Recurrence of seizures is reported in an adult after addition of folic acid for treatment of a macrocytic anemia. He had previously been seizure free for 3 years while receiving phenytoin 300 mg/day. After folate, the phenytoin serum level was 4.5 mcg/mL; prior to the addition of 5 mg oral folate, the phenytoin levels were consistently between 12 and 18 mcg/mL Despite treatment with fosphenytoin (500 and 1000 mg), seizures recurred and the level of serum phenytoin was unchanged (4.8 mcg/mL). After reduction of folic acid to 1 mg/day, all seizure activity was controlled by the maintenance 300 mg dose of phenytoin, and serum levels increased to 17.6 and 11.3 mcg/mL. [1]

COMMENT. This case report underscores the risks of adding folic acid to the drug regimen of patients with epilepsy treated with phenytoin. Folic acid appears to be a cofactor in the metabolism of phenytoin. The initial dose of folic acid should be small, and the dose of phenytoin should be increased to maintain therapeutic levels.

Phenytoin pharmacokinetics before and after folic acid administration were reported from University of Iowa (see Ped Neur Briefs Sept 1992) [2]. All subjects showed decreased serum folic acid following initiation of phenytoin treatment. Folate and phenytoin are interdependent. In an earlier report [3], phenytoin levels fell significantly during folic acid therapy, with recurrence of seizures in one case.