Profound Hypothermia Secondary to Clobazam Use in Epilepsy: A Novel Association

Abstract

Clobazam, a 1-5 benzodiazepine, was introduced in the 1970s for the treatment of anxiety and agitation. Antiepileptic properties were recognized, and efficacy in a number of epilepsy syndromes was demonstrated in humans, with good tolerance. Recent reviews are generally favorable, with a relative minimum of medication-related side effects. However, a number of benzodiazepines have been associated with causing hypothermia. To date, this side effect has not been reported with clobazam. We report two cases of profound hypothermia associated with the use of this medication for the treatment of epilepsy. Both children had significant cerebral dysgenesis and were developmentally impaired, but neither had experienced hypothermia before. Temperature dysregulation was resolved with medication withdrawal after an extensive work-up for alternative causes. Hypothermia should be considered as a possible side effect of clobazam, although the exact mechanism is unknown. Appropriate monitoring of temperature is appropriate, and precautions should be offered by caregivers.

Hypothermia in an Adolescent Due to Probable Drug-Drug Interaction Involving Clobazam

“…Our case is similar to previous reports of CLBassociated hypothermia; however, unlike previous reports, we report serum drug concentrations. In one previously published case, 4 there is some indication that hypothermia from CLB may be related to dose. A 3-year-old with a history of epilepsy secondary to diffuse cerebral dysgenesis experienced hypothermia (36.1°C) at a dose of 0.6 mg/kg/day.…”

“…2 A review of the literature found published case reports of clobazam-associated hypothermia that occurred in one adult and 2 pediatric patients. 3,4 CLB is metabolized primarily by cytochrome (CYP) 3A4 to an active metabolite (i.e., N-desmethylclobazam [NCLB]), which represents about 20% of its activity (Figure 1). 2,5,6 NCLB is further metabolized by CYP2C19 to an inactive metabolite.…”

Hypothermia associated with clobazam use in adult epilepsy

“…Clobazam and other benzodiazepines allosterically activate GABA A receptors, potentially causing this response [1] . There are many other possible mechanisms of clobazam-induced hypothermia [4] . Although the exact mechanism remains unknown, future studies of patients with less comorbidities and known serum drug levels could further investigate this association.…”

“…Clobazam had been started one year prior, and it was the last drug added. Because of this and the fact that clobazam had been recently linked to hypothermia [4] , the drug was tapered from 10 to 5 mg bid over one week. During this period, the patient experienced one more hypothermic episode.…”

“…Clobazam usually has only mild side effects such as sedation, dizziness, and ataxia [3] . However, a recent case report linked clobazam to the development of hypothermia in two pediatric patients [4] . Here, we describe the novel finding of hypothermia associated with clobazam use in an adult patient.…”