Blue-gray mucocutaneous discoloration: a new adverse effect of ezogabine

Many drugs have been reported to induce skin and/or mucous membrane discoloration. Ezogabine (retigabine) was recently approved as an add-on drug for the treatment of partial seizures in adults with epilepsy. Mucocutaneous discoloration induced by antiepileptic drugs in general and ezogabine in particular has not been previously reported.

Two patients who had received multiple antiepileptic drugs for several years presented with a blue-gray skin dyspigmentation that was most pronounced on the face and lips and was associated with nail pigmentation, blue pigmentation on the hard palate, and black pigment deposits on the conjuctivae. The sole drug common to the therapeutic regimens of both patients was ezogabine. Histopathologically, the main finding was perivascular and periadnexal dermal cells heavily laden with coarse melanin granules, which appeared ultrastructurally as intracellular electron-dense granules. Four months after discontinuing ezogabine, our first patient showed a significant improvement in the mucocutaneous and nail dyspigmentation.

The temporal relationship, clinical features, histologic and ultrastructure findings, and improvement following withdrawal of ezogabine indicate that the dyspigmentation was drug induced. Ezogabine should be added to the list of drugs that can induce mucocutaneous discoloration. The incidence of this significant adverse effect requires further investigation.