Cerebral glucose hypometabolism is associated with mitochondrial dysfunction in patients with intractable epilepsy and cortical dysplasia.

Abstract

Metabolic imaging studies, such as positron emission tomography (PET), allow for an assessment of physiologic functioning of the brain, and [(18)F]fluoro-2-deoxyglucose (FDG)-PET is now a commonly used technique in presurgical epilepsy evaluations. Focal interictal decreases in glucose consumption are often but inconsistently concordant with the ictal onset area, and the underlying mechanisms are poorly understood. The current study tests the hypothesis that areas of glucose hypometabolism, determined by FDG-PET, are associated with mitochondrial dysfunction in patients with medically intractable epilepsy associated with isolated focal cortical dysplasia (FCD). Measures of electron transport chain (ETC) functioning and mitochondrial abnormalities (ETC complex biochemistry, protein kinase B subtype 1 (Akt1), glial fibrillary acidic protein (GFAP)) were assessed in surgical resection specimens that had hypometabolic abnormalities and those that were normal on FDG-PET. Determination of FDG-PET abnormalities was based on coregistration of statistical parametric mapping (SPM) results with postsurgical images. Twenty-two patients (11 male, 11 female; mean age at the time of surgery 10.5 ± 4.4 years), with pathologically confirmed FCD, were included in this retrospective review. Complex IV function was found to be significantly reduced in areas of hypometabolism (p = 0.014), whereas there was a trend toward a significant reduction in complex II and III function in areas of hypometabolism (p = 0.08, p = 0.059, respectively). These decreases were independent of cortical dysplasia severity (p = 0.321) and other clinical epilepsy measures. This study suggests an association between glucose hypometabolism and reduced mitochondrial complex IV functioning, which is independent of the degree of cortical dysplasia. This supports the role of cellular energy failure as a potential mechanism for intractable epilepsy.