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Among the long term adverse effects of anticonvulsants, gum hyperplasia is cosmetically disturbing and can give rise to complications such as bleeding and gingivitis.1,2 Long term use and high doses of phenytoin sodium (diphenylhydantoin) have been implicated in the occurrence of gingival hyperplasia.3 Serum phenytoin level in these patients are high.3 Rarely other drugs such as primidone, sodium valproate, nifedipine, and cyclosporin have also been implicated.1,2 Treatment consists of stopping the offending agent and providing corrective surgery.4 Phenobarbitone (phenobarbital) has not yet been reported to cause gum hyperplasia. We describe a patient who developed this complication in association with the long term use of phenobarbitone.
A 26 year old man had been suffering from hot water reflex epilepsy and primary generalised tonic-clonic seizures since he was 12 years of age. The seizures were poorly controlled because of his inability to avoid taking hot baths, inadequate dosage of anticonvulsants, and poor compliance. Since 1987, he had been taking phenobarbitone, 60 to 90 mg/day. In 1988, phenytoin (100 mg twice daily) was added for six months but was stopped because there was no benefit. In 1989, carbamazepine (200 mg twice daily) was added but was discontinued by the patient in 1996 for unspecified reasons. From 1996 onwards he had been receiving only phenobarbitone 120 mg/day. He was referred to us for progressive gum hyperplasia with bleeding from the gums, both spontaneously and with tooth brushing, since 1996. There was no history suggesting any haematological malignancy, and he was not on any other drug treatment.
On examination, he had gingival hyperplasia involving both the upper and the lower jaws (fig 1). There was occasional bleeding from the hyperplastic gum tissue. General physical examination did not reveal any pallor, hepatosplenomegaly, or lymphadenopathy and neurological evaluation was unremarkable.
Haematological investigations, including haemoglobin, white blood count, erythrocyte sedimentation rate, and peripheral smear, were all normal. Blood glucose, renal and liver function tests, serum electrolytes, and urine analysis were normal. Scalp electroencephalography and cranial computed tomography were normal. Serum concentrations of phenobarbitone, phenytoin, and carbamazepine were measured. Phenobarbitone was within the therapeutic range (11.2 μg/ml) while the other two drugs were not detectable.
This patient with longstanding epilepsy probably had phenobarbitone induced gingival hyperplasia. He had used phenytoin in 1988 for only six months without developing this symptom, and it only appeared later in 1996 when he was on phenobarbitone alone. After that time it ran a progressive course. Primidone, the metabolites of which contain phenylethylmalonamide and phenobarbitone, has also been reported to be a rare cause of gingival hyperplasia.1,2 However, it is difficult to state which of the two components contributes to the hyperplasia.
Phenytoin sodium is known to be the most common cause of gingival hyperplasia.1,4 A minor degree of hyperplasia occurs quite commonly and this generally causes only cosmetic problems, especially for women. However, when phenytoin is used for prolonged periods in high dosage a severe degree of gingival overgrowth occurs. In such cases the hyperplastic gingiva bleed with minimal trauma or spontaneously, and may sometimes become secondarily infected.3
The mechanism of anticonvulsant induced gingival hyperplasia is not known. It is believed that these drugs cause tissue collagen proliferation but the reason for this is unknown. It has been speculated that a high phenytoin concentration in the pituitary and adrenal glands may be related to hirsutism and gingival hyperplasia. However, there is at present no evidence that high concentrations of phenytoin in these tissues produce changes in their secretion rate, or indeed that these alterations cause hirsutism and gingival hyperplasia.5
Antiepileptic drug levels are generally high in cases of gingival hyperplasia. However, in our case the phenobarbitone level was within normal therapeutic limits, while phenytoin and carbamazepine were undetectable. Buchnann et al reported nine cases of phenytoin induced moderate to severe gingival hyperplasia who underwent corrective gingivectomy. It was found that in eight of these cases the tissue diphenylhydantoin levels were higher than the plasma levels.5
Treatment consists of stopping the offending drug and providing supplements of folic acid and ascorbic acid. If regression does not occur, reconstructive surgery of the hyperplasic gingival tissue is advised. Our patient has been switched to sodium valproate, and reconstructive cosmetic surgery is planned.
In conclusion, we report a case of phenobarbitone induced gingival hyperplasia because of its rarity. The mechanism of this side effect remains unclear. Accurate drug history, thorough investigations, and punctilious reporting of such cases may help us gain a better understanding of the condition.
We acknowledge with thanks the secretarial assistance of Mr M V Srinivas and Mr K Bhaskar, Department of Neurology, and the staff of the Department of Medical Illustration and Health Education, NIMHANS.
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