Neural tube defects (NTDs) affect 0.5 to 2 per 1000 established pregnancies worldwide and are the second most common group of severely disabling birth defects, following congenital heart defects. Myelomeningocele (MMC) is the most complex congenital anomaly compatible with life and is the second most common disabling condition in childhood after cerebral palsy. It makes up more than 98% of the “open” spinal dysraphic states and exists in a spectrum of NTDs, ranging from conditions that are incompatible with life such as anencephaly and cranioschisis (complete failure of neurulation) to disorders of secondary neurulation causing spina bifida occulta with minimal or no neurologic involvement. MMC, along with meningocele, makes up the bulk of what is commonly known as spina bifida. Although the most severe NTDs result in stillbirth or death shortly after birth, the majority of patients with a spinal dysraphism survive. The varying degrees of organ involvement seen with these conditions have major implications for long-term health and physical function, as well as the psychological and social well-being of the affected individual. Survival and quality of life for those with MMC have improved because of advances in medical, surgical, and rehabilitative care during the past 60 years, with prenatal folic acid food fortification and fetal surgical repair having the greatest impact. Many challenges remain, however, regarding understanding etiology, advancing prevention, maximizing health-related outcomes, transitioning to adult-based health care systems, and improving activity and participation at the societal level. These challenges are best met by a team of specialists working with patients, their families, and the community.
Historical Background, Terminology, and Nomenclature
The first clear description of spinal dysraphism was given by Caspar Bauhin, a Swiss physician, anatomist, and botanist, in his publication Theatrum Anatomicum in 1592. The term spina bifida , however, is often historically associated with Nicolaes Tulp, a Dutch physician who published a sketch ( Figure 48-1 ) and description of several patients with the condition in 1641. In 1875, Rudolf Virchow described spina bifida occulta, which refers to a hidden bony defect as well as other potential hidden anomalies.
A need for clarification of terminology exists because midline fusion defects of the spine have been described using several nomenclatures. The term spina bifida is sometimes used nonspecifically with regard to all patients with a spinal dysraphism or those with incomplete closure of the posterior neuropore. Spina bifida literally translates as “spine split in two” and is technically correct in describing any patient with incomplete closure of the posterior elements of the spinal column. The degree of variation of anatomic malformations associated with the condition, however, requires the use of more specific terminology. Spina bifida aperta refers to a midline defect that communicates with the external environment and includes MMC and meningocele. The term spina bifida cystica is also sometimes used and refers not only to a sac filled with cerebrospinal fluid protruding from the spinal column but also to MMC and meningocele. MMC at the level of the spine refers to protrusion of the meninges through a defect in the posterior elements of the spine, with involvement of the spinal cord or nerve roots. Meningocele refers only to protrusion of the meninges and cerebrospinal fluid through a defect in the posterior elements of the spine into the tissue beneath the skin, without involvement of functional neural elements. These distinctions are important and will be further explained later.
Bony spina bifida occulta with just incomplete closure of the posterior elements of the spine without neurologic involvement is incidentally noted in 17% of the general population and 30% of normal children aged 1 to 10 years. It is often not included in the group constituting spina bifida because there is no associated neurologic deficit. More complex occult closed spinal dysraphism, including diastematomyelia, lipomyelomeningocele, and tight filum terminale, among others, are a result of disordered secondary neurulation and can present with neurologic compromise or orthopedic deformity. There may be associated cutaneous anomalies such as a hairy patch without any other external anatomic abnormality. Modern imaging studies reveal these underlying defects and provide a system of classification based on neuroradiologic and clinical findings.
This system of classification divides the various forms of spinal dysraphism into open spinal dysraphisms (i.e., open spina bifida) and closed spinal dysraphisms (i.e., closed spina bifida) ( Box 48-1 ). It is useful for prognostication because those with open defects generally have lesions with visible neural elements, often leaking cerebrospinal fluid, which are associated with malformations that involve the entire central nervous system, including Chiari II malformations, midline defects, and hydrocephalus. In contrast, closed spinal dysraphisms (meningocele and occult spinal dysraphism) are lesions that are fully epithelialized with no neural tissue exposed, and generally have the malformation limited to the spine and spinal cord, with only rare involvement of the brain. Box 48-1 displays a complete listing of spinal dysraphic states. Although most of the conditions listed in Box 48-1 can result in a patient having rehabilitation needs, the most severely affected and vast majority of affected individuals will have a history of MMC. For this reason, the remainder of this chapter refers to rehabilitation concepts as they apply to MMC, although they can be applied to the various other spinal dysraphisms as appropriate.
Open Spinal Dysraphism
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Myelomeningocele
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Myelocele
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Hemimyelomeningocele
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Hemimyelocele
Closed Spinal Dysraphism
With a subcutaneous mass
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Lumbosacral
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Lipoma with dural defect
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Lipomyelomeningocele
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Lipomyeloschisis
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Terminal myelocystocele
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Meningocele
Cervical
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Cervical myelocystocele
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Cervical myelomeningocele
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Meningocele
Without a subcutaneous mass
Simple dysraphic states
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Posterior spinal bifida
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Intradural and intramedullary lipoma
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Filum terminale lipoma
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Tight filum terminale
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Abnormally long spinal cord
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Persistent terminal ventricle
Complex dysraphic states
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Dorsal enteric fistula
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Neurenteric cysts
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Split cord malformations (diastematomyelia and diplomyelia)
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Dermal sinus
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Caudal regression syndrome
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Segmental spinal dysgenesis
Terms and definitions of terms used when discussing spina bifida include the following:
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Craniorachischisis: Near-complete absence of neural tube closure, sometimes sparing forebrain.
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Anencephaly: Degenerate brain and absent skull vault and scalp.
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Myelomeningocele: “Open spina bifida”; failure of closure of lumbosacral neural tube.
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Spina bifida cystica: Meningeal sac containing open spinal cord herniating through a vertebral defect.
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Myelocele: Open spinal cord exposed to open lesion.
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Encephalocele: Herniation of the brain through opening of skull (defect of skeletal development). This condition may be compatible with life and some may even have normal intelligence.
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Meningocele: Herniation of meninges through opening on vertebral column (defect of skeletal development).
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Dysraphic defect: Mild end of NTD spectrum, with closed abnormalities. Associated with tethered cord.
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Diplomyelia: Spinal cord longitudinally duplicated.
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Diastematomyelia: Spinal cord longitudinally split.
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Lipomeningocele: Spinal cord associated with fatty tissue deposit.
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Spina bifida occulta: Neural arches of one or several vertebrae are incomplete in the lumbosacral region.
Epidemiology
Incidence and Prevalence
Epidemiologic studies of spinal dysraphisms typically include both MMC and meningocele, which are collectively referred to as spina bifida. Incidence worldwide is approximately 1 to 10 per 1000 depending on the region and in the United States is less than 0.7 per 1000. According to the U.S. Centers for Disease Control and Prevention (CDC), each year there are approximately 1500 babies born with spina bifida in the United States. In the United States, incidence rates have varied from as high as 2.31 per 1000 births in Boston during the 1930s to as low as 0.51 per 1000 births in Atlanta in the early 1990s. Worldwide, some of the highest prevalence rates have been reported in the Shanxi province of China, Ireland, Wales, and Hungary, although these rates have generally decreased in a manner similar to that in the United States.
The reasons for the decreasing prevalence of MMC are multifactorial and not completely understood. A proportion of the decrease can be attributed to the advent of prenatal screening and elective termination of pregnancy. The most influential factor has been the increased consumption of folic acid among women of childbearing age. The role of undernutrition and vitamin deficiency, especially folate deficiency, was first expressed by Smithells et al. in 1976, and the first studies demonstrating that folate supplementation decreased the rates of NTDs were performed in Wales in the early 1980s. Multiple observational and controlled trials followed, leading up to the landmark Medical Research Council study, which involved seven countries and 3012 women. The study was ended early after supplementation with folic acid (4 mg/day) was shown to prevent 72% of NTDs in women with a previously affected pregnancy. A subsequent Hungarian randomized control trial proved the efficacy of a more physiologic dose of 800 mcg of folic acid in preventing the first occurrence of an NTD and a Chinese-U.S. study further demonstrated that even a 400-mcg dose of folate supplementation brought about a 79% reduction in areas with high rates of NTDs in northern China. In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent NTDs, but drastic improvements in the prevalence rate were only noted after the U.S. Food and Drug Administration mandate in January 1998 requiring the fortification with 140 µg of folate per 100 g of all cereal grain products.
In August 2014, a total of 19 population-based birth defects surveillance programs in the United States reported to the CDC the number of cases of spina bifida ( International Classification of Diseases, 9th Revision, Clinical Modification , codes 741.0 and 741.9) and anencephaly (codes 740.0 and 740.1) among deliveries occurring during 1995 to 2011 in non-Hispanic whites, non-Hispanic blacks, and Hispanics, as well as all racial/ethnic groups combined. Although improved in all groups, birth prevalence rates still remain highest among Hispanics, then whites, and were lowest in non-Hispanic blacks similar to the prefortification era. This report demonstrates a persisting effect from fortification and an overall decline of 28% in all participating programs from 1999 to 2011 ( Figure 48-2 ). A greater reduction (35%) was observed among programs with prenatal ascertainment than for programs without prenatal ascertainment (21%). They estimate that approximately 1300 NTD-affected births have been averted annually during the postfortification period with an annual saving in total direct costs of approximately $508 million for the NTD-affected births that were prevented.
The reduction in NTD cases during the postfortification period inversely mirrors the increase in serum and red blood cell (RBC) folate concentrations among women of childbearing age in the general population. Fortification has led to a decrease in the prevalence of serum folate deficiency from 30% to less than 1% and a decrease in the prevalence of RBC folate deficiency from 6% to no measureable deficiency. To substantially attenuate the risk for NTD, women of childbearing age must have RBC folate concentration greater than 1000 nmol/L at least at a population level. Data from the National Health and Nutrition Examination Survey (NHANES) for 1988 to 2010 show that almost a quarter (21.6%) of women of childbearing age in the United States still do not have RBC folate concentrations associated with a lower risk for NTDs, illustrating the need to further educate all women of childbearing age on the importance of daily folic acid intake of 400 mcg for those who could become pregnant and 4 mg for those with a previously affected pregnancy or a history of MMC themselves. Additional measures such as health care provider participation in the education effort as well as fortification of corn masa flour may help further reduce rates by especially targeting the Hispanic population. Williams et al. speculate that this may lead to at least another 40 cases of NTD being prevented annually.
Risk Factors/Etiology
Despite a significant drop in the birth prevalence of spina bifida following fortification, rates are still high enough to suggest there are other factors at play. Additional nutritional deficiencies have been implicated such as vitamins B 6 and B 12 , as well as other factors such as geographic variation, low socioeconomic status, maternal age, maternal hyperthermia, maternal obesity, maternal diabetes mellitus, hyperzincemia, paternal and maternal occupations and exposure to agrochemicals, and certain drug exposures to, including, carbamazepine, valproic acid, diuretics, antihistamines, and sulfonamides. Acetaminophen, used commonly for pain or fever control in pregnancy, is fortunately not associated with an increase in birth defects and in fact use in the first trimester for febrile illnesses is associated with a lower incidence of anencephaly and craniorachischisis, possibly resulting from control of maternal hyperthermic states. A further interesting environmental teratogen with proven effect in humans is the fungal product fumonisin that was responsible for a two-fold increase in NTD prevalence along the Texas-Mexico border in the early 1990s ( Table 48-1 ). Hyperglycemia is noted to cause cell death in the neuroepithelium. It has been noted that hyperinsulinemia is a strong risk factor for neural tube defects and it may be the driving force for the observed risk in maternal obesity and maternal diabetes. Race and acculturation also seem to be factors with observed differences in the magnitudes and patterns of selected demographic and maternal risk factors for Hispanics and whites, particularly for parity, gestational diabetes, and socioeconomic status among cases of spina bifida. Canfield et al. demonstrated that Hispanic parents who were least acculturated to the United States were at increased risk for spina bifida and anencephaly, relative to whites.
| Risk Factors | Relative Risk |
|---|---|
| Established Factors | |
| History of previous affected pregnancy with same partner | 30 |
| Inadequate maternal intake of folic acid | 2 to 8 |
| Pregestational maternal diabetes | 2 to 10 |
| Valproic acid and carbamazepine | 10 to 20 |
| Suspected Factors | |
| Maternal vitamin B 12 status | 3 |
| Maternal obesity | 1.5 to 3.5 |
| Maternal hyperthermia | 2 |
| Maternal diarrhea | 3 to 4 |
| Maternal age | >35 years: OR = 5.21, 95% CI = 2.42 to 11 <25 years: OR = 3.36, 95% CI = 1.89 to 5.36 |
| Paternal and maternal occupation and exposure to agrochemicals and pesticides | Appears increased but not exactly established |
| Gestational diabetes | Appears increased but not exactly established |
| Fumonisin (fungal protein) | Appears increased but not exactly established |
| Acetaminophen | Seems to have a protective effect |
Genetic Factors
Both genetic and nongenetic factors are involved in the etiology of NTDs, with up to 70% of the variance in NTD prevalence attributable to genetic factors.
Possible nongenetic factors have been addressed earlier. Several observations support genetic risk factors as important in NTD formation. First, a priori risk of NTDs for some ethnic/racial groups (e.g., Irish and Mexican) is higher than others (e.g., white and Asian). Second, NTDs recur within families, with first-degree relatives of a patient with NTD possessing a 3% to 5% risk of having offspring with an NTD and second-degree relatives a 1% to 2% risk. Third, more than 250 mouse models with NTDs have been described, with some naturally occurring and others the result of genetic engineering in the laboratory. Evidence for genetic causation includes an increased recurrence risk for siblings of index cases (2% to 5%) compared with the 0.1% risk in the general population, together with a gradually decreasing frequency in more distant relatives. Women with two or more affected pregnancies have a higher risk (approximately 10%) of further recurrence. NTD prevalence is greater in like-sex twins (assumed to include all monozygotic cases) compared with unlike-sex pairs, consistent with a significant genetic component. Nevertheless, NTDs rarely present as multiple cases in families; instead, a sporadic pattern is usually observed. NTDs are also seen associated with certain syndromes such as Meckel-Gruber syndrome and Joubert syndrome.
The genomics revolution over the past 15 years has led to a burgeoning of studies to determine candidate genes for causation both in mouse models as well as in human embryos. Copp et al. speculate that in the near future, a full genome-wide assessment of interacting variants, including coding, regulatory, and epigenetic marks, will be possible to determine an individual’s risk of developing an NTD. To date, genes in three main areas of biology have yielded positive findings with regard to NTD etiology: folate metabolism, noncanonical Wnt signaling (the planar cell polarity pathway), and cilia genes.
Methylenetetrahydrofolate reductase ( MTHFR ) encodes a key cytoplasmic enzyme of folate metabolism that generates 5-methyltetrahydrofolate for homocysteine remethylation. The MTHFR polymorphism C677T (rs1801133) is associated with a roughly 1.8-fold increased risk of NTDs, although the predisposition is detectable only in non-Hispanic populations. A further significant risk factor is the R653Q variant (rs2236225) of MTHFD1 , a trifunctional enzyme that catalyzes the conversion of tetrahydrofolate to 5,10-methylenetetrahydrofolate.
In the mouse, mutations in Pax3 give rise to the Splotch ( Sp ) phenotype, which includes spina bifida and other neural crest abnormalities in homozygotes. In humans also, mutations in Pax3 (MIM: 606587 ) cause Waardenburg syndrome, an autosomal dominant condition that affects neural crest derived structures and includes spina bifida as part of its phenotypic spectrum.
Thus far, genome-wide association study using human single nucleotide polymorphism panels has not been possible because no individual research group has a sufficient sample size to achieve the statistical power necessary to detect an elevation of risk between 1 and 2 for complex traits such as NTDs. In exploring the Pax3 and T genes, Agopian et al. attempted to get over this hurdle by comparing their sample of 114 (predominantly non-Hispanic whites) with predominantly (81%) lumbar level lesions to controls (non-Hispanic whites) from multiple large public databases such as the HapMap, 1000 Genomes, and the Exome Sequencing Project. They were able to identify 38 variants of Pax3 in cases, and 8 of which were new variants. The allele frequencies for two were significantly different in cases as compared with at least one reference dataset.
The human T (Brachyury) gene (MIM: 601397 ) was suggested as a candidate for spina bifida because mice lacking T protein (i.e., Brachyury mutants) have defective mesoderm formation and abnormal axial development, and several studies have identified an association between a common variant in T (i.e., TIVS7-2, rs3127334) and the risk of NTDs in humans. The study sequencing by Agopian et al. identified 28 variants in non-Hispanic white cases. Of these, 27 were previously reported, and the allele frequencies for 3 were significantly different in cases as compared with non-Hispanic whites in the 1000 Genomes dataset.
More than 130 studies attempting to find association of selected genes with NTDs were published between 1994 and 2010. These studies included approximately 132 candidate genes with known functions involving various aspects of biological activity. Readers are referred to a few detailed reviews for a more thorough understanding of the progress and challenges in identifying genetic variants linked with NTDs.
Gene-gene and gene-environment interactions are well documented in mouse models of NTDs. It seems likely that the majority of sporadic human NTDs will also ultimately prove to result from two or more heterozygous genetic risk factors coexisting in individuals who are also exposed to adverse environmental influences, such as suboptimal folate or vitamin B 12 intake or environmental toxins.
Embryology
The availability of more than 250 different models of open NTDs in mice is enabling increasingly sophisticated analysis of the neurulation events, at tissue, cellular, and molecular levels.
NTDs are known to occur as a result of failure of neurulation between the seventeenth and thirtieth days of gestation. Primary neurulation refers to the development of the neural tube, which forms the brain and spinal cord. Secondary neurulation refers to formation of the remainder of the neural tube from a cell mass caudal to the caudal neuropore, which forms the lower sacral and coccygeal segments ( Figure 48-3 ).
Figure 48-4 contrasts the process in both mice and humans. The initial de novo closure event (closure 1) occurs at the hindbrain/cervical boundary and closure spreads bidirectionally from this site. Failure to initiate closure 1 results in craniorachischisis and failure to close the anterior neuropore results in anencephaly. In the mouse, a second de novo closure site (closure 2) occurs at the forebrain/midbrain boundary with closure also spreading rostrally and caudally. Closure 2 does not appear to occur in human embryos. A third de novo initiation event (closure 3) occurs in both species at the rostral extremity of the neural plate, with closure spreading caudally from here. Hence, in mice, closure is completed sequentially at the anterior neuropore, hindbrain neuropore, and posterior neuropore. In humans, owing to the lack of closure 2, there are likely to be only two neuropores: anterior and posterior (caudal). Failure in closure 3 results in MMC (see Figure 48-4 ). The caudal neuropore closes around the twenty-sixth day of gestation, and, as a result, teratogenic events that take place after this closure cannot cause thoracic or lumbosacral MMC. Failure of primary neurulation can lead to an open NTD, consisting not only of a spinal anomaly but also other defects, including a Chiari II malformation and hydrocephalus, possibly resulting from cerebrospinal fluid loss during early development. Most posterior lumbar and sacral meningoceles are thought to occur during secondary neurulation, with those higher on the spinal axis resulting from defects in primary neurulation that do not cause an open NTD. Encephaloceles are thought to primarily be a defect of cranial mesoderm development.
Prenatal Diagnosis and Management
Prenatal screening now allows for diagnosis of the majority of cases of MMC before birth. Ultrasound (US) is the current “gold standard” for the prenatal diagnosis of MMC, with three-dimensional US and fetal magnetic resonance imaging (MRI) further enhancing characterization of lesions. Although maternal serum alpha-fetal protein is a sensitive screening tool for NTDs and is useful for early detection for women considering termination of pregnancy, its role has been questioned in routine screening. Although amniocentesis for collection of amniotic fluid and acetylcholinesterase levels was once used to confirm the diagnosis of an NTD, high-resolution US now makes this practice obsolete. Functional motor outcome can be predicted by high-resolution US before delivery. One study using fetal MRI showed that worsening cerebellar herniation was associated with childhood seizure activity, high-risk bladder dysfunction, and lack of independent ambulation. A 2008 study demonstrated the diversity of physician views regarding prenatal screening, selective termination, and disability, suggesting a need to better understand how these differences affect reproductive technology, health care policy, and medical practice.
Prenatal detection of MMC is important to educate the patient and family regarding management options. Early detection also allows for consideration of fetal MMC surgery at an experienced center or time to prepare for a safe delivery in a medical center that offers neurologic closure. Previous consideration has been given to performing cesarean section for all mothers with an affected pregnancy to avoid further damage to neural structures. One study reported a less severe lower extremity paralysis in infants delivered by cesarean section before the onset of labor, but showed no difference in those who received cesarean section after the onset of labor. Subsequent studies, however, have found no difference in motor outcome with cesarean section.
Intrauterine Surgical Procedures
The rationale for intrauterine surgical intervention for MMC is predicated on the “two-hit” hypothesis stating that damage to the neural elements is the result of both failure of neurulation, resulting in an open NTD, and exposure of the spinal cord to amniotic fluid and traumatic injury within the uterus. Following early fetal surgery work at a select number of surgical centers starting in the mid-1990s, the Management of Myelomeningocele Study (MOMS) was launched in 2003 to compare prenatal fetal surgery with standard postnatal repair. The results were published in 2011 after the study was terminated early as a result of interim analysis of 183 patients, which indicated clear efficacy compared with standard neonatal management. The results showed a reduction in ventriculoperitoneal (VP) shunt placement at 1 year of age, substantial improvement in neuromotor function at 30 months, and reversal of hindbrain herniation in the fetal surgery cohort. Although prenatal intervention resulted in overall improvement, not all participants benefited and the prenatal surgery group showed an increased risk of spontaneous rupture of membranes, oligohydramnios, and preterm delivery. The impact of fetal surgery on bowel and bladder continence remains unclear, although early reports suggest improvement in urologic function. The MOMS-II study will continue to follow outcomes to assess whether neurologic improvement is sustained and to track other specific outcomes including cognitive function and bowel and bladder function. Although proponents of the MOMS trial submit that the study established a new standard-of-care option for select patients, a recent Cochrane review concluded that evidence is insufficient to draw firm conclusions “on the benefits or harms of prenatal repair as an intervention for fetuses with spina bifida.”
Neonatal and Early Management
Back Defect
After an infant is delivered with an open NTD, a sequence of events is set in place to preserve neurologic function, prevent infection, and stabilize cerebrospinal fluid flow. Early closure (within 72 hours of delivery) reduces the risk of infection in the central nervous system. Before closure, the open defect must be protected to prevent contamination or further damage from trauma. Closure occurs in three stages: (1) The neural plaque is returned to the canal, and the dura and arachnoid are reconstructed. (2) A myofascial closure over the newly constructed neural tube is performed. (3) The skin is closed.
Hydrocephalus
Most infants with MMC require VP shunting for hydrocephalus after their back closure, and approximately 15% who are born with severe hydrocephalus require immediate shunting. The 85% who do not require immediate shunting should be watched closely after their back closure for signs of increased intracranial pressure. Persistent cerebrospinal fluid leak from the repaired spinal wound almost invariably indicates active hydrocephalus, even if the ventricular size is only modestly enlarged and the anterior fontanelle is not bulging. The leaking cerebrospinal fluid serves as a decompression before closure, and once the defect is closed, cerebrospinal fluid can accumulate in the ventricular system. The white matter of a neonate is relatively compliant, and therefore the ventricles can become enlarged before the head circumference changes. The presence of hydrocephalus correlates well with the level of the spinal defect, with thoracic lesions having a higher incidence than lumbar or sacral lesions.
Hydrocephalus usually does not progress immediately and computed tomography scans might not show increasing ventricular size until 3 to 7 days of life. Some children do not require cerebrospinal fluid diversion for months or even years. Infants with hydrocephalus develop an enlarging head with bulging fontanelle, enlarged scalp veins, macrocrania, suture diastasis, and positive Macewen sign (i.e., cracked pot). If the hydrocephalus is not treated, these infants develop signs and symptoms of raised intracranial pressure such as sunset eyes, recurrent vomiting, and, later, respiratory arrest. Similarly, older children with closed fontanelles develop clinical signs of intracranial hypertension without progressive head enlargement. They develop irritability, vomiting, headaches, blurred vision, decline in intellectual performance, and gradual drowsiness, which, if left untreated, lead to coma and death caused by respiratory arrest.
Early Bladder Management
Greater than 90% of infants with MMC will have a neurogenic bladder. In a retrospective study of 129 children, Tarcan et al. noted that children who underwent primary repair of their back lesion after 72 hours showed a significantly lower bladder capacity and a substantially higher detrusor peak leak point pressure as well as a significantly increased incidence of febrile urinary tract infections, vesicoureteral reflux, hydronephrosis, and secondary tethering of the spinal cord at 3 years of age compared with those undergoing primary repair before 72 hours. Additionally, they concluded that closure of the spinal lesion within 24 hours of birth seems to provide the best chance for favorable lower urinary tract function. Management decisions made in infancy can affect renal health as well as the eventual development of urinary continence. The importance of aggressive urinary management should be stressed to the family before the child leaves the hospital.
Baseline investigations should include renal-bladder sonography and a voiding cystourethrogram. Hydronephrosis is found in 7% to 30% of infants, and reflux occurs in approximately 20% of infants. Infants with hydronephrosis or reflux should be started on prophylactic antibiotics. Infants who are unable to void begin intermittent catheterization programs. If the infant is able to void, he or she should be checked for complete emptying by checking a postvoid residual volume, either by catheterization or bladder scan. Incomplete emptying can lead to urinary tract infections because the retained urine serves as a culture medium.
Assessment of the Neurologic Level
Even if not spoken out loud, the first question parents of a newborn with MMC often ask is, “Will my child be able to walk?” A careful neurologic examination can give them an idea even within the first few days of life. The best predictor of motor function is the actual motor examination. Information regarding the best motor examination can be obtained by observation, palpation, and postural changes. Motor examinations can improve after the initial examination, which may relate to a period of spinal shock associated with the delivery or the closure.
Therapy
The goal of any interdisciplinary MMC team should be to develop and implement a comprehensive plan that enables the affected child to attain a maximal level of function in all areas. Physical and occupational therapists and speech-language pathologists play a key role in this endeavor to develop an ongoing partnership with families of children with MMC. Therapists are invaluable in providing education and anticipatory guidance for the family. For children born with contractures at the hips, knees, ankles, or feet, a program of passive range of motion can be taught to the family even before hospital discharge. Orthoses are often fabricated soon after birth by a therapist to maintain or improve range of motion. Families should generally be referred to early intervention services to provide ongoing surveillance for monitoring development and for support services where developmental delays are detected. As a child grows, outpatient therapy and school-based therapy services should be incorporated into the outpatient treatment plan and educational plan with guidance from an experienced team of therapists. Throughout life, the MMC therapy team will help to educate and coordinate with community therapists the development and implementation of a comprehensive plan of care.
Childhood Management
Shunts
Almost all children with MMC require placement of a VP shunt for management of hydrocephalus. The two most common shunt complications are infection and obstruction. Presenting signs and symptoms of shunt malfunction vary with the age of the child. Mechanical obstructions tend to present more acutely with signs and symptoms related to increased intracranial pressure as noted earlier, and infections tend to present more insidiously ( Box 48-2 ).
Infants
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Bulging fontanel
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Vomiting
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Irritability
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Change in appetite
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Lethargy
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Sunsetting eyes (cranial nerve VI palsy with abduction paralysis)
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Seizures
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Vocal cord paralysis with stridor
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Swelling or redness along shunt track
Toddlers
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Vomiting
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Lethargy
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Irritability
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Seizures
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Headaches
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Swelling along shunt tract
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Redness along shunt tract
School-Aged Children
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Headaches
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Vomiting
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Lethargy
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Seizures
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Irritability
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Swelling along shunt track
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Redness along shunt tract
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Decreased school performance
Adults
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Headaches
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Vomiting
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Lethargy
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Seizures
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Redness or swelling along shunt tract
Infections have a greater long-term morbidity than malfunctions. The overall risk of shunt infection is 12% per child with Staphylococcus epidermidis being the most common culprit. Symptoms do not usually develop until several weeks after the shunt is placed or revised. Epidemiologic factors seem to influence the incidence of shunt infections more than surgical factors. Aside from skin contamination during shunt placement, shunts can also become infected with gram-negative rods if the distal end of the shunt erodes into an intraabdominal organ. Gram-negative infections have a much poorer prognosis.
Isolated downstream infections of the shunt system have the least morbidity. Shunt infection with ventricular meningitis carries the highest morbidity. Although controversial, several studies suggest that recurrent and frequent shunt infections affect cognitive function.
In the first year of life, 50% of all children with a VP shunt develop obstruction requiring revision. Of those children who require a revision in the first year, 31% will require a second revision in the second year, and then have a risk recurrence rate of 12% per year thereafter. Endoscopic third ventriculostomies are performed in carefully selected patients and can become an alternative to chronic VP shunts.
A controversial population is older children or young adults who have MMC and untreated ventriculomegaly. If these patients have no symptoms or MRI findings to suggest active hydrocephalus and never received shunting, suggesting “arrested hydrocephalus,” they should be serially monitored with intelligence quotient and psychometric testing. If testing results are stable, then shunting based solely on radiologic appearance should be discouraged because the risks outweigh the benefits. If positive for symptoms or with MRI findings suggestive of hydrocephalus, intracranial pressure monitoring should be pursued.
Arnold-Chiari II (A-C II) Malformations
The A-C II malformation is characterized by variable displacement of cerebellar tissue into the spinal canal, accompanied by caudal dislocation of the lower brainstem and fourth ventricle easily identified on MRI studies ( Figure 48-5 ). It is also associated with a wide range of other abnormalities throughout the neuraxis. McLone and Knepper proposed the unified theory that the spinal malformation in MMC with associated leaking cerebrospinal fluid prevents normal transient occlusion of the primitive central canal of the spinal cord and the buildup of hydrostatic pressure in the rhombencephalon. This subsequently produces a posterior fossa that is too small and hence explains the association of open spinal dysraphism and the Chiari II deformity. However, an intrauterine MRI study of 65 fetuses with open spinal dysraphism that were compared with gestationally aged matched “normal” fetuses noted that 23% of fetuses with open spinal dysraphism did not have Chiari II deformity in utero and that the bony posterior fossa was also significantly reduced in volume in cases of open spinal dysraphism without hindbrain herniation, suggesting that the relationship may not be as straightforward as had been suggested.
Although the operative mortality for closure of the spinal defect in children with MMC is very low, the operative mortality for symptomatic A-C malformations is relatively high (34% to 38%). A symptomatic Chiari II malformation remains the leading cause of death for infants with MMC. Signs and symptoms of symptomatic Chiari II malformations include intermittent obstructive or central apnea, cyanosis, bradycardia, dysphagia, nystagmus, stridor, vocal cord paralysis, torticollis, opisthotonos, hypotonia, upper extremity weakness, and spasticity. The constellation of stridor, central apnea, and aspiration is sometimes referred to as central ventilatory dysfunction .
Before hindbrain decompression for a symptomatic Chiari II malformation, the child’s shunt system should be evaluated carefully because shunt malfunctions can cause Chiari malformations to become symptomatic. Hindbrain decompressions should be performed early to minimize the progression of symptoms of the Chiari malformation. Poor preoperative prognostic signs include bilateral vocal cord paralysis, severe neurogenic dysphagia, and prolonged apnea.
Hydromyelia
Hydromyelia is the dilatation of the central canal of the spinal cord ( Figure 48-6 ). It is analogous to dilatation of the ventricles in the brain and is a relatively common occurrence in children with MMC. Hydromyelia is probably much more common than we are aware because it often does not cause obvious symptoms in patients with MMC. When symptomatic, it usually presents with rapidly progressive scoliosis, a change in strength or coordination of the upper or lower extremities, and spasticity. MRI is the best test to demonstrate this spinal cord abnormality. When suspected, the entire neuraxis should be imaged because untreated or subclinical hydrocephalus can produce hydromyelia. Hydrocephalus should be treated before surgical treatment for hydromyelia.
Tethered Cord Syndrome
In children with MMC, the spinal cord can be fixed or “tethered” at one point, causing traction, which can lead to progressive urologic, orthopedic, or neurologic decline. It was first described in 1857, and the first known detethering of the spinal cord was performed on a previously healthy 17-year-old individual who had progressive loss of lower extremity function in 1891.
The spinal cord usually terminates at the level of L1 to L2. However, MMC repair invariably is followed by the development of arachnoiditis, fibrosis, and adhesions between the intraspinal neural structures, the meninges, and the surrounding vertebral structures. These adhesions can tether the cord to the low lumbar or sacral region.
Most children with MMC will show signs of tethering on MRI. Therefore, symptoms should develop before surgical correction is pursued. Typical signs and symptoms in children include increased weakness (54%), worsening gait (54%), scoliosis (51%), pain (32%), orthopedic deformity (11%), and urologic dysfunction (6%). Surgical correction should be considered early because most symptoms will improve or stabilize if treated early. Delayed correction can result in irreversible loss of function because the natural history is for symptoms to worsen with time.
At least three other lesions can lead to tethering of the spinal cord: diastematomyelia, lipomyelomeningocele, and tight filum terminale. Diastematomyelia refers to divisions (not duplications) of the spinal cord. It is usually associated with a bony spur. Even if asymptomatic, the natural history is for symptoms to develop that can be irreversible. Lipomyelomeningocele refers to a subcutaneous lipoma, continuous with the cauda equina, which also has a meningocele with neural elements enclosed extending outside the dura. A tight filum terminale is another congenital malformation in which the filum terminale does not elongate. Prophylactic surgery is usually recommended for these three lesions.
Neurogenic Bladder
Urologic involvement in MMC and other spinal dysraphisms varies, and is not necessarily correlated with the level of the lesion as in traumatic spinal cord injury. In MMC, more than 90% of patients have partial or complete denervation of the bladder, with poor compliance and contractibility resulting in unacceptable residual urine volumes. The urethral sphincter is incompetent in 86% of patients, so that incontinence occurs with increases in intravesical pressure. Approximately one third of patients have detrusor sphincter dyssynergia, resulting in high intraluminal pressures. The external sphincter is usually partially functional and can improve in the first year after birth. Patients should be observed at least annually because deterioration or improvement can occur in the first year of life and tethering of the spinal cord with a change in bladder function can occur over the years. Although the majority of individuals with MMC have normal renal function at birth, 40% to 90% will experience a decline by age 10 years if left unattended.
Preservation of renal function and improving quality of life with continence and eventual independence in management are the primary goals of neurogenic bladder management. Urodynamic evaluation is generally performed in infants with MMC, with 75% showing a normal upper urinary tract. The remaining infants show some degree of hydronephrosis resulting from vesicoureteral reflux, detrusor sphincter dyssynergia, an enlarged bladder, or other structural abnormality. Infants with normal anatomy should receive a renal US biannually. Those with incomplete emptying and no outlet resistance can be taught the Credé maneuver. Those with detrusor sphincter dyssynergia, or who have already developed hydronephrosis, should be treated with anticholinergic medications and clean intermittent catheterization to prevent the development or worsening of hydronephrosis. Children with vesicoureteral reflux are often prescribed prophylactic antibiotics. For persistent febrile urinary tract infection or hydronephrosis, surgical intervention is often necessary. Cutaneous vesicostomy can be performed with reversal done at a later time when the patient is capable of effective clean intermittent catheterization.
Because less than 10% of children with MMC have normal urinary control, continence of urine is an issue of great concern. Although there are no effective external collection devices for females excluding diapers, condom catheters are an option for males with reflex emptying who do not have vesicoureteral reflux or large residual volumes. Appropriate sizing can be a difficult issue for some and impaired sensation can lead to skin breakdown.
The high prevalence of small bladder capacity and low outlet resistance in many children results in only approximately a quarter of children being continent with clean intermittent catheterization alone. In general, frequent catheterization less than every 4 hours is required to achieve continence. It has been reported that up to two thirds of individuals can become continent with nonsurgical management including medications and clean intermittent catheterization. Anticholinergic medications and botulinum toxin injections may be used to increase bladder capacity. Multiple surgical options are available for those who do not achieve continence with clean intermittent catheterization and medications. Although a full description of these techniques is beyond the scope of this chapter, bladder augmentation along with artificial sphincter placement can be used individually or in combination. Success for long-term continence after artificial sphincter placement is greater than 60%. In addition, for patients who have difficulty performing urethral clean intermittent catheterization, continent diversion with the appendix used as a conduit to the bladder to create an abdominal stoma, can create easier access for many patients. In recent years, lumbar to sacral nerve rerouting has been performed in an attempt to improve bladder and bowel function in patients with MMC. Although improvements have been reported in some patients, positive responders cannot be predicted before intervention and there is the potential for lower extremity weakness adversely affecting ambulation. Independence with toileting in children with MMC is delayed more than all other self-care tasks. Although most children achieve independent control of bowel and bladder function by the age of 4 years, those with MMC might not achieve this until age 10 to 15 years. The cause of this is multifactorial and includes level of paralysis, intelligence, difficulty with visuospatial tasks, kyphoscoliosis, parental support, sensation, sphincter control, and bladder perception. Children can be taught to perform clean intermittent catheterization as early as age 5 years, although they will still need assistance with maintaining a schedule. Parents need to be trained not only in their child’s bladder program but also instructed in the importance of allowing the child to accept responsibility once she or he is able. A recent study of young adults revealed that up to 60% reported urinary incontinence with approximately 70% perceiving this as a problem.
Neurogenic Bowel
Patterns of neurogenic bowel involvement in children with MMC vary from normal bowel control in approximately 20%, to incontinence caused by impaired rectal sensation, impaired sphincter function, and altered colonic motility in the remainder. Those without control of the external anal sphincter become incontinent when the pressure inside the rectum is sufficient to produce reflex relaxation of the internal anal sphincter. In those with lesions above L3, the internal anal sphincter has low tone, which further contributes to incontinence. In addition, lesions above this level generally result in absent sensation, although sensation can be present but impaired in lower level lesions. Presence of the bulbocavernosus or anocutaneous reflex has been associated with a greater likelihood of achieving bowel continence.
The goal of a bowel management program is to achieve efficient, regular, and predictable emptying before the rectum becomes full enough to stimulate reflex relaxation of the internal anal sphincter in those with innervation present. This can be achieved through the use of stool softeners, bulking agents, suppositories, digital stimulation, manual removal, or enemas. However, many patients and families prefer dietary manipulation. Clinicians often recommend performing bowel programs after a meal to take advantage of the gastrocolic reflex, although it is not clear that this is intact in patients with MMC. A recent trial of Peristeen transanal colonic irrigation in children with bowel incontinence for various reasons resulted in 83% of children achieving either social continence or a significant improvement with occasional soiling. The study concludes that transanal colonic irrigation should be considered the first line of treatment when simple pharmacologic intervention is ineffective, and should be attempted before proceeding with surgical interventions. In patients who cannot become continent with more conservative approaches, surgical options are available. Although a full description of these techniques is beyond the scope of this chapter, options include the antegrade continence enema (ACE) procedure and colostomy. In an ACE procedure the appendix is used as a conduit to the bowel, through which a catheter can then be inserted into the cecum and saline or tap water infused, with bowel emptying achieved within 15 to 45 minutes. Colostomy is another option if standard treatment and ACE have failed.
The importance of achieving bowel continence at an early age is important to provide a smooth transition into preschool and kindergarten, where children can be severely criticized by peers. Encouraging children to assume increasing responsibility for their bowel program should be emphasized. Unfortunately, one study showed that as many as 86% of teenagers (ages 13 to 18 years) with MMC needed assistance from a caregiver for their bowel program. Another study of young adults revealed that approximately 34% reported fecal incontinence regardless of their means of management, and 77% perceived this as a problem. The management of neurogenic bowel varies widely among medical providers. To measure changes, appropriate measures are needed to assess interventions. A neurogenic bowel dysfunction score has recently been validated in a small trial but needs to be further evaluated on a larger scale. Further, a recent review of management for central fecal incontinence reported that there is little research in this area and the available evidence is almost uniformly of low methodological quality.
Latex Allergy
Although the incidence of latex allergy in the general population is estimated to be less than 1% to 2%, the prevalence among children with MMC ranges from 20% to 65%. This immunoglobulin E–mediated response to natural rubber latex is related to repeated mucosal exposure during surgical, therapeutic, and diagnostic procedures, as well as atopic predisposition. The allergic response can range from dermatitis, allergic rhinitis, asthma, and angioedema to anaphylaxis. Patients with spina bifida have been determined to have a 500-fold greater risk for anaphylaxis in the operating room compared with control groups. Given that latex sensitization takes place over time, a previous lack of sensitivity or negative allergy test does not preclude the possibility of a life-threatening reaction. Parents should be educated regarding the presence or risk of latex allergy. It is generally recommended that all patients with MMC use nonlatex catheters and avoid all other latex-containing products, whether medical or nonmedical.
Endocrine Disorders
Individuals with MMC are known to have disturbed growth and development. Although spinal cord lesions, vertebral anomalies, and other skeletal deformities reduce growth of the lower limbs and spine, complex central nervous system abnormalities and hydrocephalus put the patient with MMC at risk for hypothalamic-pituitary dysfunction, including central precocious puberty and growth hormone deficiency, further contributing to short stature. Precocious puberty has been reported in 12% to 16% of patients with MMC. The mechanism of this is thought to be related to increased pressure on the hypothalamus resulting in premature activation of the hypothalamic-pituitary-gonadal axis. Treatment with gonadotropin-releasing hormone analogues has proven beneficial in several studies, halting the progression of puberty, stopping menses, and decreasing hormone levels. It is more common for girls with MMC to experience precocious puberty and it is unclear whether patients without hydrocephalus are at risk. Currently, only limited data show that treatment of growth hormone deficiency with growth hormone provides significant improvement in growth velocity, height, muscle strength, mobility, and reduction in obesity. Ongoing debate continues as to whether to treat patients with MMC with growth hormone. Clarification of the goals of treatment is required because efficacy with regard to functional improvement can be influenced by the level of the lesion and the presence of complicating factors such as syringomyelia, tethered cord syndrome, scoliosis, vertebral anomalies, contracture, and advanced pubertal development. Further studies are required to assess the ultimate role of growth hormone treatment in individuals with MMC.
Musculoskeletal Considerations
Motor Innervation
The level of motor function in MMC does not necessarily correspond to the anatomic vertebral level on radiographic studies. Although spinal defects are generally described as cervical-, upper thoracic–, midthoracic-, low thoracic–, upper lumbar–, midlumbar-, low lumbar–, lumbosacral-, or sacral-level lesions, there are several different systems to classify the neurologic level that are not entirely consistent. It is noted that cervical and upper thoracic dysraphisms might be entirely different entities because these children tend to have a better prognosis and less neurologic deficit than children with lower thoracic and lumbar lesions. The majority of children with MMC have lumbosacral-level vertebral lesions, with a quarter having midlumbar-level lesions, and one fifth having sacral-level involvement.
One third of patients with MMC present with flaccid paralysis below their anatomic lesion, with the remainder showing a combination of upper and lower motor neuron signs. Many individuals are asymmetrical on motor and sensory testing, and some have voluntary motor control below other segments of paralysis and sensory loss.
The level of neurologic impairment influences the expectations of medical providers on functional outcome, treatment strategies offered, and anticipated musculoskeletal deformities and other complications ( Table 48-2 ).
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