Toxic Epidermal NecrolysisSynonym: Lyell's syndrome, after Alan Lyell who first described four cases of toxic epidermal necrolysis in 1956as 'an eruption resembling scalding of the skin.'

Toxic epidermal necrolysis (TEN) is an acute-onset, potentially life-threatening, idiosyncratic mucocutaneousreaction, usually occurring after commencement of a new medication.

Widespread full-thickness epidermal necrosis develops, producing erythema, and sloughing of the skin andmucosa, involving internal and external surfaces. [1] The skin has an appearance similar to a scald. It usuallyaffects 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, erythemamultiforme, Stevens-Johnson syndrome (SJS) and TEN. However, this remains debatable. As erythemamultiforme is associated with infections including herpes simplex virus and Mycoplasma pneumoniae, whereasSJS and TEN are necrolytic bullous reactions to certain drugs, it may be that erythema multiforme should not beclassified as part of the same disease spectrum. [2] Many accept that SJS and TEN are variants of the samecondition. [3]

Definitions vary and another classification system works on the fact that SJS and TEN are related conditionswhich can be differentiated by the degree of skin involvement. Less of the epidermis sloughs off in SJS, whereasTEN may be defined as involving >30% of the total body surface area. [4] [5]

Aetiology [1] [6] There is thought to be an immune complex-mediated hypersensitivity reaction to the presence of toxic drugmetabolites which accumulate in the skin. This reaction results in the destruction of keratinocytes. Specifically,cytotoxic T lymphocytes cause keratinocyte damage and subsequent necrosis, mediated by granzyme B.Cytotoxic molecules including FasL and granulysin have been implicated as causing the widespread keratinocyteapoptosis.

Risk factorsCertain drugs: usually the reaction begins within a few days to two months after starting a new drug.There are many culpable medications. More than 200 have been associated with SJS/TEN. [3] Thosemost commonly involved are:

Sulfonamides.Ampicillin.QuinolonesCefalosporins.Anticonvulsants - phenobarbital, phenytoin, carbamazepine, lamotrigine and valproate.Allopurinol.Antiretrovirals.Corticosteroids.Non-steroidal anti-inflammatory drugs, especially 'oxicam' derivatives such as piroxicamand meloxicam.

The reaction is more rarely triggered by some immunisations and following bone marrow or organtransplantation. The skin manifestations of graft-versus-host disease are thought to have a similaraetiology to TEN.Infections such as mycoplasma and HIV are also associated and are known to trigger TEN without anydrug exposure.Systemic lupus erythematosus (SLE) and malignancy are thought to increase the risk of TEN.In some cases there is no identifiable cause.

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Genetic factors seem to play a part in some cases, with study results varying geographically. Forthose of East Asian descent, in particular, it may be important to perform testing for HLA-B 1502 priorto starting treatment with carbamazepine. [7]

EpidemiologyWorldwide incidence is 1-2 cases per million population per year. [4] It can affect all age groups but is more common in elderly people, perhaps due to the increasednumbers of drugs that they are prescribed.

PresentationThere is a prodromal phase usually lasting 2-3 days with fever, symptoms similar to upper respiratorytract infection, conjunctivitis, pharyngitis, pruritus, malaise, arthralgia and myalgia.Mucous membrane involvement occurs early in 90% of cases and commonly precedes othersymptoms. [6] 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 orthe 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.Nikolsky's sign may be positive: if areas of seemingly normal skin between lesions are rubbed, theepidermis easily separates from its underlying surface.

Differential diagnosisStaphylococcal scalded skin syndrome (SSSS).Burns (chemical, light or heat).Bullous impetigo.Pemphigus, pemphigoid (generally of slower onset).Epidermolysis bullosa hereditaria.SLE.Scarlet fever (desquamation but no bullae).Other drug eruptions.Erythema multiforme.Bullous lichen planus.Toxic shock syndrome (toxin-mediated reaction to staphylococcal infection - may be due to infectedmenstrual tampons).Erythroderma/exfoliative dermatitis.

InvestigationsThere are no confirmatory tests.Skin biopsy is used to distinguish from SSSS, and immunofluorescence staining is performed. Thereis full thickness epidermal necrosis in TEN plus epidermal detachment and sloughing.Percentage of body surface area affected distinguishes SJS from TEN.FBC, U&E, albumin, total protein and proteinuria must be closely monitored.Screening blood, urine and skin cultures should be collected.

ManagementManagement involves identifying the causative agent early where possible, and withdrawing it, alongwith supportive care. Early cessation of the causative drug is associated with better outcomes. [3] Patients need transfer to a unit where they can receive intensive care, ideally a burns unit or HDU/ITU.Early admission to a burns or high dependency unit improves survival and reduces infection. [3] A multidisciplinary approach to care is needed, including dermatologists, general physicians,surgeons, nurses and physiotherapists.Treatment is largely supportive. Fluid and electrolytes, infection and nutritional status all need verycareful monitoring and treatment should be started as soon as possible. [8]

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Debridement of necrotic areas of skin may be needed. The exposed dermis needs protecting with skingrafting 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, whichutilises a type of dressing that minimises the removal of delicate granulation tissue, may be helpful. [9]No specific treatment has been demonstrated to be effective in a randomised controlled trial. [10]Treatments which have been used, but for which benefit remains uncertain, include: [6] [7]

Intravenous immunoglobulins. [11] Systemic steroids. [12] [13] Plasmapheresis.Ciclosporin A. [14] Tumour necrosis factor (TNF) antagonists - eg, infliximab, etanercept. [15] [16]

Antibiotics are generally not given prophylactically.Oral hygiene and ophthalmological treatment, including lubricants and topical antibiotics, may beneeded.Anticoagulation treatment reduces the risk of thromboembolism.Topical steroids may be useful when used early in ocular disease. [17]Early ophthalmological advice isessential to reduce the risk of ophthalmological sequelae.Small numbers involved in trials and the difficulty of enrolling critically ill patients mean that definitiveevidence is hard to come by. Multicentre randomised controlled trials are needed to look at thetreatments for TEN. [18]

Complications [3] Acute phase

Widespread skin sepsis and septicaemia.Pneumonia and respiratory failure.Dehydration (increased fluid loss, inability to drink if the mouth is involved).Hypovolaemic shock and multi-organ failure.Thromboembolism, including pulmonary embolism, and disseminated intravascular coagulopathy.Thermoregulatory disturbance.

Long-term

Ocular complications, which may lead to blindness. 50% of those surviving TEN are said to developocular complications such as: [6]

Dry eyes or watery eyes (the most common - 46% of cases).Conjunctivitis.Corneal ulcers.Symblepharon.Ectropion and entropion.Trichiasis.Synechiae.

Joint contractures.Loss of nails.Stomatitis and mucositis.Gastrointestinal haemorrhage.Oesophageal strictures and dysphagia.PhimosisGynaecological and obstetric complications - premature labour, long-term painful genitourinary lesions,vaginal stenosis, adenosis and telangiectasias. [19]Hypopigmentation or hyperpigmentation of skin; there may be scarring if infection has developed.

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PrognosisMortality risk increases with the surface area involved, and is between 16-55%. [4] It also depends on the qualityof care and rapidity of diagnosis and treatment. A severity-of-illness score called the SCORTEN Scale is used,and has been demonstrated to have prognostic accuracy. [20] A score of one is given to each of the followingprognostic 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 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%

PreventionPatients who survive must be warned which drugs to avoid in the future, and the reaction documented andhighlighted in their records.

Further reading & references1. Schwartz RA, McDonough PH, Lee BW; Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical

features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013 Aug;69(2):173.e1-13;quiz 185-6. doi: 10.1016/j.jaad.2013.05.003.

2. Tomasini C, Derlino F, Quaglino P, et al; From erythema multiforme to toxic epidermal necrolysis. Same spectrum ordifferent diseases? G Ital Dermatol Venereol. 2014 Apr;149(2):243-61.

3. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis; DermNet NZ4. Abela C, Hartmann CE, De Leo A, et al; Toxic epidermal necrolysis (TEN): The Chelsea and Westminster Hospital wound

management algorithm. J Plast Reconstr Aesthet Surg. 2014 Aug;67(8):1026-32. doi: 10.1016/j.bjps.2014.04.003. Epub2014 May 9.

5. Freiman A, Borsuk D, Sasseville D; Dermatologic emergencies. CMAJ November 22, 2005; 173 (11).6. Harr T, French LE; Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010 Dec 16;5:39.7. Schwartz RA, McDonough PH, Lee BW; Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential

diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013 Aug;69(2):187.e1-16; quiz 203-4. doi:10.1016/j.jaad.2013.05.002.

8. Hanken I, Schimmer M, Sander CA; Basic measures and systemic medical treatment of patients with toxic epidermal JDtsch Dermatol Ges. 2009 Oct 21.

9. Borchers AT, Lee JL, Naguwa SM, et al; Stevens-Johnson syndrome and toxic epidermal necrolysis. Autoimmun Rev. 2008Sep;7(8):598-605. Epub 2008 Jul 9.

10. Khalifian S, Ibrahim Z, Lilo MT, et al; Toxic epidermal necrolysis. Eplasty. 2014 Mar 15;14:ic6. eCollection 2014.11. Huang YC, Li YC, Chen TJ; The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a

systematic review and meta-analysis. Br J Dermatol. 2012 Aug;167(2):424-32. doi: 10.1111/j.1365-2133.2012.10965.x.12. Kardaun SH, Jonkman MF; Dexamethasone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta

Derm Venereol. 2007;87(2):144-8.13. Yang Y, Xu J, Li F, et al; Combination therapy of intravenous immunoglobulin and corticosteroid in the treatment of toxic

epidermal necrolysis and Stevens-Johnson syndrome: a retrospective comparative study in China. Int J Dermatol. 2009Oct;48(10):1122-8. doi: 10.1111/j.1365-4632.2009.04166.x.

14. Valeyrie-Allanore L, Wolkenstein P, Brochard L, et al; Open trial of ciclosporin treatment for Stevens-Johnson syndromeand toxic epidermal necrolysis. Br J Dermatol. 2010 Oct;163(4):847-53. doi: 10.1111/j.1365-2133.2010.09863.x.

15. Meiss F, Helmbold P, Meykadeh N, et al; Overlap of acute generalized exanthematous pustulosis and toxic epidermalnecrolysis: response to antitumour necrosis factor-alpha antibody infliximab: report of three cases. J Eur Acad DermatolVenereol. 2007 May;21(5):717-9.

16. Paradisi A, Abeni D, Bergamo F, et al ; Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol. 2014Aug;71(2):278-83. doi: 10.1016/j.jaad.2014.04.044. Epub 2014 Jun 11.

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17. Sotozono C, Ueta M, Koizumi N, et al; Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermalOphthalmology. 2009 Apr;116(4):685-90. Epub 2009 Feb 25.

18. Khalili B, Bahna SL; Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermalnecrolysis. Ann Allergy Asthma Immunol. 2006 Sep;97(3):272-80; quiz 281-3, 320.

19. Niemeijer IC, van Praag MC, van Gemund N; Relevance and consequences of erythema multiforme, Stevens-Johnsonsyndrome and Arch Gynecol Obstet. 2009 Nov;280(5):851-4. Epub 2009 Mar 11.

20. Sekula P, Liss Y, Davidovici B, et al; Evaluation of SCORTEN on a cohort of patients with Stevens-Johnson syndrome andtoxic epidermal necrolysis included in the RegiSCAR study. J Burn Care Res. 2011 Mar-Apr;32(2):237-45. doi:10.1097/BCR.0b013e31820aafbc.

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Original Author:Dr Michelle Wright

Current Version:Dr Mary Harding

Peer Reviewer:Dr Jacqueline Payne

Document ID:2878 (v24)

Last Checked:22/08/2014

Next Review:21/08/2019

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