Neural tube defects (NTDs)
Definition
Broad spectrum of anomalies caused by failure or incomplete closure of neural tube
“Open”: Defect in primary neural tube closure
Anencephaly
Lethal condition
Restricted to cranial end
Absence of the cranial vault and absent or markedly diminished cerebral and cerebellar hemispheres
Holocrania if foramen magnum involved
Merocrania if the foramen magnum is not involved
Spina bifida aperta or “myelomeningocele”
Defect involves spinal portion of neural tube
Characterized by level of spinal involvement
Craniorachischisis
Lethal condition
Involves both cranium and spine
“Closed”: Skin covered lesions that involve defects in both primary and secondary neural tube closure. Closed spinal lesions are also called spina bifida occulta
Encephalocele
Meningocele
Lipomyelomeningocele
Split cord malformations
Sacral agenesis
Terminal myelocystocele
Other occult spinal dysraphisms
Incidence and prevalence
NTD is the second most common type of birth defect after congenital heart defects and remain a leading cause of death and disability in children.
Frequency varies with geographic and anatomic locations.
In the United States, incidence of 10 per 10,000 live births in American Whites; lower rates in Black Americans and Asian-Americans, and higher rates in Hispanic-Americans.
Because only a proportion of affected conceptuses survive to a stage where an NTD is likely to be recognized and some of the recognized affected fetuses are electively terminated or are stillborn, the true prevalence of these conditions is unknown, since only live-born infants are counted.
In general, prevalence of spina bifida is higher than anencephaly.
Prevalence of NTD is higher in females than males.
Pathophysiology
These lesions result from the combined effects of genetic and environmental influences.
Formation of the neural tube gives rise to the brain and spinal cord in three phases.
Gastrulation: Forms the three embryonic germ layers (ectoderm, mesoderm, and endoderm). Split cord malformations may occur during this phase.
Neurulation
Primary neurulation
Neural plate folds into neural tube forming the brain and majority of spinal cord.
Occurs during third to fourth weeks of gestation.
Defects give rise to anencephaly, myelomeningocele, meningocele, lipomeningocele.
Secondary neurulation
Occurs in fourth week of gestation.
Process of differentiation and canalization forms caudal end of spinal cord—the conus and filum terminale.
Defects give rise to occult spinal dysraphism including tethered cord malformations.
Post-neurulation rapid growth and differentiation, which is when encephaloceles are thought to occur.
There is active research concerning whether the architecture of the fetal myelomeningocele placode is normal. This is important since fetal surgery for repair is predicated on belief that it is preventing secondary injury caused by the intrauterine environment.
Risk factors
Family history increases risk from 1-2/1000 live births to 3% to 8% in children of affected individuals, and to 5% in subsequent children if one is affected. If two children are affected the risk rises to 12%. Increased risk has also been noted in second- and third-degree relatives.
Affected parent-child pairs are rare; most affected relatives are second or third degree.
NTDs are associated with other known genetic syndromes including VATERs syndrome, fragile X and Meckel syndrome, as well as trisomies 13, 18, and 13q deletion syndrome.
Folic acid
Demonstrated to reduce recurrence risk in affected families
Decreased incidence noted with global food fortification and maternal periconceptual folic acid administration
Recommended dose: 400 μg qd for all normal risk women in child-bearing age
Increased dose of 4 mg qd for “at-risk” women
Mechanism not established but is likely related to DNA and RNA biosynthesis and methylation reactions that drive conversion of homocysteine to methionine
Agent Orange exposure in Vietnam veterans was implicated in increased NTDs in their offspring.
Maternal diabetes and obesity probably due to abnormal glucose metabolism.
Antiepileptic drugs, especially valproic acid, which has greatest teratogenic effect and results in 1% to 2% incidence of spina bifida.
Clinical presentation
Signs and symptoms
Fetal
In North America, more than 60% of fetuses with open NTDs are diagnosed by prenatal evaluations. Many of these are electively terminated. It is estimated that more than 90% of anencephalics are electively terminated or are stillborn.
Fetal diagnosis of open NTD is made by fetal ultrasound findings.
Splaying of ossification centers in the spine
Lemon sign: Overlapping of frontal bones producing a lemon-shaped head
Banana sign: Effacement of cisterna magna by downward displaced cerebellum
Presence of hydrocephalus
Newborn
Open NTD is obvious at birth. Sac, which may or may not be leaking CSF, can be seen with exposed neural placode extending vertically down the center.
Closed lesions including meningoceles or skin covered terminal myelocystoceles and lipomyelomeningoceles are also obvious.
Occult lesions are not usually diagnosed in newborns, but presence of dermal sinus tract above gluteal cleft or thoracic or lumbar hair tuft should raise suspicions.
Condition variability: The extent of neurologic involvement is determined by the anatomic location of the lesion and whether it is an open or closed NTD.
Diagnosis
Prenatal ultrasound, as described under Section E.1.a.
Physical examination, as described under Section E.1.b.
Spinal ultrasound and MRI: Will assist in diagnosing closed NTDs. The extent of open lesions is usually determined during surgical closure.
Cranial ultrasound and brain MRI: The presence of associated hydrocephalus and/or chiari malformation may be screened for by cranial ultrasound and later confirmed by MRI.
Management
For the past several decades, the standard of care in the United States for perinatal care of infants with open NTDs has included early sac closure, prophylactic antibiotics, and shunting of progressive hydrocephalus. Only those babies with concomitant life-threatening anomalies or perinatal events or those with anomalies incompatible with more than brief survival, eg, anencephaly, iniencephaly, craniorachischisis, are provided only comfort care measures.
Fetal surgery
Management of Myelomeningocele Study (MOMS) study has shown encouraging results in regard to prevention of hindbrain herniation and decreased need for shunting in a selected group of patients who underwent fetal repair of their myelomeningoceles. Outcomes in regard to improved motor function were not as well demonstrated. While the authors suggest this become the standard of care for treatment of open neural tubes, it remains to be seen whether these results will be maintained with fetuses with more severe brain and spinal anomalies.
Medical management
Preop assessment to rule out other life-threatening anomalies.
Prophylactic antibiotics are administered to infants with open spina bifida until operative closure can be achieved, usually within the first 48 hours of life.
Plain spine films are done to look for evidence of an associated bony spinal defect, such as a split cord malformation, and to assess the severity of a kyphus that may impact the surgical repair strategy.
Rapid acquisition MRI, cranial ultrasound, or other brain imaging is performed to evaluate ventricular size so that a decision can be made regarding simultaneous shunting at the time of back closure versus delayed shunting.
Surgical management
Early repair of open lesions is done to reduce risk of infection and ease handling of infant by caregivers.
Most infants with closed forms of NTDs are neurologically normal and do not have associated hydrocephalus. They are expected to survive the neonatal period and often can be treated at a later time during infancy.
Postoperative care
Infant is kept prone to prevent wound breakdown or CSF leak.
Monitor head growth by daily OFC and serial imaging.
VP shunt placement when progressive hydrocephalus documented.
Assessment of bladder function by renal ultrasound and VCUG and decision about intermittent catheterization made by urology team. Parents are generally taught clean intermittent catheterization (CIC) technique.
If hydronephrosis is present, urinary prophylaxis should be started.
Parents taught positioning techniques and if club foot present, stretching or casting may be recommended.
Prior to discharge, infants will usually have a full craniospinal MRI to serve as a baseline and to identify any previously unrecognized secondary lesions.
Infants with feeding problems may require ST/OT/lactation services, or modified barium swallow study to assess safety for oral feeding.
Evidence of nasopharyngeal regurgitation, aspiration, oxygen desaturations with feedings, vocal cord paralysis, or other bulbar symptoms may signal need for Chiari decompression.
Early develovpmental/therapeutic interventions
Physical therapy
Positioning
Due to initial need for prone positioning for wound healing, especially with large defect repairs, head preferences and tone imbalances are common regardless of neurologic status.
Infants requiring shunt placement are at great risk for head preferences, plagiocephaly, and developing a torticollis. Symmetric holding and positioning should be encouraged.
Splinting: Associated orthopedic anomalies are common and need to be addressed.
Stretching/strengthening exercises: Tone abnormalities, either due to the underlying condition or acquired, necessitate PT evaluation, treatment and follow-up plan.
Feeding therapy
It is not uncommon for the infant with an NTD to have feeding difficulties that need to be addressed prior to discharge.
Prognosis
Early predictors
Anencephaly and craniorachischisis are lethal anomalies, which are generally stillborn or have very brief survival.
Infants with early onset of brainstem dysfunction including stridor, feeding difficulties, nasopharyngeal regurgitation, and/or aspiration may require G-tube and tracheostomy and have high early mortality.
Findings of vernix caseosa meningitis or meconium contamination of subarachnoid space are especially prone to irreversible brainstem dysfunction.
Brainstem symptoms do not respond as well to Chiari decompression as in older patients.
Infants with closed forms of NTDs usually will survive neonatal period.
Outcomes
Neonates with early brainstem dysfunction have high mortality.
Most other open and closed spinal lesions survive early infancy. The degree of neurological impairment is related to the lesion level and presence or absence of hydrocephalus.
At least 75% of infants with NTDs will survive to young adulthood.
Though survival rates beyond infancy are good, children with NTDs are always at risk for disabling and potentially life-threatening events and are best managed in a multidisciplinary clinic that provides access to the many specialists needed to minimize complications.
Hydrocephalus (see also Chapter 22)
Definition
The progressive accumulation of excess cerebrospinal fluid within the ventricular system.
In myelomeningocele patients, the hydrocephalus is usually associated with the Chiari malformation.
CSF outflow can be disrupted due to compression of the fourth ventricle, which is displaced into the upper cervical canal or by kinking of the aqueduct of Sylvius between the third and fourth ventricles.
In infancy, it leads to an accelerated head growth in addition to elevated intracranial pressure.
Incidence
Up to 80% of children with open NTDs have hydrocephalus requiring a shunt.
Pathophysiology, as above
Risk factors
Open versus closed NTD
Most patients with open NTDs develop progressive hydrocephalus.
Patients with spina bifida occulta rarely require shunting.
Level of lesion
Virtually all thoracolumbar myelomeningocele patients have hydrocephalus.
50% of lumbosacral level lesions develop hydrocephalus.
Only rare cervical level lesions require shunting.
Clinical presentation
Signs and symptoms
Hydrocephalus is often seen on fetal ultrasound in open NTDs.
At birth, head size may vary from macrocephalic to microcephalic.
Fontanelle may be tense and bulging.
Condition variability
Even in the presence of ventriculomegaly, not all infants require early shunting if ventricular size remains stable and head growth is normal.
Diagnosis
Clinical findings of accelerated head growth
Imaging findings of progressive ventriculomegaly
Management
Medical
Monitor head growth and tenseness of fontanelle.
Watch for signs of raised intracranial pressure including vomiting, irritability, abnormal eye movements, feeding difficulties.
Surgical
Most commonly managed by placement of ventriculo peritoneal (VP) shunt.
Endoscopic third ventriculostomy (ETV) has been successful in a minority of patients, usually after 6 months of age.
Ongoing developmental/therapeutic interventions
Again, physical therapy consultation for positioning, stretching, and strengthening exercises is very important in infants with hydrocephalus.
Periodic follow-up is necessary to monitor shunt function. Frequency of imaging studies is individualized.
Generally fast acquisition brain MRI (MR fast ac) or cranial ultrasound are done at intervals until ventricular size stabilizes.
Imaging is repeated whenever there are signs of abnormal head growth, bulging fontanelle, or other signs of shunt malfunction.
Frequency of surveillance imaging is open to debate.
Routine imaging does not detect all malfunctions.
“Silent shunt malfunctions” may present as new onset strabismus, visual loss from optic atrophy, cognitive decline, or change in neurological examination.
Silent malfunction, without change in routine imaging studies, warrants more invasive assessment of shunt patency such as fluoroscopic or radionuclide shunt injection study.
Annual dilated eye examination and attention to school performance should be part of the routine follow-up care.
Prognosis
Early predictors
Shunt infection often leads to recurrent shunt failures.
Recurrent malfunction increases risk of infection.
Severely macrocephalic infants have worse functional outcome.
Outcomes
50% of shunts fail in first year of life with subsequent 10%/year failure rate.
Unrecognized shunt failures can lead to cognitive decline and blindness.
ETV is a useful procedure to eliminate shunts in older patients but still require surveillance as failures do occur.
Shunt failure can lead to progressive syringomyelia with resultant neurological decline and spinal deformity as well as worsening Chiari symptoms.
Hydrocephalus is associated with precocious puberty even in presence of functioning shunt.
Unrecognized shunt failure accounts for many unexpected sudden deaths in older patients.
Chiari malformation
Definition
Almost all children with open NTD have a Chiari II malformation with displacement of the brainstem, fourth ventricle and cerebellar vermis into the upper cervical canal.
It is usually associated with other developmental anomalies of the brain.
Incidence
Chiari malformation is present in 95% of myelomeningocele patients though the extent of the anomaly is variable.
Early brainstem dysfunction occurs in 10% of neonates.
Pathophysiology
The displacement of the brainstem and midline cerebellum is thought to be due to lack of adequate growth of the posterior fossa caused by the leakage of CSF from the open neural tube.
Risk factors
While almost all patients with myelomeningoceles have the Chiari II malformation, only a small percentage of infants show signs of brainstem dysfunction early on.
Vernix caseosa meningitis and meconium contamination of the subarachnoid space have been associated with early brainstem dysfunction.
In older patients, increased ICP associated with shunt malfunction may precipitate Chiari symptoms.
Clinical presentation
Signs and symptoms
Neonates often present with feeding difficulties, stridor, and aspiration. Absent gag reflex and vocal cord paralysis may be seen.
Older children may develop similar symptoms as well as late-onset cranial neuropathies, snoring, and sleep apnea, which are more easily reversible with surgical intervention.
The Chiari may also be responsible for the development of syringomyelia and progressive scoliosis.
It is a reason for decreased upper extremity strength and dexterity.
Condition variability
Despite its appearance on MRI, the extent of the hindbrain herniation does not correlate with extent of symptomatology as many patients have little or no brainstem symptomatology.
Diagnosis: Almost all patients with open neural tubes have this malformation, which can be easily demonstrated by MRI of the cervical spine.
Management
Medical management is directed toward treating the symptomatology, preventing aspiration pneumonia, and identifying correctable causes for the symptoms.
Surgical
The initial treatment of Chiari symptoms is ensuring the estab-lishment of a functioning shunt to treat the hydrocephalus.
If symptoms persist despite a functioning shunt, then Chiari decompression is carried out.
Usually involves laminectomy of the involved levels of cervical spine with dural patching. Opening of posterior fossa dura is avoided because the compressed neural tissue is actually in the neck. Additionally, the transverse sinus and torcula are often displaced to the level of the foramen magnum. Opening the dura here would cause catastrophic hemorrhage.
If vocal paralysis or swallowing difficulties persist, gastrostomy tube placement and tracheostomy may need to be performed.
Ongoing developmental/therapeutic interventions
Because symptoms can occur at any age, imaging of both brain and spine should be done any time new neurologic symptoms develop.
Sleep studies may be indicated in children with restless sleep or other concern for sleep apnea.
Bedside swallow evaluation by a skilled speech therapist, in conjunction with video fluoroscopic swallow study, may identify aspiration risks.
Ongoing physical therapy evaluation and treatment, as indicated, for associated neurologic impairments.
Prognosis
Early predictors: Early age of onset of symptoms is a poor prognosticator for long-term survival and good quality of life.
Late onset symptoms associated with shunt malfunction are often reversible.
Outcomes
Mortality rate in symptomatic neonates is much higher than in those without Chiari symptoms.
Complications related to the Chiari are the most common cause of death in myelomeningocele patients.
Discharge
Teaching
Parents should be taught symptoms suggestive of increased intracranial pressure, including extreme lethargy, irritability, poor feeding, or increased vomiting.
Parents should be shown how to assess for fullness of the anterior fontanelle.
For infants who have shunted hydrocephalus, parents should understand symptoms of shunt infection (fever or hypothermia; redness, pain, or swelling around shunt tubing) and shunt malfunction (symptoms of increased ICP, full fontanelle, swelling along shunt tubing).
Parents should be taught the importance of latex precautions.
Parents should be taught, and redemonstrate, how to correctly perform intermittent catheterization with clean technique, if indicated. They should also understand signs and symptoms suggestive of a urinary tract infection (fever, lethargy, poor feeding, foul smelling urine, etc).
Parents should understand the importance of diligent skin care and monitoring for skin breakdown.
Caregivers should meet with the physical therapist prior to discharge. Parents should be taught the importance of symmetric positioning, especially those with shunted hydrocephalus, as a head preference and torticollis is a common outcome if the infant is always positioned shunt side up.
Parents should have a basic understanding of lifelong special needs that the child may have.
If available, parents should room in with their infant, demonstrating competence with all cares, prior to discharge.
Monitoring
Consider home apnea monitor for infants with persistent apnea and bradycardia spells related to either macrocephaly or Chiari malformation with sleep apnea. Ideally, this problem should be resolved prior to discharge.
Ongoing monitoring for signs of increased ICP should be done by caregiver and provider alike upon discharge.
Safety
Caregivers should be instructed in infant CPR.
Infants should have a car seat safety test for at least 90 minutes prior to discharge. Infants with hydrocephalus and poor head control at discharge may need to use the manufacturer’s insert to provide lateral head support. A car bed may be necessary in cases of severe macrocephaly, wound healing problems, or orthopedic issues preventing appropriate standard car seat usage.
An emergency plan should be established, instructing what to do (raise head of bed, call PCP, call neurosurgeon, call 911, etc) if the child has symptoms of shunt infection/malfunction and what medical facility to bring them to should be discussed.
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