Electron microscope study of erythema multiforme

Electron microscope study of erythema multiforme


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D.D.S., MS.,”




EBRA,l a German physician, was the first to report a case of erythema multiforme in the English language. His article was written in German, but was published in English in 1866. In his article he considered erythema papulatum, erythema tuberculatum, erythema annulare, erythema iris, and erythema gyratum to be descriptive terms and to be varying forms of erythema multiforme. While he described in some detail the erythematous and herpetic lesions of the skin, he made no mention of any such lesion on the mucous membranes. The earliest mention of an eruptive fever a,ssociated with ophthalmia and stomatitis was by pediatricians Stevens and Johnson2 in 1922. They described two cases of generalized eruptive fever with oral lesions which they stated did not conform to anything previously described in the literature. One of the cases had been tentatively diagnosed as erythema multiforme ; however, neither case was diagnosed definitely as such, but as a variant. In both instances stomatitis and ophthalmia were present, with bilateral blindness mentioned in one of the cases. Since the reporting of these two cases, erythema multiforme exudativum with involvement of mucous membrane has come to be known as the Stevens-Johnson syndrome. The most common feature of the syndrome is an eruptive fever in which the skin and mucous membrane may be the site of macules, papules, vesicles, blisters, blebs, and bullae. These lesions may become confluent or eroded. The lesions in the skin or mucous membrane may cause its separation from the underlying parts. The etiological factor is unknown and there is no specific therapy. There is a tendency for the lesions to recur in the spring and fall. Wheeler3 described a destructide purulent ophthalmia accompanying an The total blindness of the patient was ateruptive fever with stomatitis. Dardinski4 and Greenberg and Mess& have tributed to seconda,ry infect,ion. reported cases in which there was an erythema multiforme following the USC of sulfadiazine which terminated fatally. Bruce-Jones” reported a case in which an attack of erythema multiforme was brought on by drinking milk and by eating chocolate. Ormsby7 pointed out that, in some cases he had seen, the symptoms were limited to the mucous membrane. Jones8 mentioned that among the cases he had seen there appeared to be a predilection for young Sponsored by the Veterans Administration and published with the approval of the Chief The statements and conclusions published by the author are a result of Medical Director. his own study and do not necessarily reflect the opinion or policy of the Veterans Administration. *Chief, Dental Service, Veterans Administration Hospital, 962

Volume 9 Number 9




males. He stated that in the acute stage the temperature ranged from 100” to 105O F. and lasted three to seven days with a tendency to recur. In it,s chronic* state the disease may last for weeks or, indeed, may never entirely rcgrcss. Case Report The patient was a 35-year-old man, admitted to the hospit,al on July lS, 1951, with the complaint of “blisters” on the lips, inside of the mouth, a.rms, and hands. He stated that he first noticed the blisters on his hands, feet, and penis while in New Guinea in 1!G3 with the United States Army. He received treatment then and the lesions cleared up for a time but later reappeared. Other soldiers had the same ailment. After returning homl~. The conrlition never errt i WI> he treated himself with Mereuroehrome and gentian violet.. cleared up and in the summer of 1946 he noticed a blister on the inside of his cheek. 0th gave hirrl :I ers followed on the chest, tongue, palate, lips, ant1 uose. His local physician There was no improvement of the con-, 1951, tile I[Gour had Aureomycin, with no improvement. become much worse.


1 .-Ulcerated


on lips.

Physical Examination.-The patient at the time of a(lmisaion to this hospital was :I w&developed white man who was not acutely ill. His tenlperatuar, pulse, and blootl pressure were normal, Ulcerated lesions 1 to 2 cm. in diameter appeared on the lie*, tongue, buceal mucosa, and soft palate. These are shown in Figs. 1 and 2. The pharynx was clear, but t,here was advanced pyorrhea alveolaris with a marked generalized gingivitis. There were papillary lesions on the glans penis autl a few macular lesions on the hands. forearms, and anterior tibia1 areas which appeared to IW healing. Otherwise, the phvsirnl examination was within normal limits. Laboratory Examination.-The hemogram, urinalysis, ant1 serology were normal. (‘ui tures were made from the lip and soft palate Iesions. The predominating organisms found wc~‘~: hemolytic streptococci and nonhemolytic staphylococci. No fungi were found. Sensitivit! tests for antibiotics and sulfonamides were done, wrd the organisms present in the culture

Fig. !?.---Pa~~uln~~lesions on galate.

Fig. I.-l?iltrate

of nwuthwashings showing viral type bodies in Acation, X37.000 ; reduced ?/a.)




(1) Chloromycetin, were sensitive to the following drugs in the ortier name~l: (*illin, (3) Aureomycin, (4) streptomyrin, (5) Terranlycill. i(i) sulfadiazine, awl pyratline.

(2) peni(‘ii


Course.-At the time of a(lmission, a diagnosis of erythema nlnlt,iforme of the mootll, hytlrogen perospenis, am1 han~ls wits made. The patient was treated with half-strength Within a few (lays, the couille as a mouthwash and given penicillin int ranrn~cularl~. tlition of the mouth was improved and the penile lesions hat1 tlisappearecl. While being treated, new lesions appeared in the mouth and on the hancls. He a-as seen by the non and throat consultant, who could find no evidence of a focus of infection in the throat 01 parannsal sinuses. The lesions of the mouth were getting progres.Gvely worse by Aug. I.?, was ~tiscontinuetl an41 the patit’: I!Gl. The lip lesions are shown in Fig. 2. The penicillitl \\‘:I* given 1 grant of ~‘hlorom~c~tin daily for six clays it1111 ala0 two capsules of rrhillti

Fig. 4.-Histologic

study of section



area of palate.

vitamins daily during his stay in the hospital. Peroxide therapy was discontinued and daily the patient’s month was irrigated with half-strength essence of Caroid. The Caroid made the patient’s month more comfortable, so it was used daily during the rest of his stay in the hospital. There was some improvement in the mouth, and it was decided to remove all the teeth because of the pyorrhea alveolaris. On Sept. 20, 1951, five lower teeth were removed and healing was uneventful. At this time the patient was given 2 grams of Chloromycetin preoperatively and 2 grams postoperatively. On Sept. 25, 1951, the x-e-


0. s., 0. M., & 0. P.


maining lower teeth were removed and healing as before. On Oct. 3, 1951, five upper teeth was again used. The extraction wounds healed the original lesions on the palate, lips, and buccal

September, 19ih

was uneventful. Chloromycetin was given were removed and Chlorompcetin therapy normally, but there was an exacerbation of mimosa.

Electron Microscope Study.-On Aug. 15, 1951, washings of the mouth were taken with 0.85 per cent sterile saline solution. This solution was centrifuged and passed through a Seitz filter to remove bacteria and fungi. The filtrate was observed under the electron microscope, and the findings are shown in Fig. 3. The white areas are viral type bodies. They are uniform in shape and size and, being about 150 mp in size, are within the range of viruses. Ten white Swiss mice were inoculated intracerebrally with 0.03 C.C. of this All mice survived for six weeks with no evidence of central nervous saline suspension. system involvement. Histologic Study.-A time. The histologic study layer of keratotie debris. inflammatory cells into the



thelial tissue region there ulceration is, buccal mucosa



biopsy of a leukoplakic area on the palate shown in Fig. 4 reveals the epithelium to be In one focal area of the specimen there is superficial portion of the subepithelial tissue

scrapings as shown ~37,000 : reduced

in electron ?/4.)


was done at this surmounted by a an infiltration of and into the epi-


itself. This infiltration obscures the basement membrane. In the involved is a slight cyst formation associated with the inflammatory change. No noted. The diagnosis given by the pathologist was focal inflammation of compatible with erythema multiforme.

Final Therapy.-The lesions regressed somewhat and on Oct. 9, 1951, the remaining upper teeth were removed. The gums healed normally and the entire oral mucosa improved so much that on Oct. 16, 1951, the patient was sent home on therapeutic leave. When he returned on Nov. 14, 1951, the mouth was well healed and normal except in the upper right

quadrant, where were protruding.

the membrane This area was Fig. 5 shows the Inic:roscope. felt that the patient, was making to return in three months for tlenturcx

was very slightly inflamed and two small spicules of bone curetted and the scrapings were studied under the electron same viral type of body demonstrated in Fig. 3. It was satisfactory Ibrogress, so he was discharged and instruete(l t,he purpose of considering the construction of artificial

Further study was done with the electron lnicroscopo in which saline YUSpensions were taken from t.he mouths of ten paGents. This was done as a COBtrol to determine if the viral type bodies already demonstrated in Figs. 3 and 5 This part, of the investigation was OII ;+ c~ultl bc shown in other paCents. morphologic basis.

Cases Studied for Oral Viruses Patient 1 was under treatment in the hospital for acute suppurative appendicitis. His oral examination showed thirben ttatath missing, one tooth in whirh there were caries involving the pulp, a mod~ate generalized gingivitis, pcriodontoclasia. ant1 a. fa r-ildvallct~d

Fig. G.-Filtrate fyrmc: showing viral Tw~uced !4. ,

of washings type bodies


from the

the mouth of another microscope. electron

patient with (Magnification.

rrvthema Circa


xmnnn :

Patient 2 was being treated in the hospital for a chronic anxiety rc~ac*t~ior~. 1Iis mouth was edentnlous and there was no infection present. Patient 3 was treated in the hospital for osteomyelitis of the right femur. Iris teeth were all present. One tooth had caries involving the pulp am1 ht> had a mild gin&&s.



0. s., 0. M., & 0. P. September,1956

Patient 4 was treated for psychophysiologic gastrointestinal reaction. He had had eight teeth removed and there were no aarious teeth. He had a mild gingivitis. Patient 5 was treated for a laceration of the left eyelid. Five teeth were missing and two teeth were decayed. There was a mild gingivitis. Patient 6 was hospitalized for a fracture of the left ulna. He had all his teeth, of which two were crowned and one was impacted. He had a moderate gingivitis, incipient periodontoclasia, and leukoplakia on the right buccal mucosa. Patient 7 was hospitalized for treatment of malaria. Seven teeth were missing. He had a mild gingivitis. Patient 8, who had not been hospitalized, had fifteen teeth missing. Four teeth were carious, one root was present, the gingivitis was severe, and the pcriodontoclasia was far advanced. She had herpes zoster which had followed the extraction of the left mandibular molars. Patient 9 had twelve missing teeth and one carious tooth. She had neither gingivitis nor periodontoclasia, but did have herpetic lesions on the lower lip. Patient 10 was admitted to the hospital for treatment of erythema multiforme exudativum. He had twenty-two teeth missing and a mild gingivitis. He also had macular and papular lesions and blisters throughout his mouth and on his lips. Each of these mouthwashings was centrifuged and passed through a Seitz filter. The filtrate from each of the ten specimens was observed under the These were chrome shadowed at electron microscope and photographed. arc tangent l/5. A definite effort was made to select for photography those grids which contained viral type bodies most like the bodies in the original study. There were a few viral type bodies in most of the controls but specimen No, 10 was most like the original as to shape, size, and numbers. Specimen No. 10 is shown as a photomicrograph in Fig. 6. Summary The literature concerning erythema multiforme has been reviewed and the most outstanding things noted about this eruptive fever are that the etiological factor or factors are unknown, that there is no known cure, and that remissions are followed by exacerbations which usually occur in the spring and fall. A case is reported in which the eruptions of erythema multiforme markedly regressed following the removal of all the patient’s teeth. Viral studies were made of the oral flora with the aid of the electron microscope. Histologic examination was done on one oral section. Further studies were made with the electron microscope for the purpose of ascertaining the presence or absence, in the mouths of ten control patients, of viral type bodies like the ones in the reported case of crythema multiforme. The electron microscopic studies, while in no way complete, do show that viral type bodies were present in the patient’s mouth, and may be a causative factor.

References Diseases of the Skin Including the Exanthemata, London, 1866, Ferdinand: New Sydenham Society (translated and edited by Fagge, C. H.), Vol. 1, p. 285. Fever Associated With Stomatitis Stevens, A. M., and Johnson, F. C.: A New Eruptive and Ophthalmia, Am. J. Dis. Child. 24: 526.533? 1922. Destructive Purulent Ophthalmia Accompanying an Eruptive Fe\-el Wheeler, J. M.: With Stomatitis. Am. J. Onhth. 13: 508-514, 1930. Dardinski, V. J.: Eiythema dultiforme Bullosnm Following thr CW of Sulfadiazin(~. Am. ,T. Path. 15: 28-29, 1945. Greenberg. .,, 8. T.. and Messer. A. L.: Fatal Bullous Dermatitis Follodrtp L Atlrninist rat ion of Sulfatli~zine, J. A. if. A. 122: 944, 1943. Bruce-Jones, D. B. R.: Caseinogen as Causative Factor in Aetiology of ‘Erythema Multiforme Exudativum of Hebra, Brit. J. Dermat. 49: 498-500, 1937. Ormsb~*, 0. S.: Practical Treatise on Disease of the Skin, etl. 4, Philadelphia, l!JZ4, Lea & Febiger. Jones, Robert M.: Erythema Multiforme Exutlativum. Am. J. Orthodontics an11 Ora1

1. Hebra, S. 3. 1. 5. 6.

7. 8.




1481 1%'. TENTH ST.