Chapter 20 Acquired, induced and secondary malformations of the developing central nervous system HARVEY B. SARNAT* University of Calgary Faculty of Medicine and Alberta Children’s Hospital, Calgary, Alberta, Canada 20.1. Introduction The terms cerebral dysgenesis or malformation of the brain generally conjure up the wide range of genetically programmed defects that affect developmental pro- cesses in embryonic and fetal life. Many nongenetic insults also can affect ontogenesis, however. Acquired malformations may be induced by parenchymal infarcts or hemorrhages during fetal life or postnatally, particu- larly in infants born prematurely, by exposure to terato- genic drugs and toxins, fetal radiation exposure, intrauterine infections, fetal hydrocephalus, trauma and maternal malnutrition. Well known specific exam- ples of these events include excessive maternal vitamin A intake in the first trimester, which can result in neural tube defects, the fetal alcohol syndrome, congenital cytomegalovirus (CMV) infection and fetal exposure to maternal antiepileptic medications. This chapter con- siders these secondary malformations of the nervous system. 20.2. Ischemic/Hypoxic infarcts in the fetal brain Despite major advances in perinatal and neonatal medicine and in obstetrics, and the recognition that many causes of cerebral palsy and epilepsy cannot be attributed to ‘birth asphyxia’, hypoxic/ischemic encephalopathy remains a major cause of neonatal neurological morbidity in full-term infants as well as in prematures and is a major contributory factor in other complications such as germinal matrix hemor- rhage. However, fetuses with primary malformations frequently present intrapartum complications not anticipated in infants born with normal brains, so birth asphyxia may be overdiagnosed in some cases or may be a secondary additional insult (Montenegro et al., 2005). Neuroblast radial migration from the subventricular zone to the neocortical plate begins at about 8 weeks gestation. More than 90% of neuroblast migration is completed by 16 weeks but additional migratory cells continue to differentiate as neurons until near term, even though most of the postmitotic neuroepithelial cells of the germinal matrix are destined to become protoplas- mic astrocytes of the cerebral cortex (Sarnat, 1987, 1992). If there is damage to the cortex, even postnatally or at maturity, resident stem cells of the subventricular zone may migrate to the cortex to become new neurons (Sundholm-Peters et al., 2005). If the fetus is subjected to a period of systemic hypotension, such as might occur in maternal shock, or abruptio placentae should occur, rendering the fetus relatively hypoxic because of the barrier to gas exchange, lesions may occur in the neona- tal brain that interfere with developmental processes. The white matter is particularly vulnerable because of its immature microcirculation, with radial end-arterioles and little collateral circulation from adjacent vessels, resulting in a relatively large territory of parenchyma supplied by each such vessel. In the same region are the radial glial fibers. Fig. 20.1 illustrates three sites where injuries to the fetal or premature neonatal brain may interrupt radial glia or cause their retraction, so that migratory cells along each fiber cannot reach their intended destination and become heterotopic neurons (Sarnat, 1994). Ischemic injury also may interfere with other processes, such as synaptogenesis and myeli- nation. *Correspondence: H. B. Sarnat MD, FRCPC, Professor of Paediatrics, Pathology (Neuropathology) and Clinical Neurosciences, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta T3B 6A8, Canada. E-mail: harvey.sarnat@calgaryhealthregion.ca, Tel: þ1-403-955-7131, Fax: þ1-403-955-2922. Handbook of Clinical Neurology, Vol. 87 (3rd series) Malformations of the Nervous System H. B. Sarnat, P. Curatolo, Editors # 2008 Elsevier B. V. All rights reserved