Reappraisal of topiramate-associated metabolic acidosis: a systematic review using physicochemical acid-base analysis

Topiramate is traditionally described as causing a hyperchloremic, non-anion gap metabolic acidosis due to carbonic anhydrase inhibition. However, the underlying physicochemical mechanisms have never been systematically reassessed using the Stewart approach.

We conducted a systematic review of all published cases and re-evaluated the available biochemical data using the Stewart physicochemical model.

Among 38 identified patients, only seven had sufficient information for full or near-complete strong ion analysis. In every patient with genuine metabolic acidosis, the strong ion gap was elevated, suggesting an excess of unmeasured anions that was not detected by the conventional anion gap. Hyperchloremia, although common, was inconsistently present, and chloride physiology was frequently misclassified. Several patients had normal pH or normal bicarbonate despite significant physicochemical abnormalities, reflecting mixed disorders involving respiratory alkalosis and weak-acid effects. An illustrative case reproduced this pattern, with a high-strong ion gap and normal anion gap masked by hypocapnia.

These findings suggest that topiramate-induced metabolic acidosis is physiologically heterogeneous and often concealed within the Henderson-Hasselbalch framework. Strong ion analysis provides a more complete description of the underlying mechanism and reveals unmeasured anions as a major and previously unrecognized contributor to this drug's metabolic effects.