Can you explain Stevens-Johnson syndrome and Lyell’s syndrome (toxic epidermal necrolysis)?

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (Lyell's Syndrome)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, also known as Lyell's syndrome) are life-threatening mucocutaneous emergencies that exist on a severity spectrum, distinguished by the extent of epidermal detachment: SJS involves <10% body surface area, SJS/TEN overlap involves 10-30%, and TEN involves >30% body surface area. 1

Clinical Presentation

Prodromal Phase

The disease typically begins with a prodrome of fever, malaise, and upper respiratory tract symptoms several days before skin manifestations appear 1. Cutaneous pain is a prominent early warning sign that should immediately alert you to incipient epidermal necrolysis 1.

Skin Manifestations

• Initial lesions: Atypical target lesions and/or purpuric macules, typically starting on the face, upper torso, and proximal limbs 1
• Progression: Lesions spread to involve the trunk and distal limbs, with prominent involvement of palms and soles 1
• Advanced disease: Large areas of confluent erythema develop, followed by flaccid blisters where necrotic epidermis separates from dermis 1
• Nikolsky sign: Gentle lateral pressure causes detachable epidermis to slide over dermis—a helpful clinical indicator though not specific for SJS/TEN 1
• Maximum involvement: Typically reached 5-7 days after disease onset 1

Mucosal Involvement

Involvement of eyes, mouth, nose, and genitalia is usually an early feature, leading to erosive and hemorrhagic mucositis 1. Ocular inflammation may develop even before skin signs appear 1. In the acute phase, 80% of cases show ophthalmic involvement ranging from mild conjunctivitis to complete de-epithelialization of the ocular surface 2.

Etiology

Drug-Induced (Most Common)

Drugs are the primary cause in approximately 75% of cases 2. High-risk medications include:

• Allopurinol
• Trimethoprim-sulfamethoxazole and other sulfonamide antibiotics
• Anti-epileptic drugs (carbamazepine, phenytoin, phenobarbital)
• NSAIDs of the oxicam type
• Aminopenicillins, cephalosporins, quinolones
• Nevirapine 3

Infection-Induced

Approximately 25% of cases are triggered by systemic infections 2. Mycoplasma pneumoniae is a well-documented cause, particularly in children, and may present with predominantly mucous membrane involvement with minimal cutaneous lesions (termed "Mycoplasma pneumoniae-associated mucositis") 1.

Genetic Susceptibility

Strong associations exist between specific HLA antigens and drug-induced SJS/TEN, such as HLA-B*1502 and carbamazepine-induced SJS in Han Chinese populations 3.

Pathophysiology

The key mediator of keratinocyte apoptosis in SJS/TEN is granulysin, a 15-kDa protein found in high concentrations in TEN blister fluid 1. The disease involves drug-specific T cell-mediated cytotoxicity leading to extensive keratinocyte programmed cell death and full-thickness epidermal necrolysis 1, 3.

Diagnosis

Clinical Assessment

Diagnosis relies on clinical signs together with histopathological analysis of a skin biopsy showing full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis 3. Histologically, there is variable epidermal damage ranging from individual cell apoptosis to confluent epidermal necrosis, with basal cell vacuolar degeneration and subepidermal vesicle or bulla formation 1.

Immediate Actions When SJS/TEN is Suspected

1. Discontinue any potential culprit drug immediately 1
2. Document the index date (when first symptoms appeared: sore throat, rash, skin pain, sore eyes/mouth) 1
3. Record all medications taken over the previous 2 months, including over-the-counter and complementary therapies 1
4. Examine for prodromal symptoms: fever, malaise, upper respiratory symptoms, painful rash initially on face and chest, mucosal involvement 1
5. Assess respiratory symptoms (cough, dyspnea, bronchial hypersecretion, hemoptysis) and bowel involvement (diarrhea, abdominal distension) 1

Physical Examination

• Record vital signs, oxygen saturation, and baseline body weight 1
• Separately document the extent of erythema and epidermal detachment on a body map using the Lund and Browder chart—the detachment percentage (including Nikolsky-positive areas) has prognostic value, not the erythema extent 1
• Examine all mucosal sites for mucositis, blisters, and erosions 1

Differential Diagnosis

Critical to exclude:

• Staphylococcal scalded skin syndrome (SSSS): Distinguished by absence of mucosal involvement and intraepidermal (not subepidermal) cleavage on biopsy 4
• Pemphigus vulgaris, bullous pemphigoid, mucous membrane pemphigoid
• Erythema multiforme major
• Linear IgA bullous dermatosis
• Generalized bullous fixed drug eruption
• Bullous acute graft-versus-host disease 1, 3

Prognosis

Mortality

• SJS mortality: 1-5%
• TEN mortality: 25-35% 5, 3
• Mortality is lower in children than adults 4
• Use SCORTEN (severity-of-illness score) for mortality risk assessment 6

Recurrence

Recurrence is more common in children (up to 18% of cases) because the precipitant is usually infection (which may recur) rather than drugs (which can be avoided) 4.

Management

Immediate Measures

1. Transfer to a center with experience managing SJS/TEN, ideally with intensive care or burn unit capabilities 4
2. Patients should be seen by an ophthalmologist within 24 hours of symptom onset—acute ophthalmic treatment significantly impacts long-term eye complications 2
3. Establish multidisciplinary team including dermatology, ophthalmology, intensive care, and burn specialists 4

Supportive Care (Cornerstone of Treatment)

Wound Management:

• Regularly cleanse wounds with warmed sterile water, saline, or chlorhexidine (1/5000) 1
• Apply greasy emollient (50% white soft paraffin with 50% liquid paraffin) over entire epidermis, including denuded areas 1
• Apply topical antimicrobial agents to sloughy areas only, guided by local microbiological advice 1
• Detached epidermis may be left in situ as a biological dressing; decompress blisters by piercing and expressing fluid 1
• Apply nonadherent dressings (Mepitel™ or Telfa™) to denuded dermis 1
• Use secondary foam or burn dressing to collect exudate 1

Fluid Resuscitation: Fluid requirements are lower than predicted by the Parkland formula for burns. Use the formula: body weight (kg) × % BSA epidermal detachment to estimate fluid replacement volumes 1. Avoid overaggressive resuscitation, which causes pulmonary, cutaneous, and intestinal edema 1.

Nutrition:

• SJS/TEN causes a hypermetabolic response with energy expenditure approximately twice the predicted resting value 1
• Provide continuous enteral nutrition (oral or nasogastric if buccal mucositis precludes oral intake) 1
• Deliver 20-25 kcal/kg daily during the early catabolic phase; increase to 25-30 kcal/kg daily during the anabolic recovery phase 1

Pain Management:

• Provide adequate background simple analgesia for comfort at rest 1
• Add opiates as required (enterally, via patient-controlled analgesia, or infusion) for moderate-to-severe pain 1
• Monitor level of consciousness, respiratory rate, and oxygen saturation carefully with opiate infusions 1

Transfer to Burn Center

Consider transfer for patients with TEN (>30% BSA epidermal loss) showing clinical deterioration, extension of detachment, subepidermal pus, local sepsis, wound conversion, or delayed healing 1. Surgical approaches in burn centers may include debridement and physiological closure with Biobrane/allograft/xenograft skin 1.

Pharmacologic Interventions

Evidence for immunomodulating agents remains limited and controversial 7. The most frequently used treatments include:

• Systemic corticosteroids
• Intravenous immunoglobulins (IVIG)—some studies suggest benefit at doses >2 g/kg 5
• Cyclosporine A 6

High-quality controlled trials are still lacking, and no internationally accepted treatment guidelines exist 8, 7.

Long-Term Sequelae

Common Complications (>50% of survivors)

The most frequent long-term sequelae are cutaneous, ocular, and psychological 7. Specific complications include:

Ocular (most important):

• Up to 50% develop chronic sight-threatening ocular surface disease 2
• Requires intensive topical and surgical treatment (lubrication, anti-inflammatory agents, lid surgery, scleral lenses, corneal surgery) 2
• Early ophthalmologic intervention in the acute phase significantly improves long-term outcomes 2

Other sequelae:

• Skin pigmentation changes and scarring
• Nail abnormalities
• Oral and dental problems
• Respiratory complications (particularly bronchiolitis obliterans)
• Urogenital problems
• Fatigue (especially in initial weeks and months after discharge) 1

Follow-Up

Prolonged multidisciplinary follow-up is essential according to patient needs 7. Monitor vigilantly for complications, as many long-term outcomes (particularly ocular disorders) can be improved by early recognition and prompt intervention 1.

Critical Pitfalls to Avoid

1. Do not delay drug discontinuation—immediate withdrawal of the culprit drug improves prognosis 9
2. Do not miss early ophthalmologic consultation—see patients within 24 hours 2
3. Do not overestimate fluid requirements—use the specific SJS/TEN formula, not the Parkland burn formula 1
4. Do not confuse with SSSS in children—check for mucosal involvement and consider biopsy if uncertain 4
5. Do not forget to document the culprit drug and counsel patients to avoid it permanently, including drugs of the same class 1
6. In approximately 15% of cases, no drug can be implicated—do not withhold treatment while searching for a cause 1