Epilepsy Benchmark IIB

2005 Report submitted by Benchmark Steward(s):
Marc A. Dichter, M.D., Ph.D. (University of Pennsylvania)

Background of the benchmark goal: 
Almost unique in the field of neurology, or in medicine itself, for more than a century physicians have focused almost exclusively on treating the symptoms of epilepsy after it has developed, rather than on trying to prevent the disease from occurring.  This state of affairs applies most obviously to acquired epilepsy (such as occurs after brain trauma or intracerebral hemorrhage) where a normal individual develops epilepsy after a known risk.  However, it can also apply to genetic epilepsy, as most forms of these disorders have a developmental pattern allowing for prophylactic intervention, if such an intervention were available.     

Current Status of Field:
At the time the original CURING EPILEPSY meeting was held, there was only one ongoing, randomized double blind study of epilepsy prevention in man occurring on the planet.  This was the third in a series of such studies initiated at the University of Washington and sponsored by the NINDS.  This group had been shown previously that neither phenytoin nor valproate were capable of preventing epilepsy after traumatic brain injury, and a very recent report indicates that their third study, using MgSO4 was also negative.  Other, non-blinded or non-randomized studies had been performed with other “older” AEDs and also failed to show efficacy at reducing epilepsy.           

Activities update:
In the past year, 3 pilot clinical studies have been launched to try to prevent epilepsy after either TBI (2) or intracerebral hemorrhage (1).  Dr. Pavel Klein at the Washington Center (DC) received a pilot grant from the NINDS to study the use of levetiracetam to prevent epilepsy after TBI.   Dr. Marc Dichter received a pilot clinical trial grant from the USArmy/DOD to study the use of topiramate to prevent epilepsy after moderate to severe TBI (in a civilian population).  Dr. Marc Dichter also received a pilot grant from UCB Pharma to study the use of levetiracetam to prevent epilepsy after lobar intracerebral hemorrhage.  Both of the latter two studies will employ continuous surface EEG recordings for 7 days to evaluate the presence of early subclinical seizures and to compare the ability of the trial drugs to suppress early clinical and subclinical seizures.   Functional outcomes and imaging analyses will also be performed on all patients to determine if the treatments result in a “neuroprotective” outcome.  In addition, attempts will be made to develop other surrogate markers for epileptogenesis in man.

Top priorities for next 5-10 years:

• Complete the three pilot programs.  Determine feasibility for larger definitive studies.
• Begin definitive studies based on any promising results in the pilot studies.
• Develop a paradigm for early clinical evaluation of promising neuroprotective or antiepileptogenic compounds/strategies.
• Develop surrogate markers for epileptogenesis in man.

Roadblocks to progress:

• These studies are very complex and labor intensive.
• These studies are very expensive.
• There is no “gold standard” against which to compare any new agent or any new protocol
• More animal studies are needed in parallel with the clinical trials
• Clinical trial infrastructure needs to be stable so it can be sequentially implemented, rather than having to start each new study “from scratch”.