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Disorders of neural tube formation
and closure relate to disturbances in the inductive events involved
in primary neurulation, aberrant closure of the anterior or posterior
neuropore, or failure of the caudal regression and differentiation
events that lead to formation of the lower spinal cord. Correct
development of the neural tube is necessary for formation of the
dura and other meninges, cranium and vertebrae, and the dermal coverings.
Dysraphism refers to persistent continuity between the posterior
neurectoderm and cutaneous ectoderm. External manifestations of
abnormal cutaneous ectoderm may be the only initial clinical signs
of occult dysraphism.
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The incidence of neural tube defects varies widely by geography
and by type of dysraphism. For example, rates of myelomeningocele
as high as 3% have been reported in the United Kingdom,
but extremely low in Japan. There are also significant secular trends
with a steady decline in incidence for myelomeningocele and anencephaly
in Great Britain, northern Europe, and the United States since the
late 1980s. Further details of incidence and etiology are discussed
below.
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Cranioraschisis
and Anencephaly
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Cranioraschisis and anencephaly represent the most severe failures
of primary neurulation. Cranioraschisis is a rare and lethal condition
of essentially total failure of neurulation with a neural plate-like
structure present, but with no skeletal or dermal elements overlying
it. The incidence is unknown. The equally rare disorder of failure
of posterior neuropore closure known as myeloschisis represents
the inverse of cranioraschisis, where a neural platelike structure
without overlying vertebrae or dermis replaces large portions of
the spinal cord. This sometimes involves the base of the skull,
the condition of iniencephaly. Infants with this condition are frequently
stillborn with severe arthrogryphosis multiplex.
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Anencephaly is a defect of anterior neural tube closure
and comprises failure of formation of elements from the rostral
portion of the neural tube anywhere from the foramen magnum caudally.
The forebrain and upper brain stem are usually involved; normal
neural tissue is replaced by a formless mass of degenerated, hemorrhagic
neuronal and glial tissue; and there is an absence of the frontal,
parietal, and squamous occipital bones. The disorder varies considerably with
geographic location, race, sex and ethnic group, maternal age, and
socioeconomic status. The incidence is higher in whites, especially
those of Irish ethnicity, in very young and very old mothers, and
in those of lower socioeconomic status as well as in those with
a history of previously affected siblings. The incidence in the United
States declined from 0.5 per 1000 live births in 1970 to 0.2 per
1000 births in 1989. Polyhydramnios is a frequent prenatal finding
and the malformation is now commonly diagnosed in the second trimester
during obstetric screening, allowing for elective termination of
pregnancy. Babies born alive with anencephaly rarely survive beyond
7 days (< 2%) without intensive care, and even with
intensive care, rarely beyond 8 weeks. Neurologic findings in live
born babies are usually restricted to residual brain stem activity,
including primarily reflexive motor movements and limited basic
cranial nerve function, consistent with preservation of a rudimentary
brainstem.
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This group of disorders represents herniation of the brain or
meninges through the skull. The underlying pathogenesis is not known
but relates in part to failure of normal closure of the anterior
neuropore. It is relatively uncommon with an estimated incidence
of 1 to 3 in 10,000 live births; antenatal detection by ultrasound
examination has been increasing. More than 70% of encephaloceles
herniate through the occipital part of the skull, although nasofrontal
encephaloceles are relatively more common in Southeast Asia. Basilar,
temporal, and parietal encephaloceles are unusual. The herniated
mass may comprise one or more of meninges, cerebrospinal fluid (CSF),
and neural tissue, which may be surprisingly well organized. Hydrocephalus occurs
in 50% of occipital encephaloceles; other malformations
are common including agenesis of the corpus callosum, Chiari III
malformation, and subependymal nodular heterotopia. The degree of neural
tissue herniated and the associated brain malformations determine
outcome; encephaloceles containing CSF and/or meninges only
or patients with an isolated skull defect (cranium bifidum occultum)
usually having normal outcomes.
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Encephaloceles are found in a number of multiple congenital anomaly
syndromes, including Meckel syndrome, and Walker-Warburg syndrome,
and are associated with first trimester maternal hyperthermia. Prenatal
detection and assessment allows for potential termination of the
pregnancy in those cases in which the lesions are massive, with
a large amount of herniated neural tissue or in which there is marked
microcephaly. Prenatal detection also facilitates postnatal management.
This usually comprises neurosurgical intervention to close the defect
and to treat associated hydrocephalus. Patients with anterior defects
generally have better operative outcomes, with lower mortality and better
developmental outcome. More than 50% may be expected to
have normal intelligence. Motor deficits are common in survivors. Basal
or frontonasal encephalocele may be occult and present with later
meningitis or CSF leaks.
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Failure of posterior neural tube closure results in a malformation of
the spinal cord, myelomeningocele. This is the most commonly encountered
neural tube defect in pediatric practice as most infants born with
this anomaly survive. The lesion consists of neural plate or rudimentary
neural tube tissue herniating through a defect in the vertebra (spina
bifida) in the form of a sac containing meninges, cerebrospinal
fluid, nerve roots, and spinal cord. The dorsal cord is most commonly
affected and some dermal covering may also be present. The vast
majority of myelomeningoceles occur in the lumbar region; 10% may
contain no neural tissue and are known as meningoceles. Hydrocephalus
and Chiari II malformation are frequent associations.
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The incidence of myelomeningocele varies widely by ethnic population
and geographic location but ranges from 0.2 to 4 in 1000 live births.
Girls are more frequently affected than boys. Recurrence risk is
5%, increasing to 15% if 2 siblings are affected.
The etiology is unknown but syndromic associations are recognized
(eg, Meckel syndrome), as well as a wide range of aneuploidies.
Specific teratogens are associated, particularly thalidomide, carbamazepine,
and valproic acid. Other maternal susceptibility factors include
hyperthermia, low vitamin B12 levels, diabetes mellitus,
and obesity. Periconceptual folate supplementation has been shown
to significant reduce the incidence of neural tube defects (up to
83% reduction with 400 μg daily supplemental
folate). Factors related to folate metabolism have been identified;
defective levels of methylene tetrahydrofolate reductase have been
demonstrated in up to 20% of pregnancies affected with
neural tube defects. Prenatal diagnosis may be made from the second
trimester by screening for increased alpha fetoprotein levels in
maternal blood resulting from transudation through an open neural
tube defect, as well as by fetal ultrasonography and increasingly
by fetal magnetic resonance imaging (MRI).
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Clinical features relate to the extent and severity of the myelomeningocele,
hydrocephalus and Chiari II malformation. In addition other CNS
anomalies may be present with migrational abnormalities such as
polymicrogyria and cortical dysplasia being present in 40% to
90% of patients. The neurologic features relate primarily
to the segmental level of the lesion; the muscles of the trunk and
legs and bladder and rectal sphincters are primarily involved. The
cord distal to the site of the lesion will be nonfunctional. In
general, patients with lesions affecting L2 or above will be nonambulatory
and incontinent, often developing later severe scoliosis, while patients
with lesions at S1 and below will be ambulatory and partially continent.
Intermediate lesions will have variable degrees of ambulation. Good
strength-of-hip flexors and knee extensors are good predictors of
ambulation.
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Hydrocephalus develops in up to 80% of patients and
may be insidiously progressive. The clinical signs of full fontanel,
separated cranial sutures, and rapidly increasing head size, or signs
of raised intracranial pressure usually become evident by 4 to 6
weeks after birth. Chiari II malformation, present in nearly all
lumbar myelomeningoceles, is the primary cause of hydrocephalus.
In addition, in a minority of cases it causes severe brainstem dysfunction. The
malformation consists of inferior displacement of the fourth ventricle,
medulla, and lower cerebellum through the foramen magnum into the
upper cervical canal; elongation and deformation of the upper medulla
and lower pons, together with bony defects in the foramen magnum
or upper cervical vertebrae. The hindbrain malformation may block
cerebrospinal fluid (CSF) outflow from the 4th ventricle, and aqueductal
stenosis or atresia is present in up to 75% of patients,
leading to hydrocephalus. The brainstem dysfunction, related to
intrinsic abnormalities of the cranial nuclei and outflow tracts,
as well as mechanical traction, includes stridor, apnea, dysphagia,
facial weakness, and vocal cord paresis. These clinical features
are associated with a high mortality. Associated CNS anomalies are
responsible for some of the intellectual deficits seen in a minority
of patients, as well as the 25% incidence of epilepsy in
patients with myelomeningocele.
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Initial therapy is directed towards early closure (within 3 days
of birth) of the defect to prevent infection. Broad-spectrum antibiotic coverage
from birth until closure is also indicated; cesarean section is
strongly recommended if a postoperative surgical repair is planned.
Early treatment of hydrocephalus with ventriculoperitoneal shunting
has been shown to have a positive effect on intellectual development.
Brain stem dysfunction related to Chiari II malformation is difficult
to treat, but early decompressive cervical laminectomy and shunting
have been shown to be effective.
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Later management is most effective through multidisciplinary team
management directed at management of orthopedic and urologic sequelae.
These teams usually comprise neurologists, neurosurgeons, urologists,
orthopedic surgeons, general and developmental pediatricians, specialty
nurses, rehabilitation therapists, social workers, and psychologists. Orthopedic
management and physical therapy are directed towards the promotion
of ambulation, prevention and treatment of bony deformity, and maintenance
of posture. Urodynamic evaluation from the neonatal period onwards
is important. Strategies such as anticholinergic or pro- or antiadrenergic
medication and clean intermittent catheterization promote bladder continence
in the patient with myelodysplasia.
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The combination of selective aggressive therapy that combines careful
patient selection for neurosurgical intervention, together with
early closure and shunting, has lead to significant improvements
in survival (> 85% at age 3 years) and ambulation (> 75% ambulatory)
with preserved IQ (> 73% with IQ > 80). Multidisciplinary
management and careful attention to the psychosocial and educational
needs of children with myelodysplasia, in particular continence
and rehabilitation, has improved health-related quality of life.
A recent development has been the advent of fetal management. In
utero closure of the defect to prevent further deterioration of exposed
spinal tissue to amniotic fluid is promising with studies showing
reversal of the Chiari II malformation and reduced need for postnatal
shunting.
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Occult Spinal
Dysraphism
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This group of conditions relates to disturbances in the processes
of posterior neural tube canalization and dedifferentiation towards
the end of neurulation. These result in caudal defects and in the
vertebrae and dermal structures with subtle or absent neural abnormalities.
As the lesions are covered by skin, they are often occult and comprise
bony and soft tissue abnormalities of the conus medullaris or filum
terminale. The primary anomaly is failure of separation of the neural
tube from the overlying ectoderm and abnormal insertion of the mesoderm
between these layers. This results in a spectrum of anomalies including
ectodermal and mesodermal malformations such as excessive hair,
pigmented maculae, hemangiomata, lipomata, dermal tracts or sinuses,
division of the spinal cord by a bony or fibrous septum (diastematomyelia),
and vertebral anomalies. The failure of caudal canalization causes “tethering” of
the conus or filum by fibrous bands or lipomata.
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Dermal manifestations are the most common early findings; when
present, additional investigation should be pursued, usually spinal
ultrasound up to 6 months of age, and thereafter magnetic resonance
imaging (MRI) of the spinal cord. Later findings include back pain,
delay in walking, delay in development of continence, gait disturbance,
and foot or leg deformity or asymmetry. These symptoms relate in
part to abnormal neural tissue or to traction restricting normal
mobility and growth of the lower spinal cord. Investigation is optimal
by MRI of the entire cord supplemented by urodynamics. Neurosurgical
management of asymptomatic patients remains controversial. However,
untethering techniques designed to prevent traction injury and sudden
neurological decompensation, are considered safe in experienced
hands. Symptomatic patients are managed with neurosurgical untethering
to prevent further progression (some patients may have postoperative
improvement in symptoms) combined with orthopedic management of
bony deformity.1-8