Synonym: Lyell's syndrome, after Alan Lyell who first described 4 cases of toxic epidermal necrolysis in 1956 as 'an eruption resembling scalding of the skin'
Toxic epidermal necrolysis (TEN) is an acute-onset, potentially life-threatening, idiosyncratic mucocutaneous reaction, usually occurring after commencement of a new medication.
Widespread full-thickness epidermal necrosis develops, producing erythema, large blisters and/or exfoliation of large sheets of skin, leaving a raw base. The skin has an appearance similar to a scald. It usually affects the trunk, face and one or more mucous membranes.
It is considered by some as being part of a spectrum of disease which includes, in order of severity, erythema multiforme, Stevens-Johnson syndrome (SJS) and TEN. However, others argue that as erythema multiforme is associated with infections including herpes simplex virus and Mycoplasma pneumoniae, whereas SJS and TEN are necrolytic bullous reactions to certain drugs, erythema multiforme should not be classified as part of the same disease spectrum.
Another classification system works on the fact that SJS and TEN are related conditions which can be differentiated by the degree of skin involvement. Less than 10% of the epidermis sloughs off in SJS as compared with >30% in TEN.
There is thought to be an immune complex-mediated hypersensitivity reaction to the presence of toxic drug metabolites which accumulate in the skin. This reaction results in the destruction of keratinocytes.
Infection, malignancy and vaccination have also been suggested as other possible aetiologies. There may be no obvious trigger (idiopathic toxic epidermal necrolysis (TEN)).
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- Certain drugs: usually the reaction begins within 4 to 8 weeks after starting a new drug. There are many culpable medications. Those most commonly involved are:
- Anticonvulsants, especially phenobarbital, phenytoin, carbamazepine, valproate.
- Non-steroidal anti-inflammatory drugs, especially 'oxicam' derivatives such as piroxicam.
- The reaction is more rarely triggered by some immunisations and following bone marrow or organ transplantation. The skin manifestations of graft-versus-host disease are thought to have a similar aetiology to TEN.
- Infections such as mycoplasma and HIV are also associated.
- Systemic lupus erythematosus (SLE) and malignancy are thought to increase the risk of TEN.
- Worldwide incidence is 0.5 to 1.4 cases per million population per year.
- Females are more commonly affected.
- It can affect all age groups but is more common in elderly people, probably due to the increased numbers of drugs that they are prescribed.
- There is a prodromal phase lasting from 2-3 days to up to 3 weeks with fever, symptoms similar to upper respiratory tract infection, rash, conjunctivitis (32%), pharyngitis (25%), pruritus (28%), malaise, arthralgia and myalgia.
- Mucous membrane involvement occurs early in 90% of cases and commonly precedes other symptoms. The conjunctivae, buccal, nasal, pharyngeal, tracheobronchial, perineal, vaginal, urethral and anal mucosae may all be involved.
- An ill-defined red 'burning/painful' macular or papular rash then develops, spreading from the face or the upper trunk. Bullae form and then coalesce. They generally increase in number over 3-4 days (sometimes hours). The epidermis can then slough in sheets.
- There may be hyperpyrexia.
- Hypotension and tachycardia can develop secondary to dehydration and hypovolaemia.
- The Nikolsky sign: if areas of seemingly normal skin between lesions are rubbed, the epidermis easily separates from its underlying surface.
- Staphylococcal scalded skin syndrome (SSSS).
- Burns (chemical, light or heat).
- Bullous impetigo.
- Pemphigus, pemphigoid (generally of slower onset).
- Epidermolysis bullosa hereditaria.
- Scarlet fever (desquamation but no bullae).
- Other drug eruptions.
- Erythema multiforme.
- Bullous lichen planus.
- Toxic shock syndrome (toxin-mediated reaction to staphylococcal infection - check for infected tampons).
- Exfoliative dermatitis.
- There are no confirmatory tests.
- Skin biopsy and immunofluorescence staining should be considered if pemphigus/pemphigoid are suspected. There is full thickness epidermal necrosis in toxic epidermal necrolysis (TEN) plus epidermal detachment and sloughing.
- FBC, U&E, albumin, total protein and proteinuria must be closely monitored.
- Screening blood, urine and skin cultures should be collected.
- Multiple organ involvement occurs as TEN progresses.
- There is currently no generally accepted specific treatment regimen.
- Patients need transfer to a unit where they can receive intensive care, ideally a burns unit or HDU/ITU.
- A multidisciplinary approach to care is needed, including dermatologists, general physicians, surgeons, nurses and physiotherapists.
- Detection and withdrawal of potential causative agents are needed.
- Treatment is largely supportive. Fluid and electrolytes, infection and nutritional status all need very careful monitoring and treatment should be started as soon as possible. 
- Debridement of necrotic areas of skin may be needed. The exposed dermis needs protecting with skin grafting to prevent fluid and protein loss and infection as well as to control pain.
- Dressings, emollients and saline may be applied to the affected skin. Use of 'anti-shear' therapy, which utilises a type of dressing that minimises the removal of delicate granulation tissue, may be helpful.
- Antibiotics are generally not given prophylactically.
- Oral hygiene and ophthalmological treatment, including lubricants and topical antibiotics, are needed.
- Anticoagulation treatment reduces the risk of thromboembolism.
- High-dose steroids are sometimes used but the evidence base is contradictory and some studies have shown increased mortality. Serial skin biopsies may be useful in monitoring the response to steroids, and thus guide therapy. 
- Topical steroids may be useful when used early in ocular disease. 
- Intravenous human immunoglobulins showed positive results in some trials but this finding has been challenged.
- Other therapies that have been used, with mixed outcomes, include plasmapheresis, cyclophosphamide, pentoxifylline, thalidomide, anti-TNF-alpha antibodies and ciclosporin A.
- One study reported successful treatment with entanercept. 
- Small numbers involved in trials and the difficulty of enrolling critically ill patients mean that definitive evidence is hard to come by. Multicentre randomised controlled trials are needed to look at the treatments for toxic epidermal necrolysis (TEN).
- Widespread skin sepsis and septicaemia (50% of deaths in toxic epidermal necrolysis (TEN) are attributed to this).
- Pneumonia and respiratory failure.
- Dehydration (increased fluid loss, inability to drink if the mouth is involved).
- Hypovolaemic shock and acute tubular necrosis.
- Thermoregulatory disturbance.
- Ocular damage, corneal involvement and visual loss (5-9% of patients with TEN become blind).
- Stomatitis and mucositis.
- Gastrointestinal haemorrhage.
- Pulmonary embolism.
- Oesophageal strictures and dysphagia.
- Gynaecological and obstetric complications - premature labour, long-term painful genitourinary lesions, vaginal stenosis, adenosis and telangiectasia. 
- Hypopigmentation or hyperpigmentation of skin; there may be scarring if infection has developed.
Mortality is between 10-70%. It depends on the quality of care and rapidity of diagnosis and treatment. A severity-of-illness score has been developed called the SCORTEN Scale. A score of one is given to each of the following prognostic factors if they are present:
- Age >40.
- Heart rate >120 bpm.
- The presence of cancer or haematological malignancy.
- Involved body surface area >10%.
- Serum urea >10 mmol/L.
- Serum bicarbonate <20 mmol/L.
- Serum glucose >14 mmol/L.
A mortality risk can then be attributed to the scores achieved:
- Score 0-1: 3.2%
- Score of 2: 12.1%
- Score of 3: 35.3%
- Score of 4: 58.3%
- Score of ≥5: 90%
Patients who survive must be warned which drugs to avoid in the future.
Further reading & references
- LYELL A; Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956 Nov;68(11):355-61.
- Becker DS; Toxic epidermal necrolysis. Lancet. 1998 May 9;351(9113):1417-20.
- Freiman A, Borsuk D, Sasseville D; Dermatologic emergencies.CMAJ November 22, 2005; 173 (11).
- Cohen V et al; Toxic Epidermal Necrolysis, eMedicine, Feb 2009
- Ahmed R, Eagleton C; Toxic epidermal necrolysis after paroxetine treatment. N Z Med J. 2008 May 23;121(1274):86-9.
- Kardaun SH, Jonkman MF; Dexamethasone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144-8.
- Hanken I, Schimmer M, Sander CA; Basic measures and systemic medical treatment of patients with toxic epidermal J Dtsch Dermatol Ges. 2009 Oct 21.
- Borchers AT, Lee JL, Naguwa SM, et al; Stevens-Johnson syndrome and toxic epidermal necrolysis. Autoimmun Rev. 2008 Sep;7(8):598-605. Epub 2008 Jul 9.
- Qadir SN, Raza N, Qadir F; Drug induced toxic epidermal necrolysis: two case reports. Cases J. 2009 Sep 9;2:7765.
- Halebian PH, Corder VJ, Madden MR, et al; Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg. 1986 Nov;204(5):503-12.
- O'Donoghue JM, Cespedes YP, Rockley PF, et al; O'Donoghue JM, Cespedes YP, Rockley PF, et al; Skin biopsies to assess response to systemic corticosteroid therapy in Cutis. 2009 Sep;84(3):138-40, 161-2.
- Sotozono C, Ueta M, Koizumi N, et al; Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal Ophthalmology. 2009 Apr;116(4):685-90. Epub 2009 Feb 25.
- Tan AW, Thong BY, Yip LW, et al; High-dose intravenous immunoglobulins in the treatment of toxic epidermal necrolysis: an Asian series. J Dermatol. 2005 Jan;32(1):1-6.
- Trent JT, Kirsner RS, Romanelli P, et al; Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol. 2003 Jan;139(1):39-43.
- Khalili B, Bahna SL; Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol. 2006 Sep;97(3):272-80; quiz 281-3, 320.
- Paquet P, Pierard GE, Quatresooz P; Novel treatments for drug-induced toxic epidermal necrolysis (Lyell's syndrome). Int Arch Allergy Immunol. 2005 Mar;136(3):205-16. Epub 2005 Feb 15.
- Brown KM, Silver GM, Halerz M, et al; Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil. 2004 Jan-Feb;25(1):81-8.
- Lissia M, Mulas P, Bulla A, et al; Toxic epidermal necrolysis (Lyell's disease). Burns. 2009 Sep 17.
- Gubinelli E, Canzona F, Tonanzi T, et al; Toxic epidermal necrolysis successfully treated with etanercept. J Dermatol. 2009 Mar;36(3):150-3.
- Niemeijer IC, van Praag MC, van Gemund N; Relevance and consequences of erythema multiforme, Stevens-Johnson syndrome and Arch Gynecol Obstet. 2009 Nov;280(5):851-4. Epub 2009 Mar 11.
|Original Author: Dr Michelle Wright, Dr Laurence Knott||Current Version: Dr Hayley Willacy|
|Last Checked: 20/04/2011||Document ID: 2878 Version: 23||© EMIS|
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