A joint report calls for reconsidering the definition of drug-resistant epilepsy, with a focus on epilepsy type and etiology
“Despite progress in the development of anti-seizure medications, one third of people with epilepsy have drug-resistant epilepsy,” Aristea S. Galanopoulou, MD, PhD, and colleagues wrote in a study published as a special report in Epilepsia. “The working definition of [drug-resistant epilepsy], proposed by the International League Against Epilepsy (ILAE) in 2010, helped identify individuals who might benefit from presurgical evaluation early on.”
However, because incidence of the condition remains high, the TASK1 working group on drug-resistant epilepsy—which is part of the larger ILAE/American Epilepsy Society Joint Translational Task Force—continued to examine the heterogeneity, complex presentation, and mechanisms of drug-resistant epilepsy, as well as the confounders that impact the ability to draw mechanistic insights in testing of treatment responses. The TASK1 group also discussed barriers associated with modeling the condition across the lifespan.
This review led the researchers to “propose that it is necessary to revisit the current definition of [drug-resistant epilepsy].” Physician’s Weekly spoke with Dr. Galanopoulou to learn more about the TASK1 working group’s perspective, which was published as a special report in Epilepsia, on what such a definition might look like.
PW: Why revisit the definition of drug-resistant epilepsy?
Aristea S. Galanopoulou, MD, PhD: The current definition of drug-resistant epilepsy, proposed in 2010 by a Task Force of the ILAE Commission on Therapeutic Strategies, provided a common framework for the clinical management of people with epilepsy as well in designing clinical trials for new therapeutics. The ILAE Task Force recognized, at the time, the gaps in knowledge on epidemiology, our understanding of drug-refractory epilepsy, and the need for more systematic studies.
While this definition provides a major step toward a common way of thinking among clinicians and clinical trialists, and served clinical practice by urging for earlier referral of people who have not responded to two antiseizure medications for evaluation for epilepsy surgery, there are still areas that were not addressed satisfactorily. Epilepsy is heterogeneous, with complex clinical presentations, etiologies, and mechanisms that respond differently to available therapeutic approaches. Some cases, such as many pediatric epilepsies, do not have “appropriate” treatments available to achieve seizure freedom, while others need effective treatments to stop seizures early on to achieve the best outcomes.
PW: What were the key findings of the TASK1 working group?
Aristea S. Galanopoulou, MD, PhD: Although the current definition of drug-resistant epilepsy has been very useful, it may not encompass all the clinical manifestations of drug-resistant epilepsy and may not fully apply to all epilepsies. Failure of two appropriate medications is not a universal criterion. Some drug-resistant epilepsies may be recognized from the moment of diagnosis; in other cases, trying new medications after the second has failed may not be futile, in terms of achieving seizure freedom, when surgery is not an option.
The ILAE classifications of seizures, epilepsies, and epilepsy syndromes illustrate the complexity and heterogeneity of epilepsies across the lifespan. Different etiologies of epilepsies may have different predilections to being drug resistant. For example, certain genetic developmental and epileptic encephalopathies may be drug-resistant from the start, as is the case with Dravet syndrome. In contrast, certain genetic generalized epilepsies (idiopathic) have lower risk for being drug-resistant, and investigators have challenged the criterion of failure of two medications
PW: What does an improved definition of drug-resistant epilepsy look like?
Aristea S. Galanopoulou, MD, PhD: Our report calls for collaboration among clinicians, along with clinical and preclinical researchers as well as patient advocates, to revisit the concept of drug resistance in epilepsy and provide a new framework for future studies and clinical practice. Ideally, the new framework will provide guidance to clinicians based on epilepsy type and associated clinical needs and priorities, as well as updated knowledge of etiology and neurobiology of drug resistance in epilepsy, to inform strategies for both clinical and preclinical research on drug-resistant epilepsies that could be translatable across model systems and humans.
PW: Where is additional research needed?
Aristea S. Galanopoulou, MD, PhD: We need more research probing mechanisms of drug resistance in epilepsies in both model systems and humans as well as platforms that can validate findings across models and humans. We need tools that will enable early diagnosis and prediction of drug resistance and will monitor in vivo the treatment effects with sufficient ability to track response or failure early, to avoid unnecessary exposure to treatments that will not be effective.
