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In the Clinic-Epilepsy

Epilepsy Outcomes Show No Improvement Over Past 30 Years, Despite Availability of New Antiepileptic Drugs

Bender, Eve

doi: 10.1097/01.NT.0000533815.77383.77
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An analysis of treatment outcomes for people with newly diagnosed epilepsy found that seizure frequency has not greatly changed.

Have outcomes for treatment for epilepsy advanced in the past 30 years? Apparently not, according to a study published in the March issue of JAMA Neurology.

The analysis found that one-year seizure free rates for epilepsy patients have hovered at around 64 percent for the past 30 years, leading the study authors to conclude that “more than one-third of patients experience epilepsy that is uncontrolled.”

The newer antiepileptic drugs (AEDs), with differing mechanisms of action, have seemingly made little difference in seizure rates. “There is a biological ceiling for drugs that mainly act as anti-seizure,” the study author Patrick Kwan, MD, PhD, professor of neurology at the Central Clinical School and School of Public Health & Preventive Medicine at Monash University in Melbourne, Australia, told Neurology Today. “Current drugs do not modify the underlying pathobiology of epilepsy.”

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Dr. Kwan and his colleagues followed nearly 1,800 patients newly diagnosed with epilepsy between 1982 and 2012 who had been referred by their primary care doctors to an inpatient unit in Glasgow, Scotland, specializing in the treatment of patients with epilepsy. The researchers divided them into three subgroups based on the year that they started the initial AED treatment: between 1982 and 1991, 1992 and 2001, and 2002 and 2012. They followed all the patients for a minimum of two years; the median follow-up period was 11 years.

For patients who stayed seizure-free for a year, 87 percent (993) were taking just one AED, and 90 percent (1,028) had achieved freedom from seizures with either the first or second AEDs.

Just half of the sample (906) remained seizure-free for one year or longer with the initial AED, and if the initial AED failed, the second and third regimens provided only an additional 12 percent and 4 percent likelihood of seizure freedom, respectively. Only 2 percent of patients achieved optimal seizure control with subsequent AEDs, the authors reported.

Those with epilepsy that wasn't controlled with the first AED had a greater likelihood of not responding to treatment for each subsequent medication (OR 1.73, [95 percent CI 1.56 to 1.91], p<0.001).

The trial was characterized by changes in treatment for epilepsy patients; most took carbamazepine, valproate, and phenytoin as initial therapy in the 1980s and into the 1990s, while it was more common for those followed later in the study to start with newer AEDs such as valproate, levetiracetam, and lamotrigine as initial monotherapy.

“While some modern AEDs have novel anti-seizure mechanisms, their increasing use did not seem to have improved overall long-term seizure control,” the authors wrote. “This may be attributed to deficiencies in the preclinical and clinical strategies of AED development,” such as enrollees being required to have established epilepsy and a high frequency of seizures.



The authors noted that the prognosis for AED treatment was associated with the number of seizures that occurred prior to treatment, a family history of epilepsy in first-degree relatives, and a history of recreational drug use in epilepsy patients.

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In an accompanying editorial in JAMA Neurology, W. Allen Hauser, MD, FAAN, professor emeritus of neurology and epidemiology at the G. H. Sergievsky Center at Columbia University's College of Physicians and Surgeons, said the findings were “sobering” and “somewhat disconcerting” that despite the fact that new medications were introduced over the 30-year span of the study, response rates were static among epilepsy patients in the study.





“Certainly, attempts to develop better models and to develop anti-epileptogenic compounds as opposed to anti-seizure compounds has been a goal, but as yet this seems not to have been accomplished,” he said in comments to Neurology Today.

Dr. Hauser noted that resources need to be dedicated to developing antiepilepsy therapies that interfere with or reverse the underlying disease process, rather than merely identifying agents that suppress seizures.

“This study makes the important point that newer AEDs have not substantially increased seizure-free rates in patients with epilepsy,” Gregory L. Krauss, MD, professor of neurology at Johns Hopkins University told Neurology Today.

He observed that the findings of the longitudinal cohort trial are consistent with the results of adjunctive clinical trials treating drug resistant patients. “This is important because freedom from seizures is critical for improving quality of life in epilepsy,” said Dr. Krauss.

The study findings and editorial do not highlight the benefits of second and third generation AEDs as compared to older drugs, however, he noted. Compared to older AEDs, some newer treatments have low risks for birth defects, improved cognitive profiles, and minimal pharmacologic interactions, which are critical for treating seizures in patients with tumors receiving chemotherapy or for treating seizures in patients with HIV on anti-viral therapy. “I find also that about 20 percent of my treatment-resistant patients on each new AED benefit from marked reductions in both seizure frequency and severity — an outcome [that was] not measured in the study,” said Dr. Krauss.

He noted that new AEDs in the pipeline show promise for improving seizure-free outcomes in patients with drug-resistant epilepsy. “In an abstract presented at the AAN in Vancouver two years ago, we reported that the new drug cenobamate produced seizure freedom in 20 to 25 percent of patients treated in two pivotal trials... I have not previously had study patients who are seizure free and are able to drive to their study visits,” he remarked.

In addition, Dr. Krauss added, hope lies in the advances in new genetic findings in epilepsy and the development of treatments for these underlying genetic disorders using gene knife repair (CrispR) technology.

Sheryl Haut, MD, professor of neurology and director of the adult epilepsy program at Montefiore Medical Center and Albert Einstein College of Medicine, said “the results of this study are both remarkable and simultaneously not surprising.”

Dr. Haut said it is remarkable that the percentages of patients achieving seizure freedom with first and second-line antiepileptic therapy is so highly conserved across the decades of the study. “However, to those of us who have been treating patients throughout this era, it has been clear that we have not made very significant pharmacologic progress in terms of efficacy,” she told Neurology Today. She noted that this may be related to mechanistic similarities among many of the AEDs and similar refractory patient populations enrolled in the clinical trials. “But this is not the complete answer, as a number of AEDs with novel mechanisms of action have been approved, yet did not significantly impact on these numbers,” she noted.

In terms of new treatments under development, Dr. Haut said that immune therapies have been expanding in many disorders and are beginning to enter clinical trials in epilepsy. For instance, Biogen is conducting a phase 2 clinical trial of natalizumab versus placebo in patients with drug-resistant focal epilepsy. “The promise of immune therapies suggests a possible disease-modifying approach, which is an area still lacking in epilepsy treatment,” said Dr. Haut.

In addition, she noted, there has been extensive interest in cannabidiol and related extracts of the cannabis plant, with large randomized trials in Lenox Gastaut syndrome and Dravet syndrome recently completed. “There is a strong suggestion that new formulations with more optimal pharmacokinetics and bioavailability may also provide improved seizure control,” Dr. Haut said.

She also mentioned new preclinical technologies, which combine antiepileptic medicines with new innovative delivery systems, such as implanted devices, that release drugs responsively.

All in all, the commentators agreed that despite the findings from the study, there was reason to be hopeful about future advances in epilepsy.

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Dr. Kwan and/or his institution received speaker or consultancy fees and/or research grants from Eisai, GlaxoSmithKline, Johnson & Johnson, Pfizer, and UCB Pharma. Dr. Hauser is a member of the Sudden Unexpected Death in Epilepsy monitoring committee of Neuropace and a member of the editorial boards of Acta Neurologica Scandinavia, Epilepsy Research, and Neuroepidemiology. Dr. Haut reported that she is a consultant for Otsuka, Engage, and Eisai.

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•. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: A 30-year longitudinal cohort study JAMA Neurol 2018; 75(3):279–286.
•. Hauser WA. Editorial: Questioning the effectiveness of newer antiseizure medications JAMA Neurol 2018: 75(3):273–274.
© 2018 American Academy of Neurology