2007 Epilepsy Research Benchmarks

Epilepsy Research Benchmarks Progress Report 2007-2012 (pdf, 666 KB)

Epilepsy Research Benchmarks Progress Update 2007-2009　

2007 Epilepsy Research Benchmarks: A Guide for the General Public (pdf, 489 KB)

Background on the Epilepsy Research Benchmarks

On 29 – 30 March 2007, over 400 researchers, physicians, patients, family members and voluntary health organization leaders came together on the NIH campus to participate in the "Curing Epilepsy 2007: Translating Discoveries into Therapies" Conference. Organized by the NINDS in collaboration with epilepsy research and voluntary organizations, the meeting was a follow-up to the successful White House-initiated conference on epilepsy held in March 2000 that established the first set of Epilepsy Research Benchmarks to guide future research directions. Since the meeting in 2000, the NINDS, together with members of the scientific community who volunteered to serve as Stewards of individual Benchmarks, have guided the research areas toward the goal of finding a "cure" for epilepsy, defined as the prevention of epilepsy in people at risk, and by effective and safe therapy ("no seizures, no side effects") for those with the disorder.

The epilepsy research community has made substantial progress on many of the Benchmarks since the 2000 meeting [2005 stewards' report click here] and the nature of the scientific enterprise has also evolved considerably since this time. As a result, attendees at the 2007 Conference met to evaluate the original Benchmarks and discuss new research directions.  Participants voted on the topic areas felt to be most promising, as well as those in need of attention. The NINDS solicited public input on these changes to the Benchmarks, and the Epilepsy Benchmark Stewards gathered in October 2007 to discuss the input received and to finalize the document. The NINDS looks forward to working with the epilepsy research community in achieving these Benchmarks in the coming years.

Benchmarks Area I - Prevent epilepsy and its progression.

A. Identify as yet unrecognized causes of epilepsy (e.g., genetic, autoimmune and infectious).

B. Identify underlying mechanisms of epileptogenesis.
Short-term* goals include:

  1. Identify at least one susceptibility gene or other risk factor (e.g., viral, trauma, autoimmune) and identify how it predisposes to changes in network excitability.
  2. Identify at least one epileptogenic mechanism that is reversible, or has influence at critical developmental times.
  3. Identify at least one specific role for non-neural mechanisms (e.g., glia, immune cells, angiogenesis) in epileptogenesis.
  4. Identify at least one neuronal mechanism in microcircuits that contributes to epileptogenesis.

Longer-term** goals include:

  1. Identify convergent pathways or mechanisms of epileptogenesis in multiple models and human epilepsy syndromes.
  2. Identify the underlying cellular and molecular properties that are associated with electrophysiological and functional abnormalities.
  3. Identify homeostatic mechanisms that prevent spread of microsynchrony.

C. Identify biomarkers for epileptogenesis.
Short-term goals include:

  1. Identify and validate one biomarker to predict progressive or intractable epilepsy in new-onset patients.
  2. Identify and validate one biomarker (e.g., imaging, electroencephalographic (EEG), blood test) to predict development of epilepsy in at-risk individuals (human or animal).

D. Identify approaches to prevent epilepsy or its progression.
Short-term goals include:

  1. Identify at least one homeostatic mechanism that protects against the development of epilepsy or its progression.

Longer-term goals include:

  1. Identify interventions that prevent, interrupt or reverse the epileptogenic process.

E. Develop new animal models to study epileptogenesis.
Short-term goals include:

  1. Develop at least one new animal model of the development and progression of epilepsy.
  2. Develop at least one new animal model of the epileptic encephalopathies of infancy and childhood.
  3. Develop at least one new animal model that recapitulates the unique aspects of epileptogenesis in the aging brain.

F. Test the efficacy of prevention strategies.
Short-term goals include:

  1. Test the efficacy of prevention strategies identified above in animal models and in human clinical trials.

Stewards contributing to the Area I Benchmarks include:

Ray Dingledine, Ph.D. (Co-chair)
Emory University School of Medicine

Jerome Engel, Jr., M.D., Ph.D. (Co-chair)
University of California at Los Angeles

Matthew Anderson, M.D., Ph.D.
Harvard Medical School

Jocelyn F. Bautista, M.D.
Cleveland Clinic

Solomon Moshé, M.D.
Albert Einstein College of Medicine

Carl Stafstrom, M.D., Ph.D.
University of Wisconsin

Daniel H. Lowenstein, M.D. (Benchmark Chair)
University of California at San Francisco

Benchmarks Area II: Develop new therapeutic strategies and optimize current approaches to cure epilepsy.

(For this Benchmarks Area, the Stewards indicated that all goals should be considered as "Short-term.")

A. Identify basic mechanisms of ictogenesis (seizure generation) that will lead to the development of cures.

  1. Define underlying mechanisms of initiation, propagation and cessation of seizures in the epileptic brain as targets for treatment (electrical, biochemical, cellular, molecular, physiological).
  2. Define the functional networks in the brain that are responsible for seizure generation in clinical epilepsy using biosensors, imaging and other methods.

B. Develop tools that facilitate the identification and validation of a cure.

  1. Develop and validate biomarkers and surrogate markers to localize the epileptogenic networks and aid in the discovery and testing of new antiepileptic therapies.
  2. Identify new molecular targets for pharmacotherapy development.
  3. Develop valid screening strategies and biomarkers and surrogate markers (e.g., genetic, pharmacogenomic, electrophysiologic, imaging, biochemical) to identify patients who are likely to respond to, or develop adverse effects from specific therapies.

C. Optimize existing therapies and develop new therapies and technologies for curing epilepsy.

  1. Determine factors and approaches associated with best outcomes for surgical therapies.
  2. Develop new approaches (e.g., gene therapy, brain stimulation, cellular therapy, pharmacotherapy) for targeted therapies.
  3. Develop higher-throughput cost-effective models for screening pharmacotherapies for specific types of epilepsy.
  4. Initiate clinical trials of new, modified, and combination approaches to enhance cure rates.

Stewards contributing to the Area II Benchmarks include:

Susan Spencer, M.D. (Co-Chair)
Yale University School of Medicine

Edward Bertram, M.D., Ph.D.
University of Virginia

Tracy A. Glauser, M.D.
University of Cincinnati

Brian Litt, M.D.
University of Pennsylvania

William Theodore, M.D.
National Institute of Neurological Disorders and Stroke

H. Steve White, Ph.D.
University of Utah

Karen Wilcox, Ph.D.
University of Utah

Daniel H. Lowenstein, M.D. (Benchmark Chair)
University of California at San Francisco

Benchmarks Area III: Prevent, limit, and reverse the co-morbidities associated with epilepsy and its treatment.

(For this Benchmarks Area, the Stewards indicated that the goals highlighted in bold are priorities of the group.)

A. Identify and characterize the full range and age specificity of co-morbidities in people with epilepsy.
Short-term goals include:

  1. Determine the types, frequency and severity of various co-morbidities in the general population of people with epilepsy.
  2. Identify at least one new susceptibility factor each for cognitive, neuropsychiatric, and other medical co-morbidities in people with epilepsy.

Longer-term goals include:

  1. Delineate the natural history of co-morbidities in epilepsy including the nature of the relationship between specific co-morbidities and the underlying causes of epilepsy, specific features of epilepsy (e.g., age of onset, frequency of seizures, interictal epileptiform abnormalities), and treatment (e.g., antiepileptic drugs (AEDs), surgery).

B. Identify predictors and underlying mechanisms that contribute to co-morbidities.
Short-term goals include:

  1. Identify and utilize promising techniques and paradigms from other areas within the behavioral neurosciences (e.g., structural and functional neuroimaging, EEG, magnetoencephalography (MEG), genomics) and apply at least two of these approaches to the study of cognitive and behavioral co-morbidities in epilepsy.
  2. Develop and validate at least one animal model of a co-morbidity of epilepsy.
  3. Develop and implement a standardized protocol for screening pharmacologic and non-pharmacologic treatments of epilepsy for their amelioration or exacerbation of neuropsychiatric and cognitive co-morbidities.

Longer-term goals include:

  1. Determine contributions of epileptogenesis, seizures, interictal epileptiform events, and homeostatic protective processes to the development of comorbidities.
  2. Determine if the affective, attentional and cognitive disorders in people with epilepsy are the same as those in people without epilepsy with respect to natural history, presentation, treatment and underlying mechanisms.

C. Determine the optimal treatments for the neuropsychiatric and cognitive co-morbidities in people with epilepsy.
Short-term goals include:

  1. Determine whether the treatments used for at least two of these conditions in isolation are effective when utilized in people with epilepsy or if these co-morbidities require different strategies.
  2. Develop at least one efficacious care model for the diagnosis and treatment of epilepsy and validate that it improves the outcomes for patients with co-morbidities.

Longer-term goals include:

  1. Develop and validate novel treatments and management strategies for cognitive and neuropsychiatric disorders of people with epilepsy that are not adequately treated with currently available therapies.

D. Prevent or limit other adverse consequences occurring in people with epilepsy .
Short-term goals include:

  1. Sudden unexplained (or unexpected) death in epilepsy (SUDEP).
    1. Develop and validate at least one prevention strategy to decrease the occurrence of SUDEP.
  2. Sleep Disturbances
    1. Identify the range and frequency of sleep disorder subtypes associated with epilepsy.
    2. Identify the influence of sleep disorders on the incidence of seizures.
    3. Identify the influence of sleep disorders on at least one co-morbidity of epilepsy.

Longer-term goals include:

  1. SUDEP.
    1. Identify the mechanisms responsible for SUDEP (including effects of seizures on autonomic functioning, particularly cardiac and respiratory).
       
  2. Identify optimal strategies to avoid systemic disorders associated with epilepsy and its treatment (e.g., osteopenia, endocrine disturbances, reproductive disorders, and teratogenicity).

E. Develop effective methods for diagnosis, treatment and prevention of non-epileptic seizures (NES).
Short-term goals include:

  1. Determine the types and frequency of NES in the general population and in people with epilepsy.
  2. Identify common susceptibility factors and etiologies for NES.
  3. Validate at least one effective treatment for NES.

Stewards contributing to the Area III Benchmarks include:

Anne Berg, Ph.D. (Co-chair)
Northern Illinois University

Amy Brooks-Kayal, M.D. (Co-chair)
University of Pennsylvania

John J. Barry, M.D.
Stanford University

Bruce P. Hermann, Ph.D.
University of Wisconsin

Ruben Kuzniecky, M.D.
New York University

W. Curt LaFrance, Jr., M.D.
Brown Medical School

John W. Swann, Ph.D.
Baylor College of Medicine

Daniel H. Lowenstein, M.D. (Benchmark Chair)
University of California at San Francisco

* Short-term goals are expected to be achievable in under 5 years.
** Longer-term goals are expected to be achievable in approximately 5-10 years.