Erythema Multiforme, Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

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Erythema Multiforme, Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

Andrea Y. Ang, Florentino E. Palmon and Edward J. Holland

Introduction

Erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are considered as a spectrum of epidermal bullous diseases involving the skin and mucous membranes, usually triggered by drugs or infection. Although rare diseases, they are important since they cause high mortality and morbidity, with ocular involvement often being the most serious long-term sequela. Initial management involves early recognition, prompt hospitalization, and immediate cessation of the offending agent. During the acute self-limited course of the illness, management is primarily supportive in providing fluid management and prevention of sepsis. During the acute stage, it is important to manage the ocular surface inflammation aggressively with supportive treatment, so as to minimize the development of cicatricial changes that lead to chronic ocular surface disease.

In 1866, the Austrian dermatologist Ferdinand von Hebra first described erythema multiforme as a self-limited cutaneous disease characterized by multiform skin lesions.¹ In association with the erythematous skin lesions, his findings included a severe stomatitis and purulent conjunctivitis. In 1922, two American pediatricians, Stevens and Johnson, described two boys with a more severe mucocutaneous disease with ophthalmologic manifestations, naming the disease eruptive fever with stomatitis and ophthalmia.² This nomenclature was not adopted. However, since that time, erythema multiforme major has been most commonly referred to as Stevens–Johnson syndrome. In 1950, Thomas suggested the division of erythema multiforme into two forms: minor (von Hebra) and major (SJS).³ In 1956, Lyell introduced the term toxic epidermal necrolysis, a condition characterized by more extensive skin loss in conjunction with mucous membrane involvement.⁴

Classification

There was confusion in the nomenclature and diagnostic criteria for the erythema multiforme spectrum of diseases until an international classification was adopted in 1993.⁵ Traditionally, erythema multiforme was divided into minor and major forms, with the minor form only involving skin, with no or minimal mucous membrane involvement and not involving the eye. Table 30.1 outlines the diagnostic criteria for bullous skin diseases.⁶ Although the terms EM major and SJS are often used interchangeably, international collaborators have now differentiated them by their etiology and pattern of cutaneous lesions.⁷ The major etiologic factor for EM major (or bullous EM) is herpes simplex virus (HSV), compared to drug-induced SJS. An international consensus collaboration further classified the overlap between SJS and TEN. They defined five categories based on the pattern of skin lesions and extent of epidermal detachment as shown in Table 30.2.⁵

Table 30.1

Diagnostic Criteria for Bullous Skin Diseases

ERYTHEMA MULTIFORME MINOR

< 20% body area involvement

Target (iris) lesions (typical or atypical)

Individual lesions < 3 cm in diameter

No or minimal mucous membrane involvement

Biopsy specimen compatible with EM minor

STEVENS–JOHNSON SYNDROME (ERYTHEMA MULTIFORME MAJOR)

< 20% of body area involved in first 48 hours

> 10% of body area involvement

Target (iris) lesions (typical or atypical)

Individual lesions < 3 cm in diameter (lesions may coalesce)

Mucous membrane involvement (at least 2 areas)

Fever

Biopsy specimen compatible with EM major

TOXIC EPIDERMAL NECROLYSIS

Bullae and/or erosions over 20% of body area

Bullae develop on erythematous base

Occurs on non-sun-exposed skin

Skin peels off in > 3-cm sheets

Mucous membrane involvement frequent

Tender skin within 48 hours of onset of rash

Fever

Biopsy specimen compatible with TEN

(Adapted from Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990;126:43–7.)

Table 30.2

Proposed Classification of Cases in the Spectrum of Severe Bullous EM

EM, erythema multiforme; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

(Adapted from Bastuji-Garin. Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92–6.)

Incidence

Although EM/SJS/TEN are rare conditions, they are important because they cause high mortality and morbidity. Chan (USA) reported an overall incidence of these diseases at 4.2 per million person-years (TEN 0.5 per million person-years),⁶ and Rzany (Germany) reported an overall incidence of 1.89 per million person-years.⁸ Schöpf (Germany) reported an incidence of SJS at 1.1 per million person-years and incidence of TEN at 0.93 per million person-years.⁹ Roujeau (France) reported an incidence of TEN at 1.2 to 1.3 per million person-years.¹⁰ The reported mortality rate is 1% for EM, 1% to 7% for SJS, and 30% to 45% for TEN.^9–11 Both the incidence and the mortality appear to be higher in immunocompromised patients with these risks correlated with weaker immune function.¹² EM is more common in males, whereas TEN is more common in women, with a ratio ranging from 1.5 : 1 to 2.0 : 1.^9–11 Although these conditions can occur at any age, EM and SJS tends to occur in younger patients in their second to third decades, whereas TEN occurs in older patients in their fifth to seventh decades.^9–11

Etiology

Drugs and infections are the most common inciting causes of disease, as shown in Table 30.3. Drug-related reactions typically begin within 3 weeks of initiation of therapy. In cases of re-exposure to the drug, the reaction may begin within hours of restarting the therapy.⁶ TEN is usually drug-related. Drugs are an important cause of SJS, but infections, or a combination of infections and drugs has also been implicated. Infections, especially viral, are the most common cause of EM. In large epidemiology studies, drugs accounted for 89% to 95.5% of cases of TEN,^9,10 54% to 64% of cases of SJS,^9,11 and 18% for EM major.¹¹ In the international prospective SCAR (severe cutaneous adverse reactions) study, recent or recurrent herpes was the principal risk factor for EM major (etiologic fractions of 29% and 17%, respectively) and had a role in SJS (etiologic fractions of 6% and 10%) but not in overlap cases or TEN.¹¹ Mycoplasma pneumoniae has also been associated with EM Major in several studies.^11,13

Table 30.3

Etiologies of Stevens–Johnson Syndrome

Etiologic agent	Most frequently described
Drugs	Sulfas, NSAIDs, antiepileptics, barbiturates, allopurinol, tetracyclines, antiparasitics
Viral	HIV, herpes simplex, Epstein–Barr, influenza, coxsackie, lymphogranuloma venereum, variola
Bacterial	Mycoplasma pneumonia, typhoid, tularemia, diphtheria, group A streptococci
Fungal	Dermatophytosis, histoplasmosis, coccidiomycosis
Protozoal	Trichomoniasis, plasmodium

NSAIDs, nonsteroidal anti-inflammatory drugs; HIV, human immunodeficiency virus.

(Adapted from Hazin R, Ibrahimi OA, Hazin MI, Kimyai-asadi A. Stevens–Johnson syndrome: Pathogenesis, diagnosis, and management. Ann Med 2008;40:129–38.)

In the SCAR study, the use of antibacterial sulfonamides, anticonvulsants, oxicam nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, chlormezanone, and corticosteroids were associated with large increases in the risk of SJS or TEN.¹⁴ However, it is important to note that these reactions are rare, since for each of these drugs the excess risk did not exceed five cases per million users per week. Among drugs usually used for months or years, the increased risk was confined largely to the first 2 months of treatment. Table 30.4 lists drugs that have been associated with these diseases.

Table 30.4

Drugs Associated with EM/SJS/TEN

(Adapted from Palmon et al. Cornea. 3rd ed. Elsevier 2011. p. 604.)

Pathogenesis

The exact pathophysiologic mechanism of EM/SJS/TEN remains unknown. Prevailing evidence indicates an immune-mediated response, in particular those mediated by memory cytotoxic T cells, to drugs and infections. Histologically, keratinocyte death occurs from extensive apoptosis.¹⁵ The proposed initiating mechanism involves the interaction between Fas and Fas ligand (FasL), which is either membrane bound on keratinocytes or soluble.¹⁶ Activation of the Fas signaling cascade leads to widespread keratinocyte apoptosis and subsequent epithelial necrosis. It has been suggested that soluble FasL is secreted by peripheral blood mononuclear cells and is elevated in EM and TEN patients.¹⁷ Other studies have also linked perforin, a pore-making monomeric granule released from natural killer T lymphocytes, which is thought to initiate the keratinolysis seen early in the development of SJS.¹⁸ Granulysin has also been implicated as a key mediator for disseminated keratinocyte death in SJS/TEN. Granulysin levels are much higher in patients with SJS/TEN, compared to healthy controls, and also correlate with clinical severity.¹⁹

Genetic factors may also play a role in the development of erythema multiforme disorders. Slow acetylators and those taking medications, such as azoles, protease inhibitors, serotonin-specific reuptake inhibitors, and quinolones are at increased risk of developing SJS. The reduced rate of acetylation causes the accumulation of reactive metabolites that induce cell-mediated cytotoxic reactions against the epidermis, resulting in keratinocyte apoptosis.¹²

In studies in Western populations,14,20 antibiotics, particularly sulfonamides, are the most common drug trigger. In the largest Asian study by Chang et al.,¹³ anticonvulsants, particularly carbamazepine, and allopurinol were the most common drug triggers. A study by Chung et al.²¹ found a strong association in Han Chinese between the human leukocyte antigen (HLA) B*1502 and SJS induced by carbamazepine. Another study showed that HLA-B*5801 is highly associated with allopurinol-induced SJS/TEN.²² These associations suggest the importance of pharmacogenetic mechanisms on the risk of developing SJS/TEN.

Histopathology

The initial diagnosis of EM/SJS/TEN is based on clinical presentation; however, skin biopsies should be taken for both routine histopathology and direct immunofluorescence in order to distinguish these conditions from autoimmune blistering disorders. The typical histopathology of EM/SJS/TEN is characterized by vacuolization of epidermal cells and necrosis of keratinocytes within the epidermis, along with dermoepidermal detachment and perivascular lymphocytic infiltration.²³ The dermal infiltrate is more pronounced in EM major, compared to SJS or TEN.²⁴ In TEN, subepidermal blistering associated with full-thickness epidermal necrosis occurs.

Clinical Findings

Initial Presentation

Typically, EM/SJS/TEN begins with a systemic prodrome of vague upper respiratory tract symptoms and fever, headache, and malaise within 1 to 3 weeks of the precipitating factor. Within 1 to 3 days of the prodrome, there is rapid onset of the typical mucocutaneous lesions that may continue to erupt for up to 4 weeks. The disease is self-limited and typically lasts 4 to 6 weeks.

Systemic Features

Mucous membrane involvement occurs in more than 90% of affected patients, and the absence of such lesions should cast doubt on the diagnosis. There is no correlation between the extent and severity of mucous membrane erosions and the extent of epidermal detachment.5,8 Painful erosions of the mucous membrane may affect the lip, oral cavity, conjunctiva, nasal cavity, urethra, vagina, gastrointestinal tract, and respiratory tract. Mucous membrane ulceration can result in both short-term dysfunction and morbidity, and lead to long-term complications, due to fibrosis and stricture formation. In the study by Chang et al.¹³ the most common sites of mucosal involvement were the mouth (72%), eye(s) (60%), genitalia (37%), and anus (8%). Mucous membrane erosions sometimes persist for months after the reparation of the epidermis and may leave atrophic scars.

EM/SJS/TEN skin lesions have characteristic patterns and are described in Table 30.2 and shown in Figure 30.1.¹¹ The rash of EM is predominantly on the extremities, including the dorsal aspect of the hands and feet, and on the extensor surface of the forearms, legs, palms and soles.¹¹ Typical target lesions are < 3 cm in diameter, with a regular round shape, well-defined border, and at least three different zones, i.e. two concentric rings around a central disc (Fig. 30.1A). Raised atypical targets are round, edematous, palpable lesions, reminiscent of EM but with only two zones and/or a poorly defined border.

Figure 30.1 Characteristic skin lesions of EM/SJS/TEN. (A) Erythema multiforme: typical targets. (B) Stevens–Johnson syndrome: erythematous or purpuric macules with irregular shape and size, and blisters. (C) and (D) Toxic epidermal necrolysis: widespread detachment of > 30% of body surface area. (A, Reproduced from Werchniak, AE, Schwarzenberger, K. Poison ivy: An underreported cause of erythema multiforme, J Am Acad Dermatol 2004;51(Suppl. 5):S159–60. B, Reproduced from Weinberger, CH, Bhardwaj, SS, Bohjanen, KA. Toxic epidermal necrolysis secondary to emergency contraceptive pills, J Am Acad Dermatol 2009;60:708–9. C & D, Reproduced from Downey, A, Jackson, C, Harun, N, et al. Toxic epidermal necrolysis: Review of pathogenesis and management, J Am Acad Dermatol 2012;66:995–1003.)

The rash in SJS consists of flat atypical target lesions and erythematous macules that then develop central necrosis to form vesicles, bullae, and areas of denudation on the face, trunk, and extremities. Flat atypical targets are round, non-palpable lesions reminiscent of EM but with only two zones and/or a poorly defined border. Macules are non-palpable, erythematous or purpuric spots with irregular shape and size, and often confluent. Blisters often occur on all or part of the macule (Fig. 30.1B).

In TEN, the cutaneous lesions begin suddenly with burning and painful red skin, often symmetrically distributed on the face and chest that rapidly extends over the skin surface, including the trunk and proximal extremities. The maximal extension of the lesions is obtained in 3 to 4 days, and sometimes in a few hours.5,8 The hallmark of TEN is a widespread necrosis and detachment of full-thickness epidermis (Figs 30.1C and 30.1D). A positive Nikolsky’s sign may be present, where there is detachment of the full-thickness epidermis when light lateral pressure is applied with the examining finger. Re-epithelialization of the epidermis begins about 1 week after onset of the skin lesions, and most of the skin surface is re-epithelialized in 2 to 3 weeks.

Death usually results from sepsis or multi-organ failure. In the Power et al.²⁰ and Chang et al.¹³ studies, the most frequent causes of mortality were overwhelming sepsis, respiratory failure, and renal failure. The SCORTEN (TEN-specific severity of illness score) scale^25,26 was developed as a tool to predict the severity of the disease and risk of mortality, with prognostic factors, including age, amount of body surface area involved, heart rate, and renal function (Table 30.5).

Table 30.5

SCORTEN Scale: Prognostic Factors for SJS and TEN

Variable	Value
Age	> 40 years
Malignancy	Yes
Body surface area detached	> 10%
Heart rate	> 120 per minute
Serum urea	> 10 mmol/L
Serum glucose	> 14 mmol/L
Serum bicarbonate	< 20 mmol/L

One point is assigned for each positive variable. A patient’s mortality is predicted by the total number of points: 0–1 points=3.2%; 2 points=12.1%, 3 points=35.3%, 4 points=58.3%, ≥5 points=90.0%.

(Adapted from Guegan S, Bastuji-Garin S, Poszepczynska-Guigne E, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol 2006;126:272–6.)

Ocular Features

Incidence

Acute ocular complications develop in over half (i.e. 50% to 81%) of patients hospitalized for SJS and TEN, and 25% of these exhibit severe involvement.13,20 Chronic ocular sequelae occur in up to 35% patients with blinding corneal damage being the most severe long-term complication for survivors.²⁷ In the Power et al. study,²⁰ ocular involvement was seen in 9% of patients with EM, 50% of patients with TEN, and 69% of patients with SJS. Similarly, in the Chang et al. study,¹³ ocular involvement was more frequent in TEN (66.7%) and SJS (81.3%) than in those with EM (22.7%).

Acute Ocular Features

The acute stage may involve the entire ocular surface, including the eyelids, conjunctiva, and cornea. Initially, the eyelids may be swollen and erythematous, with crusting and ulceration of the lid margin and tarsal conjunctiva. A non-specific conjunctivitis usually occurs at the same time or may precede the onset of the skin lesions, and its severity usually parallels that of the skin lesions.²⁰ More severe involvement can result in pseudomembranous or membranous conjunctivitis. Secondary purulent bacterial conjunctivitis may occur. Conjunctival vesicles are rare. The acute inflammation may rapidly produce scarring, causing symblepharon and ankyloblepharon formation, and fornix foreshortening. In the acute stage, corneal epithelial defects may occur and these may be uncommonly complicated by corneal infiltrates and rarely by corneal perforation. Acute uveitis is uncommon but can occur. The initial eye findings usually last only 2 to 3 weeks.²⁸

Power et al.²⁰ classified severity of ocular involvement as mild, moderate, or severe. Mild involvement was defined as complications requiring routine eye care with full resolution prior to hospital discharge: lid edema, and conjunctival injection and chemosis. Moderate involvement included specific ocular complications that required specific treatment with near complete resolution of active disease upon discharge: conjunctival membrane formation, corneal epithelial loss < 30%, evidence of corneal ulceration or corneal infiltrates. Severe complications included sight-threatening disease, ongoing ocular inflammation with reduced vision, and the need for specific ongoing care after discharge: conjunctival fornix foreshortening, symblepharon formation, and ongoing active corneal disease at the time of discharge. Chang et al.¹³ used the same classification system and they both found that ocular involvement was not only more frequent but also more severe in SJS and TEN, compared to EM. Power et al. also found that the use of systemic corticosteroids had no effect on the incidence or the severity of ocular manifestations.

Chronic Ocular Features

Chronic ocular features include cicatrizing changes of the conjunctiva and eyelids, severe dry eye, and ocular surface failure. Corneal damage is the most severe long-term complication for survivors of SJS and TEN. These late features may not only result from severe ocular inflammation during the acute phase, but may also be a result of later recurrent episodes of conjunctival inflammation, and perpetuated by the severe dry eye and eyelid pathologies.29,30

Conjunctival inflammation and scarring may cause foreshortening of the fornices, symblepharon, ankyloblepharon, distichiasis, trichiasis, entropion or ectropion. Disorders of the lid–lash complex may cause microtrauma and perpetuate chronic inflammation through the mechanical rubbing of lashes against the ocular surface.³⁰ Ectropion or lagophthalmos can cause exposure keratopathy and further exacerbate the extremely dry ocular surface. Severe dry eye results from conjunctival goblet cell destruction, fornix foreshortening and destruction of the aqueous-secreting glands of Wolfring and Krause, lacrimal gland ductule scarring, and meibomian gland dysfunction.

Corneal involvement includes chronic epitheliopathy, persistent epithelial defects, fibrovascular pannus formation, stromal scarring and neovascularization, conjunctivalization, and in severe cases keratinization of the surface (Fig. 30.2). Keratinization also occurs on the posterior lid margin and tarsal conjunctiva, further abrading the ocular surface. Ocular surface failure may appear early as a consequence of the acute stage of disease, or can manifest several years later.³⁰ Destruction of the limbus during the acute phase of the disease may cause partial limbal stem cell deficiency (LSCD), but leave enough transient amplifying cells to maintain a normal corneal epithelium for some time. Further destruction of the remaining stem cells by chronic inflammation may cause late stem cell failure.

Figure 30.2 Preoperative photo of an SJS patient with total ocular surface failure. There is conjunctivalization and keratinization centrally.

Recurrent Disease

Most people do not take the inciting drug again; however, in the Chang et al. study,¹³ recurrences of EM/SJS/TEN occurred in six cases (2.4%) from 3 months to 6 years after the first attack. All initial and recurrent attacks were attributed to drugs, of which three recurrences occurred because the cause of the initial episode had not been recognized. Therefore, great care should be taken to document all medications associated with an episode of EM/SJS/TEN, and patients need to be acutely aware of the inciting medications to avoid future exposure. In other studies, most recurrences were attributable to herpes simplex virus infections. Of the 552 patients in the SCAR study,¹¹ 51 (9%) were recurrent. Recurrence rates were higher in EM (30%), compared to SJS (3%) and TEN (3%), due to the association of EM with herpes simplex virus. Prevention by oral antiviral drugs should be considered in cases of recurrent EM, due to herpes simplex virus.³¹ Recurrence episodes of conjunctival inflammation not associated with external factors may occur.^29,32

Differential Diagnosis

The differential diagnosis of the dermatological manifestations of EM/SJS/TEN is broad, due to the varying presentations of the skin lesions and unknown etiology in some cases. The most common diagnoses mistaken for these disorders are staphylococcal scalded skin syndrome, toxic shock syndrome, exfoliative dermatitis, autoimmune bullous diseases, and chemical/thermal burns.¹² It is critical to distinguish SJS and TEN from staphylococcal scalded skin syndrome and toxic shock syndrome, which are both bacterial in nature and require immediate appropriate antibiotic therapy to arrest release of the exotoxins responsible for the disease.

The chronic ocular findings of SJS most closely resemble those of ocular cicatricial pemphigoid, however, with less extensive symblepharon formation. The differential diagnosis also includes other diseases that produce cicatrizing changes of the eyelids and conjunctiva: atopic or toxic keratoconjunctivitis, severe infectious keratoconjunctivitis, ocular rosacea, linear IgA disease, chemical burns, avitaminosis A, and trachoma. Careful history taking should elucidate the diagnosis; however, conjunctival biopsy may be necessary in some cases. Immunofluorescence microscopy of the involved mucosa in ocular cicatricial pemphigoid will show linear immune deposits along the basement membrane.

Management

Systemic

Effective management of EM/SJS/TEN involves prompt recognition of the disease, and identification and immediate cessation of all potential offending agents. Immediate cessation of the involved medication reduces mortality and improves prognosis.³³ Comprehensive treatment requires a multidisciplinary approach with specialized nursing and medical care to address the complex, systemic response to the disease. Supportive care involves a similar therapeutic protocol as used in burns management: warming of the environment, minimizing transepidermal fluid loss, treatment of electrolyte imbalances, administration of high-calorie nutrition and intravenous fluids, and prevention of sepsis.¹² For more extensive cutaneous involvement, early referral to a burns unit reduces the risk of infection, mortality, and length of hospitalization significantly.^34,35 The largest trial showed a mortality of 29.8% after transfer to a burns unit with 7 days versus 51.4% (p < 0.05) after 7 days in TEN patients.³⁵ Although sepsis is a major source of mortality, prophylactic systemic antibiotics are not recommended and should be reserved for culture-proven sepsis.¹²

Skin lesions should be treated with antimicrobial materials, such as copper sulfate, silver nitrate or sulfadiazine cream (which contains sulfonamide and may cross-react with sulfonamide antibiotics) to improve barrier function and to prevent infection.³⁶ Biologic dressings, such as cadaver or porcine skin have also been used.³⁶ Nanocrystalline silver dressings, which serve as an antimicrobial agent and is released for up to 7 to 14 days, have been shown to be beneficial and reduce the frequency of painful dressing changes.³⁷

No treatment modality has been established as the gold standard for patients with EM/SJS/TEN. Given the immune-mediated background of these diseases, treatment with immunosuppressive medication should be expected to be beneficial; however, its use has met with intense debate over the years. Corticosteroids, while beneficial in many other acute inflammatory disorders, are controversial in EM/SJS/TEN. Other immunosuppressants, such as intravenous immunoglobulin (IVIG), cyclosporine, cyclophosphamide, thalidomide, infliximab, azathioprine, methotrexate, and plasmapheresis have also been tried in small case series.³⁶ However, the efficacy of these agents in the treatment of EM/SJS/TEN has not been demonstrated by any controlled clinical trial.

Several studies have shown that corticosteroid use is detrimental in the treatment of SJS or TEN, resulting in increased mortality and morbidity, most commonly infection and gastrointestinal bleeding.34,38,39 Systemic steroids may also mask early signs of sepsis, impair wound healing, and prolong recovery. However, a large retrospective review of 281 patients enrolled in EuroSCAR (case-control study of mortality risk factors in SJS/TEN patients) found that neither corticosteroids, nor IVIG showed any significant effect on mortality, compared to supportive care alone.⁴⁰ Studies have shown that IVIG arrests Fas-mediated keratinolysis in vitro,⁴¹ which provides a pathophysiologic explanation of why it has been shown to be beneficial, with rapid cessation of skin lesions and decreased mortality, in several small case series.⁴² However, other studies have found a higher mortality and a longer hospitalization,⁴³ or no benefit in outcomes with IVIG.⁴⁰

Ocular – Acute

The key to preventing long-term sequelae is early involvement of the ophthalmologist, particularly when efforts may be concentrated on life-threatening issues and hidden ocular involvement can be missed. In addition, eye examination is often difficult in the setting of an intensive care unit and in children. The aim during the acute stage is to prevent cicatricial complications of the ocular surface from developing: if the ocular surface inflammation and ulceration is not expeditiously managed, the ensuing wound healing usually results in scarring. It is important to evert the eyelids if possible, to examine for epithelial defects or ulcers involving the tarsi and fornices which may otherwise remain hidden.

Good ocular surface hygiene should be maintained by frequent lid soaks and conjunctival irrigation to remove accumulated mucous discharge. Prophylactic topical antibiotics should be used to prevent secondary infection, and the ocular surface kept well lubricated with frequent preservative-free artificial tears. Topical steroids should be used judiciously to decrease ocular inflammation; however, patients need to be monitored closely for secondary bacterial infection. Early efforts to prevent symblepharon and ankyloblepharon formation involve daily symblepharolysis with a glass rod or the use of a symblepharon ring to maintain the fornices.

If corneal epithelial defects develop, progressive stromal lysis should be prevented by the use of topical and systemic anticollagenases and frequent lubrication. Careful use of topical steroids should be employed in an effort to balance their anti-inflammatory effects with their risk of accelerated stromal lysis. If microbial keratitis is suspected, microscopy and cultures should be obtained, and fortified antibiotics started. Corneal perforation or impending corneal perforation may be managed with a lamellar or penetrating keratoplasty. An impending perforation may also be managed with a conjunctival flap, or cyanoacrylate glue and bandage contact lens.

There have been several case series reporting success with the use amniotic membrane (AMT) during the acute phase of SJS/TEN.44–46 AMT is the innermost layer of the placental membrane, consisting of a thick basement membrane and an avascular stroma. It exerts anti-inflammatory and antiscarring actions and is used to facilitate wound healing, including persistent corneal epithelial defects, acute chemical or thermal burns, or recurrent pterygiums.⁴⁶ In SJS/TEN, cryopreserved AMT is sutured to cover the entire ocular surface from lid margin to lid margin as a temporary biological bandage as shown in Figure 30.3.^45,47 The eyelashes are trimmed, and the edge of the piece of AMT is sutured to the external eyelid skin 1–2 mm from the lash line using an 8-0 nylon running suture.^44–46 The AMT is oriented stromal surface in contact with conjunctiva. It is spread to cover tarsal conjunctiva and fornix, then reflected to cover bulbar conjunctiva using muscle hooks. The AMT is anchored to skin using double-armed 6-0 prolene sutures passed through the eyelids and secured over the skin with a bolster. The AMT is fixed to the episclera with a continuous 10-0 nylon suture near the limbus. Either a symblepharon ring or Kontour bandage contact lens is used to separate eyelid from eyeball. Prokera™, a symblepharon ring with a sheet of AMT clipped to it, has also been used but has been found to provide inadequate coverage of the forniceal and palpebral conjunctiva and lid margins.^44,45 If Prokera™ is used, it is recommended that one must also use separate AMT to cover the eyelid margin and palpebral conjunctiva. Gregory⁴⁴ reported successfully treating 10 patients with AMT, with all patients having epithelial sloughing involving large areas of the ocular surface. They were treated within 10 days of onset of symptoms, and the AMT repeated every 10 to 14 days if inflammation and sloughing persisted. Dry eye severity and ocular surface and eyelid scarring was mild to moderate in all patients.

Figure 30.3 Schematic drawing showing the surgical technique of amniotic membrane transplantation (AMT). (A) Amniotic membrane is secured with two double-armed horizontal mattress sutures tied over the skin with bolsters and interrupted sutures to the lid margin. (B) Side view of AMT showing how AM covers the entire ocular surface from the upper lid margin to the lower lid margin. (C and D) Sheets of AMT are secured to cover the eyelid margin, and tarsal and bulbar conjunctiva. (A & B, Reproduced with permission from Meller D, Pires RT, Mack RJ, et al. Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology 2000;107:980–9. C & D, Reproduced with permission from Shammas MC, Lai EC, Sarkar JS, et al. Management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis utilizing amniotic membrane and topical corticosteroids. Am J Ophthal 2010;149:202–13.)

Ocular – Chronic

The goals of treatment in the chronic stages of EM/SJS/TEN are:

1. Management of dry eye

2. Restoration of eyelid function

3. Restoration of ocular surface.

Management of Dry Eye

The extent of compromise of tear function preoperatively is inversely correlated with the success rate of ocular surface reconstruction procedures.⁴⁸ Frequent non-preserved artificial tears should be used to treat the keratoconjunctivitis sicca that results from loss of goblet cells and scarring of the lacrimal ductules. Autologous serum eye drops (ASE) have been recommended as a useful alternative treatment in severe dry eye.⁴⁹ Topical transretinoic acid is commercially available and been shown to improve clinical features of dry eye in correlation with the degree of squamous metaplasia in patients with severe dry eye disorders.⁵⁰ Chronic conjunctival inflammation will perpetuate the dry eye state and should be managed with topical steroids and cyclosporine. Punctal occlusion to retain the tear film, and medial or lateral tarsorrhaphies to prevent exposure of the tear film to evaporation may also be helpful. The severe dry eye state can result in persistent corneal epithelial defects, and cause the patient to be in a constant state of photophobia and irritation. This may be improved with long-term bandage contact lenses. One study of 39 patients (67 eyes) fitted with scleral lenses for SJS/TEN found a significant improvement in visual acuity and ocular surface symptoms.⁵¹ Similarly, PROSE (prosthetic replacement of the ocular ecosystem) scleral lenses may be used to manage chronic ocular surface disease.

Management of Lid Disease

Abnormal eyelid anatomy may perpetuate corneal complications ³⁰ and should be addressed prior to any ocular surface reconstructive procedure. Trichiasis is a recurrent problem in these patients and may be managed by various techniques, including epilation, electrolysis, argon laser treatment, and cryotherapy. Symblepharon and fornix foreshortening may be addressed by symblepharolysis and conjunctival recession, with the placement of mucous membrane grafts, such as hard palate, nasal or buccal mucosa, or amniotic membrane. Symblepharon may also be addressed at the time of keratolimbal allograft. Cicatricial entropion or ectropion may be corrected by a variety of surgical methods, including placement of a skin or mucous membrane graft.

Ocular Surface Reconstruction

EM/SJS/TEN patients with LSCD have the worst prognosis for ocular surface reconstruction surgery, due to chronic ocular surface inflammation (stage c ocular surface disease),⁵² extremely dry eye, and other cicatricial complications. It is important to manage the ocular inflammation preoperatively and to wait until the inflammation is minimized before proceeding with surgery. If surgery is performed during active inflammation, there is an increased risk of delayed epithelial healing, corneal melts, and immune rejection postoperatively. A lateral and/or medial tarsorrhaphy should be strongly considered at the time of ocular surface reconstruction surgery.

EM/SJS/TEN is a bilateral disease, so a conjunctival limbal autograft from the fellow eye is not an option. The two remaining options are ocular surface stem cell transplantation (OSST) from an allograft donor with or without an optical keratoplasty, or keratoprosthesis (KPro) surgery with either a Boston KPro or osteo-odonto-keratoprosthesis (OOKP). We do not advocate Boston Type 1 KPro surgery as the primary ocular surface reconstructive procedure in these patients, and the prognosis for Boston Type 1 KPro surgery in EM/SJS/TEN patients is worse than for other disorders.⁵³ Due to the severe dry eye there is a high risk of corneal melting, infectious keratitis, endophthalmitis, and KPro extrusion. Figure 30.4 shows fungal keratitis and Figure 30.5 shows KPro extrusion in a patient with SJS who had undergone Boston type 1 KPro surgery.

Figure 30.4 SJS patient with KPro complicated by fungal keratitis. (A) Fluorescein staining demonstrates a epithelial defect. (B) A white infiltrate can be seen 360 degrees under the optic edge.

Figure 30.5 SJS patient (same eye as in Figure 30.2) with KPro extrusion.

We recommend firstly performing OSST surgery to reestablish the corneal epithelium and possibly the deficient conjunctival goblet cells (as discussed below). Once a healthy corneal epithelium has become stabilized after OSST, a penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) may be performed if there is significant stromal scarring. A KPro may be considered over a PK or DALK if there is a past history of recurrent endothelial failure from previous PKs, or if the surface fails after OSST surgery.

Allograft transplantation can be from a cadaver-donor keratolimbal allograft (KLAL) or living-related conjunctival limbal allograft (lr-CLAL), or a combination of both lr-CLAL/KLAL (the Cincinnati procedure).⁵⁴ A further option is transplantation of ex vivo cultured stem cells. Systemic immunosuppression is required in allograft transplantation to prevent immune rejection of the richly vascularized and antigenic limbal stem cells. SJS-related ocular surface disease carries a worse prognosis compared to other indications for these procedures, such as aniridia or contact lens-induced keratitis.^55–57 Aside from the chronic inflammation and cicatricial eyelid pathology, one of the major reasons for ocular surface failure is the severe dry eye and mucin deficiency seen in these patients. It has been suggested that combining lr-CLAL and KLAL is beneficial in replacing not only deficient limbal stem cells, but also conjunctival goblet cells.⁵⁴ Figure 30.6 shows the preoperative photographs of severe ocular surface failure in a patient with SJS, and the postoperative appearance after combined lr-CLAL/KLAL and penetrating keratoplasty.

Figure 30.6 (A) Preoperative appearance of a patient with SJS showing marked cicatricial ectropion and ocular surface failure. (B) Total ocular surface failure and symblepharon of the right eye of the same patient. (C) Postoperative appearance of the same patient after lr-CLAL/KLAL and penetrating keratoplasty.

In eyes with severe keratinization an osteo-odonto-keratoprosthesis (OOKP)⁵⁸ or a Boston type 2 keratoprosthesis⁵⁹ may be more suitable. However, these procedures are highly complex and performed only in a few centers around the world.