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My Take: Essential Scientific Advances in Epilepsy Treatment

Anli A. Liu, MD

Associate Professor of Medicine
Division of Epilepsy
Department of Neurology
NYU Langone
New York, New York

Anli A. Liu, MD, has no relevant conflicts of interest to report.

View ClinicalThoughts from this Author

Released: May 28, 2021

The American Academy of Neurology (AAN) Annual Meeting 2021 offered some new findings on the efficacy and safety of existing antiseizure medications (ASMs), newly approved ASMs, and ASMs in development. Here are my thoughts on the studies I found most interesting.

Epilepsy Treatment in Pregnancy
During the past 15 years, as the epilepsy community has gained valuable insights about pregnancy outcomes of women with epilepsy, there has been a profound shift in the prescribing practices of ASMs for women of childbearing age. Because valproic acid use during pregnancy has been associated with lower IQ in children, young women are either typically started on or transitioned to lamotrigine and levetiracetam during their childbearing years. Periconceptional folate and breastfeeding have also been correlated with higher IQ and better verbal abilities in children of women with epilepsy and have become integrated into evidence-based preconception counseling.

At AAN 2021, I was happy to see more evidence on the safety of lamotrigine and levetiracetam in unpublished data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drug Study (MONEAD). MONEAD is a prospective, observational multicenter study of pregnancy outcomes in US women with epilepsy receiving treatment (n = 289), healthy women (n = 89), and their children.

Enrolled women with epilepsy were mostly receiving monotherapy (78%), with 35% receiving lamotrigine and 28% receiving levetiracetam, and those on dual therapy mostly received a combination of these 2 agents (10%).

The main findings of the study were that, at 3 years of age, there was no difference in language outcomes measured by Differential Ability Scales-II (DAS-II) or general conceptual ability (similar to IQ) scores between children of women with epilepsy and children of healthy women.

The secondary finding was that there was no relationship overall between blood concentration of medication in the third trimester and verbal cognition at age 3. (On secondary analysis, there appeared to be a negative correlation between levetiracetam maximum blood concentration in the third trimester and neuropsychological outcomes, although the authors advise that these findings should be interpreted with caution until the results are replicated.)

These preliminary findings presented at AAN should give us more reassurance in prescribing lamotrigine and levetiracetam for women of childbearing age as they consider pregnancy.

Newer Epilepsy Treatments
The search continues for new epilepsy treatments with novel mechanisms of action.
Cenobamate (formerly YKP3089) was approved by the FDA in 2019 for the treatment of adults with refractory focal epilepsy and joins the growing list of more than 30 medications available in the US market. Although the exact mechanism of action is unknown, cenobamate is believed to modulate voltage-gated sodium channels and GABAA channels to decrease firing thresholds.

Since cenobamate is often added on to a patient’s existing drug regimen, the real-world experience of its efficacy and tolerability in combination with other antiseizure medications should be considered. In particular, there is suggestion that cenobamate may lower lamotrigine and carbamazepine plasma levels.

One phase III post hoc study investigated the dosing of lamotrigine and carbamazepine for patients who were started on cenobamate. Contrary to expectation, lamotrigine and carbamazepine doses were reduced in patients who continued cenobamate vs those who discontinued cenobamate.

The main reasons for dose reduction of lamotrigine and carbamazepine were adverse events of fatigue, ataxia, and dizziness. Meaningful decreases in lamotrigine (mean: 82.1 to 100 mg/day) and carbamazepine (411 to 700 mg/day) were seen in 3 groups of cenobamate patients: those who were seizure free for more than 3, 6, or 12 months.

These dose reductions in seizure-free patients support the efficacy of cenobamate as an adjunctive treatment for refractory focal epilepsy, despite its pharmacokinetic interaction with these 2 commonly prescribed medications. Doses of ASMs may be able to be reduced while receiving concomitant cenobamate, without compromising long-term efficacy

Another agent joining the list of medications for seizures is the pharmaceutical formulation of cannabidiol (CBD), approved by the FDA in 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex.

This formulation of CBD has also been available as add-on therapy for treatment-resistant epilepsy through an expanded access program. At AAN 2021, we saw long-term results out to 144 weeks suggesting that, in this context, it was associated with reduction in seizures across multiple seizure types—both convulsive and nonconvulsive.

In all 24-week windows of CBD treatment for nearly every seizure type, the reduction in seizures per 28 days was >50%, and more than one half of patients had 50% reduction in seizures. The safety profile was consistent with previous analyses of this formulation.

Soticlestat (TAK-935/OV935)
Soticlestat is an ASM in development with a novel mechanism of action: It selectively inhibits cholesterol 24-hydroxylase, which breaks down cholesterol to 24S-hydroxycholesterol (24HC) in the brain. Decreased 24HC can dampen glutamatergic signaling in the brain to reduce seizures.

The ENDYMION study is an open-label extension study of soticlestat in pediatric and adult patients with developmental and epileptic encephalopathies (DEE), including Dravet syndrome, Lennox-Gastaut syndrome, cyclin-dependent kinase–like deficiency disorder, chromosome 15q duplication syndrome, and adult DEE.

Efficacy in seizure reduction was seen in all DEE patient groups by Weeks 25-36, with varying median seizure reduction rates of 24.7% to 85.4%, depending on the group.

In the observation period, 71.6% experienced a treatment-emergent adverse event, with 26.7% determined to be related to the soticlestat treatment. The most common adverse event attributed to the study drug were decreased appetite and somnolence, with no reported serious adverse events.

Your Thoughts
What epilepsy studies did you find most interesting at AAN 2021? Answer the polling question and join the conversation in the discussion below.

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