Little Improvement in Late-Onset Epilepsy Outcomes Over 30 Years

Erik Greb

December 30, 2020

A high index of suspicion for late-onset epilepsy may help reduce the sizeable rate of delayed diagnosis in older patients and improve outcomes in this patient population.

Results of a longitudinal study of patients aged 65 years or older who were newly diagnosed with epilepsy show that despite the introduction of second-generation antiseizure medications (ASMs), outcomes have not improved over the past 30 years.

Investigators found that the median duration from initial seizure to initiation of treatment with an ASM was 8 months. They also found that 42% of patients had had more than five seizures before starting treatment. The study suggests that concomitant use of aspirin by patients with cerebrovascular and/or cardiovascular disease may lower seizure-freedom rates.

The current findings suggest neurologists should have a "high level of suspicion for new onset of epilepsy in the elderly to shorten the long time interval from onset to starting treatment and [decrease] the high number of pretreatment seizures we have observed," study investigator Patrick Kwan, MB BChir, PhD, professor of neurology at Monash University, Melbourne, Australia, told Medscape Medical News.

The data also suggest that neurologists can reassure patients that most will become seizure free while receiving their first or second regimen. "If a patient taking aspirin is responding inadequately, consider changing to other antiplatelet agents," Kwan added.

The study was published in the December issue of Epilepsia.

Diagnostic Challenges

The diagnosis of new-onset epilepsy in the elderly presents a unique set of challenges, the investigators note. Establishing such a diagnosis "is not always straightforward, as seizure semiology is often less reliable than in younger people, with more subtle clinical features, further masked by impaired cognitive profiles at baseline, leading to delay in treatment initiation."

They also note that standard investigations such as "interictal electroencephalogram (EEG) may be less sensitive and findings on brain imaging are often nonspecific."

They add that selecting an appropriate ASM for elderly patients is also challenging because these patients are often taking multiple medications for various comorbidities. This can affect drug metabolism and increase the risk for drug–drug interactions. Elderly patients also are more likely to experience adverse effects, particularly effects involving cognition and mood, they add.

Second-generation ASMs with improved tolerability and safety have been available since the 1980s, raising hopes that these agents may improve outcomes for patients with new-onset epilepsy.

To examine the management of newly diagnosed epilepsy in the elderly, the researchers examined data on 201 patients who presented to the Epilepsy Unit of Western Infirmary in Glasgow, United Kingdom, from July 1, 1982, to October 31, 2012. Eligible patients began treatment at age 65 years or older and were followed prospectively until April 30, 2016, or death.

The mean age of the participants at treatment initiation was 73 years, and 59% were men. All but one patient had focal epilepsy. Most (72.1%) had comorbidities, and 67% were taking at least one other concomitant drug.

Patients received individualized treatment with an ASM and were evaluated every 2 to 6 weeks for the first 6 weeks after treatment initiation.

Monotherapy was preferred, but adjunctive treatment was added if freedom from seizures was not achieved. Seizure freedom was defined as the absence of seizures for at least the previous 12 months without changes to drug dosage at the time of last follow-up.

Delayed Treatment

The median time from first seizure to treatment initiation was 8 months. However, for more than a third of patients, the time to ASM initiation was more than 12 months. Most patients (57.7%) had had more than five seizures before treatment initiation.

A total of 107 patients underwent EEG. The prevalence of epileptiform abnormalities in this group was 30.8%. Approximately 38% of patients had nonepileptiform abnormalities. A total of 193 patients underwent neuroimaging with MRI or CT. About 20% had potentially epileptogenic abnormalities, and 57% had nonepileptogenic abnormalities.

The median follow-up time was 7.5 years. At the final visit, 91.5% of patients were receiving monotherapy, and 8.5% were receiving two ASMs. The most common monotherapy was lamotrigine (37.8%). Among patients who received two ASMs, valproate was the most common concomitant ASM (70.6%).

At last follow-up, 158 patients (78.6%) remained seizure free. Of this group, 120 (75.9%) became seizure free with their first antiseizure regimen. Most who achieved seizure freedom were receiving monotherapy (94.3%); 5.7% were receiving combination therapy.

The researchers divided the study into two periods. The first was from July 1, 1982, to December 31, 1999. The second was from January 1, 2000, to April 30, 2016. The proportion of patients who received second-generation ASMs, which were introduced after 1980, increased from 31.5% in the first period to 70.3% in the second. However, rates of seizure freedom (67.1% vs 55.5%) and intolerable events (16.4% vs 19.5%) were similar between the two periods.

Patients who were taking potential enzyme-inducing concomitant medicines when they began ASM treatment were significantly less likely to achieve seizure freedom than were those taking non–enzyme-inducing concomitant medications or no concomitant medications (risk ratio [RR], 0.82).

The predicted terminal seizure-freedom rate was significantly lower for patients who had a history of cardiovascular or cerebrovascular diseases and were taking aspirin (67.6%) in comparison with patients who did not have a history of cardiovascular or cerebrovascular disease and were not taking aspirin (88.9%).

The reason for reduced freedom from seizures with aspirin is unclear. Possible mechanisms include the potential effect of aspirin on the cytochrome P450 enzyme system or expression of P-glycoprotein, said Kwan.

Solid Research

Commenting on the study for Medscape Medical News, Ilo E. Leppik, MD, professor of pharmacy and neurology at the University of Minnesota, Minneapolis, Minnesota, said this is the first study he has seen that suggests that "older people seem to have less severe epilepsy and are more easily controlled than younger people. This is really the first paper I’ve seen with really good, solid evidence for that."

The study's most important finding is that older patients appear to respond more favorably to monotherapy than their younger counterparts, he said.

The strengths of the analysis are the patient population, the high quality of workup, including imaging, and the record keeping, he added.

The finding that some patients had had more than five seizures before treatment was initiated was unusual, said Leppik. "That probably wouldn’t happen in the United States. I think in the US, we tend to treat people quickly after the second seizure."

It would have been helpful had the article included information about which patients received which drugs, said Leppik. Comparing outcomes between people who received various ASMs could be illuminating, he added.

He noted that previous studies have shown that newer ASMs control seizures as effectively as older agents.

The study was not supported by outside funding. Kwan receives support from a Medical Research Future Fund fellowship. He has received speaker fees from Eisai, LivaNova, and UCB Pharma that are unrelated to this research. Leppik has disclosed no relevant financial relationships.

Epilepsia. 2020;61:2720-2728. Abstract

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