Abstracts

Rationale: Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in the TSC1 or TSC2 gene and clinically characterized by the presence of hamartomatous lesions in multiple organs including cortical tubers in the brain. Epilepsy affects approximately 85% of patients with TSC (Epilepsia 1993; 34: 651-657), although the mechanisms underlying epileptogenesis in this disease remains unknown. Seizure control and outcome after epilepsy surgery do not correlate with tuber burden (J Child Neuro 2005; 20:837-841; Neurology 2004; 62: 479-481). Cortical tubers are areas of disrupted cortical architecture thought to be due to abnormal cellular migration, proliferation, or differentiation during fetal development and are primarily considered static lesions. However, tubers can develop cystic characteristics over time, evident on neuroimaging (Pediatr Radiol 2006; 36: 498-501). It is well-known that genotype-phenotype relationships exist in TSC with more severe multi-organ disease seen in TSC2 (Am J Hum Genet 2001; 68: 64-80). The purpose of this study was to determine whether TSC genotype is predictive of the presence of cystic cortical tubers and whether the presence of these cystic lesions is predictive of the development and severity of epilepsy in TSC patients. Methods: We performed a retrospective chart review of patients seen at Massachusetts General Hospital between January 2002 and July 2007. Patients were included if they had definite clinical TSC and had brain MRI images with FLAIR, T2, and T1 sequences available for review. 173 patients were included. MRI sequences were evaluated for the presence or absence of at least one cystic cortical tuber. Cysts not associated with surrounding cortical tuber were excluded. Patient charts were then reviewed for genetic mutation, a history of epilepsy, and epilepsy refractory to more than 3 medications. Statistical analyses were performed using Fisher’s exact test. Results: 29 patients in this study had TSC1 mutations, 81 patients had TSC2 mutations, and 63 patients were either not tested or had no identified disease-associated mutations. Patients' ages ranged from 2 months to 73 years at time of brain MRI (mean = 18 years 3 months, SD = 1 year 2 months, median = 13 years 0 months). 45/81 (56%) patients with TSC2 and 6/29 (21%) patients with TSC1 had at least one cystic cortical tubers present on imaging (p=0.001, relative risk (RR) = 2.7, 95% CI 1.28-5.62). 73/79 (92%) patients with at least one cystic cortical tuber and 71/94 (76%) patients without a cystic cortical tuber had epilepsy (p=0.002, RR = 1.22, 95% CI 1.07-1.40). 63/79 (80%) patients with at least one cystic cortical tuber and 51/94 (54%) patients without a cystic cortical tuber developed refractory epilepsy (p=0.0003, RR = 1.47, 95% CI 1.18-1.83). Conclusions: Cystic cortical tubers are more prevalent in patients with TSC2 than TSC1. The presence of at least one cystic cortical tuber places a patient at significantly higher risk of developing epilepsy and severe epilepsy refractory to multiple medical treatments.