Epilepsy Benchmark IIIF

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:

1. Berg AT, Vickrey BG, Langfitt J, Sperling MR, Walczak T, Shinnar S, Bazil C, Pacia SV, Spencer SS.  The multicenter study of epilepsy surgery: recruitment and selection for surgery.  Epilepsia 2003;44:1425-1433.
2. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, Langfitt JT, Walczak TS, Pacia SV, Ebrahimi N, Frobish D.  Initial outcomes in the multicenter study of epilepsy surgery.  Neurology 2003;61:1680-1685.
3. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, Langfitt JT, Walczak TS, Pacia SV, Ebrahimi N, Frobish D.  Predicting seizure outcome of anteromedial temporal lobectomy: the multicenter epilepsy surgery study.  Epilepsia 2003;44(Suppl 9):337-338.
4. Lutz MT, Clusmann H, Elger CE, Schramm J, Helmstaedter C.  Neuropsychological outcome after selective amygdalohippocampectomy with transsylvian versus transcortical approach: a randomized prospective clinical trial of surgery for temporal lobe epilepsy.  Epilepsia 2004;45:809-816.
5. Cascino GD, Buchhalter JR, Mullan BP, So EL.  Ictal SPECT in nonlesional extratemporal epilepsy.  Epilepsia 2004;45(Suppl 4):32-34.
6. Toczek MT, Carson RE, Lang L, et al. Comment: PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 2003;60:736-737.
7. Merlet I, Ryvlin P, Costes N, et al. Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG. Neuroimage 2004;22:886-896.
8. Juhasz C, Chugani HT. Imaging the epileptic brain with positron emission tomography. Neuroimaging Clin N Am 2003;13:705-716.
9. Juhasz C, Chugani DC, Padhye UN, Muzik O, Shah A, Asano E.  Evaluatin with alpha-[11C]methyl-L-tryptophan positron emission tomography for reoperation after failed epilepsy surgery.  Epilepsia 2004;45:124-130.
10. Chugani DC, Chugani HT, Muzik O, Shah JR, Shah AK, Canady A.  Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography.  Ann Neurol 1998;44:858-866.
11. Pataraia E, Simos PG, Castillo EM, et al.  Does magnetoencephalography add to scalp video-EEG as a diagnostic tool in epilepsy?  Neurology 2004;62(Suppl 6):943-948.
12. Stefan H, Scheler G, Hummel C, et al.  Magnetoencephalography (MEG) predicts focal epileptogenicity in cavernomas.  Journal of Neurology, Neurosurgery, & Psychiatry 2004;75(Suppl 9):1309-1313.
13. Wheless JW, Castillo E, Maggio V, et al.  Magnetoencephalography (MEG) and magnetic source imaging (MSI).  Neurologist 2004;10(Suppl 3):138-153.
14. Kang JK, Benar C, Al-Asmi A, et al. Using patient-specific hemodynamic response functions in combined EEG-fMRI studies in epilepsy. Neuroimage 2003;20:1162-1170.
15. Kikuchi S, Kubota F, Nichijima K, et al. Electroencephalogram-triggered functional magnetic resonance imaging in focal epilepsy. Psychiatry Clin Neurosci 2004;58:319-323.
16. Hamandi K, Salek-Haddadi A, Fish DR, et al. EEG/functional MRI in epilepsy: The Queen Square Experience. J Clin Neurophysiol 2004;21:241-248.
17. Gotman J, Benar CG, Dubeau F. Combining EEG and fMRI in epilepsy: methodological challenges and clinical results. J Clin Neurophysiol 2004;21:229-240.
18. Diehl B, Salek-haddadi A, Fish DR, et al. Mapping of spikes, slow waves, and motor tasks in a patient with malformation of cortical development using simultaneous EEG and fMRI. Magn Reson Imaging 2003;21:1167-1173.
19. Dudek FE. Commentary: High-frequency oscillations and neocortical seizures: do they have a role in seizure onset, and which mechanisms generate them? Epilepsy Currents 2003;3:80-81.
20. Staba RJ, Wilson CL, Bragin A, Fried I, Engel J Jr. High-frequency oscillations recorded in human medial temporal lobe during sleep. Ann Neurol 2004;56:108-115.
21. Worrell GA, Parish L, Cranstoun SD, Jonas R, Baltuch G, Litt B. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004;127:1496-1506.
22. Dzhala VI, Staley KJ. Mechanisms of fast ripples in the hippocampus. J Neurosci 2004;24:8896-8906.
23. Bartolomei F, Wendling F, Regis J, Gavaret M, Guye M, Chauvel P.  Preictal synchronicity in limbic networks of mesial temporal lobe epilepsy.  Epilepsy Res 2004;61:89-104.
24. Blumenfeld H, McNally KA, Vanderhill SD, Paige AL, Chung R, Davis K, Norden AD, Stokking R, Studholme C, Novotny EJ, Zubal IG, Spencer SS.  Positive and negative network correlations in temporal lobe epilepsy.  Cerebral Cortex, in press.
25. Blumenfeld H, Westerveld M, Ostroff RB, Vanderhill SP, Freeman J, Necochea A, Uranga P, Tanhehco T, Smith A, Seibyl JP, Stokking R, Studholme C, Spencer SS, Zubal IG.  Selective frontal, parietal and temporal network activation in generalized seizures.  NeuroImage 2003;19:1556-1566.
26. Spencer SS.  Neural networks in human epilepsy: evidence and implications for treatment.  Epilepsia 2002;43:219-227.
27. Li D, Zhou W, Drury I, Savit R.  Linear and nonlinear measures and seizure anticipation in temporal lobe epilepsy.  J Comput Neurosci 2003;15:335-345.
28. van Drongelen W, Nayak S, Frim DM, Kohrman MH, Towle VL, Lee HC, et al.  Seizure anticipation in pediatric epilepsy: use of Kolmogorov entropy.  Pediatr Neurol 2003;29:207-213.
29. Aschenbrenner-Scheibe R, Maiwald T, Winterhalder M, Voss HU, Timmer J, Schulze-Bonhage A.  How well can epileptic seizures be predicted? An evaluation of a nonlinear method.  Brain 2003;126:2616-2626.