PEDIATRIC /Copyright ° 1981 by The American Academy of Pedodontics Vol. 3, Special Issue

Clinical management of phenytoin-induced gingival overgrowth in handicapped children Dr. Steintorg Arnold D. Steinberg, DDS, MS

Abstract testines and reaches a peak plasma level in four to 12 Phenytoin (PHT)-induced gingival overgrowth (PIGO) hours. Serum levels of 10-15ug/ml are usually required due to chronic administration remains an unsolved problem. for seizure control. Generally, there are no side-effects The prevalence of PIGO in the general population is around at serum levels below 15ug/ml.4 40% of those taking the drug. Younger age groups experience more lesions than adults and in the handicapped the PHT, which has been tested by continuous use over prevalence appears to be highest. modifies long periods, and by a very large number of individ- PIGO and it is suggested that minimal plaque drug levels (of uals, has proven to be one of the safest of the anticon- salivary origin) and/or metabolite levels may be important vulsants currently being used. This drug has remark- for lesion production by having a direct affect on the ably few side-effects, but of those reported, gastric dis- gingiva. The most satisfactory treatment is the elimination tress, skin rash, minor central nervous system reac- of the drug, if possible. Patients who must be maintained on tions and gingival overgrowth are the most common.4 PHT respond well to a program of meticulous oral hygiene Since this review is limited to a discussion of PIGO a t home along with frequen t professional prophylaxes. in handicapped children, it is appropriate to identify Surgical removal is indicated when the severity of the lesion briefly some handicapping disorders in which PHT is such that esthetics, mastication or secondary therapy may be used. Patients having cerebral palsy becomes a problem. Use of a positive pressure appliance and maintenance of good oral care after may have cerebral cortical damage which cause seiz- has been shown to control resurgence of the ures. PHT may be used to treat certain types of psy- gingival overgrowth. chotic patients, children with behavior disorders, var- ious neuromuscular disorders (e.g., choreas and Introduction neuromyotonic syndromes), and and trau- mas affecting cortical cells.2 In 1937 Merritt and Putnam1 introduced the first PHT therapy initiated before the eruption of the successful anticonvulsant or antiepileptic drug, Phen- permanent teeth may delay eruption. It may reach a ytoin (PHT). Drugs that preceded PHT, bromide and point where surgical intervention is necessary for phenobarbital, were not specific for epilepsy and had a eruption to occur. A delayed passive eruption may broad central nervous system effect. PHT was not a also occur leaving only a partially exposed anatomical sedative and was not addictive, but controlled convul- making the teeth appear short. sions by modifying the bioelectrical activity of the af- The lesion assumes a different form when PHT fected central nervous system cells. Because of this therapy is started after the eruption of the permanent ability to regulate cellular bioelectrical activity PHT teeth. The first sign of the overgrowth is usually a has proven to be effective not only in epilepsy, but in a painless enlargement of the interdental papillae which variety of other disorders. These include mood and be- may be accompanied by swelling of the gingival mar- havior problems, stuttering, migraine and other head- gin. If there is no secondary inflammation, the gingiva aches, neuromuscular pathologies, cardiac problems, is pink, firm and does not bleed easily. Gradually the and a variety of other maladies where cellular bioelec- gingival changes become more prominent and with en- trical activity require regulation.2 largement, the interdental papillae become mulberry- Because of its wide therapeutic range, it is now esti- like in appearance. These interdental lobulations ex- mated that in the United States there are well over tend labially and, less often, lingually. If growth con- two million persons using this drug on a chronic daily tinues, they meet at the center of the labial of the basis.3 The usual adult dosage of PHT is 300mg per surface, separated by a small cleft. With further day taken orally. It is slowly absorbed by the in- enlargement the lobulations may coalesce at the mid-

MANAGEMENT OF GINGIVAL OVERGROWTH 130 Steintorg line of the labial or lingual tooth surface and gradually those on PHT will experience gingival overgrowth, encroach on the crowns of the teeth. In extreme cases, with most investigators placing the rate at about 40%.~ the gingival tissue may completely cover the anatomi- My observations at the epilepsy clinic at the Univer- cal crown with a solid mass of fu-mly resilient tissue. sity of Illinois indicate a much lower prevalence As can be expected, these tissue masses become (around 25%) and, of those so affected, approximately 20%will have a reaction severe enough to warrant sur- traps for debris and plaque, are difficult to clean and enhance secondary inflammation. With such involve- gical correction. This lower prevalence may be due to ment, esthetics becomes a serious problem and can the older population that was observed. Most in- only worsen the psychological difficulty already expe- vestigators indicate a higher incidence of gingival overgrowth in children and adolescents than in adults, rienced by patients with epilepsy or other handicaps. ~ Furthermore, with such masses of tissue extending with few lesions seen after the age of 40. The wide onto the tooth biting surfaces, mastication becomes prevalence range may, therefore, be due to age differ- difficult and tissue trauma can occur. These lesions ence in the groups studied, as well as differences in may usually be classified as purefibrotic or inflamma- other parameters such as oral hygiene. tory type of gingival overgrowth. In the mentally In a recent study1° on institutionalized, severely retarded, where oral hygiene is limited, we appear to encounter the latter lesion more frequently. retarded children, ages 4-15, we found that 94%of the patients (18 to 19) receiving PHThad a PIGO. Gard- Gingival overgrowth can be induced by factors ner et al., 11 reported 78%of a mentally retarded group other than PHT (e.g., mouth breathing, irritations 12 along the necks of teeth or hormonal alterations such exhibited some PIGOand Kapur et al., reported 68% as those at puberty). These same factors appear to en- of a similar group had PIGO. The high prevalence in hance the size of lesions in a PIGO. No matter what our study may, among other factors, be due to the the etiology, the lesions appear grossly and histologi- poor oral hygiene and limited masticatory ability of cally similar. this population. In the initial examination a signifi- cant relationship was noted between the degree of PIGOand the plaque index. 39%of these patients had Any irritant to the gingival tissues, such as an a slight overgrowth, 11% had a moderate involvement, orthodontic band or defective dental restoration, ap- while 50%had a severe PIGO. In normal, non-institu- pears to encourage an earlier onset and an enhanced tionalized populations the degree of PIG~ was found reaction of the gingival tissues to PHT. Similarily, to be approximately 45% with a slight overgrowth, irritation or inflammation induced by mechanical 40% had a moderate involvement and only 15% had a means in experimental animals receiving PHT aids in severe reaction, m4 Thus, it appears that in the men- ,~ producing the lesion; tally retarded there was a higher percentage of pa- Oral hygiene modifies the gingival overgrowth, but tients with a severe involvement of the gingiva. This the degree of the fibrosis and its relationship to oral finding may be due to the poorer oral hygiene of the hygiene is disputed in the literature. Glickman and patients and higher drug levels. 7 Lewitus found that removing plaque, and No race or sex difference in PIGO have been re- other local irritations eliminated inflammation, but ported; ~.1~ Opinions differ regarding the relationship only reduced the severity of the changes caused by between therapy duration, dosage and the severity of PHT. My own clinical observations indicated that the gingival overgrowth.3.~ There is also conflicting once the overgrowth condition begins it can be evidenceconcerning the role of plasma~2.~7.~s.19,~and sali- reduced with good oral hygiene, but is extremely diffi- vary levels~,~9,~.~ of PHTin relation to gingival enlarge- cult to eliminate completely without surgical inter- ment. Such variation may be due to the para-hydroxy vention or eliminating drug intake. The relationship metabolite~,~ of PHTbeing a responsible factor; between oral hygiene and gingival overgrowth is com- plicated by the possibility that it is the lesion that Clinical Manifestations causes the poor local hygiene. Several investigators maintain that elimination of plaque and gingival ir- The time between the initiation of phenytoin ther- ritation prior to the initiation of PHTtherapy will apy and the onset of gingival overgrowth varies. First ~.9 clinical signs of fibrosis have been reported as early as prevent the development of the lesion. Their work = supports the view that inflammation is a prerequisite two weeks after the beginning of therapy; however, for the development of the pathology and the preven- several months usually elapse. The factors responsible tion must be directed toward eliminating the causes of for such variability are unknown. It has also been this inflammatory component. reported that from two to four years are required for the overgrowth to reach its peak2 Prevalence Most investigators agree that the gingival over- Depending on the study quoted, from 3% to 78% of growth is most marked in the anterior region of the

PEDIATRICDENTISTRY 131 Volume3, SpecialIssue mouth, with the labial or buccal surfaces of all teeth plaque from gingival overgrowth as compared to non- having a greater involvement than the lingual sur- overgrowth areas. However, such an alteration in bac- faces. 5," It has been suggested that this is due to the terial population may not be causally related to the pressure exerted on these tissues by the . gingival overgrowth. It was also observed that the The severity of the overgrowth can vary within the amount of gingival plaque was not always directly re- same individual, with both normal and pathological lated to the severity of overgrowth. Apparently the areas found in the same mouth. No lesion is usually type as well as the quantity of may be observed in edentulous areas. However, occasionally crucial to the development of the lesion. It is also such~ cases are reported. possible that plaque metabolize PHT, pro- In the severely mentally retarded group we ducing a metabolite which, when absorbed into the studied ~° we found that the pattern of gingival over- sulcular tissue, induces the lesion. growth was not the same as that generally observed in ConnectiveTissue Changes normal individuals. We found that the PIGO was Pathological changes occur in connective tissue most marked on the posterior teeth even though the other than gingiva, but at lower frequency. A dermal majority of the patients were mouth breathers. It was reaction to PHT administration has been described in difficult to ascertain the cause of this discrepancy. We rats = and acceleration of woundhealing has also been speculate that severe retardation was important and noted when this drug is administeredY Thickening of that it limited masticatory abilities, resulting in food the of the cranial vault of children on long-term being swallowed whole. In addition, oral hygiene pro- drug therapy has been describedY Swelling of , cedures were limited and, due to lack of cooperation, broadened nose, and a general thickening of subcu- appeared to be restricted to the anterior teeth. taneous tissues of the face have also occasionally been This factor alone may have been responsible for our observed, especially if PHThas been initiated early in observation. life~,~ and maintained for a long time period. ~ Etiologyof PIGO Lefebvre et al., observed that among222 institu- Amongthe many suggested theories regarding the tionalized mentally retarded individuals with seizures, approximately 1/3 had obvious facial changes, an- etiology of PIGOare serum vitamin C deficiency, 5 di- other 1/3 had questionable facial changes, and 1/3 rect local effect of the drug or metabolite, ~6 depression had no changes. PHT was the principal drug used by of the pituitary -- adrenal axis, ~ and immunological all, with the affected groups exkdbiting a greater num- reaction; ~ It has also been proposed that PHT- ber of seizures, significantly higher serum drug levels, induced folic acid deficiency could render the gingival hyperphosphatasia, and increased lethargy. It was tissues more susceptible to local factors (e.g., plaque), thus enhancing the response of the gingiva to specific also noted that the affected group had a greater sever- exaggerated inflammatory reactions as in gingival ity of PIGO. These mentally retarded patient’s varied overgrowth.~ etiologies and early normal photographs indicated It is postulated that PHTis a folic acid antagonist, that the features were acquired, implying a high long- term dose response. Thus, long-term anticonvulsant interferes with normal metabolism of these tissues, and~ may decrease PHT metabolite production. Vogel therapy, initiated at an early age, may not only have a profound affect on the developing skull and cranio- reported that administration of folic acid with PHTto facial growth, but also affect the position of teeth and cats, markedly decreased the occurrence of PIG0 supporting boney when compared to a group administered PHT alone. PHTappears to affect other connective tissues, but An isolated report has claimed a decrease in PIGO lesions in humans receiving 3mg of folic acid daily on a limited basis, suggesting that all the parameters which may enhance the prevalence of the lesion in along with PHTYThis report, however, was not a gingiva are present only on a limited basis in other controlled clinical study. The uniqueness of plaque around the gingival sul- tissues. cular area and the maintenance of minimal PHT or Mechanismof Gingival Overgrowth metabolite levels in blood, and/or saliva, appear to be To date, none of these theories can explain the two important parameters. It has already been stated that major questions remaining unanswered. First, what is inflammation or an immune response to plaque may the mechanism by which phenytoin can stimulate gin- be a factor in the production of this lesion. It is pos- gival overgrowth? Second, why is gingiva the primary sible that phenytoin or a metabolite may affect the tissue in the body so involved? plaque bacteria by either limiting the population of Animal~,~,~.~ and.~ clinical studies in my laboratory bacteria or by altering the metabolism of plaque bac- have resulted in a hypothesis to explain why this teria. Staple et al.,3~ in a recent investigation in mon- unique reaction of the connective tissue predominates keys, showed some bacterial population alteration in in the gingiva. According to pharmacokinetic princi-

MANAGEMENTOF GINGIVAL OVERGROWTH 132 Steinberg ples, only the unboundor free fraction of the drug car- the drug of choice for seizure control and this usually ried by blood is therapeutically active. For PHTthis takes precedence over the gingival overgrowth. It then amounts to approximately 10%.1~ This unbound frac- becomes the ’s responsibility to control the tion found in serum is dispersed through the various overgrowth as best he can. Withdrawal of the drug body tissues, including gingiva. A number of investiga- will usually result in a spontaneous disappearance of tors have demonstrated PHT in saliva of patients on the gingival overgrowth within three to six months, if long-term administration of the drug.21.a.~ Our studies the lesions are moderate in size. It may take up to a indicate that the level of PHT in human saliva is year~ or longer if the lesions are large. about~ 10%that of the blood level/~ and Hominget al. Over the years a variety of theories regarding the have reported that PHTsecreted by saliva is in the etiology of this disorder have been presented and a unbound form. We have also shown that both PHT variety of treatments relating to these theories have and its primary metabolite, the para-hydroxyl form, been attempted. Vitamin C administration, ~,~ antihis- are present in human plaqueY Furthermore, our tamine administration, 47,~ alkaline /5,~8topi- human studies suggest that the severity of gingival cal hydrocortisones/9 and diuretics ~ have all been overgrowth tends to be associated with higher PHT attempted. These treatments have been shown to be levels in gingiva and with lower tissue levels of the ineffective. para-hydroxyl9 metabolite; The only treatment that has proved consistently effective has been the institution of a program of }aliva is a contributor to plaque formation and meticulous oral hygiene~.~,8.~8.~ along with a deep, soft may be implicated in the production of this condition tissue curettage to help further reduce secondarily in- by serving as a reservoir, concentrating PHT in, and flamed tissues. Several investigators ~,~,~ have suggested adjacent to, the gingival sulcular area. In addition, it that initiation of meticulous oral care with the begin- is possible that plaque may metabolize PHT. ning of PHT therapy will prevent the gingival over- Our animal studies have demonstrated the absorp- growth from occurring. Similar results have been tion or diffusion of PHTthrough the gingival sulcular reported in Macaque monkeys;~ The elimination of epithelium into the underlying connective tissue and plaque after the lesion is present appears to only mod- into the circulation. ~.~ We have also shown a pro- ifyTM the size of the gingival overgrowth. longed retention of PHTin the gingival sulcular tissue after~ local, topical application in the . In the severely retarded children/~ we attempted to These data indicate the presence of a pathway for the control plaque in one of two ways. During one study reabsorption of PHT from saliva into plaque and period no oral hygiene procedures were used and 1 ml through the into the underlying of a .325% stannous fluoride gel was applied topically connective tissue. once a day for five months. This resulted in a signifi- I believe that the combined effects of the unbound cant decrease in plaque and PIG0. Gingival index was, drug from saliva (10% of serum levels) reabsorbed into however, not reduced significantly. In the second the gingival connective tissues and the unbound PHT phase of this investigation, an electric was delivered to the gingival connective tissues from the used to remove plaque and massage the gingival tissue systemic circulation (10% of serum levels), combine for three minutes. This resulted in a very significant produce levels of unbound PHT, or a metabolite, decrease in plaque scores, gingival index and PIGO. which under prolonged exposure, may be important in Findings of interest in this latter phase of the study altering collagen production by the local fibroblasts. were that the majority of the children had diminished Thus, the unique parameters of plaque, local inflam- seizure activity and greater food intake with a noted mation and concentration of the drug or metabolite increase in weight and a decrease in constipation. around the gingival sulcular tissue may make this tis- Surgical removal is indicated when the severity of sue more susceptible to the gingival overgrowth than the gingival overgrowth is such that an esthetic prob- is any other tissue in the body. lem exists, speech or mastication is impeded, severe secondary inflammation is occurring, and when oral Treatment hygiene procedures have not succeeded in controlling It is customary in medical practice to treat un- the overgrowth. Surgery is not a permanent solution. toward drug reactions by eliminating the drug causing If the PHT therapy continues, the gingival over- the problem. This is probably the most satisfactory growth will invariably recur. Repeated treatment of PIGO. In patients where the gingival may be necessary in these patients and recurrence of overgrowth is severe and difficult to control, the pa- the lesion has been observed as early as three weeks tient’s physician should be warned of the situation after surgery2 ~ Meticulous oral care will, however, and consulted about the feasibility of changing the markedly delay the recurrence. anticonvulsant drug. In many cases PHTproves to be Donnenfeld, et al.,~ using supervised oral hygiene

PEDIATRICDENTISTRY 133 Volume3, SpecialIssue after , prevented PIGO from recurring appliance, and/or 3. Minimized gingival tissue expo- during a nine month observation period in a number sure to saliva. Only one, or all of these factors, maybe of patients. When early small interproximal tissue responsible for the reported success. growths do begin to recur, they can easily be removed Occasionally patients have severe PIGOand, due to by a small curved surgical scissors2 systemic conditions, surgery is contraindicated. An This procedure can be performed using a blade, effort was made to ascertain howsuccessful a series of which many practitioners feel provides better control pressure appliances, without surgery, might be in for the restoration of normal gingival architecture. reducing the gingival overgrowth in one of our clinical Following surgery a periodontal dressing is worn for a patients. The patient had first undergone three weeks week over the as protection and as an anodyne. of meticulous oral care and weekly professional pro- Electrosurgery is used by many practitioners because phylaxes to reduce inflammation and lesion size. Im- of the ease with which large amounts of tissue can pressions were taken of the upper and lower arches, be removed. A periodontal dressing is normally not stone casts were made and the gingival overgrowth required with this procedure. area on the casts trimmed about 2mm. These casts The excess tissue removal can also be achieved were sent to a dental laboratory for the construction using an internal bevel technique in which a flap is of a latex tooth positioner. 57 She wore this appliance elevated and "thinned" of excess collagenous tissues. about four hours during the day and during sleep. The flap is then contoured, apically repositioned and After four weeks, impressions were taken again, casts sutured securely to the necks of the teeth. ~ The surgi- relieved again by about 2mm,and a second latex ap- cal flap procedure heals faster than the external bevel pliance constructed which she wore for four weeks. since it leads to primary healing. In addition, this pro- Comparing the initial condition with results after cedure gives better control of post-operative eight weeks revealed a marked decrease in lesion size. and does not necessitate the use of a periodontal pack The results suggest that a series of such appliances which may be a problem to maintain in a handicapped could succeed in regressing a gingival overgrowth to patient. The external bevel procedure heals slower clinically tolerable limits. Such a procedure is too time since it heals by secondary intention, even though consuming for the average patient, but may prove patients on PHT therapy appear to have accelerated valuable in those patients where systemic conditions woundhealing. ~ In all cases, the implementation of a contraindicate surgery. presurgical oral hygiene program and prophylaxis is suggested, if possible, to minimize secondary inflam- Conclusion mation (and resulting bleeding) and decrease the size We may summarize the approach to treatment of of the lesion. gingival overgrowth as follows: 1. Wherea mild gingival overgrowth exists, initiating PositivePressure Appliance meticulous oral care along with four yearly profes- Recently, use of a positive pressure appliance after sional prophylaxes and topical SnF2 applications surgery has been shown to be a beneficial adjunct to will do much to cbntrol the lesion. The patient can daily oral care in controlling the resurgence of the gin- usually function well with a mild gingival over- gival overgrowth. Successful control has been reported growth if oral care is maintained and secondary for from seven~ to 23~ months following surgery by inflammation prevented. the use of a pressure appliance. Immediately after sur- 2. With a moderate gingival overgrowth, initiation of gery, alginate impressions of the upper and lower meticulous oral care is again indicated along with arches are taken and stone casts made for the fabrica- four office visits (one week apart for professional tion of a latex tooth positioner; 7 The interproximal prophylaxes and topical SnF~ treatment). Such and attached gingival areas are accentuated to exert regimen will usually decrease the size of the lesion active pressure on the attached gingival and inter- to a clinically tolerable size, but only ,vith complete proximal~ papilla. patient cooperation. These patients are then seen For this appliance to be successful, the patient five times each year for prophylaxes and SnF2 must wear it when asleep and about four additional treatment. hours a day while maintaining meticulous oral care. In Where the patient does not cooperate, or the the severely handicapped, I have found such an appli- lesion will not regress, contact should be made with ance of limited value because of lack of cooperation. the patient’s physician to obtain the serum levels of The exact mechanism by which pressure appliances PHTand discuss possible alterations of drug ther- work is not known. Babcock~ suggests three possibili- apy from PHT to another anti-convulsant drug. ties: 1. The pressure or stimulation on the gingival tis- Oral care by these patients should be monitored, sues, 2. Better oral hygiene habits developed in these not only by the dentist, but also by other profes- patients due to an awareness created by wearing the sionals involved in treating the patient.

MANAGEMENTOF GINGIVAL OVERGROWI"H 134 Steinberg 3. In the severe gingival overgrowth condition, the 9.Kerr,D. A.: Stomatitisand gingivitisin adolescentand pre- stops outlined in # 2 should be initiated and the pa- adolescent,JAm Dent Assoc, 44:27-31, 1952. 10.Steinberg,A. D. and Steinberg,S. C.: Phenytoininduced gin- tient seen by the dentist on a weekly basis for givalovergrowth control in severelyretarded children, Sub- curettage, professional prophylaxes, topical fluoride mitred for Publication, JPrev Dent. and monitoring of oral care for about four weeks. 11. Gardner, A. F., Copeland, C. M. and Klinze, E. E.: An investiga- An evaluation is then made as to the success of the tion of dilantin gingival hyperplasia with review of literature, conservative therapy. If drug substitution is not J Dent Aseoc S Af~ca, 18:360-375, 1963. possible and/or regression of the lesion is not to a 12. Kapur, R. N., Girgio, S., Little, T. M. and Masotti, R. E.: Di- phenylhydantoin-induced gingival hyperplasia: Its relationship tolerable size, surgery will be required. With to dose and serum level, Develop MedCldld Neurol, 15:483-487, meticulous oral care it has been shown that lesion 1973. recurrence after surgery can be prevented for up to 13. Klar, L. A.: Gingival hyperplasia during dilantin therapy; A sur- nine months52 and probably longer. If the lesions vey of 312 patients, J Pub H Dent, 33:180-185, 1973. recur to previous levels and surgery is again re- 14. Druian, M.: Effects on the of diphenylhydantoin sodium, diastemas, 3:31-33, 1970. quired, a pressure appliance should be considered as 15.Dummett, O. W.: Oral tissue reactions from dilantin medication an adjunct to oral care when there is sufficient in the control of epileptic seizures, J Periodontol, 25:112-117, patient cooperation. 1954. Meticulous oral care must be initiated in all pa- 16. Esterberg, H. L. and White, P. H.: Sodium dilantin gingival tients prior to initiation of PHTtherapy. The patients hyperplasia, JAm Dent Asset, 32:16-20, 1945. 17.Little, T. M., Girgio, S. and Masotti, R. E.: Diphenylhydantoin- and parents must be made aware, not only by the den- induced gingival hyperplasia: Its response to changes in drug tist, but by all professionals involved in their care, of dosage, Develop MedChild Netwol, 17:421-424, 1975. the means at hand to control this untoward reaction to 18. Cianscio, S. G., Yaffe, S. J. and Catz, C. C.: Gingival hyperplasia PHT. In the severely handicapped, oral care by par- and diphenylhydantoin, JPe~odontol, 43:411-415, 1972. ent or guardian is required. There will be a number of 19. Conrad, J. G., Jeffay, H., Boshes, L. and Steinberg, A. D.: Levels of 5,5-diphenylhydantoin and its major metabolite in human handicapped patients where the gingival overgrowth serum, saliva, and hyperplastic gingiva, J Dent Res, 53:1323- will not be controlled because of a lack of oral care. In 1329, 1974. these cases, treatment of a severe lesion is indeed a 20. Philstrom, B. L., Carlson, J., Smith, Q. T., Bastien, S. and problem. Drug substitution is most successful here. It Keenan, K. M.: Prevention of phenytoin associated gingival is hoped that future research will elucidate the mech- enlargement -- A 15 month longitudinal study, J Pe~odontol, 51: 311-317, 1980. anism by which PHT induces gingival overgrowth and 21. Babcock, J. R. and Nelson, G. H.: Gingival hyperplasia and provide better means of controlling this untoward dilantin content of saliva: A pilot study, J Am Dent Aseoc, 68: reaction of a very useful drug. 195-198, 1964. 22. Hassell, T. M. and Cooper, C. G.: Phenytoin-induced gingival overgrowth in a mongrel cat model, in Phenytoin-Induced Tera- Dr. Steinberg is professor, department of periodontics, Univer- tology and Gingival Pathology, ed. Hassel, T. M., Johnston, M. sity of Illinois College of Dentistry, 801 South Paulina, Chicago, and Dudley, K., NewYork: Raven Press, 1980, pp. 147-162. 23. Jurgens, P. E.: Gingival hyperplasia in dilantin sodium therapy, Illinois 60612. Requests for reprints should be sent to him at that address. J PeHodontol, 23:117-122, 1952. 24. Gardner, A. F., Gross, S. G. and Wynne,L. E.: An investigation of gingival hyperplasia resulting from diphenylhydantoin ther- apy in soventy-seven mentally retarded patients, Exp Med Surg, References 20:133-140, 1962. 1. Merritt, H. H. and Putnam, T. J.: Sodium diphenylhydantoin in 25.Deryer, W. P. and Thomas, C. J.: Diphenylhydantein-induced the treatment of convulsive disorders, J Amer Megingival enlargement during the administration hyperplastic tissues, JPe~qodontol, 51:25-29, 1980. of diphenylhydantoin in eats, J Pe~odontel, 7:102-105, 1972. 29.Vogel, R. I.: Relationship of folic acid to phenytoin-induced gin- 7. Glickman, I. and Lewitus, M.: Hyperplasia of the gingiva associ- gival overgrowth, in Phenytoin-Induced Teratology and Gin- ated with dilantin therapy, JAmDent Assoc, 28:199-204, 1941. gival Pathology, ed. Hassel, T. M., Johnston, M. and Dudley, K., 8. Hall, W. B.: Prevention of dilantin hyperplasia, Bull Acad Gen NewYork: Raven Press, 1980, pp. 163-178. Dent, 4:20-23, 1969. 30. Folic acid seen controlling gingival enlargements in Clinical Den-

PEDIATRICDENTISTRY 135 Volume3, Special Issue t/stxy, Mar, 1974, p. 8. 43. Steinberg, A. D., Steinberg, J., Allen, P. and Jeffay, H.: The ef- 31. Staple, P. H., Reed, M. J., Mashimo, P. A., Sedranek, N. and fect of alteration in the sulcular environment upon the move- Umemoto, T.: Diphenylhydantoin gingival hyperplasia in ment of C~4-DPHthrough rabbit sulcular tissues, J Pe~odont Macaca arct~ides: Prevention by inhibition of dental plaque lies, 11:47-53, 1976. deposition, J PeHodont~l, 49:310-325, 1978. 44. Steinberg, A. D., Allen, P. and Jeffay, H.: A new model for the 32. Houck, J. C., Jacob, R. A. and Maengwyn-Davis,G. C.: The ef- study of transport of C14-diphenylhydantein through the gin- fect of sodium dilantin administration upon the chemistry of the gival crevicular tissues in the rabbit, Arch Ora] Bin], 20:865-869, skin, J Clin Invest, 39:1758-1762, 1960. 1975. 33. Shapiro, M.: Acceleration of gingival in non- 45. Livingston, S.: Comprehensive Management of Epilepsy in epileptic patients receiving diphenylhydantoin, Exp Med Surg, Infancy, Childi~ood and Adolescence, Springfield.: Thomas, 1972, 16: 41-53, 1958. p. 38. 34. Falconer, M. A. and Davison, S.: Coarse features in epilepsy as a 46. Ziskin, D., Stowe, L. and Zegaralli, E.: Dilantin hyperplasia gin- consequence of anticonvulsant therapy, Lancet, 2:1112-1114, glvitis, AmJ Or~hod and Ora/S~rg, 27:350-353, 1941. 1973. 47. Bery, W. R. and Falcetti, J. P.: Ineffectiveness of antihistamine 35. Lefebvre, F,. B., Halning, R. G. and Labbe, R. F.: Coarse facies, therapy for gingival hyperplasia due to diphenylhydantoin calvarial thickening and hyperphosphatasia associated with sodium, NEnglJM~d, 257:1128-1130, 1957. long-term anticonvulsant therapy, New Engl J Med, 286:1301- 48. Brinker, G. N.: Six months with antihistamine and gingival hy- 1302, 1972. perplasia due to dilantin, JIndiana DentAssoc, 37:12-15, 1958. 36. Harris, M. and Goldhaber, P.: Root abnormalities in epileptics 49. Strean, L. R. and Horton, C. P.: Hydrocortisone in dental prac- and the inhibition of the parathyroid hormone-induced bone re- tice, Dent Digest, 59:8-10, 1959. sorption by diphenylhydantoin in tissue culture, Arch Oral Biol, 50. Strean, L. R. and Loeni, E.: Dilantin gingival hyperplasia: 19:981-984, 1974. Newer concepts related to etiology and treatment, N Y St~e 37. Steinberg, A. D., Jeffay, H. and Allen, P.: Lack of relationship Dent J, 25:339-347, 1959. between the degree of induced gingival hyperplasia and the con- 51. Steinberg, A. D.: Periodontal evaluation and treatment consid- centration of diphenylhydantoin in various tissues of ferrets, erations with the handicapped patient, in Dentistry for the J Dent lies, 52:267-271, 1973. Handicapped Patient ed. Nowak, A. J., St. Louis: C. V. Mosby 38. Steinberg, A. D., Allen, P. and Jeffay, H.: Distribution of metab- Co., 1976, pp 302-328. olism of diphenylhydantoin in oral and nonoral tissues in ferrets, 52. Donnenfeld, O. W., Stanley, H. R. and Bagdonoff, L.: A nine J Dent lies, 52:267-270, 1973. month clinical and histological study of patients on diphenyl- 39. Steinberg,~4 A. D., Jeffay, H. and Allen, P.: Transport of C hydantoin following gingivectomy, J Pe~odontol, 45:547-551, diphenylhydantoin and C~4 leucine through rabbit crevicular 1974. epithelium, JDent Res, 53:1387-1391, 1974. 53. Vandersall, D. C. and Salde, D.: Periodontic orthodontic 40. Homing, M. G., Brown, L., Kellay, P. and Zion, T. E.: Use of management of diphenylhydantoin gingival hyperplasia: Case saliva in therapeutic drug monitoring, Clin Chem, 3:57-164, report, J Pe~iodontol, 34:17-24, 1963. 1977. 54. Babcock, J. R.: The successful use of a new technique for dilan- 41. Svensmark, O., Schiller, P. and Buchtol, F.: 5,5-Diphenylhydan- tin gingival hyperplasia, Pe~odontics, 3:196-200, 1965. toin blood levels after oral or intravenous dosage in man, Acta 55. Davis, R., Baer, P. N. and Palmer, J. H.: A preliminary report on Pharm Toxica/, 16:331-346, 1960. a new therapy for dilantin gingival hyperplasia, J Pe~odontol, 42. Steinberg, A. D., Conard, C. J., Boshe, L. and Kienast, J.: Levels 34:17-24. of phenytoin and its major metabolite in human gingiva and 56. Sheridan, P. J. and Reeve, C. M.: Effective treatment of dilantin other areas of the oral cavity, Paper presented at the Sixth gingival hyperplasia, Oral Surg, 35:42-46, 1973. International Symposiumon Epilepsy, Brussels. Sept. 1974. 57. Kesling, H. D.: The philosophy of the tooth positioning appli- ance, AmJ Ortho, 31:297-302, 1945.

MANAGEMENTOF GINGIVAL OVERGROWTH 136 Steinberg