Congenital Malformations of the Central Nervous System

Normal Prosencephalic Development

The prosencephalon refers to the future forebrain, which includes the telencephalon and the diencephalon; these structures give rise to the cerebral hemispheres, thalamus, and hypothalamus. The prosencephalon develops after the closure of the anterior neuropore, through processes that induce the bifurcation of the rostral extent of the fluid-filled neural tube ( Fig. 53.1 ) to form the right and left forebrain structures. During the fifth and sixth weeks of development, the structure of the forebrain is defined by cleavage along three major planes. As the anterior neuropore is closing, the first major event is the formation of the optic vesicles and nasal placodes, separated along the horizontal plane. When the embryo has reached a length of about 5 mm, both anterior and posterior neuropores have closed, isolating the developing ventricular system from the amniotic fluid. The retinal and lens placodes also develop at this time. In the hindbrain, the cerebellum begins to form, along with somatic and visceral efferent nuclei, the common afferent tract, and the ganglia for most of the cranial nerves. At about day 32 of gestation, when the embryo is 5 to 7 mm long, the forebrain divides in the sagittal plane to give rise to the paired structures. Specific areas, including the hypothalamic, amygdala, hippocampal, and olfactory regions, are identifiable at this time. The third major event in forebrain development occurs shortly thereafter when the forebrain divides in the coronal plane. This event separates the telencephalon from the diencephalon, defining the epithalamus, subthalamus, and hypothalamus. During the remainder of the second and third months of gestation, multiple midline structures form, including the corpus callosum, anterior and hippocampal commissures, optic nerves, optic chiasm, and hypothalamus.

Aprosencephaly and Atelencephaly

Aprosencephaly and atelencephaly are two rare and very severe cerebral malformations. In aprosencephaly, neither telencephalic nor diencephalic structures develop. In atelencephaly, there remains a rudimentary prosencephalon. Craniofacial abnormalities associated with this condition are secondary to deformation brought on by the absence of the telencephalon, rather than true malformation. These disorders may result from possible autosomal recessive inheritance versus an abnormality of chromosome 13. Aprosencephaly/atelencephaly has also been reported in a family with pathogenic variants in the SIX3 gene, which has also been associated with HPE. Typically, these are diagnosed prenatally by ultrasound and fetal magnetic resonance imaging (MRI). Although considered “lethal” malformations, it is important for the neonatologist to be prepared for infants with severe malformations to live longer than expected and even go home from the hospital.

Holoprosencephaly

HPE represents a spectrum of defects in forebrain development and is the most common brain malformation, although most affected fetuses are miscarried early in gestation. HPE represents a variable degree of incomplete separation of the prosencephalon along one or more of its three major planes during the third and fourth weeks of gestation (discussed earlier). The DeMyer classification scheme groups the degree of separation as “alobar,” “semilobar,” and “lobar” as well as a milder middle interhemispheric variant subtype, also referred to as syntelencephaly ; however, HPE can be difficult to classify in a given patient. In alobar HPE ( Fig. 53.2 ), a single anterior ventricle is contained within a holosphere with complete lack of separation of the prosencephalon. Alobar defects may be classified by fetal imaging findings. Depending on the severity of the defect, other midline structures such as olfactory bulbs/tracts, the corpus callosum, the anterior commissure, and the optic nerves may be affected. In addition, midline deep structures such as the basal ganglia, hypothalamus, and thalamic structures are fused, and vascular malformations may also be present. The milder semilobar and lobar forms have distinct hemispheres and the presence of at least a portion of the corpus callosum. In “semilobar” HPE, the frontal lobes are more than 50% fused, and the thalami and hypothalamus may also be fused. “Lobar” HPE is associated with the fissure along almost the entire midline, separation, or near separation, of the thalami and absence of the CSP. A middle hemispheric variant has been described in which the posterior, frontal, and parietal lobes fail to separate, with an absence of the body of the corpus callosum. Typically, patients with the middle interhemispheric variant are not identified in the neonatal period unless the variant was diagnosed prenatally. Finally, a septo-preoptic type has been suggested, where the nonseparation is restricted to the septal and preoptic areas.

Agenesis of the Corpus Callosum

The corpus callosum consists of approximately 190 million axons and is formed by a complex, multistep process that involves midline patterning, cellular proliferation, migration, and axonal growth. Initial formation of the corpus callosum proceeds over 11 weeks or so and is mediated by multiple gene networks. Development continues through adolescence as these connections are refined. Genetic as well as environmental factors affect callosal formation.

ACC results in abnormal gyration of the medial portion of each hemisphere, eversion of the cingulate gyri, and sulcation perpendicular to the long axis of the hemisphere. The external angles of the lateral ventricle are oriented parallel and upward, and the fornices are widely separated. If present, a useful distinguishing feature is Probst bundles ( Fig. 53.3 ), which are fiber bundles that run parallel to the ventricle in an anterior-to-posterior direction. ACC can be partial, more often involving loss of posterior segments.

ACC often occurs in association with other structural abnormalities. These may be minor, such as cysts or lipomas (see Fig. 53.3 ), or more severe, such as heterotopia, polymicrogyria (PMG), microcephaly, abnormal sulcation, commissural and white matter abnormalities, and malformations of the posterior fossa.

Epidemiology and Etiology

The prevalence of ACC ranges from 0.5 in 10,000 in the general population to 600 in 10,000 in children with neurodevelopmental disabilities. ACC can also be associated with prenatal infections, vascular accidents, and teratogen effects. Infection results in a thinner corpus callosum with a typical rostral-to-caudal extent and is a rare cause of isolated ACC. Ethanol exposure has the strongest association with ACC, which was reported in 7% of children with fetal alcohol syndrome in one series.

ACC is a feature of hundreds of different disorders, and all modes of inheritance have been observed. Glass et al. (2008) found that callosal anomalies were associated with a chromosomal abnormality 17% of the time, commonly aneuploidy (chromosomes 13, 18, and 21). ACC may be associated with either inherited or de novo copy number variants, some overlapping with those found in patients with autism. ACC is also a primary feature of several important disorders, such as Mowat–Wilson, Aicardi, acrocallosal syndromes, L1CAM -related spastic paraplegia, and X-linked lissencephaly with ACC and ambiguous genitalia. Given the number of genetic syndromes associated with ACC, some authors have suggested a subdivision of groups based on the associated conditions (craniofacial, metabolic, ocular, ciliopathies), which aids in the diagnostic evaluation of these patients.

Prenatally, fetal MRI at 20 to 22 weeks’ gestation maximizes the identification of additional cerebral findings when pregnancy decision-making is still an option. Earlier MRI scans yield more false-negative results and miss structural changes. Additional diagnostic options include genetic (chromosomal microarray, cell-free fetal DNA) and infectious (serologic tests, polymerase chain reaction testing on amniotic fluid) disease testing. Given the challenges with accurate prenatal diagnosis, newborns should be evaluated by brain MRI shortly after birth and by subspecialty consultations (neurology, ophthalmology, genetics, developmental pediatrics, audiology). Laboratory testing (chromosome microarray, DNA sequencing, metabolic testing) should be considered, depending on the examination and MRI findings. Surveillance for neurodevelopmental issues, visual impairment, and pituitary insufficiency is recommended.

Septo-Optic Dysplasia

Classic SOD is the triad of the absence of the septum pellucidum, optic nerve hypoplasia, and pituitary dysfunction. The diagnosis of SOD is made when two or more features of the triad are present ; 30% of patients have all three features. SOD is a clinically and etiologically diverse group of disorders and overlaps with isolated optic nerve hypoplasia. This diversity makes it difficult to provide counseling about prognosis and associated medical issues.

Absent Cavum Septi Pellucidi

The presence of the CSP is a normal finding on ultrasonography and MRI of fetuses and premature infants. This normal finding represents a fluid-filled space between the lamellae of the septi pellucidi, which typically fuse as the fetal brain matures. The absence of the CSP in fetuses and premature infants may be associated with neuroanatomic anomalies. It may be an isolated finding ( Fig. 53.4 ), but MRI is recommended for further evaluation. In addition, a larger than expected CSP width should prompt a detailed ultrasound evaluation as this anomaly can be seen in fetuses with aneuploidy.