462 Postgrad Med J: first published as 10.1136/pgmj.33.383.462 on 1 September 1957. Downloaded from

A CASE OF ERYTHEMA MULTIFORME MAJOR (STEVENS-JOHNSON'S SYNDROME) By DENNIS G. BROWN, M.B., Ch.B.(Leeds) Junior Hospital Medical Oficer, Scalebor Park Hospital, Burley-in-Wharfedale, near Leeds; late Deputy Resident Medical Officer, St. James's Hospital, Leeds, Yorkshire

It is considered that this case of the so-called said to be enlarged, and since then his mother has Stevens-Johnson's syndrome is of interest because thought the left side of his abdomen to be full. of the allergic background; the history of chronic From the age of 9 months he has had almost yearly nasal infection in earlier life, with the revelation of attacks of urticaria, mainly in the summer, but recent antral infection; the generalized lymph- without other recognized provoking factors. gland enlargement; the exhibition of sulphona- Until aged 8 or 9 he had constant nasal catarrh. mides during the illness; and the response to Otherwise his health had been good, and he had a treatment with cortisone. liking for physical pursuits, notably weight-lifting. H.A., a schoolboy, aged 14 years 8 months, was He is an only child, his twin having died at admitted to St. James's Hospital, Leeds, under birth. His parents are well. His maternal the care of Dr. E. W. Jackson on January 6, 1955. grandmother is said to have had eczema of the forearms whenever

pregnant. Protected by copyright. History Physical examination showed a poorly-looking Largely from the mother. Prodromal symp- fair-haired boy of good average physique; of toms had begun three weeks previously; he was adenoid facies, flushed particularly under the eyes feverish for one day and continued weak and and on the upper lids. There was an intense anorexic for nine days. He then developed a sore injection of the conjunctivae, especially the throat and dry cough, and in the next three days, palpebral portion, and possibly some episcleritis. successively, soreness of the mouth, eyes and penile The lips were thickly blood-scabbed with a tip with scalding pain on micturition (but no suggestion of old bullae at the periphery of some frequency). His cough became productive of lesions. The mouth showed an intense stomatitis yellow sputum, and large amounts of yellow and pharyngitis, with purulent ulceration near to mucus were produced in his nose and mouth. the lips and under the tongue, and along the On the I2th day (nine days before admission) he tongue margins; apart from involvement in this was put on to two tablets of sulphadimidine four affection the tonsils were normal. The urethral times daily, and lozenges and eyedrops of peni- meatus was red, pouting and ulcerated and there cillin. The eyes and mouth improved greatly was low grade balanitis. The skin itself showed http://pmj.bmj.com/ on this regime, which continued until entry into a ham-coloured erythematopapular rash on the hospital. In the last two days micurition had trunk and arms, confluent on the upper trunk been painless. On the day before admission his and extensor aspects of the arms, scanty on the temperature, which had probably been raised hands, neck and round the pelvis; absent on the slightly from the onset rose much higher. The face, head and legs apart from a trace above the boy appeared flushed, and a rash 'like measles' patellae. was noticed on the arm. This There were non-tender discrete firm right steadily glands, on September 30, 2021 by guest. became generalized. Systematic enquiry revealed medium to large in both anterior triangles of neck that ten days before admission his fingers felt and groins; and smaller ones in the axillae and stiff for one day, and that a few days later he posterior triangles of the neck; the right epitroch- complained of transient numbness in the left lear gland was felt. Palpation of the abdomen thigh. He had been taking no drugs previously. revealed, on inspiration, a firm spleen descending When aged 3 months, he was seen by a below the costal margin; the liver was not paediatrician because of frequent vomiting since palpable. Examination of the heart, lungs and birth; he benefited from three weeks in hospital, nervous system revealed no abnormalities. There but the mother remembers no information about was no tenderness over the paranasal sinuses. diagnosis or treatment, and the hospital records Blood pressure, i20/8o; pulse rate, 92/min.; have been destroyed. However, his spleen was respiratory rate, zo/min.; temperature, 97.8°F. September 1957 BROWN: A Case of Erythema Multiforme Major 463 Postgrad Med J: first published as 10.1136/pgmj.33.383.462 on 1 September 1957. Downloaded from The following investigations were done: and broadened. The pulse rate was 8o/min. Haemoglobin: 17.I g. %. The spleen was still palpable on inspiration. White Blood count: io,6oo/c.mm. (neutrophils There has been no relapse since. 65%, eosinophils 6% (636/c.mm.), lympho- cytes 25%, monocytes 3%, Turck i%). Discussion Blood sedimentation rate: 2I mm. in one Hebra (i866) is credited with first recognizing hour (Westegren). the unity of the polymorphous erythemata so Paul-Bunnell: negative. carefully differentiated by earlier physicians. Wassermann reaction: negative (August 9, 1955). He gave to the group, the now-established name Swabs: From eye: negative. Erythema Exudativum Multiforme. He declared From throat: negative for haemolytic his ignorance of the cause of the eruptions, but streptococci and Staphyllococcus was aware of rare febrile cases with extensive, aureus. 'even confluent rashes, and recorded one case with From urethra: direct, no pus cells or fatal pneumonia. By the end of the century cases gonococci seen; culture, scanty had been described with oral lesions and consti- growth of Staphyllococcus albus, tutional symptoms, and in 1876 Fuchs reported a coagulase negative. case with pseudomembranous conjunctivitis. At X-ray of chest and sinuses (reported on by Dr. the beginning of this century other writers, such J. Wall): ' Chronic sinus infection in both antra. as Barkan (1913) and Stark (1918), described cases Fluid level in right antrum. No pulmonary of generalized erythema multiforme with consti- lesion noted.' tutional symptoms and lesions of the membranes Treatment was as follows: Cortisone acetate of conjunctivae, mouth and genitals; but it was (oral) 50 mg. 6-hourly for two days, then 25 mg. not until Stevens and Johnson (1922) published the 6-hourly for three days, and finally tapered off histories of two children with resultant blindness, over four days. Potassium chloride i g. t.d.s. that the dramatic entity now often termed Protected by copyright. Erythromycin 300 mg., 6-hourly. Streptomycin Stevens-Johnson's Syndrome, became well known. 0.5 g. b.d. Guttae argyrol t.d.s. Benzocaine and Bronchitis or pneumonia have since been shown Bradosol lozenges. Light diet and plentiful fluids. to be associated fairly commonly. Thomas (1950) Complete bed rest. suggested that the condition be called Erythema Progress was rapid. By next day he was Exudativum Multiforme Major to point the feeling better, and the signs were less intense. relation to and difference from Hebra's Erythema A day later the eyes were distinctly less red, and Exudativum Multiforme, to be suffixed Minor. the stomatitis and rash fading. By the fourth day The terms are good but clumsy; and as the condi- of treatment the mouth, throat and urethral tion described by Hebra is well known as Erythema meatus were clear, the conjunctivae only slightly Multiforme, the shorter forms, Erythema Multi- injected, and the skin showed only residual forme Major (Stevens-Johnson) and Erythema staining. The glands were smaller. The tem- Multiforme Minor (Hebra) would be easier to use. perature remained normal apart from evening The relationship of so-called Stevens-Johnson's of and IoI°F. on the to Behcet's Reiter's disease and spikes Ioo0, 99.4°, Ioth, IIth Syndrome disease, http://pmj.bmj.com/ and 12th days; cortisone was stopped on the 9th Ectodermosis Erosiva Pluriorificialis has been day. On the x5th day, Mr. 0. C. Lord kindly did boldly discussed and classified by Robinson (I95I). a bilateral antral washout, in view of the X-ray He considers them part of the same entity, the findings. He reported the left antrum to be Ocular-Mucous Membrane Syndrome. However, clear but from the right one were obtained strings Behcet's and Reiter's diseases are both clinically of muco-pus, typical of the end of an infection; distinct from Stevens-Johnson's Syndrome; 100,000 u. penicillin were instilled. At discharge Behcet's disease on account of its absence of on the i9th day, resolution was complete. constitutional symptoms, the high incidence of on September 30, 2021 by guest. Because of the question of sulphonamide hyper- hypopyon, and the infrequency of skin eruptions sensitivity, the patient attended as an outpatient other than erythema nodosum; Reiter's disease for patch testing to 5% sulphadimidine and 5% because of its emphasis on arthritis and urethritis, sulphadiazine, separately, in Paraff. Moll. Flav; the longer course, and the relative infrequency of these were negative after 24, 48 and 72 hours. cutaneous manifestations, prominent amongst When seen on April I5, I955, he was fit and well, which is keratosis blenorrhagica. Ectodermosis and physical examination revealed no abnormality Erosiva Pluriorificialis, first introducted into apart from a pulse rate of Ioo/min., and the firm English literature by Klauder (I937), having hadits spleen which still emerged under the costal margin origins in French reports in the First World War, on deep inspiration. When last seen on August 9, does not seem to differ significantly from the con- 1955, he had remained well and had gained weight dition under discussion. However, as Soll (1947) POSTGRADUATE MEDICAL 464 JOURNAL September 1957 Postgrad Med J: first published as 10.1136/pgmj.33.383.462 on 1 September 1957. Downloaded from pointed out, the cases that Klauder originally used mides, barbiturates, salicylates, bromides, cin- the term for, were midway in severity between cophen, phenolphthalein-and at times with Hebra's Erythema Exudativum Multiforme and acute rheumatism, chorea, endocarditis, tonsillitis, the full Stevens-Johnson Syndrome, the ocular and arthritis. Hebra believed the roseola of lesions never progressing beyond purulent con- cholera to be Erythema Papulatum. The major junctivitis and the rash usually remaining peri- form has been seen in association with an epidemic pheral. Now that we have the pituitary and of primary atypical pneumonia with antibody adrenal hormones for treatment, we should be able reactions (Finland et al., 1948), and with Sonne to protect the eyes and make the differentiation dysentry and Vincent's angina (Thomas, 1950); between the groups of Klauder and Stevens- with the exhibition of drugs, notably sulphona- Johnson unnecessary. Although Klauder's term mides (Fletcher and Harris, 1945; Thomas, 1950; has the merit of drawing attention to the body Caldwell, 1953); after vaccination and in circum- orifices, it is clumsier and less euphonious than stances suggesting an allergic basis (Schwartz and Erythema Multiforme Major. Brainerd, 1946). The evidence for the condition The diagnosis in our case seems firmly based, being a primary infection, of virus type, are the with involvement of the skin, conjunctivae, and reporting of epidemics by a few writers, e.g., oral and genital mucosae, and constitutional upset. Leipner (I935), the demonstration of cytoplasmic In their analysis of 8i cases, Ashby and Lazar inclusion bodies in the cells of a rabbit cornea (195I) showed the disease to affect mainly males scarified with vesicular fluid from a patient by in the first three decades of life, to be commoner Anderson et al. (I949), the isolatiori of herpes in the winter months, and to have commonly a simplex virus from a fatal case by Womack and prodromal period of i to 13 days. (Erythema Randell (I953), and the good results of treatment Multiforme Minor appears to have its main with chlortetracycline. incidence in spring and autumn.) When the Our patient's history of urticaria, and his grand- skin is involved, as is usual, it generally shows some mother's of pregnancy eczema, are notable in viewProtected by copyright. vesicles or bullae. In our patient, although the of the allergive hypothesis of causation. The mild rash was purely maculopapular with confluence, eosinophilia, absolute and relative, is said to be as in Stevens and Johnson's two children, it will usual (Whitby and Britton, 1953). The relation- have been noted that the appearances of the lip ship to the disease of the antral infection is lesions suggested a bullous phase in their develop- problematical; it may have developed as part of ment. In the cases reviewed by Ashby and Lazar, the infected exudation in the respiratiory tract, or none had lymph gland enlargement elsewhere it may have been present before the onset of the than in the neck. However, Soll (1947) who disease, and played a provoking part as a source of presented 20 cases of his own, none of which had bacterial allergens. The history of chronic nasal any enlargement, reviewed 22 cases from the catarrh up to the age of 8 or 9, and the adenoid literature; three had cervical lymphadenopathy, facies, may therefore be significant. and one had generalized lymph gland enlargement. Again, the relationship of the sulphadimidine to It may be noteworthy that he grouped all his own the development of the disease is not clear. It is cases, with Klauder's cases of Ectodermosis that it no at for all the likely played part all, http://pmj.bmj.com/ Erosiva Pluriorificialis, intermediate between symptoms had developed before the drug was Erythema Exudativum Multiforme and Stevens- started, with the exception of the rash. However, Johnson's Syndrome; 16 had no rash, and in the the patient took if for eight days before he de- remainder it was confined to the hands and feet. veloped the eruption, which could have passed for a In our case the rash was more central in distribu- sulphonamide rash, and was not peripheral in tion. It is unlikely that the chronic splenomegaly, distribution and contained no vesicular or iris first noted when the patient was aged 3 months, is lesions. The negative patch tests do not, of ofdirect relevance to the condition being discussed. course, exclude hypersensitivity, which is probably on September 30, 2021 by guest. Sternal marrow and splenic puncture were there- vascular rather than epidermal. I think the fore not considered advisable, and the cause of the factors of atopy and upper respiratory infection enlarged spleen must remain in doubt. As there are more likely to be of significance. has been no personal or family history of anaemia, Recent treatment has chiefly consisted in the there is the possibility that it is due to a mutation new broad spectrum antibiotics, particularly causing a subclinical form of Gaucher's disease. chlortetracycline, and adrenocorticotropin Like Hebra we do not know the cause of the (ACTH). Since Wammock et al. (195I) treated condition, although infective, toxic, and allergic a case with adrenocortocotropin, several others bases have been postulated. However, eythema have used it. Ereaux (1952) stated that ' a panel multiforme lesions are known to occur rarely as a on therapeutics at the meeting of the American complication of treatment with drugs-sulphona- Academy of Dermatology and Syphilology in September 1957 BROWN: A Case of Erythema Multiforme Major 465 Postgrad Med J: first published as 10.1136/pgmj.33.383.462 on 1 September 1957. Downloaded from Chicago in December I951, was of the opinion the summation of evidence points to the need for that ACTH and cortisone are indicated in the controlled trials in this sphere of therapeutics. treatment of erythema multiforme, especially of the Stevens-Johnson type.' Caldwell (I953) Summary quotes three previous cases treated with ACTH A case of so-called Stevens-Johnson's Syndrome in addition to that of Wammock et al., and one is presented, with a past history of recurrent case of his own. Bleier and Schwartz (1951) urticaria, maxillary antral infection, and a history started treating a 24-year old male with cortisone of the exhibition of Sulphadimidine during the on the 8th day of the disease with excellent results, development of the disease. Treatment with but the only other cases reported as being success- Cortisone and antibiotics was rapidly ameliorative. fully treated with cortisone that I can find in the Patch tests to Sulphonamides were negative. literature are one of Ferloni and Giordano (I954), Attention is drawn to the generalized lymphadeno- which was complicated by the excretion of urinary pathy, and the fact that the patient had had a porphyrins, and an interesting case described by chronic splenomegaly since infancy. Causation Agostas and his colleagues (I952). In the last and treatment are discussed, with special reference case, the patient was a 14-year-old boy who was to the steroids, and the need for controlled trials. started on ACTH on the 8th day and responded dramatically in 12 hours; two months later, in a Acknowledgment relapse of the condition, ACTH failed to produce I have pleasure in thanking Dr. E. W. Jackson a response after four days, but when he was for his advice and permission to report the case, changed on to cortisone, the therapeutic response and Dr. F. F. Hellier for kindly reading the script. was excellent within 48 hours. Further, Lozano (1955) treated the second and third relapses in a BIBLIOGRAPHY old with ACTH and AGOSTAS, W. N., REEVES, N., SHANKS, E. D., Jr., and 3i-year man, cortisone SYDENSTRICKER, V. P. (I952), New Engl. J. Med., respectively. Only the last episode seemed 246, 2I7. Protected by copyright. shorter than the first ANDERSON, J. A., BOLIN, V., SUTOW, W. W., and KITTO, significantly two attacks, W. (1949), Arch. Derm. Syph. (Berl.), 59, 25I. treated with antibiotics, the lesions after ASHBY, D. W., and LAZAR, T. (i95I), Lancet, i, o091. receding BARKAN, H. (I913), Arch. Ophthal. (Chicago), 42, 236. five days. Finally, Mauriello (1954), describing BLEIER, A. H., and SCHWARTZ, E. (951), Amer. J. Ophthal., his with cases in a 34, 6I8. experience 14 U.S. Army CALDWELL, W. G. D. (1953), Lancet, i, 1127. hospital, concluded that the ACTH used in six EREAUX, L. P. (1952), ' Proceedings of Ioth International Congress of Dermatology,' London. Published by B.M.A., 1953. patients and cortisone used in two patients did not FERLONI, A. V. J., and GIORDANO, A. F. (I954), Rev. Sanid. alter or shorten the course ofthe milit. argent., 53, 333. materially disease, FINLAND, M., JOLIFE, L. S., and PARKER, F., Jr. (x948), and in one in each new skin lesions Amer. .. Med., 4, 473. patient group, FLETCHER, M. W. C., and HARRIS, R. C. (i945), J. Pediat., appeared while they were on treatment with the 27, 465. FUCHS, E. (I876), Klin. Mbl. Augenheilk., 14, 333; quoted by hormones; in all cases the mouth lesions took Barkan. V. S. to 21 to heal. HEBRA, F. (I866), ' On Disease of the skin, including the Exanthe- 7 days mata,' I, 285, New Sydenham Society, London. The variability of the effects of the hormones in KLAUDER, J. V. (I937), Arch. Derm. Syph. (Chicago), 36, o167. different are in due to LEIPNER, S. (I935); Derm. Wschr., IO1, 1178; abstracted Arch. reports probably part Derm. Syph. (Chicago), 35, 304 (I937). different modes of administration and R., Oral LOZANO, Jr. (I955), Surg., 8, i6I. http://pmj.bmj.com/ dosages, MAURIELLO, D. A. (I954), J. Amer. med. Ass., 156, 1495. and it would appear that an inadequate response ROBINSON H. M. (I95I), Med. Clin. N. Amer., 35, 3I5. be rectified an increased or a SCHWARTi, M. H., and BRAINERD, H. D. (1946), J. Pediat., may by dose, change 29, 512. of hormone. In our case the effect of the SOLL, S. S. (I947), Arch. intern. Med., 79, 475. STARK, H. H. (19I8), Amer. J. Ophthal., x, 9I. cortisone, although late in the course of the disease STEVENS, A. M., and JOHNSON, F. C. (1922), Amer. J. Dis. seemed dramatic in How- Child., 24, 526. alleviating symptoms. THOMAS, B. A. (I95o), Brit. med. J., I, 1393. ever, the condition did not appear WAMMOCK, V. S., BIEDERMAN, A. A., and JORDAN, R. S. completely (I95I), J. Amer. med. Ass 147, 637. inactive for almost two weeks after the start of WOMACK, C. R., and RANDALL, C. C. (x953), Amer. 7. Med., and one wonders whether in fact the i5, 633. on September 30, 2021 by guest. treatment, WHITBY, L. E. H., and BRITTON, C. J. C. (i953), ' Disorders duration of the disease was shortened. All in all, of the Blood,' 7th ed., Churchill, London.