Abstracts

Rationale: An 11 year old girl inherited Tuberous sclerosis (TSC) from her father and Neurofibromatosis type 1 (NF1) from her mother.Methods: At 5 years of age, she developed seizures characterized by staring and atonic falls to the ground. Examination showed right eye proptosis from a stable optic glioma and neurocutaneous lesions consistent with TSC and NF1. Her initial electroencephalogram showed left frontal and anterior temporal spikes and sharp waves as well as intermittent focal temporal slowing. She was treated with carbamazepine but continued to have breakthrough seizures as well as new seizures with rhythmic head movements and eye deviation. She progressed to trials of valproate, levetiracetam, lamotrigine and clonazepam at therapeutic levels with no decrease in seizure frequency. At 7 years of age, she was started on felbamate and weaned to monotherapy on which she has remained seizure free with no adverse clinical or laboratory effects.Results: Of the neurocutaneous syndromes, TSC, the most common, has a 78% prevalence of epilepsy. NF1, the second most common, has a 3-12% prevalence of epilepsy.[1] Both NF1 and TSC in a single patient is expected to occur in only one out of 27 million people at the genotype level.[2] Both TSC and NF1 have been shown to signal through the mammalian target of rapamycin (mTOR) pathway which leads to phosphorylation of downstream targets that drive protein synthesis and cell proliferation. This pathway has been linked to epileptogenesis in that mTOR overactivation could alter synaptic plasticity or affect neurotransmitter and ion channel expression.[3] Specifically, the mTOR pathway is noted to be involved in N-methyl-D-aspartate (NMDA) receptor-dependent dendritic GFP synthesis in neuron cultures and NMDA induction of synaptogenesis in rats.[4] Felbamate modulates the glutamate receptor function at the NMDA receptor and displaces competitive antagonists at the glycine binding site.[5] It is possible that our patient responded particularly well to felbamate because of its specific interactions at the NMDA receptor site where the mTOR pathway also interacts. Because of this unusual combination of genetic neurocutaneous syndromes, there is a higher risk of mTOR overactivation which may be very sensitive to felbamate treatment. Conclusions: References: 1. Cross JH. Neurocutaneous syndromes and epilepsy-issues in diagnosis and management. Epilepsia 2005;46 Suppl 10:17-23 2. Alaraj AM et al. Double phakomatosis; neurofibromatosis type-1 and tuberous sclerosis. Acta Neurochir. 2007;149(5):505-9; discussion 509 3. De Vries PJ. Targeted treatment for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics 2010 Jul;7(3):275-82 4. Gong R et al. Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J Biol Chem 2006; 281(27):18802-15 5. White H. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 1999; 40 Suppl 5:2-10