'Unexplained' Drug Load in Patients With Epilepsy

Erik Greb

December 30, 2020

There is a largely 'unexplained' anti-epileptic drug (AED) load in patients with epilepsy that is unrelated to disease severity or seizure frequency, new research shows.

Results of a large, single center, cross-sectional study reveal only a marginal link between total drug load indices and markers of disease severity.

"The current findings do not support the view that a higher AED load necessarily reflects more severe epilepsy, but rather indicate that the individual AED load is determined by additional factors in the majority of patients," the investigators, led by Juri-Alexander Witt, PhD, clinical neuropsychologist, University of Bonn Medical Center, Bonn, Germany, write.

The study was published in the December issue of the journal Epilepsia.

Hazards of AED Overload

Patients with chronic epilepsy who seek care at epilepsy centers often receive AED polypharmacotherapy. However, a heavier drug load is associated with an increased risk of negative side effects, the investigators note.

The researchers also point out that "high drug loads do not leave many options for further drug escalation when the epilepsy worsens."

To understand clinical factors that may influence AED load, including disease severity associated with AED drug load, the investigators examined data from a large cohort of 1135 conservatively treated outpatients and conducted a separate analysis in a smaller sample of 91 presurgical patients who subsequently had surgery for mesial temporal lobe epilepsy.

Clinical variables examined in both study groups included the presence of an underlying cerebral lesion, age at epilepsy onset, epilepsy duration, seizure frequency, seizure type, ictal impairment of awareness and history of convulsive status epilepticus.

In the presurgical group, the researchers substituted the degree of hippocampal pathology for cerebral lesion pathology and added the clinical rating of epilepsy severity as measured by the Global Assessment of Severity of Epilepsy (GASE).

The researchers gauged patients' total AED load using the number of concurrent AEDs and the accumulated total drug load, as measured by the defined daily dose (DDD).

Weak Links

In the outpatient group, 38.8% of patients were receiving two concurrent AEDs. A further 25.6% of patients were receiving three AEDs, 8% were receiving four, and 2% were receiving five. In addition, 20.3% of outpatients were taking AED monotherapy, and 5% were on no AED therapy.

The prevalence of cerebral lesion in the outpatient group was 53.8%, and 42.2% had recurrent generalized or focal to bilateral tonic-clonic seizures. About 92% of patients had ictal impairment of awareness. The average monthly seizure frequency was 12.8.

Markers of disease severity had significant but weak correlations with AED load (r ≤ 0.15). Ictal impairment of awareness had no correlation with AED load. In descending order, age at epilepsy onset (r = −0.15), presence of an underlying lesion (r = 0.13), and monthly seizure frequency (r = 0.13) had the strongest correlations with number of AEDs.

Seizure frequency was the most relevant predictor of the DDD and explained the greatest variance in the number of AEDs.

Overall, the clinical markers explained 6% of the variance in the number of concurrent AEDs and 10% of variance in total DDDs. Epilepsy duration alone explained 5% to 8% of the variance in AED load.

Additional findings provide context to the latter observation. The median epilepsy duration was 9.0 years for patients on monotherapy, 17 years in those receiving two AEDs, and 21 years in patients receiving three AEDs.

"Thus, the accumulation of concomitant AEDs seems to follow an exponential time function," the investigators note.

Most patients in the presurgical cohort (56%) were receiving two concurrent AEDs. An additional 26.4% were receiving three AEDs, and 17.6% were receiving monotherapy.

Call to Action

All patients in the presurgical cohort had an underlying structural brain lesion and ictal impairment of awareness. A history of convulsive status epilepticus was associated with a higher total DDD (r = 0.35). None of the other clinical factors was related to drug load. The researchers found no significant correlations between GASE score and drug load.

Clinicians' highest priority for patients with newly diagnosed epilepsy is to strive for complete seizure control, Witt told Medscape Medical News. About two thirds of patients achieve this objective, but the remainder have a lower chance of achieving it.

The assumption that an increasing AED load would steadily enhance seizure control is intuitive, but apparently false, Witt added.

"This could be one major reason that AEDs are not discontinued, but rather accumulated. The other main reason may simply be that both patients and physicians may view tapering of AEDs as risky," said Witt.

However, the investigators note that previous research shows enhanced seizure control and improved tolerability after systematic AED withdrawal.

"We hope to encourage neurologists to avoid and critically reevaluate high AED loads in their patients with epilepsy," he added.

The researchers plan to explore AED drug load further, said Witt.

"We are interested in the rationale behind medical decisions leading to higher drug loads and the role of patient expectations. This would call for prospective longitudinal studies. On the other hand, we also want to evaluate the effect of systematic withdrawal of AEDs on seizures and cognition," he added.

The study was conducted without funding. Witt reports receiving personal fees from Eisai that are unrelated to this study.

Epilepsia. Published December 2020 issue. Full text

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