Original article Epileptic Disord 2003; 5: 77-91 Prenatal contributions to epilepsy: lessons from the bedside Mark S. Scher Professor of Pediatrics and Neurology, Case Western Reserve University, Division Chief Pediatric Neurology, Rainbow Babies and Children’s Hospital, Director of Pediatric Epilepsy and Sleep Programs, Director of Fetal and Neonatal Neurology Programs Received March 6, 2003; Accepted April 17, 2003 ABSTRACT − While epilepsy can present at any age, this condition often occurs because of adverse events early in life. Pathogenetic mechanisms also cause deleterious consequences to the brain during prenatal life. For the epileptologist to fully appreciate developmental epileptogenesis, one must apply an ontogenetic approach (i.e. “nature-nurture-niche”) in order to study the epileptic condition from a fetal neurology perspective. Genetic susceptibil- ity can involve pre-fertilization and post-fertilization mechanisms that dictate the timing and form of major malformations associated with specific epileptic syndromes. Maternal, fetal, and placental disease conditions also contribute to either brain malformations or injuries, depending on events during the first or second half of pregnancy. Sequential stages during prenatal brain development, from embryonic through perinatal periods, specify which gray and white matter structures may be adversely altered, with later expression of seizures in the context of motor, cognitive and behavioral deficits. Translational research from bench to bedside should consider the acquired causes of pediatric and adult epilepsies in the context of the patient’s genetic environment. KEY WORDS: epilepsy, prenatal, maternal diseases, placenta, fetus, neonate Children and adults can suffer from anomalous brain development can be epileptic conditions that are prenatal developed [4]. Such a classification in origin [1, 2]. Most investigations scheme closely reflects the matura- have focused on the genetic origins of tional sequences of brain develop- selected generalized and partial epi- ment, from neural tube closure to neu- lepsies [3]. Dramatic advances in ge- ronal differentiation and proliferation, netic markers for specific forms of epi- migration, dendritic organization and lepsy indicate that certain epilepsies synaptogenesis, neurotransmitter ela- are determined at conception, as rep- boration and myelination. resented by malformations in cortical Regressive processes incorporating development. The most severe programmed cell death (i.e. apoptosis) anomalies are structurally visible dur- and activity-dependent development, ing the embryonic and fetal stages of remodel neuronal networks in the ma- Correspondence: brain development (i.e. less than Pr Mark S. Scher, MD turing brain, accelerating during the Division of Pediatric Neurology 24 weeks after conception). third trimester, and continuing into the University Hospitals Health System Advances in magnetic resonance im- third decade of postnatal life [5, 6]. Rainbow Babies and Children’s Hospital aging techniques provide the epilep- This process of resculpting also plays a 11100 Euclid Avenue Cleveland, Ohio 44106 - 6090 USA tologist with the diagnostic means by crucial role in epileptogenesis [7-9]. E-mail: [email protected] which a more strict classification of While newer techniques utilizing Epileptic Disorders Vol. 5, No. 2, June 2003 77 Scher volumetric magnetic resonance imaging offer greater in- equivalent for every clinical scenario. Improvements in sight concerning specific changes in quantities of gray and neuroimaging techniques, particularly magnetic reso- white matter that appear during maturation [10, 11], re- nance imaging, provide a greater likelihood of detecting modeling of brain structure and function at the neural certain major anatomical markers that may be associated network or cellular levels are not readily detected by with epilepsy. However, there will always be limits of present neuroimaging techniques. resolution using either neuroimaging or neurophysiologi- Comparatively less attention has focused on pathogenetic cal monitoring with respect to anatomical and neural mechanisms leading to epileptogenesis during the perina- network disruptions in brain development, which contrib- tal stage of brain development that begins at 24 weeks ute to epilepsy. Therefore, epileptologists must continue to gestational age through to one month of postnatal life. practice accurate history-taking and clinical examinations Acquired brain injury from maternal-placental-fetal- to more fully appreciate epilepsy risk, even when test neonatal diseases can have profound effects on brain results are inconclusive. Cognizance of the prenatal stages development during this period, contributing to a spec- in brain development will help the epilepsy specialist trum of neurological sequelae, which include epilepsy, formulate a more comprehensive differential diagnosis for and cognitive and behavioral sequelae. These disease seizures which includes maternal, placental and fetal con- processes are also more prevalent in fetal/neonatal popu- tributions, while also considering postnatal events such as lations than major brain malformations such as lissen- closed head injury, encephalitis/meningitis and cardiopul- cephaly, schizencephaly or holoprosencephaly. monary arrest, which further lower the threshold for sei- Investigations over several decades have indicated that zure initiation at older ages. diseases of the mother, placenta and fetus contribute sub- Classifications concerning malformations in cortical de- stantially to developmental disorders ranging from cere- velopment have applied the sequential stages in prenatal bral palsy [12] and mental retardation [13, 14] to learning brain development to categorize generalized and focal disabilities and neurobehavioral deficits [15]. Pathoge- anomalies of the brain by magnetic resonance imaging. netic mechanisms leading to acquired brain injury during This classification scheme applies to both generalized as fetal life include chorioamnionitis, asphyxia and stroke well as localization-specific epilepsies. Barkovich et al., syndromes. These same disease processes may also con- [4] for example, described malformations that can be tribute to the epileptic condition. Our understanding of broadly classified to represent four general stages in brain epilepsy therefore must integrate prenatal mechanisms of development; brain injury into models of developmental epileptogen- 1) malformations due to abnormal neuronal/glial prolif- esis, to study how inflammatory, asphyxial and throm- eration; boocclusive conditions contribute to the genesis of vari- 2) malformations due to abnormal neuronal migration; ous epilepsies. 3) and malformations due to abnormal cortical organiza- tion; Prenatal considerations 4) malformations, not otherwise specified. Table 1 lists by the epilepsy consultant the generalized and focal/multifocal anomalies that can be identified by MRI, as later verified by neuropathology at Formulating a differential diagnosis for any medical con- the time of epilepsy surgery or on postmortem examina- dition begins with fact finding; such a strategy pertains to tion. both the pediatric and adult epilepsy patient. Consider- This neuroimaging classification scheme provides the in- ation of maternal and prenatal histories, as well as cogni- tellectual scaffolding upon which clinicians can better zance of preconceptional medical risks, family histories identify patients who have epilepsy with documented and environmental conditions add important perspectives cortical malformations. Leventer et al., [17] for example, to our understanding of the genesis of the epileptic condi- described 109 children with abnormal of cortical devel- tion. Epileptologists must frame the clinical neurological opment documented on MRI images from 8 days to profile of the patient in the context of the developmental 18 years old. Seventy-five percent of these children pre- niche or gestational maturity during which a maturational sented with seizures, an abnormal neurological examina- disorder or acquired disease process occurs which later tion being noted in less than half of this population. Almost presents as epilepsy for the patient. Historical data, clini- two-thirds exhibited developmental delay or mental retar- cal examination findings, and laboratory information must dation, and nearly 20% of the patients also had associated be placed along a timeline that considers prenatal as well non-CNS anomalies. A spectrum of cortical development as postnatal time periods when brain damage may have abnormalities included generalized, hemispheric or mul- occurred, or was exacerbated in the context of the pa- tifocal forms for 70% of patients, and involved both corti- tient’s genetic endowment [16]. cal and white matter lesions in 60%; noncortical anoma- Structural and functional descriptors of the epileptic con- lies were also noted in over two-thirds of the patients. The dition are useful and complementary, but not always incidence of various abnormalities are listed in table 1 and 78 Epileptic Disorders Vol. 5, No. 2, June 2003 Prenatal contributions to epilepsy: lessons from the bedside Table 1. Classification scheme for malfomations of cortical development*. I. Malformations due to abnormal neuronal and glial proliferation or apoptosis A. Decreased proliferation increased apoptosis: microcephalies 1. Microcephaly with normal to thin cortex 2. Microlissencephaly (extreme microcephaly with thick cortex) 3. Microcephaly with polymicrogyria/cortical