Researchers at the Division of Pediatric Neurology, Neurosciences Centre, New Delhi, India, performed a randomized, double-blind, placebo-controlled 6-month trial of oral folic acid supplement (0.5 mg/day) in children aged 6-15 years treated with phenytoin for epilepsy. Of 62 patients who received folic acid supplement, 21% developed gingival hyperplasia whereas of 58 receiving placebo, 88% developed hyperplasia (p<0.001). Risk reduction of phenytoin-induced gingival hyperplasia by folic acid was 67%. The mean phenytoin dose was similar (6.8 and 7.0 mg/kg/day respectively) in folic acid and placebo groups at the end of the study. Mean serum levels of phenytoin were therapeutic (13 mcg/ml) in both groups. Seizures were symptomatic, and 76% were due to neurocysticercosis. 
COMMENT. Gingival hyperplasia associated with phenytoin treatment of epilepsy is reported in as few as 3% of cases (Lennox WG, 1940) to as many as 78% (Gardner AF et al, 1962). It occurs more frequently in children than in adults. Numerous mechanisms have been proposed but few of proven significance. Other hydantoin anticonvulsants (mephenytoin, ethotoin, and albutoin) cause little or no gingival hyperplasia. The above investigators have discovered an important and correctable factor in the mechanism in their clinic population. The authors allude to a lack of dental hygiene in a high proportion of patients, a known contributing factor associated with tissue inflammation and irritation. Hyperplasia does not occur in edentulous adults. Phenytoin has an affinity for gingival tissue, and its effect on collagen and keratin in connective tissue has been used in the promotion of healing of wounds and leg ulcers (Shafer WG et al, 1958; Houck JC et al, 1972). In addition to man, only the ferret is susceptible to phenytoin gum hyperplasia, an interesting companion in science. Mechanisms largely disproven include a deficiency of ascorbic acid, adrenocortical dysfunction, and allergy (Gardner, 1962). Hyperglycemia induced by phenytoin, an effect discovered in our neurology research laboratories at Children’s Memorial Hospital , warrants investigation as a potential contributing cause of gingival inflammation and overgrowth.