topiramate and Hypothermia

This article presents an additional case of concomitant topiramate and phenobarbital administration that resulted in 8 hospital admissions for hypothermia that resolved after discontinuation of phenobarbital.. A 56-year-old white female with cerebral palsy and quadriplegia, epilepsy, and hypothyroidism was admitted to a community teaching hospital multiple times with documented hypothermia. These admissions followed a subsequent dose increase of topiramate in December 2014. In February 2015, the patient was admitted with 35°C rectal temperature. Her 2 admissions in April were for hypothermia with temperatures of 34.6°C and 33.6°C, respectively. The patient had 5 other admissions with hypothermia through December 2015. All other causes of hypothermia were ruled out. The hypothermia resolved when phenobarbital was discontinued.. A recent case series noted an association between phenobarbital and topiramate causing hypothermia. The patient's hypothermia developed while on concomitant phenobarbital and topiramate but only after an increase in topiramate. No other causes for hypothermia were found based upon physical examination or lab work. The Naranjo nomogram noted a probable causation.. This case report points to an association of hypothermia with concomitant topiramate and phenobarbital with resolution after phenobarbital discontinuation. Improvement after discontinuation of phenobarbital seems to support a drug-effect relationship.

Topics: Anticonvulsants; Drug Interactions; Epilepsy; Female; Hospitalization; Humans; Hypothermia; Middle Aged; Phenobarbital; Topiramate

Compounds with anti-glutamatergic properties currently in clinical use for various indications (eg Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, and topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (by comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (by chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, whereas oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiate ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J, or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with an NMDAR blocker, genetic background, or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history.

Topics: Alcoholic Intoxication; Animals; Ataxia; Carbamazepine; Central Nervous System Depressants; Conscious Sedation; Dextromethorphan; Ethanol; Excitatory Amino Acid Agents; Fructose; Haloperidol; Hypothermia; Lamotrigine; Male; Memantine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Oxcarbazepine; Species Specificity; Stress, Psychological; Topiramate; Triazines

Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia.. We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia.. This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs.. We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected.. We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Algorithms; Ammonia; Anticonvulsants; Bicarbonates; Child; Child, Preschool; Databases, Factual; Drug Interactions; Female; Fructose; Humans; Hypothermia; Male; Middle Aged; Retrospective Studies; Topiramate; United States; United States Food and Drug Administration; Valproic Acid; Young Adult

Topiramate is a new antiepileptic drug, used for treatment of partial onset seizure and refractory seizures. Although it is well tolerated in children, some adverse effects including hypohidrosis and hyperthermia are reported. We present two children with epilepsy who were treated with topiramate and developed hypohidrosis and hyperthermia.

Topics: Anticonvulsants; Carbonic Anhydrases; Child; Child, Preschool; Female; Fructose; Humans; Hypohidrosis; Hypothermia; Male; Risk Factors; Topiramate

We present three children with severe therapy-refractory epilepsy who tolerated valproate (VPA) well in various combinations with other antiepileptic drugs (AEDs) but developed typical VPA side effects in combination with topiramate (TPM).. The clinical symptoms began with apathy in all three children; two of them also had hypothermia. Furthermore all children had elevated blood ammonia levels, one child in combination with increased liver transaminases and one with thrombocytopenia.. All children recovered completely after discontinuation of VPA or TPM.. TPM seems likely to enhance the risk of side effects usually attributed to VPA and not described in TPM monotherapy. Our case reports suggest that possible adverse effects of VPA should be given particular attention when VPA is combined with TPM.

Topics: Affective Symptoms; Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Hypothermia; Infant; Liver; Liver Diseases; Male; Risk Factors; Thrombocytopenia; Topiramate; Transaminases; Valproic Acid