Topiramate Induced Hypohidrosis: Epidemiological Analysis And Possible Mechanisms

Topiramate is a monosaccharide D-fructose derivate that functions as a sulfamate and is currently used for the treatment of epilepsy and other neuropsychopathy. Topiramate is generally well tolerated, while decreased sweat secretion is a primary side effect of topiramate in pediatric patients. Topiramate induced hypohidrosis is reversible, but can be clinically significant during heat stress and exercise challenge. This side effect challenges patients'confidence of long term drug therapy. On the other hand, although hypohidrosis is an adverse effect of topiramate when used for other indications, its anti-sweat producing effects may be beneficial in conditions of hyperhidrosis.How topiramate induces its antiperspirant effects is unclear. A better understanding of these mechanism(s) will provide rational precautionary measures for topiramate–related hypohidrosis and a new therapy for hyperhidrosis. Therefore, in this study, baseline data as well as therapeutic effect and adverse events of 10,106 patients with epilepsy participated in national topiramate post-marketing surveillance (PMS) were reviewed. Incidence rate, clinical characteristic and risk factors for hypohidrosis were analyzed to provide clues for possible mechanisms underlying topiramate-induced hypohidrosis. Then this study aimed to better understand how topiramate decreases sweat secretion by examining if topiramate decreases sweat secretion in mice, as it can in humans, and, if so, to examine its effects on carbonic anhydrase II (CA II) and AQP5 expression in sweat glands. In addition, CA activity, Na, K-ATPase activity and tissue morphology of sweat glands were examined following topiramate administration. Main results are as follow:396 patients (3.73%) developed hypohidrosis and the incidence rate in children was much higher than that in adults. Most hypohidrosis occurred during drug titration and in warmer seasons. It was well tolerated and seldom resulted in drug discontinuation and inpatient care. Symptoms of most patients disappeared in a few months and coincided with the onset of cool weather, while long-lasting symptoms were scanty. Gender, frequency and type of seizure, therapeutic effect or add-on drug therapy did not have a significant effect on the onset of hypohidrosis. On the other hand, patients with younger age or higher dosage were susceptible to hypohidrosis in summer. There was no significant difference in the average dosage between patients with and without hypohidrosis in each age group. However, there was a significant difference in the average age between patients with and without hypohidrosis in each dosage group.Both developing and mature mice were treated with a low (20 mg/kg/day) and high dose (80 mg/kg/day) of topiramate for four weeks. Each group contained 12 mice. Sweat secretion was investigated by an established technique of examining mold impressions of hindpaws. In mature mice, two weeks of topiramate treatment decreased sweat output per gland from baseline in both the low and high dose groups. Four weeks of topiramate treatment decreased the number of pilocarpine reactive sweat glands from baseline in both the low and high dose groups. A similar decrease was seen in developing mice. In addition, topiramate did not have a significant effect on body temperature in mice.Immunofluorescence confirmed that sweat glands in normal mice did not present gamma-aminobutyric acid (GABA) receptor subtype GABAA andα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainic acid (KA) subtype of glutamate receptor.Mature mice with reactive sweat glands that declined more than 25% compared to baseline were defined as anhidrotic mice. Sweat gland morphology was examined in toluidine blue-stained plastic-embedded sections. CA II and AQP5 expression levels were determined by immunofluorescence and immunoblotting, while CA activity and Na, K-ATPase activity by a colorimetric assay. Anhidrotic mice treated by topiramate did not differ from controls in average secretory coil diameter, CA II expression, CA activity and Na, K-ATPase activity. In contrast, anhidrotic mice did show a reduction in membrane AQP5 expression in sweat glands after topiramate delivery.To our best knowledge, the present study is the largest sample-size clinical investigation concerning topiramate induced-hypohidrosis. In summary, our results indicate that hypohidrosis is a frequent adverse effect in children with topiramate therapy. Younger age and hot weather rather than drug dosage are independent risk factors for topiramate-associated hypohidrosis. The resultes also rule out the possibility that topiramate act on its known mechanisms of action, such as potentiating GABA activity at GABAA receptors and antagonizing the AMPA/KA subtype of glutamate receptor in the secretory cells of sweat glands to inhibit sweat secretion. Our data also suggest that topiramate impairs sudomotor function in mice and leads to a significant reduction in AQP5 expression in sweat glands of anhidrotic mice, thus raising the possibility that dysregulation of AQP5 may contribute to topiramate related hypohidrosis. CA inhibition may not be an important contributor since CA II expression and CA activity was intact in anhidrotic mice treated with topiramate.