REVIEW

TOXIC EPIDERMAL NECROLYSIS JEROME M. PARSONS, M.D.

Toxic epidermal necrolysis is a severe mucocutaneous reaction pattern characterized by fever, systemic toxicity, tenderness, erythema, and widespread exfoliation. Lyell' of Glasgow, Scotland, atid Lang and Walker-^ of Cape Town, South Africa, independently described this syndrome in 1956. Lyell was responsible for coining the term "toxic epidermal necrolysis." Toxic referred to a presumed circulating toxin responsible for producing both the prodrome and the eruption. Epidermal referred to the presence of significant epidertnal damage with comparatively slight dertnal reaction. Necrolysis was a neologism combining the pathologic finding of necrosis with the clinical finding of epidermolysis.'•''''

migrans."^" Finally, Ruskin described "fulminating dermatitis bullosa medicamentosa" associated with mesantoin in 1948.''

DEMOGRAt>HICS

Although toxic epidermal necrolysis is considered to be uncommon, its true incidence may be underestimated because of failure to report milder forms of the disease. The incidence has been estimated as 0.93 cases per million of population in West Gerrnany;-' 1 per million in Barcelona, Spaing' and between 1.2 and 1.3 per million iti France.^'' The disease most commonly occurs in adults and is often related to the administration of tnedications; however, cases have also been reported in children."'^'' The youngest patients were neonates.'^"^' The oldest patient was 93.^"^ Wotnen appear to be affected more frequently than mcn.^--^" While sporadic occurrence is the rule, an epidemic followed the longterm, mass administration of sulfonamidcs for meningitis prophylaxis." Multiple recurrences have been reported occasionally.'^-^'' Although uncommon in the veterinary population, toxic epidermal necrolysis has been described in dogs,'^^" cats,'''-^^ and a research tnotikey."*

HISTORY

Approximately 140 cases of toxic epidermal necrolysis were reported between 1939 and 1964.'' Prior to 1956, such diagnoses as erythema multiforme rnajor (StevensJohnson syndrome), acute febrile pemphigus, butcher's pemphigus, pemphigoid, acquired epidertnolysis bullosa, dermatitis tnedicamentosa, and bullous erythroderma with cpidermolysis were made.^-'' By 1969, 5000 cases had been reported.^ Although Walker* attributed Ruskin with the first description of the syndrotne in 1948, Lowney and Shoss credited Neff with the first description of a case complicating measles in 1920.'' " Morton used the term "morbilli buUosi" to report a similar case in 1932.'^ In 1926, Hamilton reported a case associated with phenobarbital." In 1939 and 1942, Lamy described cases associated with phenobarbital and diphenylhydantoin as "erythrodermie bulleuse avec epidertnolyse.'"''-'*' In 1940, Wile reported two additional cases associated with phenobarbital as a "universal, bullous, ulcerative, and exfoliative dermatitis."'-i^ In 1942, Raffetto described pemphigus-like eruptions associated with sulfadiazine.'** In 1945, Fletcher described a grave, bullous, erythema exudativum multiforme associated with Fowler's solution (arsenic).'' In 1946, Costello described an additional case associated with phenobarbital as "erythema buUosum

CAUSES

Many factors have been associated with toxic epidermal necrolysis. Walker speculated that there were many triggering agents including "drugs, microorganisms, food substances, and possibly even autogenous antigens."^ By 1974, 100 different drugs had been implicated.^'' Nonsteroidal anti-inflammatory agents (including aspirin, oxyphenbutazone, and piroxicam), antibiotics (including sulfatnethoxazole/trirnethoprim and amoxicillin), anticonvulsants (including phenobarbital, carbamazepine, and phenytoin), and allopurinol are among those drugs rnost frequently implicated.--•^''•^''-''^ Table 1 provides a more comprehensive list. The association of one specific drug with the production of the disease has been difficult to prove because of the lack of reliable skin and laboratory tests and the hazards associated with provocative testing. To further complicate matters, many patients are taking more than one drug simultaneously. Thus, it is often difficult or impossible to identify the sole offending agent.'"

In private practice. Address for correspondence: Jerome M. Parsons, M.D., 3105 Western Branch Blvd., Chesapeake, VA 23321. 749

International Journal of Dermatology Vol. 31, No. t t, November 1992

The number of cases of toxic epidermal necrolysis caused by a drug depends upon the volume of sales of the drug and the frequency with which the reaction occurs.'"* Drug-related cases typically begin within 3 weeks of the initiation of therapy. In cases of re-exposure, the reaction may begin within hours of restarting

the drug;'^'' however, there are cases in which readministration has resulted in no adverse effects. It has been postulated that one or more cofactors such as infection, malignancy, or connective tissue disease may be required to facilitate the reaction.''''•'" This would help to explain why a normally safe drug could at times be associated with a severe reaction. Toxic epidermal necrolysis has been associated with measles,'"''^'' influenza,'''' and smallpox'^ vaccinations. There have been a few, isolated pre-Medline case reports incriminating other childhood vaccines; however, a critical review of the original reports reveals that the authors often attributed the reactions to other causes, such as hypersensitivity to penicillin'^ or the staphylococcal scalded skin syndrome.'^' Toxic epidermal necrolysis has been reported to occur during the course of serious infections. It was the terminal event in a patient suffering from pulmonary aspergillosis.'-''' It has been a complication of measles,"''" varicella,'" herpes zoster,'" herpes simplex,'" and hepatitis A.^-'^ Septicemia with Clostridium septicum,^''^ Escherichia coli,^^^ Klebsiella pneumoniae.^'^'^^^'^^'^ Pseudomonas aeruginosa.,^'^'' and Streptococcus pyogenes'^^ has produced the clinical features of the syndrome; however, the causative microorganisms were cultured from the blisters in these patients.'"'""'' This is a contrast to most other cases of toxic epidermal necrolysis in which the fluid from intact blisters was sterile. Because isolated bullae may be a cutaneous manifestation of bacterial

Table 1. Drugs Associated with Toxic Epidermal Necrolysis Alka-Seltzer^ Amoxapine" Amoxicillin/Clavulanic

Butazolidin''* Carbimazole^" Cefaclor" Cefamandole''^ Cefuroxime''"'" Cephalexin'''' Cephalothin*"' ChJoramphenicol''" Chloroquine^' Chlorpromazine''''^'''" Ciprofloxacin* Colchicine^'' Demeclocycline" Dicloxacillin''^ Disulfiram^' Dover's Powder' Doxycycline^^ Etretinate^' Eenoprofen^^ Fowler's solution'^ Gentamicin'''' Griseofulvin^'-"' Heparin^"* Hydroxychloroquine'' Imipramine^

hidapamide*" Indomethacin"'^''''"' Levamisole^-' Mesantoin^' Methotrexate"' Mezlocillin^'* Mithramycin*' Naproxen^' Nitrofurantoin"^""' Oil of chenopodium^t Oxytetracycline'"' Penicillamine'"'''' Pentamidine" Pentazocine""'

Phenylbutazone ""'"^''"''""-""'

162-166 more extensive cases resembling toxic septicemia epidermal necrolysis most likely represent the same phenomenon. "*' They probably do not represent secondarily infected drug-induced bullae.'''^ Toxic epidermal necrolysis has occurred in association with several malignancies. These include ovarian carcinoma,^^ prostatic carcinoma,""^ Hodgkin's disease,^*^"'^^ non-Hodgkin's lymphoma,"'^"'^' and leukemias;^^''^''^^ however, all of the patients with lymphogenous malignancies had received prior treatment with radiation, chemotherapy, or both. But, in at least one patient, readministration of the chemotherapy reproduced the reaction.*^ The occurrence of toxic epidermal necrolysis during graft-versus-host disease has been reported in humans and in laboratory animals."'''''^'"'^' Krueger at the University of Cologne in collaboration with Graw and Merritt at the National Cancer Institute reviewed biopsy and necropsy material from 17 humans, 40 rhesus monkeys, and 60 dogs with bone-marrow transplants. They concluded that there was no immediate causal relationship between graft-versus-host disease and toxic epidermal necrolysis.'^^ Confirmation of the diagnosis of graft-versus-host-induced toxic epidermal necrolysis is difficult because of the variety of therapeutic insults that transplant patients undergo. Infections, especially Pseudomonas aeruginosa septicemia, may also be an unrecognized factor predisposing bone-marrow transplant re-

Primidone"" Proch lorperazine' Quinine" Rifampin'"*''"''" Streptomycin' ^'''' ^ Sulfadoxine/ Sulfamethoxazole'^^ Sulfamethoxazole/ 75.92,109,118,134-141

Thiabendazole'"" Tolmetin'" Trimethoprim''" Valproic acid''^ Vancomycin'^' Zomepirac'^^

* Pulverized ipecac and opium t Methylsalicylate with capsicum * Tham TCK, Allen G, Hayes D, et al. Possible association between toxic epidermal necrolysis and ciprofloxacin. Lancet 1991; 338:522.

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Toxic F.pidcrmal Necrolysis Parsons

cipients to toxic epidermal necrolysis. To further complicate matters, the primary underlying disease, prior chemotherapy, radiation toxicity, infections, and hypersensitivity reactions may mimic many of the features of graft-versus-host disease and make confirmation of its diagnosis difficult.'^" For this reason, some prefer to use the term "bullous stage" of graft-versus-host reaction rather than toxic epidermal necrolysis.'^' Table 2 summarizes the non-drug related factors that have been associated with toxic epidermal necrolysis. The idiopathic group, as originally described by Lyell, consisted of 11 elderly women who were not taking any medications and who were prone to recurrent attacks of increasing severity. Their eruptions lacked the features of erythema multiforme and often eventually had a fatal outcome.^'^" Additional cases of unknown etiology have been reported by others;-'--"-^^'^'''^'' however, the small number of these cases casts doubt upon the accuracy of inquiries into drug history.•'•''•^'' Toxic epidermal necrolysis may sometimes represent a terminal phenomenon in very ill patients."*^

CLINICAL MANIFESTATIONS

A variety of signs and symptoms may precede the onset of toxic epidermal necrolysis. Perhaps the most striking features include pruritus, pain,''"*^-'*'' tender95,102,112,184 or a burning sensation of the skin.' ness, Fever characteristically begins abruptly and reaches a

peak of 40.5 to 4t°C anxiety,"' confusion, photophobia," ex'** rhinitis,"*^ sore cessive tearing ''*' periorbital dysphagia,"*^ hiccups,' throat,"'•"*^''*'** hiccups,'"^ angina pectoris,* nausea,*'''^''*'''-"** vomiting,^''*'''*'''"*'* hematemesis,*^ diarrhea,'^'"*'* hematochezia,*"^ abdominal pain,'''''"'' dysuria,"" malaise,'^'«''o^'"2''85''8« myalgias,« and arthralgias''''''-^ have all been reported. Approximately 24 to 72 hours later skin lesions begin to appear.^'' One reaction pattern begins as typical erythema multiforme, including the presence of target lesions, progresses to bullous erythema multiforme, and finally evolves into toxic epidermal necrolysis.''^'''^'*'''^'''''' The other pattern consists of either a morbilliform eruption,'"'^'*'*'^'^^'"*''"*' or discrete erythematous*''*'' or purpuric^'''^ macules that evolve into a generalized erythrodema."'''''''-''"''"^ Vesicles and large flaccid bullae appear within the areas of erythema."'''^' The Nikolsky's-'''''''^'''''''"'''*'*''^^''" and Asboe-Hansen''''' signs are positive. The flaccid bullae are filled with clear fluid which is virtually acellular and yellow in color.'' The epidermis subsequently detaches in large sheets similar in appearance to wet wallpaper peeling off a wall.'"**''"'•"'

Table 2. Other Factors Associated with Toxic Epidermal Necrolysis Vaccinations Influenza^' Measles'"'!" Smallpox'^ Infections Fungal

Additional physical findings include superficial hemorrhagic ulcerations of the conjunctivae, oronasal, urogenital, and anal areas.''''"* Endoscopy and postmortem examination have verified similar involvement of the trachea, bronchi, esophagus, stomach, small and large intestines, gallbladder and pancreas.'»^'"'*''"0'"'''i'7.i98 Involvement of the tracheobronchial tree may range from diffuse erythema to extensive confluent ulcerations covered by a fibrinous exudate."* Similar findings within the stomach may range from diffuse gastritis to frank ulceration." As the patient begins to recover, cutaneous sequellae of toxic epidermal necrolysis become apparent. Listed among the nail findings are loss of the nail-

Aspergilhis fumigatus^^'^ Viral Measles "•'» Varicella'" Herpes zoster'" Herpes simplex^" ttepatitis A ' " Bacterial Clostridiian Escherichia Klebsiella pne Pseudomonas Streptococcus Neoplasms Hodgkin's • Non-Hodgkin's lymphoma"'''

plateS,20't3''''»-",54,75,95,103,108,109,113,129,189,199 p t e r y g i u m

formation,^"" Terry's nails,'^'^ and Beau's lines.*''" Hair loss has been variously described as alope^•13^58,95,108,113 starring alopecia,'''* and telogen effluvium.*'*'' Darkening of the hair may occur.^ Denuded areas may heal with milia,^"'*'''"' keloids,^'^ or hypertrophic scars."'•'''''^''^*'^"- Postinflammatory hyperpigmentation''20'2*'t3'54,57,5S,io.i,i89,i90,203 and hypopig-

Ovarian carcinoma^^ Prostatic adenocarcinoma'^^ Graft-versus-host disease"•"•' ^•'-' '^ Black widow spider bite'*" Systemic lupus

mentation,-"'^*'^'''"'^''*''"'' universal cutaneous depigmentation,"^ and eruptive melanocytic nevi have also been reported.3.200'203-205 751

Iiiternarional Journal of Dermatology Vol. ,31, No. 1 1, November 1992 LABORATORY

The results of routine laboratory tests generally reflect the underlying severity of the disease. Among the hematologic abnormalities reported are anemia.,^''''"'^"'''^"^ '-«^-"i-'i''''^«-''-'

Toxic epidermal necrolysis.

REVIEW TOXIC EPIDERMAL NECROLYSIS JEROME M. PARSONS, M.D. Toxic epidermal necrolysis is a severe mucocutaneous reaction pattern characterized by fev...
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