Congenital Malformations of the Central Nervous System

Neural Tube Defects: Dysraphic Disorders Malformation of Prosencephalon:

Holoprosencephaly Malformations of Cerebral Hemispheres Malformations of the Midline Structures and

Ventricles Malformations of the Cerebellum Malformations of the Brainstem Disorders of Brain Weight Meningeal and Vascular Anomalies Phakomatoses: Ectomesodermal Dysgenetic

Syndromes Congenital and Neonatal Hydrocephalus Chromosomal Disorders

Congenital malformations of the central nervous system (CNS) constitute one-third of all congenital malformations and account for 75% of fetal deaths and 40% of deaths during the first year of life. Malformations have many causes: genetic mutations, chromosomal aberrations, maternal disease states, and maternal exposure to teratogens (Table 13.1). Some malformations are associated with hereditary metabolic diseases (Table 13.2). Genetic defects, chromosomal aberrations, and known teratogens are responsible for about 25% of malformations. The etiology of the rest remains unknown. Malformations of the CNS are often multiple, some are features of particular syndromes, and others are associated with malformations of various organ systems.

The development of the CNS depends on genetically regulated sequences of interdependent events: simplisti-cally—induction, proliferation, differentiation, and migration. When these sequences are disrupted, certain events fail to occur or take an abnormal course: These result in malformations. The gestational age when a disruption occurs is critical in determining the pattern of a malformation; that is, different etiologies can produce the same kind of malformation by acting at the same gestational age (Table 13.3). The earlier the disruption, the more severe the malformation. A malformation may also occur secondarily as a result of a destructive process, commonly a hypoxic-ischemic insult or an infection. When these occur at a very early stage of development, they are not traceable, because the immature nervous tissue is not able to react and repair: Macrophage reaction does not occur until the second table 13.1.

Major Etiologies of CNS Malformations table 13.1.

Major Etiologies of CNS Malformations

Chromosomal alterations

Teratogenic drugs

Genetic mutations


Maternal diseases






Alcohol consumption


Illicit substance abuse

Ionizing radiation


Metabolic diseases

Industrial chemical

Diabetes mellitus



Malformations Associated with Hereditary Metabolic Diseases

Peroxisomal disorders

Cortical dysplasia Congenital disorder of glycosylation

Pontocerebellar hypoplasia/atrophy Nonketotic hyperglycinemia Agenesis of corpus callosum Cortical dysplasia Cerebellar hypoplasia trimester, and astrocytic repair only begins during the second half of the gestational period. Thus, differentiation between primary and secondary malformation is difficult; still, it is important for genetic counseling because primary malformations carry the risk of recurrence.

Most fetuses with major malformations are stillborn or die during the neonatal period. Those who survive for some time are seriously incapacitated, ranging from unresponsiveness throughout their entire life to profound mental retardation, muteness, severe motor deficits, and seizures. Minor anomalies manifest with mental retardation, behavioral changes, motor disorders, and seizures.

The antenatal detection of major malformations is possible with maternal ultrasound examination. Chromosomal aberrations are diagnosed by the karyotyping of cultured amniocytes performed from 12 weeks' gestational age. DNA studies for the diagnosis of inherited diseases are carried out on chorionic villi from as early table 13.3.

Approximate Timing of Major Developmental Events table 13.3.

Approximate Timing of Major Developmental Events

Major Events

Gestational Age

Development of neural plate

18 days

Development of neural tube

23 days

Closure of neural tube

23-26 days

Development of primary vesicles and

cleavage of prosencephalon appears

4-8 weeks

Cerebellar primordium

4 weeks

Cerebellar development completed

24 weeks

Beginning of migration of neuroblasts

4 weeks

Completion of migration

20 weeks

Corpus callosum develops

12 weeks

Opening of foramen Magendie

12 weeks

Opening of foramina Luschka

16 weeks

Sylvian fissure appears

14 weeks

Rolandic and calcarine fissures appear

24-26 weeks

Secondary and tertiary sulci appear

7-9 months

as 8 weeks gestational age. Magnetic resonance imaging (MRI) and computed tomography (CT) scan make the early postnatal diagnosis of a number of malformations possible.


The nervous system develops from the neural plate, a derivative of the ectodermal layer of the embryonic disc. The neural plate folds into the neural tube, which closes by the third gestational week (Fig. 13.1). The anterior part develops into the brain, and the posterior part develops into the spinal cord. Disorders of closure of the neural tube and its mesenchymal coverings—the future meninges, skull, and spinal column—constitute the group of neural tube defects (NTDs) or dysraphic disorders, the commonest malformations of the nervous system. The prevalence is estimated at 0.5 to 2 per 1,000 births. NTDs are associated with genetic risk factors, maternal diabetes mellitus, and the use of the anticon-vulsants valproic acid and carbamazepine. The malformations may involve either the brain or the spinal cord, or both, with their coverings. Diagnosis, early in pregnancy, is possible using ultrasound and by determining the a-fetoprotein in the amniotic fluid or maternal serum. Elevated levels support the diagnosis.

Neural Plate

figure 13.1

Schematic drawing of neural tube development.

Neural Tube figure 13.1

Schematic drawing of neural tube development.

figure 13.3

Occipital meningoencephalocele in a newborn. A. Lateral view of the head. The skin-covered encephalocele is almost as large as the head. B. A deep indentation on the dorsal aspects of the cerebral hemispheres is caused by the margin of the bony defect. The encephalocele contains the occipital lobes, portions of the brainstem, and the cerebellum.

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