Excerpt from Toxic Epidermal Necrolysis

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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.

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