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Dilantin hyperplastic gingivitis
DILSNTIN
I)ANIEI,
HYPERPLASTIC
1.
ITS
2.
DIFFERENTIAL
CAU3E
D.D.S.,
14;. ZJHKIN, ~DW.IJ~D
V. New
ASD
GINGIVITIS
!hE~4TMENT APPR;\IX~I,
LF,WIS R.
STOWE,
D.D.S.
AND
ZE~.\REI,IJ, S.B., D.D.S. I’ORK, N. IT.
the establishment of dilantin (Merritt and PutnamI) as an efficacious SINCE measure in the treatment of cpilcpsy, and its general use in many epileptic cases, prominent not,ice has hcen drawn to a side action of the drug involving the gingivae. This oral manifestation is known as dilantin hypertrophy of the gums and may be described as an enlargement caused by tissue hyperplasia. As the growth often proceeds to the extent of covering the entire tooth, mastication becomes painful as well as difficult and esthetics enter as a factor. Dilantin hypertrophy bears a close clinical rcscmblancc? to other forms of gingivitis. Outstanding among these is the t,ype of gum disorder associated with scurvy. Kimball,2 in a report on 152 dilantin patients, of whom 57 per cent showed gingival hyperplasia in varyin g degrees, considered the possibility of scurvy even though other signs such as sore joints, purpura, etc., were absent. He tested the ascorbic acid content of the blood serum in a number of cases and concluded that the degree of hyperplasia directly paralleled the deficiency of ascorbic acid. That is, those individuals with the most marked hyperplasia showed the lowest, level of ascorbic acid, as low as 0.1 mg. per 100 C.C. The administration of large doses of vitamin C (300 mg. daily by mouth) did not materially improve the gingirae, alt~hough the plasma level was raised to a, high normal. Merritt and Putnam,” dealing mostly with adults, cited a much lower incidence of dilantin gingival hypcrplasia (4 per cent as compared with 5’7 per cent by Kimball). This study “shovved no evidence of a deficiency of ascorbic acid. ” l?rankeJ4 observing a mixed group of children and adults (mostly adults), states that 62 per cent of his series showed hyperplasia of the gums. The degree of gingival involvement paralleled the dilantin dosage, while the A study of ascorbic acid level of the blood decreased as the gums grew larger. the table accompanying this report leaves doubt as to the justification of the author’s conclusions. with Merritt and Thoma,5 in a published case report, is in agreement is not in relation to Putnam in their view that the gingival hpperplasia vitamin C levels in the blood. in guinea pigs, found Grunzhit,F after inducing scurvy csperimentally that large doses of dilantin did not, alter the course of the scurvy or interfere with t,he utilization of vitamin c. Lennox7 Supports Grunzhit, in the opinion that vitamin C deficiency is not related to dilantin hpperplasia of the gingivae. *prom
the
School
of Dental
and
Oral
Surgery, 360
Columbia
University.
New
York
City.
Dilantin
Hyperplastic
Gingivitis
351
Our own findings, based on clinical observation and histologic evidence cited herein, rule out scurvy as an etiologic factor. This report deals with a group of patients under treat,mcnt for cpilcpsy The series comwith dilantin at the Columbia-Presbyterian Medical Cent,rr. prises males and females, children and adults, in about equal proportions. APPEARANCE
OF
TISSUE
Proliferations appear growing Gross-The gums bleed easily on probing. out of the inferior surface of the free gum margin of the interdental papillae (Fig. 1). They resemble gum polypi or proliferations frequently seen during pregnancy in areas subject to chronic irritation. They are congested, shiny, and friable, with a definite line of demarcation separating them from the stippled gingivae. As they yrow in size they are subjected to various forms of trauma. Their appearance is that of inflamed and markedly swollen tissue (Figs. 2 and 3). In t,he next phase the swelling changeq character. The gums become hard, firm, and a more normal color. Stippling returns and the inflammation (if it persists) is confined to t,he margin. The affection at t,his stage resembles a generalized fibromatosis (Fig. 4). The course as described usually covers a period of about six months, after which it may persist in the final form indefinitely. Dilantin hypertrophy of the gingivae is more pronounced in children than in adults. It is found in t.he presence of teeth, while grossly not apparent, in normal edentulous regions. In case extraction becomes necessary, the hypcrplastic gums return to normal appearance in the operated areas. It is more exaggerated under conditions of local irritat,ion such as overhanging margins, ill-fitting crowns and bridges, food impactions, tartar, and debris. It is seemingly absent in edent,ulous mouths except in areas where there is denture irritation. Here the hypertrophy is visibly present. As the proliferative tissue grows the teeth are moved out of alignment (Figs. 5, 6, and 7). In some cases alveolar bone is lost and teeth loosen. The affection is more pronounced where poor hygienic care is evident,. In well-rarcd-for mouths the reaction is comparatively mild. Those cases included in this study which were given vigorous and continuous prophylactic treatment from the time dilantin was first ingested were free from the gingival hypertrophy. In a group of children whose epileptic seizures were controlled wilhout the use of dilantin, the gingival hypertrophy did not develop even though many of the local irritants mentioned were present. Microscopic.-Epithelium. The keratin layer is not markedly altered. The epithelium shows a proliferat,ive change evidenced by the largely increased number of nuclei in the prickle- and basal-cell layers. The hyperehromatic nuclei take a deep stain and show an increased number of mitotic figures. is again accentuated There is some hydropic change. The epit,helial proliferation by the downgrowth of the epithelial pegs fairly deep into the corium, and their pointing and splitting (Fig. 8). Another evidence of hyperplasia is the frequency with which epithelial pearls are seen (Figs. 9 and 10). These structures, reported by Thoma,” are found normally, but not as often as observed here, They may bc due to the growth and sectioning at right angles of the
352
Daniel E. Ziskin,
et al.
epithelial pegs and may possess a much lower degree of keratinization than Fig. 11, which is a highly keratinized epithelial pearl formed as the result of injections of large doses of an estrogenic hormone.8 This illustration is included herein for the purpose of comparing the state of keratinization seen here with that present in the dilantin pearl. A closer similarity to the estrogenic effect on epithelium is seen in Fig. 12. This is a section of areolar found) from a patient t.aking dilantin.
Fig.
2.
Fig.
L-Early stage of dilantin hyperplasia in a boy, aged 12 years, who had taken three capsules of dilantin daily for one year. Drug was discontinued for seven weeks because of hyperplastic gums. (Regression noted. ) Dilantin therapy was resumed for two weeks before this photograph was taken. A is a polyp, B the spread of proliferation from the inferior surface of the margin of the interdental papilla. Fig. Z.-Inflamed and swollen tissues partially covering the teeth of a g-year-old girl. who was taking dilantin, three capsules daily. The photograph was taken approximately four months after dilantin therapy was started.
Fig.
3.
of the gingival hyperplasia about six months after Fig. 3.-Same case as IFig. 2. Progress The line of demarcation between the hyperFig. 2. The tissues are still inflamed and swollen. plastic and stippled gingivae is evident. The gums are Arm an.d stippled. Fig. 4.-Generalized flbromatosis in a boy 16 years old. Dilantin, four capsules per day, had been taken for two years.
The flattened nuclei and the deeper eosin stain give the appearance of a keratinized surface. While special staining methods failed to disclose the presence of mature keratin such as is seen when large doses of the estrogenic hormone are used therapeutically, it is possible that the stimulating action of dilantin does produce an immature stage in the process of keratinization.
Dilantin
Hyperplastic
353
Gingivitis
The early hyperplasia in the dilantin gingivitis resembles the changes previously reported for pregnancy gingivitis” (Fig. 13) although the epithelial pegs incline to a greater extent of down-growth and the papillary layer of the corium lies closer to the surface. Connective Tissue.-The corium shows even more marked proliferation than the epithelium and seemingly accounts for most of the gingival enlargement. Many large young fibroblasts in an apparent state of hyperactivity
Fig.
5.
Fig.
‘Fig.
S.-Teeth imbeddcd in hyperplastic gum. in a girl. 9 years capsules daily, had been taken for two years. The gingivae are present at the margins. Fig. B.-Same patient as Fig. 5, after surgical removal of the graph was taken about four months after ‘Fig. 5.
Fig.
‘I.-Same Note
case as Figs. 5 and additional separation
6. of
Extent the
of the regrowth teeth caused by
old. Arm,
6. Dilantin. four to five and inflammation is
hyperplastic
in about three the proliferating
tissue.
months tissue.
Photo-
is shown.
are seen throughout the stroma. There are masses of inflammatory exudate, chiefly perivascular, and composed mainly of round cells with some plasma cells and a few polymorphonuclears. This inflammatory reaction, although fairly prominent in the alveolar corium, is especially conspicuous at the crest of the interdental papilla. There is an increase in the size and number of blood vessels and lymph channels. Endothelial proliferation resulting in the formation of new capillaries is seen in the pcriosteal portion of the corium in some sections. Edema is a prominent feature in some cases and not in
354
Dnniel E. Ziskin,
et al.
Dilnntin
Hyper-plnstic
Gin&&s
355
others. The papillae of the corium lie abnormally close to the outer surface of the epithelium and usually contain groups of young fibroblasts (Figs. 9 and 12). The proliferation of t,he connective tissue extending over the surfaces of the teeth becomes covered with cpithelium probably as a direct extension of the epithelial covering (Fig. 81. We have stated that edentulous areas or edentulous mouths do not show, grossZy, the hyperplastic changes noted. Microscopic data on this point are at a variance and were derived from tissue studies of two patients taking two to four capsules of dilantin daily.
Fig.
IO.
Fig.
11.
Fig. lO.-Higher power view of one of the pearls shown in Fig. 9, X900. Prickle are normal and the highly keratinized center is absent. Compare with Fig. 11. Fig. Il.-Epithelial pearl in a castrated monkey (No. 209). that was treated large doses of estrogen. Biopsy lower right No. 3 papilla, X400. Alveolar gingivae. keratinized center. Compare with Fig. 10.
cells with Note
CASE I.--A female, aged 57, wearing full upper, and lower partial dentures. Irritation was created by both appliances. Hyperplasia of the gums was apparent in the traumatized regions. Tissue biopsies were taken from normal and from hyperplastic-appearin,rr areas of the maxilla. CASE 2.-A male, aged 22. Tissue biopsies were taken from an edentulous field where a tooth had been ext,racted previously, and from a hyperplastic gingival interdental papilla. The microscopic findings in these eases are similar to each other and also to other dilantin specimens examined. In both, the grossly involved and uninvolved areas appear alike. The only difference is the degree of change. (See
Fig. 12.-Same case as Figs, 8. 9. and 10, showing dilantin effect on are&w gingivae, X620. The flattened nuclei and deeper eosin stain give the appearance of a keratinized surface, but special staining failed to disclose any mature keratin.
Fig. It.-Hypertrophic gingivitis of pregnancy (eighth month). Lower left No. 2 papilla. (Note similarity to dilantin gingivitis in Fig. 3.) Lowpower view of alveolar gingiva. A, Hyperplasia and pointing of the epithelial pegs. B, Inflammatory exudate. C, Dense bundles of collagenous fibers.
Dilantin
Hyperplastic
Gingivitis
357
Figs. 14, 15, 16 and 17.) The mucous membranes which, grossly, appear uninvolved, show the familiar dilantin changes microscopically (Figs. 12 and 18).
Fig. terdental as already epithelial rich with cularity.
Fig.
14.-Case 2. Man aged 22 years. Biopsy of upper right No. 3 grossly involved inpapilla, alveolar gingiva showing crest, X79. Note characteristic dilantin changes B, Slender epithelial pegs with described in IFig. 8. A, Epithelial hyperplasia. D, Cellular connective tissue pearls. C, Papillary layer close to the outer surface. hyperchromatic fibroblasts. E, Increased collagenous bundles. F, Increased vas-
15.-High-power
view
of Fig. 14, flbroblasts.
X680. Connective tissue B, Collagenous bundles.
hyperactivity.
A,
Young
Thus, areas seemingly normal disclose microscopic changes characteristic of dilantin hyperplasia and have enlargement potentials when the necessary irritation is provided.
358
Daniel E. Z&kin,
et al.
A
trplasia
of the
K
I
zousarea, grossly
Fig.
I?‘-High-power
view A,
of Fig. Young
16, X680. flbroblasts.
Connective tissue B, Collagenous
hyperactivity bundles.
;. 14 is shown
for
similar
15.
to Fig.
Dilantin
Hyperplastic
Gingivitis
359
At certain stages in their development, the clinical manifestations appear to be the same. It should be noted that the scurvy affection is caused by swelling and not by hyperplasia as is the case in dilantin. Other indications of scurvy are: pain, marginal necrosis of the gums, occasional petechial hemorrhage, and inaariable loosening of the teeth. These signs are absent, in dilantin hyperplasia, as are const,itntional symptoms such as purpura, sore joints, etc.
Fig. 18.-Same case as Figs. 14, 15, 16. and 17, X680. Upper right No. 3 grossly involved interdental papilla. Areolar gingiva. Connective tissue hyperactivity. This Agure together with Fig. 12 shows the dilantin effects microscopically on the mucous membrane grossly uninA, Cellular connective tissue rich with hyperchromatic flbroblasts. B, Increased volved. collagenous bundles. C, Increased vascularity. D, Epithelial hyperplasia.
Fig. lg.-Case 3, man aged 68 years. Bismuth stomatitis. Heavy bismuth line can be seen in marginal gingivae. The remaining lower anterior teeth are heavily coated with tartar. Bismuth is seen deposited only in that portion of the mwous membrane of the lip which rubs against the coated teeth.
360
Daniel E. Zislcin, et al.
The microscopic differences between the two are even more emphatic. In scurvy, the outstanding features are : (1) failure of the cells of the supporting connective tissues to form or maintain intercellular substances ; (2) failure of capillary formation due to inability of endothelial cells to form intercellular cement substances ; (3) prevention or suspension of the proper maturation of structural embryonic. conective tissue; (4) reduced immunologic response on the part of the gums, thus permitting marked inflammations and surface ulcerations, caused by the impeded ability to form collagen ; (5) atrophic changes in the periodontium resulting in its inability to support the teeth, with consequent loosening.lO, 11,12! 13,I4 The prominent findings in dilantin stimulation are: increased collagen formation and an increase in capillary formation. 2. The Estrogenic Homzon~e and Dilantin.--In some of the women studied it was noted that the epileptic seizures occurred a short time before or after the menstrual period. Even in instances where dilantin therapy controlled the seizures fa.irly well, relapses were seen chiefly in connection wit,11 the menstrual cycle. Similar observations have been made by othersl” Because of these factors, and because of the nonspecific hyperplasia induced by dilantin, we attempted to determine by the following experiment whet& or not dilantin has an estrogenic effect. Three white female albino rats, each weighing about 150 grams, were smeared daily for approximately two weeks, and two normal estrus cycles noted. Xubsequent,ly, intraperitoneal injections of dilantin (dosage: 114 mg. in 24 days) were given, and two of the rats smeared daily for eighteen days, one No smeared daily for twenty-three days. The estrus cycles were recorded. change occurred to warrant the conclusion that dilantin has an estrus effect. A histologic study of the rat gums and ovaries was made. For this purpose colchicine16s I73I8 was injected nine hours before sacrificing the animals. The colchicine dosage was 0.15 m,.v for each rat. Bilantin was found to have a stimulating action on the gums, but not on the ovaries. On the strength of these observations, it may be concluded that the changes noted following dilantin administration are not of the character found after treatment with the estrogenic hormones. ETIOLOGY
Neither the systemic disease, the magnitude of the symptoms, the amount of daily medication, nor the beneficial results of dilantin therapy show evidence of having a bearing on the degree of severity of the gingivitis. While the length of treatment is seemingly a factor in that the longer a case is treated the more pronounced arc the gum enlargements (Figs. 2 and 3), yet some cases receiving dilantin over a long term disclose less involvement than others ingesting the drug for a shorter period. The mucous membranes (other than the alveolar gingivae) and edentulous parts show no noticeable change. The most severely affected areas seem to bc those which harbor gingiral irritants such as tartar, debris, or ill-fitting dental restorations with overhanging margins. The same mouth may have both normal-appearing tissue and tissue grossly involved. In extreme instances, the entire alveolar gingivae is affected.
Dilantin
Hyperplastic
Gingivitis
361
These experiments point to hygienic care as a relevant factor. Gross pathology is usually apparent in mouths showin g careless application of the toothbrush (especially noticeable in children). In scrutinizing the toothbrush habits of both children and adults it was seen that in the same mouth areas receiving the best care were not involved to the same degree as other parts where signs of negligence were present. These factors lead to the hypothesis that because of the stasis produced in the terminal capillary circulation of the gums by local inflammation, the action of dilantin in producing tissue hyperplasia is facilitated. The exact method by which dilantin exerts its action remains to be determined. In the case of children, an a&iv& growing organism may enhance the tissue stimulation produced by the dilantin. This, plus careless oral hygiene, may account for the greater incidence of dilantin hypertrophy in children. Gingival inflammation plays an important role in many gum affections, For example, during pregnancy, it has as it does in dilantin hypertrophy. been observed that certain gum portions of a mouth may appear normal while others are grossly enlarged. Microscopic examination discloses that, as with dilantin, the seemingly normal gingivae have also undergone change and t,hat this change is hyperplasia (Fig. 13). The action of bismuth is another illustration. When a patient receives large quantities of bismuth t,herapentically, some of the bismuth is deposited in the marginal gingivae and appears familiarly as a blue line. It is assumed that the bismuth is deposited because of a preexisting inflammation. Fig. 19 is a photograph of Case 3, male, aged 68 years, who received bismuth treatment for syphilis. The mandibular anterior They were heavily coated with tartar. teeth were the only ones remaining. The lip opposite these tartar deposits was irritated and became inflamed. Bismuth can be seen only in this area on the lip and in the marginal gingivae of the remaining teeth. TREATMENT
Surgical removal of the enlargements, per se, was found to be ineffectual due to the rapid regrowth (Figs. 5, 6, 7). The most successful therapy consisted of vigorous massage of the interdental papillae and efficient toothbrushing. All forms of irritation were removed from the teeth and their surfaces rendered smooth. In cases where the gums grew to such size as to constitute an obstruction in carrying out these measures, surgery was employed, supplemented by interdental massage (rubber interdental stimulators or toothpicks were used) and continuous prophylactic treatment as outlined. Satisfactory results were obtained without discontinuing systemic therapy. The following case is descriptive of the procedure. Case 4, female, aged 26, single, had been given dilantin treatment for two years. Present dosage: 3 or 4 capsules (0.1 Gm. each) per day. Patient unusually intelligent and cooperative. History revealed enlargement of the gums was obvious within six months after ingestion of the drug was begun. The dentist consulted, without recognizing the pathosis, instituted routine prophylactic care with some resultant improvement.
362
Daniel E. Z&kin,
et al.
Considerable enlargement was present (Fig. 20) when the case came to our attention. Therapeutic measures were instituted as follows: In the maxilla, vigorous massage was employed consisting of the interdental method of toothbrushing, plus the USC of a rubber interdental stimulator or a round toothpick. In the mandible the proliferations were removed surgically, followed by massage as soon as the gums were sufficiently healed. The method of massage was as described. Therapy in the upper and lower gingivae was started at the same time.
Fig.
20.-&w
4, woman 25 Dilantin
years three
old, with general involvement to four capsules daily for two
before years.
gingival
treatment.
The upper gingivac returned to normal in three weeks. The lower gums also healed, but much more slowly (Fig. 21). After the entire mouth had been restored to an apparently healthy condition, the massage was continued Here, the patient as before in all but the upper right quadrant of the mouth. was instructed to discontinue home care. The dilantin gingivitis returned in this area. Within two weeks it was visible, and Fig. 22 is a photograph taken fourteen weeks later showing the extent of growth at that time. The rest of the
Dilantin mouth
remained
of
case
this
the
normal
and
extreme
The both
enlargement
seen
in
the
under
surface
part,
the
crown
of
epithelium.
The
This the
extent the
that size
Due
to
response
slight
and tissue
firm.
It
clinical
takes
hyperplasia
of
being
most
growing
covering
wholly
becomes
covered
on
resemblance
administrat,ion
dissimilar. where
of
Surgical
plus the
gum
to
the
out or
in
with
appearance
C. of
massage growth
be
that
vitamin removal
interdental cannot
is
obtained
elimination
the
apparent the
when
and
marked hyperplasia proliferates,
margin,
hard
measures
prcvcrning Dilantin
arc the
tissue
gum
proliferative
the
entirely
instances
following
possibly
progress prevented
of
has
employed
of
scurvy
and
94icroscopically, the
hypertrophied
and
hygienic
advanced
care,
to
without
first
such
an
reducing
gums.
best
massage,
erably
the
but by
prophylactic
of
The
dilantin
The
Surgery,
in
The have
enlarged.
inadequate.
advisable
is
care. may
CONCLUSIONS
epithelium,
free
tooth.
home
prophylaxis
connective
the
363
cases.
by
the
The
has are
early
produced and
altered
diseases is
AND
tissue
hyperplasia
two
are
the
greatly
significantly
tissue
SUMMARY
of
new
gingivae
is not
untreated
corium.
the
the
in
tissue
Gingivitis
supervised
that
changes
from
normal
continuous
suggests
connective
pronounced
with
others
important
the
Hyperplastic
dilantin medication
of
by
routine
all
traumatic
therapeutic affection therapy
is need
value
, gingival
home
care
including
int,erdental
influences. of
treatment
this
method should
in
minimizing
he begun
early,
and pref-
started. not
bc
discontinued
because
of
the
gingiral
hyperplasia. REFERENCES 1. Merritt, 2. Kimball. -3. Merritt.‘H.
4. 5. 6. 7. 9”. 10: 11. 12. 13. 14. 15. 16. 17. 18.
H. H., and Putnam. T. J.: J. A. M. A. 111: 1068, 1938. 0. P.: J. A. M. A. 112: 7244. 1939. H.. and Putnam. T. J.: J. A. M. A. 112: 2190. 1939. Franked, S. I. :’ J. A. M. A.‘114: 1320, 1940. Thoma, Kurt 1%: A31. J. ORTITODONTICS AND OIiAI, STTR~. 26: 394, 194:). Grunzhit, 0. M.: Arch. Path. 28: 761, 1939. Lennox, W. G.: J. A. M. A. 114: 1347, 1940. Ziskin, D. E., Blackberg, S. N., and Slanetz, C. A.: J. Dent. Res. 15: Dec., 1936. Ziskin, D. E., Blackberg, S. X., and Stout, A. P.: Surg. Gynec. & Obst. 62: 719, 1933. Boyle, P.: Am. J. Path. 14: 843, 1938. Wolbach, S. B., and Howe, P. R.: Arrh. Path. 1: I, 1926. Menkin, V., Wolbach, S. B., and Menkin, M. F.: Am. J. Path. 10: 569, 1934. Rinehart, J. F., and Mettier, S. R.: Am. J. Path. 10: 61, 1934. Holt, L. E., and McIntosh, R.: Halt’s Diseases of Infancy and Childhood, Ed. 11, D. Appleton-Century Co., p. 271. Schaefer, R. L., and Brosius, W. L.: Endocrinology 17: 133, 1933. Dustin, A.: J. SC. Med. de Lille 49: 561, 1934. Dustin, A. : Leeumenhoekvereeniging, IV ihme confbrence, Amsterdam, 7.36, 1935. Lits, F.: Compt. rend. Sot. de biol. 115: 1421, 1934.
I)ANIEI,
HYPERPLASTIC
1.
ITS
2.
DIFFERENTIAL
CAU3E
D.D.S.,
14;. ZJHKIN, ~DW.IJ~D
V. New
ASD
GINGIVITIS
!hE~4TMENT APPR;\IX~I,
LF,WIS R.
STOWE,
D.D.S.
AND
ZE~.\REI,IJ, S.B., D.D.S. I’ORK, N. IT.
the establishment of dilantin (Merritt and PutnamI) as an efficacious SINCE measure in the treatment of cpilcpsy, and its general use in many epileptic cases, prominent not,ice has hcen drawn to a side action of the drug involving the gingivae. This oral manifestation is known as dilantin hypertrophy of the gums and may be described as an enlargement caused by tissue hyperplasia. As the growth often proceeds to the extent of covering the entire tooth, mastication becomes painful as well as difficult and esthetics enter as a factor. Dilantin hypertrophy bears a close clinical rcscmblancc? to other forms of gingivitis. Outstanding among these is the t,ype of gum disorder associated with scurvy. Kimball,2 in a report on 152 dilantin patients, of whom 57 per cent showed gingival hyperplasia in varyin g degrees, considered the possibility of scurvy even though other signs such as sore joints, purpura, etc., were absent. He tested the ascorbic acid content of the blood serum in a number of cases and concluded that the degree of hyperplasia directly paralleled the deficiency of ascorbic acid. That is, those individuals with the most marked hyperplasia showed the lowest, level of ascorbic acid, as low as 0.1 mg. per 100 C.C. The administration of large doses of vitamin C (300 mg. daily by mouth) did not materially improve the gingirae, alt~hough the plasma level was raised to a, high normal. Merritt and Putnam,” dealing mostly with adults, cited a much lower incidence of dilantin gingival hypcrplasia (4 per cent as compared with 5’7 per cent by Kimball). This study “shovved no evidence of a deficiency of ascorbic acid. ” l?rankeJ4 observing a mixed group of children and adults (mostly adults), states that 62 per cent of his series showed hyperplasia of the gums. The degree of gingival involvement paralleled the dilantin dosage, while the A study of ascorbic acid level of the blood decreased as the gums grew larger. the table accompanying this report leaves doubt as to the justification of the author’s conclusions. with Merritt and Thoma,5 in a published case report, is in agreement is not in relation to Putnam in their view that the gingival hpperplasia vitamin C levels in the blood. in guinea pigs, found Grunzhit,F after inducing scurvy csperimentally that large doses of dilantin did not, alter the course of the scurvy or interfere with t,he utilization of vitamin c. Lennox7 Supports Grunzhit, in the opinion that vitamin C deficiency is not related to dilantin hpperplasia of the gingivae. *prom
the
School
of Dental
and
Oral
Surgery, 360
Columbia
University.
New
York
City.
Dilantin
Hyperplastic
Gingivitis
351
Our own findings, based on clinical observation and histologic evidence cited herein, rule out scurvy as an etiologic factor. This report deals with a group of patients under treat,mcnt for cpilcpsy The series comwith dilantin at the Columbia-Presbyterian Medical Cent,rr. prises males and females, children and adults, in about equal proportions. APPEARANCE
OF
TISSUE
Proliferations appear growing Gross-The gums bleed easily on probing. out of the inferior surface of the free gum margin of the interdental papillae (Fig. 1). They resemble gum polypi or proliferations frequently seen during pregnancy in areas subject to chronic irritation. They are congested, shiny, and friable, with a definite line of demarcation separating them from the stippled gingivae. As they yrow in size they are subjected to various forms of trauma. Their appearance is that of inflamed and markedly swollen tissue (Figs. 2 and 3). In t,he next phase the swelling changeq character. The gums become hard, firm, and a more normal color. Stippling returns and the inflammation (if it persists) is confined to t,he margin. The affection at t,his stage resembles a generalized fibromatosis (Fig. 4). The course as described usually covers a period of about six months, after which it may persist in the final form indefinitely. Dilantin hypertrophy of the gingivae is more pronounced in children than in adults. It is found in t.he presence of teeth, while grossly not apparent, in normal edentulous regions. In case extraction becomes necessary, the hypcrplastic gums return to normal appearance in the operated areas. It is more exaggerated under conditions of local irritat,ion such as overhanging margins, ill-fitting crowns and bridges, food impactions, tartar, and debris. It is seemingly absent in edent,ulous mouths except in areas where there is denture irritation. Here the hypertrophy is visibly present. As the proliferative tissue grows the teeth are moved out of alignment (Figs. 5, 6, and 7). In some cases alveolar bone is lost and teeth loosen. The affection is more pronounced where poor hygienic care is evident,. In well-rarcd-for mouths the reaction is comparatively mild. Those cases included in this study which were given vigorous and continuous prophylactic treatment from the time dilantin was first ingested were free from the gingival hypertrophy. In a group of children whose epileptic seizures were controlled wilhout the use of dilantin, the gingival hypertrophy did not develop even though many of the local irritants mentioned were present. Microscopic.-Epithelium. The keratin layer is not markedly altered. The epithelium shows a proliferat,ive change evidenced by the largely increased number of nuclei in the prickle- and basal-cell layers. The hyperehromatic nuclei take a deep stain and show an increased number of mitotic figures. is again accentuated There is some hydropic change. The epit,helial proliferation by the downgrowth of the epithelial pegs fairly deep into the corium, and their pointing and splitting (Fig. 8). Another evidence of hyperplasia is the frequency with which epithelial pearls are seen (Figs. 9 and 10). These structures, reported by Thoma,” are found normally, but not as often as observed here, They may bc due to the growth and sectioning at right angles of the
352
Daniel E. Ziskin,
et al.
epithelial pegs and may possess a much lower degree of keratinization than Fig. 11, which is a highly keratinized epithelial pearl formed as the result of injections of large doses of an estrogenic hormone.8 This illustration is included herein for the purpose of comparing the state of keratinization seen here with that present in the dilantin pearl. A closer similarity to the estrogenic effect on epithelium is seen in Fig. 12. This is a section of areolar found) from a patient t.aking dilantin.
Fig.
2.
Fig.
L-Early stage of dilantin hyperplasia in a boy, aged 12 years, who had taken three capsules of dilantin daily for one year. Drug was discontinued for seven weeks because of hyperplastic gums. (Regression noted. ) Dilantin therapy was resumed for two weeks before this photograph was taken. A is a polyp, B the spread of proliferation from the inferior surface of the margin of the interdental papilla. Fig. Z.-Inflamed and swollen tissues partially covering the teeth of a g-year-old girl. who was taking dilantin, three capsules daily. The photograph was taken approximately four months after dilantin therapy was started.
Fig.
3.
of the gingival hyperplasia about six months after Fig. 3.-Same case as IFig. 2. Progress The line of demarcation between the hyperFig. 2. The tissues are still inflamed and swollen. plastic and stippled gingivae is evident. The gums are Arm an.d stippled. Fig. 4.-Generalized flbromatosis in a boy 16 years old. Dilantin, four capsules per day, had been taken for two years.
The flattened nuclei and the deeper eosin stain give the appearance of a keratinized surface. While special staining methods failed to disclose the presence of mature keratin such as is seen when large doses of the estrogenic hormone are used therapeutically, it is possible that the stimulating action of dilantin does produce an immature stage in the process of keratinization.
Dilantin
Hyperplastic
353
Gingivitis
The early hyperplasia in the dilantin gingivitis resembles the changes previously reported for pregnancy gingivitis” (Fig. 13) although the epithelial pegs incline to a greater extent of down-growth and the papillary layer of the corium lies closer to the surface. Connective Tissue.-The corium shows even more marked proliferation than the epithelium and seemingly accounts for most of the gingival enlargement. Many large young fibroblasts in an apparent state of hyperactivity
Fig.
5.
Fig.
‘Fig.
S.-Teeth imbeddcd in hyperplastic gum. in a girl. 9 years capsules daily, had been taken for two years. The gingivae are present at the margins. Fig. B.-Same patient as Fig. 5, after surgical removal of the graph was taken about four months after ‘Fig. 5.
Fig.
‘I.-Same Note
case as Figs. 5 and additional separation
6. of
Extent the
of the regrowth teeth caused by
old. Arm,
6. Dilantin. four to five and inflammation is
hyperplastic
in about three the proliferating
tissue.
months tissue.
Photo-
is shown.
are seen throughout the stroma. There are masses of inflammatory exudate, chiefly perivascular, and composed mainly of round cells with some plasma cells and a few polymorphonuclears. This inflammatory reaction, although fairly prominent in the alveolar corium, is especially conspicuous at the crest of the interdental papilla. There is an increase in the size and number of blood vessels and lymph channels. Endothelial proliferation resulting in the formation of new capillaries is seen in the pcriosteal portion of the corium in some sections. Edema is a prominent feature in some cases and not in
354
Dnniel E. Ziskin,
et al.
Dilnntin
Hyper-plnstic
Gin&&s
355
others. The papillae of the corium lie abnormally close to the outer surface of the epithelium and usually contain groups of young fibroblasts (Figs. 9 and 12). The proliferation of t,he connective tissue extending over the surfaces of the teeth becomes covered with cpithelium probably as a direct extension of the epithelial covering (Fig. 81. We have stated that edentulous areas or edentulous mouths do not show, grossZy, the hyperplastic changes noted. Microscopic data on this point are at a variance and were derived from tissue studies of two patients taking two to four capsules of dilantin daily.
Fig.
IO.
Fig.
11.
Fig. lO.-Higher power view of one of the pearls shown in Fig. 9, X900. Prickle are normal and the highly keratinized center is absent. Compare with Fig. 11. Fig. Il.-Epithelial pearl in a castrated monkey (No. 209). that was treated large doses of estrogen. Biopsy lower right No. 3 papilla, X400. Alveolar gingivae. keratinized center. Compare with Fig. 10.
cells with Note
CASE I.--A female, aged 57, wearing full upper, and lower partial dentures. Irritation was created by both appliances. Hyperplasia of the gums was apparent in the traumatized regions. Tissue biopsies were taken from normal and from hyperplastic-appearin,rr areas of the maxilla. CASE 2.-A male, aged 22. Tissue biopsies were taken from an edentulous field where a tooth had been ext,racted previously, and from a hyperplastic gingival interdental papilla. The microscopic findings in these eases are similar to each other and also to other dilantin specimens examined. In both, the grossly involved and uninvolved areas appear alike. The only difference is the degree of change. (See
Fig. 12.-Same case as Figs, 8. 9. and 10, showing dilantin effect on are&w gingivae, X620. The flattened nuclei and deeper eosin stain give the appearance of a keratinized surface, but special staining failed to disclose any mature keratin.
Fig. It.-Hypertrophic gingivitis of pregnancy (eighth month). Lower left No. 2 papilla. (Note similarity to dilantin gingivitis in Fig. 3.) Lowpower view of alveolar gingiva. A, Hyperplasia and pointing of the epithelial pegs. B, Inflammatory exudate. C, Dense bundles of collagenous fibers.
Dilantin
Hyperplastic
Gingivitis
357
Figs. 14, 15, 16 and 17.) The mucous membranes which, grossly, appear uninvolved, show the familiar dilantin changes microscopically (Figs. 12 and 18).
Fig. terdental as already epithelial rich with cularity.
Fig.
14.-Case 2. Man aged 22 years. Biopsy of upper right No. 3 grossly involved inpapilla, alveolar gingiva showing crest, X79. Note characteristic dilantin changes B, Slender epithelial pegs with described in IFig. 8. A, Epithelial hyperplasia. D, Cellular connective tissue pearls. C, Papillary layer close to the outer surface. hyperchromatic fibroblasts. E, Increased collagenous bundles. F, Increased vas-
15.-High-power
view
of Fig. 14, flbroblasts.
X680. Connective tissue B, Collagenous bundles.
hyperactivity.
A,
Young
Thus, areas seemingly normal disclose microscopic changes characteristic of dilantin hyperplasia and have enlargement potentials when the necessary irritation is provided.
358
Daniel E. Z&kin,
et al.
A
trplasia
of the
K
I
zousarea, grossly
Fig.
I?‘-High-power
view A,
of Fig. Young
16, X680. flbroblasts.
Connective tissue B, Collagenous
hyperactivity bundles.
;. 14 is shown
for
similar
15.
to Fig.
Dilantin
Hyperplastic
Gingivitis
359
At certain stages in their development, the clinical manifestations appear to be the same. It should be noted that the scurvy affection is caused by swelling and not by hyperplasia as is the case in dilantin. Other indications of scurvy are: pain, marginal necrosis of the gums, occasional petechial hemorrhage, and inaariable loosening of the teeth. These signs are absent, in dilantin hyperplasia, as are const,itntional symptoms such as purpura, sore joints, etc.
Fig. 18.-Same case as Figs. 14, 15, 16. and 17, X680. Upper right No. 3 grossly involved interdental papilla. Areolar gingiva. Connective tissue hyperactivity. This Agure together with Fig. 12 shows the dilantin effects microscopically on the mucous membrane grossly uninA, Cellular connective tissue rich with hyperchromatic flbroblasts. B, Increased volved. collagenous bundles. C, Increased vascularity. D, Epithelial hyperplasia.
Fig. lg.-Case 3, man aged 68 years. Bismuth stomatitis. Heavy bismuth line can be seen in marginal gingivae. The remaining lower anterior teeth are heavily coated with tartar. Bismuth is seen deposited only in that portion of the mwous membrane of the lip which rubs against the coated teeth.
360
Daniel E. Zislcin, et al.
The microscopic differences between the two are even more emphatic. In scurvy, the outstanding features are : (1) failure of the cells of the supporting connective tissues to form or maintain intercellular substances ; (2) failure of capillary formation due to inability of endothelial cells to form intercellular cement substances ; (3) prevention or suspension of the proper maturation of structural embryonic. conective tissue; (4) reduced immunologic response on the part of the gums, thus permitting marked inflammations and surface ulcerations, caused by the impeded ability to form collagen ; (5) atrophic changes in the periodontium resulting in its inability to support the teeth, with consequent loosening.lO, 11,12! 13,I4 The prominent findings in dilantin stimulation are: increased collagen formation and an increase in capillary formation. 2. The Estrogenic Homzon~e and Dilantin.--In some of the women studied it was noted that the epileptic seizures occurred a short time before or after the menstrual period. Even in instances where dilantin therapy controlled the seizures fa.irly well, relapses were seen chiefly in connection wit,11 the menstrual cycle. Similar observations have been made by othersl” Because of these factors, and because of the nonspecific hyperplasia induced by dilantin, we attempted to determine by the following experiment whet& or not dilantin has an estrogenic effect. Three white female albino rats, each weighing about 150 grams, were smeared daily for approximately two weeks, and two normal estrus cycles noted. Xubsequent,ly, intraperitoneal injections of dilantin (dosage: 114 mg. in 24 days) were given, and two of the rats smeared daily for eighteen days, one No smeared daily for twenty-three days. The estrus cycles were recorded. change occurred to warrant the conclusion that dilantin has an estrus effect. A histologic study of the rat gums and ovaries was made. For this purpose colchicine16s I73I8 was injected nine hours before sacrificing the animals. The colchicine dosage was 0.15 m,.v for each rat. Bilantin was found to have a stimulating action on the gums, but not on the ovaries. On the strength of these observations, it may be concluded that the changes noted following dilantin administration are not of the character found after treatment with the estrogenic hormones. ETIOLOGY
Neither the systemic disease, the magnitude of the symptoms, the amount of daily medication, nor the beneficial results of dilantin therapy show evidence of having a bearing on the degree of severity of the gingivitis. While the length of treatment is seemingly a factor in that the longer a case is treated the more pronounced arc the gum enlargements (Figs. 2 and 3), yet some cases receiving dilantin over a long term disclose less involvement than others ingesting the drug for a shorter period. The mucous membranes (other than the alveolar gingivae) and edentulous parts show no noticeable change. The most severely affected areas seem to bc those which harbor gingiral irritants such as tartar, debris, or ill-fitting dental restorations with overhanging margins. The same mouth may have both normal-appearing tissue and tissue grossly involved. In extreme instances, the entire alveolar gingivae is affected.
Dilantin
Hyperplastic
Gingivitis
361
These experiments point to hygienic care as a relevant factor. Gross pathology is usually apparent in mouths showin g careless application of the toothbrush (especially noticeable in children). In scrutinizing the toothbrush habits of both children and adults it was seen that in the same mouth areas receiving the best care were not involved to the same degree as other parts where signs of negligence were present. These factors lead to the hypothesis that because of the stasis produced in the terminal capillary circulation of the gums by local inflammation, the action of dilantin in producing tissue hyperplasia is facilitated. The exact method by which dilantin exerts its action remains to be determined. In the case of children, an a&iv& growing organism may enhance the tissue stimulation produced by the dilantin. This, plus careless oral hygiene, may account for the greater incidence of dilantin hypertrophy in children. Gingival inflammation plays an important role in many gum affections, For example, during pregnancy, it has as it does in dilantin hypertrophy. been observed that certain gum portions of a mouth may appear normal while others are grossly enlarged. Microscopic examination discloses that, as with dilantin, the seemingly normal gingivae have also undergone change and t,hat this change is hyperplasia (Fig. 13). The action of bismuth is another illustration. When a patient receives large quantities of bismuth t,herapentically, some of the bismuth is deposited in the marginal gingivae and appears familiarly as a blue line. It is assumed that the bismuth is deposited because of a preexisting inflammation. Fig. 19 is a photograph of Case 3, male, aged 68 years, who received bismuth treatment for syphilis. The mandibular anterior They were heavily coated with tartar. teeth were the only ones remaining. The lip opposite these tartar deposits was irritated and became inflamed. Bismuth can be seen only in this area on the lip and in the marginal gingivae of the remaining teeth. TREATMENT
Surgical removal of the enlargements, per se, was found to be ineffectual due to the rapid regrowth (Figs. 5, 6, 7). The most successful therapy consisted of vigorous massage of the interdental papillae and efficient toothbrushing. All forms of irritation were removed from the teeth and their surfaces rendered smooth. In cases where the gums grew to such size as to constitute an obstruction in carrying out these measures, surgery was employed, supplemented by interdental massage (rubber interdental stimulators or toothpicks were used) and continuous prophylactic treatment as outlined. Satisfactory results were obtained without discontinuing systemic therapy. The following case is descriptive of the procedure. Case 4, female, aged 26, single, had been given dilantin treatment for two years. Present dosage: 3 or 4 capsules (0.1 Gm. each) per day. Patient unusually intelligent and cooperative. History revealed enlargement of the gums was obvious within six months after ingestion of the drug was begun. The dentist consulted, without recognizing the pathosis, instituted routine prophylactic care with some resultant improvement.
362
Daniel E. Z&kin,
et al.
Considerable enlargement was present (Fig. 20) when the case came to our attention. Therapeutic measures were instituted as follows: In the maxilla, vigorous massage was employed consisting of the interdental method of toothbrushing, plus the USC of a rubber interdental stimulator or a round toothpick. In the mandible the proliferations were removed surgically, followed by massage as soon as the gums were sufficiently healed. The method of massage was as described. Therapy in the upper and lower gingivae was started at the same time.
Fig.
20.-&w
4, woman 25 Dilantin
years three
old, with general involvement to four capsules daily for two
before years.
gingival
treatment.
The upper gingivac returned to normal in three weeks. The lower gums also healed, but much more slowly (Fig. 21). After the entire mouth had been restored to an apparently healthy condition, the massage was continued Here, the patient as before in all but the upper right quadrant of the mouth. was instructed to discontinue home care. The dilantin gingivitis returned in this area. Within two weeks it was visible, and Fig. 22 is a photograph taken fourteen weeks later showing the extent of growth at that time. The rest of the
Dilantin mouth
remained
of
case
this
the
normal
and
extreme
The both
enlargement
seen
in
the
under
surface
part,
the
crown
of
epithelium.
The
This the
extent the
that size
Due
to
response
slight
and tissue
firm.
It
clinical
takes
hyperplasia
of
being
most
growing
covering
wholly
becomes
covered
on
resemblance
administrat,ion
dissimilar. where
of
Surgical
plus the
gum
to
the
out or
in
with
appearance
C. of
massage growth
be
that
vitamin removal
interdental cannot
is
obtained
elimination
the
apparent the
when
and
marked hyperplasia proliferates,
margin,
hard
measures
prcvcrning Dilantin
arc the
tissue
gum
proliferative
the
entirely
instances
following
possibly
progress prevented
of
has
employed
of
scurvy
and
94icroscopically, the
hypertrophied
and
hygienic
advanced
care,
to
without
first
such
an
reducing
gums.
best
massage,
erably
the
but by
prophylactic
of
The
dilantin
The
Surgery,
in
The have
enlarged.
inadequate.
advisable
is
care. may
CONCLUSIONS
epithelium,
free
tooth.
home
prophylaxis
connective
the
363
cases.
by
the
The
has are
early
produced and
altered
diseases is
AND
tissue
hyperplasia
two
are
the
greatly
significantly
tissue
SUMMARY
of
new
gingivae
is not
untreated
corium.
the
the
in
tissue
Gingivitis
supervised
that
changes
from
normal
continuous
suggests
connective
pronounced
with
others
important
the
Hyperplastic
dilantin medication
of
by
routine
all
traumatic
therapeutic affection therapy
is need
value
, gingival
home
care
including
int,erdental
influences. of
treatment
this
method should
in
minimizing
he begun
early,
and pref-
started. not
bc
discontinued
because
of
the
gingiral
hyperplasia. REFERENCES 1. Merritt, 2. Kimball. -3. Merritt.‘H.
4. 5. 6. 7. 9”. 10: 11. 12. 13. 14. 15. 16. 17. 18.
H. H., and Putnam. T. J.: J. A. M. A. 111: 1068, 1938. 0. P.: J. A. M. A. 112: 7244. 1939. H.. and Putnam. T. J.: J. A. M. A. 112: 2190. 1939. Franked, S. I. :’ J. A. M. A.‘114: 1320, 1940. Thoma, Kurt 1%: A31. J. ORTITODONTICS AND OIiAI, STTR~. 26: 394, 194:). Grunzhit, 0. M.: Arch. Path. 28: 761, 1939. Lennox, W. G.: J. A. M. A. 114: 1347, 1940. Ziskin, D. E., Blackberg, S. N., and Slanetz, C. A.: J. Dent. Res. 15: Dec., 1936. Ziskin, D. E., Blackberg, S. X., and Stout, A. P.: Surg. Gynec. & Obst. 62: 719, 1933. Boyle, P.: Am. J. Path. 14: 843, 1938. Wolbach, S. B., and Howe, P. R.: Arrh. Path. 1: I, 1926. Menkin, V., Wolbach, S. B., and Menkin, M. F.: Am. J. Path. 10: 569, 1934. Rinehart, J. F., and Mettier, S. R.: Am. J. Path. 10: 61, 1934. Holt, L. E., and McIntosh, R.: Halt’s Diseases of Infancy and Childhood, Ed. 11, D. Appleton-Century Co., p. 271. Schaefer, R. L., and Brosius, W. L.: Endocrinology 17: 133, 1933. Dustin, A.: J. SC. Med. de Lille 49: 561, 1934. Dustin, A. : Leeumenhoekvereeniging, IV ihme confbrence, Amsterdam, 7.36, 1935. Lits, F.: Compt. rend. Sot. de biol. 115: 1421, 1934.