AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

Described in 1956 by Alan Lyell, 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 sepsis and death. Mucous membrane involvement can result in gastrointestinal hemorrhage, respiratory failure, and ocular and genitourinary complications.

TEN and Stevens-Johnson syndrome (SJS) are severe cutaneous reactions and represent variants of the same disease process. 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. EMM is characterized by acrally distributed, raised target lesions. The skin lesions of SJS and TEN are predominately central, consist 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 helps in differentiating the disease entities.

• Bullous erythema multiforme (EM) - Typical round targets with 3 different zones and well-defined borders, prominent on the extremities characterize bullous EM. Confluence of the lesions and epidermal detachment is limited to less than 10% of the body surface area.
• SJS - Widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule characterize SJS. Confluence of individual lesions and epidermal detachment is limited, involving less than 10% of the body surface area.
• Overlap SJS-TEN - Widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule characterize overlap SJS-TEN. Blisters become confluent and result in detachment of the epidermis and erosions on 10-29% of the body surface area.  
• TEN "with spots" - Widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule characterize TEN with spots. Blisters become more confluent and result in detachment of the epidermis and erosions on greater than 30% of the body surface area. 
• TEN "without spots" - Widespread, large erythematous areas with no discrete lesion characterizes TEN without spots. Epidermal detachment is greater than 10% 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 or paraneoplastic pemphigus. Initial ED management is supportive.

Pathophysiology

Multiple pathophysiologic mechanisms for the development of TEN have been proposed. Current opinion suggests that epidermolysis is the result of keratinocyte cell apoptosis—an organized series of biochemical reactions leading to cell changes and cell death. Cytotoxic T-cell lymphocytes, found in the blister fluid of patients with TEN, is believed to induce a cascade of intracellular enzymes that results in a rapid, triggered cell death. In addition, a strong association between HLA-B*1502 and carbamazepine-induced TEN among Han Chinese has been identified.⁴

Frequency

International

Worldwide, 0.4-1.2 cases per million population occur each year.

Mortality/Morbidity

TEN has a mortality rate of 30-40%. Epithelial loss results in vulnerability to bacterial and fungal infections and predisposes to septicemia, the leading cause of morbidity and mortality. Mucosal membranes are affected to a varying extent and can cause GI hemorrhage, respiratory failure, ocular abnormalities, and genitourinary lesions. Significant fluid loss from extensive skin lesions as well as an inability to tolerate oral intake can lead to hypovolemia, acute tubular necrosis, and shock.

• A severity-of-illness score that estimates the risk of death in TEN has been developed and validated (SCORTEN).³
• • 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 (28mg/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.

Age

SJS and TEN usually occur in adults but may be seen in children. Age older than 40 years is an independent risk factor for mortality.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

Most cases of 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.

TEN 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 is often the predominating symptom.

Mucous membrane erosions (seen in 90% of cases of TEN) 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 sore or burning sensations. 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 may include the following:

• Pyrexia is usually present.
• The rash of TEN usually begins as centrally distributed, flat, atypical targets or purpuric macules. 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). 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 aphthouslike 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, and bronchiolitis obliterans.

Causes

Medications are the major precipitating cause of TEN. Many drugs are cited in the literature as the causative agent. However, no laboratory test is able to confirm a specific drug etiology. A causal link is suggested when TEN 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

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Paraneoplastic pemphigus

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• No definitive or specific emergent laboratory tests are indicated. Basic laboratory tests may be helpful in planning symptomatic or supportive therapy.
• • Diffuse skin involvement may cause significant fluid loss and electrolyte abnormalities. Renal failure can result from hypovolemic shock or sepsis.
  • Surveillance cultures of blood, skin, and urine should be obtained.

Imaging Studies

• No specific imaging studies are indicated.
• Chest radiography should be performed in the setting of respiratory distress because tracheobronchial inflammation may predispose to diffuse interstitial pulmonary disease or pneumonia.

Other Tests

• TEN is diagnosed by histopathologic analysis. Skin biopsy, harvested at the earliest possible stage, is important in establishing an accurate diagnosis and directing specific therapeutic modalities. Therefore, early involvement of a dermatologist and dermatopathologist is recommended.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital care is similar to that of burns.

• In severe TEN, the barrier function of the skin is compromised. Thus, contamination and evaporation must be minimized. The patient should be treated as a patient with extensive burns is treated, that is, with the application of sterile coverings.
• Fluid and pulmonary status must be carefully monitored.

Emergency Department Care

The two most important elements in the treatment of TEN is discontinuation of the offending drug and admission to a burn unit. Early recognition, prompt withdrawal of the causative agent, and referral to a burn center is key to successful outcome. Evidence suggests that early withdrawal of the offending agent and rapid admission to a burn unit is associated with a more favorable prognosis.^{5, 8} 

Emergency department care should be directed at minimizing fluid and electrolyte loss and preventing secondary infection. Aggressive fluid and electrolyte management, pain control, and meticulous skin care are important. Patients with extensive skin involvement require reverse isolation and a sterile environment.

• Areas of skin erosion should be covered with nonadherent protective dressings such as petroleum gauze.
• Respiratory distress may result from mucosal sloughing and edema and may necessitate endotracheal intubation and ventilation.
• Silver sulfadiazine should be avoided because it is a sulfonamide derivative and may precipitate TEN.
• Antibiotic prophylaxis is not indicated unless sepsis or staphylococcal scalded skin syndrome is strongly suspected.
• No specific treatment modality has been proven effective, including plasmapheresis, corticosteroids, cyclophosphamide, cyclosporin, TNF-alpha inhibitors, and intravenous immune globulin.  
• Immediately discontinue any potentially offending medications (if identified).

Consultations

In general, patients with TEN benefit from a team approach to diagnosis and management, including a dermatologist, dermatopathologist, a burn surgeon, and an intensivist.

• Patients with suspected TEN should be admitted to a burn unit as quickly as possible.
• Dermatologists may assist with diagnosis, biopsy, and inpatient treatment.
• Inpatient ophthalmology consultation is useful for assisting in the treatment of ocular manifestations and long-term sequelae.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• The mainstay of treatment is supportive care until the epithelium regenerates. Supportive measures include isolation, fluid and electrolyte balance, nutritional support, pain management, and protective dressings. Anesthetic mouthwash may alleviate the discomfort associated with oral erosions. Meticulous wound care is necessary to prevent secondary infection. Cutaneous lesions heal in approximately 2 weeks; mucosal membrane lesions take longer.

Transfer

• Patients with suspected TEN should be transferred to a burn unit for expert wound management and comprehensive, multidisciplinary care.

Complications

• Numerous complications can arise as a result of the widespread cutaneous and mucosal membrane inflammation and necrosis.
• • Skin: Epithelial loss predisposes to septicemia (Pseudomonas aeruginosa, Staphylococcus aureus, gram-negative species, and Candida albicans)
  • Mucosal membranes: Ulceration of various mucosal membranes results in pain, scarring, and stricture formation. Affected surfaces include oral, ocular, and urogenital mucosa.
  • Pulmonary: Inflammation of respiratory epithelium results in bronchial hypersecretion, hypoxemia, interstitial infiltrates, pulmonary edema, bacterial pneumonia, and bronchiolitis obliterans.
  • Gastrointestinal: GI hemorrhage results from intestinal inflammation.
  • Renal: Hypovolemia results from poor oral intake and/or septic shock results in renal hypoperfusion, acute tubular necrosis, and renal insufficiency.

Prognosis

• The overall prognosis of TEN is poor, with a mortality rate as high as 40%. Major sequelae are generally limited to the affected organ systems, that is, the skin and mucosal membranes. Mucosal lesions characteristically heal with scarring.
• • Cutaneous: Scarring may occur in areas of infection or over pressure points. Postinflammatory hyperpigmentation and nail growth abnormalities are frequent sequelae.
  • Ocular: Complications generally result from abnormal keratinization of the tarsal conjunctiva. A Sjögrenlike syndrome with decreased lacrimal secretion causes dry eye and predisposes to corneal abrasions and corneal scarring with neovascularization. In addition, patients have been reported to have palpebral synechiae, entropion, or symblepharon (adhesion of the eyelids).
  • Oral: Oral and lip lesions usually heal without complications, but strictures of the throat and esophagus have been reported.
  • Genitalia: Vulvovaginal synechiae and phimosis have been reported in the literature.

Patient Education

• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Life-Threatening Skin Rashes.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to refer suspected cases of TEN to a burn unit. 
• Failure to withdraw potentially offending drugs or institution of unnecessary pharmacologic therapies that may further exacerbate TEN.

Special Concerns

• Geriatric patients have an unfavorable prognosis.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

1. Ayangco L, Rogers RS 3rd. Oral manifestations of erythema multiforme. Dermatol Clin. Jan 2003;21(1):195-205. [Medline].
2. Bachot N, Roujeau JC. Differential diagnosis of severe cutaneous drug eruptions. Am J Clin Dermatol. 2003;4(8):561-72. [Medline].
3. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. Aug 2000;115(2):149-53. [Medline].
4. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. Apr 1 2004;428(6982):486. [Medline].
5. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?. Arch Dermatol. Mar 2000;136(3):323-7. [Medline].
6. Magina S, Lisboa C, Leal V, Palmares J, Mesquita-Guimaraes J. Dermatological and ophthalmological sequels in toxic epidermal necrolysis. Dermatology. 2003;207(1):33-6. [Medline].
7. Neff P, Meuli-Simmen C, Kempf W, Gaspert T, Meyer VE, Künzi W. Lyell syndrome revisited: analysis of 18 cases of severe bullous skin disease in a burns unit. Br J Plast Surg. Jan 2005;58(1):73-80. [Medline].
8. Palmieri TL, Greenhalgh DG, Saffle JR, Spence RJ, Peck MD, Jeng JC, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil. Mar-Apr 2002;23(2):87-96. [Medline].
9. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol. Feb 2007;56(2):181-200. [Medline].
10. Prendiville J. Stevens-Johnson syndrome and toxic epidermal necrolysis. Adv Dermatol. 2002;18:151-73. [Medline].
11. Roujeau JC, Guillaume JC, Fabre JP, Penso D, Fléchet ML, Girre JP. Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985. Arch Dermatol. Jan 1990;126(1):37-42. [Medline].

Article Last Updated: Sep 26, 2007