PanOph

Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis

CorneaHigh YieldAlso: SJS, TEN, SJS-TEN Spectrum

Key Points

  • •Early ophthalmology consultation and amniotic membrane transplantation (within the first 2 weeks) in acute SJS/TEN significantly reduces the severity of chronic ocular surface disease
  • •Daily symblepharon lysis with a glass rod swept through the fornices is a simple but critical intervention that prevents permanent adhesion formation in the acute phase
  • •The most common causative drugs to remember: sulfonamides, carbamazepine, phenytoin, lamotrigine, allopurinol, and oxicam NSAIDs
  • •HLA-B*15:02 screening before prescribing carbamazepine is mandated in many Southeast Asian countries and FDA-recommended for at-risk populations

Hallmark Features

1

Mucocutaneous blistering/necrosis

2

Fever and malaise

3

Cicatrizing conjunctivitis with symblepharon

Finder Clues

Skin blistering and epidermal necrosisMucosal erosions (oral, genital, respiratory)Acute membranous/pseudomembranous conjunctivitisSymblepharon formationCorneal ulceration and epithelial defectsSevere dry eye (lacrimal duct destruction)Lid margin keratinizationHigh fever and malaiseTrichiasis and distichiasisCorneal neovascularization and opacification
1. Definition

Severe mucocutaneous reaction, most commonly triggered by medications, characterized by widespread epidermal necrosis and mucous membrane involvement. SJS (<10% BSA detachment) and TEN (>30% BSA) represent a spectrum.

2. Genetics

Strong pharmacogenomic associations:

  • HLA-B*15:02 — predisposes to carbamazepine-induced SJS/TEN (common in Southeast Asian populations)
  • HLA-B*58:01 — predisposes to allopurinol-induced SJS/TEN
  • HLA-A*31:01 — associated with carbamazepine-induced reactions in European and Japanese populations
  • Genetic screening before prescribing these drugs is recommended in at-risk populations
3. Pathogenesis

SJS/TEN is primarily a drug-induced cytotoxic T-cell-mediated reaction targeting keratinocytes expressing drug-modified MHC class I molecules.

Key effector mechanisms:

  1. Cytotoxic CD8+ T cells and NK cells recognizing drug-hapten complexes on keratinocytes
  2. Fas-FasL interaction causing apoptosis of keratinocytes
  3. Granulysin — key mediator of widespread keratinocyte death, released by NK cells and cytotoxic T cells
  4. Perforin-granzyme pathway contributing to epidermal destruction

Result:

  • Massive keratinocyte apoptosis leading to full-thickness epidermal necrosis and detachment
  • Mucous membranes (conjunctival, oral, genital, respiratory) affected due to their epithelial nature

Ocular surface destruction:

  • Conjunctival inflammation, goblet cell loss
  • Lacrimal duct scarring, meibomian gland dysfunction
  • Creates a devastating cicatricial ocular surface disease
4. Clinical Features

Prodrome (1-3 weeks after causative drug):

  • Fever, malaise, myalgia, upper respiratory symptoms

Skin involvement:

  • Sudden painful erythematous or purpuric macules that rapidly coalesce
  • Central necrosis with flaccid blisters — positive Nikolsky sign
  • Mucous membrane involvement in >90% (oral cavity, conjunctivae, urogenital tract)

Classification by BSA detachment:

  • SJS — <10% BSA
  • SJS-TEN overlap — 10-30% BSA
  • TEN — >30% BSA

SCORTEN severity score (predicts mortality):

  • Based on: age >40, malignancy, heart rate >120, serum urea >10 mmol/L (BUN >28 mg/dL), serum bicarbonate <20 mmol/L, serum glucose >14 mmol/L, BSA detachment >10%
  • Mortality: 1-5% for SJS, 25-35% for TEN

Most common causative drugs:

  • Sulfonamides (especially TMP-SMX)
  • Anticonvulsants — carbamazepine, phenytoin, lamotrigine
  • Allopurinol
  • NSAIDs (oxicam type)
  • Antibiotics — fluoroquinolones, aminopenicillins
5. Ocular Manifestations

Ocular involvement occurs in 50-88% of SJS/TEN patients and represents the most devastating long-term complication.

Acute phase:

  • Bilateral conjunctival hyperemia
  • Membranous or pseudomembranous conjunctivitis
  • Corneal epithelial defects
  • Lid margin inflammation
  • Without intervention, membranes organize into symblepharon (fusion of bulbar and palpebral conjunctiva) and ankyloblepharon (fusion of lid margins)

Chronic phase sequelae (30-60% of those with ocular involvement):

  • Severe dry eye — lacrimal gland duct destruction and conjunctival goblet cell loss
  • Cicatricial entropion with trichiasis and distichiasis — mechanical corneal damage
  • Lid margin keratinization — destroying the mucocutaneous junction
  • Persistent corneal epithelial defects
  • Corneal neovascularization and pannus
  • Corneal opacification and limbal stem cell deficiency (LSCD)
  • Symblepharon restricting ocular motility

Visual outcomes range from mild impairment to total bilateral blindness.

6. Systemic Manifestations

Skin:

  • Widespread epidermal necrosis with blistering and skin sloughing (resembling a burn)

Mucosal:

  • Painful erosions of oral, genital, and respiratory mucosae

Systemic complications:

  • High fever
  • Hepatitis
  • Pneumonitis (from tracheobronchial mucosal involvement)
  • Renal tubular necrosis
  • Sepsis — the leading cause of acute mortality
  • Massive fluid and electrolyte losses from denuded skin
7. Diagnosis

Clinical diagnosis:

  • Characteristic mucocutaneous findings in the context of recent drug exposure

Skin biopsy:

  • Full-thickness epidermal necrosis with sparse lymphocytic infiltrate at the dermoepidermal junction
  • Subepidermal blister formation — distinguishes from other blistering diseases
  • Frozen section biopsy can rapidly confirm by showing necrotic keratinocytes throughout the epidermis

Drug causality:

  • ALDEN algorithm (Algorithm of Drug Causality for Epidermal Necrolysis) helps identify the culprit medication

Ophthalmologic assessment (acute phase):

  • Document conjunctival membrane formation
  • Assess corneal epithelial integrity
  • Evaluate for early symblepharon
  • Conjunctival impression cytology can assess goblet cell density and predict chronic disease severity
8. Differential Diagnosis

Skin/systemic differentials:

  • Staphylococcal scalded skin syndrome (SSSS) — superficial cleavage plane, no mucous membrane involvement, Nikolsky-positive, primarily children
  • Erythema multiforme major — typical raised target lesions with three-zone pattern in acral distribution, distinct entity from SJS (does not progress to SJS/TEN), usually HSV-triggered rather than drug-induced
  • Pemphigus vulgaris — acantholytic blisters, positive direct immunofluorescence for IgG
  • Bullous pemphigoid — subepidermal blisters, linear IgG and C3 at basement membrane
  • Generalized bullous fixed drug eruption (GBFDE) — history of prior fixed drug eruption, well-demarcated round plaques that become bullous and coalesce, less severe mucosal involvement than SJS/TEN, better prognosis
  • Linear IgA bullous dermatosis — drug-induced form can mimic TEN
  • Acute graft-versus-host disease — in stem cell transplant recipients

Ocular differentials for acute pseudomembranous conjunctivitis:

  • Ligneous conjunctivitis
  • Gonococcal conjunctivitis
  • Diphtheric conjunctivitis
  • Ocular mucous membrane pemphigoid
  • Chemical burns
9. Management

Acute systemic management:

  • Immediate withdrawal of the causative drug — most critical intervention
  • Burn unit or intensive care setting
  • Fluid/electrolyte management, wound care, nutritional support, infection prevention, pain management

Systemic immunomodulation:

  • Cyclosporine A (3-5 mg/kg/day) — most promising evidence for reducing mortality
  • IVIG — inconsistent evidence
  • Systemic corticosteroids — debated; short-pulse high-dose may benefit if given very early
  • Etanercept (anti-TNF) — promise in small studies

Acute ophthalmic management (critical):

  • Frequent preservative-free artificial tears
  • Topical corticosteroids (prednisolone acetate 1% hourly initially)
  • Prophylactic topical antibiotics
  • Daily symblepharon lysis with a glass rod swept in the fornices
  • Amniotic membrane transplantation (AMT) to entire ocular surface and lid margins — ideally within 2 weeks
  • Scleral contact lenses

Chronic management:

  • Preservative-free tears and ointment; punctal occlusion
  • Autologous serum tears
  • Scleral lenses (PROSE)
  • Mucous membrane grafting for symblepharon
  • Lid surgery for entropion/trichiasis
  • Limbal stem cell transplantation for LSCD
  • Keratoprosthesis (Boston KPro or modified osteo-odonto-keratoprosthesis) for end-stage corneal disease
10. Prognosis

Acute mortality:

  • 1-5% for SJS, 25-35% for TEN (predicted by SCORTEN score)

Ocular prognosis:

  • 30-60% of patients with acute ocular involvement develop chronic cicatricial complications
  • Severity of acute ocular surface inflammation predicts chronic disease
  • Early and aggressive ophthalmic intervention (especially AMT) significantly improves long-term outcomes

Long-term:

  • Many patients develop progressive ocular surface disease requiring repeated interventions
  • Keratoprosthesis may be the last option for visual rehabilitation in severe cases
  • Long-term multidisciplinary follow-up is essential

Clinical Pearls

1

In the acute phase, never forget to sweep the fornices daily with a glass rod — symblepharon formation can begin within days of onset and becomes permanent if not disrupted early

2

Chronic SJS/TEN ocular surface disease is a limbal stem cell deficiency syndrome — standard penetrating keratoplasty will fail; consider limbal stem cell transplantation or keratoprosthesis instead

3

Ocular involvement can be the presenting feature before skin lesions fully develop — maintain a high index of suspicion in any patient with acute bilateral pseudomembranous conjunctivitis and recent medication change

Mnemonics

SJS/TEN Culprit Drugs

S—Sulfonamides (TMP-SMX)

C—Carbamazepine

A—Allopurinol

L—Lamotrigine

P—Phenytoin

O—Oxicam NSAIDs

Most common drugs causing SJS/TEN (mnemonic: SCALPO)

SJS BSA rule: SJS <10%, overlap 10-30%, TEN >30% body surface area detachment

References

  1. guidelineUK Guidelines for the Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Adults— British Journal of Dermatology (2016)
  2. paperTreatment of Acute Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Using Amniotic Membrane: A Review of 10 Consecutive Cases— Ophthalmology (2011)
  3. textbookExternal Disease and Cornea (BCSC Section 8)— American Academy of Ophthalmology (2023)
  4. paperGranulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis— Nature Medicine (2008)
Was this helpful?
← PreviousSjogren Syndrome