|Epilepsy Research Benchmarks|
| The 2007 Epilepsy Research Benchmarks are now available
|Judith Hoyer Lecture on Epilepsy|
|Anticonvulsant Screening Program (ASP)
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|Brandy Fureman, Ph.D.
Program Director, Channels Synapses & Circuits Cluster
Epilepsy Benchmark IIIF
Benchmark Area III. Create and implement new therapies free of side effects that are aimed at the cessation of seizures in patients with epilepsy.
C. Specific Benchmark: Widen the use of epilepsy surgery including its use as a form of early intervention. Develop new surgical approaches such as the use of robotic arms.
2005 Report submitted by Benchmark Steward(s):
Susan Spencer, M.D. (Yale University)
Background of the benchmark goal:
Resective surgery is the single obvious true cure in existence, but applies to limited patients, traditionally late in the course of their epilepsy, at great cost, and only after intensive, extended, variably successful evaluation. We will restrict this benchmark discussion to surgical approaches exclusive of stimulation procedures which may be addressed elsewhere.
Current Status of Field:
A restricted number of true operative interventions remain in common use. Resective surgery is preferred and is the only current cure (incorporating hemisherectomy). Callosotomy and MST are palliative, disconnection procedures.
Only resective temporal lobe surgery is established to be effective through a randomized trial. All of these approaches depend on definition of a region of seizure onset to which the therapy is directed. If this is accomplished, the location and extent of the seizure-generating area determine the applicable procedure. Evaluation is multi-faceted, expensive, extensive, may entail risk, and has been progressively but only modestly modified as new technology allows novel methods for evaluation. Predictors of outcome have been examined repeatedly but in small studies and with few reproducible factors emerging (see below). Procedural details have also been modified (based on philosophical views more than scientific information.) Quality of life and other outcome measures are only in rudimentary stages of consideration.
Two ongoing studies are examining outcome of epilepsy surgery, one of early surgery for temporal resection and one of long-term follow-up of all resective approaches; these are the only currently funded studies investigating outcomes of surgical interventions of any type. These may potentially provide data to allow extended use of surgery by expanding the time in the disorder at which surgery is used, and by increasing means of evaluation for more accurately or more simply detecting potential candidates. Unfortunately, early enrollment has been difficult and the multi-center outcome study has so far shown only 2 predictors of seizure remission in temporal resections (hippocampal atrophy, absence of generalized tonic clonic seizures) (1-3). Furthermore, the multi-center study established a moderate (20%) incidence of relapse with the only identifiable predictor being delayed remission in the temporal group only. A randomized study of the transcortical versus the transsylvian approach to amygdalo-hippocampectomy found no difference in seizure or cognitive outcomes (4).
Expanding use of surgery could potentially be approached by: a) refining evaluation (to greater simplicity, more accuracy, or more predictive ability); b) modifying surgical techniques (different resection, extent, or approach, e.g. amygdalo-hippocampectomy versus standard temporal lobectomy, transsylvian vs. transcortical, depth of MST); c) instituting novel surgical approaches (as new pathways for disconnection, or new targets for drug or other neurochemical or substance delivery); d) developing novel concepts of the epileptogenic region and how it develops or progresses (allowing some form of “interference” with those processes); e) re-evaluating the ways in which the post-operative interval is handled (considering that medication use (type/duration/dose) could alter long-term seizure status); f) examining the influence, impact and possible roles of common cormobidity and its treatment, on patient evaluation or eventual response to surgical treatment. Progress in any of these directions, or potentially others, has been slow.
Methods of evaluation are still evolving. The literature of the last five years is replete with reports regarding the use of ictal SPECT, but the technique remains difficult to implement, with the necessity of very early injection to obtain worthwhile localization of epileptogenic area (5). There is promise for development of more PET radioligands to image neurochemical markers of the epileptogenic substrate (6-8). Most notable, PET with 11 C- Alpha-methyl tryptophan (AMT) can image epileptic regions in patients who fail cortical resections, and can image the epileptogenic tuber (among many) (9, 10). Much current literature addressing diagnostic methods in selection for surgery is in the area of magneto-encephalography and magnetic source imaging, said to provide incremental and accurate localizing data in both mesial temporal and neocortical epilepsies (11-13). Currently, NIH is funding 15 grants studying various imaging methods in localization for epilepsy surgery (3 fMRI, 3 MRS, 3 PET, 1 MEG, 5 OSI).
EEG methods of localization continue to be explored, utilizing fMRI for spike localization, as well as defining background or ictal patterns of particular relevance for identification of the epileptogenic brain (14-18). One such phenomenon, high frequency oscillations or fast ripples, may be a marker for epileptogenesis as well as epileptic regions, and has received considerable attention (19-22).
Consideration and exploration of novel concepts of the epileptic region or of its development (epileptogenesis) may also allow expansion of surgery. Several groups are investigating and incorporating the role of epileptogenic and epileptic networks in development, expression, and modification of seizures (23-26). This knowledge could provide entirely new targets for disconnection, lesioning, targeted drug delivery, or targeted drug development. Combined approaches to interrupting seizure development and expression through specific cortical and subcortical components of these processes that might allow the least risk and maximal success may be in the future. Anticipation or prediction of seizures based on analyses of such networks, or by the use of various quantitative EEG analyses, is an area that may allow novel approaches to treatment (27-29). Five separate grants in current funding are these types of investigations.
Top priorities for next 5-10 years:
Roadblocks to progress:
Trained clinical researchers are disappearing, and no other group is qualified to lead these directions of research. We need support for training as well as career development of these future clinical researchers.
Last updated January 12, 2010