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Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis
Key Concepts
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Although historically considered as part of a continuum of vesiculobullous disease, erythema multiforme is currently thought to be a disease entity separate from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
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SJS and TEN are potentially blinding conditions. Intensive ophthalmologic management during the first 1–2 weeks of the illness is crucial for preventing long-term ocular sequelae.
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Eye involvement in the acute phase of SJS/TEN may be severe, even in cases where the overall systemic involvement is not. Thus all SJS/TEN patients need an urgent ophthalmologic evaluation.
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Amniotic membrane transplantation (AMT) to the ocular mucosae in the first week of the illness significantly decreases scarring sequelae and long-term visual problems.
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The effectiveness of AMT rapidly declines after the first week of illness. Thus AMT must be applied urgently in cases with significant sloughing of the lid margins, tarsal conjunctiva, or ocular surface.
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Although worthwhile, treatments for the chronic scarring problems remain challenging and prone to failure, further emphasizing the importance of scar prevention during the acute phase.
Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are severe, acute blistering disorders that affect the skin and mucous membranes. Although rare, both diseases can be life threatening, and many survivors suffer significant scarring of the ocular surface and eyelids. The resultant pain and visual problems can be debilitating or even blinding. Recent literature suggests that amniotic membrane transplantation (AMT) to the ocular mucosae in the first week of the illness can greatly reduce the cicatricial damage that characterizes the chronic phase of the disease. The ophthalmologist’s role in the acute phase management of the diseases is crucial because the severe, chronic eye problems are difficult to repair completely but are largely preventable with the newer treatments that will be discussed in this chapter. Historically, erythema multiforme (EM) major has been included with SJS and TEN as part of a continuous spectrum of vesiculobullous disease, but it is currently considered a distinct disease entity that rarely causes long-term ophthalmologic sequelae.
History
In 1866, Ferdinand von Hebra first described EM, which was historically considered part of the SJS/TEN spectrum of disease. He coined the term erythema exudativum multiforme to describe a cutaneous disease with erythematous lesions of the skin. His findings included a severe stomatitis and a purulent conjunctivitis associated with the cutaneous lesions. Von Hebra was very accurate in specifying the disease’s clinical course, distribution, and evolution of skin findings, as well as systemic symptoms. In 1876, Fuchs described a generalized cutaneous eruption of the herpes virus type in association with pseudomembranous conjunctivitis. In 1917, Fiessinger and Rendu noted that the classic dermatologic presentation of EM could accompany severe mucosal involvement. Two American physicians, Stevens and Johnson, reported two classic cases in children and named the disease “eruptive fever with stomatitis and ophthalmia” in 1922. That nomenclature was not adopted, but since that time EM major has most commonly been referred to as SJS. In 1950, Thomas coined the terms EM minor and major: EM minor referred to the disease described by von Hebra as EM, while EM major was applied to patients with oral mucosal involvement, similar to what Stevens and Johnson described. In 1956, Lyell introduced the term TEN to describe four patients with large amounts of skin loss in conjunction with mucous membrane involvement.
Classification
Due to similarity in some clinical and histopathologic aspects, SJS has historically been classified in a spectrum with EM with mucosal involvement (also called EM major), but it is currently considered to be a distinct disease entity. , This change in classification was proposed in 1993 by Bastuji-Garin et al. In reviewing European disease registry data, it became clear that SJS and EM differed with respect to clinical course, prognosis, cause, and treatment. EM skin lesions are typically targetoid and mostly occur on the extremities. The disease is benign and self-limited but prone to recurrence. It infrequently involves the eye and is most commonly caused by viruses, particularly the herpes simplex virus. In contrast, the skin lesions of SJS and TEN are small blisters, which may become confluent and arise from flat, atypical targetoid lesions. The lesions are distributed more on the head and trunk, the eyes are frequently involved, and medications are the most common cause. The classification proposed by Bastuji-Garin et al. has proven useful both clinically and in creating uniform study populations for research purposes. Because of its utility it has become the current classification scheme and is outlined in Table 46.1 .
TABLE 46.1
Classification of Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis
Adapted from Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129 :92–6.
| Classification | Detachment | Distribution | Typical Target Lesions Present? | Morphology of Atypical Target Lesions | Spots |
|---|---|---|---|---|---|
| Bullous EM | <10% BSA | Localized (acral) | Yes | Raised | |
| SJS | <10% BSA | Widespread | Flat | Yes | |
| SJS-TEN overlap | 10%–30% BSA | Widespread | Flat | Yes | |
| TEN with spots | >30% BSA | Widespread | Flat | Yes | |
| TEN without spots | 10% BSA | Widespread |
EM, Erythema multiforme; BSA, basal surface area; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.
Incidence
SJS and TEN are uncommon disease entities. In an American study, Chan et al. reported an incidence of EM, SJS, or TEN resulting from all causes at 4.2 per million person-years. They also described the incidence of TEN as 0.5 per million person-years. Schöph et al. found an overall risk of 0.93 per million person-years for TEN and 1.1 per million person-years for SJS. Roujeau et al. described an incidence of 1.2–1.3 cases per million per year. Bottinger et al. reported an incidence of 5–10 cases per million persons per year in a Swedish population for EM and TEN. Combined SJS, TEN, and SJS/TEN overlap have an incidence estimated at 1.89 per million per year in European studies. , However, in a large, population-based observational study performed in the United States, White et al. found an SJS-spectrum incidence rate of 12.35 per million people per year, nearly double the rate found in other studies. If extrapolated to include the rest of the world, this would yield more than 86,000 new cases per year worldwide. Another study has also found that the incidence of SJS in the pediatric population is significantly higher than in adults, with an incidence of 38.4 cases per 100,000 in children aged 11–15 years.
Clinical Findings
Initial Presentation
Drugs and infections are the most frequent identifiable precipitating factors in SJS/TEN. A systemic prodrome of malaise, fever, and headache or symptoms of an upper respiratory tract infection may precede the ocular and dermatologic manifestations and can begin 1–3 weeks after initial exposure and within hours after reexposure to an inciting agent. The prodrome may sometimes be more severe and can include high fever, muscular pain, nausea, vomiting, diarrhea, migratory arthralgias, and pharyngitis. , Within days, the typical dermatologic and mucosal lesions begin to break out. In SJS/TEN the mucosal involvement may begin at the same time as, or shortly after, the skin manifestations. The acute disorder is usually self-limited, with a typical total duration of 4–6 weeks. It is important to have frequent ophthalmologic exams in the early phase of the disease as the skin manifestations and their severity do not always correlate with the severity of the eye findings. ,
Eye Findings
The ocular findings in SJS are best divided into two categories: acute and chronic. The acute phase includes the period of initial skin and mucosal sloughing, and initial healing. It can last 2–6 weeks. Papers discussing acute phase interventions for the eye generally refer to the first 7–10 days following the onset of symptoms. This is the period when interventions are most likely to be effective at preventing the cicatricial problems that characterize the chronic phase. The chronic phase begins to set in after a few weeks and can last the remainder of the patient’s life.
Acute Eye Findings
The initial eye involvement in SJS/TEN is a nonspecific conjunctivitis that usually occurs around the same time as lesions on the skin and other mucous membranes. However, the conjunctivitis may precede the skin eruption. The bilateral conjunctivitis may be somewhat asymmetric and range from simple conjunctival hyperemia to extensive sloughing of the ocular surface, tarsal conjunctiva, and lid margins. Conjunctivitis in some form occurs in 15%–75% of patients with SJS ( Fig. 46.1 ). Extensive areas of sloughing can lead to eyelash loss and early symblepharon formation. Historically, a severe anterior uveitis has been reported, but this has not been noted in any of the case series from the past 2 decades and does not seem to be a major issue in acute SJS and TEN. Uncommonly, corneal ulceration may occur during the acute stage of the disease. Any corneal epithelial defect is concerning due to the risk of infection. In a hospitalized patient who has been treated with topical antibiotics and corticosteroids, the causative organisms may be multidrug-resistant or fungal. The initial, acute eye findings usually resolve in 2–4 weeks.
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