expert roundtables

Examining the Need for Improved Epilepsy Therapies

by Brian D. Moseley, MD; John M. Stern, MD; and James W. Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES

Overview

Advances with regard to the newer antiepileptic drugs (AEDs) include fewer side effects and more forgiving therapeutic windows. Our featured experts discuss the continued progress toward improved therapies, including precision medicine, gene therapy, and medications with improved pharmacokinetic profiles.

Q: Considering the development of newer AEDs, what advances have occurred in recent years, and what advances would you predict for the near future?

Brian D. Moseley, MD

Associate Professor
Department of Neurology and Rehabilitation Medicine
University of Cincinnati
Cincinnati, OH

“One advantage of the newer therapies is that they generally do not have a laundry list of drug-drug interactions or issues with protein binding, making them safer to prescribe.” 

Brian D. Moseley, MD

Considerable progress has been made, particularly in the past 2 decades, in the development of new AEDs that have fewer side effects than their predecessors. First-generation AEDs (eg, phenytoin) were effective in seizure control, but suffered from very narrow therapeutic windows, making accurate dosing quite difficult. Accidental underdosing and overdosing were frequent occurrences, along with toxicity and multiple side effects.

The newer AEDs are generally as effective but have better pharmacokinetic profiles (ie, fewer side effects, fewer drug-drug interactions). This is particularly advantageous for elderly patients with epilepsy who tend to have more medical comorbidities and take multiple medications. Awareness of drug clearances is critical, especially in individuals who may have altered kidney and liver function. One advantage of the newer therapies is that they generally do not have a laundry list of drug-drug interactions or issues with protein binding, making them safer to prescribe.

There is still much work to be done, however. One-third of patients remain drug resistant. Although newer AEDs are associated with fewer side effects than past generations with similar efficacy, they have not reduced the rates of treatment resistance. Newer combinations and attempts at rational polytherapy continue to be explored, but the available evidence suggests that there has been no dramatic improvement in efficacy resulting from this approach. Alternative treatment modalities, such as surgical resection of epileptic foci and devices for epilepsy (eg, vagus nerve stimulation, deep brain stimulation), show increasing promise in addressing the needs of treatment-refractory patients.

John M. Stern, MD

Professor, Department of Neurology
Director, Epilepsy Clinical Program
Director, Epilepsy Fellowship Program
David Geffen School of Medicine at UCLA
Los Angeles, CA

“I wonder if future improvements in pharmacotherapy outcomes will come from a more precise identification of patients and subpopulations that respond better to one medication than another.”

John M. Stern, MD

The care of patients with epilepsy has improved with the development of AEDs that are safer and better tolerated, but, as Dr Moseley pointed out, these advances have not reduced the overall rates of treatment resistance. The more significant advancement for seizure freedom during the past few decades has been achieved in surgical resection, and this is not as much in the development of new surgical techniques but rather in diagnostic techniques that have greater sensitivity and thereby can identify resectable abnormalities that can render a person seizure free.

Building on this attention to imaging as a means to achieve seizure freedom, I wonder if future improvements in pharmacotherapy outcomes will come from a more precise identification of patients and subpopulations that respond better to one medication than another. For example, treatments for focal seizures have emerged from randomized controlled trials that include all forms of focal epilepsy, and the trials have shown similar results irrespective of the medication being studied. These similar results could reflect a heterogeneity of participants in the trials and potentially an averaging of responses. The challenge is to identify specific patients in clinical trials who are more likely to respond to one specific AED. In addition to differentiating patients according to the seizure localization, another approach may be to differentiate according to the abnormal cerebral networks—essentially taking the anatomic approach of the functional technique provided by the electroencephalogram (ie, focal vs general onset), which has been helpful for AED selection, and moving it into the 21st century to assess brain function at a higher resolution.

Although precision medicine–based approaches are currently limited in epilepsy, there are some early examples of success. For instance, a glucose transporter mutation found to cause absence epilepsies responds well to diet therapy. Additionally, mTOR inhibitors can be effective for epilepsy associated with tuberous sclerosis complex. Additional pharmacologic precision is clearly needed.

James W. Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES

Professor and Chief of Pediatric Neurology
Le Bonheur Chair in Pediatric Neurology
University of Tennessee Health Science Center
Director, Neuroscience Institute and Le Bonheur Comprehensive Epilepsy Program
Le Bonheur Children’s Hospital
Memphis, TN

“Studies of gene therapy are expected to start this year on children and adults with Dravet syndrome, with the goal of targeting the actual genetic defect and curing the disease. Gene therapy could be a real game changer for these families.”

James W. Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES

As current statistics bear witness, seizure freedom remains beyond reach for a substantial proportion of patients with epilepsy. However, it is an exciting time for those of us who treat epilepsy because we are in the midst of significant advances that are enabling the majority of patients to achieve seizure freedom.

Most of our new drugs have either long half-lives or extended-release formulations, which help patients to stay on their medications to maintain good control. Additionally, much progress has been made in recent years to address unmet needs for those patients with genetically based epilepsy syndromes, who comprise niche subsets of the population. There are currently more than 200 genetically based epilepsies that we can identify, and, the last time I checked, there were 75 different lay support groups for genetic epilepsies. Other special populations have always represented treatment challenges, such as infants, women, and the elderly. Research concentrating on patient-derived pluripotent stem cells could provide a platform for genetic epilepsies, high-throughput drug screening, and personalized medicine.  

Further, it is expected that this year, for the first time, we will target the genetic makeup of epilepsy in patients with Dravet syndrome, which could potentially cure the underlying cause of the epilepsy and improve the cognitive impairments and other neurological manifestations in these patients. This is a novel concept, as most treatments prevent seizures (a symptom); however, they do not cure the epilepsy. Studies of gene therapy are expected to start this year on children and adults with Dravet syndrome, with the goal of targeting the actual genetic defect and curing the disease. Gene therapy could be a real game changer for these families.

References

Billakota S, Devinsky O, Kim KW. Why we urgently need improved epilepsy therapies for adult patients. Neuropharmacology. 2019:107855. doi: 10.1016/j.neuropharm.2019.107855. [Epub ahead of print]

Iffland PH II, Carson V, Bordey A, Crino PB. GATORopathies: the role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia. 2019;60(11):2163-2173.

Lybrand ZR, Goswami S, Hsieh J. Stem cells: a path towards improved epilepsy therapies. Neuropharmacology. 2019 Sep 17:107781. doi: 10.1016/j.neuropharm.2019.107781. [Epub ahead of print]

Niibori Y, Lee SJ, Minassian BA, Hampson DR. Sexually divergent mortality and partial phenotypic rescue after gene therapy in a mouse model of Dravet syndrome. Hum Gene Ther. 2020 Jan 16. doi: 10.1089/hum.2019.225. [Epub ahead of print]

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