Equally important as the cause of the CNS insult is the timing. By 3 weeks gestation, the primitive neural tube has begun to develop. CNS growth and maturation continues throughout the embryonic period (0–8 weeks), the fetal period (9–38 weeks), infancy, and well into late childhood. The characteristics of the malformation depend on the timing of the CNS developmental disruption although some insults, such as genetic mutations, may disrupt development over extended periods causing a variety of defects. In addition, multiple abnormalities may occur from a single primary deficit in early morphogenesis causing a cascading process of secondary and tertiary errors in morphogenesis. Insults that affect the CNS from week 3 to 6 usually produce major morphological abnormalities while insults occurring later may produce more subtle or localized dysfunction. Thus, it is possible to determine the latest time in gestation a malformation could occur but not the earliest. Table 17.2 presents the gestational timing of some neurodevelopmental milestones.

The basic steps of brain and spinal cord development are as follows: neurulation, neuronal and glial proliferation, migration, differentiation of neurons with axonal, dendritic and synaptic development, programmed cell death, and myelination . During neurulation, primitive cells destined to become neurons originate close to the neuroepithelium of the neural tube. These cells begin rapidly replicating by the fourth week producing cells that differentiate into bipolar neuroblasts. Some radial glia appear early and serve as scaffolding for neurons to migrate to the marginal layer, which will become the gray matter of the cerebral cortex. Ultimately the radial glia divide and become astrocytes. The migration of these post-mitotic neurons occurs in a precise orderly manner that is largely completed by the end of the fifth month but does continue at a slow rate until birth. This process appears to produce an excess number of neurons that are subsequently pruned to the appropriate number by a process of programmed cell death called apoptosis. Somehow neurons that do not establish correct neuronal connections by late pregnancy are triggered to die. Apoptosis does not elicit inflammation or gliosis, so there is no histologic evidence of their premature death.

Many terms describe abnormal brain tissue. The term dysplasia refers to abnormal cellular organization resulting in structural and functional consequences. Dysplasias may be localized (such as a hemangioma) or generalized, affecting a variety of structures from widespread distribution of the tissue defect. Heterotopias are portions of an organ displaced to an abnormal site within the same organ of origin, such as nodules of gray matter located in deep white matter due to incomplete neuronal migration. A hamartoma is a portion of tissue at the proper site but is architecturally disorganized, such as a focus of abnormal cortical lamination due to disorganization of pyramidal neurons. Malformation refers to a structural defect arising from a localized error in morphogenesis and may contain one or more of the features described above. Deformation occurs when normally formed tissue is secondarily damaged.