Abstract
Purpose:
To correlate changes in subfoveal choroidal thickness (SCT) with the degree of anterior inflammatory activity in chronic Vogt-Koyanagi-Harada (VKH) disease.
Methods:
Anterior segment inflammation was assessed using SUN anterior chamber cell grading criteria, and SCT was measured using EDI-OCT in patients with VKH at multiple visits. ANOVA was used to compare the mean SCT for each anterior chamber cell grade. Regression analysis was used to correlate the anterior segment cell grade and the SCT.
Results:
14 patients were included in the study. A total of 432 data points consisting of SCT and anterior segment cell values were analyzed. ANOVA demonstrated significant difference between the mean SCT for different anterior chamber cell grades (p < .0001). Regression analysis demonstrated significant correlation between SCT and grade of anterior chamber cells (R2 = 0.37, p < .001).
Conclusions:
Chronic VKH is characterized by a dynamic change in SCT that correlates with anterior segment inflammatory activity.
Introduction
Vogt-Koyanagi-Harada (VKH) disease is an autoimmune multisystem disorder commonly found in people with pigmented skins such as Hispanics (Mestizos), Asians, Native Americans, Middle Easterners, and Asian Indians, but not blacks of sub- Saharan African descent.1–3 It can involve various organs including the eye, ear, central nervous system, and skin.4 Although the underlying mechanism of the disease is not well understood, it is thought to be mediated by Th-1 and Th-17 cells.2,5–8
The ocular manifestation of VKH consists of bilateral granulomatous panuveitis with diffuse choroiditis. The course of VKH can be divided into four phases consisting of prodromal, acute uveitic, convalescent, and chronic phase.5,9 The acute phase of the disease is characterized by active posterior segment disease including multifocal choroiditis, multiple exudative retinal detachments and may or may not also have anterior uveitis. On the other hand, the chronic phase of VKH classically presents with anterior segment inflammation. An increase in the anterior segment inflammatory activity serves as marker for a relapse of the disease in the chronic phase and is generally used to initiate treatment.9
As VKH primarily affects the choroid with subsequent involvement of the retinal pigment epithelium (RPE) and outer retina, multiple imaging modalities have been utilized to study the changes in the choroid in different phases of the disease.10–12 The advent of enhanced depth imaging optical coherence tomography (EDI-OCT) imaging has allowed clinician scientists to study the qualitative and quantitative choroidal changes in VKH due to improved visualization of the outer retina and the choroidal layers.10,13,14 The subfoveal choroidal thickness has been shown to increase in acute stage of the disease and serve as a biomarker for the response to treatment as it decreases with the resolution of the active disease.15–18 On the other hand, previous studies have shown marked decrease in choroidal thickness as the disease progresses into chronic stage.19
To our knowledge, no study has correlated the degree of anterior segment inflammation in chronic stage of VKH to the change in the subfoveal choroidal thickness. The index study correlates the change in the subfoveal choroidal thickness to the degree of anterior segment inflammation in patients with chronic VKH, potentially highlighting the role of anterior segment inflammation as a biomarker for increased diseased activity in the posterior segment.
Methods
The index study employed a cross-sectional design. Patients with a confirmed (having met specific criteria) diagnosis of VKH managed at a tertiary care center were included. The study was conducted in compliance with the Declaration of Helsinki, and the Harmonized Tripartite Guidelines for Good Clinical Practice (1996). The study was approved by the local institutional review board. An informed consent waiver was obtained as charts of the selected patients were reviewed retrospectively.
Patient Eligibility Criteria
Patients were included in the study if they met the following criteria: 1) Confirmed diagnosis of VKH; 2) Patient must be in chronic recurrent stage of VKH; 3) Availability of gradable enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT) images; 4) Documentation of anterior segment inflammatory activity as assessed by Standardization of Uveitis Nomenclature (SUN) anterior chamber cells grading criteria.
Patients were excluded from the study if they were in acute stage of VKH or free drug remission for ≥3 months, had incomplete clinical records, or did not have EDI SD-OCT scans available.
Grading of Anterior Chamber Inflammatory Activity
SUN working group criteria published in 2005 for the grading of anterior chamber inflammatory cells was utilized to assess the anterior chamber inflammatory activity.20 A 1 mm by 1 mm slit beam is used to count the number of the cells in the field area.
Spectral Domain Optical Coherence Tomography
Heidelberg Spectralis (Heidelberg Engineering, Germany) was utilized to capture the SD-OCT scans of the patients in the study. The Spectralis SD-OCT device captures 40,000 A-scans/ second and has an axial resolution of 3.9 μm and a transversal resolution of 14 μm. The EDI function of the device with an automated real-time tracking (ART) setting of 100 was utilized. The EDI function allows better visualization of the choroidal structures from the Bruch’s membrane to the sclera, whereas, maximum ART allows capturing of high-resolution images but capturing multiple images per b-scan.
Sub-foveal Choroidal Thickness Measurement
The Heidelberg Heyex (Version 6.8, Heidelberg Engineering, Germany) software was utilized to calculate the sub-foveal choroidal thickness values for each patient. A vertical line using the measurement tool of the Heyex software was used to draw sub-foveally extending from the outer border of the retinal pigment epithelium/Bruch’s membrane complex to the inner edge of the sclera. The thickness values calculated by the measurement tool were noted.
Study Population
The medical records and SD-OCT scans of the patients who fulfilled the inclusion and exclusion criteria of the study were analyzed. Duration of the disease, time of follow-up with EDI OCT, anterior and posterior segment clinical findings observed in each patient during follow-up were consigned. In particular, the presence of fine or granulomatous keratic precipitates, iris nodules, posterior synechiae, sunset glow fundus, and nummular chorioretinal depigmented scars in each patient were recorded. In addition, macular complications (epiretinal membrane, macular edema, macular hole, choroidal neovascularization), and lens status at baseline and during follow up also were described. Immunosuppressive therapy and management of the recurrences were described for the total patient population. Each patient had multiple follow-up visits and the anterior segment and SD-OCT scans were analyzed for both eyes at every visit. The data from each eye at a single visit was treated as an individual data point for this study. Only those choroidal measurements that were carried out with high quality were included. In case of significant cataract development, the obtained EDI OCT images without an adequate quality were not included in the study. Every data point was stratified based on their anterior chamber cells grading score into groups and their choroidal thickness values measuring using the SD-OCT scans were compared.
Secondarily, we studied case by case those eyes with choroidal thinning (subfoveal choroidal thickness less than 240 μm) at some point of the follow-up. We analyzed the subfoveal choroidal thickness variation before, during, and after the exacerbation of anterior segment inflammation which occurred in those eyes during the follow-up after the identification of choroidal thinning.
Outcome Measures
The mean choroidal thickness corresponding to individual anterior segment cell grading score was calculated and compared. Correlation between the anterior segment inflammatory cell score and the mean sub-foveal choroidal thickness was also calculated.
Statistical Analysis
Stata V14.1 (Stata Corp, TX) was used to perform statistical analysis. ANOVA was used to compare the mean subfoveal choroidal thickness for each anterior chamber cell grade. Regression analysis was utilized to find a correlation between the anterior segment inflammatory cell score and the mean subfoveal choroidal thickness while controlling for age of the patients.
Results
Patient Population
Fourteen 14 patients (28 eyes) were included in the study based on the inclusion and the exclusion criteria. All patients had bilateral disease. Each patient had multiple follow-up visits and the anterior segment and SD-OCT scans were analyzed for both eyes at every visit. The mean age of the patients was 44.44 ± 14.54 years. Twelve patients (85.7%) of the patients were female. The average duration of the disease was of 73.35 ± 64.97 months (range 15–158 months). The time of follow up with EDI OCT was of 24.28 ± 12.77 months (range 2–39 months). During follow up, six patients (42.8%) had fine keratic precipitates (KP), eight (57.1%) had granulomatous KP, seven (50%) had iris nodules, four had posterior synechiae (28.6%), 12 (85.7%) had nummular chorioretinal depigmented scars, and all of the patients had sunset glow fundus. Four patients were pseudophakic at baseline, while two (three eyes) out of 14 patients developed visually significant cataract during follow up. These two patients underwent cataract surgery without complications. Five patients had vitreomacular interface disorders: three patients developed epiretinal membrane, three developed macular edema (macular edema and epiretinal membrane occur in the same patient in two cases), and one had vitreomacular traction. None of the patients developed choroidal neovascularization. One patient developed extensive chorioretinal atrophy. None of the patients developed hypopyon or posterior vitreous cells during follow up.
Regarding immunosuppressive therapy of the disease, seven patients were treated with mycophenolate mofetil, four with methotrexate, two with azathioprine, and one with chlorambucil. In three patients, during recurrences, adalimumab was added (two cases treated formerly with mycophenolate mofetil, and one case with methotrexate). In 11 patients, recurrences were managed with posterior subtenon injection of 40 mg of triamcinolone acetonide. In three patients, high dose oral corticosteroids were administered when recurrences occurred.
The data from each eye at a single visit was treated as an individual data point for this study. A total of 432 data points consisting of subfoveal choroidal thickness and anterior segment cell values were analyzed for this study.
Subfoveal Choroidal Thickness and Anterior Chamber Inflammation
The mean subfoveal choroidal thickness corresponding to different grades of anterior chamber cells as assessed by SUN grading scale is shown in Table 1. ANOVA analysis demonstrated significant difference between the mean subfoveal choroidal thickness for different grades of anterior chamber cells (p < .0001). Figure 1 outlines the box and whisker plot showing the distribution of subfoveal choroidal thickness data for each SUN grade of anterior chamber cells and also demonstrates the change in subfoveal choroidal thickness with an increase in the anterior segment inflammation. Regression analysis controlled for age demonstrated significant correlation between the change in subfoveal choroidal thickness and the change in the grade of anterior chamber cells (R2=0.37, p < .001).
Table 1.
The mean subfoveal choroidal thickness corresponding to the various levels of anterior chamber inflammation as assessed by the Standardization of Uveitis Nomenclature (SUN) anterior chamber cell grading scale.
| SUN grade of anterior chamber Mean | subfoveal choroidal thickness ± SD cells (n) |
|---|---|
|
| |
| 0+ | 334.37 ± 55.85 (87) |
| 0.5+ | 314.55 ± 103.64 (281) |
| 1+ | 441.67 ± 156.38 (46) |
| 2+ | 421.29 ± 134.69 (7) |
| 3+ | 509.75 ± 199.13 (8) |
| 4+ | 596.33 ± 130.33 (3) |
ANOVA: p < 0.0001.
Figure 1.
Box-and-Scatter plot showing change in the mean subfoveal choroidal thickness with the change in the Standardization of Uveitis Nomenclature (SUN) anterior chamber cells grade.
In six patients there was choroidal thinning (less than 240 μm) at certain point of the follow-up. In two out of these six patients, there were nine episodes (considering each episode occurring in one eye) of exacerbation of anterior segment inflammation during follow up after the choroidal thinning (Table 2). An increase in the subfoveal choroidal thickness (more than 50 μm) was observed in five out of nine of the episodes of exacerbation. In three out of nine of the episodes, there was no change, and in one out of nine, there was a persistent reduction of the subfoveal choroidal thickness. In addition, in the group with choroidal thinning, a comparison was made between subfoveal choroidal thickness means before, during and after an exacerbation of anterior segment inflammation. Mean of the subfoveal choroidal thickness was higher during exacerbation of anterior segment inflammation (181.33 ± 57.16 μm, 237.56 ± 81.96 μm, 180.56 ± 45.42 μm before, during, and after an exacerbation of anterior segment inflammation, respectively). Notwithstanding, Friedman’s test yielded that the difference between the means of choroidal thickness did not reach statistical significance (p = .053).
Table 2.
Subfoveal choroidal thickness values before, during, and after an episode of exacerbation of anterior segment inflammation, in patients with choroidal thinning.
| Change of the subfoveal choroidal thickness during exacerbation | Patient number | Anterior segment inflammatory activity before the exacerbation | Subfoveal choroidal thickness before the exacerbation (μm) | Anterior segment inflammatory activity during the exacerbation | Subfoveal choroidal thickness during the exacerbation (μm) | Anterior segment inflammatory activity after the exacerbation | Subfoveal choroidal thickness after the exacerbation (μm) |
|---|---|---|---|---|---|---|---|
|
| |||||||
| Increase | 1 | 1 | 109 | 3 | 356 | 1 | 183 |
| Increase | 1 | 0,5 | 145 | 2 | 237 | 0.5 | 196 |
| Increase | 2 | 0,5 | 227 | 1 | 310 | 0.5 | 232 |
| Increase | 2 | 0,5 | 243 | 1 | 294 | 0.5 | 227 |
| Increase | 2 | 0,5 | 222 | 1 | 280 | 0.5 | 201 |
| No change | 1 | 0,5 | 111 | 2 | 139 | 0.5 | 120 |
| No change | 1 | 0,5 | 126 | 1 | 109 | 0.5 | 109 |
| No change | 2 | 0,5 | 237 | 1 | 232 | 0.5 | 212 |
| Reduction | 1 | 0,5 | 212 | 3 | 181 | 1 | 145 |
Both patients are female.
Patient 1 and 2 are 52 and 70 years old, respectively. Friedman’s test: p = 0.053.
Discussion
VKH is a chronic multisystem disorder of an autoimmune etiology and is characterized by both ocular and systemic organ manifestations.5,7 The ocular disease primarily involves the choroid with progressive involvement of the RPE and outer retina layers.21 Clinically the course of VKH can be divided into four distinct phases.5 Anterior segment inflammation is generally more characteristic of patients with chronic VKH and is used to monitor their disease activity.13 Various studies have highlighted the changes in the choroid of patients with VKH using multiple imaging modalities.10–12 The chronic stage of VKH is normally associated with a marked thinning of the choroid.19 The result of the index study showed that in chronic stage of VKH, choroidal thickness changes more dynamically with an increase in the anterior segment inflammatory activity as measured by SUN anterior chamber cell grade. An increase in the anterior chamber inflammation is generally associated with a corresponding increase in the subfoveal choroidal thickness. This highlights the role of anterior segment inflammation as a potential biomarker for subfoveal choroidal thickness changes in chronic VKH.
The main foci of the autoimmune attack leading to inflammation in VKH disease is in the choroid. Even though there are several physiological factors such as age, gender, and circadian rhythm that can affect choroidal vascular characteristics and therefore its thickness, the changes in choroidal thickness secondary to the inflammation as noted in VKH are far more significant than the physiological changes.22,23 This is demonstrated by a significant increase in the choroidal thickness in the acute uveitic phase of the disease as shown by the EDI- OCT.14,15,18 The EDI-OCT has been a revolutionary leap that allows high-resolution imaging of the full choroid from RPE/ Bruch’s membrane complex to the sclerochoroidal interface. Several choroidal parameters such as choroidal thickness and luminal-to-stromal ratio have been considered as potential biomarkers of the disease activity in the acute phases of the disease.13,17 Nakayama et al. and Egawa et al. also demonstrated the use of choroidal thickness as a biomarker for response to corticosteroid treatment.14,17 In chronic cases of VKH, one study has utilized EDI-OCT to demonstrate significant choroidal thinning.19 Similar to these studies, we utilized EDI-OCT imaging to monitor changes in the choroidal thickness of the VKH patients in the chronic recurrent phase of the disease. In our study, a more dynamic variation in the choroidal thickness in the chronic recurrent phase of the disease was noted that correlated with the disease activity in the anterior chamber. However, it is important to note that the positive correlation between the disease activity in the anterior chamber and the choroidal thickness although present was not exactly linear in nature. This could possibly be attributed to the difference in sample size corresponding to the anterior chamber disease activity level.
Anterior segment inflammation is one of the hallmarks of the chronic recurrent phase of the VKH. Clinically, an increase in anterior chamber cells is utilized as a biomarker for the disease recurrence and is also utilized to guide the treatment of the patients. Tagawa et al. followed patients with chronic disease to a point of recurrence of disease as demonstrated by anterior segment inflammation.24 They observed an increase in the choroidal thickness prior to the disease recurrence. Our study can be considered an extension of the results demonstrated by Tagawa et al. and shows a significant correlation between the degree of anterior segment inflammation as assessed by the anterior chamber cell grade and the choroidal thickness. We demonstrated that the degree of increase in the choroidal thickness is directly correlated with the degree of VKH flare as assessed by the anterior segment inflammation.
In their study, Tagawa et al. observed that in patients with thinned choroid (less than 240 μm of subfoveal choroidal thickness), the subfoveal choroidal thickness did not increase significantly during anterior recurrences of the disease.24 In the present study, analysis of a stratified group of patients with thinned choroid cannot be done due to the small number of patients of this series. Notwithstanding, this group of patients was analyzed case by case. In those episodes of documented exacerbation of anterior segment inflammation in eyes with thinned choroid, more than half developed an increase of the subfoveal choroidal thickness. However, one third of the episodes did not experience any change, and in only one episode there was a reduction of the choroidal thickness. Therefore, there is a need to investigate the potential causes that influence this disparate behavior of the choroidal thickness during exacerbation of anterior segment inflammation, even in the same patient. Interestingly, albeit the mean of subfoveal choroidal thickness during exacerbation is higher than before and after exacerbation, the difference between the means did not reach statistical significance.
Based on the results of our study, we believe that there is significant choroidal involvement in the chronic stage of VKH in addition to the anterior chamber inflammation. Therefore, these patients should be monitored for the changes in the choroid as well as in the anterior segment to monitor their disease activity and adequate response to treatment. As noted in various studies, choroidal thickness is also affected by multiple physiological factors and systemic comorbidities. The anterior segment inflammatory activity can be utilized as a surrogate biomarker for the choroidal disease activity in the chronic stage of VKH in cases where capturing the EDI-OCT is not possible.22
The strengths of our study include significant number of visits and therefore a large set of data points for analysis. Additionally, all patients were evaluated by the same physician (AS) for their anterior chamber inflammatory activity, thus maintaining consistencies. Additionally, the same operator captured the OCT scans on all the patients. Furthermore, to our knowledge, our study is the first to highlight dynamic changes in the choroidal thickness in chronic stage of VKH. There are also limitations in our study including a retrospective design from a single center. Furthermore, the duration of disease varied for each patient and there was a significant variation in sample size for each level of anterior chamber disease activity. Fundus fluorescein angiography, indocyanine angiography, or OCT angiography would have added deeper insights about the inflammatory phenomena occurring in the posterior segment. However, indocyanine angiography and OCT angiography are not available at Hospital Universitario Austral, and fundus fluorescein angiography was not done in our patients during recurrences.
Conclusion
The chronic stage of VKH, though classically thought to involve only the anterior segment, has a more dynamic variation in the choroidal thickness. The change in choroidal thickness in chronic VKH directly correlates with the degree of anterior segment inflammation, as assessed by the SUN anterior chamber cell grading, highlighting the potential role of anterior chamber cell grade as a biomarker for the posterior segment disease activity.
Abbreviations
- ART
Automated Real-time Tracking
- EDI
Enhanced Depth Imaging
- RPE
Retinal Pigment Epithelium
- SD-OCT
Spectral Domain Optical Coherence Tomography
- SUN
Standardization of Uveitis Nomenclature
- VKH
Vogt Koyanagi Harada Disease
Footnotes
Declaration of Interest
QDN is a recipient of a Physician Scientist Award from Research to Prevent Blindness, New York, NY, and serves on the Scientific Advisory Board for AbbVie, Bayer, Genentech, Regeneron, and Santen, among others.
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