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Treatment Modalities and Clinical Outcomes in Ocular Sequelae of Stevens–Johnson Syndrome Over 25 Years—A Paradigm Shift

Iyer, Geetha FRCS (Glasg); Srinivasan, Bhaskar MD; Agarwal, Shweta MD; Pillai, Vinay S. MD; Ahuja, Ashish MD

doi: 10.1097/ICO.0000000000000680
Clinical Science

Purpose: To highlight and compare the outcomes of management for the ocular sequelae of Stevens–Johnson syndrome (SJS) over 25 years in a tertiary eye care institute.

Methods: A retrospective chart review of 798 eyes of 399 patients with SJS evaluated between January 1990 and December 2004 (group I) and of 847 eyes of 517 patients between January 2005 and December 2014 (group II) was done. The primary and secondary outcome measures were a change in the best-corrected visual acuity (BCVA) and an improvement in the symptoms and the ocular surface status, respectively. The groups were subdivided into procedures for ocular surface stabilization (A) and visual rehabilitation (B) and those managed conservatively (C).

Results: In the subgroup A of group II, an improvement/stabilization of BCVA after punctal cautery (231 eyes), mucous membrane grafting for lid margin keratinization (393 eyes), and fornix reconstruction (28 eyes) was noted in 93.6% of eyes. In subgroup B, all 10 eyes that underwent limbal allograft in group I failed when compared with an improvement of BCVA to better than 20/200 in 65.5% of the 61 eyes that underwent keratoprostheses. It was noted that the limbal status worsened in 66.9% of eyes treated conservatively in group I.

Conclusions: Stabilization procedures show a beneficial role while conservative management can lead to deterioration in chronic ocular sequelae of SJS. Keratoprosthesis, specifically the modified osteo-odonto-keratoprosthesis, forms the mainstay for visual rehabilitation in the end-stage disease. This study highlights the improved outcomes with a paradigm shift in the management modalities.

CJ Shah Cornea Services, Dr. G. Sitalakshmi Memorial Clinic for Ocular Surface Disorders, Medical Research Foundation, Sankara Nethralaya, Chennai, India.

Reprints: Geetha Iyer, FRCS (Glasg), CJ Shah Cornea Services, Dr. G. Sitalakshmi Memorial Clinic for Ocular Surface Disorders, Medical Research Foundation, Sankara Nethralaya, 18, College Rd, Chennai 600 006, India (e-mail: drgeethaiyer@gmail.com).

The authors have no funding or conflicts of interest to disclose.

Received June 14, 2015

Received in revised form September 23, 2015

Accepted September 25, 2015

The ocular sequelae of Stevens–Johnson syndrome (SJS) cause not only visual debilitation because of the chronic changes occurring on the ocular surface and associated limbal stem cell deficiency, but also lead to significant functional impairment because of the associated symptoms of photophobia, dryness, and foreign body sensation.1–4 Limbal stem cell deficiency was identified as the primary cause for loss of vision, and earlier attempts at visual rehabilitation focused on limbal transplantation techniques. Being a bilateral disease, these transplants were allografts. Despite immunosuppression, the results of limbal transplant in patients afflicted with SJS were not found to be encouraging.5–9 The disease has been considered as a chronic inflammatory condition of the ocular surface, leading to progressive worsening of the limbal deficiency and vision.

The deformities of the ocular adnexa, most commonly trichiasis and entropion, have always received considerable attention and been given corrective measures. Over the last decade, lid margin keratinization, a feature that occurs in most eyes of patients with SJS, was identified as an important cause for the continued inflammation of the ocular surface and possibly, therefore, for the worsening of limbal status as well.10,11 The need to address the same was highlighted, and we published our initial results of the impact of mucous membrane grafting (MMG) for lid margin keratinization in 54 eyes of 31 patients12 and, subsequently, reported the results of comprehensive management of SJS.13 Before the understanding of a comprehensive approach in these eyes, the management of the ocular sequelae in patients with SJS was primarily limited to the use of topical lubricants, topical steroids, punctal occlusion, tectonic procedures, attempts at fornix reconstruction, and limbal allografts.

In this article, we have analyzed the data of patients with ocular sequelae of SJS over a period of 25 years, comparing the changes in the management modalities and their outcomes over a period of 15 and 10 years, respectively. This division was based on the initiation of MMG for lid margin keratinization at our institute in 2005. It was also during the same time that the modified osteo-odonto-keratoprosthesis (MOOKP) was initiated at our tertiary eye care institute. We believe this to be the first such comparison of data from a single institute over 25 years, highlighting the need for a paradigm shift in the management of this condition.

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PATIENTS AND METHODS

Institutional Review Board approval was obtained for this study, which adhered to the tenets of the Declaration of Helsinki. The diagnosis of SJS was based on a confirmed history of acute onset of high fever, serious mucocutaneous illness with skin eruptions, and involvement of at least 2 mucosal sites including the ocular surface. Case records of patients with ocular sequelae of SJS examined at our institute were divided into 2 groups and reviewed: group I, between January 1990 and December 2004 and group II, between January 2005 and December 2014. All patients underwent a detailed ocular examination, and the following parameters were analyzed for the outcome measures:

  1. best-corrected visual acuity (BCVA);
  2. Schirmer I test (graded as 1, <5 mm; 2, 5–10 mm; 3, 11–15 mm; and 4, >15 mm); and
  3. fluorescein corneal staining scores from 0 to 9 (for group II; the same was not uniformly recorded for patients in group 1 and, hence, not included).

All patients showed significant irritation, ocular discomfort, and photophobia at presentation. Although no detailed symptom questionnaire was prepared, patients' perception of symptoms remaining the same, worsening, or improving was documented. Further division of both groups was into 3 categories. Subgroup A included procedures for surface stabilization and fornix reconstruction that included punctal occlusion (collagen or silicone plugs), adnexal corrective procedures, symblepharon release with amniotic membrane grafting in group I and punctal cautery, MMG for lid margin keratinization, prosthetic replacement of ocular surface ecosystem (PROSE) lenses, symblepharon release with amniotic membrane grafting and MMG to the lids, cultivated oral mucosal epithelial transplantation, and adnexal corrective procedures in group II.12,13

Procedures for visual rehabilitation were categorized under subgroup B that included limbal allograft with penetrating keratoplasty with systemic azathioprine (2 mg/kg) for 6 months to 1 year in group I and cataract extraction/optical iridectomy/keratoprosthesis in group II. Procedures for ocular surface stabilization and PROSE lenses were used to further improve the visual acuity for eyes that underwent cataract extraction and optical iridectomy. Subgroup C included conservative management that comprised primarily artificial tear substitutes and topical steroids in group I and artificial tear substitutes in group II. Topical steroids were used sparingly, only if required, in group II.

Tarsorrhaphy, cyanoacrylate glue, amniotic membrane grafting, lamellar corneal graft, and tectonic or therapeutic penetrating corneal graft (tectonic procedures) were performed in both groups for nonhealing epithelial defects, sterile corneal melts, corneal infections, and perforations when required.

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RESULTS

Demographics

Group I

Group I comprised 798 eyes of 399 patients (194 males:205 females), with the age ranging from 5 to 71 years (mean, 24.6 ± 15.5 years). The mean duration from the onset of SJS to presentation to our tertiary eye care center was 24.6 ± 34.2 months. The most common triggering factor was noted to be drugs (77.7%), with sulfonamides being the commonest (42.9%). Infections were the causative agent in the remaining 22.3% of cases, with varicella zoster accounting for 53.9% of these. The mean duration of follow-up was 19.5 ± 33.2 months. Surgical intervention occurred in 363 eyes of 207 patients. Mean time of the intervention from the date of presentation was 24.0 ± 34.2 months, and their mean follow-up 44.5 ± 51.1 months. Lid margin keratinization was documented in 212 eyes (26.5%). The data of all patients who presented to the institute were compiled irrespective of the follow-up.

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Group II

Group II comprised 847 eyes of 517 patients (288 males:229 females), with the age ranging from 1 year to 76 years (mean, 27.4 ± 24.7 years). The duration from the onset of SJS to presentation to our tertiary eye care center ranged from 20 days to 320 months (mean, 59.6 ± 20.4 months). The inciting events were medications in 53.3% (sulfa group, 50.3%), viral illness in 16.8%, and unknown in 29.7% of the patients. The mean follow-up was 62.4 ± 17.3 months. Of the 847 eyes, 59 showed diffuse ocular surface keratinization. Of the remaining 788 eyes, lid margin keratinization was noted in 69.8% (550 of 788) eyes. Of these, 16.2% (89 of 550) of eyes revealed a mild grade of lid margin keratinization not causing ocular surface changes and, hence, did not require surgical intervention. MMG was required for the remaining 461 eyes:393 eyes, MMG and 28 eyes, fornix reconstructive procedure with MMG. The procedure was not performed in 40 eyes because the patients were not willing for the same. Only patients with at least 3 months of follow-up were included in the data analysis.

Fifty-six eyes of 32 patients were common to both groups I and II, and 48 eyes of 24 patients managed conservatively (group I) underwent MMG later (group II). Eight eyes of 8 patients underwent the MOOKP procedure later (group II).

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Outcomes

The visual outcomes of groups I and II at the last follow-up were analyzed and compared (Table 1).

TABLE 1

TABLE 1

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Subgroup A (Procedures for Surface Stabilization)

After the procedures done for ocular surface stabilization and fornix reconstruction in groups I (222 eyes) and II (punctal cautery, 231 eyes of 129 patients; MMG, 393 eyes of 230 patients), the improvement in BCVA after intervention was statistically significant for group II (Tables 2 and 3). The symptomatic improvement (group I: 75/222 eyes; group II: punctal cautery, 189/231 eyes; MMG, 347/393 eyes) and the improvement/stabilization in the Schirmer I wetting (group I: 75/222 eyes; group II: punctal cautery, 224/231 eyes; MMG, 375/393 eyes) were statistically significant in group II (P < 0.0001). A recurrence of keratinization along the edges of the grafted mucosa causing symptoms and/or corneal staining was noted in 33 eyes of 23 patients (8.4%). A revision mucous membrane graft was performed in these eyes. No other complications related to the procedures were noted.

TABLE 2

TABLE 2

TABLE 3

TABLE 3

PROSE lens fitting was performed in 46 eyes. Subjective improvement in comfort was noted in all eyes. Improvement in BCVA was noted in 32 eyes. Previous MMG was performed in 29 of these eyes. A fornix reconstructive procedure to enable better fitting of the PROSE was performed in 5 eyes.

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Subgroup B (Procedures for Visual Rehabilitation)

All limbal allografts performed in group I failed within 1 year of the procedure. In group II, cataract extraction (phacoemulsification/extracapsular cataract extraction) was performed in 28 eyes of 23 patients after punctal cautery and/or MMG to the lid margin. BCVA improved in 22 eyes (78.5%). None of the patients developed epithelial defect or infection after cataract surgery.

Optical iridectomy beneath the area of clear cornea was performed in 5 eyes with central corneal scarring, and BCVA improved in all the eyes. Previous punctal cautery and/or MMG to the lid margin were performed in all 5 eyes.

Sixty-one eyes underwent different types of keratoprosthesis procedures, with a mean follow-up of 39.6 (3–114) months: MOOKP in 48 eyes; Boston type 1 Kpro, 4 eyes; Lucia type 2 Kpro, 4 eyes; and Boston type 2 Kpro, 5 eyes. The eyes that were unfit for the MOOKP procedure underwent either Boston type 2 keratoprosthesis or Lucia type 2 keratoprosthesis, whereas Boston type 1 keratoprosthesis was performed in moist eyes only. A comparison of the visual outcome after limbal allograft in group I and the keratoprosthesis procedure in group II was done (Table 4).

TABLE 4

TABLE 4

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Subgroup C (Conservative Management)

In 54.3% (434) of eyes in group I, which did not undergo any surgical intervention and received only medical treatment, a statistically significant deterioration in BCVA (P < 0.0001) was noted. In group II, 114 (13.4%) eyes of 57 patients did not undergo any intervention. Of these 114 eyes, 42 eyes of 21 patients (4.9%) showed mild lid margin keratinization that required no intervention. The remaining 36 patients have either refused the advised intervention or are on the waiting list for the keratoprosthesis procedure.

It was noted that the limbal status (increase in corneal vascularization) worsened in 66.9% of eyes treated conservatively and in 60.4% of eyes after intervention in group I. The limbal status stabilized/improved (decrease in corneal vascularization) in 96.6% (630/652) of eyes treated by procedures for surface stabilization (punctal cautery, MMG, and fornix reconstructive procedures) in group II.

Procedures were performed for tectonic support in 69 eyes in group I and 79 eyes in group II. The visual outcome was not compared because of the tectonic nature of the procedure. The globe was anatomically salvaged in all but 2 eyes in group I and 3 eyes in group II that underwent phthisis after tectonic/therapeutic penetrating keratoplasty.

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DISCUSSION

SJS leads to chronic ocular damage with blinding sequelae.1–4 Affected patients consult or are referred to an ophthalmologist for the chronic ocular sequelae. In 2005, the aim of a retrospective analysis (group I) was to document the presenting features, the impact of SJS on vision, and the outcome of interventions being performed routinely then. The visual acuity at presentation (group I) was indicative of the ocular morbidity with 39.6% of eyes presenting with a BCVA of less than 20/200. Lid margin keratinization was documented in 26.5% of eyes, although it was largely unaddressed. Irrespective of the management, conservative or surgical, the deterioration of vision in group I at the last follow-up was noted to be statistically significant (P < 0.0259), which warranted a need to change the approach toward these eyes. Inappropriate documentation of lid margin keratinization, a largely unaddressed finding, could have underestimated its occurrence, as it was documented in 69.8% eyes in group II.

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Surface Stabilization Procedures

Among the patients in group II, an improvement/stabilization of BCVA was noted in 93.6% of eyes. MMG for lid margin keratinization definitely has a role to play not only in improving patient comfort, the ocular surface status, and visual acuity but also in preventing a deterioration of the ocular surface.12,13

The associated dryness, another important cause for persistent inflammation in these eyes, needs aggressive management. Punctal cautery alone, in the presence of a patent nasolacrimal duct, in a moderate to severe dry eye, improved/stabilized the visual acuity along with an improvement of the ocular surface status in more than 90% of the eyes.

Fornix reconstructive procedures in the group II patients were done to enable fitting of the PROSE lenses, improve cosmesis, and/or in association with MMG for lid margin keratinization in eyes with obliterated fornices.13–15 Cultivated oral mucosal epithelial sheets16–18 were used to assist in these procedures (8 eyes) and reduce the recurrence of symblepharon, which showed reduction in the immediate postoperative inflammation.

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Visual Rehabilitation

For a bilateral end-stage ocular surface disease, limbal allograft performed in all 10 eyes belonging to group I failed, similar to other published studies where there was no encouraging outcome.5–9 The underlying immunological condition, associated dryness, risk of rejection, and, most importantly, the unaddressed lid margin keratinization could have been causes for the failure of limbal allografts. Instead of limbal allograft, the MOOKP was reported to show long-term good visual outcome for the end-stage ocular surface diseases with keratinization.19–21 The Boston type 2 and Lucia type 2 keratoprostheses were performed for patients in whom the MOOKP was not an option. The Boston type 1 Kpro was implanted in 5 moist eyes.13,22,23 Although complications do occur with keratoprostheses,22–27 they have a significant role to play in visual rehabilitation in these eyes.

The eyes that were managed conservatively in group I showed a statistically significant drop in the outcome parameters. Only 4.9% of eyes underwent conservative management in group II, indicating that most of these eyes need active interventional procedures to improve and/or stabilize the ocular surface.

The drawbacks of a retrospective study are inherent to our article. This includes a possible lack of documentation of findings, especially lid margin keratinization, in group I eyes. A correlation between the occurrence of sterile corneal melts or corneal infections with lid margin keratinization with or without the use of topical steroids was not documented and analyzed. There was an overlap of 56 eyes of 32 patients between groups I and II. None of these eyes underwent any surgical intervention in group I. There was a drop in visual acuity by a mean of 2 Snellen lines in these eyes, before they underwent MMG.

The intent of the article was to analyze the outcomes in 2 different time frames with varying techniques. The aim of this article was to highlight the lacunae in the earlier management of ocular sequelae of SJS. By performing this exercise, the detrimental effect of conservative and inadequate management has been highlighted. The improvement in the ocular surface after procedures for ocular surface stabilization in group II was statistically significant. Our comparative results between the 2 groups reiterate the need for and benefits of early intervention in these eyes. By stabilizing the ocular surface, it may be possible to avoid or delay the need for keratoprosthesis, except in eyes that present with bilateral keratinized ocular surface or total limbal stem cell deficiency. Options to improve the visual outcome with the aid of PROSE lenses have expanded the armamentarium of treatment modalities. MMG for lid margin keratinization and cultivation of oral mucosal epithelium have improved anatomical outcomes in these eyes.

It is important to create awareness regarding not only the beneficial effects of intervention, but also the detrimental effect of conservative management in these eyes. To the best of our knowledge, this is the largest series of patients with SJS with chronic ocular sequelae, analyzing management outcomes, over a 25-year period, indicating the need for a paradigm shift in the treatment of these eyes.

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Keywords:

Stevens–Johnson syndrome; lid margin keratinization; blink-induced microtrauma; mucous membrane graft; keratoprosthesis; punctal cautery; Boston type 1 keratoprosthesis; osteo-odonto-keratoprosthesis

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