SEVERE ERYTHEMA MULTIFORME OF THE PLURIORIFICIAL TYPE (STEVENS-JOHNSON SYNDROME)

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SEVERE

ERYTHEMA

MtJLTIFORME

OF

THE

PLURIORIFICIAL

TYPE

(STEVENS-JOHNSON

SYNDROME)

Resulting

in Blindness

in a Patient

Treated

with

Trimethadione

(Tridione)

By BERTRAM SHAFFER,

M.D.,

AND PAUL MORRIS,

M.D.

Philade/phia,

Pa.

T

RIMETHADIONE

**(Tridione*)**

is a drug recently introduced for the treatment of petit mal

and

disorders.1’

2

Many

toxic

effects

of

the

drug

have

been

de-scribed. Davidoff’s listing3 included abnormal psychologic behavior, irritability, fatigue,

malaise, headache, drowsiness,

stupor,

status

epilepticus,

increase

in grand

mal

seizures,

variations in

the

white

blood

cell

count

and

variations

in body

temperature.

Severe

re-actions in the form

of

fatal

aplastic

anemia

(Harrison

et a14)

and

also

agranulocytosis

(Mackay and Gottstein5) have also been reported.

Ocular

manifestations

were

quite

common.

These

consisted

of

a temporary

sensitivity

of the eyes to bright daylight, blurring of vision and changes in color perception)’

Cutaneous effects have been variously described as ‘‘skin rashes’ ‘ and ‘‘skin

erup-‘2

More

definite

entities

included

scarlatiniform

eruption,3

acneiform

skin

reac-tion’ 6

and

exfoliative

dermatitis.3

The

malignant

febrile

type

of

erythema

multiforme

in

which

the

cutaneous

mani-festations feature purpuric and/or bullous lesions and the orificial mucosae are promi-nently and severely involved has been described under a number of different names. These

included

among

others,

ectodermosis

erosiva

pluriorificalis,

a

new

eruptive

fever

associated

with

stomatitis

and

ophthalmia

(Stevens-Johnson

Syndrome

)

, and dermato-stomatitis.9 The largest series of these cases has recently been reported by Costello,10 who suggested the name “erythema bullosum malignans-pluriorificial” type.

A complete

review

of

the

literature

dealing

with

this

condition

has

been

compiled

by

Lever1’ and its essential identity with erythema multiforme exudativum has been

stressed

by Keil’2

and

Lever.”

The

introduction

of

a new

drug,

in

spite

of

the

most

meticulous

laboratory

experi-mentation

and

clinical

evaluation,

all too

commonly

is followed

by unfortunate

reactions,

which

are

discovered

only

after

extensive

clinical

trial.

The

malignant

orificial

type

of

erythema

multiforme

has

never

been

reported

follow-ing

the

use

of

trimethadione.

We

have

had

the

opportunity

of

treating

a patient

after

he

had

developed

this

disease

while

under

treatment

with

trimethadione.

Furthermore,

the severe

involvement

of the conjunctivae

resulted

in total

permanent

blindness.

For

these

reasons,

we

believe

this

case

worthy

of

a report.

CASE REPORT

A. G., a white boy, aged 6#{189}years, was admitted to the Pediatric Service #2 of the Mt. Sinai Hospital.

From the Dermatologic Service and Pediatric Service #2 of the Mt. Sinai Hospital. (Received for publication May 11, 1948.)

*

Brand

name

for

3,3,5-trimethyloxazoladine

2-4 dione, a product of the Abbott Laboratories,

North Chicago, ill.

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SEVERE

ERYTHEMA

MULTIFORME

OF

PLURIORIFICIAL

TYPE

31

Under a diagnosis of “general retardation of mental development” and petit mal, he had re ceived from his physician six injections of a polyvalent anterior pituitary extract (Polyansin) * between October 8 and October 25, 1946 in doses varying from 0.5 cc. to 1.0 cc. at intervals of two to five days. In addition, trimethadione, in a dosage of 0.3 gm. twice a day was begun on October 10 and continued until October 26.

On October 23, over the site of an injection of pituitary extract given several hours previously, a

FIG. 1. Patient on third day of hospitalization showing extensive hemorrhagic and bullous mani-festations. Orificial mucosae are involved but only the fissured, crusted and swollen lips are observ-able here.

red spot appeared on the left buttock. By the next day this region had become swollen and within

48 hours it was noticed that the lips and eyelids were swollen. On this date (October 25) another

injection of extract was administered in the opposite buttock. No local reaction appeared subsequently at this site.

The following day blisters were noted about the lips and it was at this time that trimethadione was discontinued and penicillin totalling 240,000 units over a period of 24 hours was given. By

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October 27, a generalized eruption was apparent, accompanied by fever, a severe cough and dyspnea resembling asthma.

The family history was unimportant except that the only sibling, a boy aged four years, had been

born with bilateral dislocation of the hips.

The

patient’s birth was normal. He had walked at 1#{189}years and talked at

2#{189}

years. He had escaped the exanthematous diseases of childhood.

Examination on admission revealed an acutely ill child who presented a generalized florid eruption of multiform character. Most of the lesions were red to violaceous, blotchy macules and papules. Many of these were purpuric. Bullae were present over the knees, thighs, chest and neck. Some of the blebs arose from apparently normal skin while others had developed obviously from preexisting maculo-papular lesions. They were distended with either clear or hemorrhagic fluid. The palms and soles were diffusely mottled and swollen.

The lips were fissured, bleeding and covered with blebs, erosions and exudate. The tongue was diffusely coated and enlarged. The whole interior of the mouth including the buccal mucosa, the gingivae, the tonsillar areas, the palate, and the pharynx, presented a confluent mass of swollen, boggy pseudomembranous formation. The eyelids were adherent to each other. They were separated with great difficulty and revealed the presence of a profuse purulent discharge. The genitals were swollen and the glans penis was completely encased in a bullous lesion which later ruptured, leaving a denuded glans.

In the chest, wheezing, expiratory rales were heard anteriorly and large rhonchi were detected posteriorly. The systemic physical examination was otherwise normal. The pulse was 140, the respiratory rate 30, and the rectal temperature 40#{176}C.

For a period of one week the cutaneous manifestations became more severe. In particular, the hemorrhagic phenomena become more pronounced. The disease took on the character, eventually, of a pure bullous and purpuric eruption. At the end of this period the cutaneous picture began to

subside and following another week of declining activity new skin lesions stopped appearing. The severe character of the eruption on the mucosae continued, however. Although the mouth lesions began to subside shortly following those on the skin, the glans penis remained the site of a weeping erosion until November 25.

It was on the conjunctivae that the disease was most persistent and destructive. The ophthalmo-logic consultant, Dr. I. S. Tassman, examined the child’s eyes on November 5 and stated that both upper lids on eversion show a rather thick membrane covering the tarsal surface. The membrane is adherent -.‘ ‘ ‘‘The corneae of both eyes are clear.’ Four days later he noted that the left cornea was the site of a ruptured bleb and abscess formation. Within 48 hours the right eye became simi-larly involved, and by November 13 the lens of this eye had herniated through the perforated cornea. The corneal ulcerations healed by November 28 with the formation eventually of flattened white opacities, resulting in complete blindness. The right upper lid became attached to the eyeball.

During the first two weeks stay in the hospital the boy’s condition was critical. His chance of recovery seemed very uncertain. The cough and wheezing respirations became very severe, and the fever remained high. Feeding was

carried

out

by introducing nourishing liquids through a stomach tube introduced through the nostril and allowed to remain in place. The temperature dropped slowly from a peak of 40.6#{176}

C. to

37.8#{176}C. Later it gradually became normal, The blood count on October 28 was Hgb. 11.4 gm./100

cc. blood,

WBC

16.9 thousand, polynuclear neutrophiles 69%, non.segmented neutrophiles 18%, and lymphocytes 13%. Several urine examina-tions showed the presence of occasional white blood cells, and at times a few red blood cells. Blood cultures taken on three occasions were negative. The prothrombin time was 100%. The total protein estimation of the blood was 5.7 gm./100

cc. The

blood

urea

nitrogen was 9 mg./100 cc. Cultures of the eyes revealed hemolytic Staph. aureus. A roentgenogram of the chest on November 5 showed small areas of pneumonitis in the left upper lobe and right lower lobe.

The patient’s systemic treatment consisted of intramuscular injections of penicillin and

strepto-mycin, fluids by

mouth,

saline

and glucose

solution

intravenously, and plasma intravenously.

The eyes were treated by means of frequent boric acid lavage and the local instillations of atropine

1% and penicillin solution.

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SEVERE

ERYTHEMA

MULTIFORME

OF

PLURIORIFICIAL

TYPE

33

blister fluid.’#{176}In addition, patch tests were applied over the sites where either serum or blister fluid had been injected previously in a normal subject

(

P.M.

)

according to a technic formerly described.’4

The suspected allergens injected were trimethadione 0.2% aq. suspension and pituitary extract

25% aq. sol. The patch test material consisted of 25% concentration of each of the above prepara-tions in cholesterinized petrolatum. All these tests proved to be negative.

The injection of the patient’s serum 0.1 cc. intradermally into a normal subject (B.S.), followed

24 hours later by the ingestion of 0.3 gm. of trimethadione, failed to produce a positive reaction. Fluid drawn from an early bulla was tested for the presence of virus at the Virus Laboratory of the Children’s Hospital,* with negative results.

DiscussioNs

That

drugs

give

rise

to bullous

eruptions

of

the

type

herein

described

is well

estab-lished

by

numerous

reports.

These

include

many

commonly

used

drugs

such

as

the

barbiturates,” and sulfonamides,’6 bismuth,’7 iodides,’8 and phenytoin sodium.’9 It is

unfortunate that in the case of most drug eruptions no satisfactory test exists for proving the role of the inciting agent. It is only in exceptional instances that objective tests have

given positive results.’4

It is not surprising, therefore, that we failed to substantiate our suspicions in this

case even after performing a rather large battery

of allergy

tests.

To

prove

this

diagnosis

by

the

readministration

of

the

suspected

drug

to

the

patient,

in

view

of

the

already

disastrous results, could hardly be countenanced.

In spite of the fact that anterior pituitary extract has been used extensively for many

years, we could find no report of a skin reaction attributed to its use.

On

the

other

hand,

skin

eruptions,

as

well

as

numerous

other

toxic

effects,

are

al-ready recognized as

part

of

the

known

actions

of

trimethadione,

after

only

a rather

limited clinical experience. Therefore, if one is

to attribute

the

etiology

of

the

eruption

herein described to a drug, it would seem logical to assign trimethadione the responsible role rather than pituitary extract.

The

fact

that

the

eruption

appeared

originally

at the

site

of

a preceding

injection

of

pituitary

extract

may

be a coincidence,

or

it may

be due

to

a non-specific

trau-matic

localizing

effect

(Koebner

reaction).

It will

be

recalled

that,

when

a subsequent

injection

of anterior

pituitary

extract

was

given

in the

opposite

buttock,

the

reaction

was

not repeated. This would seem

to indicate

the

incidental

nature

of this

observation.

CoNcLusioNs

A case of severe erythema multiforme

of

the

pluriorificial

type

resulted

in total

com-plete

blindness due to bilateral involvement

of

the

cornea.

This eruption followed the administration of trimethadione

and

pituitary

ex-tract. The

possibility

that

trimethadione

was

the

cause

of

the

syndrome

was

considered.

REFERENCES

1. Lennox, W. G., Petit mal epilepsies-their treatment with tridione, J.A.M.A. 129:1069, 1945. 2. DeJong, R. N., Effect of tridione in control of psychomotor attacks, J.A.M.A. 130:565, 1946. 3. Davidoff, E., Tridione therapy in institutionalized patients, New York State

J.

Med. 47:1492,

1947.

4. Harrison, F. F., Johnson, R. D., and Ayer, D., Fatal aplastic anemia following use of tridione and hydantoin, J.A.M.A., 132:11, 1946.

* Through the courtesy of Dr. Joseph Stokes, Jr., Director of the Children’s Hospital,

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5. Mackay, R. P., and Gottstein, W. K., Aplastic anemia and agranulocytosis following tridione,

J.A.M.A.

132:13, 1946. 6. Shaffer, B., Personal observation.

7. Rendu, R. M., Sur un syndrome caract#{233}ris#{233}par l’inflammation simultan#{233}ede toutes les muqueuses externes-, Rev. g#{233}n.de din. et de therap. 30:351, 1916.

8. Stevens, A. M., and Johnson, F. C., New eruptive fever associated with stomatitis and oph-thalmia, Am.

J. Dis. Child.

24:526, 1922.

9. Baader, E., Dermatostomatitis, Arch. of Derm. and Syph. 149: 261, 1925.

10. Costello, M.

J.,

Erythema multiforme exudativum (erythema bullosum malignans.pluriorificial type),

J.

Investigative Dermat. 8: 127, 1947.

1 1. Lever, W. F., Severe erythema ; two cases of type ectodermosis erosiva pluriorificialis with de-velopment of cicatricial conjunctivitis and keratitis in one case, Arch. Dermat. & Syph. 49:47, 1944.

12. Keil, H., Erythema exudativum (Hebra) ; clinical entity associated with systemic features, Ann. mt. Med. 14:449, 1940.

13. Urbach, E., and Gotlieb, P. M., Allergy, 2nd Ed., Greene and Stratton, New York, 1946, p. 150. 14. Shaffer, B., Lentz, J. W., and

McGuire,

J.

A., Sulfathiazole eruptions. Sensitivity induced by

local therapy and elicited by oral medication, J.A.M.A. 123:17, 1943.

15. Berlin, C., Ectodermosis erosiva pluriorificialis due to phenobarbital; Acta Medica Orientalis 6:67, 1947.

16. Greenberg, S. I., and Messer, A. L., Fatal bullous dermatitis following administration of sulfa-diazine, J.A.M.A. 122:944, 1943.

17. Shaffer, B., and Collins, L. H., Jr., Pemphigoid eruption associated with hemorrhagic nephritis following bismuth therapy, Arch. Dermat. & Syph. 45:57, 1940.

18. Ormsby, 0. S., Diseases of the Skin, 4th Ed., Lea and Febiger, Philadelphia, 1934, pp. 184-186. 19. Ellis, F. A., Reactions to nirvanol, phenytoin sodium, and phenobarbital, South. M.

J.

36:575,

1943.

SPANISH ABSTRACT

Eritema

Grave

Multiforme

de

Tipo

Pluriorificial.

(Sindrome

de

Stevens-Johnson)

Un caso de eritema grave multiforme buloso del que resulto completa ceguera debida a Ia affeccion bilateral de las corneas es describido.

La erupcion seguida de la administracion de trimetanione (tridione) y polyansin (extracto pi-tuitario anterior). El uso del extracto pituitario anterior despues de muchos aflos de uso no habia sido nunca reportado como causa de erupcion. La tridione despues de un uso limitado en Ia clinica es ya reconocida como Ia causa

de

muchas reacciones incluyendo las de la piel. Por consiguiente la posibilidad de se#{241}alar Ia tridione como causa de esta erupcion es seriamente considerada.

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1948;2;30

Pediatrics

BERTRAM SHAFFER and PAUL MORRIS

with Trimethadione (Tridione)

(STEVENS-JOHNSON SYNDROME): Resulting in Blindness in a Patient Treated