**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.

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