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NINDS Workshop: Anti-epileptogenesis (AEG) and Disease Modification: Alignment and Validation of Clinical Targets and Pre-Clinical Models

Outcome of an NIH Workshop, Bethesda, MD
August 26-27, 2010

The primary goal of this workshop was to develop a collaborative “proof-of-concept” experimental framework for translation of therapeutic interventions to prevent and/or modify disease progression in the epilepsies.  The ideal situation would be to have treatments in place to prevent the development of the epilepsies in individuals at risk (for example, individuals with traumatic brain injury, Dravet Syndrome, tuberous sclerosis complex (TSC), brain tumors, stroke, prior unprovoked seizure, etc.) and in individuals who have recently developed epilepsy. 

The workshop was designed to:

  • Prioritize the human epilepsy syndromes best suited for clinical proof-of-concept studies of prevention or disease modification in the near future;
  • Define what additional information about individual syndromes will be critical to facilitate development of preclinical screens or to design feasible clinical trials;
  • Promote the identification of various preclinical tools and models that can be used to identify and validate potential therapies (i.e., the use of biomarkers, surrogate markers, independent data validation);
  • Suggest working templates for clinically meaningful definitions of the terms disease modification, epileptogenesis, anti-epileptogenesis, prevention and cure and consider the regulatory implications of this terminology for labeling purposes;
  • Identify windows of opportunity (i.e., during early development) for the use of specific treatments and develop clinically relevant preclinical studies; and
  • Enumerate key resources that are available or will be necessary and to accomplish these goals.

The introductory session highlighted the NINDS goal to accelerate research in the epilepsies, the past successes of the Anticonvulsant Screening Program (ASP), as well as the priorities for anti-epileptogenesis and disease modification as viewed from the individuals with epilepsy and the non-profit organizations that represent them.  A consensus document provided by the epilepsy advocacy community underlined the need for researchers to identify models of the epilepsies in which research will most rapidly result in significant breakthroughs for affected individuals and extend these successes to other types of epilepsy.  Considerable emphasis was placed on the need for a coordinated approach to develop therapies to prevent the onset or halt the progression of the epilepsies

Anti-epileptogenesis, Disease Modification and Definitions

Prevention of the first seizure (epilepsy prevention) and disease modification (changing the progression of the disease after the onset of seizures) may be related, but distinct phenomena.  Each will likely require different approaches to study the underlying mechanisms and to identify effective interventions.

Recommendation:  Determine the mechanisms by which epilepsy first occurs and the mechanisms underlying the progression of disease to identify if these are different processes and therefore require different approaches to prevention and treatment.

Clinical Perspectives

For effective translation of preclinical studies to clinical trials, it is important to consider the specific endpoints to be evaluated.  The endpoints may be 1) prevention; 2) modification in the early latent phase (preventing resistance to treatment); 3) modification in the chronic epileptic state so that seizures are less resistant to treatment or less frequent and/or severe; or 4) total cure from the chronic epileptic state.  The more detailed the phenotype of the study population, and the more that is known about the biomarkers, risks of developing seizures,  and the likelihood of response (or lack of response) to treatment, the easier it will be to recapitulate the human condition in animal models, and therefore provide relevant and meaningful preclinical data. 

Factors that influence whether a prevention or disease modification approach is currently feasible in a given clinical population include annual or cumulative incidence, degree of population heterogeneity, available biomarkers of risk, severity or progression of epilepsy, and the burden v. benefit of a potential intervention given the severity of the disease. 

When prioritizing the strength of evidence for potential interventions, it is important to distinguish between preclinical studies that are conducted to provide biological “proof of concept” vs. those studies designed to provide evidence of therapeutic efficacy and safety in a relevant model of the disease.  For the latter, models should have a meaningful biological relevance to the human disease, interventions should be delivered using a route and time window that is clinically feasible, and endpoints should be relevant to the outcomes used in human trials.   Preclinical efficacy and safety studies should be designed, conducted, analyzed and reported with methodological rigor, including group randomization, adequate sample size to detect clinically important differences, masked evaluations, appropriate statistical methods, and commitment to reporting results even if negative.

Recommendation:  Assess the clinical information available for different populations that could be considered for epilepsy prevention or disease modifying therapy development efforts.  Encourage additional research efforts to fill critical knowledge gaps that are barriers to designing feasible clinical trials.   Provide well characterized animal models for anti-epileptogenesis that adequately recapitulate the human epilepsies.  Ensure that studies that utilize animal models to test the preclinical safety and efficacy of potential treatments are designed rigorously, and provide more transparency in reporting the methodology and results so that preclinical studies more accurately predict expected outcomes and responses in clinical trials.

Regulatory and Industry Considerations

From a regulatory perspective, Food and Drug Administration (FDA) staff indicated that the labeling for a new intervention will not include a claim of prevention or a disease modification unless one or the other effect can be established.  There is an identified need for appropriate clinical trial design to study the prevention of the epilepsies or to modify disease progression that cover the period of greatest risk (i.e., the period when seizures are most likely to begin).  Alternatively, the community could adopt a convention based on a fixed duration (i.e., 5-year seizure free survival), but there should be some evidence that the timeframe selected is useful.

From the industry perspective, there is a need for the research community to develop biomarkers that can be used in both preclinical and clinical studies, novel druggable targets – especially for drug resistant epilepsies, animal models that mimic different aspects of the disease and are predictive for screening and translational studies, short and inexpensive proof-of-concept approaches, and feasible clinical trial designs in populations with unmet clinical need. 

Recommendations:  There is a need to change the terminology for medications that treat seizures (anti-seizure medications) versus those that are anti-epileptogenic (anti-epileptic drugs).  Research to develop targeted therapies based on known mechanisms of epilepsy appear to be the most productive way forward, and may allow for both the development of new drugs and repurposing of approved drugs.  Labeling for interventions that reduce the risk of developing epilepsy or modifying its course will reflect the data provided in support of the indication, so the community should discuss potential endpoints with this in mind.

Preclinical Perspectives

Research laboratories have employed existing epilepsy models to systematically study progression of disease and the spatial and temporal patterns of cellular and molecular events related to epileptogenesis.  Several anti-epileptogenic treatments have been tested in specific models, but there are few anti-epileptogenic strategies that have been tested in multiple models, and there has yet to be a first-in-human trial for any of the existing promising strategies.  First-in-human trials directed toward pharmacologic, biologic or device therapy and biomarker development are a major priority for the community in the upcoming decade.  Preclinical studies will need to develop improved alignment with those outcome assessments that are clinically feasible.  Cellular and molecular targets for therapy must be validated in human tissue and biomarkers for disease prediction and surrogate markers for treatment trials must be developed in preclinical models and aligned with clinical markers.

Recommendations:  There is a need to better understand the critical events and time course of changes in the brain following a brain insult that leads to the first seizure and the development of epilepsy.  Accurate animal models and cost-effective ways to monitor endpoints over the long term would make it more feasible for laboratories to do this research.

How well do our pre-clinical and clinical outcome measures correlate?

The goal of targeting epileptogenic mechanisms is to prevent the formation of neural circuits that eventually result in recurrent seizures.  Long-term longitudinal studies will be required where selected biomarkers of the progression of epileptogenesis can be followed on a daily basis, and modifications by treatments can be documented.  Neurophysiological recordings should be a key technique, and signature epileptiform discharges for a given syndrome could be detected and analyzed.  These studies are now possible in animal models, but longitudinal studies in individuals with epilepsy are difficult and impractical, except possibly in the groups at the very highest risk.

High-resolution imaging studies are not restricted by the spatial limitations of the EEG, but do not correlate as directly with enhanced neuronal excitability.  Similar studies can be done in both humans and animals, but presently, resolution of human imaging far exceeds that of animals in most centers.  The challenge is to identify the key molecular mechanisms underlying epileptogenesis so that molecular probes and imaging techniques can be developed to detect them in the intact brain, follow alterations in their expression over time, and then develop drugs and/or devices that would interfere with the progression of molecular changes that result in permanent alterations in nerve and glial cells and in the formation of seizure-generating neuronal networks.

The medications that are currently used to treat seizures appear to have little effect on preventing or curing epilepsy.  This suggests that the molecular pathways for epileptogenesis are distinct from those that produce acute seizures and will require the identification of truly novel “anti-epileptic” therapeutics.  Identification and testing of potential anti-epileptic drug targets are the critical next steps in order to move beyond suppressing seizures with anticonvulsant medications to actually preventing and curing the epilepsies.  New approaches using functional genomics, proteomics and metabolomics have been applied to both human and animal epileptic brain tissues and are beginning to hone in on new therapeutic targets.  Epileptogenic targets can then be validated first in human tissues and then in carefully constructed animal models of epileptogenesis that most closely parallel the human condition.

Pre-Clinical Working Session

The participants in this working session considered the following questions:

  • What are the current gaps in our ability to create a preclinical-clinical interface for the discovery of anti-epileptogenic treatments?
  • What infrastructure can we create to develop candidate anti-epileptogenic therapies? 
  • Is a new paradigm needed for drug development?  Currently the process includes:  1) identification of a new mechanism, candidate gene, or novel drug; 2) developing the proof of concept in individual preclinical model(s); 3) validating the target in human tissue, developing a biomarker; 4) preclinical therapy trial that includes long term monitoring, EEG and other monitoring in multiple models and testing of toxicology; 5) then on to clinical Phase I, II and III trials.  What kind of multicenter collaborations are needed?
  • Are there accessible and tractable disease models in which to study anti-epileptogenesis as an outcome?  To test treatments or develop biomarkers?  Are the models we have for these disease(s) feasible and reproducible? Do they align with the human disease?  Is there potential for biomarker development?  Examples:  Status epilepticus, including febrile status; post-traumatic epilepsy (PTE), tuberous sclerosis complex (TSC), Dravet.
  • What mechanisms have been identified in common models that would be high priority for investigation? 

Clinical Working Session

The participants discussed what the clinical selection criteria are for identifying disease(s) in which to study epileptogenesis. Factors thought to be important are:

  • Prevalence, impact,  emerging public health need, (traumatic brain injury, for example);
  • Burden of disease (burden of individual experience with epilepsy, for example Dravet);
  • Generalizability (trickle-down effect of finding approach in one syndrome on others);
  • Homogeneity, collateral benefit (effect on other aspects of syndrome such as developmental delay, depression, cognition, etc.);
  • Likelihood of a feasible and reproducible animal model. 
  • Trial feasibility, including incidence of new cases (single center vs. multicenter), latency, clinical biomarkers (for entry in trial, surrogate markers, any biomarkers aligned with preclinical models), and multi-center collaborations required to run a trial (centralized services).

The participants reviewed the list of diseases and types of epilepsy compiled for the session by Dan Friedman and Jackie French (see link or attachment). Four diseases appeared to best meet the above criteria – TBI, febrile status, TSC and neonatal hypoxia with seizure, and lower on the ranking was Dravet, and first unprovoked seizure.

Bridging Clinical and Pre-Clinical Studies

The breakout sessions were designed to discuss four syndromes or types of epilepsy, and to identify for each the information needs clinically and pre-clinically, the connection between existing animal models and the human phenotype (and genotype), and the overall body of evidence available, what biomarkers exist or are needed, etc.  The aim is to identify high risk clinical and preclinical populations (clinical consortia that collect data in a standardized way, and similar for animal models), and create accurate models to represent the clinical scenario in order to identify targets for therapy and potential biomarkers of anti-epileptogenesis.

The participants selected the following four areas for further discussion:

Traumatic Brain Injury (TBI): This is a very heterogeneous population of individuals because of the different forms of trauma that lead to posttraumatic epilepsy. Individuals with penetrating head injury, for example, have rates of post-traumatic epilepsy as high as 50%.  Rates are lower for less severe head injuries.  Studies should focus on a well-defined subpopulation (direct cortical impact, sheer injury, secondary effects, for example) and get agreed upon alignment of the animal models with the human condition, as well as clinical biomarkers for both acute and chronic epilepsy. 

Neonatal hypoxia with seizures:  Current estimates suggest that 57% of full-term infants with hypoxic ischemic encephalopathy with neonatal seizures will develop epilepsy within 1-2 years.  This group is well defined and is a reasonably homogeneous group (even though the causes of the hypoxia may be different, the outcomes are the same).  There are clinically relevant animal models with potential targets, and the results from studying severe refractory epilepsies in this population and in animal models may be generalizable to other populations. 

Febrile status:  There are several animal models of febrile status based on hyperthermia or inflammatory agents, but the natural history of epilepsy in these models may need to be further characterized.  MRI changes in the hippocampus are a possible biomarker that can be used to study febrile status in animal models and in humans.

Tuberous Sclerosis Complex (TSC):  Studying epileptogenesis in the context of TSC provides a known molecular target, drugs that are FDA-approved, and several animal models available for study.  However, there is a need to more closely correlate the animal models with the human pathology and to learn more about the underlying mechanisms of epilepsy by studying human tissue. 


There have been tremendous advances in the study of epilepsy over the last 10 years.  What we know about animal models is significant, and novel targets are now available.  The deliverables that would be possible moving forward are:

  •  Standards for carrying out preclinical studies and for evaluating the reliability and feasibility of using animal models to study epileptogenesis that are predictive, consistent and reliable models of the human condition(s).
  • A mechanism for publishing negative results that would be available to all so no one reinvents the wheel in epilepsy research.
  • Development and sharing of clinically relevant animal models and increased collaboration between investigators.  A change in the use of our language regarding treatments:  anti-epileptic versus anti-seizure medications.  There is also a need to revisit the definition of epileptogenesis, cure, prevention, latency period, etc. in terms that can be incorporated into animal model development, clinical trials, and regulatory labeling.
  • Methods to address how to best deal with intellectual property issues.
  • A unified tissue and DNA repository for the epilepsies, including adequate phenotypic and genotypic (where available) data, to serve as a valuable research resource for the entire research community.
  • Accelerated programs for screening new drugs for their anti-epileptogenic properties.
  • Hand-off strategies for proof-of-concept studies to move potential treatments from preclinical to human studies.
  • Affordable, long-term animal monitoring units to study the development of epilepsy over time.
  • Processes and systems for sharing data.
  • The grid of human syndromes that was developed for discussion should be shared with the community, along with a grid of relevant animal models and information on potential targets.
  • A white paper is needed that discusses the issues in preclinical methodology and clinical trials for anti-epileptogenic treatments (Galanopoulou et al., 2012).
  • Identification of endpoints for studies (outcomes) that would make moving from preclinical to human studies more feasible. There is an urgent need for preclinical researchers to work with clinicians so that study design, biomarkers, and outcomes in both settings are matched for maximum efficacy. 


Galanopoulou AS, Buckmaster PS, Staley KJ, Moshe SL, Perucca E, Engel J, Jr, Loscher W, Noebels JL, Pitkanen A, Stables J, White HS, O’Brien TJ, Simonata M for the American Epilepsy Society Basic Science Committee and the International League Against Epilepsy Working Group on Recommendations for Preclinical Epilepsy Drug Discovery (2012) Identification of new epilepsy treatments: Issues in Preclinical Methodology.  Epilepsia (*):1-12 [Epub ahead of print]

Last updated March 16, 2012