AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Alan Lyell provided an early description of toxic epidermal necrolysis (TEN) in 1956. Lyell described toxic epidermal necrolysis as "an eruption resembling scalding of the skin." This dermatological condition is characterized by extensive epidermal loss suggestive of severe scalding. In this same year, Lang and Walker also observed a patient with toxic epidermal necrolysis, which was, in fact, originally described in 1939 in French as "l'erythrodermie bulleuses avec epidermolyse." Two of Lyell's original patients were later classified by him as having another disease, staphylococcal scalded skin syndrome¹, which is due to Staphylococcus aureus infections rather than a probable drug hypersensitivity-type reaction. Histopathologic analysis of the skin remains the main tool for discrimination between the two conditions.

Toxic epidermal necrolysis is a potentially life-threatening skin disorder that most commonly is drug induced. However, other etiologies, including infection, malignancy, and vaccinations, may exist. Toxic epidermal necrolysis is idiosyncratic, and its occurrence is not predicted easily. Some authors believe Stevens-Johnson syndrome (SJS) is a manifestation of the same process, with the latter representing more extensive necrotic epidermal detachment.

Pathophysiology

The pathophysiology has not been fully elucidated; however, various theories have received wide acceptance. Toxic epidermal necrolysis is believed to be an immune-related cytotoxic reaction aimed at destroying keratinocytes that express a foreign antigen.

The condition mimics a hypersensitivity reaction, with its characteristic delayed reaction to an initial exposure and more rapid reaction with repeated exposure.

Explanations for the generalized nature of toxic epidermal necrolysis include the belief that overexpression of tumor necrosis factor-a (TNF-a) in the epidermis occurs. Therefore, TNF-a is likely to play an important role in epidermal destruction directly through apoptosis, indirectly through stimulating cytotoxic T lymphocytes, or both.

Frequency

United States

Frequency is reported to be 0.22-1.23 cases per 100,000 population.

International

The average incidence is 0.5-1.4 cases per million population per year. In 1992, the cumulative incidence in Germany of SJS-TEN was 1.9 cases per million population per year. A French survey of dermatologists and health care facilities reported a rare incidence of 1 case per million population per year.

Mortality/Morbidity

Mortality is estimated to be 10-70%, depending on the quality of care and the rapidity with which treatment is initiated. Morbidity depends on the aggressiveness of the treatment strategy. Toxic epidermal necrolysis is associated with a slow healing and recovery of 3-6 weeks, which depends on the extensiveness and severity of the lesions and associated complications.

• Survivors usually have long-term sequelae that are both debilitating and disfiguring.
• Skin typically heals without scarring unless infection develops.
• Disturbances in pigmentation are reported in 88% of cases.
• The risk of death in patients with toxic epidermal necrolysis can be accurately predicted by the toxic epidermal necrolysis–specific severity-of-illness score (SCORTEN). A score of 0-1 indicates a mortality risk of 3.2%; score of 2, 12.1%; score of 3, 35.3%; score of 4, 58.3%; and a score of 5 or more, 90%. Each of the following independent prognostic factors is given a score of one:
  
  
  • Age of greater than 40 years
  • Heart rate of greater than 120 beats per minute
  • Cancer/hematologic malignancy
  • Involved body surface area of greater than 10%
  • Serum urea level of more than 10 mmol/L
  • Serum bicarbonate level of less than 20 mmol/L
  • Serum glucose level of more than 14 mmol/L

Sex

For unclear reasons, females appear to have a greater predilection for developing toxic epidermal necrolysis than males (female-to-male ratio of 1.6:1).

Age

• Toxic epidermal necrolysis may occur in all age groups.
• The mean age of patients with toxic epidermal necrolysis is reported to be between 46 and 63 years.
• Elderly persons may be at greater risk because of their tendency to use multiple medications.

CLINICAL

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History

• Patients may describe a prodrome characterized by 2-3 days of malaise, rash, fever, cough, arthralgia, myalgia, rhinitis, headache, anorexia, and nausea and vomiting, with or without diarrhea.
• Other prodromal signs and symptoms that may develop include conjunctivitis (32%), pharyngitis (25%), and pruritus (28%). The prodrome typically lasts from one day to as long as 3 weeks.
• Toxic epidermal necrolysis is associated with an acute phase (8-12 d) consisting of persistent fevers, generalized epidermal sloughing, and mucous membrane involvement. Complications include stomatitis and mucositis, which are painful and hinder oral intake; therefore, patients are at risk for dehydration and malnutrition.
• The conjunctivae are commonly affected 1-3 days prior to the appearance of skin lesions.
• Buccal, nasal, pharyngeal, and tracheobronchial denudation and erosion may be present.
• Esophageal and perineal denudation and erosion may be present.
• Vaginal, urethral, and anal mucosal denudation and erosion may be present.
• The chief complaint is often generalized pain associated with a rash.

Physical

Vital signs may include hyperpyrexia, hypotension secondary to hypovolemia, and tachycardia.

• Skin examination
• • Skin lesions begin as painful/burning, warm, erythematous, morbilliform macules that are initially discrete. They begin symmetrically on the face and thorax before spreading to the entire body and becoming confluent. The epidermis sloughs in sheets, leaving a characteristic moist, denuded dermis. Denudation and erosions of mucous membranes precede epidermal necrolysis.
  • A positive Nikolsky sign is evident when pressure is applied laterally to the epidermal surface, and the epidermis easily separates from its underlying surface.
  • Hemorrhagic crusting of the lips is a common finding (see Image 2).
  • Conjunctivitis is commonly observed before full sloughing of the epidermis (with associated pain).
  • Pneumonia is a major complication, resulting in acute respiratory failure and the need for intubation.
  • The usual course is an intense erythema that progresses rapidly to epidermolysis and stops in 2-3 days. Dermatologic recovery typically takes 1-3 weeks, with mucosal lesions taking longer. Rarely, necrolysis can recur in areas that began to heal.

Causes

Toxic epidermal necrolysis can be drug induced, the result of infection, or without apparent cause (idiopathic). Frequent drug-induced causes include antiepileptic drugs, sulfonamides, ampicillin, allopurinol, and nonsteroidal anti-inflammatory agents.

• Antibacterial sulfonamides - 4.5 cases per million users per week
• • Chloramphenicol
  • Macrolides (erythromycin)
  • Penicillins
  • Quinolones (ciprofloxacin, trovafloxacin)

• Nonsteroidal anti-inflammatory drugs
• • Phenylbutazone and oxybutazone - Are implicated most commonly, though they are no longer available in the United States
  • Oxicams (piroxicam, tenoxicam) - Are implicated at greater frequency than other nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Ibuprofen, indomethacin, sulindac, and tolmetin

• Anticonvulsants
• • Phenobarbital, phenytoin, carbamazepine, and valproic acid: Risk has been reported to occur within 2 months of initiation. However, some cases associated with chronic use have been reported.
  • Lamotrigine

• Allopurinol
• • Risk is not constant over time.
  • Patients have a 5.5 relative risk. However, during the first 2 months of therapy, relative risk is 52, and long-term therapy risk is 0.5.

• Topical and systemic corticosteroids

DIFFERENTIALS

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Other Problems to be Considered

Burns, cauterization
Caustic agents
Generalized bullous fixed eruption
Kerosene, paraffin burns
Staphylococcal scalded skin syndrome
Stevens-Johnson syndrome
Hypersensitivity vasculitis
Pemphigus vulgaris
Pemphigus foliaceus
Pseudoporphyria

WORKUP

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Lab Studies

• Hematology studies
• • CBC and differential
  • Circulating immune complexes
  • Eosinophilia
  • Erythrocyte sedimentation rate
  • Neutropenia (minority of cases but, when present, is an unfavorable prognostic sign)

• Chemistry to assess fluid and electrolyte losses
• • Albumin
  • Blood urea nitrogen
  • Proteinuria
  • Total protein

• Liver enzyme tests
• Acute phase
• • Transient decreases of peripheral CD4⁺ T lymphocytes
  • Reduced allogeneic and natural killer cell cytotoxicity, which returns to normal in 7-10 days

• Coagulation studies
• • Prothrombin time/international normalized ratio (INR)
  • Activated partial thromboplastin time

• Blood, urine, and skin cultures
• As toxic epidermal necrolysis progresses, multiple organs are affected, causing other abnormalities in laboratory test results.

Imaging Studies

• Imaging studies are not indicated for the diagnosis of toxic epidermal necrolysis; however, radiography may be helpful to direct treatment.

Procedures

• A skin biopsy specimen must be obtained. In experienced hands, a frozen section specimen may be taken to expedite matters.

Histologic Findings

Histologically, one sees full thickness epidermal necrosis with little evidence of epidermal or dermal inflammation. There may be epidermal detachment and sloughing. Satellite cell necrosis may be seen early, progressing to extensive eosinophilic necrosis (see Procedures).

TREATMENT

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Medical Care

Management requires prompt detection and withdrawal of all potential causative agents, evaluation, and largely supportive care. Early transfer of patients to a burn or intensive care unit has been shown to reduce risk of infection, mortality rate, and length of hospitalization. No controlled prospective treatment studies or generally accepted guidelines exist. Avakian and colleagues (1991) have published the University of Florida treatment protocol for toxic epidermal necrolysis, which includes the following²:

• Monitor fluids and electrolytes. Administer fluids and titrate based on central venous pressure and urine output. On average, 3-4 L are needed for patients with 50% of the body surface area affected. Nutrition by parenteral means or enterally via a soft-fine bore nasogastric tube usually is needed. Start total parenteral nutrition in patients unable to take nourishment. Early and continuous enteral nutrition reduces the risk of stress ulcers, reduces bacterial translocation and enterogenic infection, and allows earlier discontinuation of venous lines.
• Nonpharmacological therapies include the following:
• • Withdraw all unnecessary medications.
  • Withdraw the offending agent as soon as possible. One observational study showed a reduction in mortality from 26% to 5% when the implicated drugs with short elimination half-lives were withdrawn no later than the day the blisters or erosions first developed.
  • Provide daily physical therapy for range-of-motion exercises.
  • Place a central or intravenous line in areas of uninvolved skin.
  • Consider the use of plasmapheresis, if available, daily for 3 days. Plasmapheresis may enhance elimination of the drug or offending agent or inflammatory mediators such as cytokines and should be considered.
  • Under general anesthesia, necrotic and desquamation areas are débrided within a few hours of admission.
  • Apply porcine xenografts to involved areas.
  • Irrigate the eyes every hour.
  • Provide hydrotherapy (whirlpool) twice a day. Repair and replace porcine xenografts.
  • Apply Kerlix dressings soaked in silver nitrate 0.5% to involved areas after each whirlpool session.
  • Administer Peridex mouthwash 4 times a day.
  • Rinse the mouth frequently, and apply a topical anesthetic or spray for buccal pain. Cyclophosphamide and cyclosporine have been employed with some success, but no randomized controlled studies have been performed.
  • Place patient in a heated environment to enhance reepithelialization. However, this may enhance water losses, and appropriate hydration must be maintained. Institute a bed warmer.
  • Place a Foley catheter and nasogastric tube only when needed.
  • Consider blood transfusions when hematological complications, such as marked anemia, are evident.
• Pharmacological therapies include the following:
• • Start systemic antibiotics for documented infection or signs of sepsis.
  • Emergence of resistance precludes the use of prophylactic antibiotics. Empiric antimicrobial therapy should include broad-spectrum antimicrobials that cover gram-negative, gram-positive, and anaerobic organisms. If staphylococcal infection is involved, administer an appropriate antistaphylococcal agent (ie, nafcillin/oxacillin for methicillin sensitive organisms or vancomycin for methicillin-resistant organisms).
  • Provide pain relief with patient controlled analgesia (PCA). Opiate analgesics for skin pain and anxiety are essential for comforting patients.
  • Hydroxyzine may be employed when reepithelialization begins because intense pruritus may occur.
  • Corticosteroids commonly are employed to cease progression, but this is highly controversial. In some studies, corticosteroids have increased the incidence of mortality.
  • Patients remain nonambulatory until skin begins to heal. Until that time, anticoagulant therapy is imperative. Heparin is indicated for prophylaxis of thromboembolic events.
  • Saline applied to skin hourly is important, and then emollients are smeared.
  • Chlorhexidine solution is used to bathe the patient's skin.
  • Apply chloramphenicol ointment to prevent infection. Avoid use of silver sulfadiazine cream. Silvadene cream is a sulfa medication, a category of drugs often implicated as a cause of toxic epidermal necrolysis.

Consultations

• Most patients require specialized care under the direction of physicians with experience in handling this disorder. Burn-unit care represents an option worthy of serious consideration.
• A dermatologist is consulted to identify and to confirm toxic epidermal necrolysis.
• A plastic surgeon is consulted to débride areas of skin necrosis, as indicated.
• An ophthalmologist is consulted to prevent conjunctival-corneal adhesions, especially if vision is threatened. Ophthalmological complications are common and may require long term treatment with corticosteroids.
• An internal medicine specialist is consulted to assist in patient treatment.
• Respiratory medicine consultation may be important, since respiratory mucosa may slough. Establishment of pulmonary toilet may be advisable.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Crystalloids

Employed as initial imperative medication in toxic epidermal necrolysis, which is supportive care. In cases of acute skin failure, insensible losses may be enormous, and repletion of water loss is essential.

Drug Category: Corticosteroids

While corticosteroids may be employed, their use is highly controversial. In one study, a reduction of mortality by 50% was attributed solely to not using corticosteroids. Many believe that corticosteroids should not be used because they predispose patients to infection, mask early signs of sepsis, encourage GI bleeding, and impair or delay wound healing.

However, in some published literature, high-dose corticosteroids have been employed early in the onset of the toxic epidermal necrolysis reaction (within 24-48 h) and have demonstrated a halt in the progression of the reaction.

Ultimately, the initial high dose is titrated down as quickly as possible and tapered off, usually over 7-10 days.

For many, corticosteroids still are the anchor of therapy for patients with toxic epidermal necrolysis. Withholding corticosteroids may prolong reaction and delay healing, increasing damage. However, corticosteroids also have been reported to increase morbidity and mortality, and some experts have not recommended their use.

Drug Category: Antibiotics

Patients with toxic epidermal necrolysis lose their epidermis, a major barrier to invading organisms. If patients become infected, morbidity is enhanced. Bacterial sampling of skin lesions should be performed the first day and every 48 hours. Indicators for antibiotic treatment include increased number of bacteria cultured from the skin with selection of a single strain, sudden decrease in temperature, or deterioration of the patient's condition. S aureus is the main bacteria present during the first days, with gram-negative strains appearing later.

Aspiration pneumonia is a major complication and results in increased mortality. Therefore, empiric antimicrobial therapy is essential to treat patients with signs and symptoms suggestive of sepsis. Case reports of Klebsiella species, Escherichia coli, and Pseudomonas species recovered from patients with toxic epidermal necrolysis have created concern about the possible polymicrobial nature of sepsis associated with this condition. Therefore, good gram-negative coverage may be necessary.

Drug Category: Antianxiety medications

Hydroxyzine may be employed when reepithelialization begins because intense pruritus may occur.

Drug Category: Anticoagulants

Heparin is indicated for prophylaxis of thromboembolic events. Patients remain nonambulatory until skin begins to heal. Until that time, anticoagulant therapy is imperative.

Drug Category: Analgesics

Opiate analgesics are important to alleviate pain and anxiety associated with toxic epidermal necrolysis. Much like a second-degree burn, the pain must not be ignored.

Drug Category: Antiseptics

Inhibit growth of gram-positive and gram-negative bacteria.

Drug Category: Local topical anesthetics

Topical anesthetics can be applied to mucous membranes, especially buccal, if pain occurs.

FOLLOW-UP

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Further Inpatient Care

• Plasmapheresis may enhance elimination of etiologic agents.
• Place patient in a warm environment to enhance reepithelialization. Avoid dehydration.
• Blood transfusion may be needed if anemia occurs.

Further Outpatient Care

• Avoid exposure to the causative agent by ensuring that all health care team members are aware of the initial reaction.
• Cross-reactivity may occur with agents that chemically resemble the causative agent.

Transfer

• Most patients require transfer to a burn or intensive care unit, with specialized consultation by dermatologists, pulmonologists, gastroenterologists, plastic surgeons, and others with advanced knowledge.

Deterrence/Prevention

• Educate patient about which substances to avoid.

Complications

• Complications include stomatitis and mucositis, which are painful and hinder oral intake; therefore, patients are at risk for dehydration and malnutrition.
• Cutaneous complications
• • Bacterial wound infections
  • Changes in skin pigment (hypopigmentation or hyperpigmentation) (Sun exposure must be avoided for several months because UV light can worsen hyperpigmentation. Sunblock is recommended.)
  • Nail loss and nail dystrophy
  • Hypohidrosis (inability to sweat)
  • Scarring, alopecia, and hypertrophic scarring
  • Dermal desiccation, causing deep dermal wounds


• Mucosal complications: Barrera and colleagues (1998) reported a case of hypopharyngeal stenosis and dysphagia with recurrent aspiration.³ Toxic epidermal necrolysis occurred after the patient ingested Aleve (naproxen sodium) and aspirin. Other complications include the following:
• • Chronic xerostomia
  • Esophageal strictures
  • Perianal abscesses
  • Phimosis
  • Chronic erosion of the mouth and genitalia


• Ocular complications occurred in 50% of patients in a study by WJ Power and colleagues (1995).⁴ Patients treated with steroids fared no better than those treated without steroids. Therefore, toxic epidermal necrolysis remains a common cause of visual loss in a significant number of patients. Complications include the following:
• • Conjunctivitis, ranging from mild hyperemia to purulent, crusting, or ulcerative conjunctivitis usually is painful and may result in formation of a pseudomembrane.
  • Photophobia may occur.
  • Ectropion or entropion with subsequent trichiasis may occur.
  • Symblepharon formation may occur.
  • Vascularization of the cornea may occur.
  • Corneal opacities, punctate corneal lesions, corneal ulcerations, and scarring also have been observed. Note that corticosteroid ophthalmologic drops are not effective in preventing the activity of corneal lesions.
  • Chronic dry eyes are a complication of scar formation in the conjunctiva and the resultant lacrimal duct destruction. These patients are no longer able to produce tears. Artificial tears and lubricants are often prescribed.
  • Ankylo-symblepharon results in conjunctival scarring and destruction, which causes complete fusion of the eyelids and leads to blindness.
  • Ultimately, 5-9% of patients can become blind as a result of some of these complications.


• Pulmonary complications may occur. Mucous retention and sloughing of tracheobronchial mucosa may occur, with aspiration of mucosal debris. Pneumonia and pneumonitis are frequent and sometimes fatal complications of toxic epidermal necrolysis.
• Hematologic complications: Leukopenia is common, whether a result of toxic epidermal necrolysis itself or of a bacteremia, as is a normochromic normocytic anemia. Less often, thrombocytopenia, neutropenia, and bandemia may be seen.
• Sepsis: This can be a disastrous complication, with more than 50% of deaths in toxic epidermal necrolysis attributed to it.
• Miscellaneous complications include hypovolemia, massive gut bleeding, and pulmonary emboli.

Prognosis

• Age, area of necrosis, and serum urea level are said to be the most important prognostic factors.⁵ Patients who are elderly have a poor prognosis.
• Other major prognostic factors
• • Extent of necrolysis
  • Elevated serum blood urea nitrogen and creatinine levels
  • Respiratory failure
  • Multiple drugs
  • Thrombocytopenia
  • Lymphopenia
  • Neutropenia
  • Leukopenia
  • Sepsis

Patient Education

• Counsel patients on what drugs they cannot take.

• Genetic factors are suspected in drug-induced blistering disorders, and blood relatives of the patient should not use the suspected drug.
• Patients must call a pharmacist whenever they start a new prescription.
• 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

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Medical/Legal Pitfalls

• Failure to warn patients that an agent that induced a previous episode of toxic epidermal necrolysis may also be used in a combination product is a potential pitfall. For example, a patient with a history of toxic epidermal necrolysis induced by a sulfonamide may not know that one component of Bactrim is a sulfonamide.
• Not recognizing the severity of disease
• Failure to withdraw the causative agent in time
• Failure to treat the patient with antibiotics when indicated
• Failure to monitor hemodynamics effectively
• Prescribing an agent that is structurally similar to the agent that caused the original toxic epidermal necrolysis reaction
• Failure to institute anticoagulation for prevention of thromboembolism

MULTIMEDIA

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Media file 1:  Toxic epidermal necrolysis (TEN) ulcer in great toe (initial infection).
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Media file 2:  Hemorrhagic crusting of mucous membranes in toxic epidermal necrolysis (TEN).
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Media type:  Photo

Media file 3:  Maculopapular rash in toxic epidermal necrolysis (TEN).
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Media type:  CT

Media file 4:  Diffuse maculopapular rash in toxic epidermal necrolysis (TEN).
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Media type:  Photo

Media file 5:  Toxic epidermal necrolysis (TEN) blister on the index finger.
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Media type:  Photo

Media file 6:  Epidermal sloughing in toxic epidermal necrolysis (TEN).
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Media type:  Photo

REFERENCES

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4. Power WJ, Ghoraishi M, Merayo-Lloves J. Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology. Nov 1995;102(11):1669-76. [Medline].
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28. Paul C, Wolkenstein P, Adle H. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol. Apr 1996;134(4):710-4. [Medline].
29. Petersen KM. Erythema multiforme, Steven-Johnson syndrome, and toxic epidermal necrolysis. Pediatric Pharmacotherapy. 1998;4:[Full Text].
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Article Last Updated: May 16, 2006