Ophthalmology – Stevens–Johnson Syndrome

What the Disorder Represents

Stevens–Johnson syndrome (SJS) is a rare, life-threatening severe cutaneous adverse reaction characterized by widespread keratinocyte death with epidermal and mucosal epithelial necrosis.

It lies on a spectrum with:

• SJS
• SJS–TEN overlap
• Toxic epidermal necrolysis (TEN)

The eyes are commonly involved, and ocular disease may cause permanent visual disability even when the systemic illness resolves.

The major ophthalmic threats are:

• Severe conjunctival inflammation
• Cicatrization
• Symblepharon
• Lid-margin keratinization
• Limbal stem-cell deficiency
• Chronic severe dry eye
• Corneal ulceration, neovascularization, and scarring

A Major Modern Terminology Correction

Older texts frequently described SJS as:

• “Erythema multiforme major”
• “Bullous erythema multiforme”

These are now considered distinct disorders.

Classic SJS/TEN is most often:

Medication induced

whereas erythema multiforme is more commonly associated with infections such as:

• Herpes simplex virus

and generally has a different clinical course.

How SJS and TEN Are Separated

Classification is based mainly on the percentage of body surface area with:

Epidermal detachment

Stevens–Johnson Syndrome

<10% body surface area

SJS–TEN Overlap

10–30%

Toxic Epidermal Necrolysis

>30%

They are best regarded as:

Different severities of the same disease spectrum.

How Often It Occurs

SJS/TEN is rare.

Incidence varies by:

• Population
• Medication exposure
• Genetic background
• HIV prevalence

The condition can occur at any age.

Who Is at Increased Risk

Risk is increased by:

• Previous SJS/TEN
• HIV infection
• Malignancy
• Polypharmacy
• Certain high-risk medications
• Particular HLA genotypes
• Some autoimmune disorders

The most important preventive principle is:

Never re-expose a patient to the suspected culprit drug or a closely related high-risk drug without specialist guidance.

What Causes the Tissue Injury

SJS/TEN is not primarily an immune-complex disease.

The central mechanism involves:

Drug-specific cytotoxic immune activation → massive keratinocyte apoptosis → epidermal and mucosal epithelial necrosis

Important mediators include:

• Cytotoxic T lymphocytes
• Natural killer cells
• Granulysin
• Fas/Fas-ligand pathways
• Other pro-apoptotic cytokines

Why the Eye Is So Vulnerable

The ocular surface is lined by rapidly regenerating epithelium.

Acute epithelial destruction affects:

• Conjunctiva
• Cornea
• Lid margins
• Meibomian gland orifices

Healing may occur through:

Fibrosis and cicatrization

which creates many of the devastating chronic complications.

The Most Important Triggers

Most adult SJS/TEN cases are associated with:

Medications

High-risk drugs include:

• Allopurinol
• Sulfonamide antibiotics
• Carbamazepine
• Lamotrigine
• Phenytoin
• Phenobarbital
• Nevirapine
• Oxicam NSAIDs

Other medications can also trigger the disease.

Timing After Drug Exposure

SJS/TEN typically develops within:

The first several weeks after starting a new medication

Risk is highest during the early treatment period.

A medication started many months or years previously without recent interruption is generally less likely to be the culprit than a newly introduced drug.

Important Infectious Mimics

Infections can produce severe mucositis resembling SJS.

In particular, Mycoplasma pneumoniae and other respiratory infections may cause:

Reactive infectious mucocutaneous eruption (RIME)

This is now generally considered distinct from classic drug-induced SJS/TEN.

Genetic Susceptibility

Strong HLA–drug associations are recognized.

Important examples include:

• HLA-B*15:02 with carbamazepine-associated SJS/TEN in several Asian populations
• HLA-B*58:01 with allopurinol severe cutaneous adverse reactions
• HLA-A*31:01 with carbamazepine hypersensitivity in some populations

Genetic screening is recommended in selected high-risk populations before certain medications according to:

• Ancestry
• Drug
• Local guidelines

Typical Early Symptoms

Patients often develop a prodrome resembling a severe viral illness:

• Fever
• Malaise
• Sore throat
• Cough
• Myalgia
• Headache

Ocular symptoms may begin early with:

• Burning
• Foreign-body sensation
• Photophobia
• Redness
• Tearing

How the Skin Disease Evolves

Patients develop:

• Tender erythematous macules
• Dusky or purpuric lesions
• Blistering
• Epidermal detachment

The skin may become extremely painful.

A positive:

Nikolsky sign

may be present, with epidermal separation after gentle pressure.

Mucosal Involvement

Severe mucosal disease commonly affects:

• Oral mucosa
• Eyes
• Genital tract
• Nasal mucosa
• Respiratory tract

Patients may have:

• Painful oral erosions
• Difficulty eating or drinking
• Dysuria
• Respiratory involvement

Acute Ocular Manifestations

Ocular disease may range from mild conjunctivitis to severe epithelial necrosis.

Findings include:

• Conjunctival hyperemia
• Chemosis
• Mucous discharge
• Conjunctival epithelial defects
• Pseudomembranes
• Corneal epithelial defects
• Lid-margin ulceration
• Early symblepharon

Why Eyelid Margin Disease Is Important

Ulceration of the lid margin may heal with:

• Keratinization
• Meibomian gland destruction
• Trichiasis
• Cicatricial entropion

These chronic lid abnormalities can continuously traumatize the cornea.

Pseudomembranes

Conjunctival pseudomembranes may form during the acute phase.

They should be:

Carefully removed when clinically appropriate

because retained inflammatory material can promote:

• Adhesion formation
• Cicatrization
• Symblepharon

Symblepharon Formation

Opposing raw conjunctival surfaces can adhere, producing:

Symblepharon

which may cause:

• Forniceal shortening
• Restricted ocular motility
• Tear-film abnormalities
• Chronic surface disease

Early prevention is therefore essential.

Corneal Disease During the Acute Phase

Corneal involvement may include:

• Punctate epithelial keratopathy
• Large epithelial defects
• Stromal inflammation
• Rare ulceration

Severe epithelial injury increases the later risk of:

Limbal stem-cell deficiency.

How Ocular Severity Should Be Assessed

Patients with suspected SJS/TEN should receive:

Early ophthalmology assessment

ideally within the first day of hospitalization.

The examination should document:

• Lid-margin epithelial loss
• Conjunctival epithelial defects
• Pseudomembranes
• Corneal involvement
• Forniceal shortening
• Symblepharon

Moderate-to-severe ocular disease may progress quickly, so:

Daily examination is often appropriate during the acute phase.

How the Systemic Diagnosis Is Established

Diagnosis is primarily clinical, supported by:

• Medication history
• Skin examination
• Mucosal involvement
• Percentage of epidermal detachment

Skin biopsy may be performed when diagnosis is uncertain.

What the Biopsy Shows

Histopathology typically demonstrates:

• Full-thickness epidermal necrosis
• Subepidermal separation
• Sparse dermal inflammatory infiltrate
• Extensive keratinocyte apoptosis

These findings help distinguish SJS/TEN from other blistering disorders.

Important Diagnostic Alternatives

The differential includes:

• Erythema multiforme
• RIME
• Staphylococcal scalded skin syndrome
• Acute generalized exanthematous pustulosis
• Drug reaction with eosinophilia and systemic symptoms
• Pemphigus vulgaris
• Paraneoplastic pemphigus
• Mucous membrane pemphigoid
• Linear IgA bullous dermatosis

The First Systemic Treatment Step

The suspected offending medication should be:

Stopped immediately

This is one of the most important interventions affecting outcome.

Unnecessary medications should also be minimized.

Where Patients Should Be Managed

SJS/TEN is a:

Medical emergency

and generally requires hospitalization.

Management may occur in:

• Intensive care unit
• Burn unit
• Specialized dermatology unit

depending on severity and local expertise.

Core Supportive Treatment

Systemic management includes:

• Fluid and electrolyte replacement
• Temperature control
• Nutritional support
• Pain control
• Wound care
• Infection surveillance
• Respiratory monitoring

Supportive care remains fundamental regardless of which systemic immunomodulatory treatment is used.

Why Prophylactic Antibiotics Are Not Routine

Broad systemic antibiotics are generally not given solely to prevent infection.

They are reserved for:

Documented or strongly suspected infection

because unnecessary antibiotics can:

• Promote resistance
• Cause additional adverse reactions
• Potentially complicate culprit-drug assessment

Assessing Systemic Severity

Severity and mortality risk can be estimated using tools such as:

SCORTEN

which incorporates systemic clinical and laboratory factors.

Higher scores correlate with increased mortality.

Systemic Immunomodulatory Therapy

There is no universally accepted single regimen worldwide.

Treatments used in specialist centers include:

• Systemic corticosteroids
• Cyclosporine
• Etanercept
• IV immunoglobulin in selected settings
• Combination regimens

Choice depends on:

• Disease severity
• Timing
• Comorbidities
• Center experience

Important Modern Perspective on Systemic Therapy

Older recommendations favored prolonged high-dose steroids or IVIG relatively broadly.

Current practice is more individualized.

Evidence increasingly supports selected use of:

• Cyclosporine
• Etanercept

while corticosteroids remain widely used early in some protocols.

IVIG has:

Variable evidence and is not uniformly effective as monotherapy.

Immediate Eye-Surface Management

Acute ocular treatment may include:

• Frequent preservative-free lubrication
• Topical corticosteroid
• Topical antibiotic when epithelial defects are present or infection risk is significant
• Pseudomembrane removal
• Forniceal sweeping when needed

The regimen is individualized according to surface severity.

Role of Topical Corticosteroids

Topical corticosteroids are commonly used during the acute inflammatory stage to reduce:

• Conjunctival inflammation
• Cicatrization

They require ophthalmic monitoring for:

• Infection
• IOP elevation
• Epithelial healing

The Major Modern Advance – Early Amniotic Membrane

One of the most important changes in modern ophthalmic management is:

Early amniotic membrane transplantation (AMT)

for moderate-to-severe acute ocular involvement.

AMT should ideally be considered:

Within the first several days, generally within the first week

before extensive cicatrization develops.

Why Amniotic Membrane Is Used

Amniotic membrane can:

• Reduce ocular surface inflammation
• Promote epithelial healing
• Protect exposed conjunctiva
• Reduce scar formation
• Lower the risk of severe chronic cicatricial disease

What Must Be Covered

For severe SJS/TEN, effective AMT should ideally cover:

• Cornea
• Bulbar conjunctiva
• Palpebral conjunctiva
• Lid margins
• Fornices

Treating only the cornea may leave the patient vulnerable to severe conjunctival and lid-margin scarring.

Methods of Amniotic Membrane Placement

Approaches include:

• Sutured AMT
• Adhesive techniques
• Ring-supported membrane systems

The choice depends on:

• Disease severity
• Patient stability
• Local expertise

Why Waiting Can Be Harmful

Once mature conjunctival fibrosis and lid-margin keratinization develop:

AMT can no longer reverse established cicatricial damage.

This is why early ophthalmology involvement is so important.

Preventing Adhesions

During the acute phase, management may include:

• Gentle removal of pseudomembranes
• Forniceal sweeping
• Symblepharon rings in selected patients
• AMT

These strategies aim to preserve:

Forniceal depth and conjunctival mobility.

Chronic Dry Eye After SJS/TEN

Long-term tear dysfunction may result from:

• Lacrimal gland injury
• Conjunctival goblet-cell loss
• Meibomian gland destruction
• Cicatricial lid abnormalities

This can cause:

Severe aqueous-deficient and evaporative dry eye.

Chronic Eyelid Problems

Common late abnormalities include:

• Trichiasis
• Distichiasis
• Cicatricial entropion
• Lagophthalmos
• Lid-margin keratinization

These abnormalities can produce continuous mechanical trauma to the cornea.

Lid-Margin Keratinization

Posterior lid-margin keratinization is particularly damaging because keratinized epithelium repeatedly rubs across the:

Corneal surface during blinking

and can cause:

• Persistent epithelial defects
• Corneal neovascularization
• Scarring

Treating Chronic Lid-Margin Keratinization

Options include:

• Protective scleral lenses
• Epilation for focal lashes
• Lid surgery
• Mucous membrane grafting for significant posterior lid-margin keratinization

Mucous membrane grafting can replace the keratinized surface with healthier nonkeratinized epithelium.

Severe Chronic Ocular Surface Disease

Long-term therapy may include:

• Preservative-free artificial tears
• Lubricating ointment
• Autologous serum tears
• Tear-conservation strategies
• Management of lid abnormalities
• Scleral lenses

Role of Scleral Lenses

Large-diameter scleral lenses, including:

PROSE-type devices

can provide major functional benefit by creating a fluid reservoir over the cornea.

They may improve:

• Pain
• Vision
• Epithelial protection
• Photophobia

Limbal Stem-Cell Deficiency

Severe acute epithelial destruction may damage the limbus, causing:

Limbal stem-cell deficiency

Signs include:

• Conjunctivalization of the cornea
• Persistent epithelial instability
• Neovascularization
• Corneal opacity

This is one of the most difficult chronic consequences to treat.

Why Conventional Corneal Transplantation Often Fails

A standard penetrating keratoplasty may fail when the ocular surface remains:

• Dry
• Inflamed
• Keratinized
• Stem-cell deficient

Therefore surface rehabilitation should generally precede consideration of corneal transplantation.

Advanced Visual Rehabilitation

Selected severe cases may require:

• Limbal stem-cell transplantation
• Keratolimbal allograft
• Keratoprosthesis

These procedures are complex and require specialized ocular surface expertise.

Corneal Infection Risk

Chronic epithelial defects and severe dry eye increase risk for:

Microbial keratitis

Patients should seek urgent care for:

• New pain
• Increased redness
• Photophobia
• Sudden decline in vision
• Corneal opacity

Other Long-Term Ocular Complications

Late complications include:

• Symblepharon
• Forniceal shortening
• Dry eye
• Trichiasis
• Entropion
• Keratinization
• Corneal neovascularization
• Corneal scarring
• Persistent epithelial defects
• Limbal stem-cell deficiency
• Infectious keratitis
• Severe permanent visual loss

Long-Term Systemic Follow-Up

Patients should maintain a clear record of:

• Culprit medication
• Suspected cross-reactive medications
• Date and severity of reaction

The offending drug should be listed prominently as a:

Severe life-threatening allergy.

Why Rechallenge Is Dangerous

Re-exposure to the causative medication can trigger:

Rapid and potentially more severe recurrence

Therefore intentional drug rechallenge is generally avoided.

Expected Systemic Outcome

Mortality depends primarily on:

• Extent of epidermal detachment
• Age
• Comorbidities
• Systemic severity

SJS generally has lower mortality than TEN, but both can be life-threatening.

Expected Visual Outcome

Visual prognosis depends heavily on:

• Severity of acute ocular involvement
• Early ophthalmic treatment
• Extent of lid-margin injury
• Development of conjunctival cicatrization
• Limbal stem-cell damage

Early ocular intervention, particularly:

Timely amniotic membrane treatment when indicated

can substantially reduce severe chronic surface disease.

High-Yield Takeaways

• SJS and TEN are severe mucocutaneous adverse reactions characterized by extensive keratinocyte apoptosis and epithelial necrosis.
• SJS involves <10% epidermal detachment, SJS–TEN overlap 10–30%, and TEN >30%.
• SJS/TEN is distinct from erythema multiforme, despite older terminology linking them.
• Most adult cases are medication related.
• Important culprit drugs include allopurinol, sulfonamide antibiotics, carbamazepine, lamotrigine, phenytoin, phenobarbital, nevirapine, and oxicam NSAIDs.
• Strong pharmacogenetic associations include HLA-B*15:02 with carbamazepine and HLA-B*58:01 with allopurinol in susceptible populations.
• Respiratory infection-associated mucositis, especially from Mycoplasma, is increasingly classified as RIME rather than classic SJS.
• The first systemic treatment step is immediate withdrawal of the culprit drug.
• SJS/TEN requires hospital-level multidisciplinary care, often in an ICU or burn unit.
• Ocular assessment should occur very early, because surface damage may progress rapidly.
• Acute ocular signs include conjunctival epithelial defects, pseudomembranes, lid-margin ulceration, corneal epithelial defects, and early symblepharon.
• Early amniotic membrane transplantation is a major modern intervention for moderate-to-severe ocular disease and is most useful when performed before established cicatrization.
• Pseudomembrane removal, lubrication, topical anti-inflammatory therapy, and prevention of conjunctival adhesions are important components of acute care.
• Chronic ocular disease may include severe dry eye, symblepharon, trichiasis, cicatricial entropion, lid-margin keratinization, corneal neovascularization, and limbal stem-cell deficiency.
• Posterior lid-margin keratinization can be treated with mucous membrane grafting in selected patients.
• Scleral lenses/PROSE devices can markedly improve comfort and vision in chronic severe ocular surface disease.
• Conventional corneal transplantation alone often performs poorly unless the underlying ocular surface has first been rehabilitated.
• The best chance of preserving long-term vision comes from rapid systemic recognition plus aggressive early ocular-surface protection.