Preliminary investigation on the relationship between the central nervous system and the oral cavity

RESEARCH .

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PRELIMINARY

INVESTIGATION

THE CENTRAL

NERVOUS

Giulinno

Quintarelli,

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SYSTEM

M.D., D.M.D.,”

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ON THE RELATIONSHIP

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BETWEEN

AND THE ORAL CAVITY and Howard

II.

Chauncey, Ph.D.,

Boston, Mass.

M

than a century ago RIagcndie*O and SamuelI presented information showing that stimulation of the gasserian ganglion produced ocular disturbances, conjunctivitis, and keratitis. Their studies provided early investigators with data for the formation of the theory of trophic function by the nervous system. Using dogs and rabbits, XchifP~ I6 found that hemisection of the brain stem (at the level of the cerebral pedunclcs and optic layer) and artificial lesions of the pons produced blood stasis and softening of the gastric mucosa. Epstein5 encountered similar changes in the gastric mucosa after section of the sciatic nerve and injection of chromic acid into the superior colliculi. Burdenko and Mogelnitski* observed hemorrhagic erosion of the gastric and duodenal mueosa in dogs with lesions of the hypothalamic region. Describing his clinical experiences, in which antimortem gast,rointestinal changes occurred following intracranial operation, Cushing3 emphasized the frequent association between alimentary tract disturbances and tumors of the hypothalamic area. Similarly, Watts and Fulton,‘” as well as Hoff and Sheenan,F noted the occurrence of gastric and duodenal erosions following lesion production in the anterior portion of the hypothalamus of monkeys. TJpon performing various intracranial operations, certain workers7+ casually noticed t,hat the first deviation of the digestive tract from normal consisted of excessive salivation and edema of the oral mucosa. Examination of the oral cavity revealed progressive penetrating ulcers which usually involved the entire mouth. In an effort to demonstrate a relationship between the hypothalamus and the alimentary tract, Skoblo,17 Pigalew,ll and Speranski,j18 irritated the tuber cinereum and not only produced erosion of the ORE

From the Department of Dental Research, Tufts University School of Dental Medicine. This work was supported by Grants D-402 and D-741 of the National Institutes of Health, United States Public Health Service. *Present address: University of Alabama School of Dentistry, Birmingham, Alabama. 1257

Twenty-three tlogs, ranging treated as shown in Table 1.

iti

weight

frotlt

L t.o IS kilogrnn~s,

were

Operutive Technique. ~--Itlt~‘;~\~(~l~ousl)etltoba.rbital (30 mg. per kilogram) was the anesthetic c~ml)loyc~l. Tl11, aniitlals wcrc subjected to immersion hypothermia (28 to LW (1.)? which 1)rcventetl excessive bleeding during the surgical procctlu~. A teal tclnl)c.t.at,ut.c~ was rrcortlctl through out the ol)cratiyc period. An incision was matlc front thcb l~cw of the now to the first wrviral vertebra. On one side of the head the skin and platysma were separated up to the lcvcl of the zygomativ boncl. The auriculo-ternpo~al art,ery was ligated. The tem])oral musclt~ was srparat,ed from its upper attachment to the parietal bone by a longitudinal cut along t,hc line of its insert,ion and folded outward. An electric drill was used to make the initial opening in the skull; this opening was later cnlargetl with a rongcur forceps. The dura mnt,er was separated from the inner surface of t,he skull with a blunt instrument, a.nd cc~rtbrospinal fluid was t~cmovrtl through the forarnen magnum. Removal produced shrinkage of t.he cerebral hemispheres so that they did not prot,rude when the skull opening was enlarged. Furthermore, extraction of the fluid aided in maintaining a dry, clear operating field. The dura mater

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was then detached from the underlying bone, in all directions, care being taken not to injure the venous sinuses, Cranial bones were removed from the lateral margin of the eye socket to the crista occipitalis. The mouth of the animal was opened ; this caused the coronoid process to move downward, and the remaining temporal bone could bc removed along the line of the zygomatic bridge. With a spatula, the temporal pole and the gyrus pyriformis were detached and lifted. The dura mater was cut into a large flap and It was then possible to lift the temporal lobe. Slight pressure folded upward. with any smooth instrument was usually sufficient to permit visualization of the oculomotor nerve and the internal carotid artery, which concealed the Stimulation of the st,alk of the pituitary gland and t,he tuber cinereum. hypothalamus was applied in the first group of animals %ith the blunt end of a No. ‘7 milliner’s needle. A needle holder was used so that the traumatic lesion could be induced in the desired area. In Group II the stimulating When located into agent was a small gla,ss bead, 5 to 6 mm. in diameter. the sella turcica, this produced a mild continuous stimulation on the tuber cinereum, hypophysis, infundibulum, and mammillary bodies. The dogs subjected to sham operations (Group III) were operated on in a similar manner, The dura mater, muscles, with the exception that no irritant was introduced. and skin were then sutured. For five days following the surgery 150,000 units of penicillin and 0.5 mg. of streptomycin were injected daily. During the first postoperative week the diet consisted of powdered milk and soft food. Within a few hours after t,he operation, two experimental animals (one in Group I ; and one in Gro~rp II) and one control animal died as a result of accidental damage to the internal carotid artery. The remaining animals were sacrificed at various times ranging from the first postoperative day to the sixteenth postoperative week. Time of sacrifice was dependent The dogs were mainupon the severity of the manifest clinical condition. taincd until an obvious terminal stage had been reached or the clinical symptoms appeared static. Biochenzistry.-In order to determine whether the surgically induced lesions had any effect on the elect,rolyte concentration of body fluids, the sodium, potassium, and chloride levels of serum and spinal fluid were measurcd. Ten milliliters of venous blood was removed, clotted, and centrifugated. The supernatant serum was then removed for analysis. In addition, 4 to 6 ml. of spinal fluid was collected; one sample was obtained just prior to the operative procedure, and a second sample was collcctcd immediately before the animals were sacrificed. Six animals (Group II) were employed in this preliminary evaluation of the effect of hypothalamic stimulation on the elecSodium and potassium values were trolytes of serum and spinal fluid. Chloride was measured arcording to deterrnincd by flame photometry. Benotti’sl modification of the Van Slyke principle. POSTOPERATIVE

four

OBSERVATIONS

The animals in Group I showed their first clinical changes within twentyThese changes were characterized by shivering, t.o forty-tight hours.

Pia.

Hig.

I.-Chronic

marginal

Fig.

2.

gingivitis

antI

pingival

hyperplasia

with

areas

:L of acute

eXaCer-

bation. anin

Fig, Z.-Chronic margimtl gingivitis and hyperplasia somewhat observed by intense meipigmentation. Note the hematogenous staining on the surfaces of the teeth. Fig. 3.-Superficial erosion am1 intense hemorrhagic area on the left tip of the tongue.

The initial deviation from normal was a dripping of saliva. Examination of the mout)h rc~t~lccl bl(~cding of the gingivac, especially around the molat area. The gingivae al)l)cared swolle~~ alit1 edematous (Fig. 1). Bleeding was somet,imcs cxtcnd(4 to th(b checks alld t,hc upper lips, while the teeth were covered with a sticky, atlherent re:ltlish film that was fina.lly replaced by a

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areas appeared on the dorsal and thick calculus (Fig. 2). Hemorrhagic ventra.1 surfaces of the tongue (Figs. 3 and 4), lips, cheeks, and gingivae. These often turned into deep, pen&rating ulcers (Fig. 5). At the point of maximum reactivity the mouth was wet with bloody saliva. Pocket formation appeared in the succeeding days (Figs. 6 and 7). Although the bleeding points and ulcers abruptly healed in some animals, the periodontal changes continued, gradually subsiding and reappearing until death.

Fig. Fig.

4.-Lesion, 5.-Large

Fig.

4

Fig.

5.

similar to that shown in Fig. 3, on the right tip penetrating ulcer on the mucosa of the left cheek.

of the

tongue.

Three animals of Group II showed neurotrophic keratitis during the second postoperative day. The first change was a grayish white spot which involved only a small portion of the cornea. In a few days this white macula had spread out so that the entire cornea was involved, while at the same time the ot,her eye became affected (Fig. 8). These changes had completely disappeared in about ten days. Animals in Group III did not manifest any changes. Five deaths (Group II) occurred during the fourth to the sixth weeks,

I ‘kc ?t I

itis

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These dogs 1w rere all young (4 to 12 months old). The termin; 31 clinic :a1 condition was al most identical with that seen in the animals of G ro up I. HowCVW, excebis11re salivation appeared approximately four to fiv .e days before Fig. 9.

Fig. 9.-Extensive Fig. IO.-Normal

area of gastric hemorrhage. color of gmtric mucosa in control

animal.

l’OST3IORTE3I

PJSl)ISGS

Fig. 12. Fig. 13. Fig. 1 l.-Two duodenal ulcers undergoing resolution. Fig. lZ.-Deep hemorrhagic ulcer of duodenum. Fig. 13.-Focal punctiform hemorrhage of the anal mucosa.

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Fig. 14.- -1 infla .mmat OrY Fig. 15.- i;

CENTRAL

NERVOUS

SYSTEM Fig.

14.

Fig.

15.

AND

ORAL

er surface of the tongue of animal shown ation with signs of edema and vacuolar ler-power view of the previous section.

CAVITY

in Fig. 3. degeneration

1265

N rote in1 mse ch ronic

PJ710rim CR, 9 and 11 CO 'ated

tl

01’

Fig. net

Fil 5. 1 6.-Photonlicrog~agil

:rosis is accompanied Fig :. 1 7.-Control

17

of mucora rlf the cheek of animal by edema and lymphocytic infiltration. animal. Normal periodontal membranr.

shown

in

Fig.

SW< ?R?

erosions and ulcers in the cl1uot lenu 111 1011ger (( ~iroup 1 I) showed crnteriform (F ‘igs. I1 and 1%). In the .jejunum and ileum these changes wt:re not eT rider 1t. Hc)wev ‘er, , pin-point heulorrhages were nfteu recortled in the anal (XV 4ty at

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SYSTEM

-Gingival papilla from an infrabony F$.l;.; Iium ‘ight and sulcus epithelium on the inflltr ation in relation to the periodontal pocket. to thl 3 level of the alveolar bone.

AND

ORAL

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CAVITY

periodontal pocket showir Note the ulceration left. The epithelial attachment I

cot 1nfl to

Cthestory

.pical

Pig.

19.

Fig.

20.

Fig. I Y.-High-power yhotounicl,ogl-ay11 of periodontal membrane. Note tbc tic reaction and the active osteoclastic resorption of the alveolar bone. Fig-. 20.-High-power study of pfr’iodontium. Note the arra of cemental resorption to the intense inflanlrllatory infiltration.

dense

phloais-

:in~i


henrath the rpithelial layer of ulcerated areas, Ornl cw1dy: Immediately connective tissue fihcrs WCI~Cdisrnptcd hy edema and infiltratctl by lymphocytes and histiocyt,es (Fig. 14). Th(> ovt~-all picture showed connective tissue fiber% ~\crcl,~- damaged hy vacnolar degenera.tion, while blood and lymph vessels ~~erc greatly cwgorgd and dilated. ~~ndothelial cells of the arterioles were tumid and swollen. Idayers of initial hyalinosis were also seen. Striated muscles had lost their no1x1n1 strnctnre and were affected by the degenerative process. Areas of nclcrosis were fuuntl scattcrcd thronghont the sections (Figs. 15 to 20). In the stomata11the hist,ologic pictxre was one of Gastt&ztestinnl truct: cngorpement! particularly on the mucosal surface and in the capillaq

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tnuscularis mueosae. No inflammatory infiltration was seen. Degenerative changes were found in the duodenal mucosa, with necrosis and crater formation surr~ounded by edema (Fig. 21). There was marked lymphocyte and plasma-cell infiltration, with disruption and invasion of the submucosa (Fig. 22). Vasculnr~ stasis wa.s evident in the muscularis mucosa~.

Fig. X-Crater formation Fig. ZZ.-Photomicrograph inflammatory cells penetrating BIOCHEMICAL

Fin.

21

Fig.

22.

in the duodenal mucosa. of duodenum showing the ulceration of into the mucosa and muscularis mucosae.

the

mucosa

and

the

OBSERVATIOW

Table II cont.ains the mean electrolyte values. A marked rise in both the serum and spinal fluid levels of sodium, potassium, and chloride occurred after the surgical intervention.

Animals in Gmnp 11 ditl not show chaugcs until the fourth postoperative clay. The primary i11Rliii’est,i\tiolls wcw swelling and hemorrha.ge of the oral mucosa. This condition progrt~t~tl until aphthous-like lesions wt’rt: cvidcnt on the mucosa of the lips, cheek, nntl tongue. Seven of the nine animals ill this g2:l*onp eshibitctl thtlse lesions. Regression and repair occurred in thrctr CNSC’S after the erosion renehetl it sllI)t~rfi&l stage, while in four c10p the process continut~tl until the ld~t~t~s l)L’Cillll(. clct~p iIllt1 pcnctratitig. EYcll ilt the animals having tleep Icsiolts there were ])eriotls of remission illld t,t~mporary rt’pair which were followc~l I)y a rc~tt~wal of the ulccrativc Ibrocess. Tn six dogs (five yorunp a 11tl otle oltl) the whole piugivill area Leea.ltle cdcmatous and inflamtvl, il. t~ontlition which cvcntually tlc~eIt~pd into marginal pcriotlorit,itis, During this tlevelo~~lne~~tn.1 periotl the animals ate well ant1 exhibited a ~lortnal bt~havioral ntti%utlth. The mauifest;ltit)lls which arose it] the ;lCuds surviving fur four weeks and longer wt~i’t1 quite t~ousistt~tit. Ilt~nlorrhagcs were, in most cases, Iocdizctl in the same :lrea. of tltt> ~~~stroitltt~st~in;11tr>LCt. Du0de11al <*hi~Ilgrs nl)~)~;t~*~tl as a focal type 01’ lesiotl ilr thtb I’orlrl of erosions, piu-point heltIorrh;tges. illl tlcttvnlinc the Two 01’ the) ;Inilll>lls stirrlulatetl with iI bluut l)rube sht)wetl site of injury. t,hrvugh t,he anterior portion of t,hc hylesions that psstd t ratlsvcrsely pothalamus at t,he level OC the optic chiasma. 1n two ot,hrr animals the

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prechiasmatic region a.nd the stalk of the hypothysis were damaged, while the remaining two dogs had lesions in the substantia perforata posterior with blood clots in the third ventricle. Animals stimulated with glass beads demonstrated injury mainly at t.he level of the tuber cinereum, infundibulum, mammillary bodies and substantia perforata posterior. In two cases the beads were located in the vicinity of the lobus temporalis. Scct.ioning of t.he brain indicstcd that the beads in situ were at least 2 cm. from the gasserian ganglion and could not have exerted pressure on it. Thus, t,hc fift,h nerve could not hnvc been directly injured. The ulcerative lesions which developed were similar to certain oral ulcers observed clinically. Although the severity of the response varied among t.he animals, the basic pathologic changes observed were common to all. This suggests that the effective stimulation points are so situated as to activate fiber tracts and nuclear masses which are conccmcd with a variety of functions. The profound vasoconstriction and the consecutive vasodilat.ation which lead to tissue anoxemia and increased capillary permeability are probably due to irritation of an overactive sympathetic cent,cr located in the hypotechnical problems thalamus (tuber-rnammillary bodies) .I2 Many difficult are encountered in this type of experiment, and considerably more animal work is required before the exact relationship bctwccn the brain st,em and the viscera can be established. The present investigation, however, adequately demonstrates that irritation of certain areas of the brain stem directly affect the gastrointestinal tract and oral cavity. SUMMARY

The purpose of the present investigation was to determine the effect on the oral cavity of chronic visceral stimulation of the brain stem. Experiments were performed on seventeen clogs in which the stimulus was applied to two different procedures. Seven animals received traumatic irritation by means of a blunt probe. Ten animals were stimulated with glass beads located in the sella turcica which produced a rniltl continuous stimulation on the tuber eiwreum, infundibulum, and mammillary bodies. Six a.nimals scrvcd as controls and were operated upon in the same ma,nner as the experimental animals but received no cerebral stimulation. All animals in the first group died by the eleventh postoperative day, showing severe hemorrhage of the gastric and intest,inal mucosa and superficial erosion of the intestinal tract. No oral lesions were encountered. Six animals of the second group showed changes in the oral cavity. These changes were bleeding, ulcerous stomatitis, and periodontal disturbancts. This latter group also rxhibit.ed gastric bleeding, focal lesions, and ulcers in the duodenum and jejunum. Control animals kept in the same environment show4 no changes in either the oral cavity or the intestinal tract. The authors gratefully acknowledge Professor, Department of Pharmacology,

the assistance of Tufts University

Dr. Benjamin Covino, Assistant School

of Medicine.

1. 2. 3 4: 5. (i. 7. s. !). IO. I I. IL’. 13. 14. 1.5. 16. Ii. IS. 19.