Epilepsy Benchmark IIIC

2005 Report submitted by Benchmark Steward(s):
Brian Litt, M.D. (University of Pennsylvania)

Background of the benchmark goal: 
Multifocal epilepsies and conditions in which seizures spread rapidly throughout the brain (symptomatic generalized epilepsies) are among the most difficult epileptic disorders to treat.  This is because they are often refractory to medical therapy and not treatable by resective epilepsy surgery.  For these reasons, there is great interest in understanding pathways regulating seizure generation and spread that may be dysfunctional in these disorders, and in modulating their activity to suppress seizures that arise from multiple foci or networks regulating seizure spread.

Current status of the field:
Current research in the field is focused on several pathways, including those centered on the striato-nigral, anterior, central and subthalamic regions for seizure spread.  Other investigation is focused on connected regions, including periaqueductal gray.  Currently, these areas are being investigated in animal models of epilepsy with array recordings from these regions during acute and less commonly spontaneous seizures.  Equally important as these ongoing studies is the great interest in devices to treat medically refractory epilepsy, and the need for research to support this task.  This includes renewed interest in mapping epileptic networks, understanding seizure generation and spread, developing quantitative tools to predict seizures and guide intervention strategies, and methods to translate animal work in this area rapidly into human therapy.  While multifocal and symptomatic generalized epilepsies present specific challenges, specifically that seizures spread so rapidly that focal onset may vary or not be indentifiable by current methods, they have much in common with simpler cases which are the subject of clinical trials of implantable devices.  Functional imaging, electrophysiological and modeling studies in patients with multifocal and symptomatic generalized epilepsies are getting underway.  These include individuals with cortical dysplasia, tuberous sclerosis and genetic causes of multifocal and symptomatic generalized epilepsies (band and multinodular periiventricular heterotopias, lissencephaly, schizencephaly, hypothalamic hamartoma, and similar disorders).  This is also interest in new imaging tools to study non-invasive, real-time imaging correlates of seizure generation and spread.  It is hoped that these types of studies may help identify central regions that are and can be activated to suppress poorly localized, multifocal or refractory seizures.  It is clear from ongoing clinical research that even surgical therapy can be very effective in this patient population, with proper electrophysiologic evidence of discrete seizure onset.           

Activities update: 

1. Significant progress is being made in understanding seizure generation, brain stimulation, and seizure localization.  These activities are noted in Benchmark IIIE.
2. Continued evidence is being accumulated that focal surgery in properly selected patients with tuberous sclerosis, with proper seizure localization by electrophysiology (often intracranial), can have excellent results (1-5).
3. There is considerable ongoing work regarding the genetics of multifocal and symptomatic generalized epilepsy syndromes.  Identification of underlying channelopathies and other mutations, in a subset of these patients, may open new therapeutic options in the future, and perhaps guide selection of appropriate antiepileptic drugs (6-11).
4. See Benchmark IIIE       

Top priorities for next 5-10 years:

1. To localize the epileptic network, understand seizure generation and spread, and to develop methods to predict, intervene and prevent seizures in multifocal and symptomatic generalized epilepsies (see Benchmark IIIE for details).
2. To understand genetic and other processes that lead to the development of multifocal and symptomatic generalized epilepsies, and methods to affect this process.
3. To develop specific tools, such as less invasive, high resolution electrophysiology and function imaging to identify regions important to seizure generation in individuals with multifocal abnormalities.

Roadblocks to progress:

1. The relative inaccessibility of brainstem and other functional brain structures to interventions such as functional Neurosurgery and diagnostic electrphysiologic recording.
2. The lack of imaging methods to noninvasively distinguish regions of functional/ dysfunctional importance from those that are structurally abnormal but functionally quiet, with respect to seizure generation. 
3. Lack of good animal models of multifocal and symptomatic generalized epilepsy on which to perfect and validate new methods to localize and treat dysfunctional areas to prevent seizures. 

References:

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