The majority of relapses in patients with newly diagnosed epilepsy were due to modifiable factors rather than drug resistance, with only 7% ultimately meeting criteria for drug-resistant epilepsy (DRE).

Results of a retrospective cohort study showed that nearly 70% of seizure relapses after antiseizure medication (ASM) initiation were attributable to potentially modifiable factors, with inadequate treatment and poor adherence accounting for most relapses.

“Clinicians should always check to see what the reasons were for a relapse,” study investigator Margitta Seeck, MD, Department of Clinical Neurosciences, EEG and Epilepsy Unit, University Hospitals of Geneva, Geneva, Switzerland, told Medscape Medical News. 

“Doctors in the emergency room or in private practice should obtain a drug level from the patient right away. If the problem is noncompliance, then it’s addressed differently than if the dosage was too low, or if the epilepsy doesn’t respond.”

The findings were published online on June 11 in Epilepsia.

A Common Problem

Seizure relapse is common in newly diagnosed epilepsy and is often assumed to reflect treatment failure or the development of DRE. However, relapses can also result from potentially modifiable factors, such as poor adherence or inadequate ASM dosing, and the relative contribution of these factors has not been well defined, the investigators noted.

To better understand the causes of seizure relapse and the emergence of DRE during the first 5 years after diagnosis, researchers conducted a retrospective, longitudinal cohort study.

The study included 330 patients aged 16 years or older from the Geneva University Hospital new-onset epilepsy registry; mean age at epilepsy onset was 49.3 years and 42% women, who were started on an ASM. The most commonly prescribed ASM was levetiracetam (42%), followed by valproate (31%) and lamotrigine (16%).

A total of 181 experienced a seizure relapse during the 5-year follow-up. Relapse was defined as a seizure identical to the index event or one with clinical features consistent with the patient’s epilepsy type.

After reviewing the circumstances surrounding each relapse, researchers classified events as resulting from inadequate ASM dosing, poor adherence, treatment ineffectiveness despite appropriate therapy, acute symptomatic seizures (ASyS), functional/dissociative seizures (FDS), multiple causes, or unknown causes.

The overall relapse rate declined significantly over the 5-year follow-up, from 38% in the first year to 18% by year 5. Relapse rates did not differ significantly among the various ASMs.

Treatment ineffectiveness emerged as the leading cause of relapse over time, accounting for 22% of relapses in the first year and increasing to 41% by year 5. By contrast, poor adherence remained a persistent contributor, accounting for 27%-38% of relapses throughout the study.

Strategies to improve adherence include prescribing once daily ASMs, selecting newer generation agents with fewer adverse effects, regularly monitoring ASM blood levels, and implementing behavioral interventions.

Subtherapeutic Dosing

Inadequate treatment accounted for 37% of relapses in the first year but declined significantly to 10% by year 5. In every case, inadequate treatment reflected subtherapeutic ASM dosing.

Patients older than 60 years, who comprised 36% of the cohort, often received lower ASM doses because of concerns about adverse effects. In other patients, ASMs were intentionally started at low doses and titrated upward to improve tolerability.

Relapses due to ASyS, FDS, or unknown causes were uncommon, each accounting for fewer than 10% of relapses annually.

The findings underscore the importance of evaluating the cause of each seizure relapse to avoid misclassifying patients as having DRE. Optimizing ASM dosing and addressing poor adherence may improve long-term outcomes, the investigators noted.

Researchers also assessed the emergence of DRE, defined as persistent seizures despite trials of two appropriately selected and adequately dosed ASMs. During the 5-year follow-up, 23 of 330 patients (7%) met criteria for DRE; the rate increased to 8% when patients who underwent epilepsy surgery were included.

The study had several limitations. Reliance on patient reports and medical records may have affected data accuracy, and the single-center design may limit the generalizability of the findings.

The high proportion of patients lost to follow-up may have introduced selection bias, and the sample size for subgroup analyses, including patients with DRE, may have been too small to detect statistically significant clinical associations.

In addition, the study sample size for subgroup analyses, including patients with DRE, may have been too small to detect statistically significant associations with clinical variables.

Look Beyond Drug Resistance

The findings underscore the need to investigate the cause of breakthrough seizures before concluding that a patient has DRE, said Aatif M. Husain, MD, professor of neurology and division chief of epilepsy, sleep, and neurophysiology at Duke University Medical Center in Durham, North Carolina, told Medscape Medical News.

“When a patient is having breakthrough seizures, it really behooves the practitioner to probe further as to the causes of that rather than assuming this is all refractory,” he said.

However, Husain cautioned that the 7% rate of DRE, which he described as “one of the lowest we’ve seen,” should be interpreted “with a little bit of a grain of salt.” He noted that the study was conducted at a single center, whereas more recent multicenter studies have reported drug-resistance rates of “about 15%-20%.”

The study findings also resonated with Jacob Pellinen, MD, PhD, associate professor of neurology at the University of Colorado School of Medicine in Aurora, Colorado, who said they are broadly consistent with his clinical experience. 

In his experience, relapse is more often driven by barriers to taking medications than by “true drug resistance.” The most common barriers are medication side effects and simply forgetting to take medications, he said.

Barriers may vary across populations, he added. For example, access to medications may be more difficult in areas with fewer resources including access to health insurance.

Offering a pediatric perspective, Renée Shellhaas, MD, professor of neurology at the Washington University School of Medicine in St. Louis, and an American Epilepsy Society Board Member-at-Large, cautioned that the findings should not be extrapolated to children younger than 16 years.

“The etiologies of new onset epilepsy and the circumstances around treatment decisions and adherence to prescribed treatments are different for adults than for children,” she said.

The study was supported by the Swiss National Science Foundation. The authors disclosures can be found in the original study. Husain, Shellhaas, and Pellinen reported no relevant disclosures.