Erythema Multiforme


A 22-year-old African American woman noted 2 lesions on her lip that she thought were insect bites. The lesions were painful and red, and within the next 2 days they had spread to her tongue and oral cavity. She developed odynophagia, bleeding of the oral mucosa, and throat tightness. She presented to an emergency department (ED) where she was diagnosed with herpes simplex virus (HSV) infection and was discharged with prescriptions for ibuprofen and cephalexin. Although the reason is not clear, the cephalexin presumably was given for what the ED provider diagnosed as a bacterial superinfection.

Immediately after starting the cephalexin, the woman developed pruritic cutaneous eruptions on her neck, trunk, and upper extremities, which later progressed to her lower extremities, vaginal mucosa, and lastly to her ocular mucosa. She reported discharge from the vaginal and ocular lesions, as well as subjective fevers, blurry vision, dysuria, nausea, and vomiting. She denied cough. She stopped taking the cephalexin, but she did not seek medical attention until 11 days later, when she began having difficulty swallowing saliva.

Physical examination. The patient was afebrile, with a heart rate of 92 beats/min, blood pressure of 106/58 mm Hg, respiratory rate of 19 breaths/min, and oxygen saturation of 98% on room air. She was in mild to moderate distress, was unable to speak without pain, and communicated by writing on a notepad. She had small ulcerations involving the medial canthus of the eye bilaterally, as well as blistering and erosions on the vermilion border of her lips (Figure 1). On her left forearm was a 2-cm coalescence of vesicular papules with a raised, erythematous border (Figure 2). She also had multiple 0.5-cm targetoid lesions with excoriation marks on her neck, arms, trunk, and legs, with sparing of the palms and soles (Figure 3). A speculum examination of the vagina was not tolerated due to pain; however, multiple herpetic-appearing lesions were noted externally on the left labial fold and posterior fourchette, associated with diffuse erythema and copious yellowish discharge.

Diagnostic tests. Laboratory studies showed an elevated erythrocyte sedimentation rate of 62 mm/h and an elevated C-reactive protein level of 59 mg/L. The Epstein-Barr virus (EBV) viral-capsid antigen test result was positive. The remainder of her laboratory tests were nonreactive, including herpes antigen direct fluorescent antibody, gonorrhea and chlamydia, HIV, hepatitis B and C, rapid plasma reagin, and antinuclear antibody tests. Complete blood count and comprehensive metabolic panel findings were within normal limits.

Hospital course. A dermatologist was consulted to evaluate erythema multiforme (EM) versus Stevens-Johnson syndrome (SJS). The patient was started on empiric intravenous acyclovir out of concern for HSV infection, as well as methylprednisolone sodium succinate injection for suspected drug reaction.

On day 2 of admission, the patient’s oral and cutaneous lesions started to improve. A skin biopsy showed focal epidermal necrosis and superficial and perivascular infiltrate, consistent with EM. She was started on artificial tears and Lacri-Lube eye ointment, “magic mouthwash” (aluminum hydroxide/magnesium
hydroxide/simethicone/diphenhydramine/lidocaine) for mucositis and odynophagia, mupirocin for the open cutaneous lesions, and topical lidocaine and betamethasone dipropionate for the vaginal lesions.

The patient showed marked clinical improvement on day 5 of hospitalization, and she was able to tolerate food without difficulty. She was discharged the following day on famciclovir, 500 mg, 3 times a day for an additional week, with outpatient follow-up in ophthalmology and dermatology clinics.

Discussion. EM is characterized by an eruption of macules, papules, and target lesions that often are symmetrically distributed on the extremities.1,2 The target lesions help distinguish EM from SJS, a similar skin condition that tends to present with confluent purpuric macules and severe mucosal erosions.1 Mucosal involvement in EM usually is minimal. In both conditions, sites include the oral mucosa (most common), the labial mucosa, the ocular mucosa, and, less frequently, the upper respiratory and pharyngeal mucosa.3,4 Skin desquamation, if present, usually does not exceed 10%.5 EM is thought to be the result of an immune-mediated hypersensitivity reaction that most commonly is mediated by HSV-1 and -2, Mycoplasma pneumoniae, or drugs.1 EBV is another potential cause, although it is more rare.6 EM typically is self-limited, with symptoms lasting 1 to 2 weeks on average.4

Diagnosis. The diagnosis of EM is based on the clinical history and clinical findings, with the use of skin biopsies and histopathology tests to help rule out imitators of EM.4 HSV infection testing can be done via Tzanck smear, polymerase chain reaction tests, or viral culture4; however, HSV testing is not required for the diagnosis of EM.1

Treatment. If the etiology of the patient’s EM is determined, the first step in management is to treat the underlying infection or to stop the offending drug.1 In mild cutaneous cases of EM, management often is conservative, consisting of topical corticosteroids and topical analgesics, and oral antihistamines for pruritus if needed.3,4 Mucosal involvement that is painful and leads to insufficient oral intake may require more aggressive care such as systemic glucocorticoids.4 Lidocaine mouth rinses, lidocaine gel, high-potency topical corticosteroid gel, and oral antiseptic washes are other mainstays of oral care.3


  1. Lamoreux MR, Sternbach MR, Hsu WT. Erythema multiforme. Am Fam Physician. 2006;74(11):1883-1888.
  2. Habif TP. Hypersensitivity syndromes and vasculitis. In: Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 4th ed. New York, NY: Mosby; 2004:626-634.
  3. Ayangco L, Rogers R III. Oral manifestations of erythema multiforme. Dermatol Clin. 2003;21(1):195-205.
  4. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902.
  5. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J. 2003;9(1):1.
  6. Nakai H, Sugata K, Usui C, et al. A case of erythema multiforme associated with primary Epstein-Barr virus infection. Pediatr Dermatol. 2011;28(1):23-25.