Toxic Epidermal Necrolysis: Symptoms, Types, Causes and Treatment

Toxic epidermal necrolysis (TEN) is a rare, life-threatening skin condition that demands prompt recognition and intervention. Characterized by widespread skin detachment and mucous membrane involvement, TEN often presents suddenly and can progress rapidly, leading to severe complications. Understanding its symptoms, types, causes, and current treatment strategies is crucial for clinicians and patients alike. This article provides a comprehensive, evidence-based overview of TEN, drawing from the latest research and clinical insights.

Symptoms of Toxic Epidermal Necrolysis

Toxic epidermal necrolysis typically begins with subtle, flu-like symptoms but quickly escalates to dramatic and dangerous skin and mucosal manifestations. Early recognition of these signs can be lifesaving.

Symptom	Description	Severity/Timing	References
Prodrome	Fever, malaise, sore throat, anorexia	Initial phase	4 5 7
Skin Lesions	Painful red or purplish macules, blistering	1–3 days after prodrome	2 3 4 5 7
Skin Detachment	Sloughing, denuded skin, "scalded" appearance	Rapid progression	1 2 3 4 7
Mucosal Involvement	Erosions: mouth, eyes, genitals, anus	Frequent/severe	2 4 5 7
Systemic Symptoms	Multi-organ involvement, infection risk	Severe/late	5 9

Table 1: Key Symptoms

Early Symptoms: The Prodromal Phase

TEN often starts with non-specific flu-like symptoms—fever, malaise, sore throat, and anorexia—occurring several days before the skin involvement becomes apparent. This initial phase can be misleading, making early diagnosis challenging 4 5 7.

Skin Manifestations

Within a few days, patients develop widespread, painful red or purplish macules. These rapidly evolve into flaccid blisters and areas of skin detachment, giving the appearance of scalded skin. The hallmark "Nikolsky sign" (skin sloughs off with gentle pressure) is often present 1 2 3 4 7. The skin may peel off in sheets, leaving large, raw, denuded areas that resemble severe burns.

Mucosal Involvement

Mucous membranes are affected in almost all cases. Painful erosions develop in the mouth, eyes, genitals, anus, and sometimes the nasal passages 2 4 5 7. This can make eating, drinking, urinating, and even breathing difficult.

Systemic and Long-Term Effects

As the disease progresses, complications can include dehydration, sepsis, respiratory distress, and multi-organ failure 5 9. Even survivors often experience long-term sequelae such as chronic eye problems, scarring, and psychological distress 9.

Types of Toxic Epidermal Necrolysis

TEN does not exist in isolation but is part of a spectrum of severe skin reactions, most notably alongside Stevens-Johnson syndrome (SJS). Understanding the subtypes helps clinicians assess severity and guide management.

Type	Skin Involvement (BSA)	Distinguishing Feature	References
Stevens-Johnson Syndrome	<10%	Less extensive, overlap with SJS/TEN	2 4 5 7
SJS/TEN Overlap	10–30%	Intermediate severity	2 4 7
Toxic Epidermal Necrolysis	>30% (global)	Extensive sloughing, high mortality	2 4 7
(Japan) TEN Definition	>10% (Japan-specific)	Regional diagnostic criteria	7

Table 2: Classification of TEN and Related Conditions

Stevens-Johnson Syndrome (SJS)

SJS is the milder end of the spectrum, involving less than 10% of the body surface area (BSA). It shares many features with TEN but is less extensive 2 4 5 7.

SJS/TEN Overlap

If 10–30% of the BSA is involved, the condition is classified as SJS/TEN overlap. This intermediate stage shares morbidity and management approaches with both SJS and TEN 2 4 7.

Toxic Epidermal Necrolysis (TEN)

TEN represents the most severe form, with more than 30% of the BSA affected (globally accepted definition). Skin loss is massive, and the risk of complications and death is high 2 4 5 7. In Japan, however, TEN may be defined as detachment of over 10% of BSA, reflecting local diagnostic criteria 7.

Key Distinguishing Features

• Skin loss severity is the main differentiator.
• Mucosal involvement is common to both SJS and TEN and tends to be more severe as the spectrum progresses.
• Mortality rates increase with greater skin involvement, with TEN carrying the highest risk 2 4 7.

Causes of Toxic Epidermal Necrolysis

Identifying the trigger is essential for effective management and prevention. Most cases are drug-induced, but infections and genetic factors also play important roles.

Cause/Trigger	Examples	Risk Factors/Notes	References
Medications	Allopurinol, sulfonamides, carbamazepine, NSAIDs, cephalosporins	Main cause	2 4 5 6 7
Infections	Mycoplasma pneumoniae, Herpes simplex virus	Children/rare cases	2 4
Genetic Susceptibility	HLA-B15:02, HLA-B58:01, others	Ethnic associations	2 6 7 9
Unknown	Idiopathic in rare cases	Unclear mechanism	2 4

Table 3: Causative Factors and Predisposing Risks

Medications: The Leading Cause

The vast majority of TEN cases are triggered by medications. High-risk drugs include:

• Antibiotics: Sulfonamides, aminopenicillins, cephalosporins, quinolones
• Anticonvulsants: Carbamazepine, phenytoin, phenobarbital
• Allopurinol
• NSAIDs: Especially oxicam-type 2 4 5 6 7

TEN often develops 4–28 days after starting the offending drug 5.

Infections

Some cases, especially in children, are linked to infections such as Mycoplasma pneumoniae or Herpes simplex virus. However, these are far less common than drug-induced TEN 2 4.

Genetic Predisposition

Genetic factors significantly influence susceptibility:

• HLA-B*15:02: Strong association with carbamazepine-induced TEN in Han Chinese populations
• HLA-B*58:01: Linked to allopurinol reactions across multiple ethnicities
• Other HLA alleles (such as HLA-A02:06, HLA-A31:01, HLA-B*51:01) have also been implicated 2 6 7 9

Screening for these alleles is recommended in some populations before prescribing high-risk drugs.

Other and Unknown Causes

In rare cases, the cause remains idiopathic. The underlying mechanisms are thought to involve immune dysregulation and cytotoxic T cell responses against keratinocytes, often triggered by the interaction between a drug (or its metabolite) and specific HLA molecules 3 6 9.

Treatment of Toxic Epidermal Necrolysis

TEN is a medical emergency requiring specialized, multidisciplinary care. While supportive management is the mainstay, certain systemic therapies are being explored, though none are universally accepted.

Intervention	Purpose/Outcome	Controversy/Evidence	References
Drug Withdrawal	Remove causative agent	Essential, first step	2 5 7 12
Supportive Care	Fluid/electrolyte balance, wound care	Universally recommended	4 5 7 12 14
Burn Unit Transfer	Specialized care	Improves outcomes	4 7 14
Systemic Corticosteroids	Immunomodulation	Conflicting evidence	10 12 13
Intravenous Immunoglobulin (IVIG)	Block immune mediators	Mixed results, some benefit in children	10 11 12
Cyclosporine	T-cell inhibition	Promising, more studies needed	10 12 13
Other Immunotherapies	TNF inhibitors, plasmapheresis	Under investigation	10 12 13

Table 4: Treatment Modalities for TEN

Immediate Actions: Drug Withdrawal

The first and most critical step is to identify and discontinue the offending drug as soon as possible. Early withdrawal can halt disease progression and improve prognosis 2 5 7 12.

Supportive Care: The Cornerstone

Supportive care is the foundation of TEN management and is distinct from standard burn care. Key aspects include:

• Fluid and electrolyte management: Due to skin loss, patients are at high risk for dehydration and shock.
• Nutritional support: High metabolic demands and mucosal involvement necessitate careful feeding strategies.
• Pain control and infection prevention: Open skin and mucosal surfaces are highly susceptible to infection and require expert wound care.
• Temperature regulation: Loss of skin impairs thermoregulation.
• Specialist care: Patients should be managed in burn units or intensive care centers with expertise in wound and critical care 4 7 12 14.

Systemic Therapies: Immunomodulation

Several therapies have been used to dampen the immune response driving TEN, but data are mixed.

Corticosteroids

Systemic corticosteroids have been widely used, aiming to suppress immune-mediated epidermal destruction. However, evidence about their efficacy and safety is conflicting. Some analyses suggest a survival benefit, while others report no significant improvement and increased risk of infection 10 12 13.

Intravenous Immunoglobulin (IVIG)

IVIG is used to block Fas-mediated keratinocyte apoptosis. Some studies, particularly in pediatric populations, report positive outcomes, but large systematic reviews offer mixed results 10 11 12.

Cyclosporine

Cyclosporine, a T-cell inhibitor, has shown promise in reducing disease progression, hastening re-epithelialization, and lowering mortality in some case series. However, more robust trials are needed 10 12 13.

Other Treatments

• TNF inhibitors, plasmapheresis, and other immunomodulators are being investigated but lack definitive evidence of benefit 10 12 13.
• Antishear wound care protocols borrowed from burn management may also improve outcomes 14.

Long-Term Management and Sequelae

Survivors need ongoing multidisciplinary care for skin, eye, and psychological complications. Long-term sequelae can severely impact quality of life 9.

Conclusion

Toxic epidermal necrolysis is a devastating condition requiring immediate recognition and coordinated care. Here’s what to remember:

• Early symptoms are non-specific; rapid progression to severe skin and mucosal involvement is typical.
• TEN is part of a spectrum with SJS, classified by percentage of body surface area involved.
• Most cases are triggered by medications, with genetic factors influencing risk.
• Immediate withdrawal of the culprit drug and specialized supportive care are essential.
• Systemic therapies (corticosteroids, IVIG, cyclosporine) are used, but no single regimen is universally accepted.
• Long-term complications are common, emphasizing the need for multidisciplinary follow-up.

Staying current with evolving management strategies and understanding risk factors can help improve outcomes for patients facing this life-threatening disease.