Neuropathology and Classification of Cortical Malformations: Where Do They Develop?

During development, a spatially and sequentially ordered sequence of migratory events is necessary for generation of a normal cerebral cortex (1). Although we are still learning about the detailed processes that result in the mature cortex, it is evident that both intrinsic and environmental factors contribute to corticogenesis. Disturbances in individual developmental programs may lead to a multitude of pathogenetically relevant alterations, ranging from severe generalized brain malformations to local and subtle disturbance of cortical structure. Modern advances in high-resolution imaging techniques, particularly magnetic resonance imaging (MRI), have substantially improved the in vivo identification of a variety of malformations of cortical development (MCDs) in patients with epilepsy (2–4). Several types of partial epilepsies that had previously been defined as cryptogenetic are now increasingly recognized as secondary to cortical malformations. As a consequence, subsequent correlations between imaging and electroclinical data have enlarged the number of patients that emerge as candidates for surgical treatment. Surgical removal of the epileptogenic area, for seizure control in pharmacoresistant epilepsy patients, also provides investigators with access to biopsy tissue samples for neuropathologic and molecular biologic analyses. The histopathologic appearance and immunophenotype of MCDs have supported the hypothesis that impaired proliferation, migration, and differentiation of neural precursor cells play a pathogenetic role in some forms of epilepsy. In recent years, our knowledge has substantially increased about distinct molecular, pathogenetically relevant features of epileptic brain (5). These insights have come from the generation and analysis of various animal models for MCDs (6), as well as from the examination of immediate clinicoelectrographic correlations (7,8), and have in turn improved surgical strategies (9,10) for management of the various types of MCDs associated with epilepsy. Based on these advances, several classification systems for MCDs have been proposed, aiming to provide a basis for improved communication at clinical, electrographic, neuropathologic, and basic science levels of research on individual MCD entities. A variety of classification schemes with different levels of complexity have addressed specific aspects of these MCD-related disorders (2,3). A highly comprehensive classification with a neuroradiologic focus was proposed by Barkovich et al. (3), which further integrates embryologic, neuropathologic, and genetic characteristics. Individual types of MCDs are organized within a framework of compromised ontogenic events. The underlying hypothesis is that types of MCDs are caused by abnormalities at specific stages of cortical development, including neuroglial proliferation and differentiation, neuronal migration, and postmigratory cortical organization. Other groups have developed well-defined histopathologically based classification systems and introduced individual nomenclatures for cortical malformations (11–13). The sporadically occurring focal lesions with occasionally subtle microscopic alterations constitute a particular neuropathologic challenge. Detailed studies of focal cortical dysplasias (FCDs) suggest that distinct histologic subtypes exist. According to a widely applied comprehensive classification (11), cortical dysplasia may be categorized according to increasing histoand cytologic disruption as “mild malformation of cortical development” (mMCD); FCD type Ia (isolated architectural abnormalities); FCD type Ib (with additional “immature” or giant neurons); FCD type IIa (with additional dysmorphic neurons); and FCD type IIb (with additional balloon cells). Certainly, patients with FCDs manifest with substantial variability of type or severity of epilepsy. The distinct clinicopathologic and molecular bases of this variability, and the therapeutic implications of such neuropathologic subtyping approaches, are intensely debated. Several types of cortical malformations are frequently located within the temporal lobe. In approximately two thirds of pharmacoresistant patients with temporal lobe epilepsy (TLE), the hippocampal formation is affected