Posted November 14, 2013

Epilepsy, a disorder involving repeated and spontaneous seizures, is a common manifestation of tuberous sclerosis complex (TSC) that is estimated to affect up to 80%-90% of individuals with TSC at some point during their lifetime. Seizures result from abnormal electrical impulses in the brain and, in TSC, they are thought to be related to the presence of cortical tubers. Seizures can also result from an increase in pressure in the brain due to the presence and growth of a subependymal giant cell astrocytoma, or SEGA, which occurs in about 15% of TSC patients. There are many different seizure types associated with TSC including simple partial, complex partial, and generalized tonic-clonic seizures. Infantile spasms, severe single or clustered seizures that begin in infancy, are common in TSC but adult-onset seizures also occur. There is a variety of medications available to treat seizures, although not all seizures will respond well to all medications and some may remain intractable, or unresponsive, to medication. Alternative treatment options include dietary changes, vagus nerve stimulation, and surgery.

The Tuberous Sclerosis Complex Research Program (TSCRP) has funded a number of studies investigating epilepsy and seizures in the context of TSC. Following are brief descriptions of some of the current TSCRP awards addressing this important topic (with links to the investigators' public and technical abstracts):

Dr. Stuart LiptonDr. Stuart Lipton (Sanford-Burnham Medical Research Institute, La Jolla): Dr. Lipton is evaluating the efficacy of the FDA-approved drug Memantine in correcting the neurological and behavioral abnormalities in a mouse model of TSC, including electrophysiological abnormalities. Memantine is currently approved for use in Alzheimer's disease and is under investigation in clinical trials for children with autism, intellectual disabilities, and epilepsy. Dr. Lipton also plans to evaluate a novel class of Memantine derivatives called NitroMemantines.

Dr. David SulzerDr. David Sulzer (Columbia University): Dr. Sulzer hypothesizes that the development of epilepsy in TSC results from a failure of astrocytes to remove, or prune, excess excitatory synapses in the brain. He is evaluating the effect of TSC1 and TSC2 mutations in astrocytes on synaptic function in mice and whether astrocyte dysfunction results in a deficit in pruning. He also plans to analyze human brain tissue for biomarkers of astrocyte function.

Dr. Michael WongDr. Michael Wong (Washington University in St. Louis): Inflammation has been implicated in the pathophysiology of some types of epilepsy and evidence for the activation of proinflammatory pathways has been identified in human TSC tubers. However, it remains unclear whether inflammation in TSC is pathogenic or in response to neurological damage. Dr. Wong is testing the hypothesis that brain inflammation promotes the development of epilepsy in TSC. He will also test whether anti-inflammatory agents can prevent epilepsy in a mouse model of TSC.

Dr. Akira YoshiiDr. Akira Yoshii (Massachusetts Institute of Technology): Dr. Yoshii is investigating whether the imbalance in excitatory and inhibitory neuronal signals in TSC is caused by altered synaptic protein synthesis. Specifically, he is testing whether the balance between excitatory and inhibitory synaptic proteins is altered in TSC mutant mice and whether this imbalance can be corrected by treatment with the mTOR inhibitor rapamycin. He also plans to identify synaptic proteins with enhanced synthesis in TSC and characterize their functions in TSC neurons.

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