PATHOGENESIS
SJS and TEN are hypersensitivity reactions to infectious diseases (eg, due to herpes simplex virus, adenovirus, or streptococcal bacteria) or, predominantly, to drugs. Approximately 80% of TEN and 50%–80% of SJS cases are thought to be drug induced; the conjunctiva and oropharynx are the tissues most frequently involved. Although more than 100 drugs of various classes have been found to be associated with SJS–TEN, sulfonamides, anticonvulsants, NSAIDs, and allopurinol are frequently implicated.
Although the pathogenesis of the disease is not completely understood, in cases of drug-induced SJS and TEN, the keratinocyte apoptosis is thought to be triggered by drug-specific cytotoxic T lymphocytes via the perforin–granzyme pathway. As granzyme enters a target cell through the perforin channels, it leads to keratinocyte apoptosis. If Fas is the death receptor protein on the target cell membrane, extension of the apoptosis can result. Granule-mediated exocytosis, mainly of perforin and granzyme B or Fas-Fas ligand (FasL, or CD95L) interactions, is thought to play a role. One report demonstrated that blister cells from skin lesions of patients with SJS or TEN consisted mainly of cytotoxic T lymphocytes and natural killer cells and that both the blister fluid and the cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule. Results of studies investigating the association between HLA class I and II antigens and SJS–TEN suggest that there are strong ethnic differences in the HLA– SJS associations.
Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Stevens-Johnson syndrome and toxic epidermal necrolysis. Autoimmun Rev. 2008;7(8):598–605.
Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12):1343–1350.
Ueta M, Tokunaga K, Sotozono C, et al. HLA class I and II gene polymorphisms in Stevens-Johnson syndrome with ocular complications in Japanese. Mol Vis. 2008;14:550–555.
CLINICAL PRESENTATION
Fever, arthralgia, malaise, and upper or lower respiratory tract symptoms are usually sudden in onset. Skin eruption follows within a few days, with a classic “target” lesion consisting of a red center surrounded by a pale ring and then a red ring, although maculopapular or bullous lesions are also common. The mucous membranes of the eyes, mouth, and genitalia may be affected by bullous lesions with membrane or pseudomembrane formation. New lesions may appear over 4–6 weeks, with approximately 2-week cycles for each crop of lesions.
The primary ocular finding is a mucopurulent conjunctivitis and episcleritis. Conjunctival and corneal epithelial sloughing and necrosis with severe inflammation and scarring may develop (Fig 11-9). Patients are at risk of infection because of loss of the epithelial barrier. Ocular surface cicatrization results in long-term ocular complications such as conjunctival shrinkage, eyelid margin keratinization, trichiasis, and tear deficiency. Eyelid margin keratinization and scarring are important risk factors for poor long-term outcomes in these patients.
Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Crit Care Med. 2011;39(6):1521–1532.
Jain R, Sharma N, Basu S, et al. Stevens Johnson syndrome: the role of an ophthalmologist. Surv Ophthalmol. 2016;61(4):369–399. Epub 2016 Jan 30.
MANAGEMENT
Management of acute and chronic disease should be distinguished.
Acute phase. Acute SJS, SJS/TEN overlap, and TEN are medical emergencies with significant risk of morbidity and mortality. Management requires a team-based approach, similar to that used for thermal burn victims, and includes intensive care providers, anesthesiologists, surgeons who specialize in the treatment of burns, and ophthalmologists. The offending agent must be immediately discontinued. Systemic therapy is mainly supportive and is aimed at managing dehydration and superinfection. Systemic treatment with immunosuppressive or immunomodulatory agents remains controversial.
The mainstay of acute ocular therapy is lubrication with preservative-free artificial tears and ointments and vigilant surveillance for the early manifestations of ocular infections. Topical antibiotics are sometimes used as prophylaxis. The efficacy of topical corticosteroids for the ocular manifestations of this condition remains controversial. Symblepharon may form during the acute phase because the raw, necrotic palpebral and bulbar conjunctival surfaces can adhere to one another (Fig 11-10). Repeated conjunctival lysis of the symblepharon may exacerbate inflammation and surface morbidity. Significant long-term benefit has been demonstrated with early amniotic membrane transplantation covering the entire ocular surface, including the eyelid margins. This is one of the few potentially beneficial therapeutic interventions for this devastating disease. Amniotic membrane grafting should be performed very early in the course of this disease to prevent serious sequelae. Various techniques can be used, and the procedure can be done in the operating room or at the bedside for patients who cannot be taken to the operating room immediately.
Chronic phase. Management of chronic SJS, SJS/TEN overlap, and TEN, as summarized by Jain et al, is targeted at treating dry eye and mechanical abnormalities of the eyelids and eyelashes (which cause ocular surface trauma and inflammation), as well as rehabilitation of vision.
Dry eye is a significant problem secondary to scarring of the ocular surface and damage to the meibomian glands. Chronic dryness contributes to the development of further ocular surface damage, epithelial defects, symblephara, and limbal stem cell deficiency. Eyelid sequelae such as entropion, trichiasis, and keratinization, which result from cicatrizing conjunctivitis, cause chronic ocular surface irritation and inflammation. Treatment of dry eye includes lubrication (preservative free), punctal occlusion, and eyelid hygiene. Topical and systemic corticosteroids have been reported to help reduce active inflammation but must be used with caution and under close monitoring. Depending on the extent of the chronic disease, other treatment options include debridement of keratin from eyelid margins, use of scleral lenses, salivary gland transplantation, and mucous membrane grafting.
Vision rehabilitation in patients with chronic disease is challenging and high risk. Prosthetic replacement of the ocular surface ecosystem (PROSE; BostonSight, Needham, MA), a custom-designed prosthetic device to support impaired ocular surface system functions, may improve patient comfort and vision and help certain patients avoid surgery. Surgical treatments should be avoided unless there are no other options, as they carry significant risks and limitations, which must be fully explained to the patient. Limbal stem cell transplantation and cultivated oral mucosal epithelial transplantation have been reported. Penetrating keratoplasty in patients with chronic disease is associated with an extremely poor prognosis and is generally reserved for eyes with progressive thinning or perforation. In desperate cases, rare favorable results have been achieved with a keratoprosthesis. Unfortunately, many patients with chronic SJS, SJS/TEN overlap, or TEN are young and left with lifelong ocular morbidity. Rehabilitation is hindered not only by sequelae of the acute disease, but also by ongoing, chronic immune deviation of the ocular surface.
Ciralsky JB, Sippel KC, Gregory DG. Current ophthalmologic treatment strategies for acute and chronic Stevens-Johnson syndrome and toxic epidermal necrolysis. Curr Opin Ophthalmol. 2013;24(4):321–328.
Gregory, DG. New grading system and treatment guidelines for the acute ocular manifestations of Stevens-Johnson syndrome. Ophthalmology. 2016;123(8):1653–1658.
Iyer G, Srinivasan B, Agarwal S, Pillai V, Ahuja A. Treatment modalities and clinical outcomes in ocular sequelae of Stevens-Johnson Syndrome over 25 years—a paradigm shift. Cornea. 2016;35(1):46–50.
Jain R, Sharma N, Basu S, et al. Stevens Johnson syndrome: the role of an ophthalmologist. Surv Ophthalmol. 2016;61(4):369–399. Epub 2016 Jan 30.
Kohanim S, Palioura S, Saeed HN, et al. Stevens-Johnson syndrome/toxic epidermal necrolysis— a comprehensive review and guide to therapy. I. Systemic disease. Ocul Surf. 2016;14(1):2–19. Epub 2015 Nov 5.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.