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Conservative management in neurogenic bladder dysfunction A few decades ago, urinary diversion, usually with an ileal The neurological conditions that cause urinary tract conduit, was the ultimate outcome for most children with spina damage in children may be congenital, idiopathic, or less bifida. The revolutionary institution of clean intermittent frequently are secondary to a trauma. The details of the catheterization has changed the algorithm totally. Furthermore etiological factors are beyond the scope of this paper, but many new drugs have been developed during the past decade it is important to realize that the vast majority of and have decreased the need for surgery dramatically. In this neurogenic bladder dysfunction in the pediatric popula- article, we will focus on the most recent data on new modalities tion is secondary to neural tube defects, in particular of therapy to help avoid urinary diversion or bladder The outcome of the upper urinary tract is related to the In addition to clean intermittent catheterization and oxybutynin combination of the detrusor and sphincteric function. A treatment, a new generation of anticholinergic medications, hyperre¯exic detrusor has a detrimental effect on the such as tolterodine, has been developed. For patients who drop upper urinary tract only when the sphincter fails to relax out because of the side-effects of oral administration, new simultaneously, a situation called detrusor±sphincter methods of administration are now available, including extended dyssynergia. When the sphincter is weak or are¯exic, release and intravesical instillation. For those unresponsive, the kidneys are protected, but in this situation incon- botulinum-A toxin and resiniferatoxin are two relatively new tinence becomes a problem. Based on these basic drugs in the field, administered as intravesical injection and concepts, the objectives of therapy for neurogenic instillation, respectively. Intravesical or transdermal electrical bladder dysfunction are well de®ned: protecting the stimulation, sacral nerve stimulation and biofeedback therapy kidneys from progressive damage by reducing the are under development, but as currently administered, are not intravesical pressure during both ®lling and emptying, and improving the quality of life by providing urinary continence. Therapy is individualized, e.g. to reduce Although life-saving in many respects, bladder augmentation high intravesical pressure in a patient with detrusor introduces life-long risks of its own. Our goal in describing hyperre¯exia, or clean intermittent catheterization (CIC) `conservative' management is to prevent this step. Many in a child who cannot empty his/her bladder adequately.
alternatives to surgery are available now and more effectivestrategies are under development.
It is well known in spinal cord injuries that there is a spinal shock period that lasts typically 6±12 weeks (but Children, conservative, myelomeningocele, treatment may be as long as 1 year), characterized by an are¯exic bladder and urinary retention. After this, the detrusor Curr Curr Opin Urol 12:473±477. # 2002 Lippincott Williams & Wilkins.
may be hyperre¯exic or are¯exic, and coordination or dyssynergia with the urethral sphincter occurs depending on the level of spinal cord injury. It is likely that closure Division of Urology, Albany Medical College, Albany, New York, USA of the neural tube defect (or the placement of a Correspondence to Barry A. Kogan, MD, Division of Urology, Albany Medical College, ventriculoperitoneal shunt) causes spinal shock, as in Tel: +1 518 262 3296; fax: +1 518 262 6050; e-mail: koganb@mail.amc.edu children with myelomeningocele. Baskin et al. [1] found ®ve patients (out of 35) in whom an are¯exic bladder Current Opinion in Urology 2002, 12:473±477 matured to a hyperre¯exic bladder over the ®rst few months of life. In a more recent study, Stoneking et al.
[2.] con®rmed this ®nding. In a retrospective analysis of 54 children who underwent myelomeningocele repair, nearly all patients required CIC for urinary retention after surgery. In 74% this lasted less than 2 weeks, but in 26% the effect was seen for up to 6 weeks after surgery [2.].
Baskin et al. [1] obtained excellent results in preventing upper urinary tract changes with an aggressive program of anticholinergic agents combined with CIC. In contrast, after the period of spinal shock, Stoneking et al. [2.] observed their patients and ultimately 38% of children available that enable the production of very low friction needed CIC or vesicostomy before toilet training. This catheters. These have been shown to have less suggests that preventive institution of therapy would be hematuria than traditional catheters, as well as a high bene®cial. In a retrospective analysis of 46 children rate of patient/family satisfaction [8]. However, they are treated before or after 1 year of age, Wu et al. [3] reported not disposable and are signi®cantly more expensive than con®rmatory results. There was a signi®cantly lower rate the traditional technique. We consider them very of bladder augmentation in the group treated early. In valuable in high-risk patients with urethral/stomal false addition, the early institution of CIC also seems to have passages or very tense sphincters, but unnecessary in psychological bene®ts, with an apparent improvement in family compliance and the ability to assist the child in coping with their disease and with CIC. In a similar Children with voiding dysfunction without neurological comparison of prophylactic treatment to observation in a and anatomical pathology also bene®t from the use of high-risk group of 45 patients with myelodysplasia, the CIC. In a review of 23 patients with non-neurogenic group treated early again had a decreased rate of neurogenic bladder, detrusor hyperre¯exia was detected augmentation cystoplasty (17 versus 41%) and improved in 13 and all had a high post-void residual urine [9.]. Of the 23 children, 16 accepted the use of CIC. This group was completely dry during the follow-up while on CIC, These data suggest a bene®cial effect of early evaluation either with or without anticholinergic therapy (eight in and therapy, especially in high-risk groups. Initial evaluation should include renal/bladder ultrasound and ¯uoro-urodynamic study. The urodynamic study is crucial because the intravesical pressure and the Patients with an are¯exic detrusor and high post-void coordination of the detrusor with the external sphincter residual urine are the best candidates for CIC therapy.
are good predictors of future renal and bladder function Patients with hyperre¯exic detrusor require conversion [5]. If sophisticated urodynamic studies are not possible, to a lower pressure detrusor. Although this can be a relatively simple leak point pressure has been shown to performed surgically, the preference is to do this by non- be predictive of upper tract outcome [6]. A leak point pressure higher than 40 cm of water will result in a high rate of upper tract changes. Both anticholinergic therapy Oxybutynin chloride is a well-known anticholinergic and and CIC should be instituted in this group in order to antispasmodic agent. Its ef®cacy on clinical and urody- avoid damage secondary to high intravesical pressures.
namic parameters has been documented in infants and neonates [1,10]. In a study of 41 children with myelomeningocele and detrusor hyperre¯exia [11], who Thirty years of worldwide experience has made CIC the were evaluated urodynamically before and within 3 primary choice for bladder emptying in the treatment of months after the initiation of combined therapy, children with neurogenic bladder dysfunction. Although oxybutynin signi®cantly increased the maximal bladder there are some concerns about the risk of infection and capacity, and decreased the detrusor pressure at maximal patient/family compliance, CIC remains the best method capacity. Continence was improved also in 70% of to empty are¯exic bladders with maximum ef®cacy and patients over 6 years of age who were incontinent before minimal side-effects. In a recent study of the risks of infection [7.], two techniques of intermittent catheter- ization were compared in patients with myelomeningo- The major problem with oxybutynin is the high rate of cele. Ten patients compared using a sterile catheter four side-effects. Dry mouth, constipation and heat intoler- times a day for 4 months with a reusable clean catheter ance may be seen in almost a third of patients and are for another 4 months. The results showed that bacter- the main reason for dropout. Because of the pharmaco- iuria was present in almost 75% of patients, but there kinetics of the drug, oxybutynin should be administered was no difference in its frequency with either regimen.
three times a day, which results in reduced patient Only two symptomatic urinary tract infections were seen compliance. To overcome this problem, a slow-release in each group in a total of 158 urine samples. These data form of the drug has been developed. Studies in adults show that the use of sterile catheters is an unnecessary have demonstrated the same success rate with better expense, and con®rm that CIC with a reusable catheter tolerability with the slow-release formulation [12], and is an excellent method of bladder emptying in this we studied retrospectively the ef®cacy and safety of the extended-release oxybutynin in children with bladder dysfunction (neurogenic or urge incontinence without Although traditional, reusable catheters have been neurological abnormalities) [13.]. We con®rmed that shown to be effective, some newer technologies are treatment with extended-release oxybutynin was effec- Conservative management in neurogenic bladder dysfunction Aslan and Kogan 475 tive and well tolerated. This formulation is suggested for Di Stasi et al. [21.] looked at the plasma levels of any children who require anticholinergic medication and oxybutynin and its metabolite N-desetyl oxybutynin after oral administration, intravesical instillation (passive diffusion), and intravesical instillation combined with Another promising drug is tolterodine tartrate. Like electric current (electromotive administration). The oxybutynin, it is a muscarinic receptor antagonist, and its authors found that electromotive administration in- ef®cacy in treating the overactive bladder has been creased the intravesical uptake of the oxybutynin, demonstrated in adults [14]. Compared with oxybutynin, resulting in an improvement in urodynamic parameters its selectivity for the bladder is similar, but it is eight compared with oral administration or passive diffusion.
times less potent at the antimuscarinic receptor in the They concluded that some part of the intravesical parotid gland [15], suggesting that it will cause less dry oxybutynin (3 of 15 mg in their study) must be mouth. In a study of 22 children (0.1 mg/kg) with sequestered in the urothelium during intravesical detrusor hyperre¯exia (21 myelomeningocele and one instillation, and electric current might be useful for spinal cord trauma), Goessl et al. [16] used tolterodine as either a replacement therapy for oxybutynin or as an initial therapy. Tolterodine was found to be equal to Another new medication that has been shown to be oxybutynin in ef®cacy and had fewer adverse effects in effective in the treatment of patients with `overactive the group that had previously been treated with bladder' is resiniferatoxin. It acts via desensitization of oxybutynin. Although not directly applicable to patients unmyelinated C ®bers (afferent nerves of the bladder).
with neurogenic dysfunction, in a study of 33 children Whether this mechanism of action will be effective in with overactive bladder (urgency, frequency and urge patients with spina bi®da is questionable. There is a incontinence), different dosages of oral tolterodine single case report in the literature on the use of demonstrated linear pharmacokinetics and excellent resiniferatoxin in a child with myelomeningocele [22.].
ef®cacy in decreasing voiding frequencies and incon- A 9-year-old boy with low bladder compliance and grade tinence episodes [17.]. Only two patients discontinued II bilateral vesicoureteral re¯ux failed both oral and the treatment because of adverse effects. A new form of intravesical oxybutynin. Resiniferatoxin was tried intra- extended-release tolterodine has been introduced re- vesically. Three months after one instillation, the boy cently. It should have equal ef®cacy and fewer side- was without evidence of re¯ux and had improved effects. In summary, extended-release formulations of bladder compliance. Because the results in adults with either oxybutynin or tolterodine are excellent new `overactive bladder' are promising, this medication has options for the treatment of children with detrusor signi®cant potential for use in children with spina bi®da, but many more studies are needed to determine the ef®cacy and safety of the drug in this population.
Another alternative to reduce side-effects is the intravesical administration of oxybutynin. Many differ- Since the 1980s, botulinum-A toxin (BTX) has been ent preparations have been described, and there are used for the treatment of various conditions such as therefore many discrepancies in results and particularly strabismus, dystonia, spasticity and other disorders that patient compliance [18]. One popular method consists cause inappropriate striated muscle contraction. It is a of the dissolution of a 5 mg tablet of oxybutynin selective blocker of acetylcholine release at the neuro- chloride in 30 ml sterile saline and the instillation of muscular junction [23]. In urology, it was ®rst studied in this suspension into the bladder via a catheter. The adult patients with spinal cord lesions that resulted in daily dosage and frequency of intravesical instillation either detrusor/sphincter dyssynergia [24] or detrusor remain controversial, but most authors recommend hyperre¯exia [25]. Promising results in temporarily using the medication three times a day. It has been paralyzing the sphincter in the adult population have demonstrated that intravesical oxybutynin chloride is led the investigators to study the ef®cacy of BTX in the absorbed rapidly, and greater serum levels are obtained bladders of children with high intravesical pressure. In a than after oral administration [19]. In a study that prospective study of a highly selected group [26.], BTX compared the side-effects, Ferrara et al. [20] demon- was injected under anesthesia at 30±40 sites into the strated that intravesical administration was safer and bladder wall of 17 children. All had intravesical pressures better tolerated than oral oxybutynin chloride. How- greater than 40 cm of water despite a high dosage of ever, out of 34 children, six still had side-effects such as anticholinergic medication. A repeat urodynamic study drowsiness, hallucinations and cognitive changes. In 2±4 weeks after the injection showed a signi®cant contrast, though, out of 67 children who underwent increase in maximal bladder capacity and detrusor treatment with oral oxybutynin, 11 discontinued the compliance. Although there was a decrease in incon- tinence episodes, this difference was not statistically signi®cant. No side-effect was noted, except one child investigated how effective neuromodulation would be who had increased post-void residual urine. To date, when applied at home, via a self-applied surface long-term results on the ef®cacy and safety of BTX use electrode in the sacral area instead of a traditional anal in children are not available. Moreover, in other settings electrode. After at least one month of application lasting the effects last only for a few months, making repeat 1 h twice a day, a 73% improvement in continence was treatments necessary. Although promising, much more observed. However, only seven out of 15 children were research is needed on this therapy before it can be completely dry. To date, the long-term results of considered an alternative to augmentation cystoplasty.
transcutaneous neuromodulation are not available. More prospective studies of this modality are needed.
Intravesical electrical stimulation of the After an experience of almost 45 years in Europe and 20 Biofeedback therapy is an alternative treatment to CIC years in North America, the bene®ts from the use of and anticholinergic agents for children who have voiding electrical stimulation of the bladder in children with dysfunction and are unable to relax their pelvic ¯oor myelomeningocele are still controversial. The technique during voiding [34,35]. The basic technique involves is not complicated and consists of ®lling the bladder with learning to contract and relax the pelvic ¯oor muscles saline and giving the electrical stimulation transureth- using visual and auditory monitors of electromyographic rally via an electrocatheter. The technique is however activity. Like many of the techniques described above, very labor intensive. A series of 20±90-min sessions is this technique is very labor intensive, and motivation performed before evaluating the response. Unfortu- and patient cooperation are very important for successful nately, a multi-institutional study of 335 patients [27] treatment. A recent study [36.] suggested combining a demonstrated that only 16% of patients responded and non-invasive urodynamic method with various psycho- those had only a 53% increase in bladder capacity and a logical techniques (such as externalizing the problem, 25% decrease in detrusor pressure. A smaller study [28] empowerment and homework), to overcome the dif®- demonstrated an increase in bladder capacity in 33% and culties with conventional treatment. A total of 77 chil- a decrease in pressure in 28% after 4 years' follow-up of dren with detrusor/sphincter dyssynergia were treated, 25 patients. Although these data are not convincing and after a relatively short follow-up period (mean of 8.6 scienti®cally, controversy continues regarding the bene- months), 61% had improvement in both urinary symp- ®ts of this therapy [29,30]. A fair summary would be that toms and urodynamic parameters. Experience in myelo- transurethral electrical stimulation of the bladder is very meningocele patients is very limited. Only one out of six labor intensive, and has failed to enable volitional girls with spina bi®da had improvement after biofeed- voiding in these patients. Nor are there data to suggest back, probably because there were so few healthy nerves that this technique reduces the rate of surgical interven- remaining. It appears that biofeedback has great tions. Therefore it is not used commonly at this time.
potential in children with non-neurological voiding dysfunction, but limited ef®cacy in children with There has been an increase in popularity of this therapy for patients with voiding dysfunction in the past few years. Unfortunately there are few studies of its use in CIC and oral pharmacological agents are the ®rst-line children with myelomeningocele. In an original work treatment in most patients with bladder dysfunction and [31], this modality had signi®cant effects in children with incontinence regardless of the etiology. The early intact sacral nerves. Unfortunately, volitional voiding was institution of therapy seems very bene®cial. Highly not possible. Moreover, the optimal use of the technique selected patients may also bene®t from new forms of is to increase outlet resistance in those children with anticholinergic agents, as well as electrical stimulation inadequate sphincteric function; however, this is the and biofeedback. Surgical therapy should be reserved for group that has maldeveloped sacral nerves and therefore cases that are totally unresponsive to conservative is least amenable to the technique. Further modern studies with this interesting modality are warranted.
Low-frequency electrical current has been used com- Papers of particular interest, published within the annual period of review, have monly in adults and less frequently in neurologically normal children to inhibit detrusor activity and treat urge incontinence [32]. The stimulator can be applied over the anterior tibial nerve, but most commonly the stimulation Baskin LS, Kogan BA, Benard F. Treatment of infants with neurogenic bladder dysfunction using anticholinergic drugs and intermittent catheteriza- is performed via an anal electrode. A recent study [33.] Conservative management in neurogenic bladder dysfunction Aslan and Kogan 477 Stoneking BJ, Brock JW, Pope JC, et al. Early evolution of bladder emptying 19 Massad CA, Kogan BA, Trigo-Rocha FE. The pharmacokinetics of after myelomeningocele closure. Urology 2001; 58:767±771.
intravesical and oral oxybutynin chloride. J Urol 1992; 148:595±597.
This paper shows the similarity of clinical findings after myelomeningocele closure 20 Ferrara P, d'Aleo CM, Tarquini E, et al. Side-effects of oral or intravesical oxybutynin chloride in children with spina bifida. BJU Int 2001; 87:674±678.
Wu HY, Baskin LS, Kogan BA. Neurogenic bladder dysfunction due to myelomeningocele: neonatal versus childhood treatment. J Urol 1997; 21 Di Stasi SM, Giannantoni A, Navarra P, et al. Intravesical oxybutynin: mode of action assessed by passive diffusion and electromotive administration with pharmacokinetics of oxybutynin and N-desethyl oxybutynin. J Urol 2001; Kaefer M, Pabby A, Kelly M, et al. Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with An important paper trying to explain the action mechanism of intravesical myelomeningocele. J Urol 1999; 162:1068±1071.
oxybutynin and also how to improve its efficacy.
Tanaka H, Kakizaki H, Kobayashi S, et al. The relevance of urethral 22 Seki N, Ikawa S, Takano N, et al. Intravesical instillation of resiniferatoxin for resistance in children with myelodysplasia: its impact on upper urinary tract neurogenic bladder dysfunction in a patient with myelodysplasia. J Urol 2001; deterioration and the outcome of conservative management. J Urol 1999; This is the single report about the treatment of resiniferatoxin in children.
McGuire EJ, Woodside JR, Borden TA, et al. Prognostic value of urodynamic 23 Brin MF. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology.
testing in myelodysplastic patients. J Urol 1981; 126:205±209.
Muscle Nerve Suppl 1997; 6:S146±S168.
Schlager TA, Clark M, Anderson S. Effect of a single-use sterile catheter for 24 Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with each void on the frequency of bacteriuria in children with neurogenic bladder on botulinum A toxin: a double-blind study. Arch Phys Med Rehabil 1990; intermittent catheterization for bladder emptying. Pediatrics 2001; 108:E71.
A very good comparison of standard CIC to single-use sterile catheters. It is important to know that the cost-effective treatment is safe and the urinary tract 25 Schurch B, Stohrer M, Kramer G, et al. Botulinum-A toxin for treating infection rate is also similar to the sterile technique.
detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164:692±697.
Sutherland RS, Kogan BA, Baskin LS, et al. Clean intermittent catheterization in boys using the LoFric catheter. J Urol 1996; 156:2041±2043.
26 Schulte-Baukloh H, Michael T, Schobert J, et al. Efficacy of botulinum-a toxin in children with detrusor hyperreflexia due to myelomeningocele: preliminary Pohl HG, Bauer SB, Borer JG, et al. The outcome of voiding dysfunction results. Urology 2002; 59:325±327; discussion 327±328.
managed with clean intermittent catheterization in neurologically and anatomi- An elegant study showing that BTX may also be used in children with high cally normal children. BJU Int 2002; 89:923±927.
intravesical pressure refractory to anticholinergic therapy.
This study demonstrates that CIC may be a reasonable therapeutic alternative in 27 Cheng EY, Richards I, Balcom A, et al. Bladder stimulation therapy improves bladder compliance: results from a multi-institutional trial. J Urol 1996; 10 Kasabian NG, Bauer SB, Dyro FM, et al. The prophylactic value of clean intermittent catheterization and anticholinergic medication in newborns and infants with myelodysplasia at risk of developing urinary tract deterioration.
28 Decter RM, Snyder P, Laudermilch C. Transurethral electrical bladder stimulation: a followup report. J Urol 1994; 152:812±814.
11 Goessl C, Knispel HH, Fiedler U, et al. Urodynamic effects of oral oxybutynin 29 Kaplan WE. Intravesical electrical stimulation of the bladder: pro. Urology chloride in children with myelomeningocele and detrusor hyperreflexia.
30 Decter RM. Intravesical electrical stimulation of the bladder: con. Urology 12 Anderson RU, Mobley D, Blank B, et al. Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS 31 Schmidt RA, Kogan BA, Tanagho EA. Neuroprostheses in the management Oxybutynin Study Group. J Urol 1999; 161:1809±1812.
of incontinence in myelomeningocele patients. J Urol 1990; 143:779±782.
13 Youdim K, Kogan BA. Preliminary study of the safety and efficacy of extended- 32 Trsinar B, Kraij B. Maximal electrical stimulation in children with unstable release oxybutynin in children. Urology 2002; 59:428±432.
bladder and nocturnal enuresis and/or daytime incontinence: a controlled This study underlines the major difference between immediate-release and study. Neurourol Urodyn 1996; 15:133±142.
extended-release oxybutynin: 21 out of 25 children were still taking the extended-release oxybutynin at last follow-up.
33 Bower WF, Moore KH, Adams RD. A pilot study of the home application of 14 Appell RA, Abrams P, Drutz HP, et al. Treatment of overactive bladder: long- transcutaneous neuromodulation in children with urgency or urge incontinence.
term tolerability and efficacy of tolterodine. World J Urol 2001; 19:141±147.
Sacral transcutaneous electromodulation seems a promising alternative to the 15 Nilvebrant L, Andersson KE, Gillberg PG, et al. Tolterodine ± a new bladder- therapies performed with an anal electrode, but we need long term results with selective antimuscarinic agent. Eur J Pharmacol 1997; 327:195±207.
16 Goessl C, Sauter T, Michael T, et al. Efficacy and tolerability of tolterodine in 34 Yamanishi T, Yasuda K, Murayama N, et al. Biofeedback training for detrusor children with detrusor hyperreflexia. Urology 2000; 55:414±418.
overactivity in children. J Urol 2000; 164:1686±1690.
17 Hjalmas K, Hellstrom AL, Mogren K, et al. The overactive bladder in children: a 35 Porena M, Costantini E, Rociola W, et al. Biofeedback successfully cures potential future indication for tolterodine. BJU Int 2001; 87:569±574.
detrusor-sphincter dyssynergia in pediatric patients. J Urol 2000; 163:1927± A very nice paper investigating dose-escalation of tolterodine in the child population. Unfortunately, the study group does not include patients with spina 36 Chin-Peuckert L, Salle JL. A modified biofeedback program for children with detrusor-sphincter dyssynergia: 5-year experience. J Urol 2001; 166:1470± 18 Kasabian NG, Vlachiotis JD, Lais A, et al. The use of intravesical oxybutynin chloride in patients with detrusor hypertonicity and detrusor hyperreflexia. J An elegant paper that may positively change the results of biofeedback therapy and in turn the outcomes of children with detrusor-sphincter dyssynergia.

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