Cause Matters: A Neuropathological Challenge to Human Epilepsies

Epilepsy is the most common neurological disorder, affecting 1% of the population worldwide. However, epilepsy cannot be regarded as one specific disease entity as it includes many different etiologies, that is, single genetic point mutations, metabolic dysfunction or acquired brain lesions. Indeed, any brain can generate seizures and any lesion may lower a brain’s seizure threshold. A major challenge is to identify reliable factors and biomarkers predicting a given patient’s risk for epilepsy onset and progression, for cognitive and psychiatric comorbidities, and for response to available treatment. Hence, the clinicopathological spectrum of epilepsies is broad and it remains another challenging issue to understand how a genetic or acquired brain lesion will generate seizures by recruiting and synchronizing large epileptogenic networks. Indeed, the causality between a detectable brain lesion and the patient’s epilepsy is difficult to prove. In order to promote joint efforts between basic and clinical research, the International League Against Epilepsy (ILAE) has proposed new concepts for the classification of seizure disorders in 2010 (2). This most recent classification system follows a long-standing and often controversial dialog about the impact of etiology, dating back to the early work of Sir John Russel Reynolds (1861), John Hughlings Jackson (1870), William Gowers (1881), Henry Gastaud (1953) or William Lennox (1960; for review, see (7)). In all of these classification schemes, circumscribed brain lesions were recognized and classified as symptomatic (synonyms: organic or structural) epilepsy with a highly precipitating risk to develop spontaneous seizures. Our survey of 5392 surgical epilepsy brain tissue specimens collected at the European Epilepsy Brain Bank (founded by the European EpiCure consortium) confirms the broad spectrum of structural brain lesions resected in patients with drug-resistant localized epilepsies (Table 1). Indeed, the list is similar to those categories of epilepsy-associated brain lesions proposed by Walter Dandy early in 1932 (4). Nevertheless, our knowledge about underlying molecular and pathophysiological pathways of epileptogenesis remains largely unknown. In the last few decades, neuropathology has not always been acknowledgeable as a leading discipline addressing the impact of etiology on seizure disorders. More recently, this notion has changed and evoked a “neuropathology renaissance. ” The opportunity to specify clinicopathologic subtypes that allows prediction of the patient’s risk of either favorable or unfavorable seizure control following surgery will make the difference, and many epilepsy surgery programs appreciate an advanced neuropathology workup of resected human brain tissue. A prominent example of such joint efforts promoting the notion that “cause matters” is the ILAE’s first consensus classification system for focal cortical dysplasias (3). According to this proposal, neuropathology assessment of surgical epilepsy specimens and reports should apply consensus terminologies and should follow standardized protocols. These efforts will be highlighted by this Brain Pathology Mini-Symposium reviewing the neuropathologic impact of brain lesions in the scenario of drug-resistant, focal epilepsies. Each article will no only review the state-of-the-art histopathological diagnosis, but also refer to most recent attempts to identify clinically relevant phenotypes and subtypes predicting etiology and/or differences in postsurgical outcome. A survey of the European Epilepsy Brain Bank indicates hippocampal sclerosis as the single most frequent brain lesion. Blümcke, Coras, Miyata and Özkara will summarize histopathological findings in patients suffering from mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS), and characterize four distinct clinicopathological subtypes. Different patterns of pyramidal cell loss make a difference and correlative studies suggest unfavorable atypical variants with respect to postsurgical seizure control. Granule cell loss is another hallmark of the disease. It was shown, however, to relate with memory impairment rather than predicting postsurgical seizure control. This pattern recognition may present a basis for an international consensus classification system in the near future. It may also be translated into clinical perspectives if high-field magnetic resonance imaging (MRI) or other imaging tools will be able to detect subfield specific hippocampal lesion patterns prior to surgery. Notwithstanding, we cannot prove causality between hippocampal sclerosis and mesial temporal lobe epilepsy as neuronal cell loss will secondarily be aggravated by Brain Pathology ISSN 1015-6305