eMedicine Specialties > Emergency Medicine > Infectious Diseases

Toxic Epidermal Necrolysis

Author: Gregory P Garra, DO, Clinical Assistant Professor, Department of Emergency Medicine, Stony Brook University School of Medicine; Residency Program Director, Department of Emergency Medicine, Stony Brook University Hospital
Coauthor(s): Elizabeth D Turner, MD, Clinical Assistant Instructor and Resident Physician, Department of Emergency Medicine, State University of New York Stony Brook University Hospital
Contributor Information and Disclosures

Updated: Jun 24, 2009

Introduction

Background

Described in 1956 by Alan Lyell,¹ toxic epidermal necrolysis (TEN) is a life-threatening skin disorder that is commonly drug-induced. The mucocutaneous reaction is characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes resulting in exfoliation and possible sepsis and/or death. Mucous membrane involvement can result in gastrointestinal hemorrhage, respiratory failure, ocular abnormalities, and genitourinary complications.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe cutaneous reactions, with more than 90% of cases involving mucosal surfaces. Erythema multiforme major (EMM), once thought to be a mild variant of this disease spectrum, differs from SJS/TEN in its distribution, lesion morphology, and etiology. Erythema multiforme major (EMM) is characterized by acrally distributed, raised target lesions. In contrast, the skin lesions of Stevens-Johnson syndrome and toxic epidermal necrolysis are predominately central, consisting of blisters that arise on erythematous or purpuric macules and involve two or more mucosal surfaces. A classification system, based largely on the extent of epidermal detachment and morphology of the skin lesions, aids in differentiating the disease entities.²

• Bullous erythema multiforme (EM) consists of typically round targets with 3 different zones and well-defined borders; it is most prominent on the extremities. Confluence of the lesions and epidermal detachment is limited to less than 10% of the body surface area.
• Stevens-Johnson syndrome (SJS) consists of widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Confluence of individual lesions and epidermal detachment is limited, involving less than 10% of the body surface area. Mucosal surfaces are usually involved.
• Toxic epidermal necrolysis (TEN) "with spots" is defined as widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Blisters become more confluent and result in detachment of the epidermis and erosions on greater than 30% of the body surface area. Mucosal surfaces are usually involved.
• Toxic epidermal necrolysis (TEN) "without spots" is defined as widespread, large erythematous areas with no discrete lesion. Epidermal detachment is greater than 10% of the body surface area. Mucosal surfaces are usually involved.
• Overlap Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) is characterized by widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Blisters become confluent and result in detachment of the epidermis and erosions on 10-29% of the body surface area.

Histopathologic examination is necessary in differentiating these disorders from other severe bullous skin diseases such as staphylococcal scalded skin syndrome, toxic shock syndrome, phototoxic skin reactions, drug reaction with eosinophilia, acute generalized exanthematous pustulosis, or paraneoplastic pemphigus.³ TEN and SJS are characterized by apoptotic keratinocyte cell death in the epidermis with dermal-epidermal separation that results in bullae formation. Initial ED management is supportive.

Pathophysiology

The mechanisms underlying the severe dermatologic manifestations of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are poorly understood. Medications are the leading cause of Stevens-Johnson syndrome and toxic epidermal necrolysis, although bacterial (mycoplasma) and viral infections also contribute. Exposure to the inciting agent is thought to initially cause activations of cellular immunity, including both cytotoxic lymphocytes and natural killer (NK) cells. Widespread epidermolysis is the result of keratinocyte cell apoptosis—an organized series of biochemical reactions leading to cell changes and cell death.⁴  

Evidence supporting several immunopathologic pathways includes the following: ligation of Fas on keratinocyte membranes,⁵ cytotoxic T lymphocyte (CTL)–mediated activation of perforin/granzyme B pathway,⁶ overproduction of T cell and/or macrophage derived cytokines (INF-γ, TNF-α, and various interleukins),⁷ and/or CTL release of granulysin (a cationic cytolytic protein).⁸

Multiple risk factors for the development of Stevens-Johnson syndrome or toxic epidermal necrolysis exist, including HIV infection, impaired liver function including "slow" N -acetylation as well as immunologic and genetic factors. 

Frequency

International

Worldwide, 0.4-1.3 cases per million per year.⁹

Mortality/Morbidity

Toxic epidermal necrolysis has a mortality rate of 30-50%. Septicemia and multisystem organ failure are the primary causes of death. Epithelial loss results in vulnerability to bacterial and fungal infections. Sloughing of stratified epithelium of mucosal membranes can result in GI hemorrhage, respiratory failure, ocular abnormalities, and genitourinary lesions. Significant fluid loss from extensive skin exfoliation as well as an inability to tolerate oral intake can lead to hypovolemia, acute tubular necrosis, and shock. Age at onset, as well as extent of epidermal involvement correlate with mortality.

Complications of Stevens-Johnson syndrome or toxic epidermal necrolysis include adhesions and scarring, including stricture formation of mucosal surfaces such as the esophagus, eyelids and cornea, as well as the genitourinary system.

• A severity-of-illness score that estimates the risk of death in toxic epidermal necrolysis (TEN) has been developed and validated (SCORTEN).¹⁰
  • Age >40 years
  • Heart rate >120 beats per minute
  • Cancer or hematologic malignancy
  • Involved body surface area >10%
  • Blood urea nitrogen level >10 mmol/L (28 mg/dL)
  • Serum bicarbonate level <20 mmol/L (20 mEq/L)
  • Blood glucose level 14 mmol/L (252 mg/dL)
• Mortality rates based on the number of positive criteria are as follows:
  • 0 to 1 factor = 3%
  • 2 factors = 12%
  • 3 factors = 35%
  • 4 factors = 58%
  • 5 or more factors = 90%

Race

A genetic predilection toward carbamazepine-induced TEN among HLA-B1502–positive Han Chinese patients has been observed.¹¹

Sex

Some series of TEN and SJS have demonstrated a female preponderance. 

Age

Stevens-Johnson syndrome and toxic epidermal necrolysis occurs in all age groups. Infection is more commonly implicated in children, whereas medication exposure is a more common etiology in adults. Age older than 40 years is an independent risk factor for mortality.

Clinical

History

Most cases of toxic epidermal necrolysis (TEN) are drug induced, typically occurring within the first 8 weeks of therapy. Fewer than 5% of patients report no history of medication use. First-degree relatives are at risk if a family history of a severe cutaneous drug reaction to a particular medication is present.

Toxic epidermal necrolysis is generally preceded by a prodrome of high fever, cough, sore throat, and malaise. The cutaneous eruption begins as a poorly defined, erythematous macular rash with purpuric centers. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment. The lesions predominate on the torso and face, sparing the scalp. Pain at the site of the skin lesions is often the predominating symptom and is often out of proportion to physical findings in early disease. 

Mucous membrane erosions (seen in 90% of cases of toxic epidermal necrolysis) generally precede the skin lesions. The most frequently affected mucosal membrane is the oropharynx followed by the eyes and genitalia. Oral cavity involvement typically presents as a sore or burning sensation. Intake may be limited because of pain associated with the oropharyngeal lesions. Genital involvement may result in painful urination. Other mucosal surfaces such as the esophagus, intestinal tract, or respiratory epithelium may be affected.

Physical

Physical examination findings of toxic epidermal necrolysis (TEN) may include the following:

• Pyrexia is usually present.
• The rash of toxic epidermal necrolysis (TEN) usually begins as centrally distributed, flat, atypical targets or purpuric macules. Skin lesions involve greater than 30% of the skin surface and usually involve mucous membranes as well. The skin lesions coalesce and fill with fluid producing large, flaccid blisters. These lesions may wrinkle, slide laterally, and separate with slight pressure (Nikolsky sign). Separation of skin layers occurs at the basement membrane. The underlying denuded skin is erythematous and tender.

• Involvement of the oral mucosa results in edema and erythema, followed by blistering. Ruptured blisters may form extensive hemorrhagic erosions with grayish white pseudomembranes or shallow aphthous-like ulcers.

• Ocular involvement varies in severity and can result in mild inflammation, conjunctival erosion, purulent exudates, or pseudomembrane formation.
• Involvement of respiratory epithelium may result in bronchial hypersecretion, hypoxemia, interstitial infiltrates, pulmonary edema, bacterial pneumonia, or bronchiolitis obliterans.

Causes

Medications are the major precipitating cause of toxic epidermal necrolysis (TEN). Numerous medications have been associated with the development of toxic epidermal necrolysis.¹² However, no laboratory test is able to confirm a specific drug etiology. A causal link is suggested when toxic epidermal necrolysis occurs during the first 4 weeks of medication therapy, usually between 1 and 3 weeks. The most widely implicated medications are as follows:

• Sulfonamide antibiotics
• Anticonvulsants (phenobarbital, phenytoin, carbamazepine, valproic acid)
• Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs)
• Allopurinol
• Antiretroviral medications
• Corticosteroids

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