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17 Neural Tube Defects Takayuki Inagaki, Jodi L. Smith, Marion L. Walker, and Gary C. Schoenwolf 1. Introduction We start with a quote by Rupert Willis (1), who said “Malformations of every conceivable kind, degree, and combination occur, and no two of them are ever alike,” to emphasize the difficulty of what we attempt to do in this chapter: provide a simplified, useful scheme for classifying neural tube defects. The difficulty results from the fact, as stated above, that individual birth defects are part of a continuum of anomalies rather than unique members of distinct classes of defects; terminology is not always logical nor is it universally accepted among embryologists, pathologists, neurosurgeons, and so forth; and the etiology of birth defects, including neural tube defects, is virtually unknown. Nevertheless, in this chapter, we provide a classification scheme, albeit an imperfect one, to help embryologists begin to understand the clinical consequences of development when it goes awry. In addition, we believe this classification scheme will be useful to clinicians for categorizing neural tube defects and will help to facilitate communication among basic scientists and clinicians as they work together in the important task of understanding neural tube defects. In this chapter, we briefly discuss open and closed neural tube defects. A neural tube defect is an anomaly of the central nervous system and/or its membranes, resulting either from faulty neurulation or from abnormal development of the neural tube during the early postneurulation period. Simply speaking, an open neural tube defect is an abnormal neural tube with abnormal membranous coverings, which lacks the overlying skin. In contrast, a closed neural tube defect is defined as for the open one, except that it is skin covered. In addition, in this chapter, we discuss anomalies occurring secondarily to open or closed neural tube defects, such as tethered cords, the Chiari II malformation, and hydrocephalus, as well as other major anomalies of the neural tube, such as holoprosencephaly and lissencephaly. Ideally, the classification of congenital malformations of the brain and spinal cord would be based on the cause of abnormality. However, as stated earlier, the causes of such defects are not known in many cases. Therefore, in this chapter, we classify neural tube defects based on their anatomical features. More exhaustive coverage of neural tube defects appears elsewhere (2,3). From: Methods in Molecular Biology, Vol. 136: Developmental Biology Protocols, Vol. II Edited by: R. S. Tuan and C. W. Lo © Humana Press Inc., Totowa, NJ

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Our classification scheme is as follows: A. Open neural tube defects 1. Anencephaly 2. Spinal rachischisis a. Myeloschisis b. Myelomeningoceles (meningoceles) 3. Iniencephaly 4. Encephaloceles B. Closed neural tube defects 1. Spina bifida occulta 2. Lipomas and lipomeningoceles 3. Split cords (diastematomyelia, diplomyelia) 4. Neurenteric cysts 5. Dermal sinuses 6. Sacral agenesis (caudal regression)

Each of these neural tube defects will now be defined briefly. 2. Classification of Neural Tube Defects 2.1. Open Neural Tube Defects 2.1.1. Anencephaly Failure of the cephalic part of the neural tube to close results in a condition called exencephaly. Because the malformed brain tissue is exposed on the surface of the body and is not covered by skin, the vault (i.e., roof or calvarium) of the skull does not form. During subsequent gestation, the exposed brain tissue degenerates, resulting in anencephaly (literally, absence of the brain).

2.1.2. Spinal Rachischisis (Spina Bifida Operta) Failure of the neural tube to close in the spinal cord region results in spinal rachischisis (literally, cleft spine). The term spina bifida aperta refers to the fact that the spines of the vertebrae are bifid. Thus, spinal rachischisis involves defects both of soft tissues (i.e., neural, meninges, muscle, and skin) and hard tissues (bone). There are two main types of spinal rachischisis: 1. Myeloschisis: The neural tube at the site of the defect is broadly open and the central canal is absent. This is the most deleterious type of neural tube defect. Myeloschisis commonly occurs at the thoracolumbar junction. 2. Myelomeningoceles: A central canal forms, although it may be open on its dorsal surface. The membranous coverings (i.e., meninges), as well as the malformed spinal cord (i.e., myelo), protrude through a defect in the skin. Myelomeningoceles tend to occur in the lumbar and sacral regions. Rarely, another malformation occurs at the spinal cord level in which the membranous coverings of the spinal cord protrude through the defect in the skin, but the spinal cord does not; this defect is called a meningocele. In meningoceles, the spinal cord can still be abnormal, but the abnormality is usually less severe than in myelomeningoceles.

2.1.3. Iniencephaly Iniencephaly is a defect in which the occipital bone is deficient and the brain is exposed. It is usually combined with cervicothoracic spinal retroflexion and may be

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accompanied by rachischisis. Iniencephaly differs from anencephaly in that it is associated with the formation of the cranial vault and spinal retroflexion.

2.1.4. Encephaloceles Encephaloceles are characterized by herniation of the brain and/or meninges through an opening in the skull. If the hernia contains both brain tissue and meninges, the defect would best be described by the term encephalomeningocele. However, the term encephalocele has been used traditionally by clinicians to describe this defect, and this tradition continues today. If the hernia contains only meninges, it is called a cranial meningocele.

2.2. Closed Neural Tube Defects 2.2.1. Spina Bifida Occulta The term spina bifida occulta refers to the fact that the spines of the vertebrae are bifid. In contrast to spina bifida aperta (spinal rachischisis), the spinal cord and its meninges are normal in spina bifida occulta. Thus, spina bifida occulta is usually only an asymptomatic defect of the bony components of the spine. As such, it is not a true neural tube defect.

2.2.2. Lipomas and Lipomeningoceles A lipoma is a benign fatty tumor. It can form along any level of the spinal cord. Lipomas associated with the cauda equina (the spinal nerve roots that descend from the inferior part of the spinal cord) and with the presence of an caudal cyst (i.e., an abnormal expansion of the dural sac that contains cerebrospinal fluid) are called lipomeningoceles. Despite the fact that the name for this defect includes the term meningocele, lipomeninogoceles are closed neural tube defects not open neural tube defects; that is, they are covered with skin.

2.2.3. Split Cords The use of the term split cord is growing in popularity and is equivalent to the more cumbersome term diastematomyelia. Diastematomyelia is a localized abnormality of the spinal canal in which the dura mater is perforated by a bony spike or fibrous band, creating two chambers. Each chamber contains a half-spinal cord, split by the central partition, but joined together both superiorly and inferiorly to the partition. Diplomyelia is a type of split cord that is considered to be a “true” duplication. Thus, each cord has two dorsal and two ventral horns and paired nerve roots, but the two cords are contained within a single dural sac.

2.2.4. Neurenteric Cysts Neurenteric cysts are rare cysts occurring within the spinal canal or cranial cavity. These cysts are lined with epithelium resembling that of the gastrointestinal tract and are of endodermal origin. Neurenteric cysts most frequently occur at low cervical and upper thoracic levels. Their origin is not well understood.

2.2.5. Dermal Sinuses A dermal sinus is a fistula extending from the skin to some deeper structure. The inside of the fistula is lined with skin. The dermal sinus can be a blind pouch or can

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attach to the dura mater or to the spinal cord. Dermal sinuses may occur any level of the neuraxis, although they tend to occur in the sacrococcygeal and occipital levels.

2.2.6. Sacral Agenesis Sacral agenesis or caudal regression is a variable defect of the lumbar vertebrae, sacrum, and coccyx. The severest form is sirenomelia (mermaid deformity; not to be confused with syringomyelia described below) in which there are abnormalities of the anorectal region, urogenital system, and lower limbs—the latter consisting of a fused thigh and leg with partial or complete fusion of the feet. The caudal spinal cord is also abnormal, and the severity of its abnormality is proportional to the degree of abnormality of the vertebral column. Sacral agenesis may be combined with a presacral mass, which can include a teratoma (a tumor of embryonic origin containing cells derived from all three germ layers) or an anterior sacral meningocele 3. Defects Occurring Secondarily to Neural Tube Defects Three defects that occur secondarily to neural tube defects will now be defined: tethered cords, hydrocephalus, and the Chiari II malformation.

3.1. Tethered Cords Tethered cords may occur secondarily to an open neural tube defect or to a closed neural tube defect such as spinal lipoma, lipomyelomeningocele, or diastematomyelia. As the vertebral column grows during early childhood, the inferior end of the spinal cord (the conus medullaris) normally “ascends” within the vertebral canal. Tethered cord results when the abnormal spinal cord adheres to its meninges and prevents this ascension. Thus, the growth of the vertebral column exerts traction on the lower spinal cord and spinal nerves, causing neurological deficits.

3.2. Chiari II (Arnold Chiari) Malformation Four types of Chiari malformations are recognized. Type I malformations are characterized by minor herniation of the cerebellar tonsils. Patients with type I malformations often have hydromyelia (dilation of the central canal of the spinal cord) and syringomyelia (presence of ectopic, fluid-filled cavities within the spinal cord tissue; not to be confused with sirenomyelia described earlier). Type II malformations are more extensive, involving descent of both cerebellar tonsils and the vermis below the level of the foramen magnum. The medulla and at times the pons are also displaced below the foramen magnum, and the cervical cord is displaced caudally by the herniated tissue. Type II malformations are associated with open neural tube defects of the spinal cord, namely myeloschisis, myelomeningoceles, and meningoceles. This association suggests that Chiari II malformations occur secondarily to the open neural tube defect. Type III malformations also involve herniation of the cerebellum (and possibly medulla and pons) into the spinal canal and are associated with lower occipital/high cervical encephaloceles. Type IV malformations are rather different. In type IV malformations, most of the cerebellum is hypoplastic.

3.3. Hydrocephalus In patients with hydrocephalus, the cerebral ventricles are dilated with an excess of cerebrospinal fluid. Flow of cerebrospinal fluid from the ventricles to the subarachnoid

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space is blocked, often at the foramen of Magendie. Like the Chiari II malformation, hydrocephalus is associated with open neural tube defects, suggesting that it occurs secondarily to such defects. 4. Other Major Anomalies of the Neural Tube 4.1. Holoprosencephaly The term holoprosencephaly indicates that only a single brain ventricle, rather than paired ventricles, forms in the area that arises from the prosencephalon. Holoprosencephaly has three important clinical subclassifications: (1) alobar holoprosencephaly, the subclassification used when only one hemisphere is present; (2) semilobar holoprosencephaly, the subclassification used when there is a slight midline depression in the single hemisphere; and (3) lobar holoprosencephaly, the subclassification used when two distinct hemispheres (but with only one ventricle) are present. Holoprosencephaly, especially the alobar type, is frequently associated with cyclopia (a single midline eye).

4.2. Lissencephaly Lissencephaly—literally, smooth brain—is considered to be a defect of cell migration within the wall of the cerebral hemispheres. As a consequence, the normal histological layers of the brain do not form and gyri and sulci are absent. 5. Conclusions During the process of neurulation, the neural plate rolls up, forming a neural groove flanked laterally by neural folds, which, in turn, fuse to establish the closed neural tube. The cause of open neural tube defects is generally considered to be nonclosure of the neural tube during neurulation. However, in rare cases reopening of the closed neural tube may occur shortly after neurulation. The cause of closed neural tube defects is understood even less. Although a neural tube may form normally during neurulation, many other developmental events must occur properly to convert this simple epithelial tube into a regionally organized, complex central nervous system. Thus, many opportunities exist for development to go awry and generate neural tube defects. Overall, neural tube defects occur in about 1–8 per 1000 live births (4), but this incidence is dropping with improvements in prenatal detection of neural tube defects (e.g., with ultrasound) and with periconception supplementation of vitamins containing folic acid (5). Nevertheless, neural tube defects are still a major cause of postnatal morbidity and mortality and are responsible for significant health care costs. Continued research on mechanisms underlying neural tube defects offers hope that some day these serious developmental anomalies may be fully prevented. Acknowledgments Original work described herein from the Schoenwolf laboratory was supported by Grant Nos. NS 18112 and HD 28845 from the National Institutes of Health. References 1. Willis, R. A. (1962) The Borderland of Embryology and Pathology, 2nd ed., Butterworth, London.

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2. Norman, M. G., McGillivray, B. C., Kalousek, D. K., Hill, A., and Poskitt, K. J. (1995) Congenital Malformation of the Brain. Pathologic, Embryologic, Clinical, Radiologic and Genetic Aspects. Oxford University Press, Oxford. 3. Warkany, J. (1971) Congenital Malformations. Notes and Comments. Year Book Medical, Chicago. 4. Campbell, L. R., Dayton, D. H., and Sohal, G. S. (1986) Neural tube defects: a review of human and animal studies on the etiology of neural tube defects. Teratology 34, 171–187. 5. Czeizel, A. E. (1996) Prevention of neural tube defects. CNS Drugs 6, 399–412.