Myelodysplasia and Neurogenic Bladder Dysfunction - Dia...

Myelodysplasia and Neurogenic Bladder Dysfunction

Myelodysplasia and Neurogenic Bladder Dysfunction
March 27, 2008
Terry F Favazza, MD
eMedicine.com

INTRODUCTION

Background

The term myelodysplasia includes a group of developmental anomalies that result from defects that occur during neural tube closure. Lesions may include spina bifida occulta, meningocele, lipomyelomeningocele, or myelomeningocele. Myelomeningocele is by far the most common defect seen and is the most devastating. This article focuses on identifying neurogenic bladder dysfunction and treatment options and describes follow-up care in children with myelodysplasia.
Pathophysiology

Spinal cord and vertebra formation begin at approximately 18 days' gestation. Closure of the spinal canal begins at the cephalad end, proceeds caudally, and is complete by 35 days' gestation. The exact cause of neurospinal dysraphism is unknown, but it appears to be multifactorial. Genetic, environmental, and nutritional factors have been implicated; however, no specific etiology has been pinpointed. An increased frequency of neural tube defects appears to occur in the offspring of mothers who had folic acid deficiency during pregnancy. Based on these data, the current recommended daily allowance (RDA) of 400 mcg/d of folic acid was established for women during pregnancy.

Spina bifida is a broad term that may be used to describe a number of open defects of the spinal column. A meningocele occurs when the meningeal sac (the sac that envelops the spinal cord) extends beyond the confines of the vertebral canal but does not contain any neural elements. A myelomeningocele occurs when neural tissue (nerve roots, spinal cord tissue, or both) is included in the sac. A lipomyelomeningocele is defined by the presence of fatty tissue and neural elements within the sac.

Myelomeningoceles account for 90% of open spinal dysraphic states. The overwhelming majority of myelomeningoceles are directed posteriorly, with most defects involving the lumbar vertebrae. In decreasing order of frequency, sacral, thoracic, and cervical vertebrae are affected. In the rare case of an anteriorly directed defect, the sacral vertebrae are most commonly involved. An Arnold-Chiari malformation is associated in 85% of children with a myelomeningocele. This occurs when the cerebellar tonsils herniate through the foramen magnum and obstruct the fourth ventricle, which prevents cerebrospinal fluid (CSF) from entering the subarachnoid space. These children require shunting of the ventricles, most commonly to the peritoneum. A small number (approximately 5%) of patients with myelomeningoceles do not have a neurogenic bladder, but this is an exception.

Congenital defects of spinal column formation that are not open defects are often termed spina bifida occulta. The lesions can be subtle, often with no obvious signs of motor or sensory denervation; however, in many patients, a cutaneous abnormality can be seen overlying the lower spine. This can vary from a dimple or a skin tag to a tuft of hair, a dermal vascular malformation, or an obvious subdermal lipoma. Alterations may be found in the arrangement or configuration of the toes, along with discrepancies in lower extremity muscle size and strength, weakness, or abnormal gait. Back pain and an absence of perineal sensation are common symptoms in older children. Frequency of abnormal lower urinary tract function in patients with spina bifida occulta has been reported to be as high as 40%.

Sacral agenesis, defined as the absence of 2 or more lower vertebral bodies, is another defect that can produce voiding dysfunction. Because perineal sensation is usually intact and lower extremity function is normal, the only clue is often a flattened buttock and a short gluteal cleft. However, in many patients, no external signs are evident. If suspected, diagnosis is made using a lateral film of the lower spine. Even at best, only 50% of affected infants are identified in the newborn period.

The neurologic lesion produced by the dysraphism can widely vary, depending on the neural elements that have everted with the meningocele sac. The bony vertebral level correlates poorly with the neurologic lesion produced. Additionally, different growth rates between the vertebral bodies and the elongating spinal cord can introduce a dynamic factor to the lesion. Fibrosis may surround the cord at the site of meningocele closure, and the cord can become tethered during growth. This can lead to changes in bowel, bladder, and lower extremity function. If these are noted, investigation is warranted to exclude cord tethering.
Frequency
United States

Reported prevalence of spinal dysraphism is 1 case per 1000 live births in the United States.1 For unknown reasons, spinal dysraphism is more common in the eastern United States. Studies conflict regarding whether a seasonal variation occurs in prevalence. A genetic component to the disease appears to be present; if spinal dysraphism is present in one child, the chance of having a second child with the same condition is 2-5%. In addition, prevalence is increased in children born to mothers older than 30 years. Prevalence of spina bifida occulta (myelodysplasia with a closed vertebral canal) is 1 case per 4000 live births. Prevalence of sacral agenesis in children of mothers with insulin-dependent diabetes mellitus is higher than average (1%).
International

A large range in prevalence has been recorded internationally. Studies have demonstrated rates from 0.12-4.5 cases per 1000 live births. Prevalence of spinal dysraphism appears to be lower in Asian countries.
Mortality/Morbidity

The meningocele sac is often nothing more than a very thin transparent tissue that may be open and leaking CSF. This is a potential source of CNS infection, which can lead to death if untreated in the perinatal period. Prompt closure of the defect is imperative. The closure itself producing neurologic symptoms is a concern, but this appears to happen in fewer than 5% of patients.

Urologic morbidity rates in patients with myelodysplasia are significant. Myelodysplasia can contribute to voiding dysfunction, urinary tract infections (UTIs), vesicoureteral reflux, and renal scarring. Surgery may be required to establish adequate bladder drainage. If not managed appropriately, myelodysplasia can cause significant urologic problems that can potentially lead to progressive renal failure, requiring dialysis or transplantation.

* UTIs are common in infants with myelodysplasia, and patients must be promptly treated when UTIs are recognized. Recurrent infections, especially associated with poorly compliant bladder and vesicoureteral reflux, can lead to pyelonephritis, renal scarring, and an eventual loss of renal function. In the absence of reflux, patients with infections are usually treated symptomatically, but in children who experience recurrent infections, prophylactic treatment can be instituted.
* Vesicoureteral reflux occurs in 3-5% of infants with myelodysplasia and is usually associated with detrusor hyperreflexia or dyssynergia. If the neurogenic bladder remains untreated, incidence of vesicoureteral reflux increases with time until, by age 5 years, 30-40% of children are affected. Treatment of reflux consists of antibiotic prophylaxis to prevent infection, anticholinergic medications to lower detrusor filling pressures, and use of a method to empty the bladder, most commonly, intermittent catheterization (IC). In the most severe cases of reflux or if evidence of progressive renal scarring is apparent, surgery can be performed to lower bladder storage pressures or to provide an antireflux mechanism.
* Renal damage or failure can occur as a product of repeated infections with progressive renal scarring and damage or as a result of obstruction caused by inability to empty the bladder. This can occur slowly over a period of years or with surprising rapidity, underscoring the need for regular lifelong follow-up care in patients with myelodysplasia. Even with maximal medical and surgical therapies, renal failure can occur (although rarely), and dialysis or transplantation may be needed.

Race

Studies have not shown a significant difference between races in the prevalence of myelodysplasia. However, a study from California demonstrated a slightly higher prevalence in children born to Hispanic mothers.2 White mothers were the second most likely to have children with myelodysplasia, followed by black and Asian mothers.
Sex

Myelodysplasia is more common in females than in males.
Age

* Antenatal detection of myelodysplasia can be made using prenatal ultrasonography. If myelodysplasia is prenatally detected, cesarean delivery may improve neurologic function by reducing the trauma caused by vaginal delivery. Neural tube defects can be suspected if amniocentesis shows increased levels of a fetoprotein, but these results can be misleading, with large numbers of both false-positive and false-negative results.
* In many infants, myelodysplasia is detected immediately at birth; however, spina bifida occulta may not become apparent until later in life, and voiding dysfunction may be the only sign of occult disease.


CLINICAL

History

* Obtain a birth history from the parents. Asking about any difficulties with pregnancy or delivery is important, as is obtaining a history of spinal dysraphism in either parent, their families, or siblings.
* When myelodysplasia is present, observe the voiding patterns of the child and gather a specific voiding history from caregivers. Admittedly, this may be difficult in newborns.
* Pay attention to the presence of straining, the force and caliber of the urinary stream, dry diaper intervals, a history of UTIs, and attempted treatments (if any).
* Often, the urologist sees the newborn before discharge from the hospital, either before or following closure of the spinal defect, and voiding habits may not be known. In this setting, check postvoiding residual volumes and, if elevated, institute the use of IC or an indwelling catheter in the perioperative period.

Physical

* The open myelodysplastic defect is obvious, and contents of the sac can often be detected within the membrane, helping to establish the diagnosis. If the patient is stable, closure of the spinal defect usually takes precedence over other issues. Once closure is complete, a full physical examination is necessary.
* Search for any other abnormalities and assess neurologic function. Careful inspection of the genitalia is necessary to evaluate for any ambiguities regarding the sex of the child and to look for hypospadias and cryptorchidism in males. Pay attention to the abdominal musculature, lower extremity function, anal sphincter tone, and the presence of a sacral reflex arc (bulbocavernosus reflex), which is tested for by gently squeezing the penis or clitoris and watching for an anal wink. Additionally, during the abdominal examination, attempt to assess renal size and the presence and degree of bladder distension. In patients who require ventriculoperitoneal (VP) shunting, communicating hydroceles and hernias need to be identified for surgical correction.
* If the child is apparently unable to spontaneously empty the bladder, the use of IC is initiated. The expected bladder capacity of the newborn is 10-15 mL, and residual volume should be less than 5 mL. The definitive examination of bladder function is a urodynamic study, which is discussed in Other Tests.
* Although physical examination focuses on looking for other anomalies and assessing neurologic function in patients with open defects, the presence of skin discoloration, a mole, a tuft of hair, or a dimple may be the only sign of underlying spinal defect in patients with occult dysraphic states. Evaluate these children with the appropriate imaging studies and a urodynamic study to define the defects.

Causes

The exact cause of dysraphism is unknown, but many factors appear to be involved. Genetic, environmental, and nutritional factors have been implicated, although no specific etiology has been pinpointed.

* Genetic: If myelodysplasia is present in one child in a family, the chance of having a second child with the same condition is 2-5%. Prevalence of myelodysplasia is increased in children born to mothers older than 30 years. Currently, no genetic markers have been linked to the presence of myelodysplasia.
* Environmental: Studies of open in vivo neural tube defects indicate that the exposed tissue in the myelomeningocele sustains secondary injury from mechanical and chemical factors during its prolonged exposure to the uterine environment. The additive effects of the congenital defect and the superimposed trauma appear to combine to determine the total neurologic deficit displayed by the infant.
* Nutritional: Prevalence of neural tube defects appears to be increased in the offspring of mothers who had folic acid deficiency during pregnancy. Based on these data, the current RDA of 400 mcg/d of folic acid was established for women during pregnancy.
* Diabetes: Sacral agenesis appears to be associated with diabetes, specifically, with the presence of insulin during fetal development. Maternal diabetes mellitus is seen in 12-18% of patients with sacral agenesis, and 1% of children born to mothers who are insulin dependent have the condition. Although the mechanism is unknown, the defect has been reproduced when chick embryos are exposed to insulin.


DIFFERENTIALS

Myelodysplasia

Other Problems to be Considered

Spina bifida occulta
Sacral agenesis
Nonneurogenic/neurogenic bladder
Vesicoureteral reflux

WORKUP

Lab Studies

* Obtain urinalysis, urine culture, and serum electrolytes with BUN and creatinine levels before the infant leaves the hospital. BUN and creatinine levels should be tested at least 24 hours after birth to reflect the infant's levels rather than the mother's.

Imaging Studies

* Abdominal ultrasonography: Perform abdominal ultrasonography as soon as possible after birth to detect hydronephrosis or other upper genitourinary (GU) tract pathology. Once the child has recovered from the closure of the spinal defect and is stable for transportation, renal ultrasonography is performed to evaluate upper GU tract anatomy.
* Voiding cystourethrography
*
o Following ultrasonography, voiding cystourethrography (VCUG) is performed to evaluate the lower GU tract. These studies provide a baseline for the appearance of the upper and lower GU tracts, can facilitate the diagnosis of hydronephrosis or vesicoureteral reflux, and can help identify children at risk for upper GU tract deterioration.
o VCUG is the radiographic test of choice to evaluate for vesicoureteral reflux. The procedure is as follows:
o
+ A supine film of the abdomen is obtained first, including the bladder and kidneys. A small catheter is placed in the child's bladder, and the bladder is filled with contrast.
+ A cystogram is obtained with the patient in the supine and oblique positions. The size, shape, and capacity of the bladder are evaluated, as is the presence of trabeculae or diverticula.
+ The next film is obtained as the child voids or leaks. When vesicoureteral reflux is present, the bladder, urethra, and ureters are demonstrated. In higher-grade reflux, the renal collecting system also may be seen.
+ A final film is obtained after the bladder has been emptied. The presence of reflux is an indication to start prophylactic antibiotics.
* Lateral spine radiography: In suspected sacral agenesis, a lateral spine film is the appropriate imaging study.
* MRI: Ultrasonography of the spinal canal can be useful in infants younger than 5 months; however, once the vertebrae begin to ossify, ultrasonography becomes much less sensitive. The criterion standard for evaluation of spinal cord anatomy is MRI. This is the test of choice when a change in neurologic symptoms causes cord tethering to be suspected.

Other Tests

* Measure of residual urine: As soon as possible, measure the residual urine to determine if IC is necessary. The normal capacity of the newborn bladder is 10-15 mL, and consistent catheterized residual volumes of 10 mL or more should raise concerns regarding detrusor areflexia.
* Urodynamic study
*
o This test provides the most information regarding the impact of myelodysplasia on bladder function and is used to assess bladder function and guide treatment. Because the bony level often does not always correspond with the neurologic defect that is present, and because the effect of the lesion on bladder function cannot be entirely determined by radiographic studies or physical examination, the information gained from a urodynamic study is invaluable.
*
o The urodynamic study provides a measurement of several variables related to bladder function. Bladder capacity, compliance, detrusor and abdominal storage, voiding pressures, urine flow rate, postvoiding residual volume, and the relationship between detrusor contraction and the urinary sphincter can be evaluated. In addition, if contrast is instilled in the bladder, the anatomy can be imaged during voiding.
o The core of the urodynamic study is cystometrography (CMG). A small catheter is placed in the bladder, and the bladder is slowly filled with liquid. Pressures within the bladder (intravesical) and the abdominal compartment are measured, and by subtracting the abdominal pressure from the intravesical pressure, the pressure generated by the detrusor muscle can be calculated. Because the child is monitored through a filling and voiding phase, bladder capacity can be quantified, and the urine flow rate, postvoiding residual volume, and the force generated by a bladder contraction can be measured.
* Electromyography: If more information is desired, electromyography (EMG) can be used to demonstrate the relationship between the detrusor muscle and the external urinary sphincter. During normal voiding, the sphincter relaxes as the detrusor muscle contracts to allow unobstructed urinary flow. Spinal cord injury can lead to discoordination so that the sphincter is closed when the detrusor contracts, creating high pressures within the bladder but low flow rates. This is known as detrusor-sphincter dyssynergy (DSD). In infants with DSD, increased EMG activity occurs during voiding. The presence of DSD places infants at a much greater risk of upper GU tract deterioration.
* Fluoroscopy
*
o Fluoroscopy can be used to perform video-urodynamic imaging with contrast enhancement of the bladder, which allows the bladder to be depicted during voiding. In addition, reflux may be revealed (identical to findings in VCUG) or, if a closed sphincter is revealed during voiding, findings strongly suggest the presence of DSD, often obviating the need for EMG studies.
o Remember that a great number of artifacts can be introduced into urodynamic studies when they are performed in infants and children.
o Comparison of adjunctive data from radiographic studies and voiding or catheterized volume diaries is always advisable during planning of individualized bladder management.
o Common findings are as follows:
o
+ A common diagnosis made using urodynamic studies is detrusor areflexia or a bladder that does not generate contractions. The result is that the bladder will not empty (stasis). These patients can occasionally void with abdominal straining, but, except in rare cases, they need to be managed with IC.
+ Another diagnosis is DSD, in which increased sphincter activity occurs during detrusor contractions. This finding is important because DSD has been associated with an increased risk of upper GU tract deterioration in as many as 70% of patients. DSD is typically managed with IC and anticholinergic medications.
+ In older patients, sphincterotomy (surgical ablation of the urinary sphincter) can be considered, but this procedure dramatically reduces outlet resistance and usually renders patients incontinent and reliant on an external collection device.
+ Detrusor hyperreflexia is defined as the presence of involuntary detrusor contractions, usually at low volumes. This can produce symptoms of urgency and urge incontinence. Treatment is composed of anticholinergic medications to reduce contractions and timed voiding or use of IC.
+ Urodynamic studies can also reveal outflow obstruction. In patients with obstruction, high voiding and/or storage pressures are seen, which have been correlated with increased risk of upper GU tract deterioration. This is managed with IC, surgical resection of the obstructing tissue, or urinary diversion (in extreme cases).
* Genetic testing: If multiple anomalies are present, if the sex of the child is in question, or if a specific genetic syndrome is suspected, a karyotype may be of value but is not routinely required.


TREATMENT

Medical Care

Medical care of children with myelodysplasia who have a neurogenic bladder requires constant vigilance and adaptation to new problems. Therapy is based on a few basic goals: to ensure safe intravesical pressures, to prevent urinary stasis and UTIs, and to promote urinary continence. The ultimate goal of medical therapy is to preserve renal function. In older children, medication may help maintain continence.

* Infection
*
o UTIs are common in children with myelodysplasia. In the absence of reflux, patients with UTIs are treated symptomatically.
o Patients with vesicoureteral reflux are often placed on prophylactic antibiotics to reduce the chance of upper UTI or pyelonephritis.
o Bacteriuria is seen in as many as 55% of individuals who have received clean intermittent catheterization (CIC). Patients who are completley asymptomatic do not need treatment.
* Reflux
*
o Reflux occurs in 3-5% of infants with myelodysplasia and is usually associated with detrusor hyperreflexia or DSD.
o Treatment consists of antibiotic prophylaxis to prevent infection, anticholinergic medications to lower detrusor filling and voiding pressures, and a method of bladder emptying, most commonly IC. In children with lower-grade reflux who empty their bladders completely, treatment may be limited to prophylactic antibiotics. In children with high-grade reflux, IC is started to ensure complete emptying.
o Children unable to empty their bladders, regardless of reflux, are treated with CIC.
o Children with detrusor hyperreflexia (with or without hydronephrosis) are started on anticholinergic therapy to decrease intravesical pressures and possibly decompress the upper GU tracts. Reflux treated in this manner has shown a dramatic response, resolving in 30-55% of children.
o Avoid the Crede maneuver (voiding by suprapubic pressure) in children with reflux because it can increase pressures and aggravate the degree of reflux.
* Intermittent catheterization
*
o Because most patients with myelodysplasia are unable to spontaneously empty their bladders, numerous methods have been devised to potentiate bladder emptying. Initially, large numbers of patients underwent urinary diversion; however, frequency of renal failure was substantial. This changed dramatically with the introduction of CIC.
o Bladder catheterization on a regular basis is a safe, effective method of emptying the bladder and, if performed under clean conditions, does not appear to significantly increase the risk of infection. More than any single concept, the practice of CIC has changed the treatment of and approaches to patients with neurogenic bladders.3
o Currently, urinary diversion is rarely performed in pediatric patients.
* Continence
*
o Although not an issue in infancy, continence becomes more important as patients age. When children reach school age and social interactions increase, managing incontinence becomes more of a priority.
o Medical therapy consists of anticholinergic medications to increase the functional bladder volume and to reduce involuntary contractions. Additionally, alpha agonists have been used infrequently in children to increase sphincter tone at the bladder neck.
* Bowel function
*
o Often, children with myelodysplasia have disturbances of bowel as well as urinary function. This is managed most commonly with mild laxatives, such as mineral oil, combined with enemas or digital stimulation to facilitate removal of bowel contents.
o Constipation can affect bladder emptying adversely via a mechanism not yet fully understood but likely related to altered tone of the pelvic floor musculature or the physical compression of hard stool distorting the geometry of the bladder. The need for a program to combat constipation by maintaining soft stools and facilitating complete evacuation of bowel contents is an integral part of treatment in children with myelodysplasia.

Surgical Care

Surgery for neurogenic bladder, although once performed on most patients, is now primarily reserved for patients who have progressive renal damage despite maximal medical therapy or for patients with a noncompliant bladder. Most procedures are designed to allow adequate low-pressure bladder storage (thereby protecting the upper GU tract), to correct persistent reflux and prevent renal scarring, or to aid with continence. Experimental intrauterine fetal surgery performed to limit future morbidity is under investigation at some centers.4, 5, 6, 7

* Intrauterine surgery
*
o Studies of surgically created neural tube defects in rats demonstrate that the exposed tissue in the myelomeningocele sustains secondary injury from mechanical and chemical factors during its prolonged exposure to the uterine environment. This has led to research on the effects of in utero closure of the defect.
o Although considered experimental because of the limited numbers performed, preliminary findings appear to indicate that intrauterine closure can be accomplished with minimal morbidity to the fetus and the mother and that it may decrease the need for VP shunting later in life.
o Whether in utero repair improves the neurologic outcome in these patients remains unclear.
* Ureteral reimplantation
*
o Uretal reimplantation can be performed in patients with recurrent symptomatic UTIs despite adequate bladder drainage and antibiotic prophylaxis or in patients with persistent high-grade reflux with demonstrated renal scarring.
o The purpose of the procedure is to create a nonrefluxing connection between the ureter and the bladder.
o Most often, the procedure is performed by tunneling the ureter beneath the detrusor muscle.
o This treatment is very effective, provided that a regimen is implemented to ensure a low-pressure reservoir and bladder emptying.
* Vesicostomy
*
o In infants who cannot be catheterized or who demonstrate worsening renal function despite medical therapy and IC, cutaneous vesicostomy can be performed to establish adequate bladder drainage.
o The bladder is brought out to the skin, and urine drains continually into a diaper.
o Vesicostomy is an effective temporary procedure that may be reversed at any time.
* Bladder augmentation
*
o Bladder augmentation is an option in patients with small bladder capacity and poor bladder compliance despite maximal medical therapy.
o By anastomosing a detubularized segment of bowel to the bladder, capacity can be increased and storage pressures can be lowered, minimizing upper GU tract deterioration and improving continence.
o Depending on the segment of bowel used, problems with metabolic derangements, mucous production, stone formation, and hematuria can develop but usually respond to medical therapy.
o If incontinence is a significant problem, a bladder neck sling procedure can be performed along with bladder augmentation.
* Urinary diversion and undiversion
*
o Formal urinary diversion for neurogenic bladder is very rarely performed today. The risks of major abdominal surgery, metabolic derangements, and long-term upper GU tract deterioration are present with urinary diversion.
o Since the advent of CIC, some patients who underwent incontinent urinary diversion as infants have undergone successful undiversion with bladder augmentation.

Consultations

Patients with myelodysplasia have a multitude of issues that require constant observation.

* Intervention by a neurosurgeon is needed, starting at birth. Patients require initial closure of the spinal defect, CSF shunting, and monitoring for cord tethering or shunt malfunction.
* Often, consultation with a neurologist is required to define defects and watch for any change in symptoms.
* If significant bone abnormalities are present, consultation with an orthopedist may be necessary.
* Parents, and eventually the child, undoubtedly need the support of a psychologist to help deal with the struggles inherent in raising a child or growing up with myelodysplasia.
* Physical therapy may also be needed.

Diet

Generally, dietary management is the first step to achieving fecal continence.

* Constipation and diarrhea both need to be avoided. The goal is to provide enough bulk to have one bowel movement per day at a socially acceptable time. Usually, digital stimulation, suppositories, or enemas are used to regulate the timing of bowel movements.
* Additionally, if the child has difficulty with constipation, altering the diet to include more fiber and the addition of bowel lubricants, such as mineral oil, may help regulate bowel movements. Adequate bowel and bladder management are crucial to optimizing social, school, and work activities.
* In addition due to neurologic and orthopedic issues, mobility is limited, reducing the patient's ability to exercise. These patients are at high risk for obesity.

Activity

Children with myelodysplasia often have limited development and/or motion of the extremities; however, no specific activity limitations are required. Children are encouraged to be as active as possible within the limitations of the defect.

MEDICATION

Pharmacologic therapy plays an integral role in the treatment of patients with neurogenic bladder dysfunction. Treatment usually centers around 3 major elements: the use of antibiotics to prevent infection, the use of anticholinergic medications to relax the bladder and (hopefully) to increase storage capacity, and the use of alpha agonists to attempt to improve continence.

Antibiotics are used when indicated to treat acute infections and, in vesicoureteral reflux, are used as prophylaxis to prevent UTIs, pyelonephritis, and renal damage. Anticholinergic medications help suppress involuntary and uninhibited bladder contractions. This decreases urgency and incontinence and increases the bladder's functional storage capacity.

The role of alpha agonists is to increase smooth muscle tone at the bladder neck, initiating a state of urinary retention in an effort to alleviate incontinence. Thus far, the use of alpha agonists has had limited use and limited success in patients with myelodysplasia.

Drug Category: Anticholinergic agents

The major stimulus for bladder contraction is activation of the detrusor muscle via muscarinic cholinergic neuronal connections. Anticholinergic medications help suppress bladder contractions, especially involuntary and uninhibited contractions. This serves to decrease urgency and incontinence and to potentially increase the bladder's functional storage capacity.
Drug Name Oxybutynin (Ditropan)
Description Synthetic tertiary amine that, similar to atropine, antagonizes the muscarinic actions of acetylcholine. Also has a direct spasmolytic effect on the detrusor muscle and the small intestine, as well as local anesthetic action. Reduces the incidence of uninhibited bladder contractions.
Adult Dose IR: 5 mg PO bid/qid
ER: 5 mg/d PO initially; may gradually titrate upward; not to exceed 30 mg/d
Pediatric Dose <1 year: Not established
1-5 years: 0.2 mg/kg PO bid/qid
5-12 years: 5 mg PO bid; not to exceed 15 mg/d
>12 years: Administer as in adults
Contraindications Documented hypersensitivity; glaucoma; myasthenia gravis, partial or complete GI tract obstruction, ulcerative colitis, and toxic megacolon
Interactions CNS effects increase when administered concurrently with other CNS depressants
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Caution in urinary tract obstruction, reflux esophagitis, and heart disease

Drug Name Tolterodine (Detrol)
Description Competitive muscarinic receptor antagonist for overactive bladder. Differs from other anticholinergic types because it is selective for the urinary bladder over salivary glands. Exhibits a high specificity for muscarinic receptors, and has minimal activity or affinity for other neurotransmitter receptors and other potential targets (eg, calcium channels).
Adult Dose 2 mg PO bid; reduce to 1 mg bid if patient cannot tolerate
Pediatric Dose Not established; limited data suggest: 0.25-1 mg PO bid based on age and size
Contraindications Documented hypersensitivity; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma
Interactions Patients treated with macrolide antibiotics or antifungal agents should not receive doses of tolterodine >1 mg bid; coadministration of CYP2D6 inhibitors and, to a lesser degree, CYP3A4 inhibitors may decrease clearance of tolterodine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Do not administer doses >1 mg bid to patients with significantly reduced hepatic function; caution in renal impairment; currently not approved by FDA for pediatric use; prescribing physician should verify dosing recommendations by checking with pharmacist

Drug Name Hyoscyamine (Levbid, Levsin)
Description Blocks action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects.
Adult Dose IR: 0.125-0.25 mg PO/SL tid/qid ac and hs
ER: 0.375-0.75 mg PO q12h
Pediatric Dose <2 years: 3 gtt (~12.5 mcg)/2.3 kg to 11 gtt (~45.8 mcg)/15 kg; not to exceed 18 gtt/2.3 kg/24h to 66 gtt/15 kg/24h
2-12 years: 32 mcg/10 kg to 125 mcg/50 kg; not to exceed 0.75 mg/24h
>12 years: Administer as in adults
Contraindications Documented hypersensitivity; obstructive uropathy; narrow-angle glaucoma; myasthenia gravis; obstructive GI tract disease
Interactions Effects decrease when used concurrently with antacids; toxicity increases when used concurrently with phenothiazines, amantadine, haloperidol, MAOIs, or tricyclic antidepressants
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in elderly patients; some products contain sodium metabisulfite, which can cause allergic-type reactions

Drug Name Propantheline (Pro-Banthine)
Description Blocks action of acetylcholine at postganglionic parasympathetic receptor sites.
Adult Dose 15 mg PO tid ac and 30 mg hs
Pediatric Dose 2-3 mg/kg/d PO divided q4-6h and hs
Contraindications Documented hypersensitivity; narrow-angle glaucoma; ulcerative colitis and obstructive disease of the GI or urinary tract
Interactions Effects decrease when administered concurrently with antacids; toxicity increases when administered concurrently with disopyramide, tricyclic antidepressants, phenothiazines, corticosteroids, and bretylium
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in renal or hepatic disease

Drug Category: Alpha agonists

The tone of the musculature at the bladder neck is mitigated by alpha-adrenergic stimulation. The role of alpha agonists is to increase tone at the bladder neck, initiating a state of urinary retention, in an effort to decrease incontinence. However, these therapies are often not very effective.
Drug Name Pseudoephedrine (Sudafed)
Description Stimulates vasoconstriction by directly activating alpha-adrenergic receptors of the respiratory mucosa. Induces bronchial relaxation and increases heart rate and contractility by stimulating beta-adrenergic receptors.
Adult Dose IR: 60 mg PO q4-6h; not to exceed 240 mg/d
ER: 120 mg PO q12h; not to exceed 240 mg/d
Pediatric Dose <2 years: 4 mg/kg/d PO divided q6h
2-5 years: 15 mg PO q4-6h; not to exceed 60 mg/d
6-12 years: 30 mg PO q4-6h; not to exceed 120 mg/d
>12 years: Administer as in adults
Contraindications Documented hypersensitivity; severe anemia; postural hypertension or hypotension; closed-angle glaucoma; head trauma or cerebral hemorrhage
Interactions Propranolol, MAOIs, and sympathomimetic agents may increase toxicity of pseudoephedrine; methyldopa and reserpine may reduce effects of pseudoephedrine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in cardiovascular disease, diabetes mellitus, prostatic hypertrophy, and increased intraocular pressure

Drug Category: Tricyclic antidepressants

These medications work by directly inhibiting bladder contractions through a mechanism unrelated to anticholinergic effects. They act to decrease bladder spasms and increase storage capacity.
Drug Name Imipramine (Tofranil)
Description Facilitates urine storage by decreasing bladder contractility and increasing outlet resistance. Inhibits reuptake of norepinephrine or serotonin (5-hydroxytryptamine [5-HT]) at presynaptic neurons.
Adult Dose 10-25 mg PO q8-24h initially; may increase gradually prn; not to exceed 25-100 mg/d
Pediatric Dose <6 years: Not recommended
>6 years: 10-25 mg PO hs; if response is inadequate after 1 wk of therapy, increase by 25 mg/d; not to exceed 2.5 mg/kg/d or 50 mg/d (6-12 y) or 75 mg/d (>12 y)
Contraindications Documented hypersensitivity; narrow-angle glaucoma; in acute recovery phase following myocardial infarction, avoid in patients taking MAOIs or fluoxetine or who took them within previous 2 wk
Interactions Increases toxicity of sympathomimetic agents (eg, isoproterenol and epinephrine) by potentiating effects and inhibiting antihypertensive effects of clonidine
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions May impair mental or physical abilities required for performance of potentially hazardous tasks; caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, or thyroid replacement therapy

Drug Category: Antibiotics

These agents are used when indicated to treat acute infections. In patients with vesicoureteral reflux, they are often used as prophylaxis to prevent UTIs, which can potentially lead to pyelonephritis and renal damage.

Of the many antibiotics, 3 agents commonly used in the pediatric population are discussed below.
Drug Name Trimethoprim and sulfamethoxazole (Bactrim, Septra)
Description Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity includes common urinary tract pathogens except Pseudomonas aeruginosa.
Adult Dose 160 mg (trimethoprim)/800 mg (sulfamethoxazole) PO q12h for 10-14 d
Pediatric Dose <2 months: Contraindicated
>2 months:
Mild-to-moderate infections: 6-10 mg (based on trimethoprim component)/kg/d PO divided q12h
Serious infections: 15-20 mg (based on trimethoprim component)/kg/d PO divided q6h for 14 d
Urinary tract prophylaxis: 2 mg (based on trimethoprim component)/kg/d PO
Contraindications Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo
Interactions May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Do not administer near term in pregnancy; discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholism, advanced age, anticonvulsant therapy, malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation

Drug Name Amoxicillin (Trimox, Amoxil)
Description Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.
Adult Dose 250-500 mg PO q8h; not to exceed 3 g/d
Pediatric Dose 20-50 mg/kg/d PO divided q8h
Contraindications Documented hypersensitivity
Interactions Reduces efficacy of PO contraceptives
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Adjust dose in renal impairment; may enhance chance of candidiasis

Drug Name Nitrofurantoin (Furadantin, Macrodantin)
Description Synthetic nitrofuran that interferes with bacterial carbohydrate metabolism by inhibiting acetylcoenzyme A. Bacteriostatic at low concentrations (5-10 mcg/mL) and bactericidal at higher concentrations.
Adult Dose 50-100 mg PO q6h
Chronic suppressive dose: 50-100 mg PO hs
Pediatric Dose >1 month: 5-7 mg/kg/d PO divided q6h; not to exceed 400 mg/d
Chronic suppressive dose: 1-2 mg/kg/d PO divided 12-24 h; not to exceed 100 mg/d
Contraindications Documented hypersensitivity; renal insufficiency (eg, <60 mL/min CrCl), anuria, or oliguria
Interactions Anticholinergics may delay gastric emptying and increase absorption, increasing nitrofurantoin bioavailability; antacids made of magnesium salts may decrease effects of nitrofurantoin decreasing absorption; high doses of probenecid concurrent with nitrofurantoin decrease renal clearance and increase nitrofurantoin toxicity
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions May cause severe and irreversible peripheral neuropathy that can be fatal; renal impairment, diabetes, electrolyte imbalance, anemia, and vitamin B deficiency increase risk for adverse effects; prolonged use of antibiotics may result in fungal or bacterial overgrowth of resistant or nonsusceptible organisms


FOLLOW-UP

Further Outpatient Care

* General follow-up care
*
o That patients require lifelong supervision and monitoring of renal function cannot be stressed enough. Renal failure can progress slowly or occur with startling rapidity.
o Check postvoiding residual volumes every 6-12 months and renal function (BUN and creatinine levels) yearly.
o Perform renal ultrasound yearly.
o Many advocate a yearly urodynamic study for the first 5 years of life, followed by biennial evaluation.
o Perform a repeat urodynamic study any time the patient experiences any change in neurologic symptoms.
* Tethered cord
*
o As children age, different growth rates of the vertebral bodies and the spinal cord can add a dynamic element to the lesion. Fibrosis surrounding the cord at the site of meningocele closure can tether it during growth. This can lead to changes in bowel, bladder, and lower extremity function. If these are noted, evaluation using MRI is indicated.
o From the urologic standpoint, an MRI and a repeat urodynamic study are warranted when the patient has a change in symptoms or undergoes any neurosurgical procedure.

In/Out Patient Meds

* Antibiotics: Antibiotics are used when indicated to treat acute infections. In patients with vesicoureteral reflux, antibiotics are often used as prophylaxis to prevent UTIs.
* Anticholinergics: Anticholinergic medications help suppress involuntary and uninhibited bladder contractions. This serves to decrease urgency and incontinence and to potentially increase the bladder's functional storage capacity.
* Alpha agonists: The role of alpha agonists is to increase tone at the bladder neck, initiating a state of urinary retention in an effort to decrease incontinence. Thus far, the therapy has had limited use in patients with myelodysplasia.
* Botulinum toxin: Studies have reported the use of botulinum toxin directly injected into the detrusor of children with myelodysplasia with some success in treating incontinence.8, 9 However, this treatment is in its infancy in respect to children with myelodysplasia.

Prognosis

The prognosis for patients with myelodysplasia has improved dramatically over the past decades.

* Neurosurgical techniques and antibiotics have improved, and far fewer infants die of CNS infections and complications related to closure of the defect.
* Since the introduction of IC, incontinent urinary diversion is no longer performed with the same frequency as in the past, leading to greatly reduced operative morbidity and mortality. Many patients can be treated with CIC alone or with adjunctive pharmacotherapy and never require surgery.
* In selected patients, bladder augmentation and continence surgery may provide medical benefits and an improvement in the patient's quality of life.

Patient Education

Starting at birth and as the patient ages, parents and patients need to be educated regarding the many issues associated with living with myelodysplasia.

* Teach parents and patients the skills of catheterization, how to recognize infection, the need to alleviate constipation, the importance of watching for changes in symptoms, and the facts regarding sexual issues.
* Constantly remind parents and patients of the need to adapt to new problems and the need for lifelong observation by health care providers.
* When they are able, encourage patients to become involved in their own care because, eventually, they will be responsible for looking after themselves.


MISCELLANEOUS

Special Concerns

* Latex allergy
*
o Believed to be related to the recurrent exposure of peritoneal and mucosal surfaces to medical devices containing latex throughout childhood, a remarkable number (in some studies as high as 45%) of patients with myelodysplasia develop hypersensitivity to latex. Reactions range from contact dermatitis to anaphylaxis and cardiovascular collapse.
o Consider all patients with myelodysplasia of spina bifida to have a latex allergy and make every effort to avoid exposure to latex from birth. Gloves, catheters, crib pads, and bottle nipples are all potential sources and may exacerbate hypersensitivity.
* Sexuality
*
o The topic of sexuality, although not an issue in childhood, becomes progressively more important as the patient ages. Sexuality has historically been ignored in individuals with myelodysplasia. Patients with myelodysplasia have sexual encounters, and studies indicate that at least 15-20% of males are capable of fathering children and 70% of females can conceive and carry a pregnancy to term.
o Additionally, although puberty in boys with myelodysplasia appears to occur at the same age as puberty in healthy boys, menarche can begin 2 years earlier than usual in girls.
o For these reasons, counseling patients in early adolescence regarding sexual development is important.


REFERENCES
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