Abstracts

Rationale: Synaptic vesicle protein 2A (SV2A), a membrane glycoprotein present in synaptic vesicles of neurons and endocrine cells, has been identified as the binding site for the anti-epileptic drug levetiracetam. Expression of SV2A in brain tumors is thought to correlate with epileptogenicity and response to levetiracetam in patients with epilepsy. The peritumoral tissue is of particular interest for its contribution to the generation, maintenance and propagation of seizure activity in epilepsy-associated tumors. We aimed to investigate the expression and cellular distribution of SV2A in surgical specimens of brain tumors and in the perilesional cortex from patients with or without chronic medically intractable epilepsy. Methods: Immunohistochemistry with an anti SV2A antibody was performed on surgically removed tumor tissue of patients with glial (30 glioblastoma multiforme, 5 grade III astrocytoma, 8 grade III oligodendroglioma, 4 grade II astrocytoma, 4 grade II oligodendroglioma) and glioneuronal (6 ganglioglioma (GG), 6 dysembryoplastic neuroepithelial tumors (DNT)) brain tumors, as well as on peritumoral (n=31) and control (n=10) cortical specimens. Results: Immunohistochemistry in control neocortical tissue specimens demonstrated strong and diffuse SV2A immunoreactivity of the neuropil, with punctate labeling over the soma and dendrites of neurons throughout all cortical layers. SV2A was co-localized with the presynaptic marker synaptophysin. Similar distribution of SV2A staining was observed in the peritumoral cortical specimens from patients with or without epilepsy. Modest SV2A immunoreactivity was observed within the tumor area, particularly within glial tumors. There was little evidence of SV2A expression in astroglial and oligodendroglial tumor cells. Glioneuronal tumors displayed variable SV2A neuropil staining. In GG strong SV2A immunoreactivity was present along the dysplastic neuronal cell borders and processes (perisomatic synapses). In both GG and DNT SV2A immunoreactivity was occasionally observed within the neuronal perikarya. Conclusions: The pattern of SV2A immunoreactivity in the peritumoral regions of glial tumor patients with chronic epilepsy suggests that treatment with levetiracetam could be effective in case of epilepsy refractory to traditional anti-epileptic drugs. The distinct pattern of SV2A immunoreactivity in glioneural tumors suggests a redistribution of the SV2A protein. How this may affect the epileptogenicity and the effectiveness of levetiracetam needs to be further investigated. This work was supported by the National Epilepsy Fund of The Netherlands.