GENERAL PRINCIPLES

Congenital abnormalities are among the leading causes of infant morbidity and mortality and fetal loss. The leading sites of congenital abnormalities are the skeleton, skin, and brain. Congenital abnormalities of the CNS can be divided into developmental malformations and disruptions. Developmental malformations result from flawed development of the brain. This may be caused by chromosomal abnormalities and single gene defects that alter the blueprint of the brain, or by imbalances of factors that control gene expression during development. Gene defects may be in the germline or may develop after conception by spontaneous somatic mutation or from the action of harmful physical or chemical agents. Some malformations are caused by multiple genetic and environmental factors acting in concert (multifactorial etiology). Disruptions result from destruction of the normally developed (or developing) brain and are caused by environmental or intrinsic factors such as fetal infection, exposure of the fetus to harmful chemicals, radiation, and fetal hypoxia. For instance, holoprosencephaly, a condition in which the forebrain is not divided into two hemispheres, is a malformation. Hydranencephaly, in which massive destruction reduces the hemispheres into fluid-filled sacs, is a disruption. The line between malformation and disruption is sometimes blurred because an extrinsic factor (e.g. radiation) may cause direct physical injury but also damage genes that are important for development. Developmental malformations are usually either midline or bilateral and symmetric and do not show gliosis. On the other hand, most disruptions are focal and asymmetric and are associated with gliosis and other reactive changes such as inflammation, phagocytosis, and calcification. However, these reactions may not be present if the disruption occurs in the first trimester, when the brain is immature. For these reasons, it is hard, sometimes, to distinguish malformation from disruption. This distinction carries important implications. Malformations carry a recurrence risk that can be calculated. Disruptions do not recur, unless the exposure recurs or continues.

Congenital CMV: microcephaly Congenital CMV: calcifications and hydrocephalus

Exposure to teratogens, viral infections, etc., can occur throughout pregnancy. The timing of exposure is critical for both, malformations and disruptions. The earlier the exposure, the more severe the defect. For instance, fetal cytomegalovirus (CMV) infection before midgestation causes microcephaly and polymicrogyria. CMV infection in the third trimester causes an encephalitis, similar to postnatal CMV encephalitis. The most critical period for malformations and disruptions is the third to eighth week of gestation, during which the brain and most organs take form.

NEURAL TUBE DEFECTS

The neural plate appears on the 17th day of gestation as a thickening of the embryonic ectoderm over the notochord. Thisneuroectoderm gives rise to the central nervous system. On day 18, the neural plate invaginates along the midline, forming theneural groove with the neural folds on either side. By the end of the third gestational week, the neural folds fuse forming theneural tube. Fusion begins at the hindbrian-cervical junction and the hindbrain-forebrain junction and proceeds rostrally and caudally from these two points. Then, the anterior and posterior ends (neuropores) close, completing the process. The cranial end of the neural tube closes by 24 days and the caudal by 25-26 days. Then, the neural tube is covered dorsally by mesenchyme that forms the vertebral ardhes and skull. Closure of the vertebral arches is completed at 11 weeks of gestation. Defective closure of the neural tube results in neural tube defects (NTDs). Depending on the point of the defect NTDs may affect the brain (anencephaly, encephalocele) or spinal cord (spina bifida).

The most severe NTD, craniorachischisis, is due to defective closure of the hindbrain-cervical junction. The conus medullaris, cauda equina, and filum terminale develop by a different process from a solid rod of progentor cells, distal to the spinal cord proper. During development also, the spinal column elongates more than the spinal cord, such that spinal cord levels end up higher than their corresponding vertebral levels. Abnormalities of this caudal portion of the spinal structures cause the tethered cord syndrome.

Exencephaly

Anencephaly

Anencephaly

In anencephaly, the brain initially protrudes through a defect in the cranial vault (exencephaly) and is gradually destroyed because of mechanical injury and vascular disruption. Eventually, all that is left is a small, vascular mass of disorganized neural tissue (cerebrovasculosa) mixed with choroid plexus. The eyes evaginate from the forebrain before it is destroyed and are preserved. The cranial vault is either absent or collapses over the base of the skull. Damage of the

hypothalamus results in adrenal hypoplasia. Anencephaly is incompatible with survival.

Myelomeningocele

Craniorachischisis

Spina bifida is a set of malformations of the spinal cord caused by failure of closure of the neural tube and lack of fusion of the vertebral arches, soft tissues, and skin that cover the back. The lesion is usually in the lumbosacral area but sometimes it can be more extensive and may involve the entire spinal cord. In its mildest form, spina bifida occulta, the vertebral arches are absent, but there is a hairy patch of skin over the defect. The spinal cord may be normal or the filum terminale may be tethered to subcutaneous tissue. Meningocele is a bulge in the lumbosacral area consisting of a meningeal sac protruding through the bone defect. Inmeningomyelocele, the sac contains malformed spinal cord tissue. In severe cases, there is no sac at all, and neural tissue from the open neural plate lies on the dorsal surface of the fetus. Anencephaly is often accompanied by spina bifida.

Encephalocele

Encephalocele is a protrusion of brain through a defect of the skull, usually in the occipital area. The protruding part is destroyed because of mechanical disruption and ischemia. The intracranial part of the brain around the defect is malformed and disrupted. Large occipital encephaloceles are incompatible with life because of damage of the brainstem. NTDs are the most common congenital abnormalities of the CNS and, overall, the second most common type of congenital abnormality after congenital heart disease. They are a significant cause of fetal loss. Live-born babies with myelomeningoceles may have paralysis of the legs and loss of bladder and bowel function. Open defects allow entry of bacteria into the CNS. The same thing happens if the skin covering the meningomyelocele becomes necrotic and infected. Some meningomyeloceles are a component of a more complex malformation, the Chiari II malformation, which includes hydrocephalus and abnormalities of the posterior fossa contents. The tethered cord syndrome (TCS) is a frequent accompaniment of meningmyelocele and other malformations of the lower spine and spinal cord. In the TCS, the conus medullaris is pulled lower than the L2 vertebra or the L1-L2 disc

space. This traction causes low back pain, scoliosis, lower extremity weakness and sensory loss, and bowel and bladder dysfunction. Neural tube defects can be detected in utero by determination of alpha-fetoprotein (AFP) and acetylcholinesterase in theamniotic fluid and maternal blood. Alpha- fetoprotein, a circulating fetal protein produced by the liver, peaks at 12-14 weeks of gestation and subsequently declines. AFP leaks from the fetus into the amniotic fluid through exposed capillaries of the NTD. This results in persistently high levels of AFP in the amniotic fluid and in the maternal blood. Elevated AFP is also seen in other lesions where fetal capillaries are exposed to the amniotic fluid such as omphalocele and sacrococcygeal teratoma. Acetylcholinesterase leaks directly from exposed neural tissue into the amniotic fluid. NTDs develop during the third to fourth week of gestation and are due to a combination of genetic and environmental causes (multifactorial). The genetic causes are largely unknown. Two polymorphisms of the folate dependent enzyme 5,10-Methylenetetrahydrofolate reductrase (MTHFR), MTHFR C677T and MTHFR A1298C, are associated with an increased risk for NTDs. Environmental causes include diabetes mellitus and the antiepileptic drug valproate. Administration of 0.4 mg of folic acid in the period from 4 weeks before to 8 weeks after conception significantly reduces the occurrence of NTDs. The mechanism of action of folic acid in preventing NTDs is not known. Women who have children with NTDs are not overtly folate deficient. However, the rapidly dividing cells of the neural tube probably require a large amount of folate for DNA synthesis. Supply of folate may be inadequate because of gene defects that result in subtle abnormalities of folate metabolism.

HYDROCEPHALUS
Hydrocephalus is dilatation of the cerebral ventricles. This dilatation results from a variety of causes, the common denominator of which is obstruction of CSF circulation. Approximately 600-700 ml of CSF is produced daily by the choroid plexuses. From the lateral ventricles, CSF enters the third ventricle through the foramina of Monro and then flows into the fourth ventricle through the aqueduct. It exits from the fourth ventricle into the subarachnoid space through the foramina of Luschka and Magendie. It bathes the spinal cord and flows over the cerebral convexities to the arachnoid villi through which it is absorbed into the venous circulation. Hydrocephalus may result from the following causes:

Hypersecretion of CSF: choroid plexus papilloma Obstructive hydrocephalus

Obstruction of the foramina of Monro (colloid cyst, tuberous sclerosis). Obstruction of the third ventricle (craniopharyngioma, pilocytic astrocytoma, germ cell tumors). Obstruction of the aqueduct (aqueductal stenosis or atresia, posterior fossa tumors). Obstruction of the foramina of Luschka or impairment of flow from the fourth ventricle (Chiari malformation, Dandy- Walker malformation, meningitis, subarachnoid hemorrhage, posterior fossa tumors). Fibrosis of the subarachnoid space (meningitis, subarachnoid hemorrhage, meningeal dissemination of tumors), obliteration of the subarachnoid space by glioneuronal heterotopias in the Walker-Warburg syndrome. Defective filtration of CSF: postulated for low-pressure hydrocephalus. Hydrocephalus ex vacuo: dilatation of the cerebral ventricles due to loss of brain tissue. This is a common sequel of wasting brain diseases (leukodystrophies, multiple sclerosis, multiple strokes, Alzheimer's disease, Huntington's disease, etc.). Idiopathic external hydrocephalus: a condition characterized by increased CSF volume and expansion of the subarachnoid space without ventricular dilatation, brain atrophy, intracranisl hypertension, or other pathology. This entity is common in infants and causes a large head and rapid growth of the head. It is not accompanied by neurological abnormality and usually resolves without treatment (benign macrocrania). It is probably due to immaturity of the arachnoid villi.
Hydrocephalus per se is not a malformation, but a deformation due to increased pressure in the ventricles. As the above list shows, some forms of it are congenital and others develop later in life. The most common congenital forms of hydrocephalus are those that are associated with the Chiari malformation, various aqueductal lesions, and the Dandy-Walker malformation (see further on).