories or retrograde enemas. If it fails or child is unwilling then an ante-grade continence enema (ACE) procedure is usually considered. In ACE Procedure, an appendix or Monti ileal tube can be implanted between caecum and anterior abdominal wall as a catheterisable channel for antegrade continent enema [37].

 

References:

1. Bauer SB. Neurogenic bladder: etiology and assessment. Pediatric nephrology (Berlin, Germany) 2008;23:541-51

2. Wertelecki W, Chambers CD, Yevtushok L, Zymak-Zakutnya N, Sosyniuk Z, et al. Chornobyl 30 years later: Radiation, pregnancies, and developmental anomalies in Rivne, Ukraine. Eur J Med Genet 2017; 60:2-11

3. Zhang T, Leng Z, Liu W, Wang X, Yan X, Yu L. Suppressed expression of mitogen-activated protein kinases in hyperthermia induced defective neural tube. Neurosci Lett 2015;594:6-11

4. Akimova D, Wlodarczyk BJ, Lin Y, Ross ME, Finnell RH, et al. Metabolite profiling of whole murine embryos reveals metabolic perturbations associated with maternal valproate- induced neural tube closure defects. Birth Defects Res A Clin Mol Teratol 2017; 109 (2), 106-119

5. Jin L, Zhang L, Li Z, Liu JM, Ye R, Ren A. Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population. Reprod Toxicol 2013;35:25-31

6. Cheng N, Bai Y, Hu X, Pei H, Li Y, et al. Prevalence of birth defects and rubella infection in pregnant women in Gansu, west China. A survey. J Reprod Med 2003;48:869-74

7. Mestas E. Congenital Cytomegalovirus. Adv Neonatal Care 2016;16:60-5

8. Parnell AS, Correa A, Reece EA. Pre-pregnancy obesity as a modifier of gestational diabetes and birth defects associations: A Systematic review. Matern Child Health J 2017; 24.

9. Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, et al. Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect. Am J Med Genet 2001; 103:128-32

10. Arata M, Grover S, Dunne K, Bryan D. Pregnancy outcome and complications in women with spina bifida. J Reprod Med 45:743-8

11. Araki I, Matsui M, Ozawa K, Takeda M, Kuno S. 2003. Relationship of bladder dysfunction to lesion site in multiple sclerosis. J Urol 2000; 169:1384-7

12. Yeo L, Singh R, Gundeti M, Barua JM, Masood J. Urinary tract dysfunction in Parkinson's disease: a review. Int Urol Nephrol 2012; 44:415-24

13. Hinman F, Jr. Nonneurogenic neurogenic bladder (the Hinman syndrome) --15 years later. J Urol 1986;136:769-77

14. Madersbacher H. The various types of neurogenic bladder dysfunction: an update of current therapeutic concepts. Paraplegia 1990; 28:217-29

15. Brown S, Marshall D, Patterson D, Cunningham AM. Chronic pyelonephritis in association with neuropathic bladder. Eur J Pediatr Surg 1999(9);1:29-30

16. Verhoef M, Lurvink M, Barf HA, Post MW, van Asbeck FW, et al. High prevalence of incontinence among young adults with spina bifida: description, prediction and problem perception. Spinal Cord 2005; 43:331-40

17. Rasouly HM, Lu W. Lower urinary tract development and disease. Wiley Interdiscip Rev Syst Biol Med 2013; 5:307-42

18. Subramaniam R, Hinley J, Stahlschmidt J, Southgate J. Tissue engineering potential of urothelial cells from diseased bladders. J Urol 2011;186:2014-20

19. Bauer SB, Austin PF, Rawashdeh YF, de Jong TP, Franco I, et al. International Children's Continence Society's recommendations for initial diagnostic evaluation and follow-up in congenital neuropathic bladder and bowel dysfunction in children. Neurourol Urodyn 2012; 31:610-4

20. Filler G, Gharib M, Casier S, Lodige P, Ehrich JH, Dave S. Prevention of chronic kidney disease in spina bifida. Int Urol Nephrol 2012; 44:817-27

21. Bauer SB, Nijman RJ, Drzewiecki BA, Sillen U, Hoebeke P. International Children's Continence Society standardization report on urodynamic studies of the lower urinary tract in children. Neurourol Urodyn 2015; 34:640-7

22. Santos JD, Lopes RI, Koyle MA. Bladder and bowel dysfunction in children: An update on the diagnosis and treatment of a common, but underdiagnosed pediatric problem. Can Urol Assoc J 2017;11:S64-s72

23. Lee B, Featherstone N, Nagappan P, McCarthy L, O'Toole S. British Association of Paediatric Urologists consensus statement on the management of the neuropathic bladder. J Pediatr Urol 2016;12:76-87

24. Kroll P, Gajewska E, Zachwieja J, Sobieska M, Mankowski P. An Evaluation of the Efficacy of Selective Alpha-Blockers in the Treatment of Children with Neurogenic Bladder Dysfunction-- Preliminary Findings. Int J Environ Res Public Health 2016;13 (3): 321

25. Carla Verpoorten, G M Buyse. The Neurogenic Bladder: Medical Treatment. Paediatr Nephrol 2008; 23(5): 717-25.

26. Faure A, Peycelon M, Lallemant P, Audry G, Forin V. Pro and Cons of Transurethral Self- Catheterization in Boys: A Long-Term Teaching Experience in a Pediatric Rehabilitation Centre. Urol J 2016;13:2622-8

27. Akil I, Ozen C, Cengiz B. Do patients with neurogenic bladder treated with clean intermittentcatheterization need antibacterial prophylaxis? Turk J Med Sci 2016; 46:1151-4

28. Godbole P WD. Surgery for neuropathic bladder and incontinence. Pediatric Surgery and Urology: Long term outcomes, ed. OK Stringer MD, Mouriquand PDE: 631-42.

29. Khan MK, VanderBrink BA, DeFoor WR, Minevich E, Jackson E, et al. Botulinum toxin injection in the pediatric population with medically refractory neuropathic bladder. J Pediatr Urol 2016; 12:104.e1-6

30. Gough DC. Enterocystoplasty. BJU Int 2001; 88:739-43

31. Fontaine E, Leaver R, Woodhouse CR. The effect of intestinal urinary reservoirs on renal function: a 10-year follow-up. BJU Int 2000;86:195-8

32. Bauer SB, Hendren WH, Kozakewich H, Maloney S, Colodny AH, et al. Perforation of the augmented bladder. J Urol 1992; 148:699-703

33. Austen M, Kalble T. Secondary malignancies in different forms of urinary diversion using isolated gut. J Urol 2004; 172:831-8

34. Cartwright PC, Snow BW. Bladder autoaugmentation: partial detrusor excision to augment the bladder without use of bowel. J Urol 1989;142:1050-3

35. Chrzan R, Dik P, Klijn AJ, Kuijper CF, de Jong TP. Detrusorectomy reduces the need for augmentation and use of antimuscarinics in children with neuropathic bladders. J Pediatr Urol 2013; 9:193-8

36. Lai JY, Chang PY, Lin JN. Bladder autoaugmentation using various biodegradable scaffolds seeded with autologous smooth muscle cells in a rabbit model. J Pediatr Surg 2005; 40:1869- 73

37. Gonzalez R, Schimke CM. Strategies in urological reconstruction in myelomeningocele. Curr Opin Urol 2002; 12:485-90

38. Lacreuse I, Becmeur F, Dheu C et al. Endoscopic Mic key button placement for continent vesicostomy. J Laparoendosc Adv Surg Tech A 2010;20(3):297-9.

39. Monfort G, Guys JM, Morissons G. Appendicovesicosomy: an alternative urinary diversion in a child. Eur Urol 1984;10(6):361-3.

40. Shimada K, Matsumoto F, et al. Surgical management of urinary incontinence in children with anatomical bladder-outlet anomalies. Int J Urol 2003;9(10):561-6

41. Cass AS, Luxenberg M, Gleich P, Johnson CF. A 22 year follow up of Ileal conduits in children with Neurogenic bladders. J Urol 1984;132(3):529-31

42. Shroder A, Thuroff JW. New strategies for medical management of overactive bladder in children. Curr Opin Urol 2010;20(4):313-7.

43. Paul A, Karl-Erik A, Jerry J B, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 2006; 148, 565–578.

44. Smulders RA, Krauwinkel WJ, Swart PJ, et al. Pharmacokinetics and safety of Solifenacin succinate in healthy young men. J Clin Pharmacol 2004;44:1023–33.