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The use of optical coherence tomography angiography in comparing choriocapillaris recovery between two treatment strategies for multifocal choroiditis: a pilot clinical trial

The use of optical coherence tomography angiography in comparing choriocapillaris recovery... Purpose: To compare differences in choriocapillaris flow deficit (CC FD) in multifocal choroiditis (MFC) between two treatment arms using optical coherence tomography angiography (OCTA). Methods: In this prospective randomized clinical trial, patients were randomized to either Group 1 which received standard tapering dose of oral corticosteroids, or Group 2 which received additional dexamethasone implant (or intravitreal methotrexate). The patients were followed-up until 12 weeks using OCTA and other imaging tools. CC FD and visual acuity between the two groups were compared at each visit. Results: Twenty-five subjects (17 males; 25 eyes) were studied (11 eyes in Group 1). There were no differences between the visual acuity or CC FD (1.12 versus 1.08 mm ; p = 0.86) at baseline between the groups. However, patients in Group 2 achieved better visual acuity (0.32 ± 0.23 versus 0.15 ± 0.11; p = 0.025) and CC FD (0.54 versus 0.15 mm ; p = 0.008) at 12 weeks. Conclusions: OCTA is a useful tool in monitoring the CC FD recovery after treatment in MFC. Patients receiving intravitreal corticosteroid/methotrexate in addition to systemic corticosteroid showed greater resolution of CC FD on OCTA compared to those receiving only oral corticosteroids. Keywords: Optical coherence tomography angiography, Multifocal choroiditis, Choriocapillaris, Flow deficit, Imaging, Uveitis Introduction entities can cause multifocal lesions of choroiditis, includ- Multifocal choroiditis is a form of posterior uveitis that is ing autoimmune white dot syndromes (such as multifocal associated with inflammation involving the choriocapil- choroiditis) [3], and tubercular serpiginous-like choroiditis laris, retinal pigment epithelium (RPE), and secondarily, (TB SLC) especially in endemic countries [4, 5]. The dis- the outer retina [1, 2]. These entities represent a manifest- ease activity can be demonstrated by using various im- ation of choriocapillaritis, suggesting that the primary site aging modalities such as fundus autofluorescence (FAF), of inflammation is the choriocapillaris [1, 2]. A number of indocyanine green angiography (ICGA) and fluorescein angiography (FA) [1, 6, 7]. Optical coherence tomography angiography (OCTA) * Correspondence: aniruddha9@gmail.com Aniruddha Agarwal and Khushdeep Abhaypal have contributed equally to is new non-invasive tool that enables the visualization of the manuscript and share first authorship the retinal and choroidal vessels in vivo without dye in- Eye Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, jection. Combined with the conventional depth-resolved United Arab Emirates Full list of author information is available at the end of the article © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 2 of 9 structural imaging capabilities of OCT, OCTAs is a envelopes. Once a patient had consented to enter the powerful tool to visualize and investigate the retinal and trial an envelope was opened, and the patient was then choroidal circulation [8, 9]. offered the allocated treatment regimen. Patients (be- Recently, lesions of TB SLC have been characterized tween 19 and 60 years of age, either gender) with the fol- using OCTA [10, 11]. In the acute stage, findings of lowing inclusion criteria were enrolled in the study: OCTA agree well with other imaging techniques such as ICGA and enhanced depth image optical coherence  Subjects diagnosed with active multifocal lesions of tomography (EDI-OCT) in determining choriocapillaris choroiditis in at least one eye involving the posterior hypo-perfusion [10, 12, 13]. After treatment, the OCTA pole. Subjects with diagnosis of either autoimmune has the capability of showing reduction in choriocapil- multifocal choroiditis or TB SLC were included in laris flow deficit (CC FD) areas on en face imaging, the study. which also correlates well with ICGA [11]. Thus, OCTA  The disease activity was confirmed on clinical has the potential to be used as a clinical endpoint in the examination, and imaging techniques such as OCT, management of subjects with macular choroiditis. fundus autofluorescence (FAF), FA and ICGA [6]. Thus far, there are no studies that have compared the  Subjects who were treatment-naïve or those who de- resolution of CC FD (i.e., hypo-perfusion) on OCTA veloped active disease with ≤10 mg/day oral based on the therapeutic interventions in multifocal corticosteroids. choroiditis. Currently, oral corticosteroids form the standard of care for treatment of multifocal choroiditis The exclusion criteria were as follows: eyes in which (with concomitant anti-tubercular therapy in tubercular media clarity was obscured by the presence of cataract, etiologies) [4, 14, 15]. We hypothesize that initial treat- vitritis or any other such coexistent pathology that did ment with adjunctive intravitreal therapy in subjects of not allow the acquisition of good images; subjects with choroiditis may result in better recovery of the CC FD active lesions outside the posterior pole that were not on OCTA imaging. In this study, we aim to compare the amenable to fundus imaging; subjects on treatment with difference in the recovery of the choriocapillaris between long-term systemic immunosuppressive therapies, or standard therapy consisting of oral corticosteroids, and a those who have received intravitreal treatments in the combination therapy consisting of both systemic and past. In addition, subjects who have undergone pars local intravitreal therapies. plana vitrectomy (at any time point), cataract surgery (within the last 3 months), or glaucoma surgery (within Materials and methods the last 3 months) were excluded; subjects who were In this prospective, randomized controlled, interven- pregnant or plan to become pregnant during the course tional study, patients were recruited from the Uveitis of therapy; subjects with placoid choroiditis character- Clinic of Advanced Eye Centre, Department of Ophthal- ized by large, plaque-like lesions involving large areas of mology, Post Graduate Institute of Medical Education the retinochoroid; subjects with concomitant ocular dis- and Research (PGIMER), Chandigarh. Twenty-five sub- eases such as diabetic retinopathy, optic neuropathy, or jects with multifocal choroiditis meeting the inclusion retinal degeneration, and patients who did not agree to and exclusion criteria (detailed below) were recruited in come for follow-up visits. the study. These subjects were randomized into two treatment arms: Group 1 and Group 2. Since this was a Study procedures pilot clinical trial, no formal sample size calculations A detailed history was taken for all recruited patients were performed for the study. The study was registered i.e., presenting ocular complaints with their respective under the Clinical Trials Registry – India (CTRI; ref.: duration, any history suggestive of other co-existing oph- CTRI/2020/09/028056) prior to the conduct of the thalmological diseases, previous treatment if taken, any study. The study was conducted after approval from the known systemic illness and any known drug allergy. Institute Ethics Committee (IEC) of PGIMER, Chandi- Best-corrected visual acuity (BCVA) of the patients was garh, India. Written informed consent was obtained recorded using the Snellen’s visual acuity chart at base- from all participating subjects, and the study adhered to line and at all follow up visits. BCVA was converted to the tenets of the Declaration of Helsinki. LogMAR units for statistical analysis. Intraocular pres- sure (IOP) measurement by non-contact tonometer was Study subjects done for all patients at baseline and at all follow up Patients were allotted in either Group 1 or 2 based on visits. Anterior segment examination using slit lamp was randomized treatment allocation by envelope method. In done in all patients at baseline and at all follow up visits. this method, the investigator was given randomly gener- Posterior segment findings were noted by slit lamp bio- ated treatment allocations within sealed opaque microscopy with + 90 D diopter lens. Peripheral fundus Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 3 of 9 examination was done using the indirect ophthalmo- steroid responsiveness), then the subjects received scope with a + 20-diopter lens at baseline and at all weekly injection of intravitreal methotrexate (400 μg/0.1 follow-up visits. mL) every week for the first 4 weeks of treatment. Color fundus photographs were captured using Carl Zeiss Visupac FF450 fundus camera setting central 50 Study duration and follow-up degrees (Carl Zeiss Meditec, Dublin, CA, USA) at base- The duration of the study was 12 weeks. All the subjects line and all follow-up visits. OCTA (DRI TopCon Tri- were examined at baseline, 1 week, 2 weeks, 4 weeks, and ton®, TopCon Inc., Tokyo, Japan) (3 × 3 mm scan) was 12 weeks. performed at baseline and all follow-up visits. The OCTA images were analyzed for the choriocapillaris al- Outcome measures and statistical analysis terations at the site of lesions. Two independent masked The main outcome measure of the study was the mean graders (uveitis specialists with experience in imaging re- difference in the CC FD areas between the two treat- search: A.A. and K.A.) performed the image analysis on ment arms (indicative of choriocapillaris recovery). OCTA (blinded to the treatment groups and the time Other outcome measures included change in the BCVA interval). The CC FD areas were measured manually in 2 between the two treatment arms, and the occurrence of mm using a third-party software (ImageJ, National In- adverse events in either arm. stitutes of Health, Bethesda, USA) [11]. Briefly, the area The statistical analysis was done with the help of of CC FD was manually mapped by the two graders on 2 SPSS© version 26 for Windows (IBM Inc., Chicago, IL, ImageJ (in mm ) after standardizing the images and set- USA). Data entries were performed in pre-designed ting the scale, and the average of the two graders’ read- forms and excel sheets using Microsoft Excel 2016© for ings were used for the analysis. Swept-source (SS)-OCT Windows. All the measurable data was checked for their (DRI TopCon Triton®, TopCon Inc., Tokyo, Japan) was normality using Kolmogorov–Smirnov test within each performed at baseline and all follow-up visits. Combined group. The data was presented with descriptive statistics FA and ICGA (Spectralis®, Heidelberg Engineering, Hei- with mean ± standard deviation along with their range. delberg, Germany was performed at baseline and 12 To observe the treatment effect within each group, weeks. The two graders also performed the manual area paired t test was applied to compare the differences in measurements of the hypofluorescent areas on ICGA in the CC FD areas before and after treatment. To see the central 3 × 3 mm (identified after drawing a central whether the treatment effect was equal between groups, 3 × 3 mm square) using the area measurement tool on Students t test was applied to compare the differences in Heyex Eye Explorer (version 1.10.4.0). the CC FD areas. Other parameters that were compared between the two groups included BCVA improvements Study arms, visits, and treatments at 12 weeks, changes in IOP, and adverse effects between Group 1 the two groups. A p value < 0.05 was considered statisti- Group 1 received standard treatment for multifocal cally significant. choroiditis which consisted of oral corticosteroids (oral prednisolone 1 mg/kg/day) initiated at baseline and con- tinued for a total of 8 weeks with tapering doses (5 mg/ Results kg/week taper). If the subjects tested positive for TB (in In the study, twenty-five subjects (17 males; 25 eyes) subjects with tubercular serpiginous-like choroiditis), with TB/SLC or MFC met the inclusion criteria and additional anti-tubercular therapy was given as per the were evaluated. Thirteen eyes were diagnosed with TB following protocol: (induction phase) isoniazid (5 mg/kg/ SLC and 12 were diagnosed with MFC. Group 1 in- day), rifampicin (450 mg/day if body weight is≤50 kg and cluded 11 subjects (11 eyes) and group 2 included 14 600 mg/day if body weight is > 50 kg), pyrazinamide (25 subjects (14 eyes). The demographic and clinical details to 30 mg/kg/day) and ethambutol (15 mg/kg/day). After of the subjects, including their mean age, BCVA, IOP 2 months, only isoniazid and rifampicin were continued and diagnosis have been summarized in Table 1. for additional 7 months (maintenance phase). Liver func- The group 1 (standard oral therapy) were given oral tion tests and hemograms were monitored every 6 corticosteroid therapy in a tapering dose (as described in weeks. the methods). All eyes with TB SLC received concomi- tant ATT (in either group). In the combination group 2 Group 2 (standard oral + intravitreal therapy), 2 eyes received in- In addition to standard treatment Group 2 patients re- travitreal methotrexate due to history of corticosteroid ceived intravitreal dexamethasone implant (0.7 mg) in- responsiveness (one eye received 3 injections and the jection at baseline. If the use of intravitreal other received 2), whereas 12 eyes received intravitreal corticosteroid was contraindicated (due to cataract, or dexamethasone implant (single injection at baseline). Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 4 of 9 Table 1 Comparison of baseline demographic and clinical parameters between the two groups Group 1 (n = 11 eyes) Group 2 (n = 14 eyes) P value Age (years ± SD) 30.4 ± 8.3 32.4 ± 11.5 0.62 Gender (n) 0.20 Male 6 11 Female 5 3 Diagnosis (n) 0.82 TB SLC 6 7 MFC 5 7 Laterality (n) 0.89 Right eye 6 8 Left eye 5 6 Treatments (n) Intravitreal DEX – 12 – Intravitreal MTX – 2 – ATT 6 7 – Oral corticosteroids 11 14 – Initial BCVA (LogMAR units) 0.41 ± 0.25 0.38 ± 0.23 0.85 Final BCVA (LogMAR units) 0.32 ± 0.23 0.15 ± 0.11 0.025 (p value)* (0.01) (< 0.001) Initial IOP 13.6 ± 1.7 13.7 ± 2.2 0.92 (mm Hg) Final IOP (mm Hg) 14.1 ± 2.1 14.4 ± 3.8 0.82 (p value)* (0.51) (0.58) *p value has been calculated compared to baseline ATT Anti-tubercular therapy, BCVA Best-corrected visual acuity, DEX Dexamethasone implant, IOP Intraocular pressure, MFC Multifocal choroiditis, MTX Methotrexate, TB SLC Tubercular serpiginous-like choroiditis Fig. 1 Fig. 1 compares the choriocapillaris flow deficit (CC FD) between the two study arms measured on optical coherence tomography angiography (OCTA). The CC FD reduced significantly at 12 weeks in the combination arm (intravitreal dexamethasone implant and oral corticosteroids) compared to oral corticosteroids alone Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 5 of 9 Analysis of OCTA in groups 1 and 2 showed a base- Table 3 Calculation of choriocapillaris flow deficit areas (in 2 2 mm ) on indocyanine green angiography (ICGA) in both the line mean CC FD of 1.12 mm and 1.08 mm , respect- groups ively (p = 0.86). During follow-up, the CC FD improved Group 1 Group 2 P value in all eyes in both the groups (statistically significant at (n = 11 eyes) (n = 14 eyes) all time points compared to baseline). In comparing Baseline 1.20 ± 0.66 1.22 ± 0.62 0.93 group 1 and 2, the recovery of choriocapillaris (mea- 12 weeks 0.61 ± 0.36 0.25 ± 0.22 0.005 sured in terms of decrease in CC FD) was significantly higher in eyes belonging to group 2 (Fig. 1). Table 2 pro- P value* < 0.001 < 0.001 vides a summary of the changes in OCTA CC FD from baseline through week 12 in both the groups. On ICGA, the mean area of flow deficit at baseline OCTA and ICGA imaging, it was observed that OCTA 2 2 was 1.20 mm in group 1 and 1.22 mm in group 2 (p = functions well in assessing the recovery of CC FD after 0.93). At 12 weeks, the mean area of flow deficit was initiation of treatment. The improvements in chorioca- 2 2 0.61 mm in group 1, and 0.25 mm in group 2 (p = pillaris during follow-up was also seen on ICGA at 3 0.005) (Table 3) (Fig. 2). months. An important highlight of the study was that le- The BCVA improved from 0.41 to 0.32 LogMAR units sions with an area greater than 0.1 mm at baseline in group 1 (p = 0.014), whereas it improved from 0.39 to showed healing but with significant choriocapillaris atro- 0.15 LogMAR units in group 2 (p < 0.001). The BCVA phy. Lesions smaller than 0.1mm in area showed near- was also significantly better in eyes belonging to group 2 complete resolution with minimal residual alterations in at 12 weeks (p = 0.025) (Fig. 3). the choriocapillaris on ICGA [11]. Thus, the bigger the The mean IOP increased from 13.6 to 14.1 mmHg in lesion area, the greater chances of choriocapillaris atro- group 1 (p = 0.518), whereas it increased from 13.7 to phy. Since then, there are very few studies published that 14.4 mmHg (p = 0.58) in group 2 (Table 1). Two eyes in demonstrate quantitative improvements in CC FD in group 2 were given topical dorzolamide 2% for 12 weeks posterior uveitis, specifically TB SLC and MFC [16–19]. (single agent) since the IOP was recorded > 21 mmHg We performed this study to assess whether adjunctive (maximum of 25 mmHg) at week 2 in both eyes (Fig. 4). treatment with intravitreal corticosteroids/methotrexate None of the eyes in either group developed worsening can aid in the greater recovery of CC FD in cases with of inflammation, increase in choroiditis lesions, develop- center-involving TB SLC and MFC. Atrophy of chorio- ment of new choroiditis lesions, or other adverse events capillaris due to inflammation involving the RPE, outer such as endophthalmitis. All the eyes in both groups retina and choriocapillaris layer is associated with per- showed healing of the choroiditis lesions at the end of manent visual loss and scarring [4]. Therefore, the aim 12 weeks. In eyes requiring ATT, the therapy was con- of the treatment is to prevent as much central photo- tinued beyond the period of the study i.e., 12 weeks. receptor loss as possible. In this study, we observed im- provements in CC FD in all eyes at week 12 compared Discussion to baseline, however, eyes receiving additional intravit- In a previously published study by our group wherein real dexamethasone implant/methotrexate performed patients with TB SLC were serially followed up using significantly better with greater resolution of CC FD on OCTA and flow deficit areas on ICGA. Table 2 Comparison of optical coherence tomography The application of quantitative metrics in posterior angiography (OCTA) derived choriocapillaris flow deficit (CC FD) uveitis may be valuable to assess the effect of therapeutic in mm in both the groups interventions. Using easily available third-party software, Group 1 Group 2 P value it is possible to measure the areas of CC FD on OCTA (n = 11 eyes) (n = 14 eyes) [11, 18, 19]. In addition, the measurement of the hypo- Baseline 1.12 ± 0.63 1.08 ± 0.58 0.86 fluorescent area on ICGA has been made possible by the 1 week 0.96 ± 0.59 0.82 ± 0.60 0.56 tools available on the Heidelberg Eye Explorer, and simi- P value* < 0.001 < 0.001 lar in-built software on other commercially available de- vices. Studies have previously shown the agreement 2 weeks 0.83 ± 0.54 0.50 ± 0.39 0.086 between OCTA and ICGA in terms of choriocapillaris P value* < 0.001 < 0.001 flow measurements [11, 19]. Serial quantitative metrics 4 weeks 0.63 ± 0.39 0.31 ± 0.31 0.030 provide an objective assessment of the choriocapillaris P value* < 0.001 < 0.001 recovery, and thus serves as an endpoint for therapeutic 12 weeks 0.54 ± 0.39 0.15 ± 0.18 0.008 interventions. In our study, the recovery of choriocapil- P value* < 0.001 < 0.001 laris after intravitreal injections was significantly better *p value has been calculated compared to baseline Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 6 of 9 Fig. 2 Fig. 2 compares the mean area of the choriocapillaris flow deficit on indocyanine green angiography (ICGA) imaging. Eyes in the combination arm (intravitreal dexamethasone implant and oral corticosteroids) had lesser flow deficit areas compared to eyes treated with oral corticosteroids alone at 12 weeks than the standard arm receiving only oral corticosteroid significantly higher visual outcomes even though there therapy at all follow-up visits. was no significant difference in the BCVA at baseline The resolution of CC FD on OCTA was accompan- between the two groups. This suggests that addition ied by significant improvements in BCVA in both the of adjunctive intravitreal therapy at baseline may not groups. While the BCVA improved from baseline in only translate into better anatomical outcomes on both groups of patients receiving treatment, the group OCTA in terms of CC FD, but also potentially better receiving adjunctive intravitreal therapy had visual results at 12 weeks. Fig. 3 Fig. 3 shows the improvement in best-corrected visual acuity (BCVA) between the two treatment arms. Eyes in the combination arm (intravitreal dexamethasone implant and oral corticosteroids) had significantly better BCVA at 12 weeks compared to eyes receiving oral corticosteroids alone Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 7 of 9 Fig. 4 The figure shows change in the mean intraocular pressure (IOP) in the two treatment arms. While the IOP increased at 12 weeks in both the treatment arms compared to baseline, there were no statistically significant changes from baseline, or between the two treatment arms In patients with TB SLC and MFC, the safety and effi- Our study has several limitations. We had a mod- cacy of intravitreal therapy with dexamethasone implant est sample size of patients. However, we included and methotrexate has been published previously [20– patients with strict inclusion criteria such as 23]. The advantages of intravitreal corticosteroid/metho- treatment-naïve macular choroiditis with no prior trexate injection include high local delivery of anti- intraocular treatment, and clear media for serial inflammatory therapy that can promptly act to reduce OCTA. In addition, we did not have automated the inflammation, avoiding systemic side-effects of pro- measurements of CC FD in our study. With im- longed oral therapy. Studies have shown that intravitreal provements in technology and application of quan- injection of these agents are not associated with worsen- titative algorithms, automated quantification is ing of choroiditis in any patient and help in the healing being increasingly employed [17, 18, 25]. In the fu- of the lesions with minimal adverse events [20–23]. ture, such automated measurements may be applied Since steroid-responsiveness is a cause of concern in pa- to OCTA imaging of lesions of choroiditis as well. tients receiving dexamethasone implant, we used intra- Since patients in group 2 received either dexa- vitreal methotrexate in patients who had history of high methasone implant or methotrexate therapy, it may IOP after corticosteroid use. None of the subjects in our be argued that group 2 included patients receiving cohort had uncontrollable rise in IOP, and 2 subjects re- two different drugs. However, the aim of the study quired a short course of single topical anti-glaucoma was not to compare the treatment strategies them- medication for IOP rise. selves, but the utility of imaging modality (i.e., Our study is a pilot clinical trial which is mainly aimed OCTA) for the follow-up assessment of these at evaluating the role of OCTA in quantifying lesions of patients. choroiditis after initiation of treatment. Thus, we do not In conclusion, OCTA is not only useful in asses- propose use of intravitreal corticosteroids/methotrexate in sing areas of CC FD in eyes with choroiditis, but it every case of macular choroiditis. There are several chal- can be used as a tool to monitor recovery of the lenges in the management of choroiditis due to ocular TB, choriocapillaris and assess the efficacy of systemic as well as MFC and these patients require individualized and intravitreal anti-inflammatory therapies. In pa- therapy to tackle persistence of lesions, development of tients with TB SLC and MFC who receive adjunctive new lesions, and other aspects such as drug resistance [14, intravitreal corticosteroid/methotrexate therapy in 24]. However, our study does demonstrate that adjunctive addition to systemic corticosteroids, greater decrease intravitreal agents may have an role in improving the vis- in the CC FD area can be visualized on OCTA, and ual outcomes of these patients, and such therapies may be this may translate into superior visual outcomes due increasingly employed for our future patients. to decreased choriocapillaris atrophy. Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 8 of 9 Acknowledgements 7. Marchese A, Agarwal A, Moretti AG, Handa S, Modorati G, Querques G, None. Bandello F, Gupta V, Miserocchi E (2020) Advances in imaging of uveitis. Ther Adv Ophthalmol 12. https://doi.org/10.1177/2515841420917781 8. Pichi F, Sarraf D, Arepalli S, Lowder CY, Cunningham ET Jr, Neri P, Albini TA, Precis. Gupta V, Baynes K, Srivastava SK (2017) The application of optical coherence Patients with choroiditis may experience better improvement in tomography angiography in uveitis and inflammatory eye diseases. Prog choriocapillaris flow deficit areas and visual acuity if treated with oral Retin Eye Res 59:178–201. https://doi.org/10.1016/j.preteyeres.2017.04.005 corticosteroid therapy with intravitreal dexamethasone implant/ 9. Pohlmann D, Pleyer U, Joussen AM, Winterhalter S (2019) Optical coherence methotrexate. Optical coherence tomography angiography is useful in tomography angiography in comparison with other multimodal imaging monitoring choriocapillaris recovery. techniques in punctate inner choroidopathy. Br J Ophthalmol 103(1):60–66. https://doi.org/10.1136/bjophthalmol-2017-311764 Authors’ contributions 10. Mandadi SKR, Agarwal A, Aggarwal K, Moharana B, Singh R, Sharma A, AA and KA conceived the manuscript. KA, AA, KA2 collected the data and Bansal R, Dogra MR, Gupta V, for OCTA Study Group (2017) Novel findings analysed it. The literature search and critical review was performed by AA, on optical coherence tomography angiography in patients with tubercular KA2, RJE, TTJMB, CABW, RB and VG. AA and KA wrote the manuscript. All the serpiginous-like choroiditis. Retina Phila Pa 37(9):1647–1659. https://doi. authors critically reviewed it and approved for submission. org/10.1097/IAE.0000000000001412 11. Agarwal A, Aggarwal K, Mandadi SKR, Kumar A, Grewal D, Invernizzi A, Funding Bansal R, Sharma A, Sharma K, Gupta V, for OCTA Study Group (2021) There are no sources of funding to declare for the study. Longitudinal follow-up of tubercular serpiginous-like choroiditis using optical coherence tomography angiography. Retina Phila Pa. 41(4):793–803. https://doi.org/10.1097/IAE.0000000000002915 Availability of data and materials 12. Brar M, Sharma M, Grewal SPS, Grewal DS (2020) Comparison of wide-field The data related to the study will be available upon reasonable request from swept source optical coherence tomography angiography and fundus the corresponding author. autofluorescence in tubercular serpiginous-like choroiditis. Indian J Ophthalmol 68(1):106–211. https://doi.org/10.4103/ijo.IJO_78_19 Declarations 13. Ahn SJ, Park SH, Lee BR (2017) Multimodal imaging including optical coherence tomography angiography in serpiginous choroiditis. Ocul Ethics approval and consent to participate Immunol Inflamm 25(2):287–291. https://doi.org/10.1080/09273948.2017.12 The study was approved by the Post Graduate Institute of Medical Education and Research (PGIMER) Institute Ethics Committee (IEC), Chandigarh, India. 14. Agrawal R, Gunasekeran DV, Grant R, Agarwal A, Kon OM, Nguyen QD, Written informed consent was obtained from all the patients for the Pavesio C, Gupta V, for the Collaborative Ocular Tuberculosis Study (COTS)– participation in the study. 1 Study Group (2017) Clinical features and outcomes of patients with tubercular uveitis treated with Antitubercular therapy in the collaborative Consent for publication ocular tuberculosis study (COTS)-1. JAMA Ophthalmol 135(12):1318–1327. The consent for publication was obtained from the patients and all the https://doi.org/10.1001/jamaophthalmol.2017.4485 authors. 15. Testi I, Agrawal R, Mahajan S, Agarwal A., Gunasekeran D.V., Raje D., Aggarwal K., Murthy S.I., Westcott M., Chee S.P., McCluskey P., Ho S.L., Teoh S., Cimino L., Biswas J., Narain S., Agarwal M., Mahendradas P., Khairallah M., Competing interests Jones N., Tugal-Tutkun I., Babu K., Basu S., Carreño E., Lee R., al-Dhibi H., There are no competing interests for any author related to the manuscript. Bodaghi B., Invernizzi A., Goldstein D.A., Herbort C.P., Barisani-Asenbauer T., González-López J.J., Androudi S., Bansal R., Moharana B., Esposti S.D., Author details Tasiopoulou A., Nadarajah S., Agarwal M., Abraham S., Vala R., Singh R., Eye Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, Sharma A., Sharma K., Zierhut M., Rousselot A., Grant R., Kon O.M., United Arab Emirates. Advanced Eye Center, Post Graduate Institute of Cunningham E.T., Kempen J., Nguyen Q.D., Pavesio C., Gupta V. Tubercular Medical Education and Research, Sector 12, Chandigarh, India. Ahalia Eye uveitis: nuggets from collaborative ocular tuberculosis study (COTS)-1. Ocul Care, Delma St, Airport Road, Abu Dhabi, United Arab Emirates. Maastricht Immunol Inflamm Published online November 25, 2019:1–9. https://doi. University Medical Centre, University Eye Clinic Maastricht, Maastricht, The org/10.1080/09273948.2019.1646774 Netherlands. 16. Eser-Ozturk H, Ismayilova L, Yucel OE, Sullu Y Quantitative measurements Received: 22 December 2021 Accepted: 24 February 2022 with optical coherence tomography angiography in Behçet uveitis. Eur J Ophthalmol. Published online April 28, 2020. https://doi.org/10.1177/112 17. Chu Z, Weinstein JE, Wang RK, Pepple KL (2020) Quantitative analysis of the References Choriocapillaris in uveitis using En face swept-source optical coherence 1. Li J, Li Y, Li H, Zhang L (2019) Imageology features of different types of tomography angiography. Am J Ophthalmol 218:17–27. https://doi.org/10.1 multifocal choroiditis. 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Kim AY, Rodger DC, Shahidzadeh A, Chu Z, Koulisis N, Burkemper B, Jiang X, Pepple KL, Wang RK, Puliafito CA, Rao NA, Kashani AH (2016) Quantifying retinal microvascular changes in uveitis using spectral-domain optical coherence tomography angiography. Am J Ophthalmol 171:101–112. https://doi.org/10.1016/j.ajo.2016.08.035 Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Ophthalmic Inflammation and Infection Springer Journals

The use of optical coherence tomography angiography in comparing choriocapillaris recovery between two treatment strategies for multifocal choroiditis: a pilot clinical trial

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Abstract

Purpose: To compare differences in choriocapillaris flow deficit (CC FD) in multifocal choroiditis (MFC) between two treatment arms using optical coherence tomography angiography (OCTA). Methods: In this prospective randomized clinical trial, patients were randomized to either Group 1 which received standard tapering dose of oral corticosteroids, or Group 2 which received additional dexamethasone implant (or intravitreal methotrexate). The patients were followed-up until 12 weeks using OCTA and other imaging tools. CC FD and visual acuity between the two groups were compared at each visit. Results: Twenty-five subjects (17 males; 25 eyes) were studied (11 eyes in Group 1). There were no differences between the visual acuity or CC FD (1.12 versus 1.08 mm ; p = 0.86) at baseline between the groups. However, patients in Group 2 achieved better visual acuity (0.32 ± 0.23 versus 0.15 ± 0.11; p = 0.025) and CC FD (0.54 versus 0.15 mm ; p = 0.008) at 12 weeks. Conclusions: OCTA is a useful tool in monitoring the CC FD recovery after treatment in MFC. Patients receiving intravitreal corticosteroid/methotrexate in addition to systemic corticosteroid showed greater resolution of CC FD on OCTA compared to those receiving only oral corticosteroids. Keywords: Optical coherence tomography angiography, Multifocal choroiditis, Choriocapillaris, Flow deficit, Imaging, Uveitis Introduction entities can cause multifocal lesions of choroiditis, includ- Multifocal choroiditis is a form of posterior uveitis that is ing autoimmune white dot syndromes (such as multifocal associated with inflammation involving the choriocapil- choroiditis) [3], and tubercular serpiginous-like choroiditis laris, retinal pigment epithelium (RPE), and secondarily, (TB SLC) especially in endemic countries [4, 5]. The dis- the outer retina [1, 2]. These entities represent a manifest- ease activity can be demonstrated by using various im- ation of choriocapillaritis, suggesting that the primary site aging modalities such as fundus autofluorescence (FAF), of inflammation is the choriocapillaris [1, 2]. A number of indocyanine green angiography (ICGA) and fluorescein angiography (FA) [1, 6, 7]. Optical coherence tomography angiography (OCTA) * Correspondence: aniruddha9@gmail.com Aniruddha Agarwal and Khushdeep Abhaypal have contributed equally to is new non-invasive tool that enables the visualization of the manuscript and share first authorship the retinal and choroidal vessels in vivo without dye in- Eye Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, jection. Combined with the conventional depth-resolved United Arab Emirates Full list of author information is available at the end of the article © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 2 of 9 structural imaging capabilities of OCT, OCTAs is a envelopes. Once a patient had consented to enter the powerful tool to visualize and investigate the retinal and trial an envelope was opened, and the patient was then choroidal circulation [8, 9]. offered the allocated treatment regimen. Patients (be- Recently, lesions of TB SLC have been characterized tween 19 and 60 years of age, either gender) with the fol- using OCTA [10, 11]. In the acute stage, findings of lowing inclusion criteria were enrolled in the study: OCTA agree well with other imaging techniques such as ICGA and enhanced depth image optical coherence  Subjects diagnosed with active multifocal lesions of tomography (EDI-OCT) in determining choriocapillaris choroiditis in at least one eye involving the posterior hypo-perfusion [10, 12, 13]. After treatment, the OCTA pole. Subjects with diagnosis of either autoimmune has the capability of showing reduction in choriocapil- multifocal choroiditis or TB SLC were included in laris flow deficit (CC FD) areas on en face imaging, the study. which also correlates well with ICGA [11]. Thus, OCTA  The disease activity was confirmed on clinical has the potential to be used as a clinical endpoint in the examination, and imaging techniques such as OCT, management of subjects with macular choroiditis. fundus autofluorescence (FAF), FA and ICGA [6]. Thus far, there are no studies that have compared the  Subjects who were treatment-naïve or those who de- resolution of CC FD (i.e., hypo-perfusion) on OCTA veloped active disease with ≤10 mg/day oral based on the therapeutic interventions in multifocal corticosteroids. choroiditis. Currently, oral corticosteroids form the standard of care for treatment of multifocal choroiditis The exclusion criteria were as follows: eyes in which (with concomitant anti-tubercular therapy in tubercular media clarity was obscured by the presence of cataract, etiologies) [4, 14, 15]. We hypothesize that initial treat- vitritis or any other such coexistent pathology that did ment with adjunctive intravitreal therapy in subjects of not allow the acquisition of good images; subjects with choroiditis may result in better recovery of the CC FD active lesions outside the posterior pole that were not on OCTA imaging. In this study, we aim to compare the amenable to fundus imaging; subjects on treatment with difference in the recovery of the choriocapillaris between long-term systemic immunosuppressive therapies, or standard therapy consisting of oral corticosteroids, and a those who have received intravitreal treatments in the combination therapy consisting of both systemic and past. In addition, subjects who have undergone pars local intravitreal therapies. plana vitrectomy (at any time point), cataract surgery (within the last 3 months), or glaucoma surgery (within Materials and methods the last 3 months) were excluded; subjects who were In this prospective, randomized controlled, interven- pregnant or plan to become pregnant during the course tional study, patients were recruited from the Uveitis of therapy; subjects with placoid choroiditis character- Clinic of Advanced Eye Centre, Department of Ophthal- ized by large, plaque-like lesions involving large areas of mology, Post Graduate Institute of Medical Education the retinochoroid; subjects with concomitant ocular dis- and Research (PGIMER), Chandigarh. Twenty-five sub- eases such as diabetic retinopathy, optic neuropathy, or jects with multifocal choroiditis meeting the inclusion retinal degeneration, and patients who did not agree to and exclusion criteria (detailed below) were recruited in come for follow-up visits. the study. These subjects were randomized into two treatment arms: Group 1 and Group 2. Since this was a Study procedures pilot clinical trial, no formal sample size calculations A detailed history was taken for all recruited patients were performed for the study. The study was registered i.e., presenting ocular complaints with their respective under the Clinical Trials Registry – India (CTRI; ref.: duration, any history suggestive of other co-existing oph- CTRI/2020/09/028056) prior to the conduct of the thalmological diseases, previous treatment if taken, any study. The study was conducted after approval from the known systemic illness and any known drug allergy. Institute Ethics Committee (IEC) of PGIMER, Chandi- Best-corrected visual acuity (BCVA) of the patients was garh, India. Written informed consent was obtained recorded using the Snellen’s visual acuity chart at base- from all participating subjects, and the study adhered to line and at all follow up visits. BCVA was converted to the tenets of the Declaration of Helsinki. LogMAR units for statistical analysis. Intraocular pres- sure (IOP) measurement by non-contact tonometer was Study subjects done for all patients at baseline and at all follow up Patients were allotted in either Group 1 or 2 based on visits. Anterior segment examination using slit lamp was randomized treatment allocation by envelope method. In done in all patients at baseline and at all follow up visits. this method, the investigator was given randomly gener- Posterior segment findings were noted by slit lamp bio- ated treatment allocations within sealed opaque microscopy with + 90 D diopter lens. Peripheral fundus Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 3 of 9 examination was done using the indirect ophthalmo- steroid responsiveness), then the subjects received scope with a + 20-diopter lens at baseline and at all weekly injection of intravitreal methotrexate (400 μg/0.1 follow-up visits. mL) every week for the first 4 weeks of treatment. Color fundus photographs were captured using Carl Zeiss Visupac FF450 fundus camera setting central 50 Study duration and follow-up degrees (Carl Zeiss Meditec, Dublin, CA, USA) at base- The duration of the study was 12 weeks. All the subjects line and all follow-up visits. OCTA (DRI TopCon Tri- were examined at baseline, 1 week, 2 weeks, 4 weeks, and ton®, TopCon Inc., Tokyo, Japan) (3 × 3 mm scan) was 12 weeks. performed at baseline and all follow-up visits. The OCTA images were analyzed for the choriocapillaris al- Outcome measures and statistical analysis terations at the site of lesions. Two independent masked The main outcome measure of the study was the mean graders (uveitis specialists with experience in imaging re- difference in the CC FD areas between the two treat- search: A.A. and K.A.) performed the image analysis on ment arms (indicative of choriocapillaris recovery). OCTA (blinded to the treatment groups and the time Other outcome measures included change in the BCVA interval). The CC FD areas were measured manually in 2 between the two treatment arms, and the occurrence of mm using a third-party software (ImageJ, National In- adverse events in either arm. stitutes of Health, Bethesda, USA) [11]. Briefly, the area The statistical analysis was done with the help of of CC FD was manually mapped by the two graders on 2 SPSS© version 26 for Windows (IBM Inc., Chicago, IL, ImageJ (in mm ) after standardizing the images and set- USA). Data entries were performed in pre-designed ting the scale, and the average of the two graders’ read- forms and excel sheets using Microsoft Excel 2016© for ings were used for the analysis. Swept-source (SS)-OCT Windows. All the measurable data was checked for their (DRI TopCon Triton®, TopCon Inc., Tokyo, Japan) was normality using Kolmogorov–Smirnov test within each performed at baseline and all follow-up visits. Combined group. The data was presented with descriptive statistics FA and ICGA (Spectralis®, Heidelberg Engineering, Hei- with mean ± standard deviation along with their range. delberg, Germany was performed at baseline and 12 To observe the treatment effect within each group, weeks. The two graders also performed the manual area paired t test was applied to compare the differences in measurements of the hypofluorescent areas on ICGA in the CC FD areas before and after treatment. To see the central 3 × 3 mm (identified after drawing a central whether the treatment effect was equal between groups, 3 × 3 mm square) using the area measurement tool on Students t test was applied to compare the differences in Heyex Eye Explorer (version 1.10.4.0). the CC FD areas. Other parameters that were compared between the two groups included BCVA improvements Study arms, visits, and treatments at 12 weeks, changes in IOP, and adverse effects between Group 1 the two groups. A p value < 0.05 was considered statisti- Group 1 received standard treatment for multifocal cally significant. choroiditis which consisted of oral corticosteroids (oral prednisolone 1 mg/kg/day) initiated at baseline and con- tinued for a total of 8 weeks with tapering doses (5 mg/ Results kg/week taper). If the subjects tested positive for TB (in In the study, twenty-five subjects (17 males; 25 eyes) subjects with tubercular serpiginous-like choroiditis), with TB/SLC or MFC met the inclusion criteria and additional anti-tubercular therapy was given as per the were evaluated. Thirteen eyes were diagnosed with TB following protocol: (induction phase) isoniazid (5 mg/kg/ SLC and 12 were diagnosed with MFC. Group 1 in- day), rifampicin (450 mg/day if body weight is≤50 kg and cluded 11 subjects (11 eyes) and group 2 included 14 600 mg/day if body weight is > 50 kg), pyrazinamide (25 subjects (14 eyes). The demographic and clinical details to 30 mg/kg/day) and ethambutol (15 mg/kg/day). After of the subjects, including their mean age, BCVA, IOP 2 months, only isoniazid and rifampicin were continued and diagnosis have been summarized in Table 1. for additional 7 months (maintenance phase). Liver func- The group 1 (standard oral therapy) were given oral tion tests and hemograms were monitored every 6 corticosteroid therapy in a tapering dose (as described in weeks. the methods). All eyes with TB SLC received concomi- tant ATT (in either group). In the combination group 2 Group 2 (standard oral + intravitreal therapy), 2 eyes received in- In addition to standard treatment Group 2 patients re- travitreal methotrexate due to history of corticosteroid ceived intravitreal dexamethasone implant (0.7 mg) in- responsiveness (one eye received 3 injections and the jection at baseline. If the use of intravitreal other received 2), whereas 12 eyes received intravitreal corticosteroid was contraindicated (due to cataract, or dexamethasone implant (single injection at baseline). Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 4 of 9 Table 1 Comparison of baseline demographic and clinical parameters between the two groups Group 1 (n = 11 eyes) Group 2 (n = 14 eyes) P value Age (years ± SD) 30.4 ± 8.3 32.4 ± 11.5 0.62 Gender (n) 0.20 Male 6 11 Female 5 3 Diagnosis (n) 0.82 TB SLC 6 7 MFC 5 7 Laterality (n) 0.89 Right eye 6 8 Left eye 5 6 Treatments (n) Intravitreal DEX – 12 – Intravitreal MTX – 2 – ATT 6 7 – Oral corticosteroids 11 14 – Initial BCVA (LogMAR units) 0.41 ± 0.25 0.38 ± 0.23 0.85 Final BCVA (LogMAR units) 0.32 ± 0.23 0.15 ± 0.11 0.025 (p value)* (0.01) (< 0.001) Initial IOP 13.6 ± 1.7 13.7 ± 2.2 0.92 (mm Hg) Final IOP (mm Hg) 14.1 ± 2.1 14.4 ± 3.8 0.82 (p value)* (0.51) (0.58) *p value has been calculated compared to baseline ATT Anti-tubercular therapy, BCVA Best-corrected visual acuity, DEX Dexamethasone implant, IOP Intraocular pressure, MFC Multifocal choroiditis, MTX Methotrexate, TB SLC Tubercular serpiginous-like choroiditis Fig. 1 Fig. 1 compares the choriocapillaris flow deficit (CC FD) between the two study arms measured on optical coherence tomography angiography (OCTA). The CC FD reduced significantly at 12 weeks in the combination arm (intravitreal dexamethasone implant and oral corticosteroids) compared to oral corticosteroids alone Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 5 of 9 Analysis of OCTA in groups 1 and 2 showed a base- Table 3 Calculation of choriocapillaris flow deficit areas (in 2 2 mm ) on indocyanine green angiography (ICGA) in both the line mean CC FD of 1.12 mm and 1.08 mm , respect- groups ively (p = 0.86). During follow-up, the CC FD improved Group 1 Group 2 P value in all eyes in both the groups (statistically significant at (n = 11 eyes) (n = 14 eyes) all time points compared to baseline). In comparing Baseline 1.20 ± 0.66 1.22 ± 0.62 0.93 group 1 and 2, the recovery of choriocapillaris (mea- 12 weeks 0.61 ± 0.36 0.25 ± 0.22 0.005 sured in terms of decrease in CC FD) was significantly higher in eyes belonging to group 2 (Fig. 1). Table 2 pro- P value* < 0.001 < 0.001 vides a summary of the changes in OCTA CC FD from baseline through week 12 in both the groups. On ICGA, the mean area of flow deficit at baseline OCTA and ICGA imaging, it was observed that OCTA 2 2 was 1.20 mm in group 1 and 1.22 mm in group 2 (p = functions well in assessing the recovery of CC FD after 0.93). At 12 weeks, the mean area of flow deficit was initiation of treatment. The improvements in chorioca- 2 2 0.61 mm in group 1, and 0.25 mm in group 2 (p = pillaris during follow-up was also seen on ICGA at 3 0.005) (Table 3) (Fig. 2). months. An important highlight of the study was that le- The BCVA improved from 0.41 to 0.32 LogMAR units sions with an area greater than 0.1 mm at baseline in group 1 (p = 0.014), whereas it improved from 0.39 to showed healing but with significant choriocapillaris atro- 0.15 LogMAR units in group 2 (p < 0.001). The BCVA phy. Lesions smaller than 0.1mm in area showed near- was also significantly better in eyes belonging to group 2 complete resolution with minimal residual alterations in at 12 weeks (p = 0.025) (Fig. 3). the choriocapillaris on ICGA [11]. Thus, the bigger the The mean IOP increased from 13.6 to 14.1 mmHg in lesion area, the greater chances of choriocapillaris atro- group 1 (p = 0.518), whereas it increased from 13.7 to phy. Since then, there are very few studies published that 14.4 mmHg (p = 0.58) in group 2 (Table 1). Two eyes in demonstrate quantitative improvements in CC FD in group 2 were given topical dorzolamide 2% for 12 weeks posterior uveitis, specifically TB SLC and MFC [16–19]. (single agent) since the IOP was recorded > 21 mmHg We performed this study to assess whether adjunctive (maximum of 25 mmHg) at week 2 in both eyes (Fig. 4). treatment with intravitreal corticosteroids/methotrexate None of the eyes in either group developed worsening can aid in the greater recovery of CC FD in cases with of inflammation, increase in choroiditis lesions, develop- center-involving TB SLC and MFC. Atrophy of chorio- ment of new choroiditis lesions, or other adverse events capillaris due to inflammation involving the RPE, outer such as endophthalmitis. All the eyes in both groups retina and choriocapillaris layer is associated with per- showed healing of the choroiditis lesions at the end of manent visual loss and scarring [4]. Therefore, the aim 12 weeks. In eyes requiring ATT, the therapy was con- of the treatment is to prevent as much central photo- tinued beyond the period of the study i.e., 12 weeks. receptor loss as possible. In this study, we observed im- provements in CC FD in all eyes at week 12 compared Discussion to baseline, however, eyes receiving additional intravit- In a previously published study by our group wherein real dexamethasone implant/methotrexate performed patients with TB SLC were serially followed up using significantly better with greater resolution of CC FD on OCTA and flow deficit areas on ICGA. Table 2 Comparison of optical coherence tomography The application of quantitative metrics in posterior angiography (OCTA) derived choriocapillaris flow deficit (CC FD) uveitis may be valuable to assess the effect of therapeutic in mm in both the groups interventions. Using easily available third-party software, Group 1 Group 2 P value it is possible to measure the areas of CC FD on OCTA (n = 11 eyes) (n = 14 eyes) [11, 18, 19]. In addition, the measurement of the hypo- Baseline 1.12 ± 0.63 1.08 ± 0.58 0.86 fluorescent area on ICGA has been made possible by the 1 week 0.96 ± 0.59 0.82 ± 0.60 0.56 tools available on the Heidelberg Eye Explorer, and simi- P value* < 0.001 < 0.001 lar in-built software on other commercially available de- vices. Studies have previously shown the agreement 2 weeks 0.83 ± 0.54 0.50 ± 0.39 0.086 between OCTA and ICGA in terms of choriocapillaris P value* < 0.001 < 0.001 flow measurements [11, 19]. Serial quantitative metrics 4 weeks 0.63 ± 0.39 0.31 ± 0.31 0.030 provide an objective assessment of the choriocapillaris P value* < 0.001 < 0.001 recovery, and thus serves as an endpoint for therapeutic 12 weeks 0.54 ± 0.39 0.15 ± 0.18 0.008 interventions. In our study, the recovery of choriocapil- P value* < 0.001 < 0.001 laris after intravitreal injections was significantly better *p value has been calculated compared to baseline Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 6 of 9 Fig. 2 Fig. 2 compares the mean area of the choriocapillaris flow deficit on indocyanine green angiography (ICGA) imaging. Eyes in the combination arm (intravitreal dexamethasone implant and oral corticosteroids) had lesser flow deficit areas compared to eyes treated with oral corticosteroids alone at 12 weeks than the standard arm receiving only oral corticosteroid significantly higher visual outcomes even though there therapy at all follow-up visits. was no significant difference in the BCVA at baseline The resolution of CC FD on OCTA was accompan- between the two groups. This suggests that addition ied by significant improvements in BCVA in both the of adjunctive intravitreal therapy at baseline may not groups. While the BCVA improved from baseline in only translate into better anatomical outcomes on both groups of patients receiving treatment, the group OCTA in terms of CC FD, but also potentially better receiving adjunctive intravitreal therapy had visual results at 12 weeks. Fig. 3 Fig. 3 shows the improvement in best-corrected visual acuity (BCVA) between the two treatment arms. Eyes in the combination arm (intravitreal dexamethasone implant and oral corticosteroids) had significantly better BCVA at 12 weeks compared to eyes receiving oral corticosteroids alone Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 7 of 9 Fig. 4 The figure shows change in the mean intraocular pressure (IOP) in the two treatment arms. While the IOP increased at 12 weeks in both the treatment arms compared to baseline, there were no statistically significant changes from baseline, or between the two treatment arms In patients with TB SLC and MFC, the safety and effi- Our study has several limitations. We had a mod- cacy of intravitreal therapy with dexamethasone implant est sample size of patients. However, we included and methotrexate has been published previously [20– patients with strict inclusion criteria such as 23]. The advantages of intravitreal corticosteroid/metho- treatment-naïve macular choroiditis with no prior trexate injection include high local delivery of anti- intraocular treatment, and clear media for serial inflammatory therapy that can promptly act to reduce OCTA. In addition, we did not have automated the inflammation, avoiding systemic side-effects of pro- measurements of CC FD in our study. With im- longed oral therapy. Studies have shown that intravitreal provements in technology and application of quan- injection of these agents are not associated with worsen- titative algorithms, automated quantification is ing of choroiditis in any patient and help in the healing being increasingly employed [17, 18, 25]. In the fu- of the lesions with minimal adverse events [20–23]. ture, such automated measurements may be applied Since steroid-responsiveness is a cause of concern in pa- to OCTA imaging of lesions of choroiditis as well. tients receiving dexamethasone implant, we used intra- Since patients in group 2 received either dexa- vitreal methotrexate in patients who had history of high methasone implant or methotrexate therapy, it may IOP after corticosteroid use. None of the subjects in our be argued that group 2 included patients receiving cohort had uncontrollable rise in IOP, and 2 subjects re- two different drugs. However, the aim of the study quired a short course of single topical anti-glaucoma was not to compare the treatment strategies them- medication for IOP rise. selves, but the utility of imaging modality (i.e., Our study is a pilot clinical trial which is mainly aimed OCTA) for the follow-up assessment of these at evaluating the role of OCTA in quantifying lesions of patients. choroiditis after initiation of treatment. Thus, we do not In conclusion, OCTA is not only useful in asses- propose use of intravitreal corticosteroids/methotrexate in sing areas of CC FD in eyes with choroiditis, but it every case of macular choroiditis. There are several chal- can be used as a tool to monitor recovery of the lenges in the management of choroiditis due to ocular TB, choriocapillaris and assess the efficacy of systemic as well as MFC and these patients require individualized and intravitreal anti-inflammatory therapies. In pa- therapy to tackle persistence of lesions, development of tients with TB SLC and MFC who receive adjunctive new lesions, and other aspects such as drug resistance [14, intravitreal corticosteroid/methotrexate therapy in 24]. However, our study does demonstrate that adjunctive addition to systemic corticosteroids, greater decrease intravitreal agents may have an role in improving the vis- in the CC FD area can be visualized on OCTA, and ual outcomes of these patients, and such therapies may be this may translate into superior visual outcomes due increasingly employed for our future patients. to decreased choriocapillaris atrophy. Agarwal et al. Journal of Ophthalmic Inflammation and Infection (2022) 12:12 Page 8 of 9 Acknowledgements 7. Marchese A, Agarwal A, Moretti AG, Handa S, Modorati G, Querques G, None. Bandello F, Gupta V, Miserocchi E (2020) Advances in imaging of uveitis. Ther Adv Ophthalmol 12. https://doi.org/10.1177/2515841420917781 8. Pichi F, Sarraf D, Arepalli S, Lowder CY, Cunningham ET Jr, Neri P, Albini TA, Precis. Gupta V, Baynes K, Srivastava SK (2017) The application of optical coherence Patients with choroiditis may experience better improvement in tomography angiography in uveitis and inflammatory eye diseases. Prog choriocapillaris flow deficit areas and visual acuity if treated with oral Retin Eye Res 59:178–201. https://doi.org/10.1016/j.preteyeres.2017.04.005 corticosteroid therapy with intravitreal dexamethasone implant/ 9. Pohlmann D, Pleyer U, Joussen AM, Winterhalter S (2019) Optical coherence methotrexate. Optical coherence tomography angiography is useful in tomography angiography in comparison with other multimodal imaging monitoring choriocapillaris recovery. techniques in punctate inner choroidopathy. Br J Ophthalmol 103(1):60–66. https://doi.org/10.1136/bjophthalmol-2017-311764 Authors’ contributions 10. Mandadi SKR, Agarwal A, Aggarwal K, Moharana B, Singh R, Sharma A, AA and KA conceived the manuscript. KA, AA, KA2 collected the data and Bansal R, Dogra MR, Gupta V, for OCTA Study Group (2017) Novel findings analysed it. The literature search and critical review was performed by AA, on optical coherence tomography angiography in patients with tubercular KA2, RJE, TTJMB, CABW, RB and VG. AA and KA wrote the manuscript. All the serpiginous-like choroiditis. Retina Phila Pa 37(9):1647–1659. https://doi. authors critically reviewed it and approved for submission. org/10.1097/IAE.0000000000001412 11. Agarwal A, Aggarwal K, Mandadi SKR, Kumar A, Grewal D, Invernizzi A, Funding Bansal R, Sharma A, Sharma K, Gupta V, for OCTA Study Group (2021) There are no sources of funding to declare for the study. Longitudinal follow-up of tubercular serpiginous-like choroiditis using optical coherence tomography angiography. Retina Phila Pa. 41(4):793–803. https://doi.org/10.1097/IAE.0000000000002915 Availability of data and materials 12. Brar M, Sharma M, Grewal SPS, Grewal DS (2020) Comparison of wide-field The data related to the study will be available upon reasonable request from swept source optical coherence tomography angiography and fundus the corresponding author. autofluorescence in tubercular serpiginous-like choroiditis. Indian J Ophthalmol 68(1):106–211. https://doi.org/10.4103/ijo.IJO_78_19 Declarations 13. Ahn SJ, Park SH, Lee BR (2017) Multimodal imaging including optical coherence tomography angiography in serpiginous choroiditis. Ocul Ethics approval and consent to participate Immunol Inflamm 25(2):287–291. https://doi.org/10.1080/09273948.2017.12 The study was approved by the Post Graduate Institute of Medical Education and Research (PGIMER) Institute Ethics Committee (IEC), Chandigarh, India. 14. Agrawal R, Gunasekeran DV, Grant R, Agarwal A, Kon OM, Nguyen QD, Written informed consent was obtained from all the patients for the Pavesio C, Gupta V, for the Collaborative Ocular Tuberculosis Study (COTS)– participation in the study. 1 Study Group (2017) Clinical features and outcomes of patients with tubercular uveitis treated with Antitubercular therapy in the collaborative Consent for publication ocular tuberculosis study (COTS)-1. JAMA Ophthalmol 135(12):1318–1327. The consent for publication was obtained from the patients and all the https://doi.org/10.1001/jamaophthalmol.2017.4485 authors. 15. Testi I, Agrawal R, Mahajan S, Agarwal A., Gunasekeran D.V., Raje D., Aggarwal K., Murthy S.I., Westcott M., Chee S.P., McCluskey P., Ho S.L., Teoh S., Cimino L., Biswas J., Narain S., Agarwal M., Mahendradas P., Khairallah M., Competing interests Jones N., Tugal-Tutkun I., Babu K., Basu S., Carreño E., Lee R., al-Dhibi H., There are no competing interests for any author related to the manuscript. Bodaghi B., Invernizzi A., Goldstein D.A., Herbort C.P., Barisani-Asenbauer T., González-López J.J., Androudi S., Bansal R., Moharana B., Esposti S.D., Author details Tasiopoulou A., Nadarajah S., Agarwal M., Abraham S., Vala R., Singh R., Eye Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, Sharma A., Sharma K., Zierhut M., Rousselot A., Grant R., Kon O.M., United Arab Emirates. Advanced Eye Center, Post Graduate Institute of Cunningham E.T., Kempen J., Nguyen Q.D., Pavesio C., Gupta V. Tubercular Medical Education and Research, Sector 12, Chandigarh, India. 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Journal

Journal of Ophthalmic Inflammation and Infection – Springer Journals

Published: Mar 11, 2022

Keywords: Optical coherence tomography angiography; Multifocal choroiditis; Choriocapillaris; Flow deficit; Imaging; Uveitis

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