Spina Bifida

Etiology

Spinal dysraphisms are due to incomplete closure of the posterior spinal elements and typically occur between 17 and 30 days of fetal development. The process of neuralization occurs in 2 phases: primary and secondary neuralization. Primary neuralization refers to the closure of the neural tube, forming the brain and spinal cord. Secondary neuralization involves the formation of the caudal structures of the neural tube, which form the sacral and coccygeal portions. These caudal structures develop around day 26 of gestation, and failure to close results in varying degrees of spinal dysraphisms.[1]

Defects in neural tube development are thought to be multifactorial, including environmental and genetic influences. The most common environmental cause is folate deficiency, with most cases deemed “folic acid-sensitive.”[2] Programs for dietary folate fortification have been implemented across the globe, and these have decreased the prevalence of anencephaly and spina bifida by 28%.

Other environmental risk factors include maternal obesity, maternal diabetes, and teratogens such as valproic acid. Valproic acid has the highest association with the development of neural tube defects (NTDs), carrying about a 10-fold increase in risk. Some genetic factors have also been correlated with poor neuralization, including several chromosomal syndromes and genetic polymorphism. Research has implicated polymorphism of the gene encoding the MTHFR enzyme, which is involved in folate metabolism, as a likely genetic risk factor. While NTDs are typically isolated, some are associated with chromosomal syndromes, most often trisomy 13 and 18.[1][3]

Epidemiology

The prevalence and incidence of NTDs have varied since they were first recognized, but overall, they have decreased with several interventional programs and increased fetal screening. In the United States, the overall prevalence of spina bifida between 1999 and 2007 was 3.17/10,000 live births. Study results show that about 1300 healthy babies born each year would have had NTDs if folic acid fortification was not introduced into common prenatal practice.

Hispanic women seem to have a high rate of pregnancies affected by NTD. Worldwide, Hispanic individuals have a prevalence of spinal bifida in 3.8/10,000 live births as compared to non-Hispanic Black Americans, who have a rate of 2.73/10,000, and non-Hispanic White individuals with a prevalence of 3.09/10,000.[3][4] There is also an increased risk for recurrence associated with family history, geographic location, and defect severity. There is an increased risk of recurrence of about 3% to 8% after 1 affected pregnancy or maternal history of the defect, and the risk worsens with an increasing number of affected children.[5]

History and Physical

Patients with NTDs should be evaluated during prenatal screening, and at-risk women should be counseled before conception to improve outcomes. However, in certain areas, especially underserved communities and those of low socioeconomic backgrounds, mothers may not have access to proper screening and may present at birth or in infancy. Standard prenatal screening includes serum alpha-fetal protein levels at 16 to 18 weeks to evaluate for NTD. Follow-up can be obtained with ultrasound, which has a sensitivity of 88% to 89%.[5] Given the wide variety of neuralization, patients can present with various symptoms and conditions.

Physically, visualization of the lower portions of the spine can determine whether the patient has an open or closed spinal dysraphism. Spina bifida occulta shows no obvious deformity; however, a hairy skin patch or dimple can sometimes be seen, indicating an underlying lesion. Meningocele involves a defect of the posterior elements of the spine with extrusion of meninges and cerebrospinal fluid (CSF) without the involvement of the neural elements. Myelomeningocele involves extrusion of meninges, CSF, and functional neural elements such as nerve or spinal cord contents.

Myelomeningocele typically affords more functional limitations in the future as nervous tissue is involved in the defect. Patients may present with symptoms of spasticity, pain, motor deficits, neurogenic bowel and/or bladder, cognitive deficits, seizures, and even endocrine disorders such as precocious puberty.[1] Neurological dysfunction is common with open dysraphisms such as meningocele and myelomeningocele, as neural tissue can extrude outside the defect and be affected. Patients often also present with latex allergies, with a prevalence of 10% and 73% in those with NTDs.[6] Once these signs or symptoms are encountered, a detailed gestational, birth, and family history should be obtained to understand the likely contributors and help guide family counseling.

Evaluation

As mentioned above, women should undergo routine screening to identify NTD early and help with therapeutic intervention and counseling. Initial screening is done with serum alpha fetal protein, but amniocentesis can be pursued for confirmation in cases of high suspicion. However, given the risk of amniocentesis and the accuracy of ultrasound, the latter has become the gold standard for diagnosis in utero and can even detect abnormalities in the first trimester.[7]

Several ultrasound signs have been identified as reliably diagnostic, as many patients also have intracranial abnormalities.[8] The small biparietal diameter has been associated with NTD. However, the most cited signs include the lemon and banana signs. The lemon sign describes the overlapping of the frontal bones due to a posterior shift of intracranial contents. The banana sign is that of a curved cerebellum due to its downward displacement, often leading to Arnold-Chiari II malformation at birth.[5] 

Ventriculomegaly, even without hydrocephalus, can be seen on ultrasound as well. Ultrasound of the spine can help visualize the affected vertebral levels and give prognostic information regarding the bowel, bladder, and gait.[9] The functional level after birth correlates with prenatal ultrasound-identified level of injury in 60% of patients.[10] Magnetic resonance imaging can also be used after birth for prognostication within 1 to 2 vertebral levels in 89% of cases.[5]

Treatment / Management

The mainstay of treatment of NTDs such as spina bifida is prevention. Women of childbearing age should supplement their diet with folate to prevent NTDs. The United States began to mandate the fortification of grains with folic acid to help diminish cases.[3] Women who are trying to become pregnant should take 0.4 mg of folic acid daily before conception. In comparison, women who have a history of NTD or a previously affected pregnancy should take 4 mg of folic acid supplementation.[5] Most patients with spina bifida occulta will not require surgical correction of the defect. However, surgical intervention is warranted in cases of open spinal dyspraphism.

In some patients, an intra-uterine repair can be pursued to close the defect earlier to improve outcomes. The Management of Myelomeningocele Study (MOMS) was a randomized clinical trial that evaluated prenatal vs standard postnatal intervention to repair myelomeningocele. The study's results found that prenatal repair decreased the incidence of hydrocephalus and hindbrain herniation, reduced the need for ventriculoperitoneal shunt placement in the future, and provided improved leg function and ambulation in children 12 to 30 months of age.[1][11] However, there are risks associated with intrauterine repair, including increased risk of prematurity and maternal complications.[12] The MOMs 2 trial reevaluated patients at school age and found that the functional benefits of prenatal repair extended into school age. These children tended to be more adept in self-care tasks, were more likely to be community ambulators, and had higher mobility skills than the postnatal repair group.[13](A1)

Several implications and sequela must be monitored and managed in the neonatal stage.[8] Early closure within 72 hours is preferred to prevent significant neurologic decline and minimize the risk of infection or injury to any exposed neural tissue. Patients will often require a ventriculoperitoneal shunt for hydrocephalus after the defect is closed. Arnold-Chiari malformations are common and may require repair if they become symptomatic.

Long-term management involves an interdisciplinary approach, as several organ systems can be affected. Neurogenic bowel and bladder are common manifestations of the condition. Neurogenic bladder typically involves detrusor-sphincter dyssynergia, which can lead to renal failure if poorly managed. Patients should have biannual renal ultrasounds for surveillance and may require intermittent catheterization for long-term management. Patients also present with neurogenic bowel caused by impaired sensation and poor sphincter control. For adequate control, patients may need to learn a consistent bowel program, which includes stool softeners, motility agents, and digital stimulation.

Children with NTDs can present with a wide range of motor involvement, including weakness, flaccidity, spasticity, and contractures. Tendon lengthening procedures can be considered for patients with severe contractures that interfere with ambulation, hygiene, or positioning. Foot deformities, including equinovarus, calcaneus, and rocker bottom deformities, are common in NTDs. Splinting, passive stretching, and serial casting can help with significant spasticity and contractures.

Differential Diagnosis

The diagnosis of spina bifida is typically accurate based on the physical presentation of the disease. However, it is important to consider several differentials in cases where the physical findings or radiographic diagnosis is not clear: 

• Cord compression
• Diastematolyelia
• Isolated Chiari malformations
• Mass lesions
• Tethered cord 

Prognosis

Few recent longitudinal studies on spina bifida and long-term outcomes exist, making it challenging to prognosticate for patients, given the significant improvements in spina bifida management. Most studies also combine data from patients with both open and closed dysraphisms. Overall, the prognosis depends mainly on the presence of hydrocephalus, defect level, and Chiari malformation severity.

Results from a recent study showed that survivability up to 1 year of age was about 71% overall. Of those with and without hydrocephalus, 56% and 88% survived beyond age 1, respectively. The rates of survival drop slightly as patients with hydrocephalus age, to about 50% by age 20.[14] Most deaths beyond age 5 are attributed to seizures, pulmonary emboli, hydrocephalus, and acute renal failure/sepsis.[5] However, there is significant morbidity associated with NTDs if patients are not adequately managed.

Urinary tract infections are the most common complication faced by those with NTDs secondary to neurogenic bladder, affecting about 48% of patients, with 6% ultimately developing renal failure.[5] The severity of Chiari malformation is a significant risk factor for mortality in infants with NTDs and can have several effects, such as sleep apnea, vocal cord paralysis, and bradycardia. Patients often are concerned about functional outcomes, specifically the prognosis regarding ambulation. In the MOMS trial, only 7% of participants were wheelchair dependent for ambulation. The remaining percentage could ambulate with assistive devices, and about 29% were independent.[15]

Complications

Patients can present with several complications, a few of which have been discussed above. The most common complication is acute renal failure/urosepsis, which is secondary to ureteral reflux caused by a neurogenic bladder. Introducing aggressive treatment and surveillance of urologic dysfunction is essential. Many patients will require intermittent catheterization for urinary management. Scoliosis is also a common complication, with about 33% of patients affected, followed by chronic pain in 29% and epilepsy in 12%.[5] 

Patients may also present with tethered cords or hydromyelia, which can present with a sudden neurologic decline, spasticity, or pain. Increased fracture risk is also associated with NTD, likely secondary to osteopenia, contractures, decreased sensation, and immobilization. There is also a unique association with a latex allergy, as about 10% and 73% of patients with spina bifida present with latex allergies.[6]