Epilepsy Treatment Outcomes Unchanged in Decades

Pauline Anderson

December 29, 2017

A new study has confirmed that fewer than two thirds of patients with newly diagnosed epilepsy are seizure-free after 1 year. The seizure-free rate in this new study is almost unchanged from the 64.0% in a smaller study published in 2000.

"Despite the introduction of many new antiepileptic drugs over the last two decades, the overall outcomes of people with newly diagnosed epilepsy has not changed fundamentally," Patrick Kwan, MD, PhD, professor, neurology, Monash University, Melbourne, Australia, told Medscape Medical News.

A "paradigm shift" in treatment and research strategies is needed to improve the long-term outcomes of patients with epilepsy, said Dr Kwan, who at the time of the study was at the University of Melbourne.

Their report was published online December 26 in JAMA Neurology.

The initial study included 470 patients with newly diagnosed epilepsy at the Western Infirmary, Glasgow, Scotland, who were first treated between 1982 and 1998. The current study extended that time period to 2012.

The new analysis included 1795 patients, 53.7% male and with a median age of 33 years. About 21.5% had generalized epilepsy and 78.5% had focal epilepsy.

After diagnosing epilepsy, clinicians considered seizure type, adverse drug effects, and interaction profiles when selecting an appropriate antiepileptic drug (AED). Most patients in the study (98.8%) had experienced two or more seizures before starting treatment.

For the first 6 months after beginning treatment, patients were seen at the epilepsy clinic every 2 to 6 weeks. After that, they attended follow-up visits at least every 4 months.

Patients were asked to record the number of seizures they had between clinic visits and to describe these events.

Seizure freedom was defined as experiencing no seizures for at least the previous year. The overall 1-year seizure freedom rate was 63.7%. Most of the patients who became seizure-free (86.8%) achieved this by taking a single AED.

This 86.8% rate is lower than the proportion of patients in the earlier study whose seizures were controlled with monotherapy (90.5%).

In the new study, patients with generalized epilepsy had a better response to AED therapy than did those with focal epilepsy.

Patients who did not achieve a year of seizure freedom by taking the first AED were more likely to have uncontrolled epilepsy with each additional AED (odds ratio, 1.73; 95% confidence interval, 1.56 - 1.91; P < .001 after adjustment for disease classification, age, and sex).While a second AED regimen could render about 11% more of these patients seizure-free, the benefit was reduced by more than half for the third regimen. And trying a fourth — or more — AED provided less than 5% additional probability of seizure freedom.

Marked Increase

The use of the newer AEDs increased markedly during the study. Early on, older drugs, such as carbamazepine, valproate, and phenytoin, were used much more frequently, but by the end of the study, medications such as valproate, levetiracetam, and lamotrigine were more prevalent.

But the proportion of patients who were seizure-free was similar for subgroups categorized by three time periods of AED initiation (1982 to 1991, 1992 to 2001, and 2002 to 2012).

Newer AEDs are not necessarily better tolerated than older drugs, commented Dr Kwan. The notion that these newer drugs have fewer side effects is a "probably not true," but they may be easier to use because they don't require complex drug monitoring, he said.  

From his own practice, Dr Kwan could see that the newer epilepsy drugs were not having "a huge impact" on patient outcomes, but he thought that the study would uncover at least some improvement.

However, despite "a stark change" in drugs used, with a shift from the older to the newer agents, he and his colleagues were surprised at how little change there was in outcome.

"It wasn't just that there was little change; there was no change," he said.

The researchers analyzed treatment outcomes by using the definition of seizure freedom proposed by the International League Against Epilepsy in 2010. According to this definition, seizure freedom can be an absence of seizures for three times the longest pretreatment interval between seizures, or for at least the previous year, whichever is greater.

The reason for the update was that some patients have infrequent seizures, "so not having a seizure for a year might have nothing to do with a drug," explained Dr Kwan.

This analysis yielded findings similar to those obtained by using the original definition of not having seizures for a year.

The new study also confirmed that the prognosis of AED treatment was associated with such factors as the number of seizures that occurred before treatment, a family history of epilepsy in first-degree relatives, and a history of recreational drug use.

Although the study showed that seizure freedom rates haven't changed over time at the population level, Dr Kwan pointed out that this may not be the case at the individual level.

"In terms of the frequency of seizures and their severity in individual patients, new drugs might make a difference, and this could well have made an impact on people's lives, but we haven't measured that."

Epilepsy is "a very complex disorder" representing more than just a single disease, which makes it "very hard to find a magic bullet" that targets them all and makes "a huge impact" on outcomes, said Dr Kwan.

However, it's important to develop better epilepsy therapies, and to do so requires a change in thinking and maybe "riskier approaches," he said. He added that this change in thinking must come from "all stakeholders," including funding organizations, research groups, and the pharmaceutical industry.

Clinicians should refer patients in whom two drugs have failed to a specialist center, where they may be considered for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques, said Dr Kwan.

"Do this early; don't leave it too late," he said. "There's evidence that the earlier you treat these patients, the better the outcome."

Disconcerting Findings

Some of the new findings are sobering and somewhat disconcerting, W. Allen Hauser, MD, emeritus professor of neurology and epidemiology, Sergievsky Center, Columbia University, New York City, writes in an accompanying editorial. In an interview with Medscape Medical News, Dr Hauser elaborated on what he found so disconcerting.

"For so long, there have been efforts to develop new and more effective antiseizure medications," he said. "I suspect that in the last 30 years, there have probably been 20 or more new drugs marketed in the US or Europe, or both. And over this time, in terms of at least new-onset epilepsy, which is what this study relates to, we don't seem to be doing any better."

He noted the "dramatic change" in medications over the course of the study, with the newer medications for the most part replacing older ones.

"But in terms of objective outcomes, which from the standpoint of epilepsy is seizure control, there really has been no change."

That the newer drugs don't increase the percentage of patients who are seizure free should not be surprising because, for the most part, seizure medications have been developed to try to prevent seizures rather than eliminate the underlying cause, said Dr Hauser.

"People have brain insults like a stroke or severe head injury and then develop epilepsy, and the ideal thing would be to develop something that prevents whatever the process is that leads to epilepsy. The medications we have available now, as far as we know, only suppress seizures; they do nothing in terms of preventing the process of becoming epileptogenic."

Dr Hauser also noted that there's little evidence that tolerability has improved with the advent of newer medications. So while the hope is to find an agent that stops seizures and has no side effects, "it doesn't look like in either arena there has been any improvement with medications," he said.

It could be, said Dr Hauser, that the two-thirds seizure freedom rate represents a "ceiling" for initial control of epilepsy.

However, he agreed that most of the new drugs do have some benefit. For example, they have improved bioavailability and pharmacokinetics, which makes management easier, he said.

Dr Kwan has received research grants from the National Health and Medical Research Council of Australia, the Australian Research Council, the US National Institutes of Health, Hong Kong Research Grants Council, Innovation and Technology Fund, Health and Health Services Research Fund, and Health and Medical Research Fund. He and/or his institution also 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.

JAMA Neurol. Published online December 26, 2017. Abstract, Editorial

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