Driphenylhydantoin sodium (Dilantin) was synthesized in 1908 by Biltz1 and introduced as an antiepileptic agent in 1938 by Merritt and Putnam.2 Extensive subsequent use has confirmed its efficacy in controlling epileptic seizures, particularly major motor (grand mal) convulsions.
A number of untoward reactions have been observed in patients receiving diphenylhydantoin.3 One of the most common is hyperplastic enlargement of the gingivae. In many of our patients, the gingival hyperplasîa caused displacement of the teeth to such a degree that orthodontic and periodontal procedures were indicated (Figure 1). In addition, we have had several patients in whom the hyperplastic gingival tissue was so extensive and marked that it caused emotional disturbances which eventually became more of a problem than the epilepsy per se.
The data presented in this writing are based on an extensive review of the literature and on direct clinical observations of approximately 15,000 patients of all ages who were studied at The Johns Hopkins Hospital Epilepsy Clinic while receiving diphenylhydantoin.
In our experience, drug-induced gingival hyperplasia occurs only in association with hydantoinate therapyalmost exclusively with diphenylhydantoin. The reported incidence of diphenylhydantoin gingival hyperplasia ranges from three per cent* to 78 per cent.5 Based on observations made in our clinic, we estimate the incidence of this disturbance to be at least 40 per cent, a figure approximating those reported by Babcock6 and Panuska and co-workers.7
Diphenylhydantoin gingival hyperplasia occurs much more frequently in younger individuals than in adults, and there is neither sex nor racial predilection.
ONSET AND RELATIONSHIP TO DOSAGE AND SERUM CONCENTRATION
Gingival hypertrophy, in most cases, appears within two to three months after the initial administration of the drug and reaches maximal severity in 12 to 18 months (Figures 2 to 5). If the hypertrophy is moderate, the hyperplastic tissue usually disappears spontaneously within three to six months following complete withdrawal of diphenylhydantoin; if the hypertrophy is severe, remission may take one year or longer.
We have performed diphenylhydantoin blood level determinations in hundreds of patients exhibiting gingival hyperplasia and have found that there is no direct relationship between the occurrence or severity of this disturbance and the dosage or serum concentration of diphenylhydantoin.
CLINICALAND MICROSCOPIC FEATURES
The primary or basic lesion is a hyperplasia of the gingivae, generally occurring in a semilunar distribution circumscribing the necks of the individual teeth. The hyperplasia usually commences as painless, discrete projections of gingival mucosa that usually become mulberry-shaped and are firm, pale, pinkish, and resilient. The surface of the gingivae is minutely lobulated, and there is, as a rule, no tendency for it to bleed. The hyperplastic tissue usually has a propensity to be larger in relation to the labial surface of both the upper and lower anterior teeth.
Local irritants such as bacterial plaque, materia alba, calculus, and impacted food particles frequently modify the clinical appearance of the hyperplasia. These irritants cause secondary inflammatory changes which result in an edematous enlargement of the primary hyperplastic gingivae. In addition, the inflammation causes a red or bluish-red discoloration, a bulge away from the tooth surface, obliteration of the minutely lobulated surface demarcations, and an increased tendency to bleed.
The histologie changes observed in diphenylhydantoin gingival hyperplasia have been reported extensively in the dental literature. In his textbook, GIickman8 states that, histologically, the diphenylhydantoin-induced hyperplastic tissue consists of pronounced hyperplasia of connective tissues and epithelium. There is acanthosis of the epithelium, and elongated rete pegs extend deep into the connective tissues, which present densely arranged collagen bundles with an increase in fibroblasts and new blood vessels.
The secondary inflammatory lesion initially appears along the surface of the gingivae adjacent to the teeth. The histopathology reveals, according to GIickman,8 a considerable infiltration of Ieukocytic inflammatory exudate, predominantly a small Jymphocytic type with a scattering of plasma cells.
The mechanism or mechanisms involved in the causation of diphenylhydantoin-induced gingival hyperplasia have by no means been clearly defined or established. The reasons for the affinity of this drug for the gingival tissues also remain obscure. We have not encountered evidence that diphenylhydantoin causes similar tissue changes in any other parts of the body. However, there are several reports in the literature stating that diphenylhydantoin has produced "heating" of tissue other than gingival.9'10
Most investigators concur that there is no direct relationship between the occurrence and severity of gingival hyperplasia and the dosage or serum concentration of diphenylhydantoin. This finding suggests that diphenylhydantoin-induced gingival hypertrophy is probably due to a specific hypersensitivity to the drug per se or to one of its metabolites.
In 1939, Kimball11 reported a definite relationship between the occurrence and severity of gingival hyperplasia caused by diphenylhydantoin and a deficiency in the vitamin C content of the blood. However, investigations carried out in our clinic12 and studies by Milhon and Osterberg13 do not reveal a relationship to any disturbance in the absorption or utilization of ascorbic acid. And, according to GIickman,8 "the suspicion that the hyperplasia is associated with a decreased blood level of ascorbic acid has been discounted."
The possibility that diphenylhydantoin gingival hyperplasia may be due to an alteration in the activity of the pituitary-adrenal complex or to a fundamental derangement of metabolism involving the adrenal glands has been investigated. Bonnycastle and Bradley14 reported a definite hypertrophy of the adrenal glands in male albino rats following the chronic administration of diphenylhydantoin.
Staple and Emslie15 reported an increase in weight of the adrenal glands of experimental animals subsequent to the administration of diphenylhydantoin and upon microscopic examination found definite histopathologic alterations in the adrenal glands. These investigators suggest that diphenylhydantoin gingival hyperplasia may be an exaggerated mucosal response to injury in subjects with deranged adrenocortical function.
Reader16 applied the experiments by Staple and Emslie to humans and suggested that the suppression of adrenocortical activity may be an etiologic factor in the causation of diphenylhydantoin gingival hyperplasia.
Several investigators have proposed an allergic basis for diphenylhydantoin-induced gingival hyperplasia. Van der Kwast17 demonstrated antibody-producing plasma cells in diphenylhydantoin hyperplastic gingival tissue. Francis and Melville18 found that the extractable amount of histamine in gingival mucosa is increased following the administration of diphenylhydantoin.
In a study of 22 patients, Babcock and Nelson18 demonstrated a positive correlation between the diphenylhydantoin content of saliva and the occurrence of gingival hyperplasia, dependent upon the age of the patient. They reported that hyperplasia is more severe in patients with a higher concentration of diphenylhydantoin per milliliter of saliva and that the amount of diphenylhydantoin per milliliter of saliva is higher in younger individuals.
Following reports of a lower serum magnesium level in convulsive patients20 and the induction of experimental hyperplastic gingivitis in magnesium-deficient rats/1 Baer et al.22 investigated 20 patients receiving diphenylhydantoin and found that their gingival hyperplasia was not the result of a magnesium deficiency.
It is generally conceded that the secondary inflammatory changes occurring in association with diphenylhydantoin therapy are due to local irritants. However, the primary hyperplastic lesion may occur in mouths devoid of local irritants (Figures 2 to 4) and may be absent in mouths in which local irritants are profuse.
Many patients receiving diphenylhydantoin while undergoing orthodontic therapy have been referred to our clinic for regulation of their antiepileptic regimens. In most of these children, the gingival hyperplasia was so marked that it extended over the orthodontic appliances. These patients complained of a constant oral malodor and almost continually bleeding gums. Obviously, it is virtually impossible for these patients to keep their mouths free from residual food particles and other irritants that lodge between the hyperplastic tissue and the orthodontic appliances, which probably act as an additional local irritant.
Most investigators agree that diphenylhydantoin-induced hyperplastic tissue does not occur in edentulous areas and recedes spontaneously following removal of teeth from areas which previously exhibited hyperplasia. It is of interest to note that two of our adult epileptic patients with marked gingival hyperplasia had, of their own accord, all of their teeth extracted. The hyperplasia receded spontaneously and has not recurred despite continued diphenylhydantoin therapy for many years thereafter.
Other etiologic postulations are presented in the comprehensive paper published by Gardner et al.5 in 1962.
The occurrence or degree of hyperplasia is not related to the dosage of diphenylhydantoin and probably represents a specific sensitivity to the drug. However, the appearance of hyperplastic gingival tissue is, in itself, not an indication for discontinuing diphenylhydantoin therapy. In some instances, however, it may be necessary to withdraw the drug because the hyperplastic tissue does not respond to corrective measures and becomes so marked that it interferes with chewing or is disfiguring.
Figure 1. Severe gingival hyperplasia with marginal inflammation in a 12-year-old boy receiving diphenylhydantoin (300 mg. daily for three years). Hydantoinate blood level is 21 meg. /ml. (2.1 mg. %). Note marked displacement of teeth by the hyperplastic tissue, which caused an anterior opened bite resulting in mouth breathing, which may have enhanced the gingival enlargement.
Figure 2. Mouth of a 10-year-old boy one day before institution of diphenylhydantoin therapy (300 mg. daily). The mouth is clean and devoid of local irritants.
Figure 3. Mouth of the same patient three months later shows a mild degree of hyperplasia.
Figure 4. Six months after diphenylhydantoin was prescribed the same mouth shows a progression of the gingival tissue. Note the beginning separation o! the maxillary central incisors, apparently caused by the proliferating interdental gingivae in this area.
Figure 5. The same mouth 17 months after the start of diphenylhydantoin therapy shows a further progression of the gingiva! tissue and increase in the diastema between the central incisors. Gingivectomy was indicated and was performed.
Figure 6. Mouth of the same patient showing mandibular anterior teeth 10 days after completion of gingival resection to the cervical aspects of the teeth.
Figure 7. Mouth of the same patient showing maxillary anterior teeth 10 days after completion of gingival resection to the cervical aspects of the teeth.
Figure 8. Seven monlhs after gingivectomy the same mouth shows recurrence of gingival hyperplasia.
Obviously, the best treatment of the basic hyperplastic lesion would be withdrawal of diphenylhydantoin therapy, following which the hypertrophic tissue disappears spontaneously, usually within 3 to 12 months, depending upon the severity of the hyperplasia.
Treatment in patients in whom discontinuance of diphenylhydantoin is not feasible consists of periodontal surgery. The decision regarding this procedure must be individualized and depends upon the magnitude of the hyperplastic tissue and its effect upon mastication, speech, and aesthetics (Figure 5).
It must be noted that periodontal surgery is not a permanent solution to the problem since, if drug therapy is continued, the gingival hyperplasia invariably recurs and progresses to its previous intensity, usually within 6 to 12 months (Figures 6 to 8). Therefore, repeated gingival resections may be necessary.
It has been suggested23 that diphenylhydantoin "gum hypertrophy may be prevented in part by close attention to oral hygiene and by the use of capsules rather than suspension or uncoated tablets." The complicating secondary inflammatory changes can usually be eliminated, or at least minimized, by fastidious oral physiotherapy. However, in our experience, "close attention to oral hygiene" has little or no effect on either the development or mitigation of the primary hyperplastic lesion.
We disagree with the recommendation that diphenylhydantoin capsules rather than the suspension or uncoated tablets be employed as an endeavor to prevent "in part" the development of gingival hyperplasia. We assume that the author" means to infer that a very brief contact of the suspension or uncoated tablets with the gingivae two or three times a day plays a role in the causation of diphenylhydantoin gingival hyperplasia. Even if this supposition were correct, it should be recognized that diphenylhydantoin is normally secreted into the saliva, irrespective of the dosage form employed. Moreover, most investigators have found no correlation between the occurrence of gingival hyperplasia and the level of diphenylhydantoin in the saliva.
It has been our experience that a reduction in the dosage of diphenylhydantoin or massaging of the gums or both does not cause a recession of the primary hyperplastic lesion. However, Goldman et al.24 recommend a special massaging technique with which we have had no experience. It consists of:
. . . placing of stiff, hardbristled brush at a 45 degree angle against the gingiva in a forceful manner. The application of the brush head against the tissue should cause a blanching. The stroke should be repeated several times in a given area. The procedure is time consuming and cannot be hurried; it should be performed twice daily.
Other therapeutic procedures have been recommended. In 1957, Gaillard25 reported that the gingival hyperplasia was eliminated in two patients who were treated with chlorpheniramine (Chlor-Trimeton, Teldrin). However, we have not achieved significant results with this form of therapy, and similar negative findings have been reported by Breg and Falcetti."6
Davis and co-workers27 and Babcock-8 reported successful use of positive pressure appliances made of hard natural rubber worn as a mouthpiece nocturnally to prevent the regrowth of gingival tissue after surgery. More recently, Krämer" presented a patient in whom the recurrence of diphenylhydantoin gingival hypeiplasia was prevented by the use of a natural hard rubber pressure appliance following periodontal surgery and orthodontic realignment of the anterior teeth. The patient wore this appliance 24 hours a day, except while eating, for one year. Subsequently, the time the appliance remained in the patient's mouth was gradually reduced. After three and a half yeais, the patient wore the mouthpiece only while sleeping and for three hours diurnally.
Spira30 reported favorable results following massage of the hyperplastic gingivae with hydrocortisone ointment. On the other hand, Sackler et al.31 did not find this form of therapy to be of value in their group of patients.
1. Biltz, H. Über die Konstitution der Einwirkungsprodukte von substituierten Harnstoffen auf Benzil und über einige neue Methoden tut Darsteliung der 5,5-Diphenylhydantoine. Ber. der Deut. Chem. Gesellsch. 41 (1908), 1379-1393.
2. Merritt. H. H. and Putnam, T. J. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J.A-M.A. 111 (1938), 1068-1073.
3. Livingston, S. Comprehensive Management of Epilepsy in Infancy, Childhood and Adolescence. Springfield: Charles C.Thomas, 1972.
4. Lennox, W. G. The drug therapy of epilepsy. J.A.M.A. 114 (1940), 1347-1354.
5. Gardner, A. F,, Gross, S. G., and Wynne. L. E. An investigation of gingival hyperplasia resulting from dipnenylhydantoin sodium therapy in 77 mentally retarded patients. Exp. Med. Surg. 20 (1962), 133-158.
6. Babcock, J. R. Incidence of gingival hyperplasia associated with Dilantin therapy. J.A.D.A. 71 (1965), 1447-1450.
7. Panuska, H. J., Corlin, R. J., Bearman, J. E., and Mitchell, D. F. The effect of anticonvulsant drugs upon the gingiva-a series of analyses of 1,048 patients. J. Periodont. 32 (1961), 15-28.
8. Glickman, I. Clinical Periodontology. Philadelphia: W. B. Saunders Co., 1965, 76-78.
9. Shafew, W. G-, Beatty, R. E.. and Davis, W. B. Effect of Dilanfrn sodium on tensile strength of healing wounds. Proc. Soc. Ex.pt!. Biol. Med. 98 (1958), 348-350.
10. Simpson, G. M., Kunz, E-, and Slafta, J. Use of sodium diphenylhydantoin in treatment of leg ulcers. W. Y. St. J. Med. 65 (1965), 886-888.
11. Kimball, O. P. The treatment of epilepsy with sodium diphenyl hydantoinate. J.A.M.A. 112 (1939), 1244-1245.
12. Kajdi, L. and Livingslon, S. Studies ot viiamin C metabolism in diphenylhydantoin gingival hyperplasia. Unpublished.
13. Milhon. J. A. and Osterberg, A. E. Relationship between gingival hyperplasia and ascorbic acid in the blood and urine in epileptic patients undergoing treatment with sodium 5,5diphenyl hydantoinate. J.A.D.A. 29 (1942), 207212.
14. Bonnycastle, D. D. and Bradley. A. J. Diphenylhydantoin and the release of adrenocorticotropic hormone in the albino rat. Endocrinology 66 (i960), 355-363.
15. Staple, P. H. and Emslie, R. D. Some tissue reactions associated with Dilantin sodium. Int. Dent. J. 3 (1952). 190.
16. Reader, Z. A. Gingival hyperplasia resulting from diphenylhydantoin sodium: a review of the literature. J. Oral Surg. 8 (1950), 25-37.
17. Van der Kwast, A. M. Speculations regarding the nature of gingival hyperplasia due to diphenylhydantoin sodium. Acta Med. Scandinav. 153 (1956), 399-405.
18. Francis, L. E. and Melville, K. I. Effects of diphenylhydantoin on gingival histamine and serotonin. J. Canad. Dent. Assn. 25 (1959), 608-620.
19. Babcock, J, R. and Nelson, G. H. Gingival hyperplasia and Dilantin content of saliva: a pilot study. J.A.D.A. 68 (1964), 195-198.
20. Haury, V. G. and Cantarow, A. Variations of serum magnesium in 52 normal and 440 pathologic patients. J. Lab. Clin. Med. 27 (1942). 616622.
21. Klein, H-, Orent, E. R., and McCollum, E. V. The effects of magnesium deficiency on the teeth and their supporting structures in rats. Amer. J. Physiol. 112 (1935), 256-262.
22. Baer, P. N" Davis, R. K., and Merritt, A. D. Studies on Dilantin hyperplastic gingivitis: the role of magnesium. J. Dent. Res. 44 (1965), 1055.
23. Miliichap, J. G. Drug treatment of convulsive disorders. New Engl. J. Med. 286 (1972), 464-469.
24. Goldman, H. M., Schluger, S., Fox. L., and Cohen, D. W. Periodontal Therapy. Second Edition. St. Louis: C. V. Mosby Co., 1960, 637.
25. Gaillard, R. A. Antihistaminic therapy for gingival hyperplasia due to Dilantin. New Engl. J. Med. 256 (1957). 76-77.
26. Breg, W. R,, and Falcetti. J. P. Ineffectiveness of antihistamine therapy for gingival hyperplasia due to diphenylhydantoin sodium. New Engl. J. Med. 257 (1957), 1128.
27. Davis, R. K.. Baer, P. N., and Palmer, J. H. A preliminary report on a new therapy for Dilantin gingival hyperplasia. J. Periodont. 34 (1963). 17-22.
28. Babcock, J. R. The successful use of a new therapy for Dilantin gingival hyperplasia. Periodontics 3 (1965), 196-199.
29. Kramer, G, M. Paper presented at the meeting of the Greater Washington Society of Periodontology. Washington, D. C.. May, 1973.
30. Spira, A. Cued in Staple, P. H. Some tissue reactions associated with 5.5-diphenylhydantoin (Dilantin) sodium therapy. Brit. Dent. J. 95 (1953), 289-302.
31. Sackler, A. M.. Rockoff. S. C.. Rockoff, N. S., and Oshrain, H. I. Hydrocortisone acetate in the treatment of Ditantin gingival enlargement. W. V. S. Dení. J. 20 (1954). 125-126.