Editing Pediatrics: Neuromuscular Disorders of the Lower Urinary Tract

See Functional: Neuromuscular Dsyfunction of the Lower Urinary Tract Chapter Notes

== Causes of Neuromuscular Dysfunction of the Lower Urinary Tract ==

* '''Acquired'''
** '''Extensive pelvic surgery'''
** '''Central nervous system insults'''
*** Cerebral palsy
*** Conditions of the brain (tumors, infarcts, encephalopathies)
*** Spinal cord insults
**** Trauma
**** Transverse myelitis
* '''Congenital'''
** '''Sacral agenesis'''
** '''Anorectal malformations'''
** '''Spina bifida/Neural tube defect'''
*** '''Most common cause of neurogenic bladder dysfunction'''

== Spina bifida/Neural Tube Defects (NTDs) ==

* '''Spina bifida refers to the malformation of the vertebral arches and, commonly, malformation of the neural tube.'''
* '''Embryology'''
** '''Formation of the spinal cord and vertebral column begins at ≈18 days of gestation'''
** '''Closure of the canal proceeds in a caudal direction from the cephalad end and is complete by 35 days'''
* Epidemiology
** Worldwide incidence of 0.3-4.5 per 1000 births
* '''Risk Factors (12)'''
*# '''Folate deficiency''' (women with low levels of folic acid and impairment of folate mediated pathways or antibodies to folate)
*# '''Family history of NTDs'''
*# '''Young and advanced maternal age'''
*# '''Maternal obesity'''
*# '''Maternal diabetes'''
*# '''Maternal fever or flu'''
*# '''Maternal caffeine consumption'''
*# '''Specific maternal occupational exposures'''
*# '''Maternal low educational level and socioeconomic status'''
*# '''Maternal passive smoking'''
*# '''Maternal periconceptual stressful event'''
*# '''Low maternal weight gain'''
* '''The term includes'''
*# '''Spina bifida occulta/occult spinal dysraphism''', which involves only a bony (vertebral) arch defect
*# '''Spina bifida cystica''' (aperta), which involves a bony defect and a neural tube (spinal cord) defect
*#* '''Primary subclasses of spina bifida cystica (2):'''
*#*# '''Meningoceles''' (which contain only a herniated meningeal sac with no neural elements)
*#*# '''Myelomeningoceles'''
*#*#* The nerve roots or portions of the spinal cord have evaginated beyond the vertebral bodies
*#*#* '''Accounts for > 90% of spina bifida cystica'''
*#*#* '''Most devastating in terms of sequelae.'''
*#*#* Insert figure

== Myelomeningocele (MMC) ==

* '''Pathogenesis'''
** '''Almost all infants born with MMC have the Arnold-Chiari malformation, which includes:'''
*** '''Hindbrain herniation'''
*** '''Brainstem abnormalities'''
*** '''Low-lying venous sinuses'''
*** '''A small posterior fossa'''
** '''Of myelomeningoceles''', 2% are cervical, 5% thoracic, 26% lumbar, '''47% lumbosacral, and 20% sacral'''
** '''The bony vertebral level often provides little or no clue to the exact neurologic level or lesion produced'''
*** The neurologic lesion produced can be variable, depending on what neural elements, if any, have everted with the meningocele sac.
* '''Pre-natal Closure of MMC'''
** '''Benefits:'''
**# '''Improves neuromotor function'''
**# '''Decreases the need for ventriculo-peritoneal shunting.'''
** '''Risks''':
*** '''Increased risk of maternal morbidity and preterm labor with its resultant complications'''
** '''Bowel and bladder function are not improved''' and in some cases may be hindered with prenatal closure of MMC when compared with postnatal closure
* '''Initial Post-natal Evaluation'''
** '''Should be done as early as possible after birth'''
*** The initial evaluation can be compared with findings on subsequent assessments, so that early signs of deterioration of urinary tract function and drainage, or of progressive neurologic denervation, can be detected
*** Infants at risk for urinary tract deterioration as a result of a poorly compliant or overactive detrusor or outflow obstruction from DSD need to be identified so that prophylactic measures can be initiated before any deterioration in upper urinary tract architecture and function take place.
** '''Includes (5):'''
*** '''History and physical exam, including careful neurologic examination of the lower extremities'''
*** '''Labs:'''
**** '''U/A +/- culture'''
**** '''Serum creatinine''' (if indicated, after the first week of life when it reflects the child’s renal function)
***** Note that CUA ANH Guidelines suggest that serum creatinine should be obtained at 24 hours
*** '''Imaging:'''
**** '''Renal US'''
***** '''Once the spinal closure has healed sufficiently, a renal US is performed to assess upper urinary tract architecture and function'''
****** '''Children with spina bifida have smaller kidneys than their normal peers'''
****** '''A VCUG is recommended if the US shows hydronephrosis, ureteral dilation, renal size or contour discrepancy, or increased bladder wall thickness'''
*** '''Other: PVR'''
** '''Assessment of Renal Function in Children with Neuromuscular Dysfunction of the Lower Urinary Tract'''
*** '''Serum creatinine'''
**** '''Freely filtered and secreted''' by the kidney (and therefore overestimates GFR)
**** '''Varies by age, gender, height, and muscle mass'''
**** '''Not an accurate reflection of GFR in children with myelodysplasia, who often have diminished muscle mass'''
*** '''Cystatin C'''
**** '''Alternative marker of GFR'''
**** '''Produced at a constant rate by all nucleated cells'''
**** '''Freely filtered''' by the glomerulus, '''not secreted''' from the renal tubule; '''thus, the serum concentration of cystatin C is determined primarily by glomerular filtration'''
**** '''Superior to serum creatinine for estimating GFR in children with spina bifida'''
**** '''At early stages of renal functional impairment, cystatin C may not be as reliable as a full clearance study'''
*** '''Nuclear renal scan'''
**** '''Gold standard for measuring GFR'''
**** '''Invasive and exposes the patient to radiation'''
**** '''May be required in early stages or when mild renal functional impairment is suspected'''
** '''LUT dynamics'''
*** '''Categories that may be detected (3):'''
**** '''Synergic'''
***** '''Complete silencing of the sphincter during a detrusor contraction or when capacity is reached at the end of filling'''
***** Voiding pressures are usually within the normal range
**** '''Dyssynergic''' (with and without poor detrusor compliance)
***** '''DSD''' occurs when the external sphincter fails to decrease or actually increases its activity during a detrusor contraction or a sustained increase in intravesical pressure as the bladder is filled to capacity
***** Frequently, a poorly compliant bladder with high intravesical pressure occurs in conjunction with DSD, resulting in a bladder that empties only at high intravesical pressure
**** '''Complete denervation'''
***** '''No bioelectric potentials are detectable in the region of the external sphincter''' at any time during the micturition cycle or in response to sacral stimulation or a Credé maneuver.
**** Within the first 3 years of life,>70% of children with detrusor sphincter dyssynergy will have urinary tract deterioration, whereas <25% of those with synergy or complete denervation will have deterioration.
***** '''The highest risk for the development of urinary tract deterioration in children with myelodysplasia is in those with initial urodynamic findings of DSD'''
* '''Principles of Management'''
** '''Primary goal: preservation of renal function'''
*** '''Best achieved by (3):'''
***# '''Maintaining low bladder pressures'''
***# '''Avoiding hydronephrosis'''
***# '''Actively managing VUR if recurrent UTIs occur'''
*** '''Determinants of risk of renal dysfunction include'''
***# '''DSD'''
***# '''High detrusor pressures'''
***# '''Detrusor overactivity'''
***# '''Outflow obstruction'''
***# '''Febrile UTIs'''
***# '''VUR'''
**** These entities should be actively managed to minimize risk of renal functional decline
**** '''Bladder pressures should be maintained < 30 cm H2O to prevent urinary tract deterioration'''
** '''Secondary goals:'''
**# '''Attaining urinary and fecal continence'''
**# '''Avoidance of UTI'''
**# '''Facilitation of sexual function and fertility'''
** '''First-line: early intervention, defined as CIC and anti-muscarinic therapy'''
*** '''Benefits:'''
***# '''Decreases peak contractile pressure''' 
***# '''Decreases bladder filling pressure'''
***# '''Decreases risk of UTI'''
***# '''Decreases risk of hydrouteronephrosis'''
***# '''Decreases risk of VUR'''
***# '''Decreases risk of surgical intervention'''
***# '''Decreases risk of renal scarring'''
***# '''Decreases risk of ESRD'''
** '''Second-line: overnight indwelling catheter drainage'''
*** '''Benefits:'''
***# '''Improves or resolves hydronephrosis'''
***# '''Increases bladder capacity'''
***# '''Decreases the frequency of UTI'''
** '''Third-line: surgical intervention'''
** '''Medical Management'''
*** '''Anti-muscarinics'''
**** '''In children with detrusor overactivity, anti-muscarinics result in:'''
****# '''Increased bladder capacity'''
****# '''Increased volume to first detrusor contraction'''
****# '''Decreased number of incontinence episodes'''
****# '''Decreased number of catheterizations'''
**** Adverse events: dry mouth, constipation, blurred vision, facial flushing, dizziness, and headache
**** '''The most commonly used anti-muscarinic agent in children is oral oxybutynin (0.2 mg/kg/dose given up to three times daily)'''
*** '''Beta-3 agonist'''
**** '''Mirabegron is effective in adults but has not yet been approved by the FDA for use in children'''
*** '''Sympathomimetic Agents'''
**** '''If incontinence results from inadequate urethral resistance, sympathomimetic agents''' (e.g'''.''' ephedrine and pseudoephedrine) '''act to increase tone at the bladder neck where the concentration of α-adrenergic receptors is highest, thereby raising outlet resistance and improving continence'''
**** '''Regular use of sympathomimetic agents, however, may be limited by their side effects,''' including dizziness, nausea, nervousness, insomnia, loss of appetite, headache, mood changes, and urinary retention.
** '''Surgical Management'''
*** '''Intravesical Botulinum Toxin (BTA)'''
**** '''See Pharmalogical Managements of LUTS Chapter Notes'''
**** '''The most common minimal age for injection is 2 years'''
**** '''Most commonly injected dose is 10 IU/ kg, with a maximum total dose of up to 300 IU.'''
**** Most studies use 30 injection sites (sparing the trigone) with rigid cystoscopy and general anesthesia.
**** '''Results in improved continence and urodynamic parameters (decreased maximum detrusor pressure, increased maximum cystometric capacity, and improved compliance)'''
**** '''May avoid reconstructive surgery''' in those in whom conservative management has failed. Overall, patient and caregiver satisfaction with this treatment exceeds 70%
**** Adverse events: urinary retention, UTI, hematuria, transient muscle weakness, dysuria, and pain
**** '''Repeated injections are not associated with fibrosis or a decreased treatment effect.'''
***** '''The interval between repeated injections increasing with each series of injections.'''
**** '''Poor response to BTA intradetrusor injection is associated with pre-existing poor bladder compliance'''
**** '''Complete lack of a response to BTA injection is associated with the presence of BTA antibodies'''
*** '''Neuromodulation'''
**** Appears to be safe with some limited benefits over standard therapy, but a larger study is required to determine its efficacy.
*** '''Bladder Augmentation'''
**** '''A persistent poorly compliant, small-capacity, or overactive detrusor may be treated with enterocystoplasty'''
**** Enteric augmentation with an '''ileal segment is the preferred''' approach to increase bladder capacity in children with NLUTD
**** Autoaugmentation is not recommended because it does not improve urodynamic and clinical symptoms, and has a high a high failure rate.
**** Ileal-cecal segment is not recommended because it may aggravate bowel dysfunction.
**** Gastric segment is not recommended because it is
**** High risk of complicationswith more symptomatic side effects (such as hematuria dysuria syndrome) and metabolic complications than ileal segments.
*** '''Urinary diversion'''
*** '''Bladder neck procedures'''
**** '''Isolated bladder neck procedures, such as artificial urinary sphincter and bladder neck slings, have been noted to lead to worsening of bladder function in as many as 30% of patients, especially those with preexisting detrusor overactivity and poor compliance.'''
**** '''Patients may develop hypercontractility and poor compliance that can lead to upper tract deterioration, mandating close follow-up.'''
* '''Management of Neurogenic Bowel Dysfunction'''
** Initially, treatment is directed toward '''high dietary fiber and osmotic laxatives''' 
** An option for those who are unable to sit on the toilet is controlled constipation with manual evacuation of stool because large-volume enemas cannot easily be delivered in these children.
** In those who are able sit independently, with some anal sphincter activity, a regular '''postprandial toilet sitting regimen''' three times daily after meals has been effective, as it employs the gastrocolic reflex to initiate a bowel movement
** When continence is not achieved by defecation, digital stimulation is suggested. If manual evacuation fails or if the anal sphincter is nonfunctioning, '''retrograde enemas''' can be used
** If fecal incontinence persists at this point, the '''antegrade continence enema''' (ACE) is considered the next step in management.
*** ACE delivered through a surgically placed appendicostomy or cecostomy was first described in children with SB or anorectal malformations by Malone and colleagues in 1990.
*** '''Use of ACE is associated with:'''
**** '''Significantly improved fecal continence'''
**** '''No increase in the amount of time dedicated to bowel care'''
**** '''Improved quality of life'''
*** Long-term studies indicate that ≈40% of children discontinue use of their surgically created cecostomies after a median of 11 years.
**** Reasons for nonuse include lack of effectiveness, complications, psychological issues, and poor compliance.
**** In those who continue using the cecostomy, level of satisfaction is very high
* '''Management of Vesicoureteral Reflux''' '''(VUR)'''
** '''VUR occurs in 3-5% of neonates with NTDs, usually in association with poor detrusor compliance, detrusor overactivity, and/or DSD; it is rare to find reflux in any neonate without these urodynamic findings'''
** '''In children with VUR grades I to III who void spontaneously or have a complete lesion with little or no bladder outlet resistance and who empty the bladder completely, management consists solely of prophylaxis with antibiotics to prevent recurrent infection'''
** '''In children with high-grade reflux (grade IV or V), CIC is begun to ensure complete emptying.'''
** '''Children who cannot empty the bladder spontaneously, regardless of the grade of reflux, are treated with CIC to empty the bladder efficiently.'''
** '''Credé voiding should be avoided in children with reflux'''
*** Children with a reactive external urinary sphincter will have a reflex response of increased external urethral tone in response to the Credé maneuver, which can aggravate reflux
** '''Children with poor detrusor compliance (with or without hydroureteronephrosis) are also started on antimuscarinic agents''' to lower intravesical pressure and ensure adequate upper urinary tract decompression
** '''Indications for anti-reflux surgery is similar to children with normal bladder function:'''
*** Recurrent symptomatic (febrile) UTI while the child is receiving adequate antibiotic therapy and appropriate catheterization techniques
*** Persistent hydroureteronephrosis despite effective emptying of the bladder and lowering of intravesical pressure
*** Severe reflux with an anatomic abnormality at the ureterovesical junction.
** Anti-reflux surgery can be very effective in children with neurogenic bladder dysfunction as long as it is combined with measures to ensure complete bladder emptying
** Bilateral anti-reflux surgery for unilateral reflux is not needed
** Children with high-grade reflux undergoing augmentation cystoplasty should have concurrent ureteral reimplantation
** '''Endoscopic approach is a reasonable alternative to ureteroneocystotomy'''; however, long-term outcomes raise concerns about the durability of this approach in those with neurogenic bladder dysfunction.
* '''Management of Sexual function'''
** '''> 70% of young men with MMC are able to obtain an erection'''
*** '''Medical therapy for erectile dysfunction has been shown to be effective in this population'''
** '''Ability to ejaculate ranges from ≈40-75%'''
** '''Factors associated with worse sexual function (4):'''
**# '''Lesions above the sacral spinal cord'''
**# '''Hydrocephalus'''
**# '''Incontinence'''
**# '''Living with parents'''
** '''70-80% women with MMC are able to become pregnant and have an uneventful pregnancy and delivery'''
** '''Both females and males with spina bifida have an increased risk of having a child with spina bifida'''
** '''Poor semen quality and Sertoli cell–only histology on testis biopsy have been reported as reasons (in addition to erectile dysfunction) for infertility in males with spina bifida.'''
** '''Studies on sexual function in males with spina bifida have demonstrated that paternity is associated with an L5 or sacral neurologic level.'''
*** This neurologic level was present in 80% of patients who fathered children.
*** This is in contrast to bladder function, which does not correlate well to the neurologic level of the lesion.
*** The ambulatory status and presence of a ventriculoperitoneal shunt are other important factors associated with paternity.

== Lipomeningocele and other spinal dysraphisms ==

* '''Occult spinal dysraphism involves only a bony (vertebral) arch defect (no neural tube defect)'''
* '''Types of Occult Spinal Dysraphisms (8):Spinal Dysraphisms DIAL CT'''
*# '''Sacral meningocele'''
*# '''Diastematomyelia'''
*# '''Dermoid cyst'''
*# '''Intradural lipoma'''
*# '''Aberrant nerve roots'''
*# '''Lipomeningocele'''
*# '''Cauda equine tumor'''
*# '''Tight filum terminale'''
* '''Presentation'''
** '''A cutaneous abnormality overlying the lower spine is found in 90% of those with occult neural tube defect'''
** '''Physical exam findings in patients with occult spinal dysraphism:'''
**# '''Sacral dimple'''
**#* '''An “atypical” presacral dimple may indicate spina bifida or cord tethering if the dimple is:'''
**#*# '''Off center or'''
**#*# '''>2.5 cm from the anal verge at birth or'''
**#*# '''> 0.5 cm deep'''
**# '''Sacral skin tag'''
**# '''Sacral hairy patch'''
**# '''Sacral dermal vascular malformation'''
**# '''Sacral subcutaneous lipoma'''
**# '''Asymmetric gluteal cleft'''
**# '''High arched foot or feet'''
**# '''Hammer toes or claw toes'''
**# '''Discrepancy in leg muscle size, and strength''' (typically at the ankle)
**# '''Gait abnormality''', especially in older children
**# '''Absent perineal sensation'''
**# '''Diminished rectal tone'''
** '''Majority of children evaluated in the neonatal period have perfectly normal neurologic examination findings. Urodynamic testing, however, reveals abnormal LUT function'''
** '''Patients often present after age 3 or 4 years with back pain, secondary incontinence after a period of dryness, or constipation.'''
*** LUT function is abnormal in 40-90% of affected older individuals
*** '''May have new urologic symptoms after a growth spurt, related to tethering of the spinal cord'''
**** '''High risk of tethering with growth spurts (2):'''
****# '''Newborn to toddler'''
****# '''Adolescent to adult'''
* '''Pathogenesis'''
** '''Various occult spinal dysraphic lesions produce different neurourologic findings'''
*** The reason for this difference in neurologic findings may be related to:
***# Compression of the cauda equina or sacral nerve roots by an expanding lipoma or lipomeningocele
***# Tension on the spinal cord from tethering secondary to differential growth rates in the bony vertebrae and neural elements while the lower end of the cord is held in place by the lipoma or by a thickened filum terminale
***# Fixation of the split lumbosacral cord by an intravertebral bony spicule or fibrous band.
*** The overt stretching that invariably occurs when there is a forcible flexion and/or extension of the spinal cord with normal movement leads to changes in oxidation and reduction of cytochrome oxidase, most notably in the lumbosacral spinal neurons
*** '''Under normal circumstances the conus medullaris ends just below the L2 vertebra at birth and recedes upward to T12 by adulthood'''.
**** '''When the cord does not “rise” or is fixed in place owing to one of these lesions, ischemic injury may ensue'''
* '''Specific Recommendations'''
** '''Imaging of the spine in occult spinal dysraphism'''
*** '''In children age < 3 months, the vertebral bones have not ossified and US is a useful screening tool in visualizing the spinal canal.'''
**** '''At this age there is good correlation between the ultrasound imaging and MRI findings'''
**** '''If a spinal cord abnormality is identified, MRI should be done as it provides a better definition of the spinal cord lesion. Consequently, US should not be used as the definitive imaging modality'''
*** '''In children age ≥ 3 months, MRI is used to assess the spinal canal'''
** '''Urodynamics'''
*** '''In addition to imaging of the spine, urodynamic testing including EMG of the external urethral sphincter should be performed in every child who has a questionable cutaneous or bony abnormality of the lower spine, especially if there is a radiologic abnormality of the spinal cord.'''
**** '''Urodynamic testing may be the only way to document that an occult spinal dysraphism is actually affecting lower spinal cord function.'''
**** Urodynamic studies should be done before and after spinal cord detethering
**** The serial use of electromyography (EMG) of the external urethral sphincter using a needle electrode to monitor individual motor unit action potentials provides a precise mechanism for measuring changes in innervation that may occur over time. Detection and early intervention can either reverse or at least stabilize the progression of the lesion, which does not happen in older children
** '''Intervention with spinal cord detethering early in life is associated with better outcomes''' than when done later

== Sacral Agenesis ==

* '''Definition of sacral agenesis: absence of part or all of ≥2 lower vertebral bodies'''
* '''Risk factors: maternal diabetes and gestational diabetes'''
* '''Presentation'''
** '''Bimodal presentation; 75% detected in early infancy vs. 25% discovered between 4 and 5 years of age'''
** Because these children have '''normal perineal sensation''' and '''little or no orthopedic deformity''' in the lower extremities the underlying lesion is often overlooked. The only clue, besides a high index of suspicion, is '''flattened buttocks with a low, short gluteal cleft'''
** '''When not detected prenatally or at birth, the diagnosis is often delayed until failed attempts at toilet training''' bring the child to the attention of a physician.
*** '''Presenting urinary symptoms in those aged ≥ 4 include urinary incontinence or constant dribbling''' in 85% '''and recurrent UTI''' in 74%.
* '''Initial investigation includes urodynamics, renal ultrasound, and nuclear cystogram'''
* Long-term follow-up is required

== Conditions of the Pelvis ==

* '''Anorectal Malformation'''
** A wide spectrum of diseases involving the distal anus and rectum as well as the urinary and genital tracts
** Presentation
*** Urinary tract abnormalities in 26-52% of affected children, with '''renal agenesis (primarily left-sided) and VUR as the most common associated findings'''
*** '''The cause of neurogenic bladder in these children is most commonly associated with a spinal cord abnormality'''
** Specific Recommendations
*** Initial evaluation in the neonatal period should include a careful inspection of the perineum looking for a fistulous site from the bowel, an examination of the upper and lower extremities, and an assessment of the spine and spinal cord renal-bladder ultrasound

== Central Nervous System Insults ==

* '''Cerebral palsy'''
** '''Most common physical disability in childhood'''
** The most common urinary symptom is incontinence
*** LUTS may be related to abnormal LUT function rather than to decreased mobility or ability to communicate
*** '''Detrusor overactivity is noted in ≈30%'''

== Conditions of the spinal cord ==

* '''Traumatic Injuries'''
** '''See 2019 CUA NLUTD Guideline Notes'''
** '''During the acute phase of the injury (spinal shock)''' '''the bladder is often acontractile and the urethral sphincter nonreactive''', although normal-appearing bioelectric potentials can be recorded on sphincter EMG.
** '''Over a variable period of time, detrusor contractility and sphincter reactivity return as spinal cord edema subsides.'''
** Monitoring of blood pressure and availability of α-antagonists are mandatory during VCUG or urodynamic studies in patients at risk of autonomic dysreflexia

== References ==

* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 4, chap 142