Surgical and Nonsurgical Treatment Options for Pediatric Neurogenic Bladder

REVIEW

Surgical and nonsurgical treatment options for pediatric neurogenic bladder

The treatment of children with neurogenic bladder has evolved from the simple wearing of diapers and applying abdominal stoma, to better understanding of the bladder pathophysiology, and the introduction into clinical practice of the principles of clean intermittent catheterization, artiﬁ cial sphincter implantation, continent urinary conduits and a wide spectrum of medications that modulate the function of the lower urinary tracts. In this review we discuss the recent developments in the medical therapy of children with neurogenic bladders, examine the surgical options, and brieﬂ y refer to the future perspectives for the management of this group of patients.

1† KEYWORDS: medical treatment neurogenic bladder surgical treatment Boris CherƟ n , Jacob Golomb2 & Yoram Mor2 The most common cause of neurogenic blad- upper urinary tract damage. For these reasons, †Author for correspondence: der dysfunction in children is neurospinal dis- children with neurogenic bladder dysfunction 1Division of Pediatric Urology, ruption, such as primary open back lesion or require close urologic follow-up and evaluation, The Shaare Zedek Medical myelo meningocele (MMC) [1–5] . Other causes and prompt treatment when indicated. Center, P.O.B. 3235, Jerusalem, of neurogenic dysfunction involving the spine 91031, Israel include sacral agenesis, tethered spinal cord Medical therapy Tel.: +972 2655 5560 associated with imperforate anus, cloacal mal- It is well-known that in untreated spina bifi da Fax: +972 2655 5299 formation and spinal cord injuries. CNS abnor- patients, progressive deterioration by the age of bcherƟ [email protected] malities include spastic diplegia (cerebral palsy) 3 years may be observed in up to 58% of the 2Chaim Sheba Medical Center, and learning disabilities (i.e., attention-defi cit patients [1–3] . Several reports have shown this Tel Aviv University, Israel hyperactivity disorder [ADHD]). The main deterioration to be directly related to increased goals of the urologic management of a child intravesical pressures. In 1981, the bladder pres- with neurogenic bladder dysfunction concen- sure at which urethral leakage occurred was trate on maintenance of normal renal function found to be a useful predictor of unsafe blad- and gaining urinary continence. Over 90% of der function. The detrusor leak-point pressure, the children with spina bifi da will have a nor- as it is now commonly referred to, has become mal upper urinary tract (kidney and ureters) at accepted as one of the urodynamic parameters birth. With no follow-up, half of the children that allow clinicians to differentiate between will suffer considerable upper urinary tract patients who are at relatively low and high risk damage due to lower urinary tract (bladder of subsequent upper urinary tract deterioration. and urethra) hostility. With appropriate uro- In 1984, detrusor external sphincter dyssynergia logical management, children at risk for renal (DSD) was identifi ed as an important factor lead- damage can be identifi ed at an early stage and ing to functional obstruction, and intravesical intervention can be undertaken to prevent the pressure was recognized as the pathophysio- long-term compromise of the kidney function. logical mechanism of subsequent upper urinary During early childhood, the urological focus on tract deterioration. The cornerstone of optimal a child’s health is based on the maintenance of management of neurogenic bladder sphincter normal kidney function [6,7]. As the child begins detrusor dyssenrgia (NBSD) is early identifi ca- to approach school age, interest will be directed tion and characterization, and the institution toward gaining urinary continence. From the of proactive therapy. Crucial for the long-term beginning of the follow-up, no one will be able prognosis of patients with NBSD is the fact that to state which of the children with spinal lesions the management must start before consequences or other nervous system anomalies will be able of bladder dysfunction become apparent. From to preserve the bladder or kidney function, and the outset, the goals of management are to pre- who will be more likely to present with deterio- vent or minimize secondary damage to the upper ration of the bladder function with subsequent urinary tracts and the bladder and to achieve safe

social continence. Thus, long before continence a higher rate of urinary infections. If symptom- becomes an issue, starting from the fi rst year of atic infections occur, these are mainly caused life, management is directed at creating a low- by incomplete bladder emptying, and the CIC pressure reservoir and ensuring complete and safe technique by the child or the caregiver needs to bladder emptying. Overall, the treatment of chil- be optimized. Nonreusable low-friction catheters dren with neurogenic bladder falls into several are considered valuable in high-risk male patients major categories including behavioral therapy, with urethral false passage, or very tense sphinc- pharmacological therapy (often accompanied ters, but are unnecessary in routine cases. In order by clean intermittent catheterization [CIC] or to maintain therapeutic compliance with CISC self-catheterization [CISC]) and utilization of in adolescents, psycho-social support is often electronic stimulation. required. Neurogenic bowel dysfunction with Behavioral therapy describes a group of treat- constipation and fecal soiling can interfere with ments centered on education, whereby the incon- the institution of a successful CIC treatment. tinent patient can be educated about the condi- Retained stools may mechanically impair bladder tion and can develop strategies to minimize or fi lling, increase detrusor irritability or contribute eliminate the incontinence. There are different to urine retention. Stool incontinence increases components of behavioral therapy, such as timed the risk of bladder contamination and urinary voiding, fl uid dietary management, voiding tract infection. An effective bowel management diary, urge inhibition, reinforcement and pelvic program is therefore needed. muscle training [8]. However, CIS alone is not suffi cient to main- CIC enables complete bladder emptying, tain a low-pressure reservoir and avoid upper and thus avoids bladder residues and the con- renal tract damage. Thus, a combination of CIS sequent risks for infections [1,2,6,8] . In the high- and pharmacological therapy, aiming to decrease risk bladder with DSD, CIC also allows bladder bladder pressure, is considered as the standard empting before the occurrence of high voiding therapy in these children [2,9]. Currently, anti- pressures, which is known to be detrimental for muscarinic agents are the fi rst-line choice for the kidney function and drainage. Which of the wide pharmacologic treatment of overactive bladder variety of available materials and techniques is (OAB) (TABLE 1). Antimuscarinic therapy, such as used for CIC does not seem to affect the effi cacy oxybutynin, tolterodine, trospium chloride, dari- and safety, as long as some basic principles are fenacin and solifenacin, increases bladder capacity applied: proper education and training, clean and delays the initial urge to void, thereby reduc- and atraumatic application and achievement of ing the symptoms of OAB. Pharmacotherapy, good patient compliance on a long-term basis. most often with an anti muscarinic agent, is an For education, training and further guidance established approach to managing neurogenic- during follow-up, a dedicated continence nurse mediated OAB. Antimuscarinic agents, partic- is invaluable. It is benefi cial to begin the cath- ularly oxybutynin, are associated with typical eterization early in life, in order to identify the anticholinergic side effects that may limit treat- small group of children who are at risk for car- ment. These side effects may include dry mouth, rying signifi cant residual urine. In addition, all gastrointestinal effects such as constipation and families become familiar with the technique CNS effects. Only oxybutynin is approved for of catheterization, which can be very helpful if use in children. However, since its introduction this treatment is recommended at a later stage. into the market, tolterodine has been extensively Subsequently, CISC can be successfully taught to used in children as an off-label drug with virtual boys and girls who are motivated and who have absence of side effects [9]. developed the required dexterity, mostly around Since the new generation of the anti muscarinic the age of 6 years. The required frequency of agents may be used in children only as off-label catheterization depends on several factors includ- drugs, and ditropan has a well-known profi le ing fl uid intake, bladder capacity and bladder of side effects, alternative routes of ditropan fi lling/voiding pressures. In practice, it is recom- administration have been explored in order to mended to catheterize six times a day in infants increase the clinical effectiveness and to decrease (linked with feeding time) and fi ve times a day side effects. One of the ways to avoid the afore- in school-aged children. Although the reported mentioned side effects and to increase the clini- incidences of CIC-related infection risks are vari- cal effi cacy of oxybutynin is to deliver the agent able, it is generally agreed that the risk is low as via intravesical instillation [10] . The antimusca- long as complete bladder emptying is achieved. rinic effect of oxybutynin is comparable with Furthermore, re-used supplies are not related to oral administration, but the severity and the

158 Therapy (2009) 6(2) future science group Surgical & nonsurgical treatment options for pediatric neurogenic bladder REVIEW

Table 1. Anticholinergic therapy in neurogenic bladder. Medication Brand name Dosage Oxybutynin* Ditropan® 0.4 mg/kg per day Oxybutynin Ditropan XL® 5–10 mg once daily, extended release Oxybutynin Oxytrol® 3.9 mg per day system applied extended-release twice weekly (every 3–4 days), transdermal patch Tolterodine‡ Detrol® 1–2 mg twice daily Tolterodine Detrol LA® 2–4 mg once daily, extended release Darifenacin Enablex® 7.5–15 mg once daily Solifenacin VESIcare® 5–10 mg once daily Trospium chloride Sanctura® 20 mg twice daily Trospium chloride Sanctura XR® 60 mg once daily, extended release *Oxybutynin – the only approved agent for use in children ‡Tolterodine – off-label use with good safety profi le. frequency of side effects is lower. In most reports, although caution must be taken in interpreting intravesical oxybutynin is used in dosages of these results, as all the studies were off-label and 0.3–0.6 mg/kg per day in two or three doses. retrospective. Consideration must be given to Given its better tolerability compared with oral the fact that general anesthesia is required for treatment, if required, intravesical dosages can the administration of this medication, especially be increased up to 0.9 mg/kg per day. However, in children. Moreover, further investigation is one should be aware that in spite of intra vesical required concerning the cost and the long-term instillation, oxybutynin may still produce CNS- effi cacy and safety of prolonged botulinum-A related side effects [9]. Consequently, it is held toxin administration. that oxybutynin should be administered intra- vesically in those patients who have either failed Electronic stimulation with other antimuscarinic treatment modalities Sacral neuromodulation is an established and (such as oral) or who had unbearable side effects FDA-approved treatment for patients with from them. refractory urgency and urge incontinence In children who showed no symptoms of and idiopathic urinary dysfunctional voiding. bladder-wall relaxation and decrease of intra- It allows direct afferent nerve stimulation by vesical pressure following the administration of direct implantation of a sacral device [15] . The the antimuscarinic therapy, different methods principle of sacral neuromodulation is that the of bladder ‘denervation’ are indicated [11–14] . refl ex control of the lower urinary tract can Botulinum-A toxin injections into the detru- be ‘modulated’ through continuous low-level sor muscle have been shown to be a potentially nerve stimulation. It has been shown to signifi - valuable approach in the neurogenic overactive cantly affect all the parameters related to the bladder. Repeated botulinum-A toxin injections elimination syndrome, such as incontinence and (as an alternative or as an additive to anticho- urgency. It should be stressed that this tech- linergics) could be considered to postpone or nique is not indicated by the FDA in the spina prevent surgical procedures in the small minor- bifi da population; therefore, further studies in ity of children who do not respond to a standard this population are awaited. therapy with CIC or anticholinergics. Although the use of botulinum toxin for the treatment Surgical management of OAB and detrusor overactivity (DO) is There is a group of children with signifi cant currently not approved by the US FDA or by bladder overactivity who do not respond well the European regulatory agencies, its use in to medication, catheterization or nerve stimula- investigational protocols and ‘off-label’ con- tion. When this occurs, operative intervention tinues to grow. Botulinum-A toxin has been may be required. The most effective surgical successfully used in the pediatric population, procedure to eliminate urine incontinence and although, in most cases, more than one session to decrease the pressure in an infant is creation was required [12] . The published data support of vesicostomy, which allows the neurogenic the effi cacy of botulinum-A toxin for refrac- bladder to grow while keeping the pressure low. tory DO in the pediatric population, whether Reconstruction with closure of the vesicostomy it is of neurogenic or non-neurogenic origin, and augmentation is typically performed when

future science group www.futuremedicine.com 159 REVIEW Chertin, Golomb & Mor

the child begins school, when the patient and linear growth or bone density in children under- the family are ready to accept the responsibility going augmentation. Finally, patients with any of intermittent catheterization. type of intestinal augmentation are at risk for As the child ages and the upper urinary tract perforation, especially if compliance with cath- remains normal, the interest can be shifted to eterization is suboptimal. Since the long-term focus on gaining urinary continence. It is usu- complications following bladder augmentation ally practical to consider urinary continence can not be brushed aside and an ideal material when a child enters school. Prior to an opera- for bladder enlargement is still to be found, some tive intervention two main questions should have questioned the rational for routine blad- be answered: is the bladder volume acceptable der augmentation in all patients with urinary and the urinary sphincter competent, or does incontinence. Snodgrass et al. published their the child require augmentation and/or a proce- experience with bladder neck sling without aug- dure to improve the outlet resistance, in order mentation in 30 neurogenic bladder patients [20]. to achieve continence? [5,16,17]. Prior to the sur- All patients underwent a 360° fascial sling with- gical correction of incontinence, urodynamic out augmentation for high leak-point pressure evaluation with fl uoroscopic imaging is thus and stress urinary incontinence. Satisfactory performed. Since emptying in patients with a continence was achieved in 83% of all patients. neurogenic bladder will require intermittent Only one patient needed bladder augmentation catheterization, preoperative assessment deter- due to being refractory to the anticholinergics mines whether the catheterization should be therapy. The authors concluded that elevated performed through the urethra, or whether an bladder pressure with decreased bladder com- abdominal stoma will be necessary. pliance does not require bladder augmentation in neurogenic bladder patients. This experience Bladder augmentation needs to be supported by longer follow-up stud- Historically, various different segments of bowel ies in order to become a routine practice in this have been used for bladder augmentation [18] . group of patients. The most commonly used segment for augmentation is ileum. Classic clam augmentation Bladder neck reconstruction cysto plasty has been utilized successfully both in In children with poor urethral outlet resistance, adults and in children. It is important to isolate bladder neck reconstruction may be necessary the segment at least 10 cm from the ileocecal to obtain continence [5,21]. The literature is fi lled valve, so as not to interfere with bowel con- with a myriad of papers describing different trol, especially in patients with myelo dysplasia methods to increase urethral resistance, while at who already have bowel continence issues. the same time allowing ease of catheterization. Detubularization on the antimesenteric border In females, the majority prefer to utilize a fas- provides a low-pressure reservoir and increases cial sling that is placed just distal to the bladder capacity when fashioned into either a U or W neck, with the concomitant creation of an abdom- shape. The bladder plate needs to be widely inal stoma. The sling can be placed abdominally, opened to prevent an hourglass deformity when if a concomitant augmentation is performed. To anatomizing the patch to the bladder. Sigmoid safely identify the space between the urethra and augmentation has also been successful, although the vagina (urethra and rectum in males), the there are reports of increased rhythmic contrac- posterior midline approach behind the bladder is tion when this segment is used. In select cases, used. Since the human cadaveric fascia and xeno- gastric augmentation has been quite successful, tropic sling material are available, there is no need having the advantage of less mucous production for an abdominal incision and autologous sling and less changes in metabolic parameters. Proper harvest in every case. In the majority of cases, patient selection, which includes neurogenic the urethral sling allows catheterization through patients who are insensate, is critical to avoid the the urethra, eliminating the need to construct an clinical syndrome of hematuria/dysuria, related abdominal stoma for catheterization [22]. to irritation of native urethelium by the acidic In males, it is hard to fi nd one operation that urine [19] . can be applied to every patient. We do prefer to Patients with ileal augmentation are subject utilize Young–Dees–Leadbetter bladder neck to metabolic acidosis, mucous production and reconstruction, which consists of reimplantation urolithiasis, as well as a risk of cancer at the of the ureters to a higher position in the bladder, anastomotic site. It has been shown that meta- and tubularization of the mucosa over a 5F feed- bolic changes do not have an adverse affect on ing tube. Some prefer to use a modifi ed Kropp

160 Therapy (2009) 6(2) future science group Surgical & nonsurgical treatment options for pediatric neurogenic bladder REVIEW

bladder neck tube or Pippe–Salle bladder neck should malfunction occur [24–26]. In prepu- reconstruction [5,21]. Both procedures involve uti- bertal children, the cuff must be placed at the lization of the anterior bladder wall strip that is bladder neck, while in post-puberty it can be subsequently tubularized over the catheter and placed around the bulbar urethra. brought through the submucosal tunnel. Bladder neck closure Injectable therapy Bladder neck closure is a last resort in those Injectable (bulking) agents may be effective in patients who have undergone alternative pro- decreasing or eliminating urinary incontinence cedures with refractory incontinence [27]. The by increasing bladder-outlet resistance and/or procedure can be performed retropubically, increasing urethral length. Bulking agents are transvesically or transvaginally in girls. This injected into the submucosal tissues of the procedure is carried out in combination with urethra or bladder neck and/or into the tis- the creation of an abdominal stoma, and can be sues adjacent to the urethra [23]. The injections diffi cult in patients with previous bladder neck increase tissue bulk and thereby increase outlet surgery. The amount of scarring often requires resistance. Treatment-related adverse events are opening the bladder to gain access to the bladder uncommon and relatively minor, the most com- neck. The key to a successful operation is wide mon being dysuria, urinary urgency, transient mobilization and division of the bladder neck. urinary retention and acute urinary retention. Omentum is frequently interposed between the These procedures may be performed using local bladder neck and the urethra. anesthesia in an outpatient or offi ce setting. The best candidates for treatment with inject- Catheterizable stomas able materials are those patients with a normal All continent catheterizable stomas employ a fl ap bladder capacity and compliance, poor urethral valve (Mitrofanoff) principal to maintain con- function or intrinsic sphincter defi ciency (ISD) tinence. Continence is achieved as the bladder and good anatomic support. Contraindications fi lls and the intravesical pressure is transmitted to the use of injectable materials include to the conduit. The proximal end is brought out untreated detrusor overactivity, active urinary to the abdominal wall, either through the lower tract infection and known hypersensitivity to quadrant or through the umbilicus, and is spatu- the proposed injectable agent. A number of lated and anastamosed to a V-shaped skin fl ap materials have been proposed for the injection created to prevent stenosis. If the appendix is not into the bladder neck. Crosslinked bovine col- available, ileum and colon can also be fashioned lagen implant, autologous fat, carbon particles, into a conduit utilizing the Monti procedure: a macroplastique and polytetrafluoroethylene 2 cm segment of ileum or colon is isolated and (PTFE) have been reported to achieve improve- opened on the antimesenteric border and retubu- ment or dryness in children with incontinence. larized; if the length is inadequate, two segments However, the low safety profi le and poor long- can be fashioned and anastamosed to each other. term effi cacy did not support this therapy. Alternatively, a single segment can be split in the US FDA approval of dextranomer/hyaluronic middle, opened from opposite ends and rolled acid (Dx/HA; Defl ux®) as a tissue-augmenting over a feeding tube to create a spiral Monti. This substance for the treatment of VUR has driven provides adequate length in most cases, avoid- the introduction of this substance also for ing the need to harvest two separate intestinal the treatment of urinary incontinence due to segments. Complications of the catheterizable bladder neck incompetence. channel are a frequent and challenging problem, and include cutaneous stenosis (6%), channel Artifi cial urinary sphincter stricture (6%), stomal prolapse (5%) and chan- An artifi cial urinary sphincter (AUS) is the nel leak (21%) [28]. These complications appear only device that most closely simulates the to occur throughout the life of the channel, function of a biological urinary sphincter. The mostly developing within the fi rst 2 years. AMS-800, introduced in 1982, is the current model of the artifi cial genitourinary sphinc- Conclusion ter. The artifi cial urinary sphincter is a useful In patients with neurogenic bladder the pri- adjunct in gaining urethral continence. The mary goal is to preserve the upper tract func- disadvantages of the artifi cial sphincter include tion with concomitant attainment of urinary infections, which require removal, as well as the and fecal continence. In order to accomplish need for replacing pump, reservoir or tubing these goals, each child requires evaluation,

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with the institution of intermittent catheteriza- Several synthetic materials such as polyvinyl tion and/or medical therapy upon diagnosis. sponge, Tefl on® and silicone have been used Meticulous care prevents the need for recon- for bladder reconstruction but have failed structive surgery, and protects the upper tract in due to mechanical malfunctioning or urinary the majority of children with neurogenic blad- stone formation. It seems that only selective der. If the child develops recurrent infection or cell transplantation may provide a reasonable increasing hydronephrosis early on, a vesicos- basis for the regeneration of the urothelial and tomy is needed until the child is old enough muscular layers and provide the right condi- for reconstruction. Otherwise, patients should tions for bladder replacement. At present, the be followed until school age when continence search for the proper scaffold on which the issues can be addressed. Only when the patient matrices and cells for bladder augmentation and his/her family are ready and understand the may be implanted is still ongoing. The fi rst consequences of surgery should augmentation, clinical experience with tissue engineering of bladder neck reconstruction or the creation of human bladders was recently published by a continent catheterizable stoma be performed. Atala et al. [31]. Seven patients with myelomeningocele, aged 4–19 years, with high-pressure Future perspective or poorly compliant bladders, were identifi ed Currently, gastrointestinal segments are used as candidates for cystoplasty. A bladder biopsy in patients with neurogenic bladder whenever was obtained from each patient and the urothe- pharmacological therapy with or without CIC lial and muscle cells were grown in culture and has failed. Unfortunately, those patients are not seeded on a biodegradable bladder-shaped scaf- free of the complications such as urinary tract fold made of collagen, or a composite of collagen infections, metabolic disturbances, stones and and polyglycolic acid. Approximately 7 weeks development of malignant processes in the aug- after the biopsy, the autologous engineered blad- mented bladders. The use of tissue-engineering der constructs were implanted either with or techniques may be a good alternative to the pre- without an omental wrap. Postoperatively, the viously described surgical methods, omitting mean bladder leak-point pressure decreased at their associated complications. capacity, the volume and compliance increased, The goal of tissue-engineering techniques in bowel function and renal function were normal bladder reconstruction is to create a biological and no metabolic consequences nor urinary cal- substance that may restore and maintain a nor- culi were noted during a follow-up period of mal organ function and avoid rejection [29,30]. 46 months. Despite the advances in this fi eld,

Executive summary Medical therapy In untreated spina bifi da patients, progressive deterioration may be observed in up to 58% by the age of 3 years. The leak-point pressure, as it is now commonly referred to, has become accepted as one of the urodynamic parameters that allows clinicians to differentiate patients with relatively low and high risk for subsequent upper urinary tract deterioration. The treatment of children with neurogenic bladder falls into the following major categories: behavioral therapy, pharmacological therapy (often accompanied by clean intermittent catheterization [CIC] or self-catheterization) and utilization of electronic stimulation. CIC enables complete bladder empting and thus avoids bladder residues and consequent risks for infections. Antimuscarinic agents are the fi rst-line choice for the pharmacologic treatment of overactive bladder. The published data support the effi cacy of botulinum-A toxin administration. Surgical therapy The most effective surgical procedure to eliminate urine incontinence and to decrease the pressure in an infant is the creation of vesicostomy. The most commonly used segment for bladder augmentation is ileum. Gastrocystoplasty shows its benefi ts only in patients with chronic renal insuffi ciency, metabolic acidosis or short-gut syndrome. In children with poor urethral outlet resistance, bladder neck reconstruction may be necessary to obtain continence. Bladder neck closure is the last resort in those patients who have undergone alternative procedures with refractory incontinence. All continent catheterizable stomas employ a fl ap valve principal to maintain continence. Conclusion The primary goal of treatment in patients with neurogenic bladder is to preserve the upper tract function with concomitant attainment of urinary and fecal continence. Each child requires evaluation, with the institution of intermittent catheterization and/or medical therapy upon diagnosis. Only when the patient and his/her family are ready and understand the consequences of surgery should augmentation, bladder neck reconstruction or creation of a continent catheterizable stoma be performed.

162 Therapy (2009) 6(2) future science group Surgical & nonsurgical treatment options for pediatric neurogenic bladder REVIEW

signifi cant efforts should still be made in order refl ex pathway construction [32,33], but none of to fi nd biological materials that may improve them has been widely incorporated into routine tissue regeneration. clinical work yet. Another fi eld that should be intensively inves- tigated is bladder neuromodulation. This ther- Financial & competing interests disclosure apy directly addresses the root of the problem The authors have no relevant affi liations or fi nancial involve- in patients with neurogenic bladder, namely the ment with any organization or entity with a fi nancial interest abnormal relationship between the nerves and in or fi nancial confl ict with the subject matter or materials the bladder wall. Various approaches have been discussed in the manuscript. This includes employment, con- introduced, including transurethral bladder sultancies, honoraria, stock ownership or options, expert tes- electrostimulation, sacral neuromodulation and timony, grants or patents received or pending, or royalties. neurosurgical techniques such as selective sacral No writing assistance was utilized in the production of rhizotomy and artifi cial somatic–autonomic this manuscript.

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