Abstracts

Rationale: New strategies have been proposed to target mitochondrial dysfunction in neurological diseases. Mitochondrial dysfunction is recognized as an important contributor to many neurodegenerative diseases, but little is known about CNS mitochondria in patients with epilepsy. Young age has been associated with increased drug treatment failure and pharmacoresistance in children. Focal cortical dysplasia (FCD) is the most common pathological abnormality associated with intractable epilepsy in children. It has been postulated that epileptogenesis in patients with FCD is caused by impaired mitochondrial energy production, and is associated with local interactions between dysmature and normal postnatal neurons (Epilepsy Behav 2006;9:219). We propose to evaluate this hypothesis in tissue resected from children following epilepsy surgery. Methods: Patients were included if they had surgery for intractable epilepsy; histopathologic confirmation of FCD based upon Palmini's criteria; electron transport chain (ETC) complex testing in resected tissue; clinical assessment by a pediatric neurologist; and age <19y. Patients were excluded if they had diagnosis of epilepsy secondary to tumor, hypoxic-ischemic injury, trauma, vascular malformation, tuberous sclerosis, Rasmussen's syndrome, or were >19y. 1° ictal onset regions were identified by extraoperative electrocorticography. ETC activities, which were tested for complex "I" (NADH dehydrogenase or CI), complex I+III [NADH-cytochrome c reductase (rotenone sensitive) or CI+III], complex "II" (succinate dehydrogenase or CII), complex II+III [succinate-cytochrome c reductase (antimycin sensitive) or CII+III], complex III (decylubiquinol-cytochrome c reductase or CIII), complex IV (cytochrome c oxidase or CIV), were determined by spectrophotometric methods for ETC complex assay in brain tissue. For statistical analysis data were stratified according to age at surgery, i.e. Group 1: <25%ile; Group 2: 25th-75%ile, and Group 3: >75%ile). Data are expressed as mean (SD). This study was approved by the IRB. Results: A total of 26 patients [age 9.4(5.1)y] met inclusion criteria, including 7 in Grp 1 (age range 0.5-5.3y), 12 in Grp 2 (range 5.9-13.2y), and 7 in Grp 3 (range 14.8-18.0y). Significant differences were found between study groups for ETC complexes CI, CII+III, CII, and CIV (Table). In addition, 12 patients had two specimens tested for ETC activities, i.e. one identified as 1° onset region and a second as 2° spread region. Comparison of ETC complex activities of paired-specimens showed that mean CIV activity was decreased (P=0.017) in the 1° onset region of 9 patients with FCD types II (Figure), but not in 3 patients with FCD type I. Conclusions: Decreased ETC complex activities are associated with younger age in children with FCD. Furthermore, data showing decreased CIV in 1° onset regions, compared with 2° spread regions, support the hypothesis that energy production is impaired in epileptogenic tissue. Mitochondrial abnormalities may be important in epileptogenesis in children with intractable epilepsy and FCD.