It is important for the clinician to understand the embryogenesis of NTDs. The two forms of defects, open and closed, can occur at any point along the neuraxis with varying prevalence. Closed forms (encephalocele, meningocele, iniencephaly, lipomeningocele, sacral agenesis, and occult spinal dysraphism) and open forms (anencephaly, and myelomeningocele) may result from differing yet overlapping factors (6). Spina bifida is a complex, heterogeneous disorder whose etiology in humans appears to be multifactorial. However, spina bifida, classically defined as myelomeningocele, is the consequence of neural tube closure failure during embryonic development. The following section discusses the normal central nervous system (CNS) embryogenesis and the pathologic differences associated with these neural tube defects (7–10).

NORMAL DEVELOPMENT

During the first 2 weeks, postfertilization embryonic development involves repeated cell division and organization, resulting in a blastocyst, an embryo with two layers: the epiblast and the hypoblast. At the end of this period, on days 13 to 16, a primitive streak forms, beginning caudally and progressing toward the rostrally located prochordal plate initiating the rostral-to-caudal orientation of the embryo.

The development of the primitive streak is followed by invagination of epiblast cells, which remodels the embryo (ie, gastrulation) into a three-layered structure comprising ectoderm, mesoderm, and endoderm, the precursors of all tissue types and body structures. As the primitive streak regresses, presumptive notochord cells migrate through Hensen’s node aligning themselves along the midline of the embryo between the endoderm and the ectoderm.

In humans around day 16 the overlying ectoderm is induced by cell-to-cell contact with the notochord, thereby forming the neural plate. By about day 21, the plate bends as the groove deepens, and its walls and their adjacent cutaneous epithelium begin to oppose one another, beginning the formation of the brain and spinal cord.

The eventual closure of the neural tube proceeds over a period of 4 to 6 days and typically involves primary closure of the cutaneous ectoderm. This is followed by the neuroectoderm, which then separates from the overlying cutaneous ectoderm, resulting in a closed tube. Closure begins at a point just caudal to the developing rhombencephalon and proceeds via several waves rostrally and caudally rather than in the continuous “zipper-like” fashion previously envisioned. There is, however, an alternative view proposed by Van Allen and colleagues that describes several closure initiation sites over the same period of time (11,12). Regardless, closure of the primary neural tube is typically complete around embryo developmental day 27. This process, primary neurulation, completes the presumptive spinal cord down to the lower lumbar and/or upper sacral levels.

A secondary wave of neurulation begins around day 25 from a collection of remaining primitive streak cells and mesoderm located along the midline axis from the caudal end of the primary neural tube to the cloaca. Cavities form that coalesce into a tube, which eventually becomes continuous with the primary neural tube. This process completes the formation of the sacral levels of the spinal cord and terminal filum, and is species-specific. Understanding the process of primary and secondary neurulation is of paramount importance in comprehending the pathogenesis of spina bifida. The failure of primary neurulation is known to be associated with open spinal dysraphisms such as myelomeningocele, craniorachischisis, or anencephaly. Disruption of secondary neurulation, the mechanism for the development of the caudal spinal cord, is associated with closed spinal defects (eg, spina bifida occulta) and spinal cord tethering (13,14). The process of neurulation is completed by the end of the first month of embryonic development.

Expansion of cranial brain structures via the development of a primitive ventricular system is thought to be accomplished by temporary occlusion of the caudal (spinal) neural tube on days 23 to 27, which creates a rostral-enclosed fluid-filled space. This provides pressure to expand the cranial lumen and is the impetus for brain enlargement. Theory suggests that, in part, failure of this expansion pressure is a cause for Chiari malformation (15) seen in spina bifida.

PATHOLOGY

Spina bifida is typically considered to be the result of a primary failure of neurulation. Failure of neurulation and, thereby, loss of neural tube closure, prevents the mesoderm, adjacent to the notochord, from forming muscle and bone (ie, via somitic mesoderm). This normally forms around the tube to protect it. Therefore, the mechanisms involved in this process are suspected to be involved in the pathology of this disorder. Although this is the most popularly accepted theory, there are other proposed mechanisms. Several forms of myelomeningoceles are not failures of neurulation, but a failure of Henson’s node to lay down the notochord correctly—in other words, a failure in gastrulation (16,17) that causes significant errors in the induction of the neural tube. Further research is necessary to verify current proposed theories.

GENETIC INFLUENCES

Genetic mutations have a significant impact on CNS development, as demonstrated experimentally in rodents and documented clinically in humans. Alterations in the genes that affect metabolism, nucleotide synthesis, cell programming, and cell-to-cell signaling can all affect aspects of neural development. This ranges from the signaling aspects of the induction of neural tube formation initiated by the notochord to alterations in apoptosis (programmed cell death).

Induction of the neural plate is controlled by a variety of genes. Sonic Hedgehog (SHH) is a vertebrate gene expressed by cells within the notochord that—in conjunction with the Patched (PTC) gene—produce proteins involved in the induction of the floor plate during embryogenesis (23–25). During embryogenesis neuronal subtypes such as motor neurons proliferate, and somite development begins. The expression of various signaling proteins on the surfaces of cells allows for the sequential transmission of signals regulating the cell’s fate.

PTC is a gene that functions downstream of SHH. Its function is hypothesized to serve as negative feedback to SHH, thereby regulating the induction of numerous cell types in the developing neural tube. Failure of this system and its feedback loop and/or overexpression of one portion of the process may lead to neural tube development failure. Although not currently implicated by empirical data, research is in place to elucidate the impact of this system on human NTDs.

Alterations in genes that impact the movement of epithelial and mesenchymal cells that create and shape the body axis have also been suggested to be associated with NTDs. Planar cell polarity pathway genes such as SCRIB and PRICKLE may contribute to the multifactorial risk for spina bifida in humans (18,19).

Genes that regulate folate metabolism and methyltransferase reactions associated with methionine and homocysteine metabolism are both of major interest (26). Folate serves as a cofactor for enzymes that participate in nucleotide synthesis, and is important in the methylation processes. Evaluations of folate levels of mothers with NTDs shortly after birth have produced equivocal results, suggesting that either absolute folate deficiency is rare or that their diet and folate level may have been different at the beginning of the pregnancy. However, disturbances in the metabolic pathways that utilize folate may predispose to NTDs. This cannot be corrected with folate supplements. Metabolism of folate and homocysteine are interdependent, and the risks associated with alterations in their metabolism are thought to be connected. Elevated homocysteine levels in pregnant women are a known risk factor for NTDs. Mutations/polymorphisms in the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) have been associated with diminished plasma folate levels, with commensurate elevated homocysteine levels. These alterations have been identified in patients with spina bifida as well as in their parents. In addition, using cultures of fibroblasts from NTD-affected patients, homozygosity for defects in the MTHFR gene have been shown to have a 7.2-fold increased risk for NTDs. The prevalence of these defects appears to vary with race. Homozygosity for the C677T MTHFR mutation is a known risk factor for upper-level spina bifida lesions in those of Hispanic descent. The MTHFD1 1958G>A polymorphism is also associated with NTDs in those of Irish descent. Although folate supplementation has proven to be very successful in attenuating the prevalence of NTDs in various populations worldwide there is a portion resistant to such supplementation. Animal models show folate resistant NTDs are sensitive to the intake of inositol. Limited human experience has also suggested folate resistant NTDs may be amenable to inositol supplementation (27,28).

In early stages of nervous system development, more cells are produced than needed and that the processes of apoptosis and autophagy are coordinated during development to yield a well-defined and functioning CNS. Apoptosis, the most studied of these processes, is modulated by various members of the Bc12 gene family, the caspase family of cysteine proteases, and other genes that produce necessary intermediator proteins. The variation of genetic expression controls the development of cells within the CNS. Several mouse models have shown altering the expression of these genes (ie, knockout experiments) results in NTDs similar to that identified in humans. Such evidence strongly suggests their involvement in human neural tube pathology. Autophagy, an autodegenerative cell process, has a significant impact on the recycling of cellular components in the cytoplasm as a result of cellular organelle damage. This process can also be affected by nutritional stresses. A variety of genes that affect this process have been investigated using mouse models. Loss of Beclin 1 and Ambra 1 expression has been noted to result in overgrowth of the developing CNS. Therefore, identifying the human equivalent of these and other similar genes could yield information as to the cause of various NTDs and provide information for new therapeutic targets.

The external environment has a significant impact on embryonic development and the incidence of NTDs (29). Hyperthermia during early pregnancy, the first 28 days during neurulation, has been shown to increase the incidence of NTDs. Specifically, maternal febrile events as well as sauna and hot tub use have increased the risk of NTDs (30–34).

Parental occupation has been demonstrated to have a definitive influence on the risk for NTDs. Increases in NTD risk have been noted for occupations involving exposure to solvents (eg, painters, industrial process workers, etc.). Health care, agricultural, and transportation workers have also been noted to have an increased NTD risk (35). The etiology of this occupational increase in NTD risk can only be hypothesized at this time.

Nutritional influences have a broad impact on NTD risk and interact in many ways with environmental as well as genetic influences. As indicated earlier in this chapter, a primary example is folate metabolism. Folate is a cofactor for the enzymatic process involved in purine and pyrimidine synthesis and facilitates the transfer of methyl groups during the metabolism of methionine and homocysteine. Taken together, alterations in these folate-sensitive processes can have an impact on cellular proliferation. Lowered intake of foods containing folate in the diet is associated with an increase in NTD risk. Disorders of absorption of folate in the intestine can alter folate levels and potentially increase NTD risk. However, studies of folate receptor carrier densities in the intestines of women with NTD offspring or their progeny do not have abnormally low receptor levels (36). Studies have shown that supplementation can decrease prevalence. Mandatory supplementation of folate in grain products in the United States has caused a steadily declining NTD incidence since initiated in 1996. Since the introduction of mandatory folate supplementation, the number of NTD affected pregnancies has declined from approximately 4,000 to 3,000 per year. Studies have shown the NTD recurrence risk can be decreased by approximately 50% by taking the recommended folate supplementation.

The risk for NTDs varies for couples, depending on whether there is a prior history of such defects. U.S. couples with a prior history of NTD births have an increased risk for recurrence (2%–5%) (5). Because of this, the U.S. Public Health Service and the CDC have two separate recommendations for supplementation based on prior NTD histories. Elevated supplementation is appropriate for couples with a prior NTD birth. Limited studies have also identified zinc deficiency as a nutritional entity that can also elevate NTD risk. It was discovered that women with the genetic disorder of zinc metabolism acrodermatitis enteropathica are at high risk for NTDs and that supplementation can lower those risks.

Maternal obesity and concomitant diabetes are associated with increased NTD risk. Specifically, women with a prepregnancy body mass index (BMI) suggestive of obesity (>29 kg/m) are more inclined to have offspring with NTDs. There appears to be a direct relationship between maternal BMI and spina bifida (37).

This holds true for women with diabetes, although the etiology of this association may be linked to alterations in glucose metabolism during organogenesis. It is notable that experimentally manipulated glycosylation in rodents results in birth defects not unlike those seen in children born to mothers with diabetes. Risks for NTD-affected births have been estimated at 2% in the United States and as high as 7% in England. These risks include spina bifida as well as other significant NTDs such as anencephaly. The NTD recurrence risk for mothers with diabetes in the U.S. is around 4%, which is similar to that found in mothers without diabetes.

Teratogenic influences from the environment, such as the consumption of prescribed drugs, have been associated with NTDs, particularly myelomeningocele (38). Valproic acid taken for seizures during pregnancy has been shown to increase the incidence of NTDs. Valproic acid appears to work by disrupting folate metabolism, thereby inhibiting neural tube closure. An alteration in folate-dependent methylation of regulatory proteins is theorized to be the cause. Regardless, administration of folate during pregnancy counteracts valproic acid associated NTDs.

Of note, the 2014 edition of the British HIV association guidelines indicate nonnucleoside reverse transcriptase inhibitors such as efavirenz should be acceptable for HIV infected women wishing to conceive (39). Earlier limited studies suggested against the use of antiretroviral agents such as efavirenz due to the apparent risk of NTDs; however, a meta-analysis by Ford and colleagues did not find an increased risk of overall birth defects associated with first trimester use (40). The authors caution due to small sample size and relative low NTD incidence, conclusions should receive further prospective evaluation. World Health Organization (WHO) and U.S. guidelines advise against first trimester use but can be considered later in pregnancy (41).

Drug-induced interference with DNA synthesis during embryonic development would likely have an impact on gastrulation and neurulation. Other drugs are also associated with NTDs, such as isotretinoin (Accutane), used for acne treatment; and etretinate (Tegison), a psoriasis treatment; and anticancer agents such as methotrexate. Consumption of alcohol and coffee and cigarette use have been suggested to increase the risk of spina bifida. However, a recent study has reported confounding data (42). Fetal alcohol syndrome has an association with increased risk for abnormal CNS development, including NTDs. Ethanol-induced impairment of polyamine homeostasis has been suggested as a potential cause of NTDs and intrauterine growth restriction in fetal alcohol syndrome (43).

PRENATAL SCREENING

Prenatal screening is recommended for pregnant women to detect not only NTDs but also to screen for Down syndrome and other disorders. Prenatal diagnosis of spina bifida is important for families. It allows for decisions regarding continuation of the pregnancy, prenatal interventions, choice of appropriate birth facility, and preparation of parents and other family members for the birth to be made. Many parents choose to continue the pregnancy, although in a review of 17 studies Johnson and colleagues found that the overall frequency of termination of pregnancy ranged from 31% to 97%, and was more common for diagnosis confirmed before 24 weeks’ gestation, with defects of greater severity, and in Europe versus the U.S. (44).

Prenatal diagnosis is generally carried out by one of several methods (45–48). A quad screen blood test is done in the second trimester. The test includes alpha fetoprotein (AFP), human chorionic gonadotropin (HCG), estriol, and inhibin A. Elevated levels of AFP suggest an NTD is present, and the need for further testing is indicated. The serum AFP test is not specific for spina bifida, however, and requires the gestational age to be correct. A study of open NTDs found maternal serum biochemical markers in the first trimester did not distinguish an open spina bifida. Further testing is required, using high-resolution ultrasounds (US) and amniocentesis (49). The fetal US helps identify characteristics both of the brain and the spine, such as an abnormal shape of the head, enlarged ventricles, or abnormal vertebrae. US can detect a splaying of the pedicles and the classic “lemon and banana signs.” The lemon sign relates to the shape of the head, and the banana sign is related to herniation of the cerebellar vermis through the banana-shaped foramen magnum. Amniocentesis can also be performed, typically at 15 to 20 weeks of gestation, to identify abnormally high levels of AFP. Fetal MRI, after diagnosis, is made to determine the extent of the defect.

The spinal cord defect associated with spina bifida is often associated with other malformations. This results in a multisystemic process that leads to a variety of health problems and potentially life-threatening complications. Motor and sensory deficits vary according to the level and extent of spinal cord involvement (52–54).

In the care of individuals with spina bifida, two levels are often described: the anatomic level of the lesion and the neurologic level of functional involvement. In terms of the level, it is the neurologic or functional level that gives health care providers prognostic information with respect to long-term expectations and functional outcomes. Spinal cord involvement may result in asymmetric motor and sensory deficits. Sensory deficits usually follow a dermatomal pattern and may not affect all sensory modalities equally (52,53).

Neurogenic bladder and bowel dysfunction may be present in all patients because of the distal level of innervation of the bladder and bowel. This is true even if there is no apparent motor deficit in the legs.

In the following discussion, clinical signs of muscle weakness are described. These functional neurologic levels may not directly reflect the anatomic level of the malformation.

FIGURE 15.1 Musculoskeletal, sensory, and sphincter dysfunction by segmental level.

SENSORY DEFICIT

Partial or complete absence of sensation predisposes individuals with spina bifida to skin injuries because of decreased ability to perceive pressure, pain, trauma, or heat (52–54,57). Skin breakdown tends to occur over areas of prominence and weight-bearing. The lower back, intergluteal, perineum, feet, heels, and toes are the sites of predilection, but any area with sensory loss may be affected. Scoliotic and kyphotic prominences are areas prone to breakdown (55). Pressure ulcers often heal slowly, tend to get infected, and often recur. A refractory pressure ulcer may be a symptom of a tethered cord. Long-standing ulceration with deep tissue necrosis may spread to bone and lead to acute or chronic osteomyelitis. Weight-bearing is often on the anesthetic heel, and a deep ulcer can lead to osteomyelitis of the os calcis (56).

Other complications of denervation include vasomotor instability, neuropathic Charcot joints, and osteoporosis in individuals with extensive lower extremity weakness (54,55,57,58).

Sensation may be decreased with regard to sexual function thus causing different issues for males and females. Please see the section on Long Term Aging With a Neural Tube Defect where this is discussed in more detail.

Diastematomyelia is a postneurulation defect that results in a sagittal cleavage of the spinal cord, most commonly affecting the lumbar and thoracolumbar levels of the spinal cord. It is more common in females (73,74). Diastematomyelia may have both neurologic and orthopedic presentations. Orthopedic symptoms include scoliosis, Sprengel’s deformity (especially when associated with Klippel–Feil sequence), hip subluxation, and lower extremity limb-length discrepancies (74,75).

Neurologic symptoms include gait abnormalities, asymmetric motor and sensory deficits of the lower extremities, and neurogenic bladder and bowel (76). Symptoms of diastematomyelia may present in childhood or, less commonly, in adulthood (77).

The most common hindbrain abnormality in NTDs is Chiari type II malformation, seen in 80% to 90% of individuals with myelomeningocele (52,53,57,82).

Endoscopic management of hydrocephalus is being increasingly presented as an alternative to shunting. Endoscopic third ventriculostomy (ETV) provides direct communication between the third ventricle and the subarachnoid space by way of interpeduncular and prepontine cisterns. The success rates for ETV, as the sole management for hydrocephalus in infants with myelomeningocele, range from 12% to 53% (98–102). More recently, ETV has been combined with choroid plexus cautery (CPC). This has resulted in an improved success rate of greater than 70% for treatment of hydrocephalus in infants. Failure of ETV combined with a CPC typically is within the first 3 months (103).

ETV may also be an option in the setting of a shunt malfunction in the older child. In one study the majority of ETV failures were during the first 6 weeks postoperatively. However, failures were seen as late as 5 years postoperatively (102). Longevity of the ETV/CPC for treatment of hydrocephalus beyond 2 or 3 years has yet to be determined. It is not known if there is a difference in neurocognitive outcomes in patients treated with an ETV/CPC (shunt-independent) as compared with individuals who are shunt-dependent. Although not yet considered the “standard of care,” ETV in combination with CPC holds promise for surgical management of hydrocephalus without creating shunt dependency and the associated complications (103).

FOREBRAIN

Malformations of the forebrain are broad, and range from gross anatomic malformations to microscopic anomalies. Polymicrogyria are increased numbers of small-sized cerebral gyri with shallow disorganized sulci, and this is seen in up to 65% of individuals (104). Heterotopias are aberrant neural tissues in the form of subependymal nodules. They are present in approximately 40% of cases (59). Microscopic studies have demonstrated disordered cortical lamination, neuronal hypoplasias of the thalamus, and complete or partial agenesis of the olfactory bulbs and tracts. Dysgenesis or agenesis of the corpus callosum may be seen and may also be associated with a malformed cingulated gyrus and septum pellucidum (104). The contribution of these forebrain malformations to the development of cognitive and perceptual dysfunction remains unknown.

OTHER MALFORMATIONS

NTDs are also associated with an increased rate of malformations unrelated to the CNS. Vertebral anomalies are not uncommon and contribute to progressive kyphosis and scoliosis (56). Thoracic deformities may result from rib deformities, including absence, bifurcation, or reduction of the ribs. Malformations of the urinary system may be present and result in accelerated deterioration of renal function.

NTDs have been associated with genetic abnormalities, including trisomy 18, trisomy 13, Turner’s syndrome, Waardenburg’ s syndrome, renal aplasia and thrombocytopenia syndrome, nail-patella syndrome, 13q deletion syndrome, and others (105).

TREATMENT

TEAM APPROACH

A team approach is an important part of the care of the individual with congenital spinal dysfunction. The multidisciplinary team often includes neurosurgery, orthopedic surgery, urology, rehabilitation medicine, physical and occupational therapy, social work, nursing, nutrition, and neuropsychology. Coordination of all modes of treatment is important for a successful rehabilitation plan. Primary care for the usual childhood illnesses and health maintenance including immunizations should remain the responsibility of the pediatrician.

After birth, parents and families of individuals with spina bifida need to be informed about their child’s diagnosis and its implications. A prenatal visit with the neurosurgeon and other medical specialists is recommended. Parents often ask questions regarding anticipated functional abilities and limitations, including self-care and ambulation. Cautious predictions based on the current functional level should be given. Medical providers should be factual in their discussion of the problems that the parents and child will face. Discussions and instructions about the child’s care and handling at home may require several sessions so that the family members are not overwhelmed by the amount and complexity of the information. Families should be informed of the many issues involved and the need for seeing several medical specialists. Frequent follow-up after discharge from the neonatal unit is often necessary and typically involves visits every 3 to 4 months for a couple of years and then every 6 months thereafter (56).

NEUROSURGICAL TREATMENT

Neurosurgical repair of an open NTD, such as a cystic lesion, is usually performed on the first day of life. If hydrocephalus is present at birth, surgical management may be necessary. Ninety-five percent of children with spina bifida are likely to have hydrocephalus, and 75% to 85% require surgical management. The average revision rate is 30% to 50% (110), and after 2 years of age there is a 10% per year risk of failure (96). Most neurosurgeons believe that a child with hydrocephalus that required shunting will remain shunt-dependent (97,111). These statistics may change as ETV with CPC is performed with increasing frequency.

Neurosurgical follow-up is required, even after the neonatal period, to monitor for symptomatic hydrocephalus, shunt malfunction, and other neurosurgical complications. Pediatric patients with myelomeningocele should be followed routinely, usually on an annual basis.

NEUROGENIC BLADDER

A neurogenic bladder is found in most individuals with spina bifida. Data from the CDC National Spina Bifida Registry presented at the American Association of Developmental Medicine 2014 annual conference, reported 94% occurrence of neurogenic bladder in individuals with myelomeningocele with an over 60% urinary incontinence prevalence in those above 5 years. Furthermore, most with myelomeningocele use a catheter to empty their bladders. From the newborn period, the successful treatment of a neurogenic bladder is accomplished by the team approach including the urologist, physiatrist, nursing, and family.

PHYSIOLOGY

The fundus is made up of three layers of crisscrossing smooth muscle, called the detrusor. These three smooth muscle layers extend down the proximal urethra and stop at the external sphincter, which comprises skeletal muscle. T10 to L1 supplies the sympathetic innervation for the bladder; this causes the detrusor to relax and the bladder neck and posterior urethra to contract, effectively allowing storage of urine. S2 to S4 provide the parasympathetic innervation to the bladder primarily at the fundus and the neurotransmitter is acetylcholine causing contraction to empty the bladder. The sympathetic innervation is active during bladder filling, and the parasympathetic innervation is active during urination. Somatic nerves via the pudendal nerve (from the sacral cord S2–S4) innervate the skeletal muscle component of the external urethral sphincter: contraction occurs in the resting state for continence, and relaxation should occur during urination (112).

BLADDER CAPACITY

The prediction of normal bladder capacity aids the diagnosis of abnormal voiding patterns. It is typically accepted that the bladder capacity of a baby during the first year equals the weight of the baby in kilograms times 7 to 10 mL. A study with 200 children (132 with normal voiding, 68 frequent and infrequent voiders) demonstrated that from approximately 1 to 12 years of age, the sum of age in years plus 2-equals the bladder capacity in ounces (30 mL = one ounce). Teenagers (if normal size) assume adult-size bladders, typically around 400 to 500 mL. Clinically infrequent voiding may cause an increase in bladder capacity over normal values. Clinically frequent voiding may cause a decrease in functional bladder capacity (113). Postvoid residual (PVR) is generally accepted as less than 20% of bladder capacity, taking into account the appropriate bladder capacity for age.

DIAGNOSTICS

Checklist for Diagnosing Neurogenic Bladder

•  Is the current management preserving the kidneys and renal function?

•  If present, does bacteriuria represent infection or colonization?

•  Are the bladder and kidney studies up to date?

•  Is urination true voiding or overflow incontinence?

•  Are bladder capacity and bladder compliance appropriate for age?

•  Is PVR appropriate?

•  Is the sphincter mechanism competent?

DIAGNOSTIC TESTS

Urinalysis

The nitrate test indirectly detects urine bacteria with enzymes that reduce nitrate to nitrite in urine (eg, Klebsiella, Enterobacteriaceae, Escherichia coli, and Proteus).

THE LEUKOCYTE ESTERASE TEST. While leukocytes in the urine can disintegrate and disappear rapidly, leukocyte esterase persists.

Urine culture (UC): Culture of urine for suspected clinical infection.

Serum creatinine: Indicator of renal function, but typically lags renal function by several days.

FUNCTIONAL STUDIES

Pressure detrusor = pressure vesical (bladder) − Pressure abdominal (rectum). On urodynamic testing, detrusor leak point pressure (p vesical − p abdominal) greater than 40 cm H₂O, with a bladder capacity less than 33% of expected, was associated with renal damage (115).

It is recommended that these tests (US, UDY, and VCUG) be performed in the neonatal period, as baseline studies. The VCUG can be excluded if videourodynamics are utilized. As growth of the infant is rapid in the first 12 months, US should be repeated every 3 to 6 months during infancy. Greater frequency is encouraged if initial studies are abnormal. A common protocol incorporates US twice yearly the second year and then yearly. Abnormalities on US will likely lag those found on UDY. UDY should be repeated during the first year if the initial study shows a high detrusor leak point pressure of greater than 40 cm H₂O or detrusor sphincter dyssynergia. Many centers perform UDY yearly in all patients to aggressively detect potential bladder deterioration that could harm the kidneys, whereas others repeat only if renal changes are noted on US or continence is not obtained by school age (116). VCUG (or video UDY) are needed if VUR was noted or if there is a new onset of recurrent UTIs or hydronephrosis. UDY studies should be repeated with significant clinical changes in bowel or bladder incontinence, infections, or gait, all of which are potential signs of secondary tethered cord (117).

Other Studies

RENAL STONES. The excretory urogram (EXU) also known as intravenous pyelogram (IVP), once used to detect urinary tract (UT) stones, anatomic abnormalities, and obstruction, is rarely done anymore. Following diagnostic US for renal stones, the EXU has been replaced by CT without contrast for more precise imaging.

ANATOMIC VARIANTS. A magnetic resonance urogram with gadolinium is now used to demonstrate rare anatomic variants, particularly to delineate the ureters if ectopia is suspected. Diethylene triamine acetic acid (DTPA) and mercaptoacetyltriglycine (MAG3) are nuclear medicine studies used to evaluate differential function and excretion of each kidney; however, the MAG3 offers better imaging than DTPA to evaluate UT drainage/obstruction. The DTPA and MAG3 radioactive tracers are filtered (DTPA) or excreted (MAG3) into the renal tubules. Dimercaptosuccinic acid (DMSA), a radiotracer that binds to the tubule, is not rapidly excreted, and it is the best test for imaging the functioning renal cortex to detect congenital hypoplasia or acquired scarring. This test should be done when there is abnormality on a renal US, a history of multiple urinary tract infections (UTIs), or pyelonephritis. Cystoscopy is recommended for persistent hematuria or bladder masses. There is controversy regarding the role of routine screening cystoscopy in patients with increased risk of malignancy due to either bladder augmentation surgery or long-term indwelling catheter use (118,119).

FIGURE 15.6 Urodynamic study reflecting spastic bladder detrusor and sphincter dyssynergia.

•  Poor bladder compliance determined by UDY

•  Detrusor overactivity previously known as bladder hyperreflexia

•  Increased PVR greater than 20% of the total bladder capacity

TREATMENT

Goals

•  Preservation of renal function

•  Age—appropriate social continence

•  No significant UTIs

•  Normalized lifestyle

TREATMENT OF STORAGE DYSFUNCTIONS

Excessive storage pressures due to detrusor overactivity previously known as detrusor hyperreflexia, or decreased compliance, can be decreased with anticholinergic medications. Oxybutynin chloride is commonly used and is available as syrup, and in immediate-release and extended-release tablets [Note: The youngest child in the study was 6 years old (120)]. Oxybutynin has been used intravesically, but is an off-label use. There is a transdermal form of oxybutynin as well as other anticholinergic medications on the market, but these are not currently Food and Drug Administration (FDA) approved in children. Botulinum toxin A (off-label) can be injected into the detrusor muscle via a cystoscope for those whom anticholinergic medication is ineffective. Electrical stimulation of the bladder directly or of innervating nerves has shown some promise to improve storage characteristics but remains experimental.

Stress incontinence due to bladder outlet weakness caused by poor innervation of the internal and/or external urinary sphincters is more difficult to treat medically. Internal urethral sphincter resistance may be improved by the following alpha-sympathetic stimulation medications: phenylephrine, pseudoephedrine, and imipramine. External urethral sphincter weakness may improve with neuromuscular reeducation, but surgical treatment is typically required.

TREATMENT OF EMPTYING DYSFUNCTIONS

The typical day-to-day management of the neurogenic bladder in a majority of individuals with spina bifida is clean intermittent catheterization (CIC) every 4 hours while awake to keep bladder volumes within normal limits for age (113). In 1972, Lapides was the first to publish that the sterile single-use catheter is unnecessary in the management of persons with neurogenic bladders because it does not reduce bacteriuria (121). This continues to be substantiated in the pediatric population (122). If this intervention is unsuccessful, various pharmacologic and urologic surgical procedures may be explored. The Credé maneuver should be used with extreme caution. Using the Valsalva or Credé maneuver to empty the neurogenic bladder that has detrusor sphincter dyssynergia will likely raise the intravesicular pressure to greater than 40 cm H₂O, thus putting the kidneys at risk. Bethanechol is rarely used to treat weak expulsive force of the detrusor because emptying is typically incomplete and synergistic sphincter relaxation does not occur. Hyperactive internal sphincter mechanism may be treated with alpha-adrenergic blockers. Hyperactive external urethral sphincter may be treated with baclofen, neuromuscular reeducation of the pelvic floor, Botox injections (off label) (123), or surgery.

PRIMARY CARE TREATMENT OF CHILDREN MANAGED WITH CLEAN INTERMITTENT CATHETERIZATION

Routine urinalysis (UA) and UC are not recommended during well-child check-ups if the child looks well and is asymptomatic. If bacteriuria is detected in the urine, it is important to determine whether it represents a clinical infection or colonization of the bladder. Only clinical UTIs with symptoms of fever, abdominal/back pain, painful urination/catheterization, new or worsening incontinence or urinary symptoms, or hematuria should be treated (122). Prophylaxis in the absence of VUR is not routinely recommended.

ANTIBIOTIC PROPHYLAXIS AND BACTERIURIA TREATMENT

A number of studies were done on antibiotic prophylaxis and bacteriuria treatment with individuals with neurogenic bladders. Kass found that if there is no VUR, bacteriuria is innocuous; in his study, 17 hydronephrotic kidneys showed significant radiographic improvement since starting CIC (125). Ottolini found that asymptomatic bacteriuria requires no antibiotic therapy in the absence of VUR (126). Van Hala found that there is no correlation among the number of UTIs, the type of catheter used, and the use of prophylactic antibiotics (127). Johnson and colleagues found that nitrofurantoin is an effective prophylactic agent during a 3-month period for bacteriuria (128). Schlager and colleagues found that asymptomatic bacteriuria persists for weeks in children with neurogenic bladders with normal upper UTs managed with CIC (129). The asymptomatic bacteriuria is different from the symptomatic bacteriuria. Jayawardena and colleagues found that patients with a spinal cord injury (SCI) frequently have asymptomatic bacteriuria without data to support treatment and that routine UCs should not be done at annual evaluations (130).

(Note: It may be appropriate for a pediatric patient without a neurogenic bladder and with frequent UTIs secondary to dysfunctional voiding to receive prophylactic antibiotics for a time. Patients with VUR and with or without a neurogenic bladder routinely receive prophylactic antibiotics.)

NEONATAL VERSUS CHILDHOOD TREATMENT

Early proper management is imperative for the preservation of renal function (131). A urologist should be involved from the newborn period as 20% are born with renal anomalies and kidney damage was found to be approximately 1 in 4 without proper management of the neurogenic bladder (115).

Treatment of neurogenic bladder dysfunction due to myelomeningocele in neonates is recommended. A study of 98 individuals (46 started CIC in the first year of life, 52 began CIC after 4 years of life) reviewed the charts of those using CIC who were believed to be at risk for renal deterioration. The mean follow-up of this study was 4.9 years, and the average age of the patient at the last follow-up was 11.9 years. The study found that neonatal treatment enabled UDY to identify those infants at risk for upper tract deterioration, which was prevented by the initiation of oxybutynin and CIC. There was a similar improvement in UTI rate, hydronephrosis, and reflux. The percentage of patients with worsening hydronephrosis and persistent high intravesical pressures who needed bladder augmentation was 11% in the earlier treatment group versus 27% in the later treatment group (P < .05) (132).

FURTHER SURGICAL MANAGEMENT FOR REFLUX AND SMALL NEUROGENIC BLADDERS

Lowering the bladder pressure below 40 cm H₂O is the goal. Ureteral reimplantation may be necessary for reflux; however, most people with neurogenic bladders have reflux from a high-pressure bladder and not from a ureterovesical junction that is dysfunctional. Medical management with CIC and anticholinergic medication frequently causes reflux to resolve, and surgical correction is rarely necessary. Bladder augmentation may be considered for a small or high-pressure bladder refractory to medical treatment. Bladder augmentation may increase the risk of bladder cancer, rupture, and stone, and mucus may be excessive in the urine, obstructing CIC (133). For cancer surveillance in those with augmented bladders, cystostomy was recommended annually starting 10 years following the bladder augmentation (118). Newer recommendations may be different and a urologist should be involved to determine adequate surveillance. Augmentation should be explored only after pharmacologic management has failed and the system continues to be a high-pressure system, thus putting the kidneys at risk. The complication rate for bladder augmentation in one study was approximately 1 in 3 (134).

SOCIAL ASPECTS

The bladder focus may put considerable strain on the family (137). Children and adolescents with neuropathic bladders using intermittent catheterization have worries about peers discovering catheters used to empty their bladder and regarding leakage of urine. Urinary incontinence does affect self-esteem, and it is important to aim medical management at continence for psychological (138) as well as physical well-being. Urinary continence is an important developmental milestone in individuals with and without spina bifida (138). As mentioned in the previous edition of this book, urinary continence, although important, should not occur at the expense of the kidneys.

NEUROGENIC BOWEL

NEUROGENIC BOWEL DYSFUNCTION

The colon, rectum, and internal anal sphincter are also controlled by autonomic nerves. Parasympathetic innervation is from S2 to S4, whereas sympathetic fibers arise from the lower thoracic and lumbar segments. Voluntary somatic motor and sensory nerve supply for the external anal sphincter is from S2 to S4 through the pudendal plexus. Coursing through the spinal cord, these nerves have direct connections with the integrating supraspinal centers in the pons and cerebral cortex (56).

Colon peristalsis propels feces into the rectum. The gastrocolic reflex increases peristalsis for about 30 minutes after food intake. Rectal fullness initiates an autonomic stretch reflex, with relaxation of the internal anal sphincter, and creates a sensation of predefecation urge. In contrast, the voluntarily controlled external sphincter remains contracted to retain feces. When the situation warrants, this action is further enhanced by voluntary contraction of the levator ani, and gluteal muscles. Defecation occurs when the external sphincter is voluntarily relaxed (56).

Many children with spina bifida have a patulous anus, absent cutaneous reflex response, and perianal sensory deficit. This indicates dysfunction of S2 to S4 segments and leads to fecal incontinence. With lesions above L2, there can be an intact reflex arc to maintain perineal sphincter tone, despite absent rectal sensation.

BOWEL MANAGEMENT

Fecal incontinence and constipation are common problems with spina bifida. The external anal sphincter can be weak and patulous. The reflex arc can be interrupted, causing an interruption of innervation to the anal sphincter. There are also motility issues affecting the entire colon.

Bowel management is essential for a successful bladder program in individuals with spina bifida. Not only are gastrointestinal (GI) symptoms and incontinence, with its self-esteem issues, reduced, successful treatment of constipation may improve bladder storage and reduce the frequency of UTIs. Daily bowel movements should be a goal. Aspects of daily bowel care include drinking enough fluids, using an osmotic laxative such as polyethylene glycol, a high-fiber diet to bulk up the stool, digital rectal stimulation or a glycerin suppository in infants and younger children, a bisacodyl suppository 5 mg rectally in younger children and 10 mg rectally in those at least older than 2 years (usually school age for the higher dose). The suppository will not work if placed directly on the stool in the rectum, so careful placement on the rectal mucosal wall is essential. In those with a patulous anus, suppositories may be ineffective because of inadequate ability to retain it. Although the use of the gastrocolic reflex is questionable in the spina bifida population, it is still advised to try having the bowel movement approximately 20 to 30 minutes after the nightly meal. (The morning or afternoon meal are both okay, too, but secondary to schedules, it may be difficult to embark on a bowel program just before or during school or work.)

If the bowels are void of stool, incontinence of stool and urine is less likely. With severe constipation seen on an abdominal film, or with palpable stool still in the abdomen, the previous procedure should be followed along with an enema. If the anus is patulous, a cone tip may be needed to administer the enema and keep the fluid within the rectum for a sufficient length of time. Anatomic bowel obstruction should be ruled out by abdominal x-ray in severe constipation before a colonic cleansing enema is performed. A surgical procedure may be necessary, such as a catheterizable appendicocecostomy through the abdominal wall to flush the large intestine from the proximal end with an enema (139). This is known as the ACE (antegrade colonic enema) procedure or MACE procedure (M for Malone who popularized the procedure). The placement of a cecostomy tube is another method to access the bowel for antegrade enema. A successful bowel program maintains bowel continence and can be performed independently or with minimal supervision.

Social acceptance from peers is important and leakage of stool can be difficult in school and other social situations. Important goals include continence of stool by grade school entry as preparation for independence and increased career options.