Neural Tube Defects

Defects in the formation of the neural tube account for 0.001 to 1 percent of all human malformations, depending on the reference population, making this group of disorders among the most common major malformations. Neural tube closure defects are also among the oldest recorded malformations. For example, it was determined that a mummy from ancient Egypt, investigated by Etienne Geoffroy Saint-Hilaire, was determined had anencephaly. A curious observation in the 16th century of a child with a froglike head and face, now believed to represent anencephaly, who was born to a woman who had a frog placed on her hand during a febrile illness is the first indication that neural tube closure defects may result from environmental factors. y This example of maternal impression, a theory widely postulated for many centuries as the cause of some congenital anomalies, including the Elephant Man, is noteworthy because of the now recognized association of maternal hyperthermia and neural tube closure defects. y

Pathogenesis and Pathophysiology. The prevailing theory on the pathogenesis of neural tube defects is that they result from a failure of the neural folds to come together to form the neural tube as opposed to the reopening of a closed neural tube. Experimental models and studies in humans have supported this hypothesis. Although monoallelic disorders are occasionally associated with neural tube closure defects, y most data implicate a multifactorial etiology for the occurrence of neural tube closure defects. Neural tube closure defects are common in animals, including mice, in which mutant strains have been invaluable in identifying many genes important for neural tube closure. Strain differences in the susceptibility to neural tube closure defects have been recognized, consistent with the multifactorial model. Similarly, environmental factors have been identified that result in neural tube closure defects. Recent data also indicate that at least in the cranial region, neural tube closure occurs not in a single continuous closure but at multiple sites and in a coordinated pattern. Each defined site may be under the control of different genes and be susceptible to different environmental factors ( Fig:..2.8z1). [22] , [1]

Given that several of the known risk factors could be controlled, it is important to appreciate the embryonic timing of neural tube closure and, therefore, the gestational age at which these defects are believed to arise. Closure of the neural folds begins on approximately day 20 after fertilization and is complete by approximately day 28 after fertilization. This is approximately 1 to 2 weeks beyond the time a women is expecting her normal menstrual cycle. Thus, during this critical time of development for the nervous system, a women is frequently unaware that she is pregnant.

Epidemiology and Risk Factors. The past decades have witnessed an overall decline in the incidence of neural tube closure defects, although the etiology for this decline remains elusive. Epidemiological and experimental investigations into potential environmental risk factors, particularly in Wales and Ireland, have failed to identify an obvious source. Several environmental factors have been linked to neural tube closure defects, including maternal diabetes, maternal hyperthermia, and some anticonvulsants (valproic acid and carbamazepine in particular) y ; however, the elimination of some of these minor risk factors is not sufficient to explain the overall declining incidence. y Vitamin supplementation, particularly folate, has been linked to a reduced risk for having a second child with a neural tube closure defect.y , y Preliminary data indicate that similar supplementation may also reduce the primary risk for all mothers. y The mechanisms by which vitamin supplementation prevents neural tube closure defects are poorly understood.

As alluded to already, many factors likely play a role in the causation of neural tube closure defects, and the actual etiology is usually multifactorial. Genetic factors certainly play an important role in at least conferring a predisposition to having a child with a neural tube closure defect. The genetic and environmental factors are likely to act synergistically with a woman's risk for having a child with a neural tube closure defect.

Clinical Features and Associated Disorders. Neural tube defects can be conveniently divided into cranial and caudal types, although occasional cases may involve both (e.g., encephalocele in conjunction with myelomeningocele). The terminology of a neural tube closure defect often provides a description of the type and location of the defect. Anencephaly strictly means absence of the head;

Figure 28-1 Neural tube closure defects located at multiple sites along the neuroaxis. A CT sc(AJ and clinical photograph^) of a patient with a frontal (nasal glioma) encephalocele. An encephalocele or anencephaly isolated to the occipital r<(C). This case showed an open defect at the top of the encephalocele, with extensive loss of neural tissue placing this case in the category of anencepD), A model of neural tube closure defects (from Reference 93). A lumbosacral myelomeningocele with an intact membrane over the defect that involved the spinal cord. Defects in closures III, IV, and I may account for the examples showA, B, C, and E, respectively. (a,b, Courtesy of Dr. D. Vander Woude.)

however, it practically refers to an absence of the brain and the calvarium covering the brain. Although some cases have partial sparing of supratentorial or, more commonly, the infratentorial structures, the vast majority of cases show a complete absence of most of the brain. The anterior pituitary, eyes, and brainstem are usually spared. Although the tissue fated to become the brain is present in the embryo, it is generally believed that direct contact between the neural epithelium and the amniotic fluid results in degeneration of the neural epithelium. The remaining tissue covering the basal cranium is a highly vascular and friable membrane referred to as the area cerebrovasculosa. Rachischisis refers to cases of anencephaly with a contiguous spinal defect involving at least the cervical spine region and extending for varying degrees down the spinal column. In the majority of cases, there is associated polyhydramnios and a significant proportion are stillborn; infants who are born alive do not survive. Neurological function is primarily limited to brainstem and spinal reflexes, although seizures, at times resembling infantile spasms, have been observed in some infants.

Encephaloceles and cranial meningoceles are distinguished from anencephaly because encephaloceles and cranial meningoceles have an epidermal covering over the cranial neural tube closure defects. Both entities are associated with a defect in the skull and with protrusion of the leptomeninges either alone in the case of meningoceles, or with leptomeninges and underlying brain in encephaloceles. Occasionally, no clear bony defect or attachment to the underlying brain can be identified, particularly for those located in the frontonasal region. This form of a frontal encephalocele is sometimes called a nasal glioma, although the term is misleading because nasal gliomas are not neoplasms. These lesions may not be immediately obvious on external examination, and may present as an intranasal mass, a pharyngeal obstruction, or with recurrent meningitis. Hypertelorism, median cleft lip, or hypothalamic dysfunction can be associated with these lesions. The size of the encephalocele can vary from a barely visible bulge to those larger than the infant's head. The location of an encephalocele can be helpful in the diagnosis of specific syndromes. For example, the Meckel-Gruber and Walker-Warburg syndromes are frequently associated with occipital encephaloceles, whereas anterior encephaloceles are found more commonly in Robert's syndrome and as isolated malformations are more commonly seen in southeast Asia. Parietal encephaloceles are less common. The extent of the cortex that is herniated into the cele frequently correlates with the neurological deficits. In addition, the malformed cortex within or adjacent to the cele can give rise to seizures.

Neural tube closure defects involving the spinal cord can involve the meninges alone ( meningocele) or the meninges and underlying spinal cord (myelomeningocele). Most caudal neural tube closure defects occur in the lumbar region, followed by the lumbosacral regions, but can also be located in cervical, thoracic, or sacral regions. The terms spina bifida occulta and spina bifida cystica are also used to describe variations of these defects and encompass bony changes of the vertebral column. Spina bifida occulta is

defined as a defect in the posterior bony components of the vertebral column without involvement of the cord or meninges. These defects are often found incidentally on radiographic studies or are picked up because of a subtle clinical finding such as a tuft of hair or a cutaneous angioma or lipoma in the midline of the back marking the location of the defect. On rare occasions, a sinus tract may communicate from the skin to the underlying dura. The clinical presentation is largely dependent on the level and content of the defect. Pure meningoceles may be asymptomatic. Neurological disability is greatest in patients with myelomeningoceles. Infants with defects at or above L2 are more likely to have skeletal deformities, including kyphosis and scoliosis, dislocated hips, and clubfeet (see later). The degree of motor paresis is equally dependent on the level of the neural tube closure defect and is discussed in more detail under management and prognosis. Involvement of the kidneys, urinary tract, and bladder with various forms of incontinence and reflux is very common and depends on the level of the lesion as well (see later).

Other disorders frequently included in spinal neural tube defects are tethered spinal cord, spinal lipomas, and sacral teratomas, although these entities do not arise as a result of failed neural tube closure. Nonetheless, spinal dysraphism is occasionally associated with these defects. The etiological relationship between these disorders remains unclear. Tethering of the cord due to a short and thick filum terminale can present late and insidiously with progressive gait disturbances, atrophy of various muscle groups or the entire limb, loss of reflexes, loss of sensation in particular in the sacral dermatomes, and sphincter disturbances. y The gait abnormality results from weakness and lower extremity spasticity. Pain in the gluteal, perianal, and other pelvic areas as well as the limbs associated with cramping can occur in particular with later presentation. Early and seemingly fixed deformities, as well as sudden and dramatic deteriorations, can also be seen. Deteriorations may occur, particularly during periods of rapid growth. Diastematomyelia can give rise to a similar picture; however, the symptoms may be more strictly unilateral.

Myelomeningoceles, particularly those arising in the lumbosacral regions, are frequently associated with other defects along the neuroaxis and the surrounding mesoderm. The cranial bones may show regional thinning resulting in radiographic and transilluminative lucencies. These defects, also known as luckenschadel, are present in far greater than 50 percent of term infants with myelomeningoceles but are rarely found after 2 years of age. Although these bony lucencies frequently occur in patients with myelomeningoceles, especially in the presence of hydrocephalus, they are not specific for this disorder. They may be found incidentally or in association with hydrocephalus. The base of the skull is also abnormally flattened (platybasia) in most patients with myelomeningoceles, resulting in a shallow angle between the clinoid process and the foramen magnum.

The cerebral hemispheres may show malformations that are not clearly linked to the neural tube defect. The associated anomalies range from those that are found infrequently, such as agenesis of the corpus callosum, polymicrogyria, and pachygyria, to frequent findings like an enlarged massa intermedia. The most common finding associated with myelomeningocele is the Chiari II malformation, referred to by some authors as the Arnold-Chiari malformation. The Chiari II malformation is present in more than 95 percent of children with myelomeningoceles. Although a broad spectrum of findings are part of the Chiari II malformation, '29] the change found in virtually all cases includes displacement of the cerebellar vermis (and to a lesser extent the inferior lateral cerebellar hemispheres) over the dorsal aspect of the cervical spinal cord ( Fig 28z2 ) within the upper vertebral column. The fourth ventricle, pons, and medulla are similarly elongated and partially located in the spinal canal. The lower medulla may be kinked. Forking of the aqueduct, aqueductal stenosis, or aqueductal atresia may be present. Less common findings include fusion (beaking) of the inferior tectum and anomalies of cranial nerve nuclei. Hydrocephalus is a common complication of myelomeningoceles, and may occur prenatally or postnatally. The etiology of the hydrocephalus is not always clear, although the aqueductal changes could account for some of the cases. Clinically, the Chiari II malformation may present with lower brain stem and cranial nerve dysfunction. Dysphagia leading to feeding difficulties, drooling, nasal regurgitation, stridor, vocal cord paralysis, and life-threatening apneic spells can occur. Cyanotic episodes are ominous, carrying a considerable mortality rate. Nystagmus, retrocollis, and opisthotonos can be seen. In addition, later presentation of the Chiari II malformation may include loss of head control, development of weakness in the arms, and increasing spasticity leading to quadriparesis.

In addition to the dysraphism, other malformations may be concurrently found in the spinal cord. y The two most frequent abnormalities of the spinal cord are hydromyelia (dilations of the central canal) and syringomyelia (a glial- lined cavity within the parenchyma of the spinal cord). They may either occur in isolation, or they may be found together (hydrosyringomyelia). These disorders may be found localized to a short segment of the spinal cord or along great distances. It is also important to recognize that these conditions are not specific to dysraphisms and can even be found post-traumatically. Partial (diastematomyelia) and complete (diplomyelia) duplications of the spinal cord are occasionally present in association with myelomeningocele. These anomalies are also not specific for dysraphisms of the spinal cord, and each may be found in isolation or with other CNS malformations.

Differential Diagnosis. The diagnosis of a neural tube defect is usually obvious, except in rare cases of small encephaloceles and with forme fruste lesions. Examples include dural sinus tracts and possibly some cases of aplasia cutis congenita, in which bony skull defects can occur; however, there is no cystic outpouching of components of the CNS. Tumors such as caudal lipomas, teratomas, and dermoids may occasionally mimic a neural tube closure defect. The amniotic band sequence can also disrupt the neural folds or cranium, or both, resulting in a defect resembling a neural tube closure defect. y Disruptions due to the amniotic band sequence are often easily distinguished from neural tube closure defects by the asymmetry, the presence of facial clefts, and the presence of extremity amputations. The signs and symptoms of tethering of the cord and related anomalies have to be differentiated from

Figure 28-2 Examples of several posterior fossa anomalies. A midsagittal MRI sca(A) and photograph of a brair(B) with Dandy-Walker malformations. The cerebellar vermis is rotated anteriorly, and there is a cystlike dilation of the fourth ventricle. A Chiari I malformation(C) is characterized by a tongue of cerebellar tonsils extending over the cervical spinal cord. The cerebellar vermis is intact and shows no displacement. The Chiari II malform) is characterized by the cerebellar vermis extending as a tongue of tissue into the cervical spinal canal. The inferior vermis is white, corresponding to the extreme gliosis usually seen in this disorder. Note the beaking of the inferior tectum, and the elongated and distorted pons and medulla with the kinking of the lower medulla. (A, Courtesy of Dr. R. Robertson)

other types of progressive spinal cord disease including tumors, multiple sclerosis, spinal cord infarction, and progressive spastic paraparesis.

Evaluation. The diagnosis of anencephaly is readily made upon examination of the affected infant. The evaluation of children with less dramatic neural tube defects is more complex. Occipital encephaloceles may be part of a syndrome with important genetic and prognostic implications. For example, the Meckel-Gruber syndrome and the Walker-Warburg syndrome, both mentioned earlier, are autosomal recessive disorders with a poor prognosis. A special case is the frontonasal encephalocele. Clear (CSF) rhinorrhea following the removal of a nasal polyp requires immediate evaluation, with imaging and prophylactic antibiotic treatment instituted before surgical repair. A careful endocrine evaluation is particularly important in sphenoidal encephaloceles. In general, careful imaging, preferably using both MRI and CT scanning, is important for the evaluation of encephaloceles to outline their content and anatomical relationships for treatment planning.

In the evaluation of the infant with spinal dysraphism, particularly the lumbosacral forms, it is important to be aware of the commonly associated Chiari II malformation, as well as of the possibility of coexisting hydrocephalus. Myelomeningoceles outside of the lumbosacral region have a less consistent association with hydrocephalus.

At present, it is recommended that every child with a myelomeningocele be screened for the presence of hydrocephalus with at least transfontanelle ultrasound because the development of signs and symptoms may be delayed. Careful morphological and functional urological assessment is of major importance in children with myelomeningoceles. Only in very low lesions at S3 will there be a flaccid and, therefore, relatively easy to manage bladder. Higher lesions are often associated with incoordination of the detrusor and external urethral sphincter.

In suspected occult dysraphism and the other closed malformations of the spinal cord, careful MR imaging is essential in establishing the diagnosis. Particular attention needs to be paid to a low-lying conus medullaris and thickened filum terminale in order to recognize the presence of a tethered spinal cord.

Management and Prognosis. In anencephaly, the prognosis for survival without maximal support for these infants is dismal, and a significant proportion of infants are stillborn. Survival of liveborn infants can be prolonged with the assistance of life support systems, creating controversy over the use of anencephalic infants as organ donors.

The management for dysraphic disorders begins with the planning of an atraumatic delivery. The avoidance of labor by prelabor cesarian section significantly improves neurological outcome in children with myelomeningoceles. y Larger encephaloceles are also managed in this fashion. Decisions concerning the surgical management of encephaloceles are dependent on the clinical context in which the encephalocele occurs. This includes the identification of syndromes and other associations important for prognosis and genetic counseling (see reference 22 for a more complete list of associations and syndromes). Most encephaloceles are sporadic, however, so that prognosis and management are based on the extent of the individual defect. Generally, surgical excision is recommended, even if there are significant associated malformations; the goal of surgery in these cases may be to simply improve caregiving for the affected infant. More urgent surgery may be indicated in the case of CSF leaks to prevent meningitis. The prognosis

is significantly better in anterior encephaloceles as opposed to parietal and occipital lesions, particularly those involving the posterior fossa contents (see the discussion of Chiari III malformation later). Frequently, a frontal or occipital sporadic encephalocele can be surgically managed with fairly good outcome.

The surgical treatment of spinal dysraphism in most centers is now directed at closing all but the prognostically worst cases. Although early treatment is preferable, there are no data to support that emergency closure improves outcome. Timely closure does, however, reduce the rate of infectious complications. At present, a planned operation within the first 24 to 48 hours postnatally is the standard of treatment, although some delay of the closure under antibiotic coverage does not seem to affect outcome adversely. Concurrent shunting of co-existing hydrocephalus is often necessary and advisable even for what might appear to be arrested ventriculomegaly. Prevention of meningitis or ventriculitis is extremely important, because intellectual outcome is inversely related to the occurrence of such complications. Therefore, antibiotic prophylaxis is used before and around the time of surgery, in particular with open defects. Surgical management of the Chiari malformation itself may become necessary when prominent brain stem signs persist despite adequate treatment of the hydrocephalus. y In these selected cases, decompression via suboccipital craniectomy and cervical laminectomy can be beneficial. Urological management plays a prominent role in the care of these children.y It is very important to avoid secondary dilatation of the proximal urinary system, which has the potential to cause chronic pyelonephritis and renal damage. Urological complications continue to be a leading cause of morbidity in children with myelomeningocele. Various conservative (intermittent catheterization, anticholinergic medication) and surgical regimens for bladder management may be appropriate. y Rectal incontinence can often be successfully managed with conservative treatment such as regulated emptying of the bowel. Several late complications of myelomeningoceles can arise. Scoliosis, especially with lesions at or above L2, and traction on the cord, may result from the defect alone. Postsurgical complications include spinal cord infarction, compression of the cord by subarachnoid cysts, and inclusion cysts arising from trapped skin appendages.

The distribution of weakness and deficits on examination is an important predictor for ambulation. In general, involvement above the L3 level creates motor deficits that preclude ambulation; lesions below S1 usually allow for unaided ambulation. If the deficit level falls between S1 and L3, a number of assisting devices may be useful for ambulation. '35]

Tethering of the cord may also be found as a late complication after meningomyelocele repair y but may also occur as a primary abnormality (see the previous discussion). In all cases, surgical untethering of the cord is recommended. The associated pain responds best to surgical treatment, and ambulation and bladder function may improve as well. However, sphincter dysfunction often remains a permanent problem even after complete release. Given the potential for rapid deterioration with incomplete neurological recovery, even prophylactic surgery in an otherwise asymptomatic child with a tethered cord seems advisable.

At present, primary prevention of neural tube defects focuses on dietary folate replacement around the time of conception. Such a supplementation has been shown not only to reduce the risk for the birth of a second affected child but may also be effective in reducing the primary incidence of neural tube defects. Given the early timing of the failure of neural tube closure, supplementation may be too late when an unplanned pregnancy is noted. The question of general diet fortification with folate is being debated. y

Prenatal detection of neural tube defects has become routine through screening programs using serum and amniotic chemistry and prenatal ultrasound. Elevated serum or amniotic fluid alpha-fetoprotein (AFP) and elevated acetylcholinesterase in the amniotic fluid are found in almost all open neural tube defects. This determination is highly sensitive for open neural tube closure defects but is not always completely specific, because of other possible causes for elevated AFP in the amniotic fluid. If combined with the determination of acetylcholinesterase in the amniotic fluid, the sensitivity of the test approaches 100 percent with much improved specificity. In addition, fetal ultrasonography can provide an additional level of confidence with very high sensitivity in experienced hands at even 14 to 16 weeks' gestation. Indirect signs such as the lemon sign, referring to a symmetrical bifrontal narrowing of the skull, and cerebellar abnormalities are helpful in addition to the often difficult direct demonstration of the defect. Fetal ultrasonography can also assist in dating the pregnancy, an important factor in the calculation of the AFP values, given their dependency on the gestational age of the fetus. The peak of sensitivity for maternal serum AFP levels lies somewhat later than the amniotic fluid determination and is optimal at 16 to 18 weeks' gestation. Before that time, the levels may be normal despite the presence of a neural tube closure defect. The specificity of this test is much lower, so that careful follow-up testing needs to be performed after the determination of an elevated value. This commonly includes a high-level fetal ultrasonography and often amniocentesis.

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