Overview
Definition:
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous condition characterized by a sudden onset of target lesions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are more severe, life-threatening variants, distinguished by the extent of epidermal detachment, often triggered by medications or infections.
Epidemiology:
EM is relatively common in children, with peak incidence in adolescents and young adults
SJS and TEN are rare but carry significant morbidity and mortality, with higher incidence in adults
however, pediatric cases occur
Herpes simplex virus (HSV) is a common trigger for EM in children
medications are more frequent culprits for SJS/TEN.
Clinical Significance:
Accurate differentiation is critical due to the vastly different prognoses and management strategies
EM is typically self-limiting, while SJS/TEN requires immediate withdrawal of offending agents, intensive supportive care, and potentially specialized dermatologic or burn unit management
Misdiagnosis can lead to delayed life-saving interventions and increased mortality.
Clinical Presentation
Symptoms:
EM: Abrupt onset of symmetrical, erythematous lesions
Lesions may be pruritic or painful
Sore throat and malaise may precede rash
SJS/TEN: Prodromal symptoms of fever, malaise, myalgias, sore throat, cough, and conjunctivitis for 1-3 days
Mucosal involvement (oral, ocular, genital) is typically severe and painful
Skin pain is a prominent symptom.
Signs:
EM: Target lesions (iris lesions) are pathognomonic: dusky center, erythematous ring, and pale surrounding area
Lesions are typically distributed symmetrically on extremities, particularly palms and soles
Mucosal lesions can be present but are usually less severe than in SJS/TEN
SJS/TEN: Widespread erythematous or purpuric macules that coalesce into blisters and epidermal detachment
Nikolsky sign is positive in areas of epidermal detachment
Mucosal erosions are extensive and painful, affecting >2 oral sites, ocular surfaces, and genital areas
Ocular involvement can lead to symblepharon and blindness
Genital involvement can cause phimosis and urethral strictures.
Diagnostic Criteria:
SCORTEN score (Score for TEN) is used to predict mortality in SJS/TEN but not for initial diagnosis
Severity is based on Body Surface Area (BSA) detachment: EM minor (<1% BSA), EM major (1-10% BSA), SJS (10-30% BSA), TEN (>30% BSA)
Definitive diagnosis of SJS/TEN is often confirmed by skin biopsy showing full-thickness epidermal necrosis and subepidermal blistering, with minimal dermal inflammation.
Diagnostic Approach
History Taking:
Detailed drug history is paramount, including all prescription, over-the-counter medications, and herbal supplements, noting the timing of onset relative to drug initiation
History of recent viral infections (especially HSV), vaccinations, and underlying conditions like autoimmune disorders or malignancies
Assess the progression and severity of symptoms, particularly mucosal and ocular involvement.
Physical Examination:
Thorough examination of the entire skin surface, noting the morphology and distribution of lesions
Assess for target lesions (EM) versus atypical targets, macules, blisters, and epidermal detachment (SJS/TEN)
Meticulous examination of oral mucosa (pain, erosions), ocular conjunctiva (redness, discharge, photophobia), and anogenital region
Evaluate for signs of systemic involvement like respiratory distress or hemodynamic instability.
Investigations:
Complete Blood Count (CBC) may show leukocytosis or leukopenia
Electrolytes and renal function tests (RRT) are crucial due to fluid losses and potential organ involvement
Liver function tests (LFTs) assess hepatic involvement
Blood cultures if fever or signs of sepsis
Viral serology (HSV PCR) if suspecting herpes-associated EM
Skin biopsy is essential for differentiating severe EM from SJS/TEN, showing full-thickness epidermal necrosis and detachment in SJS/TEN
Direct immunofluorescence is typically negative in SJS/TEN but may show IgM deposits in EM.
Differential Diagnosis:
Other mucocutaneous blistering disorders: Pemphigus vulgaris, bullous pemphigoid (often older adults), dermatitis herpetiformis, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), scalded skin syndrome (Staphylococcal or Streptococcal), and viral exanthems
Differentiating features include lesion morphology, distribution, mucosal involvement, and presence of epidermal detachment.
Management
Initial Management:
Immediate and complete cessation of all suspect medications is the cornerstone of SJS/TEN management
Early consultation with dermatology, ophthalmology, and burn/critical care services
Pain management with analgesics and potentially opioids
Aggressive fluid and electrolyte resuscitation to address losses from epidermal detachment
Nutritional support is critical, often requiring nasogastric or parenteral feeding.
Medical Management:
Symptomatic and supportive care is primary
Topical corticosteroids for mucositis pain
Ocular lubrication and anti-inflammatory drops (e.g., topical corticosteroids, cyclosporine) for ocular involvement
Avoid systemic corticosteroids in SJS/TEN due to potential for increased infection and mortality
their role is controversial and generally not recommended
IVIG (intravenous immunoglobulin) is controversial but sometimes used in early SJS/TEN, though evidence is mixed
Specific treatments for underlying infections (e.g., antivirals for HSV-associated EM).
Surgical Management:
Generally not indicated for EM, SJS, or TEN
Surgical debridement is usually reserved for secondary bacterial infections of the denuded skin
Skin grafting is not typically performed as the epidermis can regenerate from adnexal structures.
Supportive Care:
Aggressive wound care with sterile dressings and emollients to protect denuded areas
Strict adherence to aseptic techniques to prevent infection
Close monitoring of vital signs, fluid balance, and organ function
Management of thermoregulation due to large surface area loss
Psychological support for the patient and family.
Complications
Early Complications:
Sepsis (due to skin barrier breakdown), dehydration, electrolyte imbalances, acute renal failure, respiratory compromise (ARDS), corneal ulceration, symblepharon, blindness, phimosis, strictures, gastrointestinal bleeding, and malnutrition
Secondary bacterial and fungal infections are common.
Late Complications:
Chronic ocular sequelae (dry eye, scarring, vision impairment), skin scarring and dyspigmentation, nail dystrophy, hair loss, chronic mucositis, esophageal strictures, and psychosexual dysfunction
Increased risk of developing further severe cutaneous adverse reactions.
Prevention Strategies:
Thorough medication history and prudent prescribing practices, especially in patients with prior history of severe cutaneous adverse reactions
Genetic screening (e.g., HLA-B*1502 for carbamazepine in certain Asian populations) where applicable and available
Educating patients about potential drug reactions and advising them to seek immediate medical attention if a rash develops
Prompt recognition and management of prodromal symptoms of SJS/TEN.
Prognosis
Factors Affecting Prognosis:
Extent of epidermal detachment (BSA), age, comorbidities, time to withdrawal of offending agent, and presence of systemic complications
SCORTEN score is a significant predictor of mortality
SJS/TEN have higher mortality rates (up to 30-50% for TEN) compared to EM
Recurrence is possible, especially with continued exposure to triggers.
Outcomes:
EM usually resolves completely within 2-6 weeks without sequelae
SJS/TEN prognosis is variable and dependent on prompt and aggressive management
Survivors often face significant long-term morbidity
Early identification and management improve outcomes significantly.
Follow Up:
Long-term follow-up is essential for SJS/TEN survivors, particularly for ophthalmologic assessment to monitor and manage ocular sequelae
Regular skin checks for scarring and dyspigmentation
Psychological support may be necessary to address long-term impact.
Key Points
Exam Focus:
The primary focus in exams is the morphological distinction of target lesions in EM versus the diffuse blistering and detachment in SJS/TEN
Recall that EM is often HSV-associated in children, while SJS/TEN are primarily drug-induced
The percentage of BSA involved is critical for classifying SJS/TEN severity
SCORTEN score is for prognosis in SJS/TEN.
Clinical Pearls:
Always inquire about recent medication changes and viral prodromes
Mucosal involvement is key to suspecting SJS/TEN over typical EM
Even mild SJS can progress rapidly, demanding aggressive supportive care
Conjunctivitis and painful oral ulcers in a child with a rash are red flags for SJS/TEN
Consider referral to tertiary care centers for severe cases.
Common Mistakes:
Overlooking early signs of mucosal involvement
Underestimating the severity of SJS/TEN
Delaying withdrawal of suspect medications
Inappropriately using systemic corticosteroids for SJS/TEN
Failing to involve ophthalmology early in SJS/TEN management
Misdiagnosing SJS/TEN as a viral exanthem or simple drug rash, leading to continued exposure to the offending agent.