Neuropathic Bladder Secondary to Spina Bifida

Peter D. Metcalfe1 and Jeff Pugh2

1Division of Urology, 2Division of Neurosurgery
Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada

INTRODUCTION
            Spina bifida is a broad diagnostic category that applies to a variety of neural tube defects (spinal dysraphisms) that can have devastating effects on multiple organ systems.  The distal spinal cord has a fundamental role in bladder function, and the dysregulation secondary to spina bifida results in the neuropathic bladder.  Management of the neuropathic bladder is complex with significant consequences with respect to quality of life and renal health.  However, any practitioner would be remiss to consider treating the bladder in isolation, as the abnormalities of the central nervous system (CNS), musculoskeletal system (MSK), and gastrointestinal systems mandate a comprehensive approach to patient care.
            In the early 1980s spina bifida was reported to occur in approximately 1/1,000 births, but this incidence has been shown to be significantly decreasing.1,2 This has been attributed to improved pre-natal care (folate supplementation) and elective termination of pregnancies3. One of the greatest advances in prenatal care over the past several decades was the discovery of the link between folic acid and neural tube defects.   The current recommendations for all women of child bearing age to consume 400 mg of folic acid daily has been responsible for a 50% reduction in incidence.4  Most developed countries mandate folate supplementation in grain products.5
            Although no specific gene has been identified, there are multiple suggestions implicating a genetic component.  There is an increased risk with chromosomal abnormalities and an increased risk when a relative is affected6.  The risk in a mother with one affected child is 20-50 per 1000 and increases to 1 in 10 if she has 2 affected children.  The risk also increases with maternal age so that a mother older than 35 years has a risk of 4%.  There is evidence for both an autosomal dominant and autosomal recessive inheritance pattern7, 8.  However, the significant phenotypic variability seen within these families suggests a pleiotropic effect, a variety of potential genetic causes, or variability in key environmental exposure during susceptible periods of pregnancy6.   Therefore, family members of patients are advised to take 4000 mg starting at least two months before conception.
            Regardless of the etiology, the pathophysiology of spinal dysraphisms involves the incomplete closure of the spinal cord and vertebral column.  This process begins at approximately 18 days and is complete by 35 days gestation.  Closure begins cranially and progresses caudally. 
            The majority of neural tube defects are myelomeningocele, which involves the evagination of neural tissue, accounting for over 90% of open neural tube defects.  A meningocele occurs when the meningeal sac extends beyond the spinal canal, but does not contain any neural elements within it.  A lipomeningocele occurs when the distal cord is compromised by fatty infiltrations.  The majority of defects are directed anteriorly, but rarely can protrude posteriorly.  The most common site of the defect is in the lumbosacral spine (47%), followed by lumbar (26%) and sacral (20%).  Less common defects occur in the thoracic spine (5%), cervical spine (2%), and anencephaly (1%)5.  85% of lesions are associated with the Arnold-Chiari Chiari – type II malformation (also referred to as Arnold-Chiari malformation), whereby the cerebellar vermis and brainstem protrude through the foramen magnum, obstructing the outflow of CSF from the fourth ventricle, and resulting in hydrocephalus5. 

Contemporary prenatal screening commonly result in a pre-natal diagnosis3.  The spinal defect can be seen on prenatal ultrasound.  Maternal serum screening with alpha-fetoprotein, alone or as part of a triple or quadruple screen, also increases detection, but may have a false positive rate up to 80%.  Therefore, its benefit has been questioned9.  High-resolution ultrasound has a reported diagnostic accuracy of up to 80%10.  Fetal MRI results in further anatomic detail and will likely supplant ultrasound as the diagnostic modality of choice11.
            Prenatal diagnosis has resulted in several fundamental changes in the management of patients of spina bifida.  It has resulted in the mother’s option whether or not to continue with the pregnancy.  It has also resulted in the potential for pre-natal counseling, whereby the parents can prepare for many aspects of their child’s condition.  At the author’s institution, parents will attend the spina bifida clinic before delivery, as this affords them the opportunity to meet many of the staff and other families of our patients.  This has proven to be an extremely valuable resource. 

            Finally, prenatal diagnosis has allowed for the development of fetal surgery, and the first pre-natal closure of a myelomeningocele occurred in 199712.  Original data from fetal closure of the myelomeningocele demonstrated a decreased need for vetriculo-peritoneal (VP) shunting secondary to hydrocephalus.  This is currently being studied with a randomized trial, which to date has accrued approximately 130 patients13.  Although the primary end-points of the trial are CNS related (the requirement for VP shunts and development) bladder outcomes have been added as a secondary measure13.  Initial data, outside the trial, describe an increased incidence of denervated pattern to the external sphincter, compared to patients with post-natal closure14. Complete results are anxiously awaited.

PATHOPHYSIOLOGY
            The precise neuroanatomic defect in spina bifida is extremely variable, and therefore, there is no single phenotypic effect on the urinary tract.   The detrusor muscle, bladder neck, and external sphincter are all independently susceptible to pathologic innervation with respect to both their afferent and efferent nerves and cell bodies.  Furthermore, the complex interactions among the interneurons of the spinal cord are inherently disrupted as well as their ascending and descending pathways.  Furthermore, it has been noted that patients with proximal lesions (i.e. thoracic) can have intact, “normal” distal spinal cords.  Therefore, it cannot be emphasized strongly enough that blanket predictions are not possible and each patient must be thoroughly investigated and their care individualized. 
            The sympathetic innervation of the bladder is via the L2, L3 and L4 nerve roots and induces detrusor contraction via the muscarinic pathways.  The predominant receptor in the detrusor muscle is the M2 subtype.  There is also sympathetic B2 activity, which can aid the relaxation of the bladder.  Afferent innervation is also fundamental to its function, as the complex reflex arcs in the bladder require the ability to detect stretch and capacity.  These interactions in the spinal cord result in an absence of contractions, with active relaxation, during filling and coordinated contraction upon the signal to void.   During normal infancy this occurs without any regulation, but during the toddler years central pathways develop to modulate the filling and emptying cycle.  Most commonly, the abnormal innervation result the inability to suppress detrusor contractility and an overactive bladder results.  If the sensory afferents are also affected, decreased sensation occurs, and the patient is unable to detect “fullness”.   The less common scenario involves a “flaccid” bladder that is unable to contract and empty.
            Both urinary sphincters are likewise affected, with abnormal sacral innervation occurring via parasympathetic outflow to the internal urinary sphincter (bladder neck) or via the pudendal nerve affecting pelvic floor and rhabdosphincter innervation.  Increased activity in either of these pathways results in increased sphincter activity, and decreased efficacy of emptying.  Decreased activity results in the inability to provide sufficient urethral resistance to store urine.  However, the greatest threat to the patient involves a dysregulation of the spinal reflex, when the urinary sphincters are not able to relax upon the initiation of a bladder contraction.   This results in the most significant voiding abnormality, detrusor sphincter dyssenergia (DSD).  The increased bladder contractility and failure of sphincteric relaxation results in significantly elevated bladder pressures and, over time, bladder decompensation.
            If the complex physiology of the bladder is reduced to its most basic functions the diagnosis and treatment options are simplified.  By separating the organ into its basic elements (detrusor or sphincter) and function categorized as normal or overactive a helpful table can be constructed (Table 2).  Individualized treat aimed at the fundamental pathophysiology can be optimized to reduce renal risk and achieve continence.

 

Bladder

Underactive

Normal

Overactive

Sphincter

Underactive

Stress incontinence

Stress incontinence

Stress and urge incontinence

Normal

Urinary retention

Normal

Urge incontinence

Overactive

Urinary retention

Urge incontinence

DSD + high pressure bladder

 

            Both upper and lower motor neuron lesions are found with equal frequency15.  Approximately 10% of newborns have hydronephrosis thereby declaring an immediate renal risk secondary to high detrusor pressures15. 

EVALUATION AND ASSESSMENT
            The initial assessment is performed as soon as possible after birth and closure of the neural defect, however this often requires the child to spend several days in the prone position.  Neonatal assessment consists of an ultrasound of the bladder and kidneys as well as intermittent catheterization every 4 hours.  Volumes are recorded to assess for urinary residuals with greater than 15 cc considered abnormal.  Frequency of catheterization can then be tailored to the residuals, but some feel that aggressive CIC results in better long-term outcomes16.  Even if minimal residuals are recorded, we find it beneficial at our institution to continue catheterization to keep the parents and child accustomed to the routine and maintain their skills.
            All of these children require thorough, regular evaluations in a multi-disciplinary clinic for the remainder of their lives.  Although many children’s hospitals have adopted a spin bifida clinic as routine care, most of our adult patients have not yet been afforded the same level of care.  Regular history and physical examination are required to assess continence status, urinary tract infections (UTI), difficulties catheterizing, and psychosocial measures.  It is of a paramount importance for the clinician to be aware of any changes in their voiding pattern, as this may be easily remedied with basic conservative measures or portend significant pathology such as a tethered spinal cord, or bladder stone.  The pediatric urologist is also paramount with the assessment and treatment of bowel function and continence.
            Although continence is readily appreciable by history, renal risk is often insidious.  Therefore, regular assessment of the upper tracts is required with ultrasound to detect any changes before irreversible damage has occurred.   While simple and effective in the newborn, patient habitus can preclude accurate examination through adolescence.  Nuclear scintigraphy has a less prominent role, as most hydronephrosis will be due to bladder pressure, but concomitant UPJ or UVJ obstruction will occur and a MAG-3 may provide additional information.  DMSA renal scans are helpful in identifying scars secondary to recurrent infections as well as congenital renal dysplasia. 
            KUB radiographs are useful for detecting bladder calculi and can be used to screen high-risk patients, such as those with an intestinocystoplasty or patients who have had prior stones. 
            Urodynamics play an integral role in the management of neuropathic bladders, for both the prevention of both renal damage and urinary incontinence.   Although it has been advocated to obtain initial urodynamics before the neonatal closure, most centers do not find this practical.   Most initial evaluations occur at 3-6 months of age, after a period of time has elapsed for “spinal shock” to resolve.   Because these patterns are noted to progress during early years, frequent urodynamics are recommended17.  Beyond the neonatal years, urodynamics should be performed annually or with any change in voiding pattern as well as in the diagnostic evaluation for a possible tethered spinal cord. 
            The clinician should be vigilant regarding the potential for a secondary tethered cord, with the highest risk periods seen during rapid growth, around the age of two and puberty.  This risk is secondary to increased traction on the distal placode which has been immobilized secondary to surgical scarring, resulting in ischemia and loss of function.
            New or progressive urinary dysfunction, or an increase in symptomatic UTIs, may be the earliest sign of a retethering of the neural placode. Associated symptoms and signs include back and leg pain, and progressive orthopedic deformity such as scoliosis or pes cavus. Neurosurgical exploration and release of the tethered spinal cord may result in improved urologic function; however, this improvement is often temporary. In non-ambulatory patients, progressive scoliosis, back pain, and loss of upper extremity function is often due to an enlarging hydrosyringomyelia. These patients can greatly benefit from a spinal cord transection immediately above their tethered neural placode, eliminating the risk for future retetherings. The future urologic function of these patients is facilitated through rudimentary spinal cord reflexes
            The use of routine urine cultures is not encouraged, as any patient undergoing intermittent catheterization will be colonized with bacteria, therefore, in the absence of pyuria, antibiotics are not recommended.  However, in an augmented bladder, the Indiana group recommends screening and treating for urease splitting organisms to prevent the formation of bladder calculi18.   Regular urine cytology has also been advocated as a screening modality for bladder cancer but its utility has not yet been validated19, 20.

            Patients who have undergone intestinocystoplasty are also at risk for a metabolic acidosis and annual serum chemistries have been advocated, as Rosenbaum et al. demonstrated a propensity to hyperchloremia without a change in CO2 levels21.  The loss of the terminal ileum also places the patient at risk for vitamin B12 deficiency, seen in 20% of the Indiana series, with serum levels normalized by oral replacement21.

TREATMENT

Medical
            Treatment is directed at the two primary functions of the bladder, the storage of urine and emptying.  Modalities can be categorized into conservative, medical, or surgical.   As per any surgical algorithm, conservative measures are initiated first, medical and surgical alternatives are sought as conservative measures fail.  Over 80% of children with spinal dysraphisms are successfully managed with clean intermittent catheterization (CIC) and anticholinergic therapy alone22. 
            Unfortunately, our ability to improve emptying remains crude and is nearly completely reliant upon CIC.   Commonplace today, Lapides revolutionized care of the neuropathic bladder with its introduction23, 24.  The inability to catheterize per urethra may be secondary to sensation, especially in a male, or rarely due to urethral stricture25, 26.  Ineffectiveness may be secondary to family compliance or a truly hostile bladder.  In infants this is very effectively treated with a cutaneous vesicostomy, whereas adolescents require another type of urinary diversion, such as an ileovesicostomy. 
            The second fundamental aspect of medical therapy involves the use of anticholinergic medications.  Muscarinic blockade will suppress detrusor contractility via the M2 (accounting for 80% of receptors) and M3 (primary medication of bladder contractility) receptors27, 28.   However, blockade is not complete, which may be due to a third, atypical, neurotransmitter29, 30.  Side effects from this class are secondary to the non-selective nature of the muscarinic receptor: dry mouth, increased constipation, blurred vision, drowsiness, cognitive dysfunction, and decreased sweating.
            Oxybutynin (Ditropan®) is the most popular and best-studied agent in children, with good efficacy seen in children and neonates31, 32.  Its anti-muscarinic activity is primarily directed at M1 and M3, but also has muscle relaxant and analgesic properties28, 33.  Its addition to CIC resulted in a 70% increase in urinary continence 34.   Dosing regimens vary, with most literature citing between 0.2-0.6 mg/kg/day.   Side effects are seen in up to 1/3 of patients, the primary cause of discontinuation35.   It has recently become available in an extended release formulation with the advantages of fewer side-effects and improved efficacy overnight36. 
            The primary cause of the side effects is a metabolite of oxybutynin, (N-desethyl-oxybutynin) which occurs with a first pass metabolism37.  Therefore intravesical and transdermal strategies have also been effective at reducing side effects.  Intravesical administration of a 5 mg tab crushed and dissolved in 10 ml of normal saline BID has been demonstrated to reduce intravesical pressures and tolerated better than oral administration38.   However, 6 of the 34 children in another study had to discontinue therapy due to drowsiness, hallucinations, and cognitive effects39.   Guerra et al. published a systematic review whereby they felt that a lack of quality studies prevented them from recommending intravesical oxybutynin as a viable alternative40.  The transdermal formulation has also been shown to have beneficial effects with better patient compliance than the immediate release formulation, but not with the extended release preparation41.   Cartwright et al. recently published a randomized control trial demonstrating comparable increases in many urodynamics parameters, and a significantly lower level of serum N-desethyloxybutynin. 12 of the 41 patients receiving the transdermal preparation reported a rash at the application site42.
            Tolterodine (Detrol®) is a second muscarinic antagonist, which is targeted at the M2 and M3 receptor, and has decreased activity at the M1 receptor in the salivary glands.  It has been extensively evaluated in adults, and efficacy and safety in children has been demonstrated.  Goessl used a dose of 0.1 mg/kg divided bid and reported equal efficacy to immediate release ditropan with decreased side effects43.  Furthermore, in a group of children unable to tolerate oxybutynin, Bolduc reported 60% able to tolerate tolterodine (1-2 mg BID) with improvements in bladder function.
            Solifenacin succinate (Vesicare®) is targeted primarily to the M3 receptor and has the added advantage of a long ½ life.    Therefore, it may be compounded into a liquid form, and maintain its daily dosing efficacy; as opposed to oxybutynin and tolterodine, which require slow-release capsules to achieve 24 hour dosing.  
            Standard medical doses are often able to control intravesical pressures sufficiently, but further dose escalations have been used to attempt to avoid intestinocystoplasty.   Bolduc et al. recently published the results of adding a second full dose anticholinergic to their standard regime, and was able to demonstrate increase capacity and decrease pressures significantly.  Adverse effects were reported as mild in 16/33, moderate in 5/33 and none in 12/3344.
            Koff has devised an intriguing adjuvant to CIC with leaving an indwelling catheter in overnight.  By leaving an indwelling catheter overnight, and the resultant absence of nocturnal over distension and elevated pressures, he was able to demonstrate a radiographic improvement in 79% of patients with hydronephrosis45. 

Surgical
            Surgery may be required if medical therapy fails to control either of the two fundamental goals of the pediatric urologist: continence or renal preservation.   Failure of medical management can be secondary to ineffectiveness, patient compliance, or prohibitive side effects.  Multiple effective surgical options exist and must be tailored to the patients’ needs, desires, and abilities.  The fundamental goal is to provide a low-pressure storage reservoir with an effective means of emptying.  Surgical procedures can be classified as continent or incontinent, and urinary diversions vs. urinary reservoirs.  Urinary diversion may also refer to a procedure to increase the capacity of the native bladder (bladder augmentation) where urinary reservoir frequently refers to the replacement of the bladder. 

           

Due to the potential morbidity of a bladder augmentation, several novel minimally invasive procedures have emerged.  Endoscopic injection of botulinum toxin has been advocated as a very effective means of decreasing contractility, improving capacity, and decreasing intravesical pressure46.   Although not approved by either the US Food and Drug Administration (FDA) or European Medicines Agency (EMEA) commercial preparations are readily available.  Although a significant degree of research has been performed, there lacks a consensus as to an optimal dose (5-12 U/kg, 100-36 0 units), and number (10-50 injection sites) and locations for injection(including or excluding the trigone)46.  One of the most concerning aspects is the temporary effect, with most studies reporting a 3-6 month duration, but a dose-escalation does not seem to be required as was once originally feared.47.   An excellent systematic review by             Game et al summarized contemporary data.  Reduction in incontinence episode is reported to be between 40-80%, with 65-87% of patients becoming completely continent46.  Mean reduction in detrusor leak-point pressure was 33-55% and increase in capacity by 110-220 ml46.  Therefore, injection of Botox has clinically significant effects, is generally well tolerated, but further rigorous study is required to optimize management.
            Urethral dilation has been re-popularized by the University of Michigan as a means of reducing bladder pressures in patients who have failed standard conservative treatments48, 49.  Kiddoo at al dilated female urethras to a maximum 36 Fr in 19 patients.  Clinical improvement was seen in 68%, with 6/7 patients demonstrating improvement in their hydronephrosis, and resolution in one50.
            Therefore, aggressive urethral dilation and Botox injection may provide some clinical and urodynamic improvement in patient after failure of CIC and anticholinergics and may prevent or delay major reconstructive surgery.
            Cutaneous Vesicostomy   Cutaneous vesicostomy is the most common form of incontinent urinary diversion in neonates and young children.  However, this technique has limited use for older children and adults, as the bladder is much more difficult to mobilize and secure outside the pelvis.  Infants with a neuropathic bladder and unsafe storage pressures may require vesicostomy if the patient’s caregivers are unwilling or unable to perform CIC, or despite maximal medical treatment, unable to maintain safe bladder pressures.  Several studies have confirmed the effectiveness of a vesicostomy, with regards to either a reduction in upper tract dilation or improvement in renal function51-56.  Although bacterial colonization of the open system is expected, symptomatic infection and urosepsis are uncommon52, 54.
            Although first described by Lapides57, most contemporary surgeons employ the technique described by Blocksom58 and Duckett59.  The Blocksom vesicostomy is fashioned through a small transverse incision half way between the umbilicus and the pubis.  A vertical incision may be used if future reconstruction is anticipated, thereby, minimizing excess cutaneous scar.  The fascia is then incised and the peritoneum is mobilized superiorly off the dome of the bladder.  The urachal remnant is divided and the dome of the bladder is mobilized to reach the skin without tension.  The fascia is secured to the bladder wall to form a 24 Fr defect, and the mucosa is everted or sewn flush with the skin. 

           

            Complications of cutaneous vesicostomy include stomal stenosis, prolapse, peristomal dermatitis, and bladder calculi.  The risk of prolapse is minimized by limited mobilization of the bladder, and securely suturing the dome of the bladder to the fascia of the anterior abdominal wall. Dermatitis is usually a result of a superficial fungal infection, and is effectively managed with a barrier cream or a topical antifungal.  Bladder calculi may indicate poor drainage, probably secondary to stomal stenosis, and this should be addressed at the time of stone surgery. 
            Incontinent Ileovesicostomy   The incontinent ileovesicostomy (ileal chimney) was reported by McGuire and associates in 199460, as a variation of the vesicostomy adapted for adults. Because the adult bladder will frequently not reach the abdominal wall, a segment of ileum can be anastomosed to the in situ bladder, and brought out as a urinary stoma (as per an ileal conduit).  This allows for a low-pressure system, the ability to use a urinary appliance, the avoidance of “diapering”, and without the inherent complications of the uretero-intestinal anastomosis.  Another advantage to the incontinent ileovesicostomy is the flexibility regarding body habitus and position of ostomy, as a significant length of ileum can be used61. Several series report excellent results with regard to preservation of renal function, incidence of urinary tract infection, urolithiasis, and stomal complications61-64.
            Preoperative preparation is identical to the ileal conduit, with bowel preparation and selection of a stoma site, usually with the expertise of a stomal therapist.  The bladder is bivalved in the coronal plane and anastomosed to the widely spatulated ileum. A rosebud stoma is fashioned at the predetermined site and with a large catheter in the stoma and a suprapubic tube is placed to ensure maximal drainage and irrigation of mucus.
            Postoperative complications secondary to an ileal conduit or chimney can be seen as intermediate in severity between a vesicostomy / ureterostomy and a continent urinary resevoir. The use of any intestinal segment predisposes the child to complications associated with a laparotomy (anastomotic leak, bowel obstruction, etc.) and effects from the loss of the segment (vitamin malabsorption, diarrhea, etc.)  Intestinal mucus promotes bacterial colonization and calculus formation in the bladder 65, 66.  Due to the non-dependant drainage of the ileovesicostomy, daily bladder irrigation may be required to reduce complications from stagnant urine and mucus.  Because the bowel retains its absorptive properties, metabolic acidosis is a possibility, but less likely than a continent diversion, due to the decreased pressure and contact time with the bowel mucosa.  Malignant degeneration is a concern whenever the gastrointestinal tract is used in the urinary tract, and although we are not aware of any cancer reported in association with an ileovesicostomy, the theoretical risk exists65, 67-69.

            Continent Urinary Diversion   When feasible, lower urinary tract reconstruction in children is facilitated by augmenting the native bladder, thereby not requiring ureteral implantation into the neo-bladder.   The most common, and effective, means of surgically reducing intravesical pressure and increasing storage capacity is via intestinocystoplasty70.   Although commonly used, there can be significant morbidity involved, and great care must be taken with respect to patient selection and pre-operative planning71.   
            The vast majority of augmentations are performed with gastrointestinal segments, as bowel segments are readily available and easily configured.  Ileum is currently the most popular segment 72-74, but sigmoid is often used.  Stomach and ileocecal segments have been used but have only a small role in contemporary management of the pediatric patient 75-78.   The abundance of ileum ensures that adequate capacity is obtained while detubularization and the natural viscoelastic properties allows for the low-pressure reservoir 79, 80.  However, the secretive81, 82 and absorptive83 nature of this tissue is also responsible for most of the common complications associated with this procedure. Maximum storage capacity requires approximation of the spherical shape79.  A widely bivalved bladder enables this, as well as helps to prevent the augment behaving as a diverticulum. The volume of the sphere is maximized by folding the ileum into a U or an S shape, which increases the potential radius and volume84.  This reconfiguration, as well as, detubularization along the antimesenteric border is critical to disrupting intestinal contractions as the intact intestine can create pressures of 40-100 cm H2O85-87.  The reconstructive surgeon should err on the side of a larger, rather than smaller augmentation81.
            Ileocystoplasty   Ileum has become the segment of choice due to its inherently low contractility, abundance, and ease of manipulation72-74.  In children 20-30 cm is harvested, with the distal margin located 15-20 cm from the ileocecal valve to prevent vitamin B12 and bile salt malabsorption 80, 88.  A recent abstract presented by Indiana University reported a 21% incidence of low B12 levels (<200 pg / ml), with an increasing incidence with increase duration of bladder augmentation21.  However, these responded very well to oral supplementation, as absorption is known to occur elsewhere along the intestinal tract.  Ileum is known to produce less mucus than colon and we noted a lower rate of perforation when compared to sigmoid89.  It has the distinct disadvantage of being difficult to create submucosal tunnels for ureteral reimplantation or catheterizable channel placement.
            Sigmoid Cystoplasty   Advantages of the sigmoid include its proximity to the bladder and its marked dilation in the neuropathic population.  Approximately 15-20 cm are isolated and irrigated with an antibiotic solution.  Due to the extreme contractile nature of the sigmoid, complete detubularization is essential77.  Spontaneous perforation rates have been shown to be higher with sigmoid as opposed to ileal augmentations90, presumably due to their increased contractile pressure91.

Ileocecal Cystoplasty   The main advantage of the ileocecal segment is the consistent blood supply.  There are two main techniques, each with multiple variations.  Either both the ileal and cecal segment are tubularized and reconfigured together, or solely the cecum is tubularized and the ileum used to create a continent stoma78or for ureteric replacement84.  This technique is infrequently used in the neuropathic population as loss of the ileocecal valve can result in intractable diarrhea92.
            Gastrocystoplasty   The stomach is much less absorptive then other intestinal segments and its secretion of hydrogen ions may be beneficial in patients with chronic renal failure and metabolic acidosis75, 93.  A 10-15 cm wedge from the greater curvature is mobilized along the right gastroepiploic vessel, and passed through the mesentery of the transverse colon to the bladder.  Originally felt to be an option for all augmentation candidates, its role now is limited those patients with short gut syndrome to minimize the use of small intestine.  This is primarily due to the very problematic phenomenon of the hematuria dysuria syndrome, occurring in up to 70% of patients94.

Surgical Complications
            Despite the popularity of using the gastrointestinal tract as a urinary reservoir, the potential complications are numerous and can be significant.  A broad categorization of these complications includes: 1) complications due to structural defects; 2) complications secondary to the loss of the intestinal segment; 3) complications due to secretions; and 4) complications from absorption.  Because their complications are similar, and the experience with bladder augmentation is much more prevalent, much of our data on complications will be from bladder augmentation series.

            Structural Complications   Structural complications include the requirement for a re-augmentation, spontaneous perforation, and long-term malignancy potential.  A secondary augmentation was required in 9.4% of augmentations in a series of 500 augmentations70.  The most common indication for re-augmentation was for persistent high intravesical pressures from bowel contractility95, 96.  The hallmark clinical signs are incontinence or hydronephrosis with screening ultrasound, and this is confirmed by urodynamic studies.   This complication occurred a mean of 7 years after the original augmentation, and was least likely when ileum was used70.
            Whenever a laparotomy is required; to perform a urinary diversion incorporating a gastrointestinal segment; this places the patient at risk for a bowel obstruction, which occurs in approximately 3% of cases 70, 90, 97, 98.
            The spontaneous perforation of an augmented bladder or continent urinary resevoir (CUR) can be a fatal complication, and must always be a consideration in any patient with a prior CUR that presents with abdominal pain.  In the immediate postoperative period urinary ascites is likely due to technical error with the anastomosis, but a late perforation usually originates in the bowel, approximately 1 cm from the posterior anastomotic line 81.  Any delay in presentation, which is common in the neuropathic population with the high prevalence of sensory abnormalities, increases the risk of sepsis and death.   A high index of suspicion with early and aggressive diagnostic studies is essential.  Diagnosis is most reliable with a CT cystogram and treatment is usually by laparotomy and primary closure99.   Conservative treatment with catheter drainage has been successful in select patients 100.  A higher risk was calculated whenever sigmoid segments were used and bladder neck surgery was performed.  However, a lower risk resulted if a catheterizable channel was present101.  Although it is commonly believed that a CUR may be less likely to perforate, the risk may be higher than previously reported102.  Perforation in a Koch reservoir was reported in 2/20 Swedish children, at 6 and 9 years post-operatively103.
            The risk of malignancy in an ileocystoplasty has recently been recognized and is an increasing concern68.  The malignant potential of combining the urinary and gastrointestinal tract was first recognized many years after the popularization of the ureterosigmoidostomy104-108.  Malignancy has been since reported in a variety of urinary diversions, and in all of the gastrointestinal segments, and have arisen from the intestinal segment, urothelium, or the ureterointestinal anastomosis67, 109, 110.  Transitional cell carcinoma (TCC), adenocarcinoma, anaplastic carcinoma, and benign polyps have all been reported107.  Husmann’s review of ureterosigmoidostomy patients reported a 33% mortality rate 107, and although a similar large-scale review of augmented bladders has not been performed, most reports indicate a very hiAusten and Kälble published a review of the world literature of all isolated gastrointestinal urinary diversions in 2004 and found a total of 81 case reports.  Their review effectively demonstrated tumors in a variety of diversions and segments.   In comparing their data to the ureterosigmoidostomy numbers, they concluded that the augmentations and continent urinary reservoirs (CUR) developed different malignancies, with a higher proportion of transitional cell carcinomas (TCC) and other malignancies in augmented bladders. Only 72.6% of these were adenocarcinoma, whereas nearly all associated with ureterosigmoidostomy were adenocarcinoma.  Location also varied as ureterosigmoid tumors developed at the ureterocolonic anastomosis nearly universally, while only 58% did so with the other diversions.  
            Although a tumor has been reported as soon as three years after augmentation109, 113, the mean latency is 21.5-26 years.  However, 11.9% of reported tumors have occurred within 5 years of augmentation67, 107.  Based on data from Indiana University, if the lag time to malignant degeneration is assumed to be 10 years, then their estimated incidence would be 1.2%, however, if a 20 year lag-time is used, the estimated incidence increases to 3.8%111.
            The etiology of malignant degeneration in this population has not been definitively established, but several theories exist.  The carcinogens responsible for TCC of the native bladder, tobacco in the adult population, are likely very applicable to this disease, and are potentiated of the effects by the incorporating the gastrointestinal tract into the urinary tract.  Further review by Husmann, encourages all urologists caring for these patients to be very proactive in counseling against smoking114. 
            Chronic irritation and inflammation has been implicated in the pathogenesis of several bladder cancers, including SCC, TCC and adenocarcinoma.  The more common etiologic agents are long-term indwelling catheters, bladder stones, and infections.  Also, the increased incidence of polyps, adenocarcinoma, and less frequently SCC in bladder exstrophy has been attributed to chronic exposure of the urothelium to air and the resultant inflammation from the abnormal environment. gh mortality rate67, 111, 112.  There is significant concern that the number of reported cases may rise dramatically, as the number of patients at risk is increasing rapidly.

Austen and Kälble published a review of the world literature of all isolated gastrointestinal urinary diversions in 2004 and found a total of 81 case reports.  Their review effectively demonstrated tumors in a variety of diversions and segments.   In comparing their data to the ureterosigmoidostomy numbers, they concluded that the augmentations and continent urinary reservoirs (CUR) developed different malignancies, with a higher proportion of transitional cell carcinomas (TCC) and other malignancies in augmented bladders. Only 72.6% of these were adenocarcinoma, whereas nearly all associated with ureterosigmoidostomy were adenocarcinoma.  Location also varied as ureterosigmoid tumors developed at the ureterocolonic anastomosis nearly universally, while only 58% did so with the other diversions.  
            Although a tumor has been reported as soon as three years after augmentation109, 113, the mean latency is 21.5-26 years.  However, 11.9% of reported tumors have occurred within 5 years of augmentation67, 107.  Based on data from Indiana University, if the lag time to malignant degeneration is assumed to be 10 years, then their estimated incidence would be 1.2%, however, if a 20 year lag-time is used, the estimated incidence increases to 3.8%111.
            The etiology of malignant degeneration in this population has not been definitively established, but several theories exist.  The carcinogens responsible for TCC of the native bladder, tobacco in the adult population, are likely very applicable to this disease, and are potentiated of the effects by the incorporating the gastrointestinal tract into the urinary tract.  Further review by Husmann, encourages all urologists caring for these patients to be very proactive in counseling against smoking114. 
            Chronic irritation and inflammation has been implicated in the pathogenesis of several bladder cancers, including SCC, TCC and adenocarcinoma.  The more common etiologic agents are long-term indwelling catheters, bladder stones, and infections.  Also, the increased incidence of polyps, adenocarcinoma, and less frequently SCC in bladder exstrophy has been attributed to chronic exposure of the urothelium to air and the resultant inflammation from the abnormal environment.
            Any neuropathic bladder requiring catheter drainage (either indwelling or CIC) will be prone to inflammation secondary to the bacterial colonization and the presence of a foreign body.  Historic data reported the incidence of bladder cancer in the spinal cord injury population at 2-10%115, but a 1999 review of American Veteran’s hospitals found 0.4% of 33,465 patients developed a malignancy over  a 5 year period115.  Of the 130 patients with a cancer, 62% had been managed with an indwelling catheter (suprapubic or urethral), with 55% of the cancers TCC and 33% SCC.  The mean time from spinal cord injury to malignancy was 23.9 years, and very few occurred in less than 10 years.  The CIC cohort was much less likely to develop SCC, but developed their TCC much sooner, approximately 8 years.  This interesting fact speaks to the different risks associated with the increased inflammation of an indwelling foreign body vs. the increased contact time with carcinogens with CIC.
Buson et al. studied 86 rats that had undergone augmentation, and followed them for a year.  Approximately ½ had evidence of metaplasia at autopsy, but no malignancy, and all urine cytology was negative116.  Shokier et al. published their series of 186 patients who underwent continent diversion, secondary to a number of diseases (including 2 cystectomies for TCC).  Of the four patients to develop a secondary malignancy, all had abnormal cytology, but there is no data regarding the specificity of the test104.  Therefore, we believe there is good evidence that malignancy can be detected with cytology from an augmented bladder, but its role in surveillance and prevention in the augmented bladder needs to be determined19.
            Loss of Intestinal Segment   The removal of a gastrointestinal segment for CUR or augmentation is usually well tolerated, however, bowel dysfunction has been reported in 10-54% of patients117, 118.  Removal of the ileocecal valve can result in problematic diarrhea and rectal incontinence, especially in the neuropathic population119, 120.   Because bile salts are absorbed in the distal ileum, their increased quantity results in a significant osmotic gradient and problematic diarrhea 121.  However, leaving the distal 15-20 cm of distal ileum intact can usually prevent this.  Treatment of mild cases is usually successful with anion–exchange resins84. 
            Vitamin B12 deficiency can develop in up to 35% of patients following an 80 cm small bowel resection for a Kock pouch122, but it is much less common following ileocystoplasty, perhaps because it is limited to a 25 cm resection in children21,123, 124.  The Swedish series on Koch reservoirs demonstrated 2/20 patients with serum levels of vitamin B12 below normal, with 5 patients having low serum folate levels125.  Indiana University reported a 21% incidence of a “low” B12 level, and this correlated to duration of augmentation.  They recently presented an abstract demonstrating good efficacy with oral replacement126.
            Complications Due to Secretions   Gastrointestinal mucosa continue to secret mucus, and this predisposes the patient to urinary tract infections (UTI) and bladder stone formation81.  Bladder stones occur in approximately 10-30% of augmentations and CURs127-129.   The high incidence of struvite composition implies a common etiology with a urease-producing bacteria, although this may also be due to high levels of calcium and phosphate in mucus130.  The systemic acidosis common to the augmented population, will decrease stone inhibitors, and also promotes stone growth131.  Prevention is aimed at regular CIC and daily bladder irrigations.  Treatment is amenable to open or endoscopic means127, 131-133, with open surgery reserved for the larger stones.
            The acidic nature of gastric secretions can result in a hematuria-dysuria syndrome (HDS) in 9-70% of gastric bladder augmentation patients81, 94, 134, 135.  However, this is much less of a problem in a composite gastro-ileal CUR, as stomal incontinence is much less likely and the ileal segment helps neutralize the secretions136.
            Bacteriuria is nearly universal in any patient performing CIC, especially when combined with mucus from a bowel segment.  A UTI most frequently presents with malodorous urine, but symptoms also include hematuria, de-novo incontinence, suprapubic pain, or increased mucus production81.  A symptomatic urinary tract infection is reported by Rink et al. in 22.7% of patients with an ileal augmentation, while in only 8% of patients with a gastrocystoplasty90.  Treatment of asymptomatic bacteriuria is not indicated unless culture indicates a urease producing or a very virulent organism.  However, treatment may decrease the risk of stone formation.

Complications Due to Absorption   The use of bowel as a urinary reservoir can be associated with profound metabolic changes due to its absorptive nature.  Colon and ileum readily absorb ammonium, hydrogen ion, and chloride and this can result in a hyperchloremic metabolic acidosis.  This is tolerated in many patients with normal renal function137, but may require medical therapy in others.  The extent of ion absorption depends primarily upon intestinal contact area and length of time for contact, therefore, significant acidosis should prompt an investigation into incomplete emptying81.  Although not all patients will be frankly acidotic, many will have a rise in their serum chloride levels, albeit still in the normal range97, 138.  The acidosis prompts mobilization of buffers, and can result in bone demineralization.  While some believe that somatic growth impairment occurs, it remains controversial.  This has been demonstrated in animal models139-141, however, in the myelodysplasia population the clinical correlation has been more difficult to prove.  The acidosis will also result in hypocitraturia, and increase the risk of both renal and bladder stone formation131.
            Finally, medications such as Dilantin and methotrexate are readily absorbed across the bowel, and levels must be closely monitored142.  Glucose is also absorbed, making urinary monitoring of hyperglycemia less reliable143.

TISSUE ENGINEERING
Due to the significant morbidity inherent to the use of a gastrointestinal segment in the urinary tract, the promise of a bio-engineered bladder substitute has generated enormous interest144.   The original experiments used simply a biocompatible scaffold, for example SIS or a collagen matrix145.  However, these resulted in excess fibrosis in the adjacent detrusor tissue84.  Anthony Atala has been a true pioneer within pediatric urology, by first incorporating smooth muscle and urothelial cells into the scaffold, known as a “seeded” scaffold; then by implanting these scaffolds into human patients144.  Further progress is promised with the use of stem cells146 147and the addition of growth factors to encourage normal tissue development148.  Although most clinicians feel that this field heralds great promise, widespread clinical application will require a great deal more time and study.

ASSOCIATED SURGERY

Bladder Neck
            If the primary indication for surgery to attain urinary continence, the surgeon must also consider the urinary sphincter.  In cases of mild to moderate sphincteric competence, decreasing bladder pressures with a bladder augmentation is often sufficient to result in continence, as bladder pressures will now be less than the sphincter pressure.  However, in patients with very low leak point pressures, surgical intervention is required.  There are a myriad of options the surgeon must be familiar with, from minimally invasive to obliterative.   Endoscopic injection of a bulking agent (Deflux®) can be performed in a retrograde149 or antegrade fashion via  suprapubic access.  Long-term continence (over 7 years) has been reported in up to 40% of patients150, but many series report lower success rates149, 151.  Therefore although a minimally invasive option, proper patient selection is mandatory and its efficacy must be appreciated.  Suburethral slings, popularized for stress urinary incontinence, can be an excellent alternative for the moderately competent bladder neck, as they are relatively simple, have reasonable continence rates, and still allow very good access for urethral catheterization.  Their use in the neuropathic population, however, usually entails a more aggressive sling, even a complete wrap around the urethra, and is more occlusive than is seen in adults with normal bladders.  Success rates are higher if used in concordance with a bladder augmentation152 153, 154and may also vary with gender and ambulatory status153, 155.  The development of out-patient perineal slings has been popularized in adult literature, and has shown promise in the properly selected pediatric patient with the neuropathic bladder156. A more definitive reconstruction will involve the tailoring or reconfiguration of the bladder neck, with a variety of lengthening and narrowing procedures described with very good success rates154, 157.   Due to the concerns of bladder deterioration, bladder neck reconstructions have a very high incidence of concomitant bladder augmentation.  Although originally described for bladder exstrophy, the Young-Dees-Leadbetter repair remains popular amongst the spinal dysraphism population, along with the Pippe Salle and Kropp bladder neck repairs154. The ultimate bladder neck surgery to attain continence involves transection of the bladder neck, which is very effective but requires a separate outlet for catheterization158.  The multiple surgical options and frequent requirement for bladder augmentation speak to the lack of an ideal option to increase urethral resistance and attain continence157.

Continent Catheterizable Channels
            Continent catheterizable channels have become very popular over the past decade, as an aggressive approach to the bladder neck may make spontaneous voiding very difficult, especially if combined with an intestinocystoplasty.  Catheterizing per urethra more is more difficult after a bladder neck repair, or the patient confined to a wheel chair.  Seattle Children’s hospital has published data confirming patient compliance with CIC is improved with a catheterizable channel159.
            What is now known as the “Mitrofanoff Principle” states that any supple tube implanted submucosally with sufficient muscle backing will act as a flap valve, and results in a reliable, continent cutaneous, catheterizable channel.   Since Paul Mitrofanoff’s landmark paper, the “Mitrofanoff Principle” has been widely embraced and applied to a variety of tissues, as the appendix is not always appropriate or available, especially with the popularity of the MACE.  The use of stomach, colon, bladder, ureter, and fallopian tube have all been reported with good success160-171.  The reconfigured ileal channel was introduced by Yang166 and Monti 161 and has assumed a leading role in genitourinary reconstruction due to its reliability with a minimal loss of bowel.  Casale introduced the spiral Monti, which increases the pThe stoma site can be hidden within the umbilicus or placed in the right lower quadrant, depending on surgeon preference and patient habitus.  The umbilicus has the advantage of being accessible above the pant line, but requires a longer intra-abdominal course, with an increased risk of an intra-abdominal revision173.   A stoma in the right lower quadrant ensures that the detrusor is securely fixed to the abdominal wall, with a shorter intraperitoneal course, less unsupported channel, and is hypothetically less likely to result in channel laxity and difficulty of catheterization.   Many ingenious skin flap techniques have been employed to minimize the chance of stomal stenosis, all inserting into the spatulated channel174-176.  An indwelling catheter is left for 3 weeks and the first catheterization is usually performed in the clinic setting.  The suprapubic tube is left in situ until everyone is certain that there are no difficulties with catheterization.  
            Stomal continence is excellent, and rates of 90-99% are reported in the largest published series163, 177-179.  Complications pertain primarily to difficulties with catheterization, and these can be categorized into those that occur at the skin level and those deeper, at the entrance to the bladder.  This is an important differentiation, as a skin revision is a simple outpatient procedure, while a deep revision requires a much more extensive dissection, usually a laparotomy.  Stomal stenosis is reported to occur in 5-25%177, 180, with nearly identical rates between appendiceal and tapered ileum channels163, 181. otential length to 14 cm with a diameter of 12-14 Fr163, 172.

Fecal Continence
            It often falls under the care of the pediatric urologist to manage the constipation and fecal continence secondary to the neuropathic bowels.  Medical treatment is dictated by the goal of “controlled constipation” where the feces is hard enough for the sphincter to be able to retain it, but soft enough so that some degree of emptying can occur.  Bowel softeners such as Lactulose and mineral oil are very effective, whereas PEG-3350 (Miralax®) has the added advantage of being nearly odorless and tasteless, will not contribute to cavities, and can be mixed in nearly any liquid.  Often, rectal stimulation via digital touch or suppository is required to create a contraction to evacuate the feces.  Rectal enemas are useful in some to evacuate the distal aspect of the sigmoid colon, but can be uncomfortable and difficult for the patient to perform independently.  The Peristeen system has recently been introduced in England and is designed to allow comfortable and independent trans-anal irrigation with very good continence results182. 
            Just as with the bladder, medical management can be very effective, and surgical alternatives are available when they fail.  The concept of an antegrade enema via the appendix was introduced by Malone183 and has achieved extreme popularity amongst surgeons and patients due to the great improvements in quality of life amongst patients and caregivers184, 185.  A minimally invasive alternative has also been used, whereby interventional radiology places a cecostomy tube into the proximal colon and flushes occur via a trap-door device, similar to a feeding tube186, 187.  Continence rates and patient satisfaction for both are excellent, therefore the most important factors in choosing between the two procedures are: technical expertise, concomitant laparotomy for bladder reconstruction, tolerance of an external device, and concerns regarding intrabdominal adhesions and shunt contamination.

Summary
            Contemporary outcomes for patients with spinal dysraphisms should focus on maximizing quality of life188.  With comprehensive spina bifida clinics the norm for pediatric patients, the vast majority are expected to reach adulthood.  Most of our patients are able to attend school and the majority graduate from high school with many pursuing post-secondary education and gainful employment.  Therefore, we believe that continence should be an important goal, although the direct benefit on the patient’s quality of life has been difficult to prove.  Although the protection of the upper urinary tracts and preservation of renal function has several very effective and low maintenance medical and surgical alternatives, continence can involve a much greater degree of effort and surgical complication.

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