Toxic epidermal necrolysis L51.2

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

epidermolysis acuta toxica; Epidermolysis necroticans combustiformis; Lyell Syndrome; Lyell syndrome drug; medicinal; Necrolysis toxic epidermal; Scalded skin syndrome; SJS/TEN; TEN; toxic epidermal necrolysis

History
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Lyell, 1956

Definition
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Severe maximum variant of a drug reaction characterized by extensive detachment of the skin and mucous membranes, severe systemic concomitant symptoms and high mortality (20-50%). The risk of TEN is highest between the 4th and 28th day after initiation of drug therapy. The disease is considered a maximum variant of SJS syndrome ( Stevens-Johnson syndrome) with a minimum infestation of > 30% of the body surface.

Occurrence/Epidemiology
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  • Incidence: About 0.15-0.18/100,000 inhabitants/year.
  • More common in patients with manifest AIDS (incidence is 100/100,000 per year for those infected with HIV).

Etiopathogenesis
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  • The pathogenesis is unknown. Clinical and histological similarities to severe cutaneous graft-versus-host reactions suggest a common pathogenesis. Various drugs such as cotrimoxazole and other sulfonamides, antiepileptic drugs, allopurinol (probably the most common cause!), oxicam (non-steroidal anti-inflammatory drug), psychotropic drugs, anticonvulsants (e.g. phenytoin and phenobarbital), serotonin reuptake inhibitors (e.g. fluoxetine) have been shown to trigger a TEN.
  • For the widely used drugs such as beta-blockers, ACE inhibitors, calcium channel blockers, thiazides, furosemide, sulfonylureas and insulin, no evidence of an increased risk could be found.
  • Vaccinations ( measles, mumps, rubella) have been described as triggers in the literature. For specific concomitant diseases such as HIV, collagenoses, tumor diseases, radiotherapy and acute infections within the last 4 weeks a significant risk could be calculated.

Manifestation
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  • Predominantly women are affected (up to 10 times more frequently than men).
  • The average age is 60-70 LJ.
  • Children and young people are very rarely affected.

Localization
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Mostly the face, trunk and the extensor sides of the extremities are affected.

Clinical features
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  • Initially finely spotted, later confluent, large-area initially macular, subsequently maculopapular and finally vesicular exanthema. Furthermore: extensive epidermal detachment (epidermal necrolysis) with skin that can be removed like a towel.
  • Early involvement of upper and lower eyelids with hemorrhagic encrusting erosions.
  • Conjunctivitis with tendency to symblepharon formation.
  • Mouth and genital mucosa: Inflammatory redness, erosions, ulcerations, haemorrhagic encrustation, possible adhesions.
  • General: High fever, possibly somnolence, fatigue
  • Frequently rapid intensive duty!

Laboratory
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Lymphopenic leukocytosis. Alpha and gamma globulin fraction are elevated.

Histology
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  • Extensive necrolysis of the epidermis with intra- and subepidermal blister formation. Bladder contents are mostly hemorrhagic. Oedematized dermis, epitheliotropic round cell infiltrates and vasodilatation are also observed.
  • Cryostat section: For a quick diagnosis a biopsy with a fresh blister cover, which is formed by the entire epidermis, is necessary.

Differential diagnosis
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Complication(s)
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  • Skin: scarring, pigmentation disorders, nail growth disorders ( Beau-Reilsche transverse furrows of the nails, nail loss). Diffuse toxic alopecia (usually reversible) (see Alopecia). Bacterial or viral infections of the skin. Risk of sepsis with development of shock and multiorgan failure (most frequent cause of death). Changes in the mucous membrane of the oropharynx, genitals or anal region.
  • Eyes: initial mucopurulent inflammation, conjunctival necrosis (destruction of goblet cells, cornification), corneal ulcers. Later consequences are scarring with trichiasis, keratoconjunctivitis sicca or synechia.
  • Kidneys: Tubular necrosis.
  • Lungs: respiratory failure.
  • Gastrointestinal tract: Bleeding.
  • Blood: Leukopenia
  • Loss of fluid, electrolytes and protein.

General therapy
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General guidelines for the therapy of TEN:
  • Intensive care in appropriately equipped therapy units.
  • Discontinuation of the medication in question.
  • Isolation/protection against infection (set up airlock).
  • Aseptic protective clothing: protective gowns, mouthguards, gloves for medical and nursing staff.
  • Sufficient heat supply (exact temperature control).
  • Ensure sufficient moisture content of the room air.
  • Use special bed for decubitus prophylaxis and store on metal foil.
  • If necessary, place a bladder catheter, urine and fluid balancing.
  • Documentation of the collected findings (extent, severity on intensive care treatment sheets).
  • If necessary, take swabs of the wound surfaces (culture with resistance behaviour; danger from Pseudomonas colonisation and other superinfections).
  • Therapy of complications (sepsis, bleeding).

Internal therapy
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Glucocorticoids: The use of systemic glucocorticoids is controversially discussed. Some studies indicate a worse prognosis with high-dose glucocorticoid medication. Nevertheless, a short-term shock therapy is still recommended (1000-250-100-20 mg prednisolone on day 1 to 4 i.v.). Ulcer prophylaxis with ranitidine (e.g. Zantic) 150 mg/day.

Ciclosporin A: Controversially discussed so far, a large Spanish study (n=26 patients) demonstrated a significant reduction of the mortality risk compared to a group not treated with Ciclosporin A (IVIG therapy) (Gonzales-Herrada C et al. (2017).

IVIG: Initial 1.0 g/kg bw for 4 days and maintenance therapy of 0.5 g/kg bw (4-weekly rhythm) over several months in case of resistance to therapy of other regimes. Data: The efficiency of IVIG therapy is controversially discussed on the basis of evidence level IIA studies.

Antibiotics (only in case of superinfection): Antibiotic coverage with cephalosporins such as cefotaxime (e.g. claforan) 2 times/day 2 g i.v., if necessary in combination with gentamicin (e.g. refobacin) 240 mg/day i.v. daily i.v. Swabs taken on the wound surfaces and if necessary conversion of the antibiotic treatment according to the antibiogram.

Pain therapy: Morphine (e.g. MST Tbl.) 10-30 mg every 8 hours or opioids such as tramadol (Tramal) 100 mg every 4-6 hours (max. 400 mg/day).

  • Fluid balancing: In case of severe courses, initiate fluid balancing and parenteral nutrition. Dosage scheme per day:
    • Colloidal solution 1 ml/kg KG x KO.
    • Electrolyte solution (physiological saline solution) 1 ml/kg KO.
      On stabilization: transition to high-calorific liquid food (e.g. meritene). Later diet with passed food; no spices, no fruit acids.
  • Notice! Check intravenous accesses regularly (high risk of contamination)!

  • Remember! With glucocorticoid administration and therapy with Ciclosporin A, a bacterial cause of TEN (Staphylogenes Lyell Syndrome) must be excluded!

Progression/forecast
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The lethality rate is about 20-25%, in smaller studies up to 60%. Intensive measures are necessary. The skin changes usually heal without scars. Bastuji-Garin et al. developed a score which should allow a predictive statement on mortality. See below for scores.

Note(s)
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Remember! Report to the Documentation Centre of Severe Skin Reactions, Dermatological Clinic of the University of Freiburg, Hauptstr. 7, 79104 Freiburg. Web: http://www.ukl.uni-freiburg.de/haut/dzh/homede.htm

Literature
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  1. Bachot N et al (2001) Physiopathology and treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 1: 293-298
  2. Boujeau JC et al (1990) Toxic epidermal necrolysis (Lyell syndrome). Arch Dermatol 126: 37-42
  3. Campione E et al (2003) High-dose intraveous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venerol 83: 430-432
  4. González-Herrada C et al (2017) Cyclosporine Use in Epidermal Necrolysis Is Associated with an ImportantMortality
    Reduction: Evidence from Three Different Approaches. J Invest Dermatol 137:2092-2100.
  5. Halvey e t al (2008) Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe in Israel. JAAD 58: 25-32
  6. Hanken et al (2010) Primary care and drug treatment of patients with toxic epidermal necrolysis. JDDG 8: 341-347
  7. Luther H, Kastner U, Altmeyer P (1999) Comment on the contribution by Lyell A (1956) Toxic epidermal necrolysis: An eruption resembling scaling of the skin. Br J Dermatol 68: 355-361
  8. Mockenhaupt M et al (2008) Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 128: 35-44
  9. Nassif A et al (2002) Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 118: 728-733
  10. Prins C et al Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 139: 26-32
  11. Roujeau JC et al (1990) Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 6: 1039-1062
  12. Schöpf E et al (1991) Toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol 127: 839-842
  13. Spornraft-Ragaller P et al (2007) Treatment of toxic epidermal necrolysis. Experiences in nine patients considering intravenous immunoglobulins. skin 2: 62-68
  14. Trent JT et al (2003) Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 139: 39-43
  15. Wolff K et al (2003) Treatment of toxic epidermal necrolysis: the uncertainty persists but the fog is dispersing. Arch Dermatol 139: 85-86

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 29.10.2020