• Infections (≥80%) : primarily HSV-1/HSV-2 (reactivation); also Mycoplasma pneumoniae (primarily mucosal manifestations; now recognized as MIRM , a distinct entity from ME/SJS). Samim 2013 , Aurelian 2003 , Canavan 2015

• Medications : less frequent than in SJS/TEN (antibiotics, NSAIDs, anticonvulsants). Leaute-Labréze 2000

• Other : Post-vaccine cases/emerging viral infections (e.g., COVID-19) reported, generally sporadic. Saleh 2024

• Elementary lesion : erythematous papule/plaque that evolves into a typical target lesion (three concentric zones; violaceous or bullous center, pale edematous ring, erythematous halo). Kechichian 2024

• Distribution : acral (dorsum of hands/forearms, feet) with centripetal extension; symmetrical. Trajectories 2019

• Mucous membranes : up to 16–70% (lips/oral, genital, ocular); major MS involves ≥2 mucous membranes ± skin; minor MS : skin ± one mucous membrane. Farthing 1995 , Scully 2008

• Prodrome : fever, malaise, sore throat; in HSV infections, herpetic lesions usually precede the infection by 3–14 days. Samim 2013

• Evolution : self-limited (2–4 weeks), recurrences possible (associated with HSV reactivation). Hafsi 2024

• Atypical forms :

  • Oral EM : extensive labial and oral erosions/hemorrhages with minimal skin involvement. Ayangco 2003

  • Persistent/recalcitrant MS : continuous activity for months/years; requires immunomodulation. Wetter 2010

  • MIRM (key differential): prominent mucositis, scant skin; separate entity. Canavan 2015

• SJS/TEN (distinct entities: extensive purpuric macules/flat “atypical targets”, diffuse epidermal necrosis, ≥2 mucous membranes, greater systemic toxicity).
• Urticaria multiforme (pediatric; whey, evanescent <24 hours; acral edema).
• Fixed Pigmentary Erythema (purple plaques, fewer lesions, recurrence in the same places).
• Pityriasis rosea, viral exanthems, polymorphic light reaction, paraneoplasia pemphigoid, pemphigus/pemphigoid, urticarial vasculitis, HFMD, Erythema Nodosum.

• Pattern : vacuolar interface dermatitis with scattered necrotic keratinocytes (keratolysis/apoptosis), papillary edema; superficial perivascular lymphocytic infiltrate ± mild spongiosis; subepidermal cleavage may be present in bullous lesions. Howland 1984 , Rzany 1996

• Direct immunofluorescence (DIF) : nonspecific findings ; frequent IgM/C3/fibrin in superficial vessels or cytoid bodies; usually negative for IgG . Bushkell ​​1980 , Finan 1984 , Kechichian 2024

• Tissue virology (MS-HSV) : detection of HSV DNA in lesions/epidermis (PCR) supports a cell-mediated hypersensitivity mechanism against viral antigens carried by monocytes. Brice 1989 , Darragh 1991 , Aurelian 2003

• SJS/TEN (epidermal necrosis) more extensive (even diffuse), little initial inflammation.
• Fixed Pigmentary Erythema (lichenoid interface dermatitis with pigmentary incontinence marked, eosinophils, melanophages).
• Drug-induced lichen planus/lichenoid (dense bands in papillary dermis, hypergranulosis).
• Pityriasis lichenoides, GVHD Graft-vs-Host Disease, cutaneous lupus, paraneoplastic pemphigoid (positive IIF), leukocytoclastic vasculitis (if there is purple).

• Trigger search :

  • HSV : PCR/culture in active herpetic lesions; serology has limited utility. Samim 2013

  • Mycoplasma : Nasopharyngeal PCR and/or IgM/IgG serology; chest X-ray/CT scan if respiratory symptoms are present. Schalock 2006

• Severity/complications : complete blood count, liver/kidney profile, electrolytes; ophthalmological evaluation if ocular involvement is present. Scully 2008

• Biopsy:

  • Type : 4–5 mm punch of early target lesion (raised border) for H&E; additional perilesional staining in physiological saline or Michel's solution for IFD if the diagnosis is doubtful. Mysorekar 2015 , Howland 1984

  • FixationFormalin 10%, for IFD place in physiological saline (coordinate with the laboratory for immediate collection)

  • Considerations : avoid ulcerated/necrotic areas; discontinue topical corticosteroids 24–48 h if safe

Objectives : relieve symptoms, prevent relapses (if EM-HSV), treat trigger, protect mucous membranes/eyes.

General measures (all forms)

• Analgesia, mucosal care (analgesic rinses), hydration/nutrition; management of severe oral pain and local infection prophylaxis. Scully 2008

Antivirals (HSV-associated MS, acute or recurrent)

• Continuous prophylaxis with acyclovir 400 mg orally every 12 hours for 6 months (RCT evidence; reduces the median number of flares during treatment to 0). Tatnall 1995

• Alternatives/failure to acyclovir: valacyclovir (e.g., 500 mg PO every 12–24 h) useful in series/CA; adjust to GFR. Kerob 1998 , Staikuniene 2015

• In pediatrics: studies support acyclovir 20 mg/kg/day divided into doses. Weston 1997

Antibiotics (suspected/confirmed Mycoplasma )

• Macrolides or doxycycline depending on age/risk, plus mucosal support ; consider that many cases correspond to MIRM (not classic MS). Schalock 2006 , Canavan 2015

Systemic corticosteroids

• Controversial use ; inconclusive evidence of benefit in MS; reserve for selected cases with severe mucosal involvement after ruling out SJS/TEN and with close monitoring. Michaels 2009

Recurrent/persistent MS refractory to antivirals (selected cases; observational evidence)

• Dapsone (e.g., 50–100 mg/d) after ruling out G6PD deficiency. Oak 2017 , Hoffman 2006

• Thalidomide (response in 2/3 of a cohort; TERATOGENIC: restricted use).

• Mycophenolate mofetil (variable responses). Wetter 2010

• Other reports: colchicine, hydroxychloroquine, levamisole (limited data). Soares 2021

Care/Safety

• Antivirals : adjust for renal function; headache, GI disturbances; minimal interactions. Tatnall 1995

• Dapsone : hemolysis/metHb (↑ risk in G6PD-), hepatotoxicity; monitor CBC, bilirubin, metHb. Oak 2017

• Thalidomide : peripheral neuropathy, absolute teratogenicity ; thrombosis.

• Mycophenolate : cytopenias, infections; teratogen . Wetter 2010

• Suspected SJS/TEN (disproportionate skin pain, flat purpuric macules, Nikolsky's sign, detached BSA): refer/admit urgently . Bastuji-Garin 1993

• Ocular involvement (pain, photophobia, pseudomembranes): early ophthalmological evaluation. Scully 2008

• Dehydration/inability to eat due to oral pain; assess IV hydration/nutrition. Ayangco 2003

• Recurrent MS : investigate and administer antiviral prophylaxis if related to HSV. Tatnall 1995

• La acral elevated “classic” target lesion favors MS over SJS/TEN (which shows flat/atypical targets and purpuric macules). Bastuji-Garin 1993

• IFD is not diagnostic (nonspecific pattern); use it to exclude other processes. Bushkell ​​1980

• Recurrent “idiopathic” MS is often subclinically associated with HSV and responds to prophylaxis with acyclovir/valacyclovir. Tatnall 1995

• In children with prominent mucositis and few skin lesions, consider MIRM and order PCR for Mycoplasma . Canavan 2015

• Kechichian E, et al. Erythema multiforme. eClinicalMedicine. 2024;67:102293. **PMID:**39583748. **DOI:**10.1016/j.eclinm.2024.102293. Abstract: Current review of etiology (HSV, Mycoplasma ), clinical presentation, immunofluorescence, and contemporary management. PubMed / PMC

• Samim F, et al. Erythema multiforme: review of epidemiology, pathogenesis, clinical features, and management. J Am Dent Assoc. 2013;144(2):166-75. **PMID:**24034067. **DOI:**10.14219/jada.archive.2013.0090. Abstract: Clinical and epidemiological review; highlights HSV as the main trigger. PubMed

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