Antiseizure Medication Tolerability Still a Significant Hurdle


Despite the introduction of second-generation ASMs, drug tolerability has been relatively unchanged over the last 30 years.

Martin J. Brodie, MD

Martin J. Brodie, MD

Results from a study recently published in JAMA Neurology suggest that the advent of second-generation antiseizure medications (ASMs) has not improved overall treatment tolerability in patients with epilepsy, suggesting there is still much work to be done to improve ASM tolerability and, in turn, ASM adherence.

The longitudinal cohort study was designed to identify factors associated with poor tolerability of ASMs. The study including a population of 1795 people (78.5% focal epilepsy; median age at treatment initiation, 33) who were newly diagnosed with and treated for epilepsy who received their first ASM between July 1, 1982 and October 31, 2012. Each individual was followed until April 30, 2016 or death. Investigators prescribed ASMs based on seizure type and other drug and personal factors. After treatment commencement, individuals were reviewed every 2 to 6 weeks for the first 6 months, and then every 4 months thereafter. The study period assessing the change in tolerability of the initial ASM treatment was divided into 3 epochs: July 1, 1982 to June 30, 1992; July 1, 1992 to June 30, 2002; and July 1, 2002 to April 30, 2016.

Adverse effects (AEs) were categorized and defined into 27 classes; including nervous system disorders, psychiatric disorders, general disorders, gastrointestinal tract disorders, and weight gain.

In total, 3241 ASMs were prescribed, with monotherapies accounting for 2346 regimens. Within the first 180 days of treatment, 646 (19.9%) of 3241 ASMs were discontinued in 436 of 1795 individuals (24.3%). Discontinuation from AEs occurred in 354 individuals (20.3%) across 504 ASM regimens (15.6%).

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Initial monotherapies prescribed during the study period included lamotrigine, valproate, carbamazepine, levetiracetam, oxcarbazepine and topiramate. Reasons for withdrawal from these 6 ASMs were: nervous system disorders (81 [4.72%]), skin and subcutaneous tissue disorders (80 [4.66%]), general disorders (54 [3.15%]), and psychiatric disorders (50 [2.92%]).

The proportion of second-generation ASMs prescribed as initial monotherapy increased from 22.3% (33 of 148) in the first epoch to 41.4% (293 of 708) in the second and 68.7% (648 of 939) in the last epoch (P <.001; Cramer v = 0.32; 95% CI, 0.28- 0.36). Despite this rise, the rate of AEs associated with the initial ASM in the 3 epochs remained similar (first epoch: 15 of 148 [10.1%]; second epoch: 98 of 708 [13.8%]; third epoch: 131 of 939 [14.0%]; P = .41; Cramer v = 0.03; 95% CI, 0.002-0.058).

Analysis revealed that patients younger than 18 had lower rates of intolerable AEs than adults (vs aged 18-64 years: adjusted hazard ratio [aHR] 1.58; 95% CI, 1.07-2.32; vs aged 65 years: aHR, 1.90; 95% CI, 1.19-3.02). In addition, female individuals (aHR 1.60; 95% CI, 1.30-1.96) and those who had more than 5 pretreatment seizures (aHR 1.24; 95% CI, 1.03-1.49) were associated with having a greater risk for intolerable AEs. Notably, the rate of intolerable AEs did not differ between elderly individuals and adults (aHR 1.20; 95% CI, 0.91-1.60; P = .20).

Other factors, such as additional concomitant ASMs (aHR, 1.31; 95% CI, 1.04-1.64; P = .02) and an increased number of previous drug withdrawals due to AEs (aHR&thinsp;1.18; 95% CI, 1.09-1.28) were associated with greater risk for intolerable AEs.

“Efficacy and tolerability are 2 sides of the same coin in achieving successful epilepsy treatment. Despite increased used of the second-generation agents, overall treatment tolerability has not improved over the past 3 decades,” the study authors wrote. “To improve the overall effectiveness of ASM treatment, future drug development should not only focus on seizure control, but also tolerability and safety profile.”


Alsfouk BAA, Brodie MJ, Walters M, Kwan P, Chen Z. Tolerability of antiseizure medications in individuals with newly diagnosed epilepsy. JAMA Neurol. Published online February 24, 2020. doi:10.1001/jamaneurol.2020.0032

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