Purpose
To investigate the relation between visual function, clinical findings, and visual symptoms in Stevens-Johnson syndrome (SJS) and to compare the results with Sjögren syndrome (SS) patients and normal subjects.
Design
Cross-sectional comparative study.
Methods
One hundred fifteen eyes of 59 consecutive patients with SJS and toxic epidermal necrolysis (TEN), 208 eyes of 104 healthy normal subjects, and 132 eyes of 66 SS patients were investigated in this multicenter study. All study subjects underwent tear function and ocular surface examinations, Landolt and functional visual acuity examinations, and the Japanese version of the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire).
Results
The mean ocular surface grading scores were significantly higher and the mean score of all 12 NEI VFQ subscales was significantly lower in the SJS patients compared to the SS patients and the normal subjects ( P < .05). The conventional and functional logarithm of minimal angle of resolution (logMAR) visual acuities in SJS patients with minimal corneal complications were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. The conventional and functional logMAR visual acuities and the mean ocular surface grading scores in SJS with aqueous deficiency were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. Strong correlations between best-corrected logMAR functional visual acuities and either ocular surface grading scores or the composite NEI VFQ-25 scores were observed.
Conclusions
The functional visual acuity examination reflects the severity of clinical ocular surface findings and vision-related quality of life more than the standard conventional visual acuity in SJS.
Stevens-Johnson syndrome (SJS) is an acute, self-limiting disease of the skin and mucous membranes associated with symblepharon, adhesive occlusion of the lacrimal puncta, and corneal opacification with conjunctivalization and severe dry eyes leading to worsening of the ocular surface health and poor quality of vision.
Previous reports have demonstrated that contrast sensitivity, contrast visual acuity, glare disability, and wavefront aberrations are useful to detect quality of vision in everyday life. Visual function assessment using these measurement methods has been reported to be useful in keratorefractive surgery, mild cataract, and dry eye diseases. To the best of our knowledge, however, there are no reports about visual function assessment in patients with SJS except a previously published report by us.
It has been our experience that SJS patients with good visual acuity and mild ocular surface morbidity may still complain of similar severe eye irritation and visual complaints as patients with Sjögren syndrome (SS). However, the differences in visual symptoms and conventional and dynamic visual acuity between these 2 entities have not been quantified and compared so far. In an attempt to investigate the visual function and ocular surface differences between SJS and SS, we performed this multicenter cross-sectional study, using a previously reported ocular surface morbidity severity questionnaire and functional visual acuity measurement.
Methods
Subjects
One hundred fifteen eyes of 59 consecutive patients (28 male, 31 female; mean age: 47.5 ± 16.0 years; range: 14–79 years) with SJS, including its more severe variant, toxic epidermal necrolysis (TEN), seen at the Cornea Subspecialty Outpatient Clinic of the Departments of Ophthalmology of Keio University, Tokyo Dental College, Tokyo Medical Center, Kyoto Prefectural University of Medicine, Hokkaido University, Ehime University, and Yamaguchi University were studied in this cross-sectional multicenter study. Clinicians participating in the study received training to standardize the conduct of examinations performed at each center. The conduct of examinations was checked by trained coordinators at each center for consistency of the examination procedures. The diagnosis of SJS or TEN was based on the history of the presence of cryptogenic fever and acute inflammation of mucosal membranes most commonly after taking cold remedies, antibiotics, or anti-inflammatory drugs, and on the presence of chronic ocular surface complications such as symblepharon, entropion, trichiasis, xerophthalmia, and/or corneal vascularization. Two hundred eight eyes of 104 healthy normal subjects (30 male, 74 female; mean age: 36.2 ± 12.0 years; range: 20–72 years) without dry eye disease and 132 eyes of 66 SS patients (66 female; mean age: 62.8 ± 11.1 years; range: 28–82 years) who were diagnosed according to Fox criteria were also investigated in this multicenter study. Patients or control subjects with other systemic or ocular diseases, history of ocular surgery within 6 months, history of ocular cicatricial pemphigoid, or chemical, thermal, or radiation injury that would have adverse ocular surface effects were excluded according to the study exclusion criteria. SJS patients with a baseline best-corrected Landolt conventional visual acuity of less than 20/2000 attributable to cataract in both eyes, ocular surface keratinization, glaucoma, or posterior segment disease were excluded from this study, since the functional visual acuity measurement system cannot assess functional visual acuity at such low visual acuity levels.
Slit-Lamp Examinations
All study subjects underwent slit-lamp examinations observing 12 components of 3 categories of ocular complications, such as corneal complications consisting of superficial punctuate keratopathy (SPK), epithelial defect, conjunctivalization, neovascularization, opacification, and keratinization; conjunctival complications consisting of hyperemia and symblepharon formation; and eyelid complications consisting of trichiasis, mucocutaneous junction involvement, meibomian gland involvement, and punctal damage. Each component was graded on a scale from 0 to 3, depending on the severity of involvement.
The severity gradings and ocular surface tests were performed under the same single protocol by the researchers of all contributing study centers. Table 1 shows the clinical severity grading criteria of the ocular surface findings.
| Grade 0 | Grade 1 | Grade 2 | Grade 3 | Comments | |
|---|---|---|---|---|---|
| Assessment of Corneal Complications | |||||
| SPK | A1D1 | A1D2, A2D1 | A1D3, A2D2, A3D1 | A2D3, A3D2, A3D3 | Using fluorescein staining based on the area and density of the lesions as described by Miyata and associates |
| Corneal epithelial defect | Absent | Less than 1/4 of the corneal surface | 1/4 to 1/2 of the corneal surface | More than 1/2 of the corneal surface | |
| Conjunctivalization | Absent | Less than 1/4 of the corneal surface | 1/4 to 1/2 of the corneal surface | More than 1/2 of the corneal surface | |
| Neovascularization | Absent | Confined to the corneal periphery | Extending beyond the pupil margin | Extending beyond the pupil margin into the central cornea | In eyes where significant opacification or extensive symblepharon formation made it difficult to evaluate corneal neovascularization, a grade of 3 was assigned |
| Corneal opacification | Clear cornea with easily visible iris details | Partial obscuration of the iris details | Iris details poorly seen with barely visible pupil margins | Complete obscuration of iris and pupil details | |
| Keratinization | Absent | Less than 1/4 of the corneal surface | 1/4 to 1/2 of the corneal surface | More than 1/2 of the corneal surface | |
| Assessment of Conjunctival Complications | |||||
| Conjunctival hyperemia | Absent | Mild or sectoral engorgement of the conjunctival vessels | Moderate or diffuse engorgement of the conjunctival vessels | Severe or significant engorgement of the conjunctival vessels | |
| Symblepharon | Absent | Involving only the conjunctival surface | Less than 1/2 of the corneal surface | More than 1/2 of the corneal surface | |
| Assessment of Eyelid Complications | |||||
| Trichiasis | Absent | Less than 1/4 of the lid margin | 1/4 to 1/2 of the lid margin | More than 1/2 of the lid margin | |
| MJ involvement | Normal MJ | Mild irregularity of MJ | Moderate irregularity of MJ | Severe irregularity of MJ | Bron grading was employed for the classification of MJ changes. Fluorescein staining of the conjunctiva was performed for evaluating the MJ involvement. In eyes where significant keratinization of the lid margin or extensive symblepharon formation made it difficult to evaluate mucocutaneous junction involvement, Grade 3 was assigned. |
| MG involvement | Oily expressible secretion | Expressible yellowish-white oily secretion | Expressible thick cheesy material | Inability to express any secretion | The severity was determined clinically by the nature of the meibomian gland secretion expressed manually at the center of the upper lid. |
| Punctal involvement | Normal | Iatrogenic punctal occlusion | Either superior or inferior punctal occlusion | Both superior and inferior punctal occlusion |
Tear Function and Ocular Surface Examinations
The standard Schirmer test without topical anesthesia was performed as previously reported. A vital staining severity grading was also assigned. A 2-μL volume of 1% fluorescein dye was instilled in the conjunctival sac by a micropipette. The minimum score for corneal fluorescein staining was 0 points and the maximum score was 9 points.
Standard Visual Acuity Measurements
Standard visual acuity testing using Landolt charts placed 5 m away from subjects was performed. Landolt visual acuity was employed instead of Snellen chart since it is a standard test in Japan, and because the optotypes in Landolt and functional visual acuity testing are similar.
Functional Visual Acuity Measurements
Continuous visual acuity testing during a 60-second period under natural blinking was performed as previously reported.
Functional Visual Acuity Indices
Briefly, the outcome parameters of the functional visual acuity measurement system were functional visual acuity (defined as the average of visual acuities measured during a 60-second testing), visual maintenance ratio (defined as the ratio of logMAR values of the functional visual acuities over the time frame for testing divided by the logarithm of minimal angle of resolution (logMAR) baseline visual acuity), maximal corrected visual acuity, minimal corrected visual acuity, standard deviation of functional visual acuity, mean reaction time (defined as the mean of the response time taken by a subject to respond to an optotype), and blink numbers during a 60-second functional visual acuity test.
Visual Function Questionnaire-25
We used the Japanese version of the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire 25) to evaluate the vision-related quality of life. NEI VFQ-25 measures the following 12 vision-targeted subscales: general health, general vision, ocular pain, near activities, distant activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. A scale of 0 to 100 points is used for subscale scores. A score of 100 indicates the best possible score, while 0 indicates the worst possible score.
Statistical Analysis
A 1-way ANOVA was performed for the comparison of conventional visual acuities, functional visual acuities, visual maintenance ratios, ocular surface grading scores, and VFQ-25 scores among SJS patients, SS patients, and normal control subjects. The Bonferroni test was used for further multiple comparisons. A paired t test was performed for the comparison between conventional and functional visual acuities in SJS patients, SS patients, and normal control subjects alone. To investigate whether the visual disturbance or quality of life are similarly affected in SJS patients compared to SS patients, conventional visual acuities, functional visual acuities, visual maintenance ratios, and VFQ-25 scores were compared among SJS patients with minimal corneal complications and SS patients by paired t test. Minimal corneal complication was defined as a grading score ≤4 points, in relation to keratinization, conjunctivalization, opacification, corneal epithelial defect, neovascularization, and SPK. Severe corneal complication was defined as a grading score >4 points. To investigate the effect of tear functions on the ocular surface complications, visual disturbance, or quality of life in SJS and SS patients, ocular surface grading scores, conventional visual acuities, functional visual acuities, visual maintenance ratios, and VFQ-25 scores were compared in SJS patients with and without aqueous tear deficiency by 1-way ANOVA. Aqueous tear deficiency was defined as a Schirmer test score ≤5 mm. The relation between ocular surface grading scores, conventional visual acuities, and functional visual acuities was analyzed by Pearson correlation analysis. The relation between ocular surface complications and conventional visual acuities, functional visual acuities, visual maintenance ratios, or VFQ-25 scores was also analyzed by Pearson correlation analysis in SJS patients with and without aqueous tear deficiency and SS patients. In the correlation analysis between ocular surface grading scores and conventional visual acuities or functional visual acuities in SJS patients, eyes were divided into 3 visual groups: good conventional visual acuity group (logMAR conventional visual acuity score ≤0), intermediate conventional visual acuity group (0 < logMAR conventional visual acuity ≤ 0.3), and poor conventional visual acuity group (0.3 < logMAR conventional visual acuity score ≤ 2.0). The relation between VFQ-25 score, conventional visual acuity, and functional visual acuity was analyzed by the same methodology, using the eye with better conventional visual acuity. The correlation between clinical findings, conventional visual acuities, and functional visual acuities was also investigated by multiple linear regression analysis. A probability level of P < .05 was considered statistically significant. SPSS (SPSS Inc, Chicago, Illinois, USA) was used as the statistical analysis software.
Results
Tear Function Tests
The mean Schirmer test values were 9.1 ± 9.3 mm in SJS patients, 4.6 ± 4.5 mm in SS patients, and 18.6 ± 9.5 mm in healthy control subjects, respectively. The Schirmer test values were significantly higher in SJS patients compared to SS patients ( P < .05). A total of 49.6 % of the patients with SJS had Schirmer test values greater than 5 mm.
Standard Conventional Visual Acuity
Table 2 shows the mean logMAR conventional visual acuity in SJS and SS patients and the normal subjects. The mean logMAR conventional visual acuity in SJS patients was significantly lower compared to the mean logMAR conventional visual acuity in SS patients and normal controls ( P < .05).
| SJS | SS | Normal | |
|---|---|---|---|
| Conventional visual acuity | |||
| logMAR | 0.76 ± 0.76 | −0.004 ± 0.13 | −0.10 ± 0.10 |
| Decimal | 0.17 | 1.01 | 1.26 |
| Functional visual acuity | |||
| logMAR | 0.98 ± 0.62 a | 0.28 ± 0.27 a | −0.008 ± 0.13 |
| Decimal | 0.10 | 0.52 | 1.02 |
| Maximal visual acuity | |||
| logMAR | 0.83 ± 0.65 | 0.10 ± 0.26 | −0.15 ± 0.12 |
| Decimal | 0.15 | 0.79 | 1.41 |
| Minimal visual acuity | |||
| logMAR | 1.19 ± 0.60 | 0.53 ± 0.36 | 0.17 ± 0.19 |
| Decimal | 0.06 | 0.30 | 0.68 |
| Visual maintenance ratio | 0.86 ± 0.12 | 0.91 ± 0.07 b | 0.98 ± 0.05 c , d |
| Reaction time | 1.0 ± 0.2 | 1.1 ± 0.2 | 1.0 ± 0.2 |
| Blink number | 11.2 ± 9.3 | 17.2 ± 9.6 b | 16.4 ± 8.7 c |
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