Clobazam Add-on to Dual ASM Effective for Glioma-Associated Refractory Epilepsy

The combination of levetiracetam, valproate, and clobazam may be as effective and well tolerated as other triple ASM therapies in patients with glioma-associated epilepsy.

The addition of clobazam to levetiracetam and valproate may be as effective as other triple antiseizure medication (ASM) therapies in patients with glioma-associated refractory epilepsy, according to study findings published in Neurology.

Due to refractory epilepsy, an estimated 10% of patients with glioma-associated epilepsy require ASM triple therapy. Researchers sought to examine the efficacy, tolerability, and ease of use of triple antiseizure combinations in this patient population.

Recently, in an observational cohort study, researchers first compared levetiracetam and valproate monotherapy in a cohort of 1,435 consecutive patients. Patients exhibiting an inadequate treatment response (n=355) were then given a trial of dual therapy (levetiracetam and valproate). Patients whose seizures were refractory to dual therapy (n=90) were entered into the study that evaluated triple therapy — specifically the addition of clobazam to levetiracetam and valproate. Forty-three (48%) of these patients received a combination of levetiracetam and valproate and clobazam and the remainder received a different type of triple therapy from among the wide range of available ASMs.

The levetiracetam, valproate, and clobazam regimen was of interest to the researchers because, although the comparative monotherapy study found levetiracetam to be superior to valproate, the combination was considered to be better tolerated with equivalent efficacy to other dual ASM regimens. Clobazam was added for triple therapy due to its ease of use, low adverse event profile, and data showing effectiveness in seizure control.

LEV+VPA+CLB might show equivalent effectiveness compared to other ASM triple-therapy combinations in glioma patients.

Researchers noted that clobazam, a 1.5 benzodiazepine, has better tolerability and a broader spectrum of anticonvulsant activity compared with traditional 1.4 benzodiazepines. They also believe it may have a synergistic effect when used with other ASMs.

The primary outcome of the study was time to treatment failure. Secondary outcomes included time to treatment failure due to uncontrolled seizures or adverse events and time to recurrent seizures.

During 36 months’ follow-up, 21 (49%) patients who received levetiracetam and valproate and clobazam and 21 (45%) who received another triple therapy experienced treatment failure, a difference which was not statistically significant (12 months: 47% [95% CI, 31-62%] vs 42% [95% CI, 27-56%], P =.892).

No statistically significant differences regarding time to treatment failure due to uncontrolled seizures (12 months: 12% [95% CI, 4-25%] vs 18% [95% CI, 8-30%], P = .445) or adverse events (12 months: 22% [95% CI, 11-36%] vs 15% [95 CI, 7-27%], P =.446), or time to recurrent seizures (1 month: 65% [95 CI, 48-78%] vs 63% [95% CI, 47-75%], P =.911) was found.

Researchers did note, however, that the ASM load at the time of treatment failure due to uncontrolled seizures was significantly higher for levetiracetam and valproate and clobazam than other triple therapy regimens. They also noted that dose escalation, thus, may have been inadequate for some of these other ASM triple therapies, possibly resulting in premature treatment failure.

They conceded that, because epilepsy refractory to mono and dual ASM therapy develops in a relatively small number of patients with glioma, accumulating a substantive study population in which standards for matching and multivariate regression analysis can be applied will be challenging. Since safeguards could not be applied in the present study, which was retrospective, unknown confounders could have influenced outcomes.

“Prospective studies are needed to determine which ASMs are the most effective and tolerable add-on treatment options for glioma patients with refractory epilepsy,” the researchers stated. They concluded, “LEV+VPA+CLB [levetiracetam and valproate and clobazam] might show equivalent effectiveness compared to other ASM triple therapy combinations in glioma patient.”


van der Meer P, Dirven L, Fiocco M, et al. Effectiveness of antiseizure medication triple therapy in glioma patients with refractory epilepsy: an observational cohort study. Neurology. Published online February 8, 2023. doi:10.1212/WNL.0000000000206852.