The natural history of epilepsy in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant, multiorgan disease with widely variable expression. TSC is estimated to occur in at least 1 in 6,000 live births, although true incidence is likely higher due to undetected mild cases (Webb & Osborne, 1995; Crino et al., 2006). Approximately 85% of patients with TSC are found to have a mutation in one of two genes, TSC1, encoding hamartin, or TSC2, encoding tuberin (Dabora et al., 2001; Sancak et al., 2005). Protein products of these genes have been shown to form a heterodimer (TSC1–TSC2 complex) that inhibits the mammalian target of rapamycin (mTOR) signaling cascade (Astrinidis & Henske, 2005; Kwiatkowski & Manning, 2005). Inadequate suppression of the mTOR pathway results in dysgenic lesions in multiple organ systems, including cortical tubers, radial glial bands, subependymal nodules, and subependymal giant cell tumor formation in the fetal and developing brain (Crino, 2004; Sarbassov et al., 2005; Sabatini, 2006). Epilepsy is the most common neurologic symptom in patients with TSC, and a significant source of morbidity and mortality (Shepherd et al., 1991; Thiele, 2004; Holmes et al., 2007). Although epilepsy is known to affect the majority of patients with TSC, reports of the prevalence of epilepsy and infantile spasms in varied, smaller TSC populations have been inconsistent (Webb et al., 1991, 1996; Roach et al., 1998; Jozwiak et al., 2000; Cross, 2005; Crino et al., 2006; Devlin et al., 2006). Furthermore, there have been few studies evaluating the natural history of epilepsy in TSC (Webb et al., 1996). In order to better characterize and understand epilepsy in TSC, we sought to describe the prevalence of epilepsy and infantile spasms in our large pediatric and adult TSC clinic. We further set out to describe in detail the natural history of epilepsy in TSC, including age of onset, frequency of multiple seizure types, evolution to refractory epilepsy, prevalence of Lennox-Gastaut syndrome, and likelihood of achieving seizure-freedom and medication-freedom. We further evaluated the relationships among epilepsy history, cognitive outcome, and genetic mutation in our patient population.