PEDIATRIC DENTISTRY/Copyright ° 1981 byThe American Academy of PedodonticsVol. 3, Special Issue

Clinical management of phenytoin-inducedgingival overgrowth in handicapped children

Dr. Steintorg

Arnold D. Steinberg, DDS, MS

AbstractPhenytoin (PHT)-induced gingival overgrowth (PIGO)

due to chronic administration remains an unsolved problem.The prevalence of PIGO in the general population is around40% of those taking the drug. Younger age groups experiencemore lesions than adults and in the handicapped theprevalence appears to be highest. Oral hygiene modifiesPIGO and it is suggested that minimal plaque drug levels (ofsalivary origin) and/or metabolite levels may be importantfor lesion production by having a direct affect on thegingiva. The most satisfactory treatment is the eliminationof the drug, if possible. Patients who must be maintained onPHT respond well to a program of meticulous oral hygienea t home along with frequen t professional prophylaxes.Surgical removal is indicated when the severity of the lesionis such that esthetics, mastication or secondaryinflammation becomes a problem. Use of a positive pressureappliance and maintenance of good oral care after surgeryhas been shown to control resurgence of thegingival overgrowth.

Introduction

In 1937 Merritt and Putnam1 introduced the firstsuccessful anticonvulsant or antiepileptic drug, Phen-ytoin (PHT). Drugs that preceded PHT, bromide andphenobarbital, were not specific for epilepsy and had abroad central nervous system effect. PHT was not asedative and was not addictive, but controlled convul-sions by modifying the bioelectrical activity of the af-fected central nervous system cells. Because of thisability to regulate cellular bioelectrical activity PHThas proven to be effective not only in epilepsy, but in avariety of other disorders. These include mood and be-havior problems, stuttering, migraine and other head-aches, neuromuscular pathologies, cardiac problems,and a variety of other maladies where cellular bioelec-trical activity require regulation.2

Because of its wide therapeutic range, it is now esti-mated that in the United States there are well overtwo million persons using this drug on a chronic dailybasis.3 The usual adult dosage of PHT is 300mg perday taken orally. It is slowly absorbed by the in-

testines and reaches a peak plasma level in four to 12hours. Serum levels of 10-15ug/ml are usually requiredfor seizure control. Generally, there are no side-effectsat serum levels below 15ug/ml.4

PHT, which has been tested by continuous use overlong periods, and by a very large number of individ-uals, has proven to be one of the safest of the anticon-vulsants currently being used. This drug has remark-ably few side-effects, but of those reported, gastric dis-tress, skin rash, minor central nervous system reac-tions and gingival overgrowth are the most common.4

Since this review is limited to a discussion of PIGOin handicapped children, it is appropriate to identifybriefly some handicapping disorders in which PHTtherapy may be used. Patients having cerebral palsymay have cerebral cortical damage which cause seiz-ures. PHT may be used to treat certain types of psy-chotic patients, children with behavior disorders, var-ious neuromuscular disorders (e.g., choreas andneuromyotonic syndromes), and infections and trau-mas affecting cortical cells.2

PHT therapy initiated before the eruption of thepermanent teeth may delay eruption. It may reach apoint where surgical intervention is necessary foreruption to occur. A delayed passive eruption mayalso occur leaving only a partially exposed anatomicalcrown making the teeth appear short.

The lesion assumes a different form when PHTtherapy is started after the eruption of the permanentteeth. The first sign of the overgrowth is usually apainless enlargement of the interdental papillae whichmay be accompanied by swelling of the gingival mar-gin. If there is no secondary inflammation, the gingivais pink, firm and does not bleed easily. Gradually thegingival changes become more prominent and with en-largement, the interdental papillae become mulberry-like in appearance. These interdental lobulations ex-tend labially and, less often, lingually. If growth con-tinues, they meet at the center of the labial of thetooth surface, separated by a small cleft. With furtherenlargement the lobulations may coalesce at the mid-

130MANAGEMENT OF GINGIVAL OVERGROWTH

Steintorg

line of the labial or lingual tooth surface and graduallyencroach on the crowns of the teeth. In extreme cases,the gingival tissue may completely cover the anatomi-cal crown with a solid mass of fu-mly resilient tissue.

As can be expected, these tissue masses becometraps for debris and plaque, are difficult to clean andenhance secondary inflammation. With such involve-ment, esthetics becomes a serious problem and canonly worsen the psychological difficulty already expe-rienced by patients with epilepsy or other handicaps.Furthermore, with such masses of tissue extendingonto the tooth biting surfaces, mastication becomesdifficult and tissue trauma can occur. These lesionsmay usually be classified as purefibrotic or inflamma-tory type of gingival overgrowth. In the mentallyretarded, where oral hygiene is limited, we appear toencounter the latter lesion more frequently.

Gingival overgrowth can be induced by factorsother than PHT (e.g., mouth breathing, irritationsalong the necks of teeth or hormonal alterations suchas those at puberty). These same factors appear to en-hance the size of lesions in a PIGO. No matter whatthe etiology, the lesions appear grossly and histologi-cally similar.

Any irritant to the gingival tissues, such as an

orthodontic band or defective dental restoration, ap-pears to encourage an earlier onset and an enhancedreaction of the gingival tissues to PHT. Similarily,irritation or inflammation induced by mechanicalmeans in experimental animals receiving PHT aids inproducing the lesion;,~

Oral hygiene modifies the gingival overgrowth, butthe degree of the fibrosis and its relationship to oralhygiene is disputed in the literature. Glickman andLewitus7 found that removing plaque, calculus andother local irritations eliminated inflammation, butonly reduced the severity of the changes caused byPHT. My own clinical observations indicated thatonce the overgrowth condition begins it can bereduced with good oral hygiene, but is extremely diffi-cult to eliminate completely without surgical inter-vention or eliminating drug intake. The relationshipbetween oral hygiene and gingival overgrowth is com-plicated by the possibility that it is the lesion thatcauses the poor local hygiene. Several investigatorsmaintain that elimination of plaque and gingival ir-ritation prior to the initiation of PHT therapy willprevent the development of the lesion. ~.9 Their worksupports the view that inflammation is a prerequisitefor the development of the pathology and the preven-tion must be directed toward eliminating the causes ofthis inflammatory component.

PrevalenceDepending on the study quoted, from 3% to 78% of

those on PHT will experience gingival overgrowth,with most investigators placing the rate at about 40%.~My observations at the epilepsy clinic at the Univer-sity of Illinois indicate a much lower prevalence(around 25% ) and, of those so affected, approximately20% will have a reaction severe enough to warrant sur-gical correction. This lower prevalence may be due tothe older population that was observed. Most in-vestigators indicate a higher incidence of gingivalovergrowth in children and adolescents than in adults,with few lesions seen after the age of 40.~ The wideprevalence range may, therefore, be due to age differ-ence in the groups studied, as well as differences inother parameters such as oral hygiene.

In a recent study1° on institutionalized, severely

retarded children, ages 4-15, we found that 94% of thepatients (18 to 19) receiving PHT had a PIGO. Gard-ner et al., 11 reported 78% of a mentally retarded groupexhibited some PIGO and Kapur et al., 12 reported 68%of a similar group had PIGO. The high prevalence inour study may, among other factors, be due to thepoor oral hygiene and limited masticatory ability ofthis population. In the initial examination a signifi-cant relationship was noted between the degree ofPIGO and the plaque index. 39% of these patients hada slight overgrowth, 11% had a moderate involvement,while 50% had a severe PIGO. In normal, non-institu-tionalized populations the degree of PIG~ was foundto be approximately 45% with a slight overgrowth,40% had a moderate involvement and only 15% had asevere reaction, m4 Thus, it appears that in the men-tally retarded there was a higher percentage of pa-tients with a severe involvement of the gingiva. Thisfinding may be due to the poorer oral hygiene of thepatients and higher drug levels.

No race or sex difference in PIGO have been re-ported;~.1~ Opinions differ regarding the relationshipbetween therapy duration, dosage and the severity ofthe gingival overgrowth.3.~ There is also conflictingevidence concerning the role of plasma~2.~7.~s.19,~ and sali-vary levels~,~9,~.~ of PHT in relation to gingival enlarge-ment. Such variation may be due to the para-hydroxymetabolite of PHT being a responsible factor;~,~

Clinical Manifestations

The time between the initiation of phenytoin ther-apy and the onset of gingival overgrowth varies. Firstclinical signs of fibrosis have been reported as early astwo weeks after the beginning of therapy;= however,several months usually elapse. The factors responsiblefor such variability are unknown. It has also beenreported that from two to four years are required forthe overgrowth to reach its peak2

Most investigators agree that the gingival over-growth is most marked in the anterior region of the

PEDIATRIC DENTISTRY 131Volume 3, Special Issue

mouth, with the labial or buccal surfaces of all teethhaving a greater involvement than the lingual sur-faces.5," It has been suggested that this is due to thepressure exerted on these tissues by the tongue.The severity of the overgrowth can vary within thesame individual, with both normal and pathologicalareas found in the same mouth. No lesion is usuallyobserved in edentulous areas. However, occasionallysuch cases are reported.~

In the severely mentally retarded group westudied~° we found that the pattern of gingival over-growth was not the same as that generally observed innormal individuals. We found that the PIGO wasmost marked on the posterior teeth even though themajority of the patients were mouth breathers. It wasdifficult to ascertain the cause of this discrepancy. Wespeculate that severe retardation was important andthat it limited masticatory abilities, resulting in foodbeing swallowed whole. In addition, oral hygiene pro-cedures were limited and, due to lack of cooperation,appeared to be restricted to the anterior teeth.This factor alone may have been responsible for ourobservation.

Etiology of PIGOAmong the many suggested theories regarding the

etiology of PIGO are serum vitamin C deficiency, 5 di-rect local effect of the drug or metabolite,~6 depressionof the pituitary -- adrenal axis, ~ and immunologicalreaction; ~ It has also been proposed that PHT-induced folic acid deficiency could render the gingivaltissues more susceptible to local factors (e.g., plaque),thus enhancing the response of the gingiva to specificexaggerated inflammatory reactions as in gingivalovergrowth.~

It is postulated that PHT is a folic acid antagonist,interferes with normal metabolism of these tissues,and may decrease PHT metabolite production. Vogel~

reported that administration of folic acid with PHT tocats, markedly decreased the occurrence of PIG0when compared to a group administered PHT alone.An isolated report has claimed a decrease in PIGOlesions in humans receiving 3mg of folic acid dailyalong with PHTY This report, however, was not acontrolled clinical study.

The uniqueness of plaque around the gingival sul-cular area and the maintenance of minimal PHT ormetabolite levels in blood, and/or saliva, appear to beimportant parameters. It has already been stated thatinflammation or an immune response to plaque maybe a factor in the production of this lesion. It is pos-sible that phenytoin or a metabolite may affect theplaque bacteria by either limiting the population ofbacteria or by altering the metabolism of plaque bac-teria. Staple et al.,3~ in a recent investigation in mon-keys, showed some bacterial population alteration in

plaque from gingival overgrowth as compared to non-overgrowth areas. However, such an alteration in bac-terial population may not be causally related to thegingival overgrowth. It was also observed that theamount of gingival plaque was not always directly re-lated to the severity of overgrowth. Apparently thetype as well as the quantity of dental plaque may becrucial to the development of the lesion. It is alsopossible that plaque bacteria metabolize PHT, pro-ducing a metabolite which, when absorbed into thesulcular tissue, induces the lesion.Connective Tissue Changes

Pathological changes occur in connective tissueother than gingiva, but at lower frequency. A dermalreaction to PHT administration has been described inrats= and acceleration of wound healing has also beennoted when this drug is administeredY Thickening ofthe bone of the cranial vault of children on long-termdrug therapy has been describedY Swelling of lips,broadened nose, and a general thickening of subcu-taneous tissues of the face have also occasionally beenobserved, especially if PHT has been initiated early inlife and maintained for a long time period.~,~

Lefebvre et al., ~ observed that among 222 institu-tionalized mentally retarded individuals with seizures,approximately 1/3 had obvious facial changes, an-other 1/3 had questionable facial changes, and 1/3had no changes. PHT was the principal drug used byall, with the affected groups exkdbiting a greater num-ber of seizures, significantly higher serum drug levels,hyperphosphatasia, and increased lethargy. It wasalso noted that the affected group had a greater sever-ity of PIGO. These mentally retarded patient’s variedetiologies and early normal photographs indicatedthat the features were acquired, implying a high long-term dose response. Thus, long-term anticonvulsanttherapy, initiated at an early age, may not only have aprofound affect on the developing skull and cranio-facial growth, but also affect the position of teeth andsupporting boney

PHT appears to affect other connective tissues, buton a limited basis, suggesting that all the parameterswhich may enhance the prevalence of the lesion ingingiva are present only on a limited basis in othertissues.

Mechanism of Gingival OvergrowthTo date, none of these theories can explain the two

major questions remaining unanswered. First, what isthe mechanism by which phenytoin can stimulate gin-gival overgrowth? Second, why is gingiva the primarytissue in the body so involved?

Animal and clinical studies in my laboratory~,~,~.~.~

have resulted in a hypothesis to explain why thisunique reaction of the connective tissue predominatesin the gingiva. According to pharmacokinetic princi-

132MANAGEMENT OF GINGIVAL OVERGROWTHSteinberg

ples, only the unbound or free fraction of the drug car-ried by blood is therapeutically active. For PHT thisamounts to approximately 10%.1~ This unbound frac-tion found in serum is dispersed through the variousbody tissues, including gingiva. A number of investiga-tors have demonstrated PHT in saliva of patients onlong-term administration of the drug.21.a.~ Our studiesindicate that the level of PHT in human saliva isabout 10% that of the blood level/~ and Homing et al.~

have reported that PHT secreted by saliva is in theunbound form. We have also shown that both PHTand its primary metabolite, the para-hydroxyl form,are present in human plaqueY Furthermore, ourhuman studies suggest that the severity of gingivalovergrowth tends to be associated with higher PHTlevels in gingiva and with lower tissue levels of thepara-hydroxyl metabolite;9

}aliva is a contributor to plaque formation andmay be implicated in the production of this conditionby serving as a reservoir, concentrating PHT in, andadjacent to, the gingival sulcular area. In addition, itis possible that plaque may metabolize PHT.

Our animal studies have demonstrated the absorp-tion or diffusion of PHT through the gingival sulcularepithelium into the underlying connective tissue andinto the circulation. ~.~ We have also shown a pro-longed retention of PHT in the gingival sulcular tissueafter local, topical application in the gingival sulcus.~

These data indicate the presence of a pathway for thereabsorption of PHT from saliva into plaque andthrough the sulcular epithelium into the underlyingconnective tissue.

I believe that the combined effects of the unbounddrug from saliva (10% of serum levels) reabsorbed intothe gingival connective tissues and the unbound PHTdelivered to the gingival connective tissues from thesystemic circulation (10% of serum levels), combine produce levels of unbound PHT, or a metabolite,which under prolonged exposure, may be important inaltering collagen production by the local fibroblasts.Thus, the unique parameters of plaque, local inflam-mation and concentration of the drug or metabolitearound the gingival sulcular tissue may make this tis-sue more susceptible to the gingival overgrowth thanis any other tissue in the body.

Treatment

It is customary in medical practice to treat un-toward drug reactions by eliminating the drug causingthe problem. This is probably the most satisfactorytreatment of PIGO. In patients where the gingivalovergrowth is severe and difficult to control, the pa-tient’s physician should be warned of the situationand consulted about the feasibility of changing theanticonvulsant drug. In many cases PHT proves to be

the drug of choice for seizure control and this usuallytakes precedence over the gingival overgrowth. It thenbecomes the dentist’s responsibility to control theovergrowth as best he can. Withdrawal of the drugwill usually result in a spontaneous disappearance ofthe gingival overgrowth within three to six months, ifthe lesions are moderate in size. It may take up to ayear or longer if the lesions are large.~

Over the years a variety of theories regarding theetiology of this disorder have been presented and avariety of treatments relating to these theories havebeen attempted. Vitamin C administration, ~,~ antihis-tamine administration,47,~ alkaline mouthwash/5,~8 topi-cal hydrocortisones/9 and diuretics ~ have all beenattempted. These treatments have been shown to beineffective.

The only treatment that has proved consistentlyeffective has been the institution of a program ofmeticulous oral hygiene~.~,8.~8.~ along with a deep, softtissue curettage to help further reduce secondarily in-flamed tissues. Several investigators~,~,~ have suggestedthat initiation of meticulous oral care with the begin-ning of PHT therapy will prevent the gingival over-growth from occurring. Similar results have beenreported in Macaque monkeys;~ The elimination ofplaque after the lesion is present appears to only mod-ify the size of the gingival overgrowth.TM

In the severely retarded children/~ we attempted to

control plaque in one of two ways. During one studyperiod no oral hygiene procedures were used and 1 mlof a .325% stannous fluoride gel was applied topicallyonce a day for five months. This resulted in a signifi-cant decrease in plaque and PIG0. Gingival index was,however, not reduced significantly. In the secondphase of this investigation, an electric toothbrush wasused to remove plaque and massage the gingival tissuefor three minutes. This resulted in a very significantdecrease in plaque scores, gingival index and PIGO.Findings of interest in this latter phase of the studywere that the majority of the children had diminishedseizure activity and greater food intake with a notedincrease in weight and a decrease in constipation.

Surgical removal is indicated when the severity ofthe gingival overgrowth is such that an esthetic prob-lem exists, speech or mastication is impeded, severesecondary inflammation is occurring, and when oralhygiene procedures have not succeeded in controllingthe overgrowth. Surgery is not a permanent solution.If the PHT therapy continues, the gingival over-growth will invariably recur. Repeated gingivectomiesmay be necessary in these patients and recurrence ofthe lesion has been observed as early as three weeksafter surgery2~ Meticulous oral care will, however,markedly delay the recurrence.

Donnenfeld, et al.,~ using supervised oral hygiene

PEDIATRIC DENTISTRY 133Volume 3, Special Issue

after gingivectomy, prevented PIGO from recurringduring a nine month observation period in a numberof patients. When early small interproximal tissuegrowths do begin to recur, they can easily be removedby a small curved surgical scissors2

This procedure can be performed using a blade,which many practitioners feel provides better controlfor the restoration of normal gingival architecture.Following surgery a periodontal dressing is worn for aweek over the wound as protection and as an anodyne.Electrosurgery is used by many practitioners becauseof the ease with which large amounts of tissue canbe removed. A periodontal dressing is normally notrequired with this procedure.

The excess tissue removal can also be achievedusing an internal bevel technique in which a flap iselevated and "thinned" of excess collagenous tissues.The flap is then contoured, apically repositioned andsutured securely to the necks of the teeth.~ The surgi-cal flap procedure heals faster than the external bevelsince it leads to primary healing. In addition, this pro-cedure gives better control of post-operative bleedingand does not necessitate the use of a periodontal packwhich may be a problem to maintain in a handicappedpatient. The external bevel procedure heals slowersince it heals by secondary intention, even thoughpatients on PHT therapy appear to have acceleratedwound healing. ~ In all cases, the implementation of apresurgical oral hygiene program and prophylaxis issuggested, if possible, to minimize secondary inflam-mation (and resulting bleeding) and decrease the sizeof the lesion.

Positive Pressure Appliance

Recently, use of a positive pressure appliance aftersurgery has been shown to be a beneficial adjunct todaily oral care in controlling the resurgence of the gin-gival overgrowth. Successful control has been reportedfor from seven~ to 23~ months following surgery bythe use of a pressure appliance. Immediately after sur-gery, alginate impressions of the upper and lowerarches are taken and stone casts made for the fabrica-tion of a latex tooth positioner; 7 The interproximaland attached gingival areas are accentuated to exertactive pressure on the attached gingival and inter-proximal papilla.~

For this appliance to be successful, the patientmust wear it when asleep and about four additionalhours a day while maintaining meticulous oral care. Inthe severely handicapped, I have found such an appli-ance of limited value because of lack of cooperation.

The exact mechanism by which pressure applianceswork is not known. Babcock~ suggests three possibili-ties: 1. The pressure or stimulation on the gingival tis-sues, 2. Better oral hygiene habits developed in thesepatients due to an awareness created by wearing the

appliance, and/or 3. Minimized gingival tissue expo-sure to saliva. Only one, or all of these factors, may beresponsible for the reported success.

Occasionally patients have severe PIGO and, due tosystemic conditions, surgery is contraindicated. Aneffort was made to ascertain how successful a series ofpressure appliances, without surgery, might be inreducing the gingival overgrowth in one of our clinicalpatients. The patient had first undergone three weeksof meticulous oral care and weekly professional pro-phylaxes to reduce inflammation and lesion size. Im-pressions were taken of the upper and lower arches,stone casts were made and the gingival overgrowtharea on the casts trimmed about 2mm. These castswere sent to a dental laboratory for the constructionof a latex tooth positioner. 57 She wore this applianceabout four hours during the day and during sleep.After four weeks, impressions were taken again, castsrelieved again by about 2mm, and a second latex ap-pliance constructed which she wore for four weeks.Comparing the initial condition with results aftereight weeks revealed a marked decrease in lesion size.The results suggest that a series of such appliancescould succeed in regressing a gingival overgrowth toclinically tolerable limits. Such a procedure is too timeconsuming for the average patient, but may provevaluable in those patients where systemic conditionscontraindicate surgery.

ConclusionWe may summarize the approach to treatment of

gingival overgrowth as follows:1. Where a mild gingival overgrowth exists, initiating

meticulous oral care along with four yearly profes-sional prophylaxes and topical SnF2 applicationswill do much to cbntrol the lesion. The patient canusually function well with a mild gingival over-growth if oral care is maintained and secondaryinflammation prevented.

2. With a moderate gingival overgrowth, initiation ofmeticulous oral care is again indicated along withfour office visits (one week apart for professionalprophylaxes and topical SnF~ treatment). Such regimen will usually decrease the size of the lesionto a clinically tolerable size, but only ,vith completepatient cooperation. These patients are then seenfive times each year for prophylaxes and SnF2treatment.

Where the patient does not cooperate, or thelesion will not regress, contact should be made withthe patient’s physician to obtain the serum levels ofPHT and discuss possible alterations of drug ther-apy from PHT to another anti-convulsant drug.Oral care by these patients should be monitored,not only by the dentist, but also by other profes-sionals involved in treating the patient.

MANAGEMENT OF GINGIVAL OVERGROWI"H134 Steinberg

3. In the severe gingival overgrowth condition, thestops outlined in # 2 should be initiated and the pa-tient seen by the dentist on a weekly basis forcurettage, professional prophylaxes, topical fluorideand monitoring of oral care for about four weeks.An evaluation is then made as to the success of theconservative therapy. If drug substitution is notpossible and/or regression of the lesion is not to atolerable size, surgery will be required. Withmeticulous oral care it has been shown that lesionrecurrence after surgery can be prevented for up tonine months52 and probably longer. If the lesionsrecur to previous levels and surgery is again re-quired, a pressure appliance should be considered asan adjunct to oral care when there is sufficientpatient cooperation.Meticulous oral care must be initiated in all pa-

tients prior to initiation of PHT therapy. The patientsand parents must be made aware, not only by the den-tist, but by all professionals involved in their care, ofthe means at hand to control this untoward reaction toPHT. In the severely handicapped, oral care by par-ent or guardian is required. There will be a number ofhandicapped patients where the gingival overgrowthwill not be controlled because of a lack of oral care. Inthese cases, treatment of a severe lesion is indeed aproblem. Drug substitution is most successful here. Itis hoped that future research will elucidate the mech-anism by which PHT induces gingival overgrowth andprovide better means of controlling this untowardreaction of a very useful drug.

Dr. Steinberg is professor, department of periodontics, Univer-sity of Illinois College of Dentistry, 801 South Paulina, Chicago,Illinois 60612. Requests for reprints should be sent to him at thataddress.

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2. Bogoch, S. and Dreyfus, J.: The Broad Range of Use of Di-phenylhydantoin, ed. Bogoch, S., The Dreyfus Medical Founda-tion; 1970, pp 61-67.

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8. Hall, W. B.: Prevention of dilantin hyperplasia, Bull Acad GenDent, 4:20-23, 1969.

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12.Kapur, R. N., Girgio, S., Little, T. M. and Masotti, R. E.: Di-phenylhydantoin-induced gingival hyperplasia: Its relationshipto dose and serum level, Develop Med Cldld Neurol, 15:483-487,1973.

13.Klar, L. A.: Gingival hyperplasia during dilantin therapy; A sur-vey of 312 patients, J Pub H Dent, 33:180-185, 1973.

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20.Philstrom, B. L., Carlson, J., Smith, Q. T., Bastien, S. andKeenan, K. M.: Prevention of phenytoin associated gingivalenlargement -- A 15 month longitudinal study, J Pe~odontol,51: 311-317, 1980.

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22.Hassell, T. M. and Cooper, C. G.: Phenytoin-induced gingivalovergrowth in a mongrel cat model, in Phenytoin-Induced Tera-tology and Gingival Pathology, ed. Hassel, T. M., Johnston, M.and Dudley, K., New York: Raven Press, 1980, pp. 147-162.

23.Jurgens, P. E.: Gingival hyperplasia in dilantin sodium therapy,J PeHodontol, 23:117-122, 1952.

24.Gardner, A. F., Gross, S. G. and Wynne, L. E.: An investigationof gingival hyperplasia resulting from diphenylhydantoin ther-apy in soventy-seven mentally retarded patients, Exp Med Surg,20:133-140, 1962.

25.Deryer, W. P. and Thomas, C. J.: Diphenylhydantein-inducedhyperplasia of the masticatory mucosa in an edentulous epi-leptic patient, Oral Surg, 45:701-706, 1978.

26.Steinberg, A. D.: Phenytoin penetration through sulcular tissuesand its possible relationship to phenytoin-induced gingival over-growth, in Phenytoin-Induced Teratology and Gingival Path-ology, ed. Hassol, T. M., Johnston M. and Dudley, K., NewYork: Raven Press, 1980, pp. 147-162.

27.Staple, P.: The effects of continued administration of dilantinsodium on the adrenal glands of mice, JR MlcroscSoc, 74:10-14,1954.

28.Setterstrom, J. A., Gross, A., D’Alessandro, S. and Godat, R. F.:Immunoglobulins in periodontal tissues: III. concentrations ofImmunoglobulins in dilantin-induced and idiopathic gingivalhyperplastic tissues, JPe~qodontol, 51:25-29, 1980.

29.Vogel, R. I.: Relationship of folic acid to phenytoin-induced gin-gival overgrowth, in Phenytoin-Induced Teratology and Gin-gival Pathology, ed. Hassel, T. M., Johnston, M. and Dudley, K.,New York: Raven Press, 1980, pp. 163-178.

30. Folic acid seen controlling gingival enlargements in Clinical Den-

PEDIATRIC DENTISTRY 135Volume 3, Special Issue

t/stxy, Mar, 1974, p. 8.31.Staple, P. H., Reed, M. J., Mashimo, P. A., Sedranek, N. and

Umemoto, T.: Diphenylhydantoin gingival hyperplasia inMacaca arct~ides: Prevention by inhibition of dental plaquedeposition, J PeHodon t~l, 49:310-325, 1978.

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33.Shapiro, M.: Acceleration of gingival wound healing in non-epileptic patients receiving diphenylhydantoin, Exp Med Surg,16: 41-53, 1958.

34.Falconer, M. A. and Davison, S.: Coarse features in epilepsy as aconsequence of anticonvulsant therapy, Lancet, 2:1112-1114,1973.

35.Lefebvre, F,. B., Halning, R. G. and Labbe, R. F.: Coarse facies,calvarial thickening and hyperphosphatasia associated withlong-term anticonvulsant therapy, New Engl J Med, 286:1301-1302, 1972.

36. Harris, M. and Goldhaber, P.: Root abnormalities in epilepticsand the inhibition of the parathyroid hormone-induced bone re-sorption by diphenylhydantoin in tissue culture, Arch Oral Biol,19:981-984, 1974.

37.Steinberg, A. D., Jeffay, H. and Allen, P.: Lack of relationshipbetween the degree of induced gingival hyperplasia and the con-centration of diphenylhydantoin in various tissues of ferrets,J Dent lies, 52:267-271, 1973.

38. Steinberg, A. D., Allen, P. and Jeffay, H.: Distribution of metab-olism of diphenylhydantoin in oral and nonoral tissues in ferrets,J Dent lies, 52:267-270, 1973.

39.Steinberg, A. D., Jeffay, H. and Allen, P.: Transport of C~4

diphenylhydantoin and C~4 leucine through rabbit crevicularepithelium, JDent Res, 53:1387-1391, 1974.

40.Homing, M. G., Brown, L., Kellay, P. and Zion, T. E.: Use ofsaliva in therapeutic drug monitoring, Clin Chem, 3:57-164,1977.

41. Svensmark, O., Schiller, P. and Buchtol, F.: 5,5-Diphenylhydan-toin blood levels after oral or intravenous dosage in man, ActaPharm Toxica/, 16:331-346, 1960.

42.Steinberg, A. D., Conard, C. J., Boshe, L. and Kienast, J.: Levelsof phenytoin and its major metabolite in human gingiva andother areas of the oral cavity, Paper presented at the SixthInternational Symposium on Epilepsy, Brussels. Sept. 1974.

43.Steinberg, A. D., Steinberg, J., Allen, P. and Jeffay, H.: The ef-fect of alteration in the sulcular environment upon the move-ment of C~4-DPH through rabbit sulcular tissues, J Pe~odontlies, 11:47-53, 1976.

44.Steinberg, A. D., Allen, P. and Jeffay, H.: A new model for thestudy of transport of C14-diphenylhydantein through the gin-gival crevicular tissues in the rabbit, Arch Ora] Bin], 20:865-869,1975.

45.Livingston, S.: Comprehensive Management of Epilepsy inInfancy, Childi~ood and Adolescence, Springfield.: Thomas, 1972,p. 38.

46. Ziskin, D., Stowe, L. and Zegaralli, E.: Dilantin hyperplasia gin-glvitis, Am J Or~hod and Ora/S~rg, 27:350-353, 1941.

47. Bery, W. R. and Falcetti, J. P.: Ineffectiveness of antihistaminetherapy for gingival hyperplasia due to diphenylhydantoinsodium, NEnglJM~d, 257:1128-1130, 1957.

48. Brinker, G. N.: Six months with antihistamine and gingival hy-perplasia due to dilantin, JIndiana DentAssoc, 37:12-15, 1958.

49. Strean, L. R. and Horton, C. P.: Hydrocortisone in dental prac-tice, Dent Digest, 59:8-10, 1959.

50.Strean, L. R. and Loeni, E.: Dilantin gingival hyperplasia:Newer concepts related to etiology and treatment, N Y St~eDent J, 25:339-347, 1959.

51.Steinberg, A. D.: Periodontal evaluation and treatment consid-erations with the handicapped patient, in Dentistry for theHandicapped Patient ed. Nowak, A. J., St. Louis: C. V. MosbyCo., 1976, pp 302-328.

52.Donnenfeld, O. W., Stanley, H. R. and Bagdonoff, L.: A ninemonth clinical and histological study of patients on diphenyl-hydantoin following gingivectomy, J Pe~odontol, 45:547-551,1974.

53.Vandersall, D. C. and Salde, D.: Periodontic orthodonticmanagement of diphenylhydantoin gingival hyperplasia: Casereport, J Pe~iodon tol, 34:17-24, 1963.

54.Babcock, J. R.: The successful use of a new technique for dilan-tin gingival hyperplasia, Pe~odontics, 3:196-200, 1965.

55.Davis, R., Baer, P. N. and Palmer, J. H.: A preliminary report ona new therapy for dilantin gingival hyperplasia, J Pe~odontol,34:17-24.

56.Sheridan, P. J. and Reeve, C. M.: Effective treatment of dilantingingival hyperplasia, Oral Surg, 35:42-46, 1973.

57.Kesling, H. D.: The philosophy of the tooth positioning appli-ance, Am J Ortho, 31:297-302, 1945.

136MANAGEMENT OF GINGIVAL OVERGROWTHSteinberg