Toxic epidermal necrolysis (Lyell syndrome).

IOURNAL of the

AmeRiCaN ACaDemy OF

DerMaTOLOGY VOLUME 23

NUMBER 6

PART 1

DECEMBER 1990

ED ITOR'S NOTE: The American Academy of Dermatology Council on Education has determined that members should earn CME credits through a variety of activities. Effective July 1, 1990, members may receive a maximum of 24 CME hours annually for CME examinations and himontWy Self-Assessment quizzes published in the JOURNAL, In addition, participants must achieve a minimum score of70% to receive Category I credit. See the May-June 1990 Academy Bulletin for complete details.

Continuing medical education Toxic epidermal necrolysis (Lyell syndrome) Jean-Claude Roujeau, MD, Olivier Chosidow, MD, Philippe Saiag, MD, * and Jean-Claude Guillaume, MD Creteil, France Toxic epidermal necrolysis is perhaps the most formidable disease encountered by dermatologists. Uncommon but not rare, toxic epidermal necrolysis occurs in 60 to 70 persons per year in France. It remains as puzzling a disorder as it was 34 years ago, when described by Lyell. Whether or not toxic epidermal necrolysis is the most severe form of erythema multiforme is still the subject of discussion. The physiopathologic events that lead to this rapidly extensive necrosis of the epidermis are not understood. Indirect evidence suggests a hypersensitivity reaction, but the search for potential immunologic mechanisms has resulted in little data to support this hypothesis. Accumulated clinical evidence points to drugs as the most important, if not the only, cause oftoxic epidermal necrolysis. Sulfonamides, especially long-acting forms, anticonvulsants, nonsteroidal anti-inflammatory agents, and certain antibiotics are associated with most cases of toxic epidermal necrolysis. Many other drugs have been implicated in isolated case reports. All organs may be involved either by the same process of destruction ofthe epithelium as observed in the epidermis or by the same systemic consequences of "acute skin failure" as seen in patients with widespread burns. Sepsis is the most important complication and cause of death. Approximately 20% to 30% of all patients with toxic epidermal necrolysis die. Elderly patients and patients with extensive lesions have a higher mortality rate. Surviving patients completely heal in 3 to 4 weeks, but up to 50% will have residual, potentially disabling ocular lesions. The prognosis is improved by adequate therapy, as provided in burn units, that is, aggressive fluid replacement, nutritional support, and a coherent antibacterial policy. Corticosteroids, advocated by some in high doses to halt the "hypersensitivity" process, have been shown in several studies to be detrimental and should be avoided. (J AM ACAD DERMATOL 1990;23:1039-58.)

W

The CME articles are made possible through an educational grant from the Dermatological Division, Ortho Pharma\J.J ceutical Corporation. From the Department of Dermatology, Hopital Henri Mondor, Uni· versite Paris XII. Reprint requests: J. C. Roujeau, MD, Service de Dermatologie, Hopital Henri Mondor, 94010 Creteil, France. *Dr: Saiag's present affiliation is Department of Internal Medicine, Hopital Tenon, 4 rue de la Chine 75970 Paris Cedex 20. ORTHO

16/2/20656

The term toxic epidermal necrolysis (TEN) was introduced in 1956 by Lyell! to describe the clinical disorder characterized by extensive epidermal loss that resembled scalding. Although the same cutaneous lesions had been described in a few patients before the publication of Lyell's article,2,3 the eponym Lyell's syndrome became widely accepted and remains more popular in Europe than the more descriptive term TEN.

1039

Journal of the American Academy of Dermatology

1040 Roujeau et al. Lyell's original publication included at least two diseases now recognized to be completely different: staphylococcal scalded skin syndrome (SSSS) and TEN. 4-10 The etiology and physiopathology of SSSS are well known. 6, 10-12 In this article we focus our attention on TEN. In 1922, Stevens and Johnson 13 reported two febrile children with a disseminated cutaneous eruption, erosive stomatitis, and severe ocular involvement. The skin lesions, discrete dark red macules, sometimes with a necrotic center, suggested "a tentative diagnosis of erythema multiforme." Because the patients of Stevens and Johnson had no blisters and no extensive detachment ofthe epidermis, Lyell1 at first drew no parallel between their case report and his. However, it soon became evident that severe forms of Stevens-Johnson syndrome could lead to extensive epidermolysis and that in most cases of drug-induced TEN targetlike lesions were present around the areas of epidermal sloughing. 4, 5, 14 It also appeared that the same drug could induce Stevens-Johnson syndrome and TEN. 15 These observations gave rise to the still controversial concept that both diseases belonged within the spectrum of erythema multiforme. 5, 7, 9,10,16-20 The controversy arises from the fact that, in a significant proportion (approximately 10 to 20%) of cases ofTEN, epidermal sloughing develops on a widespread scarlatiniform erythema, without targetlike lesions. 21 ,22 In addition, Stevens-Johnson syndrome and TEN do not have the same etiologic spectrum. As discussed later, TEN can complicate acute graft-versus-host disease (GVHD) but Stevens-Johnson syndrome has not been reported with GVHD. Conversely herpesvirus and Mycoplasma pneumoniae infections are well-recognized causes of Stevens-Johnson syndrome,16-18,20,23 but not of TEN. Until the mechanisms oflesion production in both diseases are understood, it will not be possible to clarify the nosology. As stated by Goldstein et al.,19 the status of Stevens-Johnson syndrome and TEN today can be compared with that of autoimmune blistering diseases before immunofluorescence. Unifying terms such as mucocutaneous syndrome have been suggested. 24 However, is it correct to group mild eruptions with life-threatening diseases? Our position has been to maintain the two eponyms of Stevens-Johnson syndrome and Lyell syndrome and adhere as closely as possible to the original descriptions. Thus we diagnose StevensJohnson syndrome when patients have severe mu-

cosal erosions, discrete targetlike macu1es, occasional skin blisters with erosions that cover less than 10% of the body's surface area.The prognosis for these patients is good and there have been no deaths in our experience. On the other hand, we diagnose Lyell's syndrome when the sheetlike loss of the epidermis involves more than 10% of the body surface. This is associated with a significant risk of death in our experience. 22 The use of the term acute disseminated epidermal necrosis (ADEN) type 1, 2, or 3 proposed by Ruiz-Maldonad0 21 could help to "unmuddy the waters."19 Type 1 ADEN would correspond to "classical" Stevens-Johnson syndrome, type 2 to "classical" TEN, and type 3 to transitional forms. The following data combine ADEN types 2 and 3 because the distinction is not retrpspectively feasible in most published cases. Furthermore, in our experience we have found no difference in pathology, etiology, complications, and prognosis between these two types.22,25-27 EPIDEMIOLOGY

TEN has been observed worldwide in all human races. 3,4,15,21,28-30 There are no available data on racial variations in incidence. A few cases have been reported in animals, after drug therapy.31 In human beings TEN occurs in all age groups,4, 5, 21, 22 including children, infants, and even newborns. The incidence increases sharply among the elderlY,32 as does the use of drugs. The female/male ratio is 3:2 to 2:1,4,22,24,28,29,33-36 as for most adverse drug reactions. 37, 38 More frequent drug intake by women in one possible explanation. Lyell's syndrome accounts for about 1% of skin drug reactions that require hospitalization. 37 , 39 An epidemiologic study of TEN in France and Germany from 1981 to 1985 gave the same incidence of 1 to 1.3 cases per million per year. 32,40 Fifteen years earlier, the incidence ofTEN in the region of Uppsala, Sweden, was estimated at 0.4 per million per year. 24 It is not clear whether this difference reflects a rising occurrence in recent years, a different case definition, or sampling variations. A single study found a significant increase of HLA-BI2 in patients with TEN.26 CLINICAL ASPECTS

Skin lesions The cutaneous lesions begin as a burning or painful erruption that often begins symmetrically on the face and upper part of the body and rapidly extends

Volume 23 Number 6, Part 1 December 1990

Toxic epidermal necrolysis 1041

Fig. 1. On the limbs, flaccid blisters arose over atypical targets. Fig. 2. Edematous "classical" target in case of postherpetic erythema multiforme. Note different aspect from "atypical" targets of Figs. 1 and 3. Fig. 3. Same patient as in Fig. 1. TEN patient with typical pattern of extensive detachment of epidermis. Note wrinkled aspect of necrotic epidermis, nake4 dermis over pressure zones, atypical erythema multiforme-like lesions in periphery.

to the entire body while predominating on the trunk and proximal limbs. A painful edematous erythema usually develops on the palms and soles. Most frequently, the initial individual skin lesions (Fig. l) form poorly defined macules with darker centers (more or less reminiscent of erythema multiforme) that progressively merge on the chin, chest, and back. These lesions differ from typical targets (Fig. 2) by their less regular shapes and the absence of an edematous ring. Less frequently the initial manifestation may be an extensive scarlatiniform erythema. Maximal extension of lesions usually occurs in 2 or 3 days, sometimes in a few hours. Occasionally extension may last for a week. Areas of skin that receive pressure from clothes (belt, braces, brassiere) are often less affected. Sometimes the lesions predominate in photoexposed areas. IS, 16 Most char-

acteristic of TEN is the appearance of a sheetlike loss of epidermis within the regions involved by the confluent erythema.! The epidermis is raised by flaccid blisters that spread with pressure. Nikolsky's sign is positive over large areas. Detachment of the full thickness of the epidermis over pressure areas, such as the back of the shoulders and the buttocks or on traumatized sites (which could result, for example, from the use of adhesive electrodes for electrocardiograms), will leave a dark-red oozing dermis. In other areas, the pale necrotic epidermis with a wrinkled appearance remains over the dermis (Fig. 3). The entire skin surface may be involved, with up to 100% of the epidermis sloughing. The hairy portion of the scalp is never affected. The extent of the detachment ofthe epidermis (and not the extent ofthe erythema) should be evaluated daily be-


1042 Roujeau et al. cause this is the main prognostic factor and a guide for therapy. This may be expressed as the percentage of body surface area involved, with the use of the same tables as for burns. This estimation is difficult for anatomic segments with nonconfiuent blisters.

Mucous membrane involvement Mucous membrane involvement is present in nearly all 'patients (85% to 95%)5,7,9,10 and precedes the skin lesions by 1 to 3 days in approximately one third of the cases. Several sites are usually affected, in the following order of frequency: oropharynx, eyes, genitalia, anus. Widespread painful erosions,· identical to those of Stevens-Johnson syndrome, cause crusted lips, increased salivation, impaired alimentation, photophobia, and painful micturition. Ocular lesions need special attention and daily examination by an ophthalmologist because they carry a high risk of sequelae. In the acute phase, redness and soreness of the eyes are conspicuous. Eyelids are often stuck together and attempts to separate them result in the loosening of the eyelashes and the epidermis of the eyelids. Pseudomembranous conjunctival erosions are usual and have a tendency to form synechiae between eyelids and conjunctiva. Keratitis and corneal erosions are less frequent. A sicca syndrome may appear during the first few days. PATHOLOGY

Even if the diagnosis of TEN is clinically evident, it is desirable to perform a skin biopsy in each case in which drugs may be involved. The typical advanced lesions show necrosis of the entire epidermis, detached from a little-altered dermis. 5, 7, 9,10 Examination of frozen sections of the sloughed epidermis makes it possible to distinguish rapidly between the full-thickness necrosis of TEN and the subcorneal split of SSSS.41 Earlier lesions are indistinguishable from those of the "epidermal type" of erythema multiforme. 42 The papillary dermis shows moderate infiltration by mononuclear cells without vascular alterations. Epidermal changes begin in the basal cell layer as intercellular edema with a sparse exocytosis of mononuclear cells, then spread to involve the whole malpighian layer. Close contacts between dyskeratotic and mononuclear cells ("satellite cell necrosis") are occasionally observed 43-45 (Fig. 4). At a more advanced stage, the necrosis extends from the basal cells to the entire epidermis. The epithelial lining of

sweat ducts is rapidly involved by the necrotic process, hair follicles are much less affected. In our experience, direct immunofluorescence has always been negative. 46,47 In the literature, there is a single report of immune deposits around the basal cells in two patients. 48 Electron microscopy showed an intermittently disrupted lamina densa that remains in the floor of the blister. Necrotic cells, with packed keratin, are prominent in thebasallayer. 49 , 50 COURSE AND SEQUELAE

The raw dermis bleeds easily and becomes covered with dark crusts. Regrowth of epidermis begins after a few days, sometimes while the disease is still spreading to the lower parts of the body. Progression of reepidennization under the sloughed epidermis can give a misleading histologic pattern of intraepidermal cleavage. Most of the skin surface is reepithelialized in 2 to 3 weeks. Pressure and periorificial areas often remain eroded and crusted for 1 to 3 more weeks. These localized lesions do not preclude discharge from the hospital. The hospital stay lasts 3 to 4 weeks. Usually skin erosions heal without scarring, but scarring may occur in areas of pressure or infection. Disturbances in pigmentation are almost inevitableS, 15,21,22 and usually result in a patchwork of depigmented 51 and hyperpigmented areas. These changes usually improve with time but may persist for more than 10 years. 22 The occurrence of mel~ anocytic nevi has been reported.52, 53 Nails are frequently shedS and regrowth may be abnormal and occasionally absent. 15, 21 Many patients complain of increased sweating. 22 Mucous membrane erosions sometimes persist for months after regrowth of the epidermis and may leave atrophic scars that resemble the lesions of cicatricial pemphigoid or lichen planus. 22 Phimosis in men and vaginal synechiae in women may require surgery.54 Ocular sequelae are the most severe and are indistinguishable from those that occur after Stevens-Johnson syndrome. 55 Understressed in the dermatologic literature, s they affect 40% to 50% of survivors. 34, 56 A few patients may have watery eyes because of the obstruction of the tear punctae but most have dryness, evidenced by a positive Schirmer test.57,58 Primarily attributed to stenosis of the lacrimal gland ductules, the sicca syndrome that occurs after TEN has been shown to be associated with a

Volume 23 Number 6, Part 1 December I 990


Fig. 4. Semithin section of early erythematous lesion in TEN. Note slight edema in basal cell layers, disruption of the periodic acid-8chiff-positive basement membrane by mononuclear cell in close contact with necrotic keratinocyte (satellite cell necrosis). Fig. 5. Severe ocular sequelae of TEN with squamous metaplasia of conjunctiva and corneal pannus resulting in blindness.

lymphocytic infiltration of salivary glands indistinguishable from that observed in Sjogren's syndrome. S9 This sjogren-like sicca syndrome, inturned eyelashes, epithelial proliferation with squamous metaplasia, and neovascularization of the conjunctiva and the cornea contribute to a post-TEN ocular syndrome with punctate keratitis and formation of a corneal pannus. Photophobia, burning eyes, visual impairment, and even blindness may result from these lesions s7 -6o (Fig. 5). COMPLICATIONS Specific visceral involvement

Fever and fiulike symptoms often precede the occurrence of mucocutaneous lesions by 1 to 3 days. High fever is usual and may persist until complete skin cicatrization, even in the absence of secondary infection. 22 A sudden drop in temperature is more indicative of severe sepsis than is fever. 2s Asthenia, skin pain, and anxiety are extreme. Agitation and confusion are not uncommon and often herald hemodynamic complications or sepsis. Multisystemic involvement is usual in TEN, and it may be that some of the other organic manifestations of TEN are due to the same process that destroys the epidermis.

Gastrointestinal tract. Disseminated mucosal erosions have been occasionally reported to occur in the gastrointestinal tract.5,9,29,36,61-64 The malpighian epithelium of the esophagus is the most commonly involved and leads to dysphagia and sometimes to bleeding. Endoscopy shows diffuse erosions macroscopically indistinguishable from peptic esophagitis. A mucosal biopsy specimen ofthe esophagus discloses a pattern of intraepithelial inflammatory cells with necrosis of individual epithelial cells, similar to the changes in early skin lesions. 64 Esophageal strictures may complicate TEN.5, 62 The prevalence ofesophageal involvement is probably grossly underestimated because dysphagia from oropharyngeal lesions may mask dysphagia of esophageal origin. Overt intestinal symptoms are uncommon and manifest as nonspecific exudative bloody diarrhea. A profuse protein-rich diarrhea may increase fiuid losses and hypoalbuminemia. The endoscopic appearance is reminiscent of ulcerative or pseudomembranous colitis, with histologic features that resemble those of the intestinal lesions of GVHD.64 In one of our patients, acute intestinal involvement was followed by a severe chronic diarrhea that required intestinal resection (unpublished data).

1044 Roujeau et al. Approximately half of TEN patients have a slight increase of serum aminotransferase levels up to two to three times the normal values. Overt hepatitis is present in about 10%22,65 and may be the result of drug-induced liver damage, or damage from sepsis or shock. A few cases of acute pancreatitis have been reported. 65 -67 An increase in serum amylase and lipase is often present during the first few days, without other evidence of pancreatic involvement. The few computed tomographic scans that we have performed in patients with raised serum amylase levels were normal (unpublished data). Respiratory tract. A few cases of expectoration of cylindric bronchial casts have been taken as indirect evidence of a specific involvement of the respiratory epithelium. 5, 28, 33 Tracheal and bronchial erosions have been observed in several bodies at autopsy. Clinical respiratory involvement is frequent and worrisome. Hyperventilation is usual with mild hypoxemia in blood gas. Subclinical interstitial edema is often noticed in early chest x-ray films with the frequent (30%) development of clinically apparent pulmonary edema during correction ofhypovolemia. Hemodynamic studies demonstrated that edema was linked to increased alveolocapillary permeability (unpublished observations). In 10% to 20% of patients alterations in pulmonary function will require artificial ventilation. So many factors are involved in the deterioration of lung function that it is difficult to accept that specific lesions of the alveolocapillary wall may exist. Blood. I:Iematologic abnormalities are almost always found. 68 , 69 Anemia is present in virtually every patient because of many factors, including erythroblastopenia. We have observed lymphopenia in 90% of patients, caused by the selective and transient depletion of CD4+ T helper lymphocytes.70, 71 Neutropenia indicates a poor prognosis72 and is observed in about 30% of patients. Thrombopenia is observed in 15%. Eosinophilia is unusual. Disseminated intravascular coagulation has been described. 21 , 73 Kidney involvement. Although disturbances of kidney function are frequent, only rare cases of glomerulonephritis have been reported,74 and it is not at all certain that this glomerulonephritis is the result of specific TEN-related changes. Most TEN patients with renal disease have prerenal azotemia or acute tubular necrosis that results from the hemodynamic alterations, which will be discussed later.


Consequences of extensive epidermolysis ("acute skin failure") Many of the visceral manifestations observed in TEN are the same as in extensive burns. These manifestations are not specific but are the result of skin loss and are proportional to the extent of epidermal destruction. Although all the mechanisms of the systemic effects of widespread epidermal destruction have not yet been elucidated, the skin is now understood to be a complex organ with many regulatory functions. The concept of "acute skin failure"75 may help to explain both the severity and the multiplicity of organ failure that results from widespread skin loss. Fluid loss. The most classical function of the skin is the barrier role of the stratum corneum that prevents the loss of body fluids and the entry of components from the environment. The blister fluid of TEN contains approximately 40 gm/L of proteins and electrolytes in a concentration similar to that of plasma. The total daily cutaneous fluid losses averages 3 to 4 L in adult patients with epidermal necrolysis of more than 50% of their body surface area. 25 Electrolyte, fluid, and protein losses result in a reduction of intravascular volume. The first consequence is a decrease in urinary output with a hyperosmolar urine and raised serum levels of urea nitrogen and creatinine (functional renal failure). If not corrected, hypovolemia may lead to hemodynamic alterations and renalfailure. Under these conditions, bacteremia may easily produce irreversible septic shock. Infection. Necrotic epidermis and exudates support the growth of a wide spectrum of microorganisms despite isolation and dressings. The destruction of the mechanical barrier provided by an intact integument and the alterations of the normal host defense mechanisms action concert to make patients with widespread skin erosions susceptible to systemic infection from both exogenous and endogenous sources. Severe systemic infections are the main cause of death in TEN. 22, 29, 36 During the first few days, skin lesions are usually colonized by Staphylococcus aureus. Later they are invaded by gram-negative rods from the digestive flora, especially Pseudomonas aeruginosa. S. aureus that causes systemic sepsis usually originates from the skin. Central catheters and venous lines carry a high risk of promoting systemic infection, especially when inserted near or through skin lesions. On the other


hand, sepsis from digestive flora may occur without concomitant skin colonization by the same rods. 22 The use of steroids and broad-spectrum antibiotics may contribute to the selection of less common pathogens, such as Candida albicans. 36 Cutaneous infection may slow the reepidermization, favor the occurrence of keloids, and may even result in cellulitis.76 Impaired thermoregulation. Usually patients have fever and shivering, even in the absence of overt infection. Interleukin 1 (IL-I) of epidermal origin77 probably is important in inducing fever. 78 Shivering reflects the high level ofmuscular catabolism needed to maintain an elevated central temperature despite the tremendously increased caloric losses through the diseased skin. In some patients (mainly in young children or infants) the body temperature is dependent on the external temperature, and hypothermia may be corrected by raising the room temperature. In adults, hypothermia is infrequent and is usually a harbinger of severe infection and irreversible septic shock. Altered immunologic functions. Various alterations in the immune response observed in patients with extensive burns79 have also been found in TEN patients.?o, 80 They include decreased chemotactic and phagocytic activity of granulocytes, depletion of serum immunoglobulins, decreased number of CD4 T lymphocytes in the blood, impaired responsy of lymphocytes to recall antigens in vitro, decreased cytolytic T-cell responses and natural killer activity. The respective roles of specific alterations in the "skin immune system" and of nonspecific changes secondary to stress are not yet known. IL-l and tumor necrosis factor alpha produced by keratinocytes as well as other mediators are probably involved in the systemic effects of the widespread necrolysis of the epidermis. In burn patients, these alterations in the host defense mechanisms are proportional to the extent of epidermal destruction and correlated with septic complications and with survival. Similar correlations can be expected in TEN patients. Increased energy expenditure. The metabolic response to widespread skin lesions has been extensively studied in burns. 79 , 81 82 IL-l of epidermal origin plays a key role as the mediator of the acute phase response and, with catecholamines and other catabolic hormones, contributes significantly to burn hypercatabolism. IL-l probably plays a role in the hypermetabolic state of TEN. We have found high

Toxic epidermal necrolysis 1045 levels of biologically active IL-l in the blister fluid of patients with TEN (unpublished data). The following considerations, derived from published data about burns, also apply to patients with TEN: (1) Energy expenditure increases with the extension of skin lesions to reach twice the basal metabolism when 50% or more of the body surface is involved. (2) Environmental temperature below 25° C increases energy expenditure. (3) Protein loss, from exudative skin lesions and increased urine nitrogen from hypercatabolism, may reach 150 to 200 gm per day. (4) Inhibition of insulin secretion and/or insulin resistance in peripheral tissues is frequent, resulting in elevated plasma glucose levels and often in overt glycosuria. 22 These disorders of the glycoregulation lead to increased amino acid breakdown as a source of energy and to increased caloric and fluid losses. PROGNOSIS

In contrast with SSSS, TEN is a disease associated with severe morbidity and high mortality.5, 6, 9. 1 In the first case reports, when these two diseases were considered to be the same entity, the overall mortality rate was roughly 25%.4 In recent studies the mortality rate was near zero for SSSS.83 In some recent reports of a limited number of TEN cases, as many as 60% to 70% of the patients died. 36, 72 However, when larger series ofTEN (> 10 patients) were compiled, the mortality rate averaged 30%.22 Sepsis, mainly from S. aureus and P. aeruginosa is the leading cause of death. 21 ,22, 29,36,72 Other important causes are pulmonary edema, pulmonary embolism, and gastrointestinal bleeding.22, 28, 29, 36 Analysis of prognostic factors showed that three variables were particularly important: patient's age, percentage of denuded skin, and blood urea nitrogen. 22 Age and the percentage of involved skin are well-known prognostic factors for burn patients. 79 Leukopenia and neutropenia are also significantly. associated with a poor prognosis. 72 However, the prognostic value of these factors disappeared when all criteria were submitted to a multivariate analysis. 22

°

ETIOLOGY

The role of drugs In his first description of TEN in 1956, Lyelll considered that at least one ofhis four cases could be

1046

Roujeau et al.

Fig. 6. Widespread bullous fixed drug eruption. Note well-demarcated round blisters without erythema multifonne-like lesions.

attributed to exposure to a particular drug. Mter the distinction was made between SSSS and TEN, it became generally accepted that TEN was a drug reaction. 5 In fact, cases occurring without drug exposure have been so rare as to cast doubt on the reliability of the information about drug intake obtained from patients denying exposure. In our own series of 87 patients, only three patients denied any drug intake before the onset ofTEN. 27 In a consensus workshop held in October 1985,20 it was agreed that, with the exception of GVHD, "reaction to drugs was to date the only documented cause of TEN." This conclusion, which recognized the existence of "idiopathic" cases, was derived more from the "accumulation of clinical experience"(Lyell) than it was based on scientific evidence. Proof that the disease is due to a drug reaction is usually lacking. There are no reliable in vitro or in vivo tests to demonstrate a causal relation.5,9,84,85 Only a few cases ofrecurrence ofTEN from readministration of the same drug have been published4, 15, 27, 34,86-88 and in many cases a challenge with the suspected drug failed to reproduce the disease. Ten patients cured ofTEN were administered the suspected drug 3 weeks to 3Vz years later. Only one patient, whose disease had been attributed to carbamazepine, had the disease a second time, fortunately in a mild fonn. 34 Exceptional cases of TEN have been attributed to severe bacterial infection. One case, attributed to Streptococcus pyogenes septicemia,89 in fact had the pathologic characteristics of SSSS. Two cases have


been linked to Klebsiella pneumoniae sepsis,90, 91 but with no convincing evidence that sepsis was a direct causal factor.· A few cases attributed to viral infection or to immunization are quoted in all reviews on TEN.4, 7,8,10 All these cases occurred in children and were reported before or soon after the distinction between SSSS and TEN was established. These reports usually did not mention the results of skin biopsies that would allow a retrospective classification. Thus these cases do not challenge the concept that drugs remain "the only documented cause ofTEN." Drugs as the cause of TEN must be taken in a broad sense because food additives,4,92 fumigants, 4093 and contact with chemicals8, 94-97 have also been implicated in a few cases. However, the vast majority of cases are related to chemicals systemically administered as drug therapy. The drugs repeatedly implicated in the literature (i.e., quoted several times in all or most series) are sulfonamides, anticonvulsants, allopurinol, pyrazolone derivatives, and lessfrequently other NSAIDs (Table I). Sulfonamides. Sulfonamides are the most frequently involved drugs and account for approximately one third of drug-related cases compiled in published series. 4,15, 27, 28, 32-34, 36, 99 Their relative proportion has decreased with the years. Long-acting sulfonamides were from the beginning suspected of carrying an higher risk. That risk has been emphasized by the many cases of TEN that complicated two compaigns of mass prophylaxis with long acting sulfonamides. In 1967 in Morocco, sulformethoxine was distributed to 110,000 persons for the prevention of meningococcal meningitis. Skin reactions were observed in 997 persons; several dozen cases of Stevens-Johnson syndrome and TEN resulted in 11 deaths. IS The reactions occurred 7 to 28 days after the first ingestion of sulfonamide. In 1981 in Mozambique, the distribution of sulfadoxine to 149,000 inhabitants ofBeira for the prevention of cholera was followed by 22 cases of StevensJohnson syndrome with three deaths. 100 When a combination of sulfadoxine and pyrimethamine (Fansidar) was used for malaria prophylaxis, the incidence of severe skin reaction was estimated to reach 1 in 5000 to 10,000 population with fatalities in 1in 20,000 to 50,000. 101 ,102 Now the combination drug trimethoprim-sulfamethoxazole, the most widely used sulfonamide, is also the most frequently



Table I. Distribution of the drugs implicated in the main series of toxic epidermal necrolysis

Series

Drug-related cases

Sulfonamides

Pyrazolones

Anticonvulsants

Allopurinol

Lye1l4 (1967) Kauppinen 34 (1972) Huriez et aI,33 (1972)

36 36 23

15 28 7

4 3

2 3 2

0 0 0

Bjornberg28 (1973) Halebian et a1. 36 (1983)

15 18

5 5

2 0

2 4

0 2

Chan 29 (1984)

15

1

3

3

3

Ruiz-Maldonado 21 (1985)

21

3

8

10

0

Heimbach98 (1987)

19

4

0

13

0

Sl

~

16

-.1-

.4

250

86 (34%)

44 (18%)

46 (18%)

9 (3.6%)

Guillaume et al. 27 (1987) Total

associated with TEN.27, 32, 40, 99 However, the risk seems much lower than with long-acting drugs. There has been estimated to be 0.2 case of TEN and 0.1 case of Stevens-Johnson syndrome per million daily doses. 32 Even if most cases are probably due to sulfamethoxazo1e, trimethoprim alone may also be a potential cause. 103 Anticonvulsants. In this therapeutic class, barbituphenytoin,28, 31, 34, 39, 87, 98, 104-107 rates,4, 27-29, 33, 34, 98, 104, 108 and carbamazepine24, 27, 31,33,34,43 have all been cited as inducing TEN. Phenytoin probably carries the highest risk. 32,40 Anticonvulsants are the main cause of drug-induced TEN in children. 31 ,109 In adults TEN in patients who are receiving anticonvulsant therapy is often associated with concurrent radiotherapy or chemotherapy for malignant brain tumors. 34,40 NSAIDs. Phenylbutazone caused one of the four original cases described by Lyell. 1Pyrazolone derivatives have been cited in most series and accumulated clinical experience has indicated them to be an importantcauseofTEN.4, 27-29,31,33,34,110-112 More recently, benoxaprofen112,113 and an oxicam derivative, isoxicam,27,114-116 have been implicated in

8

Other noticeable drugs (No. of cases)

Antibiotics (6) Chloramphenicol (1) Penicillin (3); cyclines (3) Penicillin (3) Erythromycin (3); ampicillin (1); naprosyn (1) Cyclines (2); "Chinese herb" (1); penicillamine (1) Penicillin (5); aspirin (1) Penicillin (3); ampicillin (1); disulfiram (1); isoxicam (5) Piroxicam (5); other NSAIDs (3); chlormezanone (3)

many cases of TEN. Every drug in all NSAID classes has been involved in at least a few cases27 , 65,112,117-120 but they appear to have different risks. 116 NSAIDs with long half-lives (pyrazolones, oxicams, fenbufen, sulindac) are suspected to have higher risks. In France, the risk linked to isoxicam was about 10 times higher than the risk linked to piroxicam,40 despite identical indications, closely related chemical structures, and the comparable long half-lives of these two oxicams. 116 Allopurinol. Allopurinol has been implicated in many series and case reports27 , 29, 36, 61, 110,121-123 but because it is so widely used, it is at a lower level of risk than other drugs classically associated with TEN.32, 40 Furthermore, allopurinol is often taken in association with colchicine, which may also provoke

TEN.

Other drugs. More than 100 other compounds have been blamed in at least one observation,5, 7, 9,10 from traditional Chinese herbs 29 to cancer chemotherapy.45, 124, 125 Antibiotics and analgesics or antipyretics deserve special mention. Attributing a case to these drugs is usually difficult because they are often administered for flulike symptoms that could be the early manifestations ofTEN. However,


1048 Roujeau et al. accumulated clinical experience has drawn attention to the probable responsibility of }3-lactam antibiotics24, 28, 31, 98, 126, 127 and, perhaps more particularly, of oral penicillins. 35 , 36,98, 128 In a recent German epidemiologic study ofTEN, ampicillin-related cases had an higher incidence per million defined daily doses sold than did trimethoprim-sulfamethoxazole. 32 In a similar French study, ampicillin was just a little belowtrimethoprim-sulfamethoxazole for the same cases/sales ratio. 4o Almost all other antibiotics have been implicated, including isoniazid,73 ethambutol,86 rifampicin,27, 129 cyclines,29, 67 erythromycin,36, 130 vancomycin,45 quinolones,32 and griseofulvin. l31 Analgesics and antipyretics, acetaminophen,35 and acetylsalicylic acid 21 , 24, 35 are occasionally cited in the literature. For most antibiotics a causal link should not be too readily accepted. In the largest series of TEN cases published,27 a drug was found to be probably responsible in 67 of 87 patients (77%). NSAIDs (mainly phenylbutazone and oxicam derivatives) were the most common cause of TEN in this series with 29 cases (43%), followed by sulfonamides with 17 cases (25%). Only seven cases (10%) were attributed to anticonvulsants. Aspirin and various antipyretics, analgesics, and antibiotics were infrequently implicated in this series, or associated with more likely suspected drugs. Assessment of drug responsibility There is no reliable test to prove the link between a single case and a specific drug. 5. 9 Drug challenge must not be performed because even if rarely positive,34 it may be life-threatening. 5 Lymphocyte transformation test in vitro has no value in TEN.lS4 Other in vitro tests have not been adequately studied. The usefulness and the safety of skin tests remain to be proved. 85 , 128 Thus the determination of the "culprit" drug relies on clinical presumption, mainly on the basis of timing of the reaction and the knowledge of other reactions attributed to the same or to a related drug. In the largest patient series, a mean time of 14 days from initial drug administration to the onset of TEN was comparable for all implicated drugs. 27 Although longer or shorter times do not completely exclude the responsibility of a drug, we suggest considering as "first suspects" drugs begun within 1 to 3 weeks before the onset of TEN.

ASSOCIATED DISEASES

Because TEN is related to drugs, patients may be expected to have underlying diseases. Many authors have emphasized the frequency of recent infections,5,9, 10,34 even in cases not related to antimicrobial drugs. However, infections with herpesvirus, M. pneumoniae, or Yersinia, which have been linked to the cause of Stevens-Johnson syndrome, 16 are not, or only very rarely, found in TEN.40 Several cases of TEN have been reported in patients with systemic lupus erythematosus. 28 ,29, 36, 98,129.132-134 Although rare, the simultaneous occurrence of these two diseases is too frequent to be simply coincidental. Other reported associations include leukemias,21,35 lymphomas,4, 124, 135 ulcerative colitis,27, 86,136 and Crohn's disease. 27 A high proportion of adult cases of TEN related to anticonvulsants occur in neurosurgical settings, in patients treated for brain tumors or head injury.39,40 It is not clear whether TEN is induced only by the drugs used for the treatment of these diseases or if the disease itself increases the risk. PARTICULAR SITUATIONS Bone marrow transplantation

A few cases ofTEN have been reported after bone marrow transplantation; therefore it has been postulated that TEN is the most severe cutaneous manifestation of acute GVHD.137-143 Several facts support this hypothesis. TEN has been observed during acute GVHD in patients taking no drugs (i.e., acute GVHD in clinical situations other than bone marrow transplantation)140; TEN has been described in an animal model of cutaneous acute GVHD.144 . The incidence of TEN among patients having bone marrow transplantation has not been yet evaluated and it seems probable that TEN could occur more frequently than previously thought. In our institution we observed nine cases of TEN among 154 bone marrow transplant recipients (6%) during a 6-year period. 145 The incidence is too high for this association to be a coincidence. TEN in transplant patients was clinically similar to TEN in other patients, except in transplant patients the disease lead a more insidious onset and a slower rate of progression of the skin lesions. Histopathologic study of early cutaneous lesions showed a variable degree of vacuolar alteration of basal cells, dyskeratosis of epidermal cells, satellite cell necrosis, and a superfi-


cial mononuclear pervascular infiltrate. In no case could the pathologist definitively attribute the histologic changes either to acute GVHD or to a drug reaction. The similarity between histopathologic findings in drug-induced TEN and acute GVHD has been previously reported. 43 , 44,143 All of our patients were receiving multiple drug therapy. They appeared to fit in two groups according to both the extracutaneous GVHD grading and the study of possible drug liability. In five cases TEN appeared clearly related to acute GVHD whereas an adverse reaction to sulfonamides was much more likely in the other four patients. Whatever the pathogenesis of TEN after bone marrow transplantation (drug-induced or GVHD-related), it is associated with a poor prognosis. Our nine patients died. All but one 141 ofthe cases reported in the literature had a fatal outcome. Further study of the relation between TEN and acute GVHD could lead to a better understanding of the pathogenesis of drugrelated TEN.143

Acquired immunodeficiency syndrome Patients with the acquired immunodeficiency syndrome (AIDS) have a higher incidence of skin drug reactions than expected. 146 Increased rates of drug eruptions are reported to occur more frequently during sulfonamide therapy147 and. probably occur with other agents. 148 During the treatment of Pneumocystis carinii pneumonia with high doses of trimethoprim-sulfamethoxazole, skin rashes occurred in 40% to 60% of patients with AIDS versus 15% of patients with other immunodeficiencies. 149 By comparison, the rate of skin reaction to conventional doses of trimethoprim-sulfamethoxazole is 3% to 4% in immunocompetent patients. 38 Patients with AIDS also seem at higher risk of severe druginduced bullous reactions. Several cases of StevensJohnson syndrome complicating prophylaxis of P. carinii pneumonia were reported up to 1986. 150,151 More recently a fatal case of TEN was reported after treatment with Fansidar 152 and another fatal case was reported related to trimethoprim-sulfamethoxazole. 153 In our institution we had observed six cases of Stevens-Johnson syndrome and six cases of TEN in patients with AIDS at a time when the total number of patients with AIDS in Paris area was below 1500. All cases were related to sulfonamides: sulfadiazine in six cases, trimethoprim-sulfamethoxazole in four, and Fansidar


in two. The only clinical peculiarities were a more insidious onset and slower extension, reminiscent of cases after bone marrow transplantation. The evolution was surprisingly favorable with rapid cutaneous healing, no deaths, and only one case of ocular sequelae. In the future, with the increasing prevalence of AIDS, AIDS patients may represent a significant proportion of TEN cases. TEN in children After SSSS was distinguished from TEN, the oversimplification was often made that in children acute acquired epidermolysis was staphylococcal whereas in adults it was related to drugs. In fact, TEN is only slightly rarer in children than in adults;32 it may occur even in neonates. 90,91 One case was attributed to maternal exposure to a drug. 154 Features ofTEN in children include a balanced sex ratio,21, 27,109 a higher proportion of idiopathic cases,27 the importance of anticonvulsants as inducers,21, 109,155 and, with the exception of one series,21 a much better prognosis than in adults with a similar extention of lesions. DIAGNOSIS SSSS affects mainly infants and children and rarely adults (who usually have severe underlying diseases).5, 8,10,12,83 Mucous membranes are not affected (with the exception offrequent conjunctivitis). A faint continuous erythematous rash extends in a few hours. Over this rash arise large sheets of epidermal detachment with a positive Nikolsky sign. There are no target, erythema multiforme-like lesions. The erosions show little or no oozing, so that even clinically they appear superficial.Histologically the separation lies within and beneath the stratum granulosum. The microscopic examination of a frozen section of detached epidermis, or preferably of a biopsy specimen, allows a rapid diagnosis. 41 SSSS is provoked by toxins ll (epidermolysins) produced by some groups ofS. aureus (mainly phage group2). The staphylococci are usually present in a purulent focal infection, often in the upper respiratory tract, but not in the skin. In contrast, in TEN S. aureus is the most prevalent organism that rapidly invades the lesions. Antibiotics stop SSSS epidermolysis in a few hours and healing occurs in a few days. Recently there has been a report of proven SSSS that showed evidence of subepidermal c1eavage. 156 Therefore it now seems possible to confuse exceptional

1050 Roujeau et al.

cases of SSSS with TEN on a histologic basis. Toxic shock syndrome (TSS)157-159 is primarily a disease of menstruating women. The usual cutaneous manifestations of TSS (diffuse erythema followed by secondary desquamation of the skin of the hands and feet) are different from those of TEN. Only exceptional cases of TSS with blisters could be confused with TEN.160 Kawasaki disease (mucocutaneous lymph node syndrome)83 occurs almost exclusively in children younger than 10 years of age. The initial rash may be morbilliform, scarlatiniform, or include erythema multiforme-like lesions. A delayed desquamation then occurs (from 1 to 2 weeks) and not by epidermal separation or blistering. Oral changes are characterized by bright red diffuse erythema and a strawberry tongue in contrast with the erosions of erythema multiforme. Disseminated pustular eruptions, acute pustular psoriasis, von Zumbusch-type, drug-induced, or postviral pustular eruptions may resemble TEN when pustules are confluent on a generalized erythroderma.161.l63 Histologic features are distinctive, with subcorneal spongiotic pustules and often a mild vasculitis. Second-degree burns, especially chemical ones, and bullae in comatose patients may resemble TEN.5,9 Mucous membranes are not usually involved and the distribution of the lesions is limited to areas exposed to the burning agent or to pressure areas in comatose patients. Clinically, a fixed drug eruption, when generalized, may closely mimic TEN (Fig. 6). In fact, one of the patients Lyell included in his original description of TEN may well have had a fixed drug eruption. The well-demarcated round lesions, the lack of erythema multiforme-like target lesions, the rarity of mucous membrane erosions, and a history of previous eruption with the same drug indicate generalized fixed drug eruption, a rare disease, probably often diagnosed as TEN.34, 164 The pathologic features of the two disorders are similar. Several drugs, including barbiturates, sulfonamides, and pyrazolone, may induce both diseases. Residual pigmentation and constant recurrence on provocation testing (best avoided in generalized cases) are hallmarks of a fixed drug eruption. 34 PATHOPHYSIOLOGY

TEN is generally considered to be an allergic reaction to drugs. 5, 8, 10 Theoretically there is no doubt that most drugs and/or their reactive metabolites


can behave as haptens capable of eliciting immune reactions after combination with "carrier" proteins. 165, 166 Some drug reactions are clearly mediated by an immune response (e.g., 19B-mediated anaphylaxis to iJ-lactam antibiotics166, 167). In TEN, however, direct evidence of an immunologic mechanism is still lacking and the hypersensitivity hypothesis is supported only by indirect arguments. The time interval between the beginning of drug intake and the reaction (mean time of 12 to 14 days for the first occurrence,15,22 less than 2 days and sometimes a few hours in rare recurrences 4, 15,27, 34, 86.88) is suggestive of primary sensitization and immunologic memory. The association of TEN with systemic lupus erythematosus 28 , 29, 36, 98,129,132·134 and other autoimmune disorders 22,29 and the occurrence of a Sjogren-like syndrome after TEN59 also support an immune reaction. The strongest argument is derived from the association of TEN with GVHD in humans after bone marrow transplantation 137-143 and in hamsters with cutaneous acute GVHD.144, 168 In hamsters, epidermal sloughing similar to TEN develops around the sites of injections of parental lymphocytes in the skin of first-generation hybrids. Surprisingly, epidermal necrolysis began several days after the peak of local inflammation produced by the cutaneous acute GVHD. This experimental model suggests that TEN may be initiated by a cellular immune reaction but also that it involves more complex steps than ordinary delayed hypersensitivity. Cytotoxic antibodies are probably not involved in epidermal destruction. The report of immune deposits on the basal cells in two patients48 has not been confirmed and the results of all further direct immunofluorescence studies have been negative. 46 ,47 There is no evidence of complement activation in the acute phase of TEN.46, 47 Serum antibodies that react with the cytoplasm of epidermal cells are occasionally found after recovery from TEN47, 169 but they are nonspecific and probably are a consequence of the disease. 170 "Drug-dependent" antibodies that react with autologous mononuclear cells only in the presence of the culprit drug have been reported in two patients,I71, 172 but these findings have not been confirmed. 47 The lack of evidence that specific antibodies are associated with TEN contrasts with the frequent finding of immune deposits in erythema multiforme and StevensJohnson syndrome,16 especially in postherpetic cases. 173 Therefore it appears that the postinfectious and drug-induced variants of the erythema multi-


forme spectrum of diseases develop by different mechanisms. Cell-mediated cytotoxic reactions against epidermal cells would more easily explain the pathologic finding of "satellite cell necrosis"43,44 (i.e., close contact between a necrotic keratinocyte and a mononuclear cell) in the early phase of TEN as in cutaneous acute GVRD. Immunohistologic studies 174 have shown that keratinocytes express HLA-DR antigens (personal observation), that CD4 T lymphocytes accumulate in the papillary dermis and that the epidermis is invaded by macrophages and T lymphocytes with a CD8 phenotype. These findings are consistent with a hypersensitivity reaction and reminiscent of the acute GVHD pattern. 143, 175 Several authors described an "allergic reaction" to drugs in TEN patients by skin testing 128 or in vitro reactions. 85 Unfortunately, adequate controls (e.g., patients who took the drug without an adverse reaction) were usually missing. When we used such controls, we were unable to demonstrate a specific reaction of patient lymphocytes to culprit drugs in vitro.84 Furthermore, the occurrence of TEN in patients with AIDS,who are usually unable to have cutaneous reactions to recall antigens on skin testing, strongly challenges the concept of a classic type of delayed hypersensitivity to drugs. An alternative hypothesis would implicate a toxic effect of the drug and/or one or more reactive metabolite, accumulated because of abnormal metabolic pathways. Hepatotoxicity from phenytoin may result from an inherited defect in the detoxification of the arene oxide metabolites of the drug. 176 Impaired sulfoxidation increases D-penicillamine toxicity in rheumatoid arthritis. 177 Slow acetylators are more prone to certain kinds of drug reactions, including hydralazine-induced systemic lupus erythematosus, and skin reactions to sulfonamides. 178 In prospective TEN patients slow acetylation of sulfonamides could promote the oxidative pathway by cytochromes P450 and the production ofreactive metabolites. 179 Thesereactive compounds could be toxic for epidermal cells or more prone to behave as haptens than the native drug or usual metabolites. 165, 179 The observation of very high serum levels of drugs in several cases of TENI80 emphasizes the need for studying systemic and cutaneous drug metabolism in these patients. The extreme rarity of the disease and the usually negative results of provocation tests are probably best explained on the basis of the combination of

Toxic epidermal necrolysis 1051 several concomitant factors (Lyell's "jackpot hypothesis"). These could include constitutional factors such as the genetic background (regulating the immune responsiveness and the pathways of drug metabolism) and temporary factors such as viral infection, altered immune reactivity, and drugs. These factors might combine either to liberate autocytotoxic cells or to enhance a specific immunologic reaction against keratinocytes modified by the drug or its metabolite(s). IL-l released by lysed epidermal cells and other lymphokines may contribute to fever, other constitutional symptoms, and complications.

TREATMENT Because TEN is a life-threatening disease, management of patients must be undertaken as soon as possible in intensive care units (ICUs) or in bum units with the combined efforts of an ICU team, dermatologic and ophthalmologic staff, and specialized nurses. Medical transport to the leU requires particular attention to the skin (i.e., aseptic handling, sterile fields, avoidance of any adhesive material) and immediate fluid replacement. Table II contains initial management guidelines for patients admitted to the hopital for the treatment of TEN. Symptomatic treatment The main principles of symptomatic therapy are the same as for major bums. 181 They include massive fluid replacement, nutritional support, antimicrobial policy, and local treatment. Fluid management. During the first few days fluids must be replaced intravenously. It is preferable to use peripheral veins at a distance from affected areas rather than central venous lines. As in bum victims the predicted volume of replacement is proportional to the area of skin lesions. However, the fluid requirements of TEN patients are less than those of patients with burns covering the same area.7 5. 98,182 Our current regimen (Table III) contains two thirds to three fourths of the fluids suggested for the first 24 hours for most burn formulas. 183 The intravenous fluids given during the first 24 hours include macromolecules and saline solutions. Phosphate salts are needed to correct the invariably present hypophosphatemia. 25,36 If left uncorrected, hypophosphatemia increases insulin resistance, alters the neurologic status, and impairs diaphragmatic functions. The rate and amount of fluid administration must be adjusted daily according to the patient's clinical status. Invasive hemody-

1052

Roujeau et al.

Table n. Emergency management of toxic epidermal necrolysis Handle the patient in a warm environment; care should be taken to avoid any skin trauma Insert a peripheral venous line and begin administra-

tion of macromolecular solutions

Evaluate the general status, paying particular atten-

tion to: Weight Respiration rate Urinary output Consciousness

Calculate the extent ofepidermal detachment (raw

dermis plus blisters and areas of positive Nikolsky sign), using burn tables or the rule of nines

Refrain from prescribing corticosteroids Withdraw all drugs (at least as many as feasible) Obtain photographs and a skin biopsy (with emer-

gency examination of frozen section if SSSS is suspected) Give bland eye drops before ophthalmologic adVice is obtained Reassure the patient about the transient nature of the cutaneous lesions and give tranquilizers if pulmonary function allows. Direct the patient as soon as possible to a burn unit or to a specialized intensive care unit

namic monitoring is usually avoided. On the following days, oral fluids are progressively increased whereas intravenous doses are decreased to shift to exclusive nasogastric support. This is rarely possible before the second week, only a few days before the skin heals. Nutritional considerations. Aggressive nutritional support is begun as soon as possible to minimize protein losses and to promote healing of cutaneous lesions.81,82 N asogastric feeding with a silicone tube is preferred to parenteral nutrition in alert patients. Two to 3 gm/kg body weight of protein 15 is given daily to adults and 3 to 4 gm/kg body weight to children. Acutely ill patients may have impaired gastric emptying,25 with the risk of regurgitation and flooding of airways. Residual gastric volume should be checked by periodic aspiration. If more than 50'ml are present, feeding should be stopped. Because of impaired glycoregulation, high doses of intravenous insulin are frequently required. 25 Antimicrobial pollcy. Infection can arise any time during the course of TEN. Sterile handling of patients is a minimal requirement to decrease the risk of nosocomial infection, and several authors have emphasized the need of reverse-isolation nursing techniques. 182, 183 All catheters, including nasa-


gastric and urinary tubes, should be changed and cultured at regular intervals. We routinely use painting and bathing with topical liquid antiseptics such as 0.5% silver nitrate and 0.05% chlorhexidine and monitor their efficiency by semiquantitative bacterial sampling on several sites of altered skin every other day. Silver sulfadiazine, popular in burn units, is avoided because sulfonamides are frequently implicated in the etiology of TEN. Prophylactic antibiotics are not recommended. 25 ,79,183 The diagnosis of sepsis is difficult and the decision to administer systemic antibiotics must be carefully deliberated. Some indications for antibiotic treatment include increase in the number of bacteria cultured from the skin with selection of a single strain, sudden drop in fever, and deterioration in the patient's overall condition. There is no ideal antibiotic and the choice will be directed against the bacterial strains present on the skin (i.e., S. aureus during the first few days and gram-negative rods later).22 The pharmacokinetics of antibiotics are altered by the decreased level of serum protein, renal and hepatic dysfunctions, and fluid and protein losses through the skin. As in burn patients the administration of unusually high doses of antibiotics may be required to obtain serum levels within the therapeutic range. 184 Frequent determination of serum levels is needed to adjust the dosage schedule. Environmental temperature. Environmental temperature should be raised t030° to 32 0 C. This will reduce caloric losses through the skin and the resultant shivering and stress. Heat loss can also be limited by raising the temperature of antiseptic baths (35 0 to 38 0 C), and by the use of heat shields, infrared lamps, and an air-fluidized bed. The airfluidized bed also has a drying antiseptic effect on the microflora of the skin and improves the comfort of the patient. 185, 186 Because patients on air-fluidized beds have an increased evaporative water loss, we use these beds only after correction of major hydroelectrolytic disturbances. Floating on an air-fluidized bed has a sedative effect, which is beneficial in most patients but in a few patients may result in mental confusion. Other supportive therapies. Because thromboembolism has been a cause of morbidity and death in our patients,22 we recommend effective anticoagulation with heparin for the duration of hospitalization. This does result in increased bleeding from the skin, but the increase is usually mild and does not require additional transfusions. Antacids reduce the


incidence of gastric bleeding. Pulmonary care includes aerosols, bronchial aspiration, and physical therapy. Emotional and psychiatric support must not be forgotten. Tranquilizers such as diazepam are used liberally, if the respiratory status permits. Local treatment By analogy with burns, some authors have advocated extensive debridement of nonviable epi· dermis 187 followed by immediate wound cover with biologic dressings, such as porcine cutaneous xen· ografts, cryopreserved cutaneous allografts, and amnionor collagen-based skin substitutes,98, 136, 182,188,189 We recommend a more conservative approach. We leave in place the involved epidermis that has not yet peeled off and use biologic dressings only on the raw dermis. Hyperbaric oxygen has also been proposed to improve healing. 190 Ocular lesions require daily examination by an ophthalmologist. Antiseptic and/or antibiotic eye drops are instilled every hour or two and developing synechiae are disrupted with a blunt instrument. Oral and nasal debris is removed and the mouth is sprayed with antiseptics several times each day. Specific therapy To date there is no specific treatment for TEN. For 30 years corticosteroids have been used and are still recommended by some authors. 7, 191,192 Pulse therapy with "megadoses" of intravenous corticosteroids has been recently proposed.106 The only rationale for steroid therapy is the unproved hypothesis of an allergic reaction to drugs. A few uncontrolled trials of treatment have been carried out in patients with erythema multiforme; no benefit from corticosteroid therapy has been demonstrated. 2o, 193, 194 In TEN, not only has the effectiveness ofcorticosteroids never been demonstrated5but many cases have occurred during treatment with high doses of corticosteroids for preexistent diseases. 8,93, 94,129,134,187,195 A recent epidemiologic study found that 9% of all cases observed in France occurred in patients treated with corticosteroids. 4o These observations strongly suggest that corticosteroids do not prevent the occurrence and extension ofthe epidermal necro1ysis. Two uncontrolled retrospective studies found that TEN patients treated with corticosteroids had a worse prognosis. 196, 197 More recently, in an American burn unit the mortality rate for severe TEN fell from 66% to 33% after withdrawal of steroid therapy as the only change in treatment. 198 The authors thought


Table III. Suggested fluid and caloric regimen for the first 24 hours Intravenous allowance

Macromolecules* (1 mljkg body weightj% BSA involved) and isotonic saline solution (0.7 ml/kg body weightj% BSA involved) For a patient weighing 70 kg with necrolysis extending to more than 40% of the epidermis, one should give 2800 ml of a solution of macromolecules and 2000 ml of saline.

N asogastric feeding

Begin with 1500 calories in 1500 ml for the first 24 hours and increase intake by 500 calories daily up to 3500 to 4000 calories per day.

BSA, Body surface area.

*Human albumin diluted to 40 gmjL in isotonic saline rather than fresh-frozen plasma because of risk of .disease transmission, or a nonprotein colloid such as dextran or starch solutions.

that steroids enhanced the risk of sepsis, increased protein catabolism, and delayed epithelialization. Taken together, these data, although uncontrolled, suggest that corticosteroids are more detrimental than useful in TEN and should be avoided. This conclusion is now shared by many authorities in the tield.5,20,21,25,54,98, 182, 198, 199 Beneficial effects of plasmapheresis have been claimed in one case report2OO and in a short uncontrolled study.ll9 There is no rationale for this therapy and we were not able to detect any interruption in the progression of epidermolysis in a preliminary study of six patients treated with early plasma exchanges (unpublished data). Beneficial effects of cyclosporine have been claimed in one recent case report. 201 Sequelae therapy

Sun exposure may worsen pigmentation disturbances and should be avoided for several months or years. Active photoprotective agents should be prescribed. Dryness of the skin can be reduced by the use of emollients. Phimosis may require circumcision. Serial esophageal dilations were successful in a patient with esophageal stricture. 155 Post-TEN ocular syndrome requires ophthalmologic follow-up. Artificial tears and lubricants are often needed. Local corticosteroids are of little help. Surgical procedures such as punctal occlusion, lysis of synechiae, and conjunctival flaps usually offer little improvement and tarsorrhaphy may be required. 55 Topical tretinoin could be a significant therapeutic advance202 in the treatment of conjunc-

1054 Roujeau et ai.

tival keratinization that probably accounts for most corneal complications. Further use of drugs

Patients should be advised to avoid not only the suspect drug(s) but also chemically related compounds. One patient has been reported to have had two episodes, each related to a slightly different barbiturate. lOB To avoid unintentional drug challenge, which may have a legal implication, suspected drug(s) must be listed and the patient should carry a cautionary note mentioning the suspected drug(s). In situations in which there is no alternative drug, the potential effectiveness of desensitization should be considered. 203 It must be remembered, however, that desensitization has not yet been tested after TEN. Adverse drug reaction survey systems, such as that of the AAD, should be notified. 112 Considering the rarity and severity ofTEN, even a few cases may have profound implications on the marketing of a drug. Such an exceptional reaction is not expected to appear in premarketing clinical studies of a new drug. Therefore it is the responsibility of the physicians dealing with patients with TEN to evaluate each case fully, and, after a thorough drug inquiry, to report the case to the proper regulatory agencies and to the drug company involved. 204, 205 REFERENCES 1. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J DermatoI1956;68:355-61. 2. Debre R, Lamy M, Lamotte M. Un cas d'erythrod~rmie avec epidermolyse chez un enfant de douze ans. Bull S·~. POOiatr 1939;37:231-8. . 3. Lang A, Walker J. An unusual bullous eruption. S Mr Med J 1956;30:97-8. 4. Lyell A. A review of toxic epidermal necrolysis in Britain. Br J DermatoI1967;79:662-71. 5. Lyell A. Toxic epidermal necrolysis (the scalded skin sydreme): a reappraisal. Br J DermatoI1979;100:69-86. 6. Lyell A. The staphylococcal scalded skin syndrome in historical perspective: emergence of dermopathic strains of Staphylococcus aureus and discovery ofthe epidermolytic toxin. J AM ACAD DERMATOL 1983;9:285-94. -7. Fritsch PO, Elias PM. Toxic epidermal necrolysis. In: Fitzpatrick TB, Eisen AZ, Wolff K, et ai, OOs. Dermatology in general medicine. New York: McGraw-Hill, 1987:563-7. 8. Rasmussen JE. Toxic epidermal necrolysis: a review of75 cases in children. Arch Dermatol 1975;111:1135-9. 9. Rasmussen JE. Toxic epidermal necrolysis. Med Clin North Am 1980;64:901-20. 10. Snyder RA, Elias PM. Toxic epidermal necrolysis and staphylococcal scalded syndrome. Dermatol Clin 1983; 1:235-48. 11. Melish ME, Glasgow LA. The staphylococcal scalded


skin syndrome: development of an experimental model. N Engl J Med 1970;282:1114-9. 12. Elias PM, Fritsch PO, Epstein EH. Staphylococcalscalded skin syndrome: clinical features, pathogenesis and recent microbiological and biochemical developments. Arch Dermatol 1977;113:207-19. 13. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Report of two cases in children. Am J Dis Child 1922;24:526-33. 14. Assaad D, From L, Ricciatti D, et al. Toxic epidermal necrolysis in Stevens-Johnson syndrome. Can Med Assoc J 1978;118:154-6. 15. Bergoend H, Uiefler A, Amar R, etal. Reactions cutanees survenues au cours de la prophylaxie de masse de la meningite cerebro-spinale par un sulfamide long-retard. Ann Dermatol Syph 1968;95:481-90. 16. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J AM ACAD DERMATOL 1983;8:763-75. 17. Champion RH. Erythema multiforme. In: Rook A, Wilkinson DS, Ebling FJG, et aI, cds. Textbook of dermatology. Oxford: Blackwell, 1986: 1085-8. 18. Elias PM, Fritsch PO. Erythema multiforme. In: Fitzpatrick TB, Eisen AZ, Wolff K, et ai, OOs. Dermatology in general medicine. New York: McGraw-Hill, 1987:55563. 19. Goldstein SM, Wintroub BW, Elias PM, et al. Toxic epidermal necrolysis, unmuddying the waters. Arch DermatoI1987;123:1153-6. 20. Rasmussen JE. Update on the Stevens-Johnson syndrome. Cleve Clin Med J 1988;55:412-4. 21. Ruiz-Maldonado R. Acute disseminated epidermal necrosis types 1, 2, and 3: study of sixty cases. JAM ACAD DERMATOL 1985;13:623-35. 22. Revuz J, Penso D, Roujeau J-C, et al. Toxic epidermal necrolysis: clinical tidings and prognosis factors in 87 patients. Arch DermatoI1987;123:1160-5. 23. Yetiv J Z, Bianchine JR, Owen JA. Etiologic factors of the Stevens-Johnson syndrome. South Med J 1980;73:599602. 24. Bottiger LE, Strandberg I, Westerholrn B. Drug-induced febrile mucocutaneous syndrome. Acta Moo Scand 1975;198:229-33. 25. RevuzJ,RoujeauJ-C, GuillaumeJ-C, eta!. Treatment of toxic epidennal necrolysis, Creteil's experience. Arch Dermatol 1987;123:1156-8. 26. Roujeau J-C, Huyn NT, Bracq C, et al. Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 1987;123:1171-3. 27. Guillaume J-C, Roujeau J-C, Penso D, et at. The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell's syndrome). Arch DermatoI1987;123:1166-70. 28. Bjornberg A. Fifteen cases of toxic epidermal necrolysis (Lyell). Acta Derm Venereal (Stockh) 1973;53:149-52. 29. Chan HL. Observations on drug-induced toxic epidermal necrolysis in Singapore. J AM ACAD DERMATOL 1984; 10:973-8. 30. Strobel M, Ndiaye B, Padonou F, et al. Le syndrome de Lyell a Dakar. Dakar Med 1980;25:261-7. 31. Panciera DL, Bevier D. Management of cryptococcosis and toxic epidermal necrolysis in a dog. J Am Vet Med Assoc 1987;191:1125-7. 32. Schopf E. Skin reactions to co-trimoxazole. Infection 1987;15(suppl 5):254-8. 33. Huriez C, Bergoend H, Bertez ML. 23 toxidermies bulleuses graves avec epidermolyse. Ann Dermatol Syphiligr (Paris) 1972;99:493-500.


34. Kauppinen K. Cutaneous reactions to drugs with special reference to severe bullous mucocutaneous eruptions and sulphonamides. Acta Derm Venereal (Stockh) 1972; 52(suppI68):1-89. 35. Gerard A, Roche G, Presles 0, et al. Syndromes de Lyell mooicamenteux a propos de neuf observations. Therapie 1982;37:475-80. 36. Halebian PH, Corder VJ, Herndon D, et al. A burn center experience with toxic epidermal necrolysis. J Burn Care RehabilI983;4:176-83. 37. Alanko K, Stubb S, Kauppinen K. Cutaneous drug reactions: clinical types and causative agents. Acta Derm Venereol (Stockh) 1989;69:223-6. 38. Bigby M, Jick S, Jick H, et al. Drug-induced cutaneous reactions. A report from the Boston collaborative drug surveillance program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986;256:3358-63. 39. Kauppinen K, Stubb S. Drug eruptions: causative agents and clinical types. Acta Derm Venereal (Stockh) 1984; 64:320-4. 40. Roujeau J-C, Guillaume J-C, Fabre J-P, et aJ. Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990; 126:37-42. 41. Amon RB, Dimond RL. Toxic epidermal necrolysis, rapid differentiation between staphylococcal and drug-induced disease. Arch Dermatol 1975;111:986-90. 42. Orfanos CE, Schaumburg-Lever G, Lever WF. Dermal and epidermal types of erythema multiforme. Arch DermatoI1974;109:682-8. 43. Breathnach SM, McGibbon DH, Ive FA, et al. Carbamazepine ("Tegretol") and toxic epidermal necrolysis: report of three cases with histopathological observations. Clin Exp Dermatol 1982;7:585-91. 44. Roujeau J-C, Dubertret L, Moritz S, et al. Involvement of macrophages in toxic epidermal necrolysis. Br J Dermatol 1985;113:425-30. 45. Heng MCY. Drug-induced epidermal necrolysis. Br J Dermatol 1985;113:597-600. 46. Revuz J, Typhagne F. Immune complexes, complement and immunofluorescence in Lyell syndrome. In: Thivolet J, Schmitt D, eds. Immunopathologie cutanee. Paris: Edition INSERM, 1978:73-6. 47. Rekacewicz I, Andre C, Bagot M, et al. Anti-epidermis antibodies and toxic epidermal necrolysis. In: Caputo R, ed. Immunodermatology. Roma: CIC Edizioni Intemazionali, 1987:143-5. 48. Stein KM, Schlappner OLA, Heaton CI, et al. Demonstration of basal cell immunofluorescence in drug-induced toxic epidermal necrolysis. Br J DermatoI1972;86:246-52. 49. Komura J, Yamada M, Ofuji S. Ultrastructure of eosinophilic staining epidermal cells in toxic epidermal necrolysis and fixed drug eruption. Dermatologica 1969;139: 41-8. 50. Nasemann T, Lee S. Elektronenmikroskopische befunde beim Lyell-syndrom. Hautarzt 1972;5:199-204. 51. Smith DA, Burgdorf WHC. Universal cutaneous depigmentation following phenytoin-induced toxic epidermal necrolysis. J AM ACAD DERMATOL 1984;10:106-9. 52. Kopf AW, Grupper C, Baer RL, et a1. Eruptive melanocytic nevi after severe bullous disease. Arch Dermatol 1977;133:1080-4. 53. Burns DA, Sarkany I. Junctional nevi following toxic epidermal necrolysis. Clin Exp Dermatol 1978;3:323-6. 54. Management of toxic epidermal necrolysis. [Editorial]. Lancet 1984;2:1250-2. 55. Arstikaitis MJ. Ocular aftermath of Stevens-Johnson

Toxic epidermal necrolysis 1055 syndrome. Review of 33 cases. Arch Ophtbalmol 1973; 90:376-9. 56. Binaghi M, Koso M, Roujeau J-C, et al. Les complications oculaires du syndrome de Lyell: notions recentes Ii. propos de 26 cas. J Fr Ophtalrnol 1985;8:239-43. 57. Bennett TO, Sugar J, Sabgal S. Ocular manifestations of toxic epidermal necrolysis associated with allopurinol use. Arch OphthalmoI1977;95:1362-4. 58. De Felice GP, Caroli R, Autelitano A. Long-term complications of toxic eipidermal necrolysis (Lyell's disease): clinical and histopathologic study. Ophthalmologica 1987;195:1-6. 59. Roujeau J-C, Phlippoteau C, Koso M, et al. Sjogren-like syndrome after drug-induced toxic epidermal necrolysis. Lancet 1985;1:609-11. 60. Bjornberg A, Bjornberg K, Giss1en H. Toxic epidermal necrolysis with ophthalmic complications. Acta Ophthalmol 1964;42:1084-95. 61. Ellman MH, Freitzin DF, Olson W. Toxic epidermal necrolysis associated with allopurinoladministration. Arch DermatoI1975;111:986-90. 62. Herman TE, Kushner DC, Cleveland RH. Esophageal stricture secondary to drug-induced toxic epidermal necrolysis. Pediatr RadioI1984;14:439-40. 63. Roupe G, AhImen M, Fagerberg B, et a1. Toxic epidermal necrolysis with extensive mucosal erosions of the gastrointestinal and respiratory tracts. lnt Arch Allergy Appl ImmunoI1986;80:145-51. 64. Zweibaum B, Cohen H, ChandrasomaP. Gastrointestinal involvement complicating Stevens-Johnson syndrome. Gastroenterology 1986;91 :469-74. 65. Klein SM, Dhan MA. Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac therapy. J RheumatoI1983;10:512-3. 66. Tatnall FM, Dodd HJ, Sarkany 1. Elevated serum amylase in a case oftoxic epidermal necrolysis. Br J Dermatol 1985;113:629-30. 67. Tagami H, Iwatsuki K. Elevated serum amylase in toxic epidermal necrolysis. Br J DermatoI1986;1l5:250-1. 68. Bombal C, Roujeau J-C, Kuentz M, et a1. Anomalies hematologiques au cours du syndrome de LyelJ. Ann Dermatol VenereoI1983;110:113-9. 69. Goens J, Song M, Fondu P, et a1. Haematological distur. bances and immune mechanisms in toxic epidermalnecrolysis. Br J Dermatol 1986;114:255-9. 70. Roujeau J-C, Moritz S, Guillaume J-C, et al. Lymphopenia and abnormal balance of T lymphocyte subpopulations in toxic epidermal necrolysis. Arch Dermatol Res 1985;277:24-7. 71. Roujeau J-C, Guillaume J-C, Revuz J, et al. Granulocytes, lymphocytes and toxic epidermal necrolysis [letter]. Arch Dermatol 1985;121:305. 72. Westly ED, Wechsler HL. Toxic epidermal necrolysis, granulocytic leukopenia as a pronostic indicator. Arch DermatoI1984;120:721-6. 73. Kvasnicka J, Rezac J, Svejda J, et al. Disseminated intravascular coagulation associated with toxic epidermal necrolysis (Lyell's syndrome). Br J Dermatol 1979; 100:551-8. 74. Krumlovsky FA, Del Greco F, Herdson PB, et a1. Renal disease associated with toxic epidermal necrolysis (Lyell's disease). Am J Med 1974;57:817-25. 75. Roujeau J-C, Revuz J. Intensive care in dermatology. In: Champion RH, pye RJ, eds. Recent advances in dermatology. Edinburgh: Churchill livingstone, 1990: 85-99. 76. Harnar TJ, Dobke M, Simoni J, et al. Toxic epidermal

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necrolysis complicated by severe wound sepsis. J Bum Rehabil 1987;8:554-7. Luger TA, Stadler BN, Katz SL, et al. Epidermal cell (keratinocyte)-derived thymocyte-activating factor (ETAF). J ImmunoI1981;127:1493-8. Oppenheim 11, Gery I. Interleukin 1 is more than an interleukin. Immunol Today 1982;3:113-9. Demling RH. Burns. N Engl J Med 1985;313:1389-98. Bagot M, Heslan M, Roujeau J-C, et al. Immune reactivity of patients with toxic epidermal necrolysis. J Invest Dermatol 1988;91:402-3. PasulkaPS, Watchel TL.1987 Nutritional considerations for the burned patient. Surg Clin North Am 1987;67: 10931. Gamelli RL. Nutritional problems of the acute and chronic burn patient. Relevance to epidermolyis bullosa. Arch Dermatol 1988;124:756-9. Hansen RC. Staphylococcal scalded skin syndrome, toxic shock syndrome and Kawasaki disease. Pediatr Clin North Am 1983;30:533-44. Roujeau J-C, Albengres E, Moritz 8, et al. Lymphocyte transformation test in toxic epidermal necrolysis. Int Arch Allergy Applimmunol 1985;78:22-4. SchOpf E, Schulz KH, Kessler R, et al. Allergologische Untersuchungen beim Lyell-Syndrom. Z Hautkr 1975; 50:865-73. Pegram PS, Mountz JD, O'Bar PRo Ethambutol-induced toxic epidermal necrolysis. Arch Intern Med 1972; 141:1677-8. Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following reexposure to phenytoin: a case report. Epilepsia 1983;24:440-3. Dreyfuss DA, Gottlieb LJ, Wilkerson DK, et al. Survival after a second episode of toxic epidermal necrolysis. Ann PlastiC Surg 1988;20:146-7. Wright KU, Ellis ME. Toxic epidermal necrolysis associated with streptococcal septicaemia. Br Moo J 1985; 291:312-3. De Groot R, Oranje AP, Vuzevski VD, et al. Toxic epidermal necrolysis probably due to Klebsiella pneumaniae sepsis. Dermatologica 1984;169:88-90. Hawk RJ, Storer 1S, Daum RS. Toxic epidermal neelolysis in a 6-week old infant. Pediatr Dermatol1985;2:l97:: 200. Callaway JL, Tate WE. Toxic epidermal necrolysis caused by "gin and tonic." [Letter] Arch Dermatol 1974;109: 909. Radimer GF, Davis JR, Ackerman AB. Fumigant-induced toxic epidermal necrolysis. Arch Dermatol 1974; 110:103-4. Thompson JA, Wansker BA. A case of contact dermatitis, erythema multiforme, and toxic epidermal necrolysis. JAM ACAD DERMATOL 1981;5:666-9. Foged EK. Toxic epidermal necrolysis from oil lamp fuel. Contact Dermatitis 1984;11:135-6. Phoon WH, Chan MaY, Rajan VS, et al. StevensJohnson syndrome associated with occupational exposure to trichlorethylene. Contact Dermatitis 1984;10:270-6. Valsecchi R, Cassina P, Cainelli T. Contact toxic epidermal necrolysis. Contact Dermatitis 1987;16:277. Heimbach DM, Engrav LH, Marvin JA, et al. Toxic epidermal necrolysis. A step forward in treatment. JAMA 1987;257:2171-5. Aberer W, Sting! G, WolfK. Stevens-Johnson-syndrom und toxische epidermale nekrolyse nach sulfonamideinnahme. Hautarzt 1982;33:484-90.


100. Hemborg H. Stevens-Johnson syndrome after mass prophylaxis with sulfadoxine for cholera in Mozambique. Lancet 1985;2:1072-3. 101. Miller KD, Lobel HO, Satriale RF, et al. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986;35:451-8. 102. Hellgren U, Rombo L, Berg B, et al. Adverse reactions to sulphadoxine-pyrimethamine in Swedish travellers: implications for prophylaxis. Br Med J 1987;295:365-6. 103. NwokoIQ,C,·J2YJl1e L, Misch KJ. Toxic epidermal necrolysis occurring during treatment with trimethoprim alone. Br Moo J 1988;296:970. 104. Pollack MA, Burk PG, Nathanson G. Mucocutaneous eruptions due to antiepileptic drug therapy in children. Ann Neurol 1979;5:262-7. 105. Gately LE, Lam MA. Phenytoin-induced toxic epidermal necrolysis. Ann Intern Moo 1979;91 :59-60. 106. Sherertz EF, legasothy BV, Lazarus GS. Phenytoin hypersensitivity reaction presenting with toxic epidermal necrolysis and severe hepatitis. J AM ACAD DERMATOL 1985;12:178-81. 107. Silverman AK, Fairly 1, Wong RC. Cutaneous and immunologic reactions to phenytoin. J AM ACAD DERMATOL 1988;18:721-41. 108. Stiittgen G. Toxic epidermal necrolysis provoked by barbiturates. Br J DermatoI1973;88:291-3. 109. Teillac D, Marsol P, Richard P, et al. Necrolyse epidermique toxique de l'enfant (syndrome de Lyell), Ii propos de 18 cas. Arch Fr Pediatr 1987;44:583-7. 110. Stratigos lB, Bartsokas SK, Capetanakis J. Further experiences of toxic epidermal necrolysis incriminating allopurinol, pyrazolone and derivatives. Br J Dermatol 1972; 86:564-7. 111. Bailin PL, Matkaluk RM. Cutaneous reactions to rheumatological drugs. Clin Rheum Dis 1982;8:493-516. 112. Stern RS, Bigby M. An expanded profile of cutaneous reactions to nonsteroidal anti-inflammatory drugs: report of a specialty based system for spontaneous reporting of ad,verse reactions to drugs. lAMA 1984;252:1433-7. 113. Fenton DA, English JS. Toxic epidermal necrolysis, leucopenia and thrombocytopenic purpura: a further complication of benoxaprofen therapy. Clin Exp Dermatol 1982;7:277-9. 114. Flechet ML, Moore N, Chedeville J-C, et al. Fatal epidermal necrolysis associated with isoxicam [Letter]. Lancet 1985;2:499. 115. Penso D, Roujeau J-C, Guillaume J-C, et al. Toxic epidermal necrolysis after oxicam use [Letter]. 1 AM ACAD DERMATOL 1986;14:275-6. 116. Roujeau J-e. Clinical aspects ofskin reactions to NSAIDs. Scand J Rheumatol 1987;65(suppl):131-4. 117. Levit L, Pearson R. Sulindac-induced Stevens-Johnson toxic epidermal necrolysis syndrome. JAMA 1980; 243:1262-3. 118. O'Sullivan M, Hanly J, Molloy M. A case of toxic epidermal necrolysis secondary to indomethacin. Br J RheumatoI1983;22:47-9. 119. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol 1985;121 :1548-9. 120. Stotts 18, Fang ML, Dannaker CJ, et al. Fenoprofen-induced toxic epidermal necrolysis [Letter]. J AM ACAD DERMATOL 1988; 18:755-7. 121. Kantor GL. Toxic epidermal necrolysis, azotemia and death after allopurinol therapy. JAMA 1970;212:478-9.

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Hypopharyngeal Synechiae in Lyell Syndrome (Toxic Epidermal Necrolysis).

Toxic epidermal necrolysis in Stevens--Johnson syndrome.

[Toxic epidermal necrolysis (Lyell's syndrome) after rubella].

Toxic epidermal necrolysis.

Toxic Epidermal Necrolysis.

Toxic Epidermal Necrolysis: Reply.

Toxic epidermal necrolysis.

Letter: Toxic epidermal necrolysis.

Toxic epidermal necrolysis.

Toxic epidermal necrolysis.

Paracetamol induced Stevens-Johnson syndrome--toxic epidermal necrolysis overlap syndrome.

Ofloxacin-induced toxic epidermal necrolysis.

Mixed signals: toxic epidermal necrolysis.

[Vemurafenib-induced toxic epidermal necrolysis].

toxic epidermal necrolysis presumably induced by norfloxacin.

Disseminated intravascular coagulation associated with toxic epidermal necrolysis (Lyell's syndrome).

toxic epidermal necrolysis: an Asia-Pacific perspective.

Otologic complications of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Ibuprofen induced Stevens-Johnson syndrome - toxic epidermal necrolysis in Nepal.

Metolazone Associated Stevens Johnson Syndrome-Toxic Epidermal Necrolysis Overlap.

Immunological response in Stevens-Johnson syndrome and toxic epidermal necrolysis.

Recurrence of Stevens-Johnson syndrome and toxic epidermal necrolysis.

Toxic epidermal necrolysis associated with deflazacort therapy with nephrotic syndrome.

Recurrence of Stevens-Johnson syndrome and toxic epidermal necrolysis--reply.