**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.

**Activities update:**

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:**

-   Develop novel diagnostic methods to image epileptogenic regions and
    epileptogenesis, and to define the networks that underlie these
    processes, that can be used for modified or novel surgical
    approaches or targets.

-   Establish more standardized protocols to test and measure
    effectiveness, efficacy, and prediction of response to various
    surgical interventions for specific epilepsies.

-   Examine the influence of post-operative manipulations and
    comorbidity in longterm outcomes of surgical interventions (and use
    this setting to study the process of epileptogenesis).

**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.

**References:**

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