ERYTHEMA EXUDATIVUM MULTIFORME INCHILDHOOD

BY

A. V. NEALE, M.D., F.R.C.P.(From the Department of Child Health, University of Bristol)

Hebra (1860) entered into a friendly rivalry withthe English dermatologist Robert Willan in hisclassical dissertations on the 'polymorphous ery-themata.' Even in these early years dermato-logical nomenclature had reached a complex state.Hebra comments that ' these various names by nomeans answer to as many distinct disese, and ourobject must be to determine which of them applymerely to appearances developed in successionduring the course of one and the same disease, and,in reference to this, expeience has taught me thatE. papulatum, E. tuberculatum, E. annulare,E. iris, E. gyratum are merely forms of the samedisea according to the period of its course; tothis malady I shall apply the name E. multiforme.'The phases and trnsitions are clearly described byHebra and some emphasis is placed upon theregional distribution of the rash, it appeariginitially on the dorsm of the hands and feet, beingin severe cases more generalized even to include, inexceptional cases, the trunk and face. In Hebra'sdescription E. papulatum represents the lowest andE. gyratum the highest grade in the eruption, and hedeprecates the notion that these are different species.Also, E. exudativum multiforme may give rise totifling subjective disorder, fever being observedonly in exceptional cases and in those in which theaffection spreads over large tracts of the surface andhaving a duration of up to four weeks. Hebraagrees with Willan that vesicular forms of theeruption may appear, but he refuses to agree thatthere is any relation uith Herpes; and he concludeshis masterly clinical description in confessing hiscomplete ignorance of the cause ofthese erythemata,although his experience indicated a preponderanceof these affections in young persons.

It is of some historical interest in this connexionthat Hebra (1860) disusses E. epidemicum, aero-dynia (which Alibert says prevailed in Paris in 1828),and classifies it as an exudative erythema. Twoyears later, Bazin (1862) described vesiculo-bullousstomatitis in association with multiform cutaneouslesions.

It is evident that in the following years there wasmuch dispute in regard to the clasiftion andetiology of the erythematous dermatoses. We nowunderstand that individual susceptibility and reac-tion is indicated by a wide variation in clinicalresponse, and this is specially so in the cutaneousand mucosal surfaces, which in their display ofcolour, form, shape, and distribution rarely fail todemand careful clinical scrutiny. Whilst, therefore,for certain practical reasons, many of the skinreactions aising out of general disease retain theiroriginal and historical descriptive names (whichmay or may not bear any clear relation to the knownetiological factors in the particular case), it has notbeen entirely favourable in general observation indisease. Dermatological aspects have inclined todominate description or to cause publication ofcases of more general interest in relatively isolatedand speializd literature. This trend in usiterms according to local signs has undoubtedly ledto considerable confusion, and this is speciallypointed out by Levy (1947) in his observatims on the' Stevens-Johnson ' syndrome. In this, a group ofsigns and symptoms have received widely divergentnames according to the viewpoint of the observer,or to certain variations in clinical character inindividual cases. There is undoubtedly reasonablecause to gather together a group of disorderswherein particular cutaneous and mucosal responsesare vanably associated, and whilst the ingenuity ofsome of the names employed, for example dermato-stomatitis, mucosal respiratory syndrome, muco-cutaneous fever, etc., is recognized, none appears tobe iently definitive for continued use. Itseems advisable to retain the name E. multiformeand to qualify the term according to' additivephenomena. As Stannus (1947) points out, thereare wide clinical variations in the disease, and theStevens-Johnson syndrome belongs to or is part ofthe condition usualy regarded as E. multiforme.Whilst Hebra in 1860 regarded E. multiforme as aprimary cutaneous disease with relatively benigneffects, it is clear from the literature since his day

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ARCHIVES OF DISEASE IN CHILDHOODthat associated visceral pathology is not iuusualand that severe illness is by no means rare. Fies-singer observed the syndrome characterized by avesicuko-bullous eruption involving the mucousmembranes, including the anal and genital regionsand associated with fever and leucopenia.

Stevens and Johnson (1922) claim description of a' new eruptive fever associated with stomatitis andophthalmia ': the notion that it is new is probablyunreal in the light of the historical facts outlined byKeil (1940) and mentioned by Levy (1947). How-ever, no doubt Stevens and Johnson were so veryimpresed by the startling clinical appearances intheir two cases in children that they were convincedof their unique character. In their clinical summarythey note the generalized cutaneous eruption ' notconforming to any recognized dermatologic con-dition,' and in both cases there was a purulentconjunctivitis. In one of the boys this proceededto panophthalmitis and total loss of vision. In theother boy severe corneal scarring resulted. A highand continuous fever was present in each case, withevidence of pulmonary involvement in one child butnot so in the other. The onset was with fever,and the eruption showed identical characteristics ineach, the rash appearing on the back of the neckand the chest, spreading to the face, arms, and legsduring a period of about eighteen days, the lastlesions to appear being on the soles and the palmsat about the time when the first eruptive zones wereshowing resolution. The eruption showed ovaldark red to purple macules which in a few dayswere raised firm brownish purple papules 0-5 to2 cm. in the longest diameter, without pain orpruritus. Some foci may reveal a yellow necroticcentre. On the forearms and shins the lesions weresmaller but more thickly disposed. There were nopustules. The scalp was uninvolved, but the mouthand lips were intensely sore and inflamed, andbullae appeared early on the oral mucosa. Resolu-tion of the skin lesions was evident after threeweeks, and residual faint pigmented areas, withoutpitting or scarring, were seen. Fall of temperaturecoincided with the period of resolution whichfinally involved the forearms and legs six weeksfrom the onset.Baader (1925) observed dermato-stomatitis with

pseudodiphtheritic ulceration of the lips andsublingual surface and similar scrotal erosion.Forman and Whitwell (1934) noted that herpessimplex often precedes an attack of E. multiforme.They suggest that a virus infection may be the causeof E. mnitiforme of the Hebra type.

Ageloff (1940) stresses the possible ocular mani-festations. In his cases of E. multiforme bullosum,severe involvement of the eyes called for urgentselective treatment. In girls, vaginitis may bepresent. Schlesinger (1904) considered that thedisease is relatively more severe in children.We are indebted to Keil (1940) for a comprehen-

sive historical and clinical survey of E. multiforme,

wherein he notes that the variable clinical courseand the complicated nomenclature has tended tocreate an artificial hiatus between internal medicineand dermatology. Keil regards Hebra's E. multi-forme exudativum as a specific entity. The termE. multiforme is used to designate erythema-papularrashes of acute onset and brief course and havingspecial favour for the extensor aspect of the limb,to which may be added vesicular or pustularcomponents. The vesiculo-bullous type is moreoften seen by paediatricians and ophthalmologists,whilst the ordinary erythematous case runs itscourse with minimal subjective complaint. Involve-ment of mucous membranes indicates a more severetype of the disease, with correspondingly increasedgeneral effects and eruptive fever. Gross haemor-rhagic bWlae with widespread lesions may render itdifficult to recognize the ordinary features ofE. multiforme exudativum. The dangers of thedisease are in proportion to the mucous membraneinvolvement. Superficial erosion in the mouthmay be the only feature. In the eyes, secondaryinfection may, similarly, change the appearances.In the mouth the initial erythematous phase isqwckly followed by vesicles and bullae which mayextend to the palate, pharynx, larynx, tracheo-bronchial, and oesophageal areas, thus creating adangerous condition. Involvement of the con-junctivae and possibly the cornea appears to followthe onset of the exanthema; pain and photophobiaare succeeded by considerable swelling of theeyelids and a muco-purulent discharge. Ocular vul-nerability is particularly prominent in children,the lesions varying in depth from a superficialcatarrhal change to purulent reaction in which thebulbar structures may be affected. A dangerexists of panophthalmitis. In the severe ocularcases there is invariably involvement of the oral andsometimes other mucosal surfaces and the cutaneoustissues. In discussing the Stevens-Johnson syn-drome Keil regards it as a variant of E. multiformeexudativum with severe ocular lesions and thatchildren are predisposed to the graver forms. Alsoexudative reaction may occur on the glans penis,prepuce, urinary meatus, urethra, labia, vaginaltract, cervix, anal canal, and the lower rectum;and ulcero-necrotic areas may quickly spread on thescrotum. Urethral reaction may be severe, and itis possible that some cases of non-specific urethritisare in this group. The literary term ' ectodermosiserosiva pluri-orificialis' (Fiessinger and Rendu,1917) represents variants of the E. multiformeexudativum syndrome in regard to the distributionof the mucous membrane lesions.Dowling (1940) observed during 1939 six cases of

a ' pemphigus-like eruption.' His description ofone of the cases is specially interesting and typicalof the group. ' A child of five years developedconjunctivitis followed in a few days by severestomatitis and almost immediately afterwards smallbullae appeared all over the skin. The childappeared severely though not dangerously ill, with

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ERYTHEMA EXUDATIVUM MULTIFORMEpyrexia. There was considerable conjunctivitis andthe mouth and tongue were covered with superficialulcers and sloughs, and the lips swollen. Blistersappeared on the penis and scrotum and similarlesions all over the surface, in largest numbers onthe face and extremities. The temperature declinedsteadily and after eleven days' illness the childrecovered.' Dowling regards E. multiforme as nota rare type of cutaneous reaction in the epidemics ofwinter sore throats but that the clinical severity inthis particular group was unusual and the appear-ance of large numbers of bullae suggested pemphi-gus; even variola was suspected.

Raffetto and Nichols (1942) suspected thatsulphadiazine was aii aggravating factor in a girlaged ten years who developed, eight days after acutetonsillitis, generalized vesiculo-bullous eruptionswith oral and conjunctival lesions. In this casethere was 20 per cent. eosinophilia.A similar but fatal case with oral necrosis is

recorded by Dardinski (1945). Soll (1947) con-cludes from observations on twenty cases thatsulphonamides should be avoided owing to theeruptive manifestations. Phenobarbitone is regardedby Moss and Long (1942) as a possible cause ofsevere toxic eruptions affecting the skin and themucosal surfaces and closely resembling E. multi-forne exudativum.Of nearly 72,000 patients in a large infectious

diseases hospital in Manhattan, twenty-eight casesof E. multiforme bullosum were recognized, allshowing multiform erythematous cutaneous lesions,bullous formations in the skin and mucous n-

branes, and constitutional symptoms compatiblewith acute infectious disease. Most cases werechildren under ten years of age. Fever, sore throat,headache, vomiting, and anorexia, together -withocular, gastro-intestinal, respiratory, and genito-urinary symptoms were present. The principalcutaneous lesions were dark red macules andpapules proceeding to vesicles and large bullae.To a less extent generalized erythema, pustules,purpura, crusted lesions, desquamation, and iritisoccurred, and conjunctivitis appeared in moderatedegree. There was somne evidence of concurrentrespiratory infection, and three cases were fatal.In this series Fletcher and Harris (1945) give specialconsideration to differential diagnosis. Consider-able confusion was evident in the pre-admissiondiagnosis, haemorrhagic varicella or variola beingsuspected, and only one case in the whole series wascorrectly diagnosed before admission to hospital.The bizarre nature of the disease is further

illustrated by the studies of Stanyon and Warner(1945), who under the term ' mucosal respiratorysyndrome' describe prostrating febrile illness withmucosal involvement as conjunctivitis, membranousstomatitis, dermal eruptions, urethral lesions, andpneumonia. The initial symptoms were likeinfluenza, with upper respiratory infection followedby lung lesions resembling the common atypicalpneumonia. Bacteriological studies were essentially

negative, although a virus was isolated in two cases-.Of great interest is the fact that cutaneous eruptionwas present in only about half the cases, althoughthere was no reason to doubt the common etiologyin the series. When present, the skin lesions werevery distinctive, being confined to the forearms,dorsum of hands and feet, legs, and scrotum. Thestomatitis was usually an early and dominantsymptom In their fatal cases these authors founda certain distinctive pathology in the viscera andbuccal mucosa but no specific infective agent couldbe isolated. The evidence was suggestive of a virusdisease; attempts to transfer the disease to animalswere unsuccessful. The Comniission on AcuteRespiratory Disease note also the prevalence ofnon-bacterial pneumonia, with essentially mono-nuclear reactions, in either the erythemato-papularor the vesiculo-bullous forms of E. multiformeexudativum.

In New York in 1947 (Williams) a considerableincrease in the incidence of E. multiforme was seenafter vaccination. In these cases there was incon-spicuous oral and no conjunctival lesion. Theusual interval was ten days. This phenomenonwas also observed by Schwartz and Brainerd (1946)to follow five cases of smallpox vaccination, one caseof tetanus toxoid injection, and in one case afterinjecting influenza virus vaccine. In such patientsthe E. multiforme response occurred at an intervalof ten days. These observations lend some supportto a suspected virus-allergic relationship in E.multiforme.

Diansis

From the descriptive literature as first outlinedby Hebra (who apparently did not record thepresence of mucosal lesions) and later more elabor-ately discussed by a long series of observers, apicture of the bizarre manifestation of this diseasemay be obtained, but direct inspection of the patientis the only means of acquiring a clinical memory ofthe remarkable appearances usually presented. AsKeil relates, the clinical pictures may be dominatedby systemic disorder, varying as a rule with theintensity of the muco-cutaneous effects. Initiallyan upper respiratory coryzal infection or a sorethroat, mild tonsilliis, pharyngitis and laryngitis,and a local lymphadenopathy may precede theexanthema by a period up to two weeks. Painfulthroat, dysphagia, and foetor oris may supervene.Severe coughing and possibly blood-tinged sputummay follow. The external areas of the nasalpassages may be intensively irrtated, and accom-panied by disharge. Pymxia may range to1050 F., and even the papular forms of the diseasemay be associated with considerable pyrexia. Nocardiac changes hve been detected. Gastro-intestinal effects are minimal, and abdominalexamination is usually negative. Eosinophilia has

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ARCHIVES OF DISEASE IN CHIEDHOODbeen recorded in a few cases, but there are usuallyno signifiant haematological fi . Haemnaturiamay be due to erosive effects of the urethral andpreputial vesicular ukeration.

Respiratory infection may arise as an extendeddisorder from the oral and nasal ulcero-necroticchanges or, as specially noted in the Canadian cases,primary consolidating diseas in hlngs may bepresent of a tye resembling atypical pneumoniawith mononuclear cell reaction.

Soil (1947) considers that cases may be dividedinto three groups based upon the severity anddistribution of the lesions (a) as originally describedby Hebra and including mild forms primarilyinvolvig the skin and showing minimal systenucdisturbance or mucosal effects, (b) an exTmelysevere form with extensive lesions on the mucousmembranes, cornea, conjunctiva, and ominouspossibilities of panophthalmitis, (c) an intermediatetype with most effects visible upon the mouth andother mucous membranes and a special tendency tourethritis and balanitis. Nellen (1947) relates avery characteristic example of erythema exudativummultiforme bullosum with ecchymotic conjunctivitis,stomatitis, and urethritis, and in which, after oneweek's illness with high fever, vesicles on an erythe-matous base appeared over the extensor surfaces ofthe arms and legs and soon the patient presented aflorid picture, pus pouring from the eyes, mouth,and urethra.The ophthalmological manifestations in E.-

exudativum multiforme may vary from mildhyperaemic changes to a severe pseudomembraneousform in which disastrous results may arise out ofcorneal ulceration. There is usually considerableswelling of the eyelids with oedema and vesicleformation, and this is well ilustrated in Nellen'spaper. Duke-Elder (1938) notes that Fuchs (1876)first recorded the ocular involvement, or 'herpesiris conjunctivae,' in a case which showed typicalskin and oral lesions.

In a recent paper, Sneddon (1947) agrees that theeruption at the maximal phase of the disease may begeneralized, but usually in the early stages theextremities, including the palms and soles, areinvolved, macules and papules being followed inthe more severe cases by bullae. He notes that theclassical target and erythema iris lesions wereuncommon in his cases and that, unlike the commonerythema multiforme, relapse is unusual. Subse-quent attacks, however, may appear with months'or years' interval and with any or all of the previoussigns, but usually with a lesened intensity. Mem-braneous sloughing in the moufti may be particularlysevere, as in the two boys reported by Murray(1947).

The disease has many of the features of a primaryinfection. Acute upper respiratory inflammatorydisorder may open up chanels of entry and aninterval of up to two weeks in such cases mayrepresent an incubation period or a phase oflatcy in the development of cutaneous andmucosal susceptibility. The association of a virustype of pulary lesions in some of the cases isprobably very sigificnt and is supportive of thegrowing evidence in relation to virus infection inerythema exudativum multiforme. Attempts totransfer the disease to animals have so far beenunsuccessful. It is significat that in their fatalcases Stanyon and Warer (1945) found in thevisceral and buccal mucosa a distict pathologysuggestive of a virus disease, but no specific infectiveagent could be isolated. The occasional appearanceof the syndrome after toxoid or vaccine injectionsuggests infection and allergy as operative agents.Biopsy of the skin by Nellen revealed non-specificinflammatory changes. Vesicle fluid gave negativereactions for variola and vaccinia antigens (Murray).Much of the primary pathology, especialy in themucous membranes, may be quickly changed bysecondary infection, and more especially withstaphylococci. Probably extended study with viruseswill yield more positive informatioa.

Ease 1. A boy aged four years had had noprevious illnes. An attack of mild respiratorydisorder with sore throat had begun two weeksprevious to the appearance of ' spots on the legs,'which were shortly followed by a similar eruptionon the legs, face, chest, and back. The wristsbecame painful. In another twenty-four hours therash became haemorrhagic. The mouth was sore,reddened, and very oedenatous, and there wassome blood-stained mucous in the throat. Theclinical picture on admission to hospital wassomewhat startling and clearly indicated an unusualdisorder. The boy had a pallid, puffy face withconsiderable oedema; suffusion and haemorrhagiceruptions were present in and around the con-junctivae. The mouth and lips were very swollen,intensely sore, and discharging haemorrhagicsecretions. The tonsils and pharynx were hyper-aemic. On the face, arms, feet, buttocks, andthighs a haemorrhagic papulo-bullous eruption waspresent, the maximum distribution of the rash beingrather peripheral and chiefly on the extensor aspects.There was pain and swelling of the joints, especiallythe knees and wrists, and moderate effusion appearedin the left knee. There were no abnormal cardiacor pulmonary signs, and the nervous system wasnormal. The spleen was not enlarged, and abdom-inal examination was negative. Blood examinationshowed no abnormality apart from a slight neutro-phil leucocytosis. There was no eosinopihilia.

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ERYTHEMA EXUDATIVUM MULTIFORME 187

FIG. 2.

FIG. 1. FIGS. I and:. Maximum phase of the eruption. Case 1.

FIG. 3.

FIGS. 3 and 4.-Maximum phase of the eruption. Case 2.Note confluence and Xvesicular formation on thetace and ioreneaa. FIG. 4.

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ARCHIVES OF DISEASE IN CHlLDHOODDuring the following week the rash did not extend,but at points of decubitus pressure a deepeningnecrosis threatened in some of the haemorrhagicareas, especially on the olecranon and gluteal parts.Anything more than temporary pressure indicated aspecial susceptibility to subcutaneous tissue damage.The swollen joints gradually subsided in about tendays. No nodular swellings occurred. Fortun-ately there was no spread of the conjunctivaleruption to the ocular strctures, and although thefacial swelling cleared slowly the clinical course ofthe illness was markedly abating after fourteen days.A mild, simple albuminuria quickly cleed. Thisboy had no signs of urethral or genital affection,although it is possible that a transient melaenaoccurred in the earliest phase. Penicillin, 15,000units three-hourly, was given over a period of tendays, with the primary object of preventing orcombating secondary coccal sepsis. (See figs. 1and 2.)Case 2. A boy aged seven years entered into an

acute illness with high fever, restlessness, andmoderate delirium. His eyes and mouth quicklybecame sore. Dysphagia and cough were trouble-some. Difficulty in micturition was associated withacute bullous eruption in the visible urethra andprepuce, with considerable local swelling. Fivedays from the first symptoms the boy was intenselymiserable, the eyes, mouth, and skin being distress-ful, and in fact all the visible mucous membraneswere in acute exudative eruption. The clinicalimpression was, however, that the boy was notdangerously ill, as he appeared unexpectedly alerton occasions. The skin showed erythematouspatches varying in size from I in. to I in. and ofirregular shape with central vesicle, and beingprincipally disposed on the limbs and the face, thescalp and back being sigificntly free. Bothanterior and posterior surfaces of the limbs wereaffected and a few papules were present on thehands and feet. Most of the skin lesions blanchedon pressure. There was bilateral purulent con-junctivitis with the lids encrusted with thick purulentexudate, but the cornea and other ocular structuresdid not appear to be involved. Some bleeding fociwere seen in the nasal mucosa, and the mouthpresented membraneous sloughs, especially on theinner cheeks and tongue, which bled easily on localswabbing. There was no visceral abnormality.Blood count was quite normal, and there was noeosinophilia. After six days the exudative reactionsshowed early resolution, but dysphagia provedtroublesome owing to the pain and immobility ofthe oral stuctures. Penkillin, 20,000 units atthree-hourly intervals, was given as a protectivemeasure, although no pyogenic bacteria were foundin the nasal or oral material. (See figs. 3 and 4.)

The varied and somewhat bizarre descriptionssurrounding the disease type initially recorded by

Hebra are an indication of the many ways in whichclinical description may differ when dominantmanifestations may be present in ditinctive tissues.The 'scattering' in medical literature is no doubtdue to the variety in leading signs, which is probablyin reference to the factors of primary virus infection,special tissue reaction (especially ectodermal),anaphylactic-like phenomena, and secondary sepsis.In the form of erythema under review some impor-tance is attached to clinical accuracy, especially inregard to possible ocular, oral, or cutaneousresemblance to other conditions. Special difficultymay arise when, as is sometimes the case, the skineffects are minimal and the clinical state is essentiallythat of acute involvement of the mucous membranesof the mouth and of the conjunctiva. Panophthal-mitis with perforation of the eye must be regardedin nearly all cases as the worst possible danger, andespecially so in young children. The absence ofvesicular or bullous changes and the quick variationsin distribution should distinguish E. marginatum.Polymorphous rashes, usually about joints, butsometimes with a more generalized tendency and asecondary haemorrhagic appearance with miutevesicles, are observed in the Henoch-Sch6nleinsyndrome. It is of considerable interest that, inone case, joint swellings were recognized during theacute phase of the illness. There was, however,complete absence of any abdominal symptoms.The condition of the membranes of the mouth

may cast a possible suspicion of diphtheria, althoughthe bullous changes in the mucous membranes andlips clearly dispose of the possibility.

Perhaps some resemblance may exist in regard tovariola, and in fact confuLsion has occurred occa-sionally. Certain atypical forms of smallpox mayhave to be considered when papular lesions,however few, quickly acquire vesicular, pustular,or haemonrhagic changes, and especially when suchlesions are disposed more particularly about theface, forehead, backs of the hands and feet, andthe wrists. Increasing familiarity with the syndromeof E. multiforme of the type discussed in this papershould, however, soon dispose of essential difficulty.Although many of the patients pass through theirillness without signiicant danger, caref watchmust be kept on certain possibilities, and probablyin the order of importance as (I) conjunctivaldisease spreading to the ocular structures, (2) pro-gressive ulceration in the mouth favouring descend-ing respiratory sepsis, (3) pressure effects on the skinleading to a deepening necrosis.

Treatment. It is in relation to these more severepossibilities that treatment is particularly directedto the affected mucous membranes and the eyes.

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ERYTHEMA EXUDATIVUM MULTIFORME 189Whilst penicillin probably has beneficial actionagainst secondary staphylococcal infection, sutphon-amides are better avoided in view of the aggravatingeffects which have been strongly suspected in someof the cases reported. Neller noted that sulpha-mezathine was without favourable effect in thesevere phase, but general improvement followedpenicillin intramuscularly. In a boy bearing theclinical features of E. multiforme bullosa, withmarked oral and ocular signs, the disease wasapparently aggravated by sulphathiazole, and, infact, this was considered to be the determining factorin the fatal termination. Nicotinic acid therapyis considered favourably by Weisberg and Rosen(1946).The photographs in this paper were taken by

Mr. J. Gregory Williamson, to whom I am extremelygrateful.

REFERENCESAgeloff, H. (1940). NVew EngL. J. Med., 223, 217.Baader, E. (1925). Arch. derm. syph., Wien., 149, 261.Bazin, E. (1862). Le!pons sur les affections de la peau.

Paris.Commission on acute respiratory disease (1946). Arch.

intern. Med., 78, 687.Dardinski, V. J. (1945). Amer. J. clin. Path., 15, 28.Dowling, G.B. (1940). Lancet, 2, 759.Downing, J. G. (1947). New Engl. J. Med., 237, 946.Duke-Elder, W. S. (1938.) Textbook of Ophthalmology,

Vol. 2.Fiessinger, N., and Rendu, R. (1917). Paris MMd., 23,

54.Fletcher, M. W., and Harris, R. C. (1945). J. Pediat.,

27, 465.Forman, L., and Whitwell, G. P. B. (1934). Brit. J.

Derm. Syph., 46, 309.

Haddad, N. N. (1945). J. Canad. med. Serv., 2, 657.Hebra, F. (1860). In Handbuch der Pathologie, 3, 198.

Virchow. R. Er .(1866). Vol. 1, Diseases of the Skin. NewSydenham Society, London.

Hotston, R. N., and Pemberton, H. S. (1947). Lancet,1,499.

KeiL H. (1940). Ann. intern. Med., 14, 449.Laurence, D. R. (1947). Lancet, 1, 888.Leading article (1947). Ibid., 1, 374.Levy, H. (1947). Lancet, 1, 537.Lever, W. F. (1944). Arch. Derm. Siph., Chicago, 49,

47.Moss, R. E., and Long, W. E. (1942-). Ibid., 46, 386.Mowbray, R. (1947). Lancet, 1, 538.Murray, J. 0. (1947). Ibid., 1, 328.Nellen, M. (1947). Ibid., 1, 326.Osler, W. (1895). Amer. J. med. Sci., 110, 629.Raffetto, J. F., and Nichols, S. (1942). J. Pediat., 20,

753.Schlesinger, E. (1904). Arch. Kinderheilk., 40, 256.Schwartz, M. H., and Brainerd, H. D. (1946). J.

Pediat., 29, 512.Sears, W. G. (1947). Lancet, 1, 427.Sheldon, J. H. (1947). Arch. Dis. Childh., 22, 7.Sneddon, I. B. (1947). Brit. med. J., 1, 925.Soll, S. N. (1947). Arch. intern. Med., 79, 475.Stannus, H. S. (1947). Lancet, 1, 538.StanYon, J. H., and Warner, W. P. (1945). Canad. med.

Ass. J., 53, 427.Stevens, A. M., and Johnson, F. C. (1922). Amer. J.

Dis. Child., 24, 526.Weisberg, A., and Rosen, E. (1946). Arch. Derm. Syph.,

Chicago, 53, 99.White, G. E. (1943). Canad. ned. Ass. J., 49, 317.Willan, R. (1799). Cutaneous Diseases. Breslau.Williams, W. (1947). Private communication.Year Book of Dermatology and Syphylology (1946).

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