Abstracts

Rationale: Recent studies have suggested that the inflammatory response encountered in cerebral lesions commonly associated with intractable seizures, such as cortical dysplasias or glioneuronal tumors, may play a role in epileptogenesis. The present study aims to further expand this knowledge by deciphering morphological correlates of microglial activation in a variety of brain specimens of children with refractory epilepsy.Methods: Formalin-fixed/paraffin-embedded brain surgical resection specimens from 12 patients with refractory epilepsy were used in this study (ages 10±7 years). They were representative of epileptogenic lesions from patients with tuberous sclerosis (TS) (n=2), focal cortical dysplasia (FCD, types Ia-IIb; n=4), low grade neuroepithelial tumors (ganglioglioma, n=4 and grade II diffuse astrocytomas, n=2) and corresponding age-matched control autopsy brain samples from patients without history of seizures (n=5 ). The distribution of CD68 and HLA-DR immunoreactivity was evaluated by immunohistochemistry using monoclonal antibodies. The labeling index (LI) was expressed as the number of immunolabeled CD68 or HLA-DR inflammatory cells of the monocyte-macrophage lineage counted in 10, non-overlapping high power/40x fields. The LI was compared among all groups (ANOVA, SPSS).Results: All epileptogenic lesions were characterized by the presence of CD68+/HLA-DR+ cells of the monocyte-macrophage lineage. Tissue samples from tubers exhibited the highest LI of CD-68+/HLA-DR+ cells, followed by FCD and intratumoral/peritumoral portions of neoplasms (Table 1). Morphologically, CD68+/HLA-DR+ cells in tubers and in FCD exhibited three distribution patterns: 1) Neuropil: Variously prominent aggregates of rod-shaped and/or ameboid microglia with thick/stout cell processes; 2) Perisomatic: Spindle/rod-shaped microglia encroaching upon the cell bodies of large (cytomegalic), dysmorphic and/or balloon neurons especially in heterotopic/heterotaxic foci; and 3) Perivascular: Varying accumulations of mononuclear inflammatory cells with a monocyte/macrophage morphology in the Virchow-Robin spaces. In peritumoral areas, CD68+/HLA-DR+ cells lacked perisomatic distribution.Conclusions: Among lesions causing refractory epilepsy, an unusually robust increase in CD68+/HLA-DR+ cells, morphologically consistent with activated microglia, is encountered in epileptogenic tubers of TS. A similar trend is detected in FCD cases. The marked variation of values in the latter -leading to a high SD- is attributed to the heterogeneity and architectural complexity of these dysplastic lesions spanning the entire spectrum of FCD types (Ia-IIb). The morphological features of microglial activation in brain areas infiltrated by tumor are distinct from those encountered in tubers and FCD. It is unclear whether this inflammatory response is functionally related to epilepsy, either as a cause of epileptogenesis or as a consequence of activation following seizure activity. Future studies are warranted to clarify this dilemma.