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Symptoms ⬇

Flu-like prodrome (fever, malaise, arthralgia, dysphagia), red eyes, eye pain/burning, and skin rash.

Signs ⬆ ⬇

Systemic

Classic “target” lesions (central red macule/papule surrounded by concentric circles of a pale/white intermediate zone and outer erythematous rim), atypical “target” lesions, dusky macules, bullous lesions, tender erythematous mucocutaneous lesions involving oral (e.g., ulcerative stomatitis; hemorrhagic lip crusting), GI, respiratory, or genital tracts.

Ocular

  • Acute phase: Mucopurulent or pseudomembranous conjunctivitis; episcleritis; iritis; corneal punctate erosions, epithelial defects, and ulcers; eyelid margin ulceration.
  • Late complications: Severe dry eye; trichiasis; conjunctival scarring, symblepharon, and ankyloblepharon; eyelid deformities (e.g., entropion); tear deficiency; corneal neovascularization, ulceration, perforation, or scarring.

Types

  1. EM minor: Mainly skin involvement; absent or mild mucosal involvement; no systemic symptoms.
  2. EM major: Skin involvement with moderate-to-severe mucosal involvement; usually has systemic symptoms.

SJS and TEN have severe mucosal involvement and are defined by the body surface area (BSA) of skin detachment.

  1. SJS: <10% BSA epidermal detachment.
  2. SJS–TEN overlap: 10% to 30% BSA epidermal detachment.
  3. TEN: >30% BSA epidermal detachment; most severe form with extensive vesiculobullous eruptions and epidermal sloughing. More common in children and immunosuppressed patients.

Etiology ⬆ ⬇

An immune complex–mediated hypersensitivity reaction precipitated by many agents.

Erythema Multiforme

  • Infectious agents (most common): herpes simplex virus, Mycoplasma pneumoniae, and adenovirus.
  • Rarely drug exposure.

Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

  • Drug exposure (most common): Antibiotics (sulfonamides, penicillins, cephalosporins), anticonvulsants (carbamazepine, phenytoin, barbiturates), NSAIDs (oxicam type), allopurinol, corticosteroids, and others. Highest risk of reaction occurs during the first 2 months of treatment.
  • Allergy and autoimmune diseases.
  • Genetics: HLA-B*15:02 and carbamazepine in Asian populations; HLA-B*58:01 and allopurinol.
  • Radiation therapy.
  • Malignancy.
  • Idiopathic (50% of cases).

Work Up ⬆ ⬇

Workup
  1. History: Attempt to determine the precipitating factor (e.g., drug exposure, recent illness).
  2. Slit lamp examination, including eyelid eversion with examination of the fornices.
  3. Conjunctival or corneal cultures if infection is suspected. See Appendix 8, CORNEAL CULTURE PROCEDURE.
  4. Consult internal medicine for a systemic workup and dermatology for a full-body examination and possible skin biopsy which may aid in the diagnosis.

Treatment ⬆ ⬇

EM: Supportive Care; Treat Underlying Infection if Identified

SJS, TEN

  1. Hospitalization, often requiring burn unit if available.
  2. Remove (e.g., drug) or treat (e.g., infection) the inciting factor.
  3. Supportive care is the mainstay of therapy.
  4. Comanagement with internal medicine and dermatology.

Ocular

  1. Ocular surface inflammation: Topical steroid drops (e.g., prednisolone acetate 1% or difluprednate 0.05% four to eight times per day).
  2. Tear deficiency: Aggressive lubrication with preservative-free artificial tears, gels, and ointments. Topical cyclosporine 0.05% to 2%, punctal occlusion, moisture chambers, or tarsorrhaphy.
  3. Iritis: Topical steroid drops (e.g., prednisolone acetate 1% or difluprednate 0.05% four to eight times per day) and cycloplegia (e.g., atropine 1% b.i.d.).
  4. Infections: Treat as outlined in 4.11, BACTERIAL KERATITIS.
  5. Conjunctival and/or eyelid margin defects: Daily pseudomembrane peel with moistened cotton swab. Symblepharon lysis and possible amniotic membrane graft (e.g., Prokera, AmnioGraft) to minimized scarring. In severe cases, consider suturing amniotic membrane over the eyelid margin, palpebral conjunctiva, and into the fornix during the hyperacute phase (<72 hours after disease onset). When epithelial defects of the conjunctiva, eyelid margin, and/or cornea are present, prophylactic topical antibiotics should also be utilized to prevent infection.
  6. Additional potential treatments:
    • Systemic or topical vitamin A.
    • Intravenous immunoglobulin.

Systemic

Manage by burn unit protocol, including hydration, wound care, and systemic antibiotics.

Follow Up ⬆

  1. During hospitalization: Follow daily, with infection and IOP surveillance.
  2. Outpatient: Weekly follow ups initially, watching for long-term ocular complications.
    • Topical steroids and antibiotics are maintained for 48 hours after resolution and are then tapered.
    • If there is severe conjunctival scarring, artificial tears and lubricating ointment may need to be maintained indefinitely.
  3. Possible late surgical interventions.
    • Trichiasis: Repeated epilation, electrolysis, cryotherapy, or surgical repair.
    • Entropion repair with buccal mucosal grafts.
    • Penetrating keratoplasty: Poor prognosis even when combined with limbal stem cell or amniotic membrane transplantation because of underlying deficiencies, such as dry eyes and limbal stem cell abnormality.
    • Permanent keratoprosthesis (guarded prognosis).

Prognosis

EM is typically self-limited but can recur. SJS and TEN are potentially fatal with average reported mortality rates of 1% to 5% in SJS and up to 25% to 35% in TEN. Ocular prognosis depends on the severity of conjunctival damage. Early amniotic membrane grafting covering the palpebral and bulbar conjunctival surfaces when indicated greatly improves the prognosis.

Erythema multiforme (EM) is distinct from Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS and TEN are considered variants along the same disease spectrum. All three conditions cause mucocutaneous lesions that can involve the eye.