SJS/TEN is essentially an idiosyncratic reaction to drug intake where the accumulation of drug metabolites in the epidermis in genetically predisposed individuals initiates an immunologic process that causes massive keratinocyte cell death, eventually leading to full-thickness necrosis of the epidermis.¹⁰ The list of implicated medications exceeds 200 drugs, but the most common ones include antibiotics (sulfonamides like trimethoprim or sulfamethoxazole, beta-lactam antibiotics, tetracyclines, or quinolones), antiepileptic medications, nonsteroidal anti-inflammatory agents, antigout medications, and vaccinations.¹,²,⁶,¹⁰ Rarely, nonpharmaceutical factors like exposure to industrial chemicals, traditional Chinese herbal medications, infections with Mycoplasma pneumoniae, herpes virus, or HIV may initiate SJS/TEN.¹,²

Regardless of the exact etiologic risk factor, the etiopathogenetic mechanisms underlying the onset of SJS/TEN complex have not yet been fully elucidated but are postulated to have both an immunologic and a genetic basis, which when acting together both lead to keratinocyte cell death by apoptosis and secondary epidermal necrosis, usually with irreversible consequences.¹,²,⁵ Granulysin, a powerful cytolytic protein secreted by the immune system, is hypothesized to play a decisive role underlying the massive epidermal cell death and mucous membrane pathology in SJS.⁵ Genetic associations include abnormalities in the HLA-B12 allele and several of its subgroups, the IKZF-1 gene, as well as several other genes.² Because each of these different genes or HLA alleles may predispose an individual of a certain race to a specific drug and not any other,²,⁵ a full review of those genetic/immune-mediated mechanisms and the various theories associated with SJS or TEN are beyond the scope of this chapter and are discussed in detail elsewhere.²,⁵

Lid margin keratinization is a chronic ocular sequela of SJS, causing progressive ocular surface damage. The exact etiopathogenesis remains elusive, but possible pathophysiologic mechanisms included loss of the mucocutaneous junction barrier leading to epidermalization, dyskeratosis involving the meibomian gland orifices, altered lid margin microbiome, and de novo squamous metaplasia of the marginal conjunctival epithelium. Findings support a role for inflammation in the pathogenesis.¹¹

SJS/TEN is a rare disease with an annual incidence that ranges from 0.4 to 7 cases per million, but with a high mortality rate of 25% to 40% in TEN and 1% to 5% in SJS.¹,⁸ SJS is predominantly a disease of children and adolescents, whereas TEN may occur in all ages, although the mortality rate is higher in the elderly. Both conditions may recur (16 recurrences/1000 person-years), but recurrences tend to decline with age.⁴ SJS is defined when 10% or less of the body surface area is involved, while in TEN 10% to 30% of the cutaneous surface area is involved.² Patients with acute SJS rarely present to the
ophthalmologist, but any bilateral conjunctivitis associated with an extremely high fever with or without oral involvement and with paronychia should alert the clinician to the possibility of SJS.⁶ Acute conjunctivitis typically precedes or occurs concurrently with skin eruptions in more than 65% of patients with SJS.⁶ If an ophthalmologist is consulted in the ICU later, after the diagnosis is established, 75% of these patients typically have bilateral conjunctivitis. This may progress to corneal ulceration in 25% of patients,² and occasionally tarsal ulceration may also be present.⁶,⁷ Patients with SJS are often seen by an ophthalmic specialist after they have been released from the hospital, but in fact, the residual ocular side effects of SJS are frequently the most debilitating part of the disease.²,³,⁴

Palpebral anomalies in SJS are mostly attributable to tarsal conjunctival hyperemia and scarring (Figure 117.1), which can result in entropion, trichiasis, distichiasis, or even ectropion.¹⁰ If not removed, misdirected eyelashes, or the distichiatic ones originating from metaplastic meibomian glands, can mechanically abrade the corneal epithelium causing repeated blink-related microtrauma.²,³,⁸ The exact incidence or prevalence of eyelid malpositions in SJS is difficult to conclude from the literature and varies from as low as 3% to as high as 71%.³,⁸,⁹,¹⁰ This dramatic variability may be attributable to the lack of medical care in some rural areas, lack of standardization of diagnostic criteria for palpebral anomalies in SJS,³ or earlier evaluation before chronic sequelae have set in.⁹ More importantly, it may also be attributable to a difference in genetic backgrounds.³ An often overlooked cause of persistent ocular inflammation in SJS/TEN is chronic irritation of the ocular surface due to lid margin keratinization.⁸,⁹ Tarsal ulceration, which occurs in the acute phase, eventually leads to destruction of the mucocutaneous junction with subsequent keratinization of the eyelid margin that usually extends 2 to 3 mm into the tarsal conjunctiva.⁸,⁹