BACKGROUND: Topiramate is a novel neuromodulatory anticonvulsant, approved for migraine prophlaxis by the FDA in 2004. It is currently the most prescribed medication for migraine prophylaxis in the US. Anecdotally, its use is associated with calcium phosphate urolithiasis. Hypocitraturia has been suspected, although its occurrence had not been prospectively demonstrated. We thus evaluated the clinical and urinary biochemical changes induced by topiramate during standard topiramate dose escalation.
METHODS: Patients seen in the neurology headache clinic and prescribed topiramate were recruited to participate in accordance with our IRB. Those with a prior medical or family history of urolithiasis were excluded. Enrolled subjects collected a pre-treatment 24-hour urine specimen with subsequent 24-hour urine collections 5 days after commencing topiramate and after each dose escalation. Neither dietary control nor dietary counseling were instituted; rather, subjects remained on self-selected diets.
RESULTS: Six subjects were enrolled, four of whom have completed at least two additional urine collections after initiating topiramate therapy. Prior to beginning topiramate, mean urinary citrate excretion was 606 mg/day and mean urinary calcium excretion was 306 mg/day. Five days after initiation of 25 mg/day topiramate, mean urinary citrate decreased to 398 mg/day (34% decrease) and the mean calcium decreased to 211 mg/day. After two dose escalations to 100mg topiramate daily, citrate decreased to 199mg/day (67% decrease from baseline) and calcium increased to 320mg/d (5% increase from baseline). At 11 months follow up, 2 of the 6 patients have developed symptomatic urolithiasis.
CONCLUSIONS: Topiramate therapy induces a profound decrease in urinary citrate levels, reminiscent of the changes induced by distal renal tubular acidosis. The effect on urine calcium excretion will require more evaluation over a longer time period. Our data underscore the need to monitor this group of patients for the onset of urolithiasis, as 2 of 6 subjects developed new stone disease while on topiramate.