Abstracts

RATIONALE: The cellular mechanisms underlying focal human neocortical epilepsy are poorly understood and it is not known if the mechanisms underlying epileptogenesis induced by tumors or vascular malformations are similar. Studies using neocortical seizure models indicate that the tissue adjacent to the lesion rather than the lesions themselves exhibit cellular hyperexcitability and thus may be critical in seizure generation. We have begun to address the question of whether these lesions have different mechanisms of epileptogenesis by examining the electrophysiological properties of neurons neighboring tumors and cerebral cavernous malformations (CM) using intracellular recordings from neurons maintained in the slice preparation.
METHODS: Slices were prepared from neocortical tissue adjacent to either CMs (n=4) or tumors (n=12) using standard techniques. The tumors were usually low grade gliomas. Intracellular neuronal recordings were obtained and the degree of spontaneous activity and the responses to orthodromic stimulation were examined.
RESULTS: Neocortical neurons adjacent to CMs had a greater propensity to show large, complex spontaneous synaptic events than neurons neighboring tumors (50% vs 4.7% of cells and 75% and 16% of patients respectively, p[lt] 0.002, by cell; p[lt] 0.03, by patient). These spontaneous events were often large enough to trigger action potentials from rest, were seen in upper and lower layer neurons and had frequencies between 0.5 and 3 Hz. Both spontaneous excitatory and inhibitory events were noted. By contrast, in tissue adjacent to tumors, low amplitude spontaneous excitatory activity predominated. Neurons neighboring CMs also exhibited more excitable responses to synaptic stimulation, with multiple action potentials riding on prolonged EPSPs being evoked in 71% of these cells, versus 32% of cells from the tumor group, p [lt]0.05. It was interesting to note that the tissue obtained from the only CM patient in which neither large spontaneous events or evoked bursts were seen was over 3 cm from the lesion; in contrast, in the other patients, the tissue was approximately 2 cm from the edge of the lesion. We did not observe a comparable effect in the tumor material. Comparable data were seen in three hippocampal cases.
CONCLUSIONS: These data show that neurons surrounding epileptogenic CMs display a greater degree of evoked and spontaneous synaptic excitability than tissue adjacent to tumors. These data suggest that CMs may induce seizure activity via a different mechanism(s) than glial tumors. Moreover, the data also suggest that proximity to the lesion is associated with the degree to which these physiological abnormalities are seen.
Support: NIH Grants NS38287 and AG00795 to PRP