eMedicine Specialties > Dermatology > Reactive & Inflammatory Dermatoses

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Author: Peter A Klein, MD, Staff Physician, Department of Dermatology, University Hospital, State University of New York at Stony Brook
Contributor Information and Disclosures

Updated: Feb 20, 2009

Introduction

Background

Toxic epidermal necrolysis (TEN) is an acute dermatologic disease, the presentation of which may constitute a true emergency. The disorder is characterized by widespread erythematous macules and targetoid lesions; full-thickness epidermal necrosis, at least focally; and involvement of more than 30% of the cutaneous surface. Commonly, the mucous membranes are also involved. Nearly all cases of toxic epidermal necrolysis are induced by medications, and the mortality rate can approach 40%.

Stevens-Johnson syndrome (SJS) may also present as a dermatologic emergency characterized by purpuric macules and targetoid lesions; full-thickness epidermal necrosis, although with lesser detachment of the cutaneous surface; and mucous membrane involvement. As with toxic epidermal necrolysis, medications are important inciting agents, although Mycoplasma infections may induce some cases. The mortality rate is much lower and approaches 5% of cases.

Erythema multiforme (EM) is generally a far more benign process characterized by target or targetoid lesions, with or without blisters, in a symmetric acral distribution. Oral lesions are common. Severe presentations may have widespread involvement of the mucous membranes and epidermal detachment with a loss of less than 10% of the cutaneous surface. Most cases are secondary to prior infection with a herpes virus. The condition generally has low morbidity and no mortality and is often recurrent. Stevens-Johnson syndrome may have features of both EM and toxic epidermal necrolysis, which has led to confusion in nosology.

Stevens-Johnson syndrome and toxic epidermal necrolysis may represent a spectrum of a single disease process. Some evidence suggests that EM may be an entirely distinct disorder.^1,2 This article discusses Stevens-Johnson syndrome and toxic epidermal necrolysis.

Pathophysiology

Stevens-Johnson syndrome and toxic epidermal necrolysis are often drug induced, but the pathophysiologic mechanism is unknown. A number of theories have been proposed that may have implications for treatment. Patients and their first degree-relatives may have genetic defects in their metabolic pathways that lead to the accumulation of toxic metabolites. For example, patients with sulfonamide-induced toxic epidermal necrolysis have been shown to have a slow acetylator genotype, resulting in increased production of sulfonamide hydroxylamine via the P-450 pathway. These drug metabolites may have direct toxic effects or act via a hapten-mediated mechanism to break self-tolerance to endogenous proteins.

Apoptosis of keratinocytes has been proposed secondary to a cell-mediated cytotoxic reaction. Keratinocyte apoptosis is rare in the healthy epidermis, but it has been shown to be increased in toxic epidermal necrolysis. In 1997, Inachi et al demonstrated perforin-mediated apoptosis in patients with Stevens-Johnson syndrome.³ Perforin, a pore-making monomeric granule released from natural killer cells and cytotoxic T lymphocytes, kills target cells by forming polymers and tubular structures not unlike the membrane attack complex of the complement system.

A second proposed mechanism of apoptosis involves interaction between a cell-surface death receptor, such as Fas, and its receptive ligand, to form a Fas ligand (FasL). In 1998, Viard et al demonstrated high concentrations of soluble Fas ligand (sFasL) in toxic epidermal necrolysis sera.⁴ In vitro, target cell death was blocked by a FasL-blocking antibody and by antibodies present in pooled human intravenous immunoglobulin (IVIG). An open trial of IVIG in 10 patients with toxic epidermal necrolysis resulted in a halt of progression within 24-48 hours, with no mortality.

Frequency

United States

Chan et al evaluated the hospital discharge diagnoses of 61 patients with EM, Stevens-Johnson syndrome, or toxic epidermal necrolysis from 1972-1986 and reported the incidence of toxic epidermal necrolysis to be 0.5 per million population per year.⁵ Strom et al reviewed Medicaid billing data from 1980-1984 in Michigan, Minnesota, and Florida to determine the incidence of Stevens-Johnson syndrome; the incidence rates were 7.1, 2.6, and 6.8 cases per million population per year, respectively.⁶

International

The incidence of toxic epidermal necrolysis in Sweden has been reported to be 0.4 per million population per year, and a French group reported 1.2 cases per million population per year. A study in West Germany reported the incidences of toxic epidermal necrolysis and Stevens-Johnson syndrome to be 0.93 and 1.1 cases per million population per year, respectively.

Mortality/Morbidity

Stevens-Johnson syndrome may prove fatal in roughly 5% of patients; toxic epidermal necrolysis may prove fatal in as many as 40% of patients. Sepsis and respiratory distress are the most common complications and ultimately the direct causes of death. Important prognostic factors include the percentage loss of body surface area (BSA), age, persistent neutropenia (defined as neutropenia lasting >5 d), hypoalbuminemia (usually <2 g/dL), and persistent azotemia. Among 247 French patients, only 1 out of 70 died when BSA involvement was less than 10%. In contrast, the mortality rate was 11% for patients with 10-30% BSA involvement and 35% for patients with BSA involvement exceeding 30%.

While some patients rapidly progress to lose very large areas of the epidermis in a matter of days, the process suddenly ceases in others and reepithelialization begins a few days later. Predicting the course of disease in a given patient at the initial presentation is not possible. Reepithelialization is usually complete within 3 weeks, but pressure and mucosal areas may remain eroded and crusted for 2 weeks or longer.

Survivors of Stevens-Johnson syndrome/toxic epidermal necrolysis may experience numerous long-term sequelae; the most disabling are those of the eye. Cicatrization of conjunctival erosions may lead to inverted eyelashes, photophobia, a burning sensation in the eyes, watery eyes, a siccalike syndrome, and corneal and conjunctival neovascularization. As many as 40% of survivors of toxic epidermal necrolysis have residual potentially disabling lesions that may cause blindness.

Cutaneous lesions may resolve with a patchwork of hyperpigmentation and hypopigmentation. Fingernails and toenails may regrow abnormally. Lesions of the genitourinary system may lead to phimosis or vaginal synechiae.

Race

Stevens-Johnson syndrome and toxic epidermal necrolysis have been described worldwide in all races. Interestingly, disease is not limited to humans, and cases have been reported in dogs, cats, and monkeys.

Sex

Numerous epidemiologic studies have shown that females have higher incidences of toxic epidermal necrolysis than males. Reported adult male-to-female ratios have ranged from 0.5-0.7. However, the epidemic of human immunodeficiency virus (HIV) is normalizing sex ratios in some studies. One study found a ratio of 1:1 in 90 patients with toxic epidermal necrolysis, 20 of whom were HIV infected and 16 of those were men. Among patients not infected with HIV, the sex ratio was 0.62. Male and female children have similar rates of toxic epidermal necrolysis.

Age

Toxic epidermal necrolysis occurs in all age groups, including newborns. Because drug exposure increases with age, Stevens-Johnson syndrome and toxic epidermal necrolysis occur more frequently in the older population. Also, adults might be metabolically more susceptible to such drug reactions than children.
 
A French study of toxic epidermal necrolysis reported a mean patient age of 46.8 years, with a range of 1-93 years. Fourteen percent of the patients were younger than 16 years. A retrospective West German study of 259 patients with toxic epidermal necrolysis and 315 patients with Stevens-Johnson syndrome found average ages of 63 and 25 years, respectively. However, only 54% of cases of Stevens-Johnson syndrome could be attributed to drugs, and some cases of EM, which typically affects younger patients, were likely included in the analysis. Lastly, HIV infection is associated with toxic epidermal necrolysis, and those patients tend to be younger, with one study reporting 14 patients being affected, with an average age of 35.4 years.

Clinical

History

• Constitutional symptoms, such as fever, cough, or sore throat, may appear 1-3 days prior to any cutaneous lesions.
• Patients may complain of a burning sensation in their eyes, photophobia, and a burning rash that begins symmetrically on the face and the upper part of the torso.
• Delineation of a drug exposure timeline is essential, especially in the 1-3 weeks preceding the cutaneous eruption.

Physical

• Primary lesions
  • The initial skin lesions of Stevens-Johnson syndrome/toxic epidermal necrolysis are poorly defined erythematous macules with darker purpuric centers. The lesions differ from classic target lesions of EM by having only 2 zones of color: central dusky purpura or a central bulla, with surrounding macular erythema. A classic target lesion has 3 zones of color: central dusky purpura or a central bulla, a surrounding edematous pale zone, and a surrounding macular erythema.
  • Lesions, with the exception of central bullae, are typically flat. Lesions of EM are more likely to be palpable.
  • Less frequently, the initial eruption may be scarlatiniform.
  • Flaccid blisters are typically present with full-thickness epidermal necrosis (see Media Files 1-2).
  • Nondenuded areas have a wrinkled paper appearance.
  • A Nikolsky sign is easily demonstrated by applying lateral pressure to bullae.
• Arrangement: Individual macules are found surrounding large areas of confluence.
• Distribution: Lesions begin symmetrically on the face and the upper part of the torso and extend rapidly, with maximal extension in 2-3 days. In some cases, maximal extension can occur rapidly over hours.
  • Lesions may predominate in sun-exposed areas.
  • Full detachment is more likely to occur in areas subjected to pressure, such as the shoulders, the sacrum, or the buttocks.
  • Painful edematous erythema may appear on the palms and the soles.
  • The hairy scalp typically remains intact, but the entire epidermis, including the nail beds, may be affected.
  • A recent classification proposes that epidermal detachment in Stevens-Johnson syndrome is limited to less than 10% of the BSA. Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis has more extensive confluence of erythematous and purpuric macules, leading to epidermal detachment of 10-30% of the BSA. Classic toxic epidermal necrolysis has epidermal detachment of more than 30%.
  • An uncommon form of toxic epidermal necrolysis (toxic epidermal necrolysis without spots) lacks targetoid lesions, and blisters form on confluent erythema. Greater than 10% epidermal detachment is required for diagnosis of these cases.
  • In contrast, bullous EM, which has been previously grouped with Stevens-Johnson syndrome, may have epidermal detachment of less than 10% of the BSA, but typical target lesions or raised atypical targets are localized primarily in an acral distribution.
• Secondary lesions: Areas of denuded epidermis are dark red with an oozing surface.
• Mucous membranes: Mucous membrane involvement is present in nearly all patients and may precede skin lesions, appearing during the prodrome (see Media File 3).
  • Painful oral erosions cause severe crusting of the lips, increased salivation, and impaired alimentation.
  • Involvement of the genitalia may lead to painful micturition.
  • Lesions have been reported in the oropharynx, the tracheobronchial tree, the esophagus, the GI tract, the genitalia, and the anus.
  • Intact expectorated cylindrical casts of bronchial epithelium have been reported.
  • Patients may develop a profuse protein-rich diarrhea.
  • Internal involvement is not necessarily limited to patients with extensive cutaneous involvement.
• Ocular lesions: Ocular lesions are especially problematic because they have a high risk of sequelae.
  • Initially, the conjunctivae are erythematous and painful.
  • The lids are often stuck together, with efforts to loosen them resulting in tearing of the epidermis.
  • Pseudomembranous conjunctival erosions may form synechiae between the eyelids and the conjunctivae.
  • Keratitis, corneal erosions, and a siccalike syndrome may develop.

Causes

For medications used on a short-term basis, the relative risk was greatest for trimethoprim-sulfamethoxazole and other sulfonamide antibiotics, chlormezanone, aminopenicillins, quinolones, cephalosporins, and allopurinol.  A case-control multinational study found that allopurinol was the drug most associated with Stevens-Johnson syndrome/toxic epidermal necrolysis.⁷   Daily doses of 200 mg or greater were associated with a higher risk.  The increased risk was limited to short-term use less than 8 weeks.

Among drugs used long term, the greatest risk of Stevens-Johnson syndrome/toxic epidermal necrolysis was seen in the first 2 months of use. The agents posing an increased risk were carbamazepine, phenobarbital, phenytoin, valproic acid, oxicam nonsteroidal anti-inflammatory drugs, and corticosteroids. The greatest excess risk was 4.5 cases per million users in 1 week for sulfonamides. 

Epidemiologic studies in France have shown a greater risk of toxic epidermal necrolysis in patients infected with HIV, especially those with acquired immune deficiency syndrome (AIDS). In the greater Paris area, 15 cases of AIDS-associated toxic epidermal necrolysis occurred over a 6-year period, whereas 0.04 cases would be expected in the general population. This finding may be due to the increased use of sulfonamides in patients infected with HIV and abnormal patterns of production or detoxification of drug metabolites.

Toxic epidermal necrolysis may be related to bone marrow transplantation and acute graft versus host disease (GVHD). In a French series of 152 allogeneic bone marrow recipients, Villada et al reported toxic epidermal necrolysis occurring in 6% of patients.⁸ This incidence is far higher than that expected in the general population. Moreover, toxic epidermal necrolysis has been described in an animal model of cutaneous acute GVHD.

Toxic epidermal necrolysis has been reported in patients with systemic lupus erythematosus, but these limited cases may be a mere coincidence. Infections with herpesvirus, Mycoplasma pneumoniae, or Yersinia have also been reported in patients with Stevens-Johnson syndrome, but these patients may have had EM. Other reported associations include leukemia, lymphoma, ulcerative colitis, and Crohn disease.

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