Bibliography

Aradhya S, Manning MA, Splendore A, et al: Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features, Am J Med Genet A 143A:1431–1441, 2007.

Stothard J, Tennant PW, Bell R, et al: Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis, JAMA 301:636–650, 2009.

585.1 Neural Tube Defects

Stephen L. Kinsman and Michael V. Johnston

Neural tube defects (NTDs) account for the largest proportion of congenital anomalies of the CNS and result from failure of the neural tube to close spontaneously between the 3rd and 4th wk of in utero development. Although the precise cause of NTDs remains unknown, evidence suggests that many factors, including hyperthermia, drugs (valproic acid), malnutrition, chemicals, maternal obesity or diabetes, and genetic determinants (mutations in folate-responsive or folate-dependent enzyme pathways) can adversely affect normal development of the CNS from the time of conception. In some cases, an abnormal maternal nutritional state or exposure to radiation before conception increases the likelihood of a congenital CNS malformation. The major NTDs include spina bifida occulta, meningocele, myelomeningocele, encephalocele, anencephaly, caudal regression syndrome, dermal sinus, tethered cord, syringomyelia, diastematomyelia, and lipoma involving the conus medullaris and/or filum terminale and the rare condition iniencephaly.

The human nervous system originates from the primitive ectoderm that also develops into the epidermis. The ectoderm, endoderm, and mesoderm form the three primary germ layers that are developed by the 3rd wk. The endoderm, particularly the notochordal plate and the intraembryonic mesoderm, induces the overlying ectoderm to develop the neural plate in the 3rd wk of development (Fig. 585-1A). Failure of normal induction is responsible for most of the NTDs, as well as disorders of prosencephalic development. Rapid growth of cells within the neural plate causes further invagination of the neural groove and differentiation of a conglomerate of cells, the neural crest, which migrate laterally on the surface of the neural tube (see Fig. 585-1B). The notochordal plate becomes the centrally placed notochord, which acts as a foundation around which the vertebral column ultimately develops. With formation of the vertebral column, the notochord undergoes involution and becomes the nucleus pulposus of the intervertebral disks. The neural crest cells differentiate to form the peripheral nervous system, including the spinal and autonomic ganglia and the ganglia of cranial nerves V, VII, VIII, IX, and X. In addition, the neural crest forms the leptomeninges, as well as Schwann cells, which are responsible for myelination of the peripheral nervous system. The dura is thought to arise from the paraxial mesoderm. In the region of the embryo destined to become the head, similar patterns exist. In this region, the notocord is replaced by the precordal mesoderm.

Figure 585-1 Diagrammatic illustration of the developing nervous system. A, Transverse sections of the neural plate during the 3rd wk. B, Formation of the neural groove and the neural crest. C, The neural tube is developed. D, Longitudinal drawing showing the initial closure of the neural tube in the central region. E, Cross-sectional drawing of the embryonic neural tube (primitive spinal cord).

In the 3rd wk of embryonic development, invagination of the neural groove is completed and the neural tube is formed by separation from the overlying surface ectoderm (see Fig. 585-1C). Initial closure of the neural tube is accomplished in the area corresponding to the future junction of the spinal cord and medulla and moves rapidly both caudally and rostrally. For a brief period, the neural tube is open at both ends, and the neural canal communicates freely with the amniotic cavity (see Fig. 585-1D). Failure of closure of the neural tube allows excretion of fetal substances (α-fetoprotein [AFP], acetylcholinesterase) into the amniotic fluid, serving as biochemical markers for a NTD. Prenatal screening of maternal serum for AFP in the 16th-18th wk of gestation is an effective method for identifying pregnancies at risk for fetuses with NTDs in utero. Normally, the rostral end of the neural tube closes on the 23rd day and the caudal neuropore closes by a process of secondary neurulation by the 27th day of development, before the time that many women realize they are pregnant.

The embryonic neural tube consists of three zones: ventricular, mantle, and marginal (see Fig. 585-1E). The ependymal layer consists of pluripotential, pseudostratified, columnar neuroepithelial cells. Specific neuroepithelial cells differentiate into primitive neurons or neuroblasts that form the mantle layer. The marginal zone is formed from cells in the outer layer of the neuroepithelium, which ultimately becomes the white matter. Glioblasts, which act as the primitive supportive cells of the CNS, also arise from the neuroepithelial cells in the ependymal zone. They migrate to the mantle and marginal zones and become future astrocytes and oligodendrocytes. The importance of other pathways of progenitor cell generation and migration are also being elucidated. It is likely that microglia originate from mesenchymal cells at a later stage of fetal development when blood vessels begin to penetrate the developing nervous system.

585.2 Spina Bifida Occulta (Occult Spinal Dysraphism)

Stephen L. Kinsman and Michael V. Johnston

Spina bifida occulta is a common anomaly consisting of a midline defect of the vertebral bodies without protrusion of the spinal cord or meninges. Most patients are asymptomatic and lack neurologic signs, and the condition is usually of no consequence. Some consider the term spina bifida occulta to denote merely a posterior vertebral body fusion defect. This simple defect does not have an associated spinal cord malformation. Other clinically more significant forms of this closed spinal cord malformation are more correctly termed occult spinal dysraphism. In most of these cases, there are cutaneous manifestations such as a hemangioma, discoloration of the skin, pit, lump, dermal sinus, or hairy patch (Fig. 585-2). A spine roentgenogram in simple spina bifida occulta shows a defect in closure of the posterior vertebral arches and laminae, typically involving L5 and S1; there is no abnormality of the meninges, spinal cord, or nerve roots. Occult spinal dysraphism is often associated with more significant developmental abnormalities of the spinal cord, including syringomyelia, diastematomyelia, and/or a tethered cord. A spine roentgenogram in these cases might show bone defects or may be normal. All cases of occult spinal dysraphism are best investigated with MRI (Fig. 585-3). Initial screening in the neonate may include ultrasonography.

Figure 585-2 Clinical aspects of congenital median lumbosacral cutaneous lesions. A, Midline sacral hemangioma in a patient with an occult lipomyelomeningocele. B, Capillary malformation with a subtle patch of hypertrichosis in a patient with a dermal sinus. C, Human tail with underlying lipoma in an infant with lipomyelomeningocele. D, Midline area of hypertrichosis (faun tail) overlying a patch of hyperpigmentation.

(A-C, From Kos L, Drolet BA: Developmental abnormalities. In Eichenfield LF, Frieden IJ, Esterly NB, editors: Neonatal dermatology, ed 2, Philadelphia, 2008, Saunders. D, From Spine and spinal cord: developmental disorders. In Schapira A, editor: Neurology and clinical neuroscience, Philadelphia, 2007, Mosby.)

Figure 585-3 Clinical features and imaging findings associated with occult spinal dysraphism. A, Spinal lipoma in a 2 mo old girl. There is a skin-covered lumbosacral mass above the intergluteal cleft in the midline, surrounded by overgrowing hair. B, Sagittal T1-weighted image shows huge intradural lipoma, merging with the conus medullaris superiorly. C, Lipoma and central dermal sinus. D and E, Dermal sinus with dermoid, 8 yr old girl. Slightly parasagittal T2-weighted image shows sacral dermal sinus coursing obliquely downward in subcutaneous fat (arrow) (D). Midsagittal T2-weighted image shows huge dermoid in the thecal sac (arrowheads), extending upward to the tip of the conus medullaris (E). The mass gives a slightly lower signal than cerebrospinal fluid and is outlined by a thin low-signal rim.

(A, From Rossi A: Spinal dysraphism. In Raybaud C, Naidich TP, editors: Pediatric neuroimaging, Philadelphia, Elsevier, in press. B, D, and E, From Rossi A, Biancheri R, Cama A, et al: Imaging in spine and spinal cord malformations, Eur J Radiol 50(2):177–200, 2004, Fig 9a. C, From Jaiswal AK, Garg A, Mahapatra AK: Spinal ossifying lipoma, J Clin Neurosci 12:714–717, 2005, Fig 1.)

A dermoid sinus usually forms a small skin opening, which leads into a narrow duct, sometimes indicated by protruding hairs, a hairy patch, or a vascular nevus. Dermoid sinuses occur in the midline at the sites where meningoceles or encephaloceles can occur: the lumbosacral region or occiput, respectively. Dermoid sinus tracts can pass through the dura, acting as a conduit for the spread of infection. Recurrent meningitis of occult origin should prompt careful examination for a small sinus tract in the posterior midline region, including the back of the head. Lower back sinuses are usually above the gluteal fold and are directed cephalad. Tethered spinal cord syndrome may also be an associated problem. Diastematomyelia commonly has bony abnormalities that require surgical intervention along with untethering of the spinal cord.

An approach to imaging of the spine in patients with cutaneous lesions is noted in Table 585-1.

585.3 Meningocele

Stephen L. Kinsman and Michael V. Johnston

A meningocele is formed when the meninges herniate through a defect in the posterior vertebral arches or the anterior sacrum. The spinal cord is usually normal and assumes a normal position in the spinal canal, although there may be tethering, syringomyelia, or diastematomyelia. A fluctuant midline mass that might transilluminate occurs along the vertebral column, usually in the lower back. Most meningoceles are well covered with skin and pose no immediate threat to the patient. Careful neurologic examination is mandatory. Orthopedic and urologic examination should also be considered. In asymptomatic children with normal neurologic findings and full-thickness skin covering the meningocele, surgery may be delayed or sometimes not performed.

Before surgical correction of the defect, the patient must be thoroughly examined with the use of plain x-rays, ultrasonography, and MRI to determine the extent of neural tissue involvement, if any, and associated anomalies, including diastematomyelia, lipoma, and possible clinically significant tethered spinal cord. Urologic evaluation, usually including cystometrogram (CMG), identifies children with neurogenic bladder who are at risk for renal deterioration. Patients with leaking cerebrospinal fluid (CSF) or a thin skin covering should undergo immediate surgical treatment to prevent meningitis. A CT scan or MRI of the head is recommended for children with a meningocele because of the association with hydrocephalus in some cases. An anterior meningocele projects into the pelvis through a defect in the sacrum. Symptoms of constipation and bladder dysfunction develop due to the increasing size of the lesion. Female patients might have associated anomalies of the genital tract, including a rectovaginal fistula and vaginal septa. Plain x-rays demonstrate a defect in the sacrum, and CT scanning or MRI outlines the extent of the meningocele and any associated anomalies.

585.6 Anencephaly

Stephen L. Kinsman and Michael V. Johnston

An anencephalic infant presents a distinctive appearance with a large defect of the calvarium, meninges, and scalp associated with a rudimentary brain, which results from failure of closure of the rostral neuropore, the opening of the anterior neural tube. The primitive brain consists of portions of connective tissue, vessels, and neuroglia. The cerebral hemispheres and cerebellum are usually absent, and only a residue of the brainstem can be identified. The pituitary gland is hypoplastic, and the spinal cord pyramidal tracts are missing owing to the absence of the cerebral cortex. Additional anomalies include folding of the ears, cleft palate, and congenital heart defects in 10-20% of cases. Most anencephalic infants die within several days of birth.

The incidence of anencephaly approximates 1/1,000 live births; the greatest incidence is in Ireland, Wales, and Northern China. The recurrence risk is approximately 4% and increases to 10% if a couple has had two previously affected pregnancies. Many factors in addition to genetics have been implicated as the cause of anencephaly, including low socioeconomic status, nutritional and vitamin deficiencies, and a large number of environmental and toxic factors. It is very likely that several noxious stimuli interact on a genetically susceptible host to produce anencephaly. The incidence of anencephaly has been decreasing in the past 2 decades. Approximately 50% of cases of anencephaly have associated polyhydramnios. Couples who have had an anencephalic infant should have successive pregnancies monitored, including amniocentesis, determination of AFP levels, and ultrasound examination between the 14th and 16th wk of gestation.