Central Nervous System (CNS)

Abstract

The human brain undergoes several stages of intrauterine and postnatal development, each with specific and nonspecific vulnerabilities to developmental anomalies. In primary and secondary neurulation, there is normal development of the brain and spinal cord. The formation of the brain and spinal cord rostral to the lumbar segments is called primary neurulation. It occurs during the third and fourth weeks of gestation and begins at 18 days with the induction, by the notochord and chordal mesoderm, of the neuroectodermal plate derived from the dorsal midline of the ectoderm. Its lateral margins invaginate and close dorsally to form the neural tube, which gives rise to the CNS. The anterior end closes at about 24 days, and the posterior end, approximately at the lumbosacral level, closes at about 26 days. The surrounding mesoderm gives rise to the dura and the skull and vertebrae.

Appendix 1: Defects of Closure of the Neural Tube

Malformation	Mechanism	Causes	Time	Comments
Craniorachischisistotalis	Total neurulation failure	Multifactorial	20–22 days gestation	Most cases abort spontaneously, 75 % stillborn
Anencephaly	Failure of anterior neural tube closure	Multifactorial, genetic and environmental influences	24 days gestation
Myeloschisis	Failure of posterior neural tube closure	Multifactorial	24 days	Often associated with anomalous formation of skull
Encephalocele	Disorder of neurulation involving anterior neural tube closure	Multifactorial (genetic [i.e., Meckel syndrome] and environmental [i.e., maternal hyperthermia])	26 days gestation	Occipital 70–80 % associated with hydrocephalus, Arnold-Chiari malformations, agenesis of corpus callosum, migration disorders
Meningomyelocele	Disorder of neurulation involving posterior neural tube closure	Multifactorial (genetic and environmental influences [i.e., folic acid])	26–28 days gestation	80 % lesions occur in lumbar area; commonly associated with hydrocephalus, Arnold-Chiari malformation, and migrational disturbances
Migrational disorders
Schizencephaly	Complete agenesis of a portion of the germinative zone	Destructive lesions involving germinative zones and migrational neurons; mutation in homeobox EMX2, cytomegalovirus	Beginning of migrational events (third month of gestation)	Neurodevelopmental disorders: Motor 77–86 %
				seizures 60–72 %
				cognitive 24–100 %
Lissencephaly: Pachygyria type I	Diffuse cellular layer contains neurons that never arrived at their final destination	Isolated (linked to chromosome 17 or X-chromosome [e.g., Miller-Dieker syndrome])	No later than the third or fourth month of gestation	Normocephalic and hypotonia at birth, later hypertonia, seizures (commonly infantile spasms, Lennox-Gastaut syndrome)
Lissencephaly type II	Autosomal recessive (deficiency in merosin laminin α-2, and other proteins)	Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy	Third to fourth month of gestation	Macrocephaly; retinal malformation, congenital muscular dystrophy, cerebellar malformations
Polymicrogyria (layered)	Probably postmigrational – “classic” related to a destructive process; postnatal evolution in preterm babies	Vascular lesions, e.g., laminar neuronal necrosis; infections, e.g., cytomegalovirus, toxoplasmosis	Postmigrational, 20–24 weeks of gestation and beyond	Associated with postnatal hypoxic events. Focal lesions are associated with seizures and learning disabilities
Disorders of neuronal proliferation
Microcephaly vera	Normal number of cortical neurons, but neuronal complement of each column is decreased	Genetic; teratogenic (irradiation, alcohol, cocaine, infections); sporadic	Approximately 18 weeks of gestation	Mental retardation, seizures
Radial microbrain	Disturbance in the number of proliferative units (reduction in the number but normal number of cells per unit)	Genetic autosomal recessive	Second month of gestation	Die in first months of life
Macrocephaly	Prolongation of time of cell proliferation or excessive rate of proliferation	Sporadic, isolated familiar (autosomal dominant or recessive); associated with growth disturbances (cerebral gigantism, Beckwith syndrome)	During third to fourth month of gestation	Isolated familiar cases without neurologic deficits, other clinical manifestations depending on etiology
		Neurocutaneous syndromes (neurofibromatosis, tuberous sclerosis, Sturge-Weber)
Hemi-megalencephaly	Focal disorder of cell proliferation also affecting neuronal migration and organization	Sporadic, linear nevus sebaceous syndrome	Third to fourth month of gestation	Severe seizure disorder usually in neonatal period; severe ­developmental delay
Disturbance in neuronal myelinization
Cerebral white matter hypoplasia	Marked deficiency in cerebral white matter, most conspicuous in centrum ovale	Unknown	Third trimester and postnatal life	Nonprogressive clinical syndrome of spastic quadriparesis, seizures, and cognitive deficits
Amino and organic acidopathies	Vacuolization of white matter that evolves into deficient myelinization	Phenylketonuria, homocystinuria, maple syrup urine disease, nonketotic hyperglycinemia	Third trimester of pregnancy and postnatal life	Alternations in organizational processes are also present in these disorders
Hypothyroidism	Alterations in oligodendroglial proliferation-differentiation and myelinization	Deficiency in thyroxine and tyrosine	First 2 years of life	Amount of thyroxine and tyrosine in first 2 years of life is correlated with intellectual outcome
Undernutrition	Reduction of 20–30 % in cerebrosides and 15–20 % in plasmalogens	Poor feeding in the first months and years of life	From birth	Severe undernutrition to 4 months of age results in a permanent reduction in IQ
	Normal myelin composition
Prematurity	Sequelae of periventricular leukomalacia or other insult associated with prematurity	Hypomyelinization, loss and destruction of oligodendrocytes	Third trimester and postnatal	Quantitative volumetric MRI has delineated the decrease of myelin in preterm babies

1. MRI magnetic resonance imaging
2. From: Acosta M, Gallo V, Batshaw ML. Brain development and the ontogeny of developmental disabilities. In: Barness LA, editor-in-chief. Advances in pediatrics. vol. 49. St. Louis: Mosby; 2002, with permission