European Journal of Cardiovascular Medicine

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent different ends of the spectrum of the same clinical entity of severe mucocutaneous reactions, usually to drugs, characterized by intraepidermal cell death leading to blistering and epidermal sloughing. SJS is the milder variant with <10% of total body surface area involvement. TEN is the more severe form with >30% total body surface area involvement. An intermediate classification is the SJS-TEN overlap in which there is 10–30% involvement. [1]

The incidence of SJS/TEN is low, approximating to about one to seven cases per million per year, the overall mortality rate is 20% to 25%.[2] The pathogenesis of SJS/TEN is controversial. The genetic risk factors are drug-specific and vary among different populations. Specific HLA subtypes A*0206 and DQB1*0601 carry increased risk for ocular complications secondary to SJS. [3] Moreover, the molecular pathogenesis of SJS/TEN is also largely unclear. Furthermore, up to 75% of cases are caused by delayed drug hypersensitivity reactions to a medication or its metabolites and appear to involve cell-mediated apoptosis of keratinocyte via the Fas signaling cascade and granulysin release. [4] Remaining 25% of cases are believed to have infectious etiology.

Initial presentation occurs in the form of a prodromal phase of malaise and fever followed by or may show concurrent development of generalized, tender cutaneous eruptions consisting of macules, papules, atypical target lesions and vesicles, or bullae. [5] Epidermal detachment leaves off large raw weepy areas like that seen in severe burns. Denuded skin predisposes the patient to bacterial superinfection, most common being Staphylococcus aureus. Sepsis, therefore, serves as the main cause of death in SJS/TEN patients. [6] At least two mucosal surfaces are affected. Painful oral erosions and crusts, conjunctivitis, and urogenital manifestations (e.g., urinary retention, urethritis, phimosis, and vaginal synechiae) accompany cutaneous manifestations in up to 90% of patients. [7] The respiratory tract may be involved causing cough, dyspnea, respiratory distress, pneumonia, and pulmonary edema. Hepatitis and glomerulonephritis may develop. [8]

The severe cutaneous manifestations of this disease spectrum may often lead to overlooking of the ocular sequelae, which are very common and may lead to loss of visual acuity. Most patients consult dermatologist or physician for skin lesions in the acute phase and consult ophthalmologist after the resolution of lesions. [9] In the acute phase of SJS/TEN, ocular involvement has been reported to occur in 80% of patients. Chronic ocular sequelae secondary to SJS/TEN develop in 21–29% of pediatric cases and 27–59% of adult cases. [10] In this report, we attempt to study the acute and delayed ocular manifestations seen in patients of SJS/TEN.  

After obtaining the ethical committee clearance from our Institutional Review Board, we conducted a retrospective observational study. We reviewed all the medical records of individuals admitted to the hospital from 2012 to 2019 with SJS and TEN's diagnosis. The patient consent is waived by IRB.

We collected demographic data, including age and gender. The systemic symptoms such as fever, mucosal involvement, skin involvement, and genital involvement were recorded. The triggering drug was identified, and any other systemic associations were noted. Ocular findings, including visual acuity, lid margin findings, conjunctival, and corneal involvement, were recorded.

As it was a retrospective study and examinations were done by multiple ophthalmologists, the recorded findings varied. Conjunctival involvement was noted as conjunctivitis if terms of “redness,” “congestion,” “conjunctivitis,” “follicles,” or “papillae” were recorded in the case sheet. If “membrane” or “pseudomembrane” was documented, it was considered as membranous conjunctivitis. If corneal involvement was not mentioned or written as normal, corneal involvement was noted as nil. We recorded corneal involvement for those cases where the corneal examination was recorded as corneal epithelial defects or haze. They were graded into mild, moderate, and severe based on the first ophthalmic documentation.

The ophthalmic treatment instituted was recorded, which could be either medical or surgical interventions. The surgical intervention included AMT with suture fixation. All patients underwent an ophthalmic examination as soon as the physician referred them, and after the first examination, each patient was examined either daily or on alternate days based on the severity of ocular involvement.

A study by Chow et al. revealed that the ocular manifestation amongst the cases of SJS/TEN is 53%.[11] Based on the study's findings with an absolute precision of 20% and desired confidence interval of 95%, it was estimated that 24 patients need to be enrolled in this study. On review of the medical records, we found that over 7 years, the number of patients admitted with the diagnosis of SJS/TEN was 45, and we included all of them as it was a retrospective study and we expected some data to be missing in some patients. We expressed the quantitative factors in terms of mean and standard deviation (SD) or median with interval range. We presented the qualitative parameters relating to visual acuity, the grade of ocular involvement, and management as percentages. Differences in mean values were tested for statistical differences by Student's t-test or by an appropriate nonparametric test of significance. Any association between the factors was studied by Chi-square or Fischer's test of significance. Data were analyzed using SPSS for Windows, Version 16.0. Chicago, SPSS Inc. Released 2008.

A total of 40 patients were included in the study during the study period, of which 19 were males and 21females. Out of these, 22 were SJS or SJS/TEN overlap and 8 were TEN patients. Ocular manifestations were observed in 27 patients (90%), with a male to female ratio of 10:17. All cases were drug-induced, except one, in which no history of any drug intake prior to the appearance of lesions could be elicited [Table 1]. All patients had bilateral ocular findings.

Table 1: Causative agents of SJS/TEN

Table 2: Classification of ocular involvement based on severity

All the patients having ocular involvement, presented to us in the acute phase, with symptoms such as redness, burning, watering, discharge, swelling, and sloughing of skin over lids and so on. The acute manifestations were classified as mild, moderate, or severe using the classification system described above. About 30.0% (12patients) had mild involvement, 55.0% (22patients) had moderate involvement, and 15.0% (6 patients) had severe involvement [Table 2].

Table 3: Ocular findings in the acute stage based on structures involved: Lids, Conjunctiva, and Cornea

All patients were treated with topical antibiotics, topical corticosteroids, and tear substitutes in the acute phase.

At the end of the study period, 8 patients (29.6%) developed chronic sequelae of ocular manifestations [Table 4]. Out of these patients, 3 patients developed severe dry eye disease, 2 patients developed trichiasis, 2 patients had a diminution of vision, and 1 patient developed severe photophobia [Figure 6]. Patients of SJS and SJS-TEN overlap had mild-to-moderate whereas patients of TEN had moderate to severe ocular manifestations. It was observed that delayed complications are more common in patients with initial severe eye involvement. More diffuse cutaneous and oral mucous membrane damage was associated with a greater risk of ocular manifestations.

Table 4: Long-term ocular sequelae after the end of 6 months

Ocular manifestations in the acute stage of SJS/TEN may vary and may not correlate with the late-stage complications, but if they are not recognized and treated appropriately by an ophthalmologist, it may result in ocular morbidity. [11] Hansen et al. in their study suggested that 50%–80% of the patients have acute ocular involvement, while 30%–50% of the initial cases continue to develop chronic ocular disease. [12] Hence it becomes important for the ophthalmologist to be part of the primary team managing the acute condition to identify and alleviate ocular involvement.

The mean age in our study was 27.5 years (SD 18.8), while many other studies showed a higher mean age of 41–52 years. [13] This dissimilarity may be because we included all the patients with ages ranging from 1 to 74 years. We saw a female preponderance with a female to male ratio of 1.37:1. Jongkhajornpong et al. also reported a similar finding in their study, [14] but other studies showed a male preponderance,[15] indicating that there might not be any gender predilection. [16]

Studies show that SJS accounts for 56%–73% of the cases, and TEN varies from 16% to 25% of all the patients requiring admission. Our study found that SJS accounted for 88.9% of the patients and TEN for 11.1% of the cases. The majority of the cases were SJS, and a relatively small proportion was contributed by TEN. We did not have any case of SJS/TEN overlap as they were not documented in the medical records. This could also be the reason for a higher proportion of SJS.

Studies have shown that antiepileptics and antibiotics are the most common triggers. [17] In our study, too, we found a similar association. However, we found that below 20 years of age, antibiotics were the most common triggering drugs and accounted for one-third of the cases, and amongst antibiotics; fluoroquinolones, and cephalosporins were commonly reported. In contrast, other studies have reported sulphonamides and clotrimazole as the most common antibiotics. [18] This variance could be due to the reduced use of sulphonamides by general practitioners. In the 40–60 years age group, antiepileptics were the most commonly reported triggers, with phenytoin accounting for over eighty percent of the cases.

Fever (84.4%) and mucosal lesions (86.7%) were the common systemic symptoms patients presented with, while ocular complaints were reported in only 48.9% of the patients. The primary treating physicians referred only 68.8% of the patients to ophthalmologists.

This is probably due to emphasis on life-saving measures in the acute stage or the primary physician's inability to recognize any involvement of the eye and thus failed to recognize the need for ophthalmology referral. We need to address this, as some ocular signs can be subtle and require an ophthalmologist to examine to identify them. The day of referral varied from 1 to 12 days, and of them, 74.2% were referred within 3 days. Nearly one-third of the patients were referred after 4 days. This needs to be considered a significant limitation in the comprehensive management of these patients. The primary physician needs to be aware that an early ophthalmology referral will result in an early ocular treatment institution. Kohanim et al. emphasize that the windows of opportunity should not be missed to provide the patient with the best possible treatment. [19]

Comprehensive management of the patient in the acute stage of SJS/TEN is crucial in preventing long-term visual morbidity. An ophthalmologist needs to be part of the primary treating team, as early recognition and management of the ocular involvement can avoid many long-term ocular complications. The grading of ocular involvement in the acute stage is a useful tool that helps the ophthalmologist identify the sentinel signs and helps in deciding about the need for surgical management in patients with severe grades

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