A double-blind randomized study is the first to suggest that folate supplementation worked to decrease the incidence of phenytoin-induced gingival overgrowth in children taking the antiepileptic drug.
DR. RAVINDRA ARYA: “In a developing country like ours, PIGO is a significant problem. Based on this study, daily folate supplementation should be considered to help minimize the occurrence of PIGO in children.”
Folate acid supplementation in children with epilepsy taking phenytoin to control seizures reduced a worrisome side effect of gingival overgrowth, according to a study published in the April 12 Neurology.
The double-blind randomized study is the first to suggest that this vitamin worked to decrease the incidence of phenytoin-induced gingival overgrowth (PIGO) in children taking the anti-epileptic drug (AED).
The study was conducted at the All India Institute of Medical Sciences in New Delhi, India. The use of phenytoin is low in the United States where there are many alternative AEDs that have a better effect profile. Still, it is an inexpensive AED that physicians commonly prescribe in many other areas of the world.
Investigators at the All India Institutes of Medical Sciences in New Delhi, India — Sheffali Gulati, MD, associate professor of pediatrics; Ravindra Arya, MD, DM, senior research associate in the Division of Pediatric Neurology; and colleagues — tested the benefits of folic acid to prevent PIGO. Gingival overgrowth creates a pocket at the interface between tooth and gum and this can lead to an accumulation of food debris and create an environment vulnerable to infections.
The scientists designed a randomized trial at a tertiary hospital and enrolled 120 children between 6 and 15 years old who were being started on phenytoin monotherapy. Anyone with pre-existing gingival overgrowth, macrocytic anemia, or who had used folic acid antagonists were excluded from the study. Sixty-two of the children were prescribed 0.5 mg/day and the rest were swallowing a placebo pill with an identical coating as the folic acid supplement.
The prevention study lasted six months. A ball tipped dental probe was used to measure gingival overgrowth every two months throughout the study period.
The researchers reported that 13 out of 62 epilepsy patients (21 percent) in the folic acid arm of the study developed gingival overgrowth compared to 51 out of 58 (87.8 percent) of those on the placebo pill (p<0.001). The folic acid reduced the absolute risk for gingival overgrowth by 67 percent. Only two patients (3.2 percent) in the intervention arm developed severe gingival overgrowth compared to 8 (13.8 percent) of the control arm (p=0.036). Gingival overgrowth was considered severe if the hyperplastic gingiva extended anywhere in the middle third to more than two-thirds of the anatomic crowns of the anterior teeth.
The dose and blood levels of phenytoin were not related to the development of gingival overgrowth in the folic acid group; while the placebo group did show a relationship between blood levels of phenytoin and the risk for developing PIGO.
Most of the gingival overgrowth was observed by two months and virtually all cases were detected by four months. The scientists did not see an increasing severity of the side effect with the continued exposure to phenytoin, but they said that they would need a longer study to back up this impression.
“In a developing country like ours, PIGO is a significant problem,” said Dr. Arya. “Based on this study, daily folate supplementation should be considered to help minimize the occurrence of PIGO in children.”
DR. MARK S. YERBY: “While the finding is interesting, you have to wonder why supplementation has not led to an observable decrease in gingival overgrowth.”
In addition to the increased risk of infections, the overgrowth gets in the way of effective brushing and maintenance of proper dental hygiene, he added. “Finally, in adolescents with increased self-image awareness, the unsightly nature of this adverse effect might create compliance issues in otherwise well controlled epilepsy,” said Dr. Arya.
There is no conclusive scientific explanation for why folic acid might work to either prevent or treat PIGO.The problem represents a complex biological process that results from selection of a particular sub-population of gingival fibroblasts, altered connective tissue turnover and inflammation on a background of genetic susceptibility, Dr. Arya explained.
It is thought that folic acid supplementation probably reduces gingival inflammation by binding to plaque derived toxin(s) and also interferes with generation of a particular metabolite of phenytoin (called 4-HPPH) which has an important role in the pathogenesis of PIGO. Preferential transport of folic acid to gingival tissue in PIGO patients has been documented.
Also, the vitamin deficiency in epilepsy patients who take phenytoin suggests that it is a folic acid antagonist.
The scientists have come to believe that PIGO is an “all-or-none” phenomenon; it does so within four months usually. “We wish to do a survival analysis of our data to further analyze this point,” Dr. Arya said.”Secondly, we are following these children long-term and we wish to see if they develop PIGO later which might provide an estimate of the duration of preventive effect of folic acid supplementation.”
Dr. Arya and his colleagues said that there has only been anecdotal evidence that folic acid supplementation could treat gingival overgrowth. Smaller studies have been done but were not powered to show an effect, he said. What's more, he added, “this is the first study to attempt to address folic acid as a preventative treatment. The most interesting lesson is that a simple, easy and cost-effective intervention of low dose oral folic acid supplementation can prevent this important adverse effect.”
Mark S. Yerby, MD, MPH, an associate clinical professor of neurology at Oregon Health and Sciences University in Portland, said that neurologists have known for more than 70 years that phenytoin leaves patients deficient of folate. Since the 1970s, clinicians have been prescribing folic acid supplementation. “While the finding is interesting, you have to wonder why supplementation has not led to an observable decrease in gingival overgrowth,” he said.
Dr. Yerby noted that the investigators acknowledged some limitations in the study design. For one thing, investigators did not measure folate levels. Also, they said that dental photographs may have been a more objective measure of gingival overgrowth than the dental probe that was used to assess whether the crown teeth were covered by the gingival overgrowth.
Despite these caveats, Dr. Yerby said, “the study was well done and the results are interesting. This observation demands replication.”