Microdysgenesis: Historical roots of an important concept in epilepsy Burkhard S. Kasper a, * , Bernard S. Chang b , Ekkehard M. Kasper c a Epilepsy Center, Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany b Comprehensive Epilepsy Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA c Division of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA article info Article history: Received 11 March 2009 Revised 17 March 2009 Accepted 18 March 2009 Available online 24 April 2009 Keywords: Epilepsy Pathology Microdysgenesis Dysplasia History abstract Microdysgenesis (MD) is a term used to refer to subtle brain dysplasia based on structural tissue characteristics seen exclusively under the microscope. Although MD is often referred to within the field of modern epileptology, the term and its implications have actually evolved over a long period in neurol- ogy, starting in the late 19th century. This article undertakes a careful evaluation of original publications in the epilepsy literature and demonstrates that the concept of MD is anchored within a set of papers written from 1890 to 1930 and their contemporaneous reception in classic neuropsychiatric handbooks. Both the text of these early publications and the development of the MD concept are examined and illustrated. This perspective provides insight into historical scientific views of epilepsy as a mental disease that was thought to be dependent largely on hereditary or developmental factors. Ó 2009 Elsevier Inc. All rights reserved. The morbid anatomy of epilepsy is confessedly an obscure question, if we confine our attention to those seizures in which coarse brain dis- ease and naked-eye changes are not appreciable. W. Bevan Lewis, 1889 1. Introduction Microdysgenesis (MD) is a term used to refer to pathological brain findings that are generally interpreted as congenital and dys- plastic in nature and are exclusively detectable by microscopic examination. MD and other related terms such as mild cortical dys- plasia [1], minor dysgenetic changes [2], glioneuronal hamartia [3], mild glioneuronal heterotopias [4], microscopic cortical dysplasia [5], architectural dysplasia [6] , and mild malformations of cortical development [7] are usually found in the epilepsy literature. The spectrum of MD encompasses a broad range of microscopic tissue findings, each of them interpreted as a sign of mild brain maldevel- opment (Fig. 1). The pathophysiological significance of MD is a matter of long- standing and ongoing controversy [8–13]. Much of this relates to the lack of commonly accepted diagnostic criteria and the diverse terminology of dysplastic lesions, notably in patients lacking unequivocal imaging findings. This has expanded the spectrum of tissue features presumed to be dysplastic and has led to an impre- cise delineation of malformations of cortical development (MCD) at the tissue level. Although some authors do not use MD as an independent diagnostic category, instead integrating its features into the normal range of cerebral microarchitecture [14], others have suggested that MD is its own entity within the range of MCD [7,15,16]. According to current consensus [7,17], selected tis- sue characteristics within the MD spectrum, for example, increased counts of molecular layer or white matter neurons, are included in the classification of mild cortical dysplastic lesions. Further com- plicating matters, studies correlating MD findings to clinical parameters have not revealed consistent results (discussed in: [11,18]). Despite these uncertainties, the concept of MD still plays a key role in important current theories of epilepsy pathogenesis: First, MD has been postulated as a substrate for the development of epi- lepsy-associated glioneuronal neoplasias [19]. The description of dysplastic features next to tumoral lesions [20] and evidence for common genetic mechanisms in both dysplasias and neoplasias [21] seem to support this notion. Second, MD is often felt to be a ‘‘dysplastic susceptibility factor” contributing to the pathogenesis of hippocampal sclerosis (HS) [12,22]. In this scenario, the dyspla- sia represents the inborn prerequisite for the brain to develop HS after a ‘‘second hit,” for example, a febrile convulsion. Support for this assumption comes from reports of dual pathology, that is, HS and signs of dysplasia [23,24] and animal data including experi- mentally induced MCD, which were shown to lower the threshold for hyperthermia-induced seizures, for example [25]. Third, a ‘‘pen- umbra of microdysgenesis”, encompassing regions surrounding larger malformative lesions that are not obviously abnormal on imaging, has been hypothesized to account for the worse surgical 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.03.026 * Corresponding author. Fax: +49 9131 8536469. E-mail address: burkhard.kasper@uk-erlangen.de (B.S. Kasper). Epilepsy & Behavior 15 (2009) 146–153 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh