Topiramate-induced severe heatstroke in an adult patient: a case report

Heatstroke is a life-threatening condition resulting in failure of normal compensatory heat-shedding mechanisms. When heat gain exceeds heat loss, the body temperature rises and can lead to heatstroke, defined as a body temperature higher than 40 °C (104 °F) associated with neurological dysfunction, ranging from mild altered mental status to coma [1]. Two forms of heatstroke can be distinguished: exertional and classical. Given the lack of evidence of strenuous exercise in our patient, although his profession could imply some physical efforts, classical heatstroke seems to better correspond to his condition: high temperature, coma, coagulation disorder, rhabdomyolysis, hepatic injury, and renal failure.

Topiramate is an antiepileptic agent with a broad spectrum of mechanisms of action, since blockage of voltage-dependent sodium channels, augmentation of gamma-aminobutyrate acid activity, antagonism of AMPA/kainate receptors, and inhibition of the carbonic anhydrase enzyme are known to contribute to its clinical efficacy [3]. Topiramate is indicated to treat certain types of seizures and to prevent migraine headaches [4]. Moreover, topiramate has also been recently designated as a first-line agent in the treatment of essential tremor [5]. The usual side effects of topiramate are nausea, fatigue, weight loss and paresthesia, but case reports in epileptic children have raised concerns about the risk of hypohidrosis and heatstroke [6‐8].

The postulated mechanism of topiramate-associated hypohidrosis is thought to be related to an inhibition of the carbonic anhydrase enzyme within the sweat glands, leading to an impaired sweat composition with a reduced water formation and an impaired sweat rate. This hypothesis is supported by small electrophysiological studies showing that autonomic functions are normal in children and adults presenting topiramate-associated hypohidrosis [9, 10]. Moreover, research in mice suggested that topiramate reduces aquaporin expression in sweat glands.

Most of the hypohidrosis cases reported among children taking topiramate showed a good clinical evolution when the drug was stopped [6, 7]. Regarding adults, we found only six cases of patients diagnosed with topiramate-related heatstroke, with unfavorable outcome for half of them (one death and two with persistent neurological dysfunction) [11‐13]. The other half, as well as our patient, completely recovered [14]. Doses of topiramate ranged between 200 and 600 mg/day. Four patients were treated for seizures, one for migraine and one for aggressive behavior. In a prospective, controlled cohort study, 10.5 % of patients on topiramate spontaneously reported hyperthermia when they were asked about side effects in general compared to 0.5 % of patients on other antiepileptics [15]. Described risk factors to develop topiramate-associated hyperthermia are young age, high doses and hot weather [15].

In our patient’s case, the dosage of topiramate was rather low, but our patient was taking ibuprofen, mefenamic acid, losartan and diuretics, which probably contributed to acute renal failure in this diabetic patient, potentially leading to an accumulation of topiramate, since this drug is eliminated by the kidney. Unfortunately, topiramate blood levels were not requested at admission. They were low (9.9 umol/L, normal 15–80 umol/L) 2 days later, after decreasing the dosage from 50 mg twice a day to 50 mg once a day. Second, the weather on the day of admission and the past few days had been exceptionally hot, reaching 39.7 °C (103.4 °F) on the day of admission.

Regarding the results of the lumbar puncture, there are no clear data describing how the CSF composition should evolve during a heatstroke. Among the six other adult patients diagnosed with topiramate-related heatstroke, four of them had had a lumbar puncture [11, 14] which was described as normal and sterile. The albuminocytologic dissociation we found may be explained by the inflammatory state, leading to an enhanced permeability of the membranes and an exudation of proteins into the CSF, as would be observed during systemic inflammation response syndrome (SIRS).

Our patient had a cerebral CT scan described as normal, which coincides with the other cases reported [11, 14]. Only one patient with persistent neurological dysfunction benefited from a cerebral magnetic resonance imaging (MRI) scan [11], which showed diffuse bilateral lesions, disappearing with time. However, a diffuse atrophy persisted, suggesting irreversible neural damage. We did not perform an MRI scan on our patient given his complete neurological recovery.

Since our patient was taking a selective serotonin reuptake inhibitor at a therapeutic dosage on the day of admission, the clinical manifestations (encephalopathy and hyperthermia) could have raised the suspicion of serotonin syndrome. Our patient was in a comatose state and needed to be quickly intubated, therefore the initial neurological examination was restricted, but clonus and hyperreflexia were not specifically documented. Serotonin syndrome was ruled out because citalopram had always been well tolerated before, and its dosage had remained unchanged over the past few weeks before admission. In addition, citalopram is partly metabolized by the cytochrome P450 CYP3A4, which is induced by topiramate. Given this mechanism, the recent introduction of topiramate would have theoretically led to a decrease of citalopram plasma concentration, thus further reducing the likelihood of serotonin syndrome. Moreover, the encephalopathy and hyperthermia resolved despite citalopram continuation.