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International children's continence society's recommendations for therapeutic intervention in congenital neuropathic bladder and bowel dysfunction in children

International Children’s Continence Society’s Recommendations for Therapeutic Intervention Y.F. Rawashdeh,1 P. Austin,2 C. Siggaard,3 S.B. Bauer,4 I. Franco,5 T.P. de Jong,6 T.M. Jorgensen7* and International Children’s Continence Society 1Pediatric Urology, Aarhus University Hospital, Denmark 2Pediatric Urology, St. Louis Children’s Hospital, and Washington University, St. Louis, Missouri 3Pediatrics, Aarhus University Hospital, Denmark 4Pediatric Urology, Children’s Hospital, Boston, Massachusetts 5Pediatric Urology, New York Medical College, Valhalla, New York 6Pediatric Urology, UMC Utrecht, and AMC Amsterdam, Netherland 7Pediatric Urology, Institute of Clinical Medicine, Aarhus University, Denmark Purpose: We present a consensus view of members of the International Children’s Continence Society on thetherapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. Material andMethods: Discussions were held by a group of pediatric urologists and gastroenterologists appointed by theboard. The following draft review document was open to all the ICCS members via the ICCS web site. Feedback wasconsidered by the core authors and by agreement, amendments were made as necessary. The final document is not asystematic literature review. It includes relevant research when available as well as expert opinion on the currentunderstanding of therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children.
Results: Guidelines on pharmalogical and surgical intervention are presented. First the multiple modalities forintervention that do not involve surgical reconstruction are summarized concerning pharmacological agents, medicaldevices, and neuromodulation. The non-surgical intervention is promoted before undertaking major surgery.
Indicators for non-surgical treatments depend on issues related to intravesical pressure, upper urinary tract status,prevalence of urinary tract infections, and the degree of incontinence. The optimal age for treatment of incontinence isalso addressed. This is followed by a survey of specific treatments such as anticholinergics, botulinum-A toxin, anti-biotics, and catheters. Neuromodulation of the bladder via intravesical electrical stimulation, sacral nerve stimulation,transcutaneous stimulation, and biofeedback is scrutinized. Then follows surgical intervention, which should betailored to each individual, based on careful consideration of urodynamic findings, medical history, age, and presenceof other disability. Treatments mentioned are: urethral dilation, vesicostomy, bladder, augmentation, fascial sling,artificial urinary sphincters, and bladder neck reconstruction and are summarized with regards to success ratesand complications. Finally, the treatment on neuropathic bowel dysfunction with rectal suppositories irrigation andtransrectal stimulation are scrutinized. Neurourol. Urodynam. ß 2012 Wiley Periodicals, Inc.
Key words: bladder; bowel; neuropathic; recommendations; theraputic intervention pressures when children have low detrusor compliance thatplaces them at risk for renal compromise. There is excellent There are multiple modalities of intervention for infants level 1 evidence for the efficacy of anticholinergics to reduce and children with neuropathic bowel dysfunction (NBD) that do not involve surgical reconstruction. These treatment The clinical efficacy from anticholinergics depends on the modalities include pharmacologic agents, medical devices, receptor subtype present in the target organ. Several musca- and neuromodulation. The non-surgical interventions should rinic receptors exist throughout the body that include the be promoted before undertaking major surgery. Indications following receptor subtypes: M1, M2, M3, M4, and M5.2 The for these non-surgical treatments depend on issues related to predominant muscarinic subtype in the bladder is the M2 intravesical pressures, upper urinary status, prevalence of UTI, receptor (66%); however it is the M3 receptor subtype (33%) and degree of incontinence. While continence is usuallyaddressed as the child reaches school age, issues such as ele-vated detrusor pressure, hydronephrosis and/or reflux, and Christopher Chapple led the review process.
chronic UTIs are treated at any time.
The review is produced in normal high ethical standards.
Conflict of interest: none.
*Correspondence to: T.M. Jorgensen, MD, Institute of Clinical Medicine, Faculty ofHealth, Aarhus University, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark.
E-mail: Received 3 March 2012; Accepted 5 March 2012Published online in Wiley Online Library Anticholinergics are the mainstay of medical treatment for NBD. They are used to diminish DO and intravesical storage that is responsible for the physiologic action of detrusor- delivery such as local skin site irritation and the necessity for mediated micturition.3,4 Antagonism of M3 receptors result in continual skin adherence. Nevertheless, transdermal oxybuty- detrusor smooth muscle relaxation; this reaction is similar for nin appears to be a reasonable alternative to oral oxybutynin neurogenic and non-neurogenic patients.
in the treatment of NBD in older children.
Oxybutynin is the first modern anticholinergic agent; it has Besides oxybutynin, there has been an emergence of undergone extensive examination in children with NBD. It is new selective anticholinergic medications that are designed the only FDA approved anticholinergic in the United States for to diminish side effects by either targeting specific muscarinic pediatric use in NBD. The dosing of oral and intravesical oxy- receptor subtypes or by altering the structural compounds so butynin is 0.2 mg/kg/dose every 8 hr. Many practitioners will that they are less likely to cross organ barriers. Tertiary use the formula 1 mg per year of age per dose, up to a maxi- amines (oxybutynin, tolterodine, darifenacin, solifenacin, and mum of 5 mg per dose. Despite its efficacy, oxybutynin propiverine) are more likely to cross the blood–brain barrier has associated systemic effects that are related to the presence (BBB) than quaternary amines (propantheline and trospium).1 of muscarinic receptors in other organ systems. Side effects Other factors such as lipophilicity, molecular size, and molecu- include: dry mouth, constipation, blurred vision, headache, lar charge are also responsible for determining permeability tiredness (somnolence), impaired school performance, facial of an anticholinergic crossing the BBB. Despite emergence of flushing, gastrointestinal discomfort, and dry itchy skin. Ex- new anticholinergics, few have been studied in children. Tol- tended release oral formulations appear to be safe in children terodine is the only other anticholinergic besides oxybutynin and may improve patient compliance while diminishing that has undergone a trial in children with NBD by the FDA.
the incidence and severity of side effects seen with immediate Study design limitations, however, prevent therapeutic label- ing for tolterodine in the treatment of children with NBD.
A significant concern with any anticholinergic is its impact Nevertheless, in small case studies of children with NBD, tol- on the brain. This potential side effect is important because all terodine appears to have similar efficacy and tolerability as five muscarinic subtypes are expressed in the brain.2 M1 receptors are particularly important in higher cognitive pro-cesses such as learning and memory. Subsequently, anticho- linergics that spare the M1 receptor are desirable. Only onetrial has assessed the impact of anticholinergic medications BTX-A is an attractive treatment for NBD because it inhibits on cognitive function in children.5 This small, double blinded acetylcholine neurotransmitter release at the neuromuscular cross-over trial demonstrated that long-acting oxybutynin junction. In addition, there is evidence suggesting that BTX-A and tolterodine for NBD do not appear to cause a deleterious modulates both sensory and motor pathways by inhibiting effect on a child’s short-term memory attention. Further stud- the release of ‘‘other’’ neurotransmitters (adenosine triphos- ies are needed to elucidate these potential issues.
phate, and substance P) and down-regulating the expression If children are unable to tolerate oral oxybutynin, other of purinergic and capsaicin receptors on afferent neurons modes of delivery can help diminish side effects. The intraves- within the bladder.11,12 Intravesical BTX-A is considered an ical route is one alternative that does not rely on gastrointesti- alternative to improving continence and urodynamic param- nal absorption and therefore largely avoids the first pass eters of NBD in children. Neither the FDA or the European hepatic metabolite, N-desethyloxybutynin that is generated Medicines Agency (EMEA) has approved the use of BTX-A for from the portal venous system.6 It is an active metabolite that the treatment of NBD; thus BTX-A use is off-label requiring shares similar pharmacologic properties with oxybutynin, informed consent. A recent review using BTX-A was con- thus increasing the potential for adverse effects. Advocates for ducted that provided a current summary of the efficacy and intravesical oxybutynin therapy tout a reduction in oral oxy- safety profile of BTX-A in children with NBD.13 Collectively, butynin-related side effects; however, there has not been a these small, uncontrolled studies demonstrate a significant single randomized controlled study investigating intravesical improvement in clinical and urodynamic parameters as evi- oxybutynin. Published studies are primarily non-comparative denced by complete continence in approximately 65% to 87% case reports with small sample sizes. A recent meta-analyses of children and a reduction in maximum detrusor pressure involving intravesical oxybutynin in children with NBD sup- and an increase in detrusor compliance in the majority of ports its efficacy in lowering the mean maximum detrusor those treated. The youngest child was 2 years old, which pressure while increasing bladder capacity, but side effects corresponds to the minimal age that has been approved by are nevertheless present, although less than with oral oxybu- the FDA and the EMEA for the treatment of spasticity from tynin.7 The incidence of side effects of oral oxybutynin ranges cerebral palsy. In most published studies, the dose of BTX-A is from 6% to 57%8 whereas side effects from intravesical oxy- 10 U/kg up to a maximal dose of 300 U involving 30 trigone- butynin are approximately 9%.7 Another consideration for sparing injections of 10 U/kg/ml in the detrusor. BTX-A using the intravesical route is the composition of the oxybuty- appears to reach efficacy levels at 2 weeks and maximum nin solution and its durability. Crushing the oxybutynin tab- effects within 4–6 weeks. Duration of the BTX-A effect ranges lets has been cited as a deterrent to patient compliance but from 3 to 8 months depending on short-term versus long-term reconstituting the purified oxybutynin into a physiologic pH repeated injections.13 Clarification, optimization, and stan- balanced sodium chloride solution seems to counteract this dardization of follow-up of BTX-A in the treatment of NBD hurdle and ensure more consistent dose delivery.7,9 remains open for future clinical trials. Furthermore, collecting Transdermal oxybutynin is another alternative to oral oxybu- detailed safety data will be necessary to support the reported tynin that has the same benefits as intravesical treatment as it avoids the initial first pass metabolite N-desethyloxybutyninthat is supposed to reduce side effects. These advantages were noted in a recent report using transdermal oxybutynin inchildren with neurogenic DO.10 The pharmacokinetics, dosing Antibiotic administration in children with NBD requires and efficacy have yet to be established with transdermal special consideration because CIC is commonly relied on for oxybutynin. There are inherent limitations with transdermal bladder emptying and the resultant frequent colonization of Neurourology and Urodynamics DOI 10.1002/nau ICCS: Therapeutic Intervention in Pediatric NBD the bladder with bacterial flora is quite innocuous. The inci- or multiple use (clean) catheters, self-catheterization versus dence of asymptomatic bacteriuria in children who perform catheterization by others, and any other strategies designed CIC ranges from 42% to 76%.14,15 The incidence of bacteriuria to reduce UTIs with respect to incidence of symptomatic is higher still when correlated with the presence of periure- UTI, hematuria, other infections, and user preference, in thral bacterial flora—93% when Escherichia coli is present on adults and children using CIC.26 This review found a lack the periurethral skin.16 Studies have shown that expression of of evidence to state that the incidence of UTI is affected specific bacterial virulence factors do not reliably predict in- by using sterile or clean technique, coated or uncoated fection in children with NBD17,18 and antibiotic prophylaxis catheters, single (sterile) or multiple use (clean) catheters, self- does not significantly alter the rate of symptomatic UTIs in catheterization or catheterization by others, or by any other comparison with no antibiotic prophylaxis.17 strategy. Additionally, current research evidence is weak and One concern when using continuous antibiotics is more vir- design flaws are significant. Therefore, it is not possible to ulent organisms may be selected that result in development state that one catheter type, technique, or strategy is better of complicated UTIs. Two randomized, placebo-controlled than another. In summary, modification of catheters and studies have examined the efficacy of antibiotic prophylaxis catheter regimens should be made on an individual basis for in reducing the incidence of symptomatic UTIs in children who perform CIC for management of their NBD.19,20 Neitherstudy found any difference in the rate of symptomatic or totalUTIs using trimethoprim/sulfamethoxazole prophylaxis com- pared to placebo or nitrofurantoin prophylaxis versus placebo.
Antibiotic prophylaxis did result in the selection of more viru- Intravesical Electrical Stimulation of the Bladder lent bacterial isolates such as Klebsiella and Pseudomonas.20 In the setting of recurrent UTIs, intravesical antibiotic Intravesical electrical stimulation of the NBD is labor inten- instillations have been used successfully to address UTIs in sive and controversial. In a large single, institutional 22-year children who perform CIC.21–23 Most report use gentamycin experience, there was favorable results with a 20% or greater instillation with good safety and few adverse events. Unfortu- increase in bladder capacity after treatment and attainment of nately, selection bias, study design, and data are limited, safe detrusor pressures <40 cm H2O.27 In a multi-institutional which prevents drawing any definitive conclusion with regard report, the efficacy of intravesical electrical stimulation was to efficacy of intravesical antibiotic treatment.
less impressive.28 Finally, in the only reported randomized, In summary, there appears to be level-1 evidence as demon- placebo-controlled trial, there was no efficacy demonstrated strated by several controlled and placebo-controlled trials that there is no medical benefit to using antibiotic prophylaxis inchildren with NBD who perform CIC. Additionally, antibiotic prophylaxis appears to alter the normal skin and bladderflora; this finding may lead to potential complications related Sacral nerve stimulation has primarily been reported in the treatment of patients with a non-neuropathic bladder. Theprocedure is FDA approved and indicated in individuals withurinary retention and/or symptoms of DO who have failed or could not tolerate more conservative treatments. The safety As mentioned previously, CIC has had a profound impact on and effectiveness have not been established for children <16 the management of NBD in children. Given the high preva- years of age or for patients with neurological disease. The only lence of latex sensitivity in the NBD population, non-latex report of sacral nerve modulation conducted in children with catheters are employed exclusively. There have been a wide NBD had mixed results and the study design was limited.30 variety of material-modifications to catheters that facilitate Comparison of urodynamic variables disclosed no significant CIC but these are typically employed in individual cases.
statistical difference except that functional bladder capacity Hydrophilic-coated catheters are helpful in the setting of was better in the oxybutynin group and leak point pressure painful catheterization or in the presence of urethral strictures was better in the sacral neuromodulation group. Evaluation of and/or false passages in boys. In two recent randomized trials inter-individual variations in the sacral neuromodulation comparing hydrophilic-coated catheters to uncoated catheters, group revealed significant improvement in compliance and there was a reduction in microscopic hematuria and better functional bladder capacity at 6 and 9 months but not at overall satisfaction with the hydrophilic coated catheters.24,25 12 months. In summary, sacral nerve stimulation is consid- The drawbacks of these hydrophilic catheters include: single use, more expense, and lack of proven, efficacious benefit overstandard catheters. Other useful modifications include a coude´ tip catheter that allows passage over a high bladder neck andpre-packaged, lubricated catheters for simplicity of use.
There is little written about transcutaneous neuromodula- One concern expressed by families and primary care tion in the treatment of children with NBD. A recent providers is the risk of re-using the same catheter for CIC and report evaluated the efficacy of percutaneous tibial nerve the incidence of bacteriuria. This concern was addressed in a stimulation (PTNS) for different types of lower urinary tract small, prospective, randomized, crossover trial comparing dysfunction in children.31 A majority of the 44 patients were new, sterile catheters versus reusing clean catheters for CIC.15 non-neurogenic but 7 had NBD. All were resistant to conven- There was no difference in the frequency of bacteriuria in tional therapy and underwent PTNS weekly for 12 weeks.
patients with NBD on CIC with a 73% incidence of bacteriuria Objective symptomatic improvement was significantly greater in the new, sterile catheter cohort and a 76% incidence in the in non-neurogenic than in neurogenic cases (78% vs. 14%, clean catheter group. A Cochrane review examined sterile P < 0.02); it was noteworthy that results in 5 of 7 NBD (71%) versus clean catheterization technique, coated (pre-lubricated) were unsatisfactory as expressed by parents after the first versus uncoated (separate lubricant) catheters, single (sterile) Neurourology and Urodynamics DOI 10.1002/nau albeit at the cost of incurring a multitude of short- and long-term complications.
The role of biofeedback has been explored extensively Reported outcomes of enterocystoplasty have generally in children with functional disorders but no significant been favorable with respect to increasing bladder capacity, de- studies of biofeedback have been reported in children with creasing storage pressures, and improving upper urinary tract drainage.40,41 Up to 90% achieve socially acceptable urinarycontinence with or without an additional bladder outlet potential serious implications, especially for children with an NBD encompasses a wide variety of presentations depend- anticipated longer residual life span than adults because en- ing on the degree of lower urinary tract involvement and the teric tissue, although incorporated into the bladder, retains its interplay between bladder storage capability and sphincter absorptive and secretory properties. Mucus formation is espe- function. No specific universal surgical procedure is suitable cially bothersome as it tends to block catheters and requires for everyone. Surgical management has to be tailored to each regular irrigation, and may predispose to stone formation.44 individual case, based on careful consideration of urodynamic The hematuria dysuria syndrome is a recognized entity fol- findings, medical history, age, and presence of other disability.
lowing gastric augmentation, which is believed to be caused The mainstay of current NBD management is non-surgical by acidic secretions from gastric mucosa.45 Additionally, re- with anticholinergics and CIC in the majority of children.
construction entails intraperitoneal surgery with its risks of A small subgroup that fails to respond to treatment may need subsequent adhesions, bowel obstruction and the need for lengthy postoperative hospital stays. Reports of surgical com-plications in up to 40% of patients are not unusual.41,44,46,47 ATTAINING SAFE BLADDER STORAGE PRESSURE AND CAPACITY Another long-term complication is stone formation (approxi-mately 15% of augmented bladders).44,46 Finally, in a recent review of 500 children undergoing enterocystoplasty, a failurerate of 9.4% was reported.47 This procedure aims at lowering the pop-off pressure of Long-term metabolic complications are also common, and a hostile neuropathic bladder by lowering DLPP to below are particularly worrisome in children as these may interfere 40 cm. H2O.32 It has been employed primarily in younger age with growth and development. Hyperchloremic metabolic groups. Dilatation is carried out under general anesthesia acidosis is the most common disturbance encountered, and using sounds up to 36 Fr in infants and Hegar dilators in those may lead to demineralization of bone and stunted linear older than 6–8 years.33 Technically, it is best suited for growth.48,49 Bowel resection may lead to malabsorption of females. In males, dilating the external sphincter using a vitamin B12 and chronic diarrhea, which may also impair balloon or by sounds is feasible via a perineostomy.34 normal development.49 Finally, there is the potential for Several studies have proven urethral dilatation effective in malignant transformation in 0.6%, which is a serious and of- lowering DLPP to safe limits and improving bladder capacity ten fatal consequence of enterocystoplasty. Therefore, these and compliance.33–36 With careful patient selection, durable patients need to be followed indefinitely with regular cytology positive outcomes can be expected in about 70%.33,35 A major and endoscopy, starting 5–10 years after augmentation,46,47 concern raised in connection with this procedure has been the although efficacy of these surveillance parameters has yet to potential risk of causing or aggravating urinary incontinence; however, these concerns have proven unfounded.33 This technique involves partial detrusorectomy or detrusor Vesicostomy effectively reduces bladder storage pressures myotomy, leaving the underlying mucosa intact and bulging, to safe levels in NBD. This procedure has been useful in as a wide mouthed diverticulum, leading to an increase in infants. Additionally, it can be considered if parents are non- bladder capacity and compliance. The technique is appealing compliant with CIC or where urethral catheterization is diffi- because it precludes the use of intestinal tissue.52 cult. Vesicostomy is easily performed. It has been shown to Conflicting outcomes and modest success rates in children effectively reverse hydronephrosis, VUR, and to decrease the with NBD has hampered widespread application of autoaug- incidence of UTIs.37,38 Complications are minor and readily mentation. There have been discrepancies between studies, managed; they include bladder mucosal prolapse, stomal ste- but it remains that autoaugmentation is a safe simple proce- nosis, stone formation, and peri-stomal dermatitis. Although dure with low morbidity that may avert the need for formal intended as a temporizing procedure in the majority, stomas enterocystoplasty in a select group of children.53,54 can be left functional as a permanent solution in childrenwho lack the mental acuity or social support to ensure reliablecompliance with CIC.39 Its greatest drawback is the inability to easily fit and maintain a collecting appliance over thestoma in older individuals.
The technique involves suspension of the bladder neck with an autologous fascial strip or artificial material secured to the rectus fascia or the pubic symphysis. It is believed the mecha-nism of action involves co-aptation of the bladder neck due to traction, and/or elevation of the urethra to an intra-abdominal Augmenting the bladder using segments of small intestine, position, which increases tension on the bladder neck with colon, or gastric patches represents the definitive method of abdominal straining. In a review regarding slings in children creating a safe, low-pressure capacious organ for storage, with NBD, Kryger et al.55 found continence rates ranged Neurourology and Urodynamics DOI 10.1002/nau ICCS: Therapeutic Intervention in Pediatric NBD between 40% and 100%. It is difficult to compare results The majority of children need help from parents until they are as techniques and concomitant augmentation rates vary between studies. Complication rates are modest and include Children under five will have difficulty using transanal difficult catheterization and rectal injury.55 colonic irrigation because the procedure requires a cooperativechild. In some instances, the retrograde transanal irrigation is too difficult and may not sufficiently stimulate the distalcolon to empty, restricting the child from achieving indepen- In 1973 Scott introduced the artificial urinary sphincter dence. In the 1980s, the MACE (Malone Antegrade Continence (AUS).56 Reported continence rates after AUS implantation Enema) procedure was introduced. It involves reimplanting have been high with different series reporting success in 70% the appendix into the cecum in a non-refluxing manner bring- to 85%.57–59 Many surgeons are reluctant to implant an AUS ing the opposite end to the abdominal wall as a continent as it consigns patients to further revision surgery, and the po- catheterizable stoma, so the channel can serve as an ante- tential risk of deterioration in bladder function and a concom- grade colonic washout. If the appendix is not available, a cath- itant deleterious effect on upper urinary tract drainage.55 eteriable channel can be fashioned from other parts of the However, with improved durability of newer models that intestine tract or the ureter. Tap water was used initially as an have an average life span of about 8 years, revision rates have irrigant with good results,60 but saline, Golytely, or macrogol become less of an issue.58 The ideal patients for AUS implanta- 3350 has been shown to be effective and safe as well.61 In a tion are post-pubertal males or females, who can void voli- recent review of MACE management, 92% were using saline tionally and empty the bladder completely.57 It is important or Golytely irrigations and 35% required additives (biscodyl, to recognize that CIC is feasible in patients with an AUS.
glycerin, etc.) to achieve acceptable continence.62 Complications specific to AUS include altered bladder Studies in adults suffering from neurogenic bowel dysfunction compliance, and worsening DO. This has necessitated bladder have shown good results with transrectal anocutaneous electric augmentation, in approximately 50%.58,59 Removal of an AUS stimulation as well as sacral nerve stimulation. Studies on chil- due to erosion, infection, or mechanical malfunction occurs dren are too few to provide meaningful recommendations.
in at least 20%.57,59 Revision rates for wear and tear have The anal plug is of benefit in a majority of patients using steadily been decreasing with ongoing refinements in AUS; it.63 The plug is recommended in certain situations to avoid the most recent long-term experience with the AMS 800 AUS fecal incontinence, for example, while swimming, it will last has a revision rate of 0.03 revisions per patient-year.59 for 12 hr and it is tolerable in some children.
In conclusion, proactive treatment of patients with spina bifida has been shown to be effective in reducing the need for The optimal bladder neck procedure should increase bladder augmentation cystoplasty and in reducing the development outlet resistance at minimal cost of decreasing bladder capaci- of ESRD by minimizing the effects of high-pressure reflux on ty, maintain easy catheterization and still allow some leakage the upper urinary tract. Postponing treatment until upper uri- at high pressure in order to protect the upper urinary tract.
nary tract dilation is seen on ultrasound or until symptomatic Different operative techniques with the aforementioned pyelonephritis occurs is not acceptable in modern times.
aims have been used with varying outcomes. The Young– Bowel management in children with neurologic conditions Dees–Leadbetter bladder neck repair has been employed can be challenging. There is a lack of research into efficacious primarily in treating incontinence associated with exstrophy– management and often the clinician has to rely on clinical epispadias complex yielding continence rates of about 70% to experience instead of randomized controlled trials. It is very 80% but it seems to have little success in children with NBD.
important to realize that children and adolescents who experi-ence bowel dysfunction require patience and sensitive sup-port from their health care providers.
TREATMENT OF THE NEUROGENIC BOWEL FUNCTION The overall aim of treatment is to obtain regular bowel emptying, continence, and independence by establishing abowel management program tailored to meet the needs of Professor Chung Kwong Young, Hong Kong, and Professor each child. Naturally, a normal healthy diet is recommended Antoine E. Khoury, Toronto, have followed the process and for these children. The diet should consist of small-portioned fiber foods and sufficient water intake to keep a good fluidbalance.
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