Managing and understanding epilepsy in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs in about 1:5,800 individuals (Crino et al., 2006). Approximately two-thirds of cases of TSC are thought to be sporadic, and in families with multiple affected individuals there often is wide phenotypic variability (Lyczkowski et al., 2007). Two genes have been associated with TSC, TSC1 and TSC2, both components of the mammalian target of rapamycin (mTOR) signaling pathway, and a disease-causing mutation can be identified in one of these two genes in 85% of individuals diagnosed with TSC (Crino et al., 2006). Brain involvement occurs in approximately 95% of individuals with TSC; the skin and the brain are the two most frequently affected organs. Neurologic symptoms are common in TSC, as epilepsy occurs in 80–90%, cognitive impairment in 50%, autism spectrum disorders in up to 40% and neurobehavioral disorders in >60% of individuals with TSC. These symptoms are attributable to the neuroanatomic abnormalities seen in TSC, which include cortical tubers, subependymal nodules, and subependymal giant cell tumors. Of the individuals with TSC who develop epilepsy, almost 70% have seizure onset during the first year of life, and approximately one-third of children with TSC will develop infantile spasms. In our center, epilepsy in TSC proved refractory to medical treatment in approximately two-thirds of individuals. The presence of refractory epilepsy and infantile spasms in TSC has been shown to be significantly associated with cognitive impairment, autism spectrum disorders, and psychiatric disorders, including self injurious behaviors (O’Callaghan et al., 2004; Winterkorn et al., 2007; Staley et al., 2008). Infantile spasms occur more commonly in those with TSC2 mutations, consistent with the finding that TSC2 mutations are usually associated with a more severe phenotype than TSC1 mutations (Dabora et al., 2001; Muzykewicz et al., 2009). However, in our TSC center, the prevalence of epilepsy, refractory epilepsy, and epilepsy remission appears similar among those with an identified mutation in TSC1 or TSC2 as well as those with no identified mutation. Antiepileptic drug (AED) therapy remains the first-line treatment of epilepsy in TSC. Because epilepsy in TSC is partial in onset, most available AEDs could be effective. Although there is anecdotal experience on the efficacy of some AEDs, there are no controlled comparison trials with the exception of the treatment of infantile spasms. Vigabatrin has been shown to be superior to other therapies in the treatment of infantile spasms in infants with TSC (Mackay et al., 2004). Dietary therapy as well as vagus nerve stimulation (VNS) are effective in treating epilepsy in TSC (Parain et al., 2001; Kossoff et al., 2005; Major et al., 2008). Epilepsy surgery has also been shown to have an important role in refractory epilepsy in TSC, with several retrospective series showing a significant reduction in seizure activity and often seizure freedom following resection of an identified epileptogenic region (Jarrar et al., 2004; Weiner et al., 2006; Jansen et al., 2007). It is not known if modulators of the mTOR pathway will be effective in treating epilepsy in TSC, and although results in animal models suggest that they may play a role (Zeng et al., 2008), experience with these medications in human epilepsy is limited. The pathophysiology of epilepsy in TSC is not well understood. It is uncertain if cortical tubers, which represent areas of dysgenesis, are themselves epileptogenic, or if instead they are irritating to the neighboring “normal” neurons and thereby lead to epileptogenesis. Recent electrocorticography (ECoG) studies have suggested that the tubers themselves may be electrically “silent,” lending support to the concept that at least in some cases the tubers themselves do not cause epilepsy (Major et al., 2009). It is also unclear if all tubers are “created equal,” or if some are more epileptogenic than others, and if so, why. Most individuals with TSC have multiple tubers involving both hemispheres and all lobes, yet the success of epilepsy surgery in this population argues that not all tubers are associated with epilepsy. Recently, the presence and location of cyst-like tubers have been shown to be associated with epilepsy in TSC, although the pathogenesis and overall significance of these cyst-like changes is unclear (Chu-Shore et al., 2009). In addition, many individuals with TSC and epilepsy have normal brain magnetic resonance imaging (MRI) studies, yet have epilepsy. This further raises the question as to the relationship of cortical tubers and epilepsy in TSC, and suggests that at least in some cases epileptogenicity is instead related to more diffuse and/or subtle cortical or subcortical abnormalities (Tavazoie et al., 2005). It is also unclear if there are factors that put particular individuals with TSC at risk for developing epilepsy, or at particular risk for developing infantile spasms. Possible factors that could influence the development of seizures as well as outcomes in TSC include genotype (TSC1 or TSC2, as well as location and type of mutation), tuber location, tuber burden, and environmental factors. Close surveillance of at-risk populations, for example, infants with multiple cardiac rhabdomyomas, hypopigmented macules, or a family history of TSC, may allow identification of biomarkers suggestive of and perhaps specific for the development of epilepsy in TSC. Such biomarkers could be useful in early identification of those with TSC who are at risk for developing infantile spasms or refractory epilepsy. Our understanding of epilepsy in TSC will hopefully continue to improve, both with a better understanding of the cellular mechanisms involved and characterization of any biomarkers that can be identified. As it does, there will likely be a role for prophylactic treatment of those at high risk. It is uncertain if any of our current treatment options would be ideal in this setting; but many new medications are under development, including both antiepileptic medications as well as modulators of the mTOR pathway. The author has served as a paid consultant for Lundbeck Pharmaceuticals.