Metabolism-based Therapies for Epilepsy Virtual Workshop

Metabolism-based Therapies for Epilepsy Virtual Workshop

November 9, 2020
November 9, 2020


Adam Hartman

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Virtual Workshop
11:00 a.m. - 4:00 p.m EST

Event Description: 

The “Metabolism-based Therapies for Epilepsy” workshop brought together experts in brain metabolism, epilepsy, clinical trials, statistics, and patient advocacy to discuss the current state of the science of brain metabolism, seizures, and metabolism-based therapies for epilepsy (MBTE) and provided an opportunity for participants to discuss gaps in research, current knowledge, and future opportunities.

Walter Koroshetz, M.D., director of the National Institute of Neurological Disorders and Stroke (NINDS), provided pre-recorded remarks before the public workshop session, emphasizing that despite the fact that there are publications going back 100 years describing use of a ketogenic diet to treat epilepsy, much is still unknown about the mechanisms of its antiseizure effects. He noted that there is a great deal of work to be done in this field to address gaps in our knowledge that would advance the field towards more tolerable and effective metabolic interventions.

During pre-recorded videos, workshop moderators and panelists discussed the latest research on the basic, translational, and clinical science of MBTE. Framing comments covered neuronal metabolism and the patient and caregiver perspective on MBTE. Other introductory sessions covered metabolic therapy in epilepsy and an overview of metabolic fuels used in the central nervous system, including both in neurons and glia. The topic of rigor and transparency was presented, including challenges related to blinding in research focused on diet manipulation.

Discussions in the preclinical series focused on   ketone bodies and ketone esters, amino acids, decanoic acid, whey protein, calorie/diet component restriction, and the interplay between diet, brain, and gut microbiome. Each of these components and strategies has been identified as a means of MBTE, albeit via different mechanisms. Each presentation discussed what is known about the mechanisms of action and roles of that factor in epilepsy and what needs to be known to translate the research from the preclinical to clinical setting.

The translational research session included a discussion of a variety of biomarkers, in different contexts of use; challenges in demonstrating efficacy of MBTE in animal models and their impact on human studies, particularly in light of metabolism-based differences between animals and humans, as rodents tend to be better adapted to fasting conditions than humans; and a discussion of NINDS funding opportunities to facilitate translation from the bench to the clinic.

The clinical research session focused on implementing new knowledge in clinical practice. Topics included advanced trial designs such as master protocols, the importance of advanced statistics in clinical trial design, challenges in implementing diet-based trials, the research dietitian perspective on MBTE, and ways to incorporate  the perspectives of individuals with epilepsy and their families andcaregivers into research in MBTE.

The live/virtual session on November 9, 2020 was preceded by panel discussions that further refined the topics to be discussed at the workshop. The live/virtual session was opened by comments from Dr. Koroshetz, the conference co-chairs, and the NINDS Office of Research Quality. These were followed by a preclinical panel that discussed ideas from the pre-recorded talks that identified common themes and potential mechanisms of metabolism-based treatments for epilepsy (e.g., breakdown of whey protein in the gut into branched-chain amino acids) and lessons from human studies of these treatments (e.g., rapid reversibility of seizure control in certain individuals on a ketogenic diet after ingestion of simple carbohydrates, which might shed light on mechanisms). The translational panel discussed the translational relevance of disease and therapeutic biomarkers developed in animal models versus humans and the comparative biology between largely rodents and humans, including pros and cons of continued studies in animal models compared to pivoting toward human biology-based studies such as those using organoids or cell-based systems. The clinical panel discussed advanced clinical trial designs that might be better suited to MBTE, including both basket and platform trials; the way in which principles of rigor can be adapted to metabolism-based studies, considering the inherent limitations, including what individuals and their families would find acceptable;, and opportunities to partner with patient advocacy groups in designing trials, including choosing outcome measures, and  optimizing recruitment and retention.

The final panel summarized many of these points and included a discussion of implementation and challenges of adopting team science approaches toward tackling fundamental questions in the field. Panelists were also polled about their enthusiasm for creating a “poly-pill” that would include components to address multiple mechanisms of MBTE.

Closing comments were made by Nina Schor, M.D., Ph.D., deputy director of NINDS, with a focus on interrelationships between epilepsy, drugs, microbiome, diet, genetics, inflammation, brain dysfunction, and sudden unexplained death in epilepsy (SUDEP). Also discussed were different types of biomarkers in MBTE, including context of use, and outcomes that will make a difference for individuals with epilepsy, ranging from studies of seizure susceptibility to treatment effectiveness.

The day after the workshop, a writing group was convened with panelists from the live session, with a discussion of the unknowns and controversies in MBTE, including how to rethink the role of the brain in epilepsy and other neurological diseases, gaps in knowledge of how new tools can inform knowledge about epilepsy and guide new treatments, and how the role of metabolism in diseases such as epilepsy should be rigorously studied.

Pre-meeting videos 

Post Event Summary: 


Metabolism-based Therapies for Epilepsy Workshop Opening Remarks and Rigor


Metabolism-based Therapies for Epilepsy Workshop Translational Panel




Metabolism-based Therapies for Epilepsy Workshop Preclinical Panel




Metabolism-based Therapies for Epilepsy Workshop Clinical Panel Part 1 and Closing Remarks




Metabolism-based Therapies for Epilepsy Workshop Clinical Panel Part 2 and Closing Remarks