Discussion

CBM is a novel ASM with dual mechanisms that reduce neuronal excitability by enhancing inhibitory signaling. It enhances fast and slow inactivation of sodium channels and preferentially inhibits the persistent component of the sodium current over the transient component. It also acts as a positive allosteric modulator of GABA_A receptors independently of the benzodiazepine binding site, potentiating both tonic and phasic inhibition produced by the receptor. Studies assessing the efficacy and safety of CBM for treating patients with refractory epilepsy compare very favorably with other adjunctive ASMs. ^{Reference Sperling, Abou-Khalil and Aboumatar14–Reference Costa, Fareleira, Ascenção, Borges, Sampaio and Vaz-Carneiro16} However, ^{Reference Lattanzi, Trinka and Zaccara15} evidence supporting the use of CBM for the management of patients with SE is limited. ^{Reference Falcicchio, Pellicciari and Graziani27–Reference Carlson, Molyneaux and Lee30}

We identified only five adult cases of SRSE treated with CBM. ^{Reference Falcicchio, Pellicciari and Graziani27–Reference Carlson, Molyneaux and Lee30} While the observed response rate in SRSE (2/5, 40% seizure cessation) was comparable to seizure – freedom rates reported for CBM as an adjunct in refractory epilepsy (11%–36%), ^{Reference Sperling, Abou-Khalil and Aboumatar14,Reference Lattanzi, Trinka and Zaccara15} this estimate is likely inflated due to the small number of SRSE cases. More importantly, concurrent medication regimens – including 5–8 ASMs, 2–4 intravenous sedatives and several other therapies – preclude definitive conclusions about CBM’s efficacy for SE because of confounding bias. Three of the five patients, including the two responders, had focal seizures, whereas the remaining two case reports did not provide sufficient detail about seizure semiology to determine whether seizures were generalized or focal. However, available evidence informing FDA and Health Canada approvals only supports CBM use for seizures that are focal in origin. ^{Reference Lattanzi, Trinka and Zaccara15,Reference Singh31} The underlying remote etiologies of patients with refractory seizures who responded favorably to CBM in earlier epilepsy studies ^{Reference Sperling, Abou-Khalil and Aboumatar14,Reference Lattanzi, Trinka and Zaccara15} were also different from the acute etiologies of the five patients with SRSE that included autoimmune, infectious and possible prion-related diseases. None of the reported patients with SRSE suffered from chronic epilepsy prior to their presentation. The impact of these etiologic differences on the efficacy of CBM remains unknown but is clinically important considering the underlying etiology of seizures influences treatment response and prognosis. ^{Reference Trinka and Leitinger3,Reference Hirsch, Gaspard, Baalen and van25}

Dosing regimens for CBM used as an adjunct for patients with refractory epilepsy have varied. Earlier studies started at a dose of 50 mg/day with weekly increments of 50 mg/day up to 200 mg/day, followed by two additional increments of 100 mg/day to reach 400 mg/day. ^{Reference Chung, French and Kowalski32} Given concerns regarding DRESS, subsequent safety-focused regimens began at 12.5 mg/day with daily doses doubling every two weeks up to 50 mg/day and then increasing by 50 mg/day every two weeks to a maximum dose of 400 mg/day. ^{Reference Sperling, Abou-Khalil and Aboumatar14,Reference Krauss, Klein and Brandt33} Dosing regimens for patients with SRSE in the included studies varied but were more aggressive upfront than the more conservative CBM titration from epilepsy studies. Two patients with SRSE received titrations of CBM from 12.5 mg/day up to 50 mg/day over 8–16 days, followed by further increases after discharge from the hospital to a maximum dose of 200 mg/d. ^{Reference Carlson, Molyneaux and Lee30} Another patient was started immediately on 100 mg/day with no adverse events and a subsequent dose escalation to 150 mg/day after discharge. ^{Reference Falcicchio, Pellicciari and Graziani27} Notably, no patient with SRSE received 400 mg/d – the dose associated with the greatest effect in epilepsy trials. ^{Reference Lattanzi, Trinka and Zaccara15,Reference Singh31,Reference Nie and Hoy34} Considering the variability in dosing and titration across case reports, no definitive conclusions can be drawn regarding the optimal CBM dose or titration strategy for SE.

If CBM is selected as an ASM for the management of SE, its pharmacokinetic and pharmacodynamic properties must be carefully considered. Although CBM is available only for enteral administration, it is rapidly and extensively absorbed, reaches maximum plasma concentration within one to four hours after administration and has a bioavailability of at least 88%. The tablets can be crushed and administered as a suspension via a gastric tube with similar bioavailability. ^{Reference Vashi, Laramy, Kamin, Ferrari and Hand35} Considering its long half-life of 50–60 hours, it takes approximately 14 days for CBM to reach steady state. ^{Reference Vernillet, Greene and Kamin26} The pharmacokinetics of CBM are not linear, and dose increases result in a disproportionate increase in plasma levels, particularly at doses higher than 300 mg. ^{Reference Singh31} As such, rapid dose adjustments of CBM, as is often done with other ASMs when managing SE, must be performed with caution. CBM is metabolized by multiple enzymes via glucuronidation and oxidation (CYP-2E1, 2A6, 2B6, 2C19 and 3A4/5). Phenytoin induces CYP3A4 and reduces the plasma concentrations of CBM by up to 28%. ^{Reference Singh31} The drug itself also inhibits several enzymes including CYP2C19, which increases the plasma concentrations of phenytoin and phenobarbital by 70% and 34%, respectively. ^{Reference Singh31} The active metabolite of clobazam, N-desmethylclobazam, is also catabolized by CYP2C19, and as such, CBM increases the plasma levels of this active metabolite. Through induction of CYP3A4, CBM causes a decline in the plasma concentration of lamotrigine, levetiracetam and carbamazepine up to 52%, 13% and 24%, respectively. ^{Reference Singh31} Dose adjustments of these ASMs may be required if CBM is used as an adjunct for SE management. ^{Reference Smith, Klein and Krauss36}

CBM may cause several side effects that clinicians must be aware of. Two out of three patients in the included case reports suffered from adverse events including somnolence, ^{Reference Carlson, Molyneaux and Lee30} diarrhea and vomiting. ^{Reference Falcicchio, Pellicciari and Graziani27} Two cases did not report on adverse events. ^{Reference Pham and Landeen28,Reference Ang, Abu-Hashish, Malik, Noori and Singh29} Studies assessing the use of adjunctive CBM for refractory epilepsy reported adverse events in 77% of patients, which were mostly rated as mild or moderate in severity. Twelve percent of patients required treatment discontinuation in clinical trials. ^{Reference Lattanzi, Trinka and Zaccara15,Reference Nie and Hoy34} The most common reported side effects for CBM in clinical trials included somnolence (25%), dizziness (23%), fatigue (16%), imbalance/gait disturbance (14%) and headache (11%). ^{Reference Lattanzi, Trinka and Zaccara15} Nausea was reported in 7%, diarrhea in 5% and vomiting in 4%, but these were not significantly different than with placebo. ^{Reference Lattanzi, Trinka and Zaccara15} Early in clinical development, when initial treatment doses of 50–100 mg/day were used, four cases of DRESS including one fatality were reported. ^{Reference Lattanzi, Trinka and Zaccara15,Reference Singh31,Reference Nie and Hoy34} However, subsequent studies utilizing a lower starting dose of 12.5 mg with biweekly titration as well as post-marketing reports have not reported any further cases of DRESS, only rashes that resolved upon discontinuation of CBM. ^{Reference Strzelczyk, von and Hamer37} CBM also shortens the electrocardiogram QT interval in a dose-dependent manner and is contraindicated in patients with familial short QT syndrome, and caution is required if it is coadministered with other drugs known to reduce QT intervals. ^{Reference Lattanzi, Trinka and Zaccara15} Studies suggest that many of the reported adverse events are more common in patients concomitantly treated with other sodium channel blockers. ^{Reference Lattanzi, Trinka and Zaccara15}

There are several limitations of this systematic review. First, the analysis relies solely on case reports and case series, as no cohort, case-control or interventional studies have been published to date, introducing significant publication bias and limiting conclusions regarding the efficacy and safety of CBM for SE. Additionally, confounding variables could not be excluded, given the concurrent initiation of multiple therapies. While we attempted to classify seizure cessation as objectively as possible considering the pharmacokinetics of CBM, many factors limit the ability to fully attribute seizure cessation to CBM. Most studies involved sequential and combined pharmacologic interventions with the number of preceding ASMs prior to CBM ranging from five to eight, in addition to other concurrent therapeutic interventions including immunotherapies, antivirals and the ketogenic diet. As such, we cannot exclude the possibility that seizure cessation reflects cumulative pharmacologic effects, delayed response to earlier interventions or synergistic drug interactions rather than a specific effect of CBM itself. Finally, the small number of patients available for analysis further limits conclusions regarding both efficacy and safety of CBM. Despite these limitations, this is the first systematic review to summarize the available literature, highlight its limitations and outline pragmatic considerations for clinicians considering CBM for SE management.