Abstracts

Rationale: Gamma knife (GK) radiosurgery can be effective treatment for several types of human epilepsy, including seizures associated with hypothalamic hamartoma (HH). The neuropathological consequences of GK on HH are unknown, as are the cellular mechanisms responsible for efficacy.Methods: We utilized surgically resected HH tissue from patients with treatment-resistant epilepsy, divided into two cohorts: those without (Group I; n=19) and with (Group II; n=10) a prior history of gamma knife radiosurgery (median dose 16 Gy to the 50% isodose margin). Techniques included thick-section stereology for total nucleated and total neuron cell counts, and thin-section immunohistochemistry. Normal human hypothalamus derived from age-matched autopsy material was used as control tissue for selected immunostains.Results: Previously untreated HH tissue shows decreased neuron abundance with increasing lesion size. GK radiosurgery results in decreased total cell density (p<0.02), and likely results in decreased total neuron density in a dose-dependent manner (p=0.06). Group II HH tissue has significantly more 1) reactive gliosis, 2) thickened capillary endothelium, and 3) microglial activation after scoring by a neuropathologist who was blinded to GK treatment history. Degenerative features, including karyorrhexis and pyknotic nuclei, were observed infrequently in Group II, but were absent in Group I HH tissue. Conclusions: Non-necrotizing doses of GK radiosurgery decrease cell density in human HH tissue, likely by initiating programmed cell death. We hypothesize that the loss of HH neurons contributes to a decrease in GABAA-mediated excitation in HH tissue.