Erythema Multiforme Major

Aka: Erythema Multiforme Major, Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Stevens Johnson Syndrome, Stevens Johnson

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II. Definitions

  1. Erythema Multiforme Major
    1. Acute Life-threatening Hypersensitivity Skin Reaction
  2. Stevens Johnson Syndrome (SJS)
    1. Affects <10% of body surface area
  3. SJS-TEN Overlap
    1. Affects 10-30% of body surface area
  4. Toxic Epidermal Necrolysis (TEN)
    1. Affects 30% of body surface area

III. Pathophysiology

  1. Severe clinical variant of Erythema Multiforme
  2. Previously thought to be part of same spectrum as Erythema Multiforme Minor
    1. Now thought to be clinically distinct

IV. Epidemiology

  1. Most common in winter and early spring
  2. More common in adult women, but affects children of either gender equally
  3. Incidence U.S.
    1. Stevens Johnson Syndrome: 1 to 7 per million people per year
    2. Toxic Epidermal Necrolysis: 0.4 to 1.5 per million people per year

V. Causes

  1. See Erythema Multiforme Causes
  2. Drug-Induced Skin Reactions are the most common cause of erythema mutiforme major
    1. Contrast with Erythema Multiforme Minor which is most often due to infection (esp. HSV, Mycoplasma)
    2. Medications cause 50% of Stevens Johnson cases
    3. Medications cause 90% of Toxic Epidermal Necrolysis cases
    4. Highest risk with higher doses and rapid drug introduction
    5. Most common with Trimethoprim-Sulfamethoxazole (Bactrim)
      1. Risk with Trimethoprim-Sulfamethoxazole is up to 40 fold higher in HIV Infection

VI. Symptoms

  1. Prodrome (onset 1-3 weeks after causative exposure)
    1. Fever
    2. Malaise
    3. Headache
    4. Cough
    5. Diffuse pain
  2. Sudden widespread skin eruption (onset 1-3 days after exposure)
    1. See below

VII. Signs

  1. Patient may appear toxic (esp. Toxic Epidermal Necrolysis)
  2. Pathognomonic target lesions
    1. Widespread skin involvement
    2. See Erythema Multiforme for course and specific description
    3. Positive Nikolsky Sign in both Stevens-Johnson and Toxic Epidermal Necrolysis
    4. Epidermal detachment is >30% in Toxic Epidermal Necrolysis (10% in Stevens-Johnson)
  3. Mucosal bullae to erosions (severe in 20% of cases)
    1. Oral Mucosal involvement is most common (genital and ocular involvement may also occur)
    2. Mucosal lesions start as red, edematous lesions that progress to superficial erosions with pseudomembrane
    3. Oral Mucosa may lead to inadequate oral intake (due to painful Oral Ulcers)
    4. Respiratory bullae may lead to respiratory distress or Respiratory Failure
  4. Ocular involvement (30% of children, 70% of adults)
    1. May cause Conjunctivitis, Keratitis, Endophthalmitis
  5. Lesion distribution
    1. Starts on face and trunk and spreads peripherally
    2. Typically symmetrical

VIII. Differential Diagnosis

  1. See Erythema Multiforme Differential Diagnosis

IX. Diagnosis

  1. Clinical diagnosis
  2. Skin biopsy confirms the diagnosis
    1. Apoptosis and necrosis
    2. Keratinocyte vacuolization
    3. Dermal-epidermal separation
    4. Perivascular Lymphocyte infiltration

X. Complications

  1. Secondary Skin Infections and Sepsis (Staphylococcus aureus, Pseudomonas)
    1. Most common cause of death
  2. Pulmonary involvement (Hypoxemia, hypercarbia, Respiratory Failure)
  3. Renal involvement (Acute Glomerulonephritis, Acute Renal Failure)
  4. Corneal scarring (related to Corneal Ulceration)
  5. Gastrointestinal conditions (ileus, Acute Hepatitis, hepatocellular necrosis)

XI. Labs

  1. No lab tests are specific for Stevens Johnson Syndrome

XII. Management

  1. Withdraw all potential causative agents
  2. Intensive Care unit (or burn unit) admission for SCORTEN Score >2
  3. Supportive care
    1. Fluid Resuscitation with 2 ml/kg/BSA%
    2. Nutritional Support
    3. Opioid Analgesics are typically required
    4. Wound care
    5. Antibiotics only where specifically indicated
    6. Avoid Systemic Corticosteroids (use not supported by evidence)
    7. Oral Ulcer symptomatic management
  4. Specific immunologic agents that have been used in stevens-johnson and TEN
    1. Intravenous Immunoglobulin
    2. Cyclosporine
    3. Methotrexate
    4. N-Acetylcysteine
    5. Infliximab
    6. Azathioprine
    7. Cyclophosphamide
  5. Other measures
    1. Ophthalmology consult for eye involvement (Corneal dehiscence)
    2. Rewetting drops

XIII. Prognosis

  1. See SCORTEN Score
  2. Mortality due to Sepsis, multi-organ failure
    1. Stevens Johnson: 1-3%
    2. Toxic Epidermal Necrolysis: 30-50%

XIV. Prevention

  1. Patient Education when prescribing drugs associated with Stevens-Johnson
    1. Immediately stop suspected drug (see causes above) if symptoms suggestive of Stevens-Johnson
    2. Skin pain, redness or Blister development with systemic symptoms (e.g. fever, Pharyngitis)
    3. Seek medical attention and do not reintroduce the suspected medication
    4. (2013) Presc Lett 20(10): 59

XV. References

  1. Behar and Claudius in Herbert (2020) EM:Rap 20(7): 8-9
  2. Long (2016) Crit Dec Emerg Med 30(7):3-10
  3. Mockenhaupt (2008) J Invest Dermatol 128(1):35-44 [PubMed]
  4. Parrillo (2007) Curr Allergy Asthma Rep 7(4): 243-7 [PubMed]
  5. Trayes (2019) Am Fam Physician 100(2): 82-8 [PubMed]
  6. Usatine (2010) Am Fam Physician 82(7): 773-80 [PubMed]

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