Epilepsy Benchmark IIIE

2005 Report submitted by Benchmark Steward(s):
Brian Litt, M.D. (University of Pennsylvania)
Dennis D. Spencer, M.D. (Yale University)

Background of the benchmark goal: 
One of the major new areas in epilepsy therapy and investigation is the design and implementation of systems to predict (or anticipate) epileptic seizures as they approach and then trigger intervention, such as focal electrical stimulation, local drug infusion or focal cooling to arrest seizures before they begin.  This work is initially targeted to helping medically refractory patients who have failed or are not candidates for resective epilepsy surgery.  There is optimism that if these systems can successfully treat this refractory population, they could offer an alternative to standard resective surgery or even multi-drug therapy in some individuals.

Current status of the field:
Research into systems for suppressing and modulating seizures continues to explode in both basic science mechanisms underlying seizure generation and in clinical translation into human clinical trials.  Leading the areas of focus is research into open loop stimulation of central brain structures, primarily in thalamic stimulation, to modulate this process and in responsive stimulation in the epileptic network.  Interest in striato-nigral, central and the subthalamic regions has been less fruitful than more recent work in the anterior thalamus, mesial temporal and neocortical regions.  Research into animal models of epilepsy continues to include acute models of seizures (e.g. pentylenetetrezole), but the focus has switched more to spontaneously seizing models, particularly systemic pilocarpine and more focal models, such as intrahippocampal kainate and focal deposition of other epileptogenic agents.  Recordings in both animals and humans are moving more from single channels at 0.1-100 Hz to arrays of electrodes at much higher frequencies (i.e. up to 1-2 KHz/ channel).  The most important developments in the field are that preliminary pilot trials of anterior thalamic and reactive cortical stimulation have progressed to FDA approval for large-scale clinical trials to prove safety and early indications of efficacy in anterior thalamic and reactive cortical stimulation.  Development of sensors and algorithms to track seizure generation continues to progress.  There continues to be active investigation into the analysis of intracranial signals from adults and children with multifocal epilepsies implanted with intracranial electrodes, to understand seizure spread in these individuals.  Some of these studies have recently pointed out the importance of high frequency activity not only in seizure generation in animal models of neocortical epilepsy, but in humans and basic clinical practice.  There is now an evolution of standard clinical EEG equipment under way to increase the bandwidth at least into the 500 Hz/ channel range.  There 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.     

The ability to sample the brain extracellular fluid space in vivo provides a critical dimension to the study of epileptogenic mechanisms.  Measurements of neurotransmitters and other neuroactive molecules provide a picture of cerebral metabolism during the interictal baseline and with continuous monitoring may identify reproducible biochemical changes preceding and during an ictal event.  Microdialysis has been a common technique employed in animal models and slices.  It enjoys picomolar detection but usually samples a large volume of 200-300 μm by 1-4 mm with a slow time resolution of minutes and must be analyzed off line under most circumstances.  The alternative and actually complimentary technique for ECF sampling is the voltammetric biosensor that uses microelectrodes (5-30 μm OD) with smaller spatial (5-30 by 30-150μm) and rapid temporal resolution (1-200 Hz).  Voltammetric detection limits are also not as sensitive as microdialysis (25-50 μm)           

Microdialysis has been used in human recordings coupled to depth electrodes.  The data has been very valuable but the technique is very labor intensive and requires a sophisticated team.  The biosensory technology has the potential to provide robust reliable sensing that might be more universally applied to human epilepsy.           

Activities update:  (Continued from Benchmark IIIC)
A multicenter clinical trial of closed-loop brain stimulation for refractory partial (focal and multifocal) epilepsy got underway (sponsored by NeuroPace, Inc.).  Rapid progress toward the goal of 200 patients enrolled is being made, with over 30 patients implanted at the present time.  Preliminary results are not yet available for publication.  A second preliminary study supporting this work was published (12).

A multicenter clinical trial of open-loop brain stimulation of the anterior thalamic nucleus for refractory partial (including multifocal) epilepsy got underway (sponsored by Medtronic, Inc.).  Rapid progress is being made toward the planned enrollment of  ~200 patients nationwide.  No preliminary results are available.  A study of reactive closed-loop brain stimulation brain stimulation, using an external version of the NeuroPace implantable device was published in Epilepsia (13).  This study focused on 4 patients treated at one center, all of who had significant clinical response and no side effects to reactive brain stimulation.

Several studies of high frequency activity ranging from 80 to >500 Hz were published in animal models and humans.  Several were very encouraging regarding the potential of these recordings to map the epileptic network and track seizure generation, particularly in the neocortex (14-17).

Significant progress has been made in beginning to understand the mechanisms through which electrical stimulation can be used to modulate neuronal function.  This progress includes studies that match computational and modeling studies together with experimental measurements in humans and animal models of neurological disorders (18-20).  Other studies, consisting primarily of computational modeling are of interest, but await validation through clinical and animal studies to determine their relevance (21-24). 

There remains active investigation into other methods of novel focal therapy for refractory multi-focal and neocortical epilepsy including focal thermocoagulation (25), focal cooling with implantable peltier devices (26), as well as continued research into local drug delivery in brain.

There continues to be incremental progress in algorithms for detecting and predicting seizures that is applicable to implementation in systems for treating refractory epilepsy.  Seizure prediction/ anticipation continues to be a field fraught with controversy, though there is growing consensus on targets, requirements for statistical validation, and for what constitutes significant results.  These ideas will be better articulated in the summary of papers and methods presented at the First International Collaborative Workshop on Seizure Prediction, currently in press in the journal Clinical Neurophysiology.

Since our last benchmark report, a collaboration has been established between the Yale Epilepsy Program and Greg Gerhardt, who directs the Center for Sensory Technology at the University of Kentucky.  His ceramic-based voltammetric electrodes have been successfully coated with glutamate oxidase and neurotransmitter data obtained in brain slices and in vivo animals.  At present, these electrodes are being adapted to the Yale microdialysis/depth electrodes and an IRB protocol is being written for human use during intracranial AVEEG recordings.           

In order to stimulate and provide guidance for this technology in epilepsy, we are planning a workshop.  An application for a NIH sponsored meeting will be submitted this spring for the late winter/early spring of 2006.  The purpose of this workshop will be to:

1. Evaluate the technological state of CNS sensing.  How do the available techniques compare and perform particularly regarding the special requirements of monitoring the dynamic state of the epileptogenic region compared to the more static requirements, in Parkinson’s disease, for example?
2. What data exists thus far in using these techniques for epilepsy investigation?
3. What data exists in using biosensors for other CNS investigations both for study of the normal ECF milieu and in disease states (trauma, neurodegenerative diseases, etc.)?
4. What new techniques are being developed for future sensing devices?  How can we guide that process especially for epilepsy’s special needs?
5. How would we like to use this technology in the future?

An outline of a one- or two-day workshop would therefore have the following structure:

I.   Introduction to measuring cerebral metabolism and neurochemical dynamics, why is it worthwhile?

II.  Comparing sensing techniques

1. Overview
2. Microdialysis
3. Voltammetric
4. Fiber Optic

Panel discussion

III. Biosensing in normal and diseased states other than epilepsy

1. Microdialysis
2. Voltammetric
3. Fiber Optic

Panel discussion

IV. Biosensing in epilepsy

1. Microdialysis
2. Voltammetric
3. Fiber Optic

Panel discussion

V.  Future sensing devices

VI. Future demands for biosensing in epilepsy

Top priorities for next 5-10 years: (Continued from Benchmark IIIC)

• To identify central pathways, circuits and mechanisms which, when activated, can suppress or modulate focal or multifocal seizures, particularly those of neocortical origin. 
• To identify methods for determining where, when and how to deliver local therapy, such as electrical stimulation, focal cooling or local drug infusion to these areas.  Very important to this goal are methods to identify periods of increased probability of seizure onset (“Seizure Prediction”).
• To validate the above two discoveries in spontaneously seizing animal models of epilepsy and translate them into human therapy though novel surgical, minimally invasive or non-invasive methods.

Roadblocks to progress: (Continued from Benchmark IIIC)

• The relative inaccessibility of large areas of brain to intracranial, high frequency electrophysiological recording in humans, due to patient safety concerns and the lack of noninvasive methods, such as scalp EEG, to capture these signals.
• Lack of understanding of mechanisms of seizure generation in human partial epilepsy.
• Lack of understanding of the mechanisms by which brain stimulation works to modulate/ inhibit neuronal function.
• Lack of methods to localize and record from the epileptic network essential to generate seizures.

References:

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3. Shields WD. Surgical Treatment of Refractory Epilepsy. Curr Treat Options Neurol 2004;6(5):349-356. 
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11. Richards MC, Heron SE, Spendlove HE, Scheffer IE, Grinton B, Berkovic SF, et al. Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction. J Med Genet 2004;41(3):e35. 
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20. McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. Journal of Clinical Neurophysiology 2004;21(1):40-50. 
21. Yang KH, Franaszczuk PJ, Bergey GK. Inhibition modifies the effects of slow calcium-activated potassium channels on epileptiform activity in a neuronal network model. Biol Cybern 2004. 
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