Inflammation and Viruses in Epilepsy

Epilepsy is one of the most common neurological disorders worldwide (prevalence approximately 0.5%). Epilepsy exists of various etiologies which share the presence of recurrent unprovoked epileptic seizures. Epilepsies with structural abnormalities such as mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS), focal cortical dysplasias (FCD) and tumors usually give rise to drug-resistant epilepsy (Blumcke and Spreafico, 2012). An emerging group are the immune-mediated epilepsies (Bauer et al., 2012) Here, seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS). The index condition for the study of epilepsies associated with chronic inflammatory processes is Rasmussen Encephalitis (RE) in which both seizure generation and inflammation occur in only one of two hemispheres. The role of inflammation in these epileptic disorders, especially in the induction of seizures, is not completely clear. Evidence in experimental models of epilepsy suggests that molecules from the innate immune system are important in the generation of seizures. Viruses are suggested to be an underlying cause of epilepsy. The aim of this project is to investigate brains from patients with epileptic disorders and identify inflammatory mechanisms and/or viral persistence. We will investigate in detail the adaptive immune response in a variety of epileptic disorders (RE, FCDs, MTLE/HS, glio-neuronal tumours) and compare this with various controls. This will be done by immunohistochemistry and quantitative analysis of immune cells in the CNS. In a second part we will investigate the innate immune system. This will be done by immunohistochemistry and by microarray analysis of specific areas and stages of the different epileptic disorders. The third part of this project deals with the identification of viruses in these brains. By staining for heat shock proteins 40 and 70 we expect to find virus-infected cells in RE. Microdissection-based harvesting of such potentially infected cells and their analysis by microarrays with virus-specific sequences will be used to identify a specific virus. Finally, we will use electron microscopical analysis to locate virus particles in RE, MTLE and FCD IIb to confirm the presence of these viruses in specific cells.

Epilepsy is one of the most common neurological group of disorders. An emerging group of epilepsies are the immune-mediated epilepsies. Here, seizures develop after infiltration of immune cells or antibodies in the central nervous system (CNS). Rasmussen encephalitis is such a type of epilepsy that is especially interesting. RE is a fascinating condition since both seizures and the prominent inflammation only are seen in one half of the brain. Like other epilepsies, such as temporal lobe epilepsy which is suspected to be associated with the human herpes virus-6 (HHV-6), RE is thought of as a possible virus encephalitis. So far however no particular virus could be associated with this disease. Besides the possible presence of a virus, RE also shows an increased infiltration of T lymphocytes in the brain. This also can be seen in other epileptic diseases, although in most the infiltration of T cells is much less than in RE. In this project we tried to find out which cells and which molecules from the immune system are important in various types of epilepsy. Encephalitis with antibodies directed against leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is a new type of epilepsy. In this epilepsy this antibody destroys nerve cells in the hippocampus. Interestingly this disease also can be found in cats. In these cats we could show that inflammatory infiltrates also could be found outside the hippocampus. Antibody leakage from the blood vessels into the brain on the other hand was restricted to the hippocampus and surrounding areas. These brain areas were affected by loss of junctions within the blood vessels. These findings also may be important for human LGI1 encephalitis thereby gaining new knowledge on this disease. Another important finding was that in Rasmussen encephalitis, normal looking brain areas contain small clusters of so-called microglial cells that are important as local cells of the immune system in the brain. These cells showed upregulation of molecules involved in detection of viruses and thus this finding again is new evidence that a local infection might be responsible for the inflammation and local seizures in this disease. We extended our work on T cell infiltration in other epileptic disorders such as temporal lobe epilepsy. We compared the T cell distribution in the hippocampus of patients with temporal lobe epilepsy due to various reasons such as febrile seizures, the presence of a tumor (ganglioglioma) or patients who developed seizures after a viral infection. Here our results suggest that T cell infiltration in the brains of patients with temporal lobe epilepsy might be related to neurodegeneration rather than to the epilepsy and its seizures.