Despite the arrival of newer anti-epileptic drugs (AEDs), seizure control hasn’t improved in the last several decades, researchers found.
In a large longitudinal cohort study in Scotland, the 1-year seizure-free rate was unchanged over the study period of 1982 to 2012, hovering in the low 60% range, reported Patrick Kwan, MD, PhD, of Royal Melbourne Hospital in Australia, and colleagues.
That means more than a third of epilepsy patients still won’t have adequate seizure control: “Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved,” they wrote online in JAMA Neurology.
In 2000, this same research group published outcomes for patients treated from 1982 to 1998, showing that more than a third of epilepsy patients remained uncontrolled. They also found several predictors of poor treatment response, including unknown disease etiology, a high number of seizures before starting therapy, longer duration of epilepsy before the first treatment, history of recreational drug use, family history of epilepsy, history of psychiatric disease, and history of febrile seizures — all of which were again confirmed to predict poor response in this extended version of the study, they said.
More than a dozen new AEDs with different mechanisms of action have come on the market since the earlier study was published, and while some have touted improved safety, all have been reported to have similar efficacy to established AEDs.
For the latest study, Kwan’s group looked at data on 1,795 patients newly treated for epilepsy at Western Infirmary in Glasgow, Scotland, from July 1, 1982 to Oct. 31, 2012. All were followed for a minimum of 2 years (the median follow-up was 11 years) and their median age was 33.
At the end of the study, about 64% had been seizure-free for at least a year, and the proportion of patients who were seizure-free at last follow-up was similar across the three time period subgroups, ranging from 61% to 64%, they reported.
Among those achieving 1-year seizure freedom, 87% were taking monotherapy and 90% achieved seizure control with the first or second AED regimens.
Overall, about half of patients remained seizure-free for at least a year with the initial AED, but if this drug failed, the second and third regimens provided only an additional 12% and 4% likelihood of seizure freedom, respectively. Only 2% of patients achieved optimal seizure control with subsequent AEDs, they 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% CI 1.56 to 1.91, P<0.001) -- lending support to the definition of drug-resistant epilepsy as "failure of two appropriately selected and tolerated AED regimens," they wrote.
Throughout the trial, there was a marked increase in the use of newer AEDs: the first decade was dominated by carbamazepine, valproate, and phenytoin as initial therapy, while the latter decade was dominated by 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.
“This finding also suggests that the modern AEDs still lack the capacity to rectify the underlying neuropathological processes and reverse epileptogenesis,” they continued. “Our results provide further evidence that current AEDs are seizure-suppressing and not disease-modifying. Future research should focus on novel treatments that can modify the development or progression of epilepsy, ideally guided by biomarkers.”
In an accompanying editorial, Allen Hauser, MD, of Columbia University in New York City, called the findings “sobering and somewhat disconcerting.”
“The results of this study suggest that the advent of new pharmacological therapies has had little impact on the proportion of newly diagnosed people rendered seizure-free” — a finding that “is not new and should not be surprising.”
Even with the best management, Hauser wrote, “only about two-thirds of people with newly diagnosed epilepsy will be successfully treated … Resources need to be dedicated to developing anti-epilepsy therapies that interfere with or reverse the underlying disease process, rather than merely identifying agents that suppress seizures.”
Kwan and co-authors disclosed relevant relationships with Eisai, UCB Pharma, GlaxoSmithKline, Lundbeck, Bial, GW Pharmaceuticals, Takeda, Sanofi, Abbott, AbbVie, AstraZeneca, Amgen, Johnson & Johnson, and Pfizer.
Hauser disclosed no relevant relationships with industry.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner