2021 AES/NINDS Epilepsy Research Benchmarks

On January 4-6, 2021 NINDS hosted Curing the Epilepsies 2021: Setting Research Priorities conference virtually via Zoom. This conference was the fourth in a series of Curing the Epilepsies conferences held approximately every 7 years since 2000. The goal of the conference is to bring together all stakeholders—including researchers, clinicians, patients, families, and advocates—to evaluate the current state of epilepsy research and consider priorities for future efforts. As an important outcome, the Curing the Epilepsies conferences have led to the development of Benchmarks for Epilepsy Research, which reflect priorities shared across the epilepsy community for research toward clinically meaningful advances in understanding and treating the epilepsies.

In late 2019 the Epilepsy Benchmark Stewards Committee, coordinated by the American Epilepsy Society, started the process of revising the Epilepsy Research Benchmarks by publishing progress reports for each of the four benchmark areas. Revisions were drafted based on these reports and public comments received through a 2019 NINDS Request for Information (RFI) and were posted as draft 2020 epilepsy research benchmarks as part of a crowdsourcing campaign conducted in September and October 2020. The final 2021 AES/NINDS Epilepsy Research Benchmarks incorporate revisions in response to public comments from the crowd sourcing campaign and the priorities identified during the conference. These Benchmarks are intended to anchor research over the next 5-7 years in the issues that are key to understanding the epilepsies and improving meaningful outcomes for people with epilepsy through research.

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2021 AES/NINDS Epilepsy Research Benchmarks

Area I: Understand the causes of the epilepsies and their relationship to epilepsy-associated neurologic, psychiatric, and somatic conditions.

A. Identify the many genes and molecular pathways associated with the epilepsies and epilepsy-related conditions. Define the many trajectories to hypersynchrony and demonstrate how these trajectories are modified by genetic background.

B. Identify and understand the mechanisms by which infections, inflammation, environment, vascular changes, perinatal exposures or insults, trauma, and other causes and risk factors, alone and in combination, contribute to the development of the epilepsies and epilepsy-related conditions.

C. Determine how alterations in molecular and cellular function interact with alterations in circuit and network function in the pathogenesis of cortical hyperexcitability and the clinical epilepsies.

D. Identify and understand the mechanisms by which factors related to age, sex, race/ethnicity, socioeconomic status, and other demographic features modulate epilepsy risk, drawing from discoveries in basic, translational, clinical, and population-level investigation.

E. Define the various mechanisms that explain why seizures commonly present with neuropsychiatric and neurodevelopmental comorbidities, drawing from discoveries in basic, translational, clinical, and population-level investigation.

Area II: Prevent epilepsy and its progression.

A. Understand epileptogenic processes involved in epilepsies with neurodevelopmental origins, including those due to genetic or epigenetic causes.

B. Understand epileptogenic processes involved in the development of epilepsy following traumatic brain injury, stroke, brain tumor, infections, neurodegeneration, or other insults to the brain.

C. Identify biomarkers that will aid in identifying, predicting, and monitoring epileptogenesis and disease progression, including markers early after injury/insult that identify those people at risk for epilepsy.

D. Develop or refine models aligned with the etiologies of human epilepsies to enable improved understanding of epileptogenesis and rigorous preclinical therapy development for epilepsy prevention or disease modification.

E. Identify new targets and develop interventions to prevent or modify epileptogenesis and the progression of epilepsy and epilepsy-related conditions.

F. Combine complex systems and/or machine learning approaches with laboratory studies in order to identify convergent phenotypes or pathways, examine background genetic or epigenetic effects, or consider novel molecular reclassifications of disease and the epileptogenic process.

Area III: Improve treatment options for controlling seizures and epilepsy-related conditions while limiting side effects.

A. In order to identify new antiseizure or disease-modifying therapeutic targets and mechanism-based therapies, we need to (1) understand the mechanisms of initiation, propagation, and termination of seizures at the cellular and network level for different seizure types, including status epilepticus, and in different forms of epilepsy, (2) understand the neural circuits, cell types, cellular interactions, and genetic factors that participate in interictal activity, different seizure types in different forms of epilepsy, and (3) understand the cellular, molecular, and network and systems basis for treatment side effects.

B. Identify genetic, molecular, imaging, immunological, and electrophysiological biomarkers, determine mechanisms of pharmacoresistance, and develop clinical informatics tools so that the most appropriate pharmacological, biological, surgical, or device therapy can be selected for an individual with a common or rare epilepsy. These efforts should take into consideration time, an individual’s unique set of personal characteristics, including sex and life stage (e.g., childhood, pregnancy, elderly), and consider inclusion of non-seizure outcome measures reflecting other epilepsy-related risks.

C. Develop, refine, fully characterize, and deploy epilepsy and seizure models (including in non-rodents) that align with the etiologies, clinical features, rhythmicities, treatment responses, and development of resistance of human epilepsies to improve understanding of epileptogenesis, ictogenesis, seizure initiation, seizure termination, disease progression, and therapeutic targets. Explore the utility of new technologies to model human epilepsies and screen for therapies in a high throughput fashion, including iPSCs and organoids.

D. Identify, develop, and improve pharmacological, surgical, genetic, epigenetic, neuromodulatory, dietary interventions and devices to detect, predict, prevent, or terminate seizures and mitigate other epilepsy-related health risks while minimizing adverse effects.

E. Develop, improve, implement, and validate strategies, protocols, and interventions for epilepsy self-management in the home or other non-medical settings that allow ongoing assessment of treatment response, therapy adherence, and adverse effects of therapies.

Area IV: Limit, treat, or prevent co-occurring conditions associated with epilepsy across the lifespan in general and special epilepsy populations.

A. Understand and limit the impact of epilepsy on non-seizure outcomes such as neurodevelopment, mental health, cognition, health-related quality of life, and other functions.

B. Understand and limit the impact of anti-seizure treatments (medical, surgical, and other interventions) on non-seizure outcomes, such as neurodevelopment, mental health, cognition, health-related quality of life, and other functions.

C. Understand mechanisms (psychiatric and neurological) involved in non-epileptic seizures (NES). Develop effective pediatric and adult treatments and assess outcomes in NES including psychopathology and quality of life.

D. Identify causes, risk factors, and potential preventative strategies for sudden unexpected death in epilepsy (SUDEP) and other epilepsy-related mortality due to co-occurring conditions including depression, anxiety, and suicide in people with epilepsy.

E. Identify the impact of epilepsy on women’s health outcomes (fertility, pregnancy, bone health, hormones, mental health, QOL) and health of their offspring (fetal and neonatal development).

F. Understand the role of sleep and circadian rhythms in cognitive and psychiatric and other health related outcomes. Identify and treat sleep as a target to improve non-seizure outcomes, such as neurodevelopment, mental health, cognition, health-related quality of life, and other functions.

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