An Update on Noninfectious Retinal Vasculitis.

BACKGROUND: Retinal vasculitis (RV) signifies the inflammation of various retinal vessels. Noninfectious RV differs from infectious RV with regard to its pathogenesis and treatment. It can have varied clinical presentations and may be associated with systemic vasculitic diseases. SUMMARY: Noninfectious RV can be caused due to type-III hypersensitivity reactions, increased expression of intracellular adhesion molecules, and genetic susceptibility. Noninfectious RV is primarily classified on the basis of the type of retinal vessels involved. It can be further classified as an occlusive or nonocclusive. RV can be a major association of systemic diseases like Behcet's disease, sarcoidosis and systemic lupus erythematosus. Newer modalities, like ultra-widefield fundus fluorescein angiography, can help in the management of RV. Effective treatment of noninfectious RV requires anti-inflammatory and immunosuppressive therapy. The patients may require treatment with high-dose corticosteroids and biological agents. Anti-vascular endothelial growth factor injections and laser photocoagulation may be indicated to treat the occlusive disease. Prompt treatment may prevent complications like vitreous hemorrhage, neovascular glaucoma, and tractional retinal detachment. The treatment more often requires a multidisciplinary approach. KEY MESSAGES: This review provides a comprehensive update on the various causes of noninfectious RV, including both systemic and isolated ocular conditions. It also details various complications and management strategies for this condition.

Automated quantification of uveitic keratic precipitates by use of anterior segment optical coherence tomography.

BACKGROUND: Evaluation of ocular inflammation via common imaging modalities like optical coherence tomography (OCT) has emphasised cell visualisation, but automated detection of uveitic keratic precipitates (KPs) remains unexplored. METHODS: Anterior segment (AS)-OCT dense volumes of the corneas of patients with uveitic KPs were collected at three timepoints: with active (T0), clinically improving (T1), and resolved (T2) inflammation. At each visit, visual acuity and clinical grading of the anterior chamber cells were assessed. A bespoke algorithm was used to create an en face rendering of the KPs and to calculate their volume and a ratio of the volume of precipitates over the analysed area. The variation of AS-OCT-derived measurements over time was assessed, and compared with clinical grading. RESULTS: Twenty eyes from 20 patients (13 females, mean age 39 years) were studied. At T0, the mean volume of the corneal KPs was 0.1727 mm3 , and it significantly reduced to 0.1111 mm3 (p = 0.03) only at T2. The ratio between the volume of the KPs and the corneal area decreased from T0 (0.007) to T1 (0.006; p = 0.2) and T2 (0.004; p = 0.009). There was a statistically significant correlation between the AC cell count and the AS-OCT volume measurements of the KPs at the three time points. CONCLUSIONS: AS-OCT can image uveitic KPs and through a bespoke algorithm we were able to create an en face rendering allowing us to extrapolate their volume. We found that objective quantification of KPs correlated with inflammatory cell counts in the anterior chamber.

Fundus autofluorescence in uveitis: from pathogenesis to imaging interpretation.

PURPOSE: This review aims to summarize the current fundus autofluorescence (FAF) ailment for diagnosis and follow-up of uveitis. METHODS: A thorough literature search was performed in the PubMed database. RESULTS: FAF maps the retinal pigment epithelium's (RPE) health. Therefore, several posterior infectious and non. This fast, easy-to-perform, noninvasive technique can detect and manage infectious uveitis. CONCLUSIONS: FAF serves to understand pathophysiologic mechanisms of uveitis and is a valuable prognostic indicator of themselves.

LONGITUDINAL FOLLOW-UP OF CHOROIDAL GRANULOMAS WITH INDOCYANINE GREEN ANGIOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY: A Lesion-Based Analysis.

PURPOSE: To investigate choroidal granulomas visualized by indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA) in response to treatment. METHODS: Ten eyes of eight patients with tubercular, sarcoid, or Vogt-Koyanagi-Harada-associated choroidal granulomas were evaluated in this multicentric study. All patients underwent ICGA and OCTA at baseline, 1, and 3 months after treatment onset. Granulomas were identified as hypofluorescent lesions on intermediate ICGA phases. Late ICGA behavior and OCTA visualization were assessed. RESULTS: On baseline intermediate ICGA, 222 choroidal granulomas were detected. Overall, 174/222 granulomas were detected on baseline OCTA images. At 1 month, 28% of lesions were healed and 48 late ICGA hyperfluorescent lesions were identified. At 3 months, 63% of baseline lesions were healed, with 33 persistent late hyperfluorescent lesions. Optical coherence tomography angiography sensitivity was reduced at 1 and 3 months compared with baseline. Some flow-voids detected on OCTA at 1 and 3 months did not correspond to any visible lesion on ICGA. CONCLUSION: Different healing behaviors of choroidal granulomas were identified combining ICGA and OCTA analysis. Late ICGA hyper-fluorescent lesions may be the consequence of a possible fibrotic shift. Structural changes in the choroid may persist after active granulomas resolution resulting in persistent flow voids on OCTA.

CHOROIDAL GRANULOMAS VISUALIZED BY SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To assess the visualization of choroidal granulomas with swept-source optical coherence tomography angiography (OCTA). METHODS: Consecutive patients with granulomatous choroiditis due to tuberculosis, sarcoidosis, or Vogt-Koyanagi-Harada disease underwent baseline OCTA images using a 12 × 12-mm field of view, and the choroidal slabs were analyzed by two independent examiners who counted the oval areas of flow void. Simultaneously, indocyanine green angiography (ICGA) and enhanced-depth imaging OCT were performed to mark visible choroidal changes corresponding to granulomatous lesions. The lesion areas on OCTA and ICGA were assessed using the in-built caliper tool. RESULTS: Three hundred and one round-shaped areas of flow void on OCTA, 209 hypofluorescent round lesions on ICGA, and 42 hyporeflective choroidal lesions on enhanced-depth imaging OCT were identified in 23 eyes from 14 patients. Of the 209 ICGA granulomas, 197 (94.3%) had a corresponding round area of flow void on OCTA that was interpreted as a granuloma. One hundred and four additional round flow voids were identified on OCTA that did not correspond to any hypofluorescent lesion on ICGA. The mean area of the 197 granulomas detected with both imaging modalities was significantly larger on ICGA (mean 0.33 mm2) than that on OCTA (mean 0.28 mm2). CONCLUSION: Optical coherence tomography angiography seems to be an optimal imaging method for the visualization of choroidal granulomas.

New pharmacotherapy options for noninfectious posterior uveitis.

INTRODUCTION: Noninfectious inflammation of the posterior eye segment represents an important cause of visual impairment. It often affects relatively young people and causes a significant personal and social impact. Although steroids and nonbiologic- Disease-Modifying Antirheumatic Drugs (nbDMARDs) are effective both in acute and long- lasting diseases, however they are increasingly being replaced by biologic (DMARDs). bDMARD. This article therefore aims to identify recent advances in the therapy of noninfectious posterior segment uveitis. METHODS: A Medline-search was conducted using the terms: nbDMARD, bDMARD, posterior uveitis, intermediate uveitis, treatment, corticosteroid. In addition, clinical studies were included as registered at ClinicalTrials.gov. RESULTS: Currently two major lines of treatments can be identified: (1) the intraocular application of anti-inflammatory agents and (2) the introduction of new agents, e.g., (bDMARDs) and small-molecule-inhibitors. Whereas intravitreal treatments have the advantage to avoid systemic side effects, new systemic agents are progressively earning credit on the basis of their therapeutic effects. CONCLUSION: Even when current treatment strategies are still hampered by the limited number of randomized controlled trials, promising progress and continuous efforts are seen.

Wide-field optical coherence tomography angiography for the detection of proliferative diabetic retinopathy.

PURPOSE: To compare the ability of wide-field optical coherence tomography angiography (WF-OCTA) to that of ultra-wide field fluorescein angiography (UWF-FA) and ultra-wide-field color fundus photography (UWF-CP) to detect retinal neovascularization (NV) in eyes with proliferative diabetic retinopathy (PDR). METHODS: In this cross-sectional study, naïve patients with active PDR underwent UWF-FA and UWF-CP using the Optos 200Tx and WF-OCTA with 12 × 12 mm fields of five visual fixations using the PLEX Elite 9000. NV was defined on OCTA when the co-registered B-scan with flow overlay of the vitreoretinal interface (VRI) segmentation showed extraretinal proliferation. Three masked readers examined the UWF-FA, UWF-CP, and WF-OCTA independently for the presence of NV. Statistical analysis was performed to compare the diagnostic accuracy of the 3 wide-field imaging modalities using OCT B-scan as the reference standard. RESULTS: In 82 eyes with PDR, neovascularization of the disc (NVD) was detected in 13 eyes by UWF-CP, 35 eyes with UWF-FA, and 37 eyes with OCTA using the VRI slab. Upon review of the 2500 OCT B-scans with superimposed flow overlay of each eye, NVD was confirmed in 37 eyes. The sensitivity and specificity of NVD detection were 35.1% and 97.8%, respectively for UWF-CP; 94.6% and 100%, respectively, for UWF-FA; and 100% and 100% for WF-OCTA. One hundred ninety-six foci of neovascularization elsewhere (NVE) were identified with the OCT B-scan with superimposed flow overlay. UWF-CP analysis was able to detect 62 foci of NVE of the 196 confirmed by B-scan (31.6% detection rate). An additional 11 foci of NVE seen on UWF-CP were not confirmed by B-Scan (15% false positive rate). There were 182 foci of NVE identified by UWF-FA (detection rate 91.3%), while WF-OCTA detected 196 retinal NVEs (detection rate 100%). The rate of false positives for both UWF-FA and WF-OCTA was low (< 2%). CONCLUSION: WF-OCTA can identify NV that is not evident in UWF-CP and represents a faster and safer alternative to UWF-FA for surveillance of PDR with comparable diagnostic accuracy.

Multimodal imaging patterns of posterior syphilitic uveitis: a review of the literature, laboratory evaluation and treatment.

PURPOSE: To review the multimodal imaging patterns of posterior syphilitic uveitis. METHODS: A systematic review. RESULTS: The percentage of syphilis has started to increase again: The World Health Organization has reported 12 million new cases of syphilis each year. In addition, syphilis was responsible for 0.3% of deaths globally in 2002. Eye manifestations happen prevalently in secondary and tertiary stages of syphilis, even though ocular involvement can occur in all stages. Syphilis has the nickname: "the great imitator" since it has no unique clinical presentation, even though posterior uveitis is considered the most common form. Syphilis is known as "the great imitator," making its diagnosis in the presence of posterior uveitis particularly challenging as it presents similarly to other ocular conditions such as acute retinal necrosis. However, with the advent of multimodal imaging some particular patterns of pre-retinal, retinal, retinochoroidal and optic nerve involvement from syphilis can be identified to guide the diagnosis and the laboratory workup. CONCLUSION: This review highlights the various patterns of pre-retinal precipitates, multifocal retinitis, retinochoroiditis (confluent and placoid) and optic neuritis caused by syphilis, the appropriate laboratory work to be obtained and the treatment to be initiated.

Optical coherence tomography angiography findings in systemic lupus erythematosus patients with no ocular disease.

PURPOSE: Retinal manifestations are present in 10% of patients with systemic lupus erythematosus (SLE) and consist of vascular changes that can be sight-threatening. Optical coherence tomography angiography (OCTA) is a novel imaging modality that detects movement inside the blood vessels without dye injection and transforms this movement into an angiographic map. The aim of this study is to describe subclinical vessels changes in the eyes of patients with SLE but no retinal manifestations. METHODS: In this cross-sectional study, 15 patients with SLE but no clinical ophthalmic manifestations were scanned through OCTA of the iris and at the level of the macula. Qualitative aspects of the iris vessels, and measure of the foveal avascular zone (FAZ) and vessel density were compared to a cohort of 15 normal controls. RESULTS: Patients with SLE, even in the absence of ophthalmic manifestations, present a qualitative increase in the iris vessels flow, and enlargement of the FAZ (0.22 ± 0.12 mm2) and a decrease in the vascular density (11.221 ± 1.933 mm-1) of the superficial capillary plexus on OCTA that cannot be highlighted clinically. DISCUSSION: OCTA can be used in a noninvasive way to detect subclinical vascular changes in patients with SLE. How this information will influence the follow-up and management of these cases will require further prospective studies with a collaborative effort between ophthalmologists and rheumatologists.

Standardization of red flags for referral to rheumatologists and ophthalmologists in patients with rheumatic diseases and ocular involvement: a consensus statement.

Ocular involvement is a common manifestation of inflammatory rheumatic diseases, often requiring a multidisciplinary collaboration between rheumatologists and ophthalmologists. The aim of this study was to standardize "red flags" for referral for rheumatologists and ophthalmologists using a Delphi consensus for the management of rheumatic diseases with ocular involvement. The scientific board comprised 11 Italian hospital-based rheumatologists (N = 6) and ophthalmologists (N = 5). A systematic review identified potential red flags for referral. The panel developed 19 statements consisting of (a) referral from ophthalmologist to rheumatologist (b) referral from rheumatologist to ophthalmologist and (c) overarching principles relating to multidisciplinary roles/goals and management. Voting was performed anonymously using an online Delphi method. Each participant expressed a level of agreement on each statement using a 5-point scale (1="strongly disagree"; 5="strongly agree"). Total cumulative agreement was defined as the sum of the percentage of response to items 4 ("agree") and 5 ("absolutely agree"), consensus defined as ≥ 80% cumulative agreement for each statement. Positive consensus among 11 participants was reached for 15/19 (78.9%) statements. Statements not reaching consensus were discussed in a face-to-face meeting prior to the second vote (10 participants). Positive consensus was reached for all 19 statements, with final total cumulative agreement of 90-100%. This is the first Delphi consensus undertaken to standardize red flags for referral to rheumatologists and ophthalmologists for patients with rheumatic diseases and ocular involvement.

Optical coherence tomography angiography findings in Susac's syndrome: a case report.

PURPOSE: To report clinical features of Susac's syndrome (SS) using optical coherence tomography angiography (OCTA). METHODS: Case report. RESULTS: A 25-year-old Caucasian female with a history of non-pulsatile migraine, tinnitus, and verbal apraxia complaining of peripheral scotoma in left eye due to branch retinal arteriole occlusion (BRAO) was diagnosed as having SS after audiometric test, brain magnetic resonance imaging, and multimodal retinal imaging. Fundus biomicroscopy and fluorescein angiography (FA) revealed the presence of retinal ischemia in the area of BRAO. The OCTA images showed decreased vascular perfusion of both superficial and deep plexuses in the area of the occluded arteriole with increase of vascular density values after treatment with intravenous glucocorticoids, cyclophosphamide, and aspirin. CONCLUSIONS: OCTA offers a valid alternative to the standard invasive FA, evaluating vascular perfusion in all capillary plexuses, and monitoring retinal microvascular flow changes during the course of BRAO, without dye injection.

PERIPHERAL RETINOSCHISIS IN INTERMEDIATE UVEITIS.

PURPOSE: To examine cases of intermediate uveitis complicated by retinoschisis and review the pathogenetic hypothesis. METHODS: A retrospective chart review of patients with intermediate uveitis. Data were collected at three uveitis referral centers on sex, age, best-corrected visual acuity, degree of vitritis, extent and location of snowbanking, presence of hard exudates, neovascularization, vitreous hemorrhage, and extent and nature of retinal elevations. RESULTS: A series of 23 eyes of 20 patients were examined; patient's age ranged from 10 years to 70 years and follow-up period from 8 months to 6 years. Twenty-two eyes had retinoschisis (95.6%), and 1 had retinoschisis associated with serous retinal detachment (4.3%). Extensive inferior pars plana exudates with snowbanking were present in 12 eyes (52.2%), whereas 3 eyes had inferior snowballs over the elevated retina. Neovascularization of the vitreous base accompanied by vitreous hemorrhage occurred in one eye. There was no coexisting macular pathology in 16 eyes, whereas 4 eyes had cystoid macular edema. CONCLUSION: The appearance of peripheral retinoschisis in this series of uncontrolled intermediate uveitis patients seems to be secondary to a complex balance between the persistent fluorescein leakage, a subclinical peripheral ischemia, and the constant low-grade vitreous inflammation that causes vitreous shrinkage and traction. The results of this study suggest that the absence of macroscopic changes in the retina does not preclude ischemic peripheral abnormalities, and the detection of a peripheral retinoschisis in an intermediate uveitis patient with active fluorescein leakage must suggest the need for a more aggressive form of treatment despite the good visual acuity.

Acute macular neuroretinopathy associated with subclinical cytomegalovirus infection.

PURPOSE: To report a case of bilateral acute macular neuroretinopathy (AMN) occurring in a 32-year-old woman, analyzed using the multimodal imaging technique. CASE REPORT: A 32-year-old Caucasian woman presented with 20 days history of acute onset of blurred vision in the right eye. The best-corrected visual acuity (BCVA) was 0.8 and 1.0 in the right and left eyes, respectively. She reported a lower urinary tract infection associated with fever, 7 days before the onset of the ocular symptoms. Serological tests demonstrated the presence of IgM specific for cytomegalovirus (CMV), while all the other laboratory tests were negative. SD-OCT exhibited the disruption of the inner segment-outer segment junction, associated with hyper-reflectivity of a thickened outer plexiform layer overlying such area associated with thinning of the outer nuclear layer. The patient was diagnosed with AMN and received a corticosteroid treatment. During all the follow-up, OCT features did not change, although BCVA improved. Four months after the first visit, we found also in the left eye a subfoveal IS/OS disruption but differently from the right eye, in which the abnormalities persisted during all the follow-up visits, in the left one they disappeared only after a month. The IgM specific for the CMV remained positive during the whole follow-up. CONCLUSIONS: To our knowledge, this is the first patient reported with a diagnosis of AMN associated with persisting presence of IgM specific for CMV.

EN FACE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF MULTIPLE EVANESCENT WHITE DOT SYNDROME: New Insights Into Pathogenesis.

PURPOSE: To localize the various levels of abnormalities in multiple evanescent white dot syndrome by comparing "en face" optical coherence tomography (OCT) and OCT angiography with various conventional imaging modalities. METHODS: In this retrospective case series, multimodal imaging was performed in 9 retinal centers on 36 patients with multiple evanescent white dot syndrome and included widefield fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography, and B-scan and "en face" C-scan enhanced depth imaging and spectral domain OCT. Optical coherence tomography angiography was also performed at the level of the superficial and deep retinal capillary plexus and choroid. RESULTS: Multiple evanescent white dot syndrome lesions were more numerous and more easily detectable with FA and FAF. Two types of lesions were identified with FAF, FA, and indocyanine green angiography: larger widely scattered "spots" (approximately 200 µ in diameter) that were hyperfluorescent with FA, hyperautofluorescent with FAF, and hyporeflective in indocyanine green angiography, representing abnormalities primarily at the retinal pigment epithelium/photoreceptor junction; and punctate "dots" (less than 100 µ in diameter) that were hyperfluorescent with FA, hyperautofluorescent, or isoautofluorescent with FAF, and hypofluorescent with indocyanine green angiography and that localized to the outer nuclear layer. These lesions colocalized with "en face" OCT. The larger confluent "spots" were hyporeflective and colocalized to the level of the ellipsoid zone, whereas smaller hyperreflective "dots" colocalized to the outer nuclear layer. The location of the "dots" in the outer nuclear layer was further confirmed by structural spectral domain optical coherence tomography which showed coalescence of the dots into hyperreflective lines extending from the external limiting membrane to the outer plexiform layer in certain cases. Optical coherence tomography angiography analysis of the retinal microvasculature and choriocapillaris and choroid were entirely unremarkable in 100% of our patients. CONCLUSION: By combining multimodal imaging, the authors propose that multiple evanescent white dot syndrome is primarily the result of inflammation at the outer photoreceptor level leading to a "photoreceptoritis" and causing loss of the inner and outer segments. Its evanescent nature suggests that the photoreceptor cell bodies remain intact ensuring complete recovery of the photoreceptor inner and outer segments in most cases, compatible with the clinical course of spontaneous resolution of white spots and dots.

Genetic of uveitis.

Immune-mediated uveitis may be associated with a systemic disease or may be localized to the eye. T-cell-dependent immunological events are increasingly being regarded as extremely important in the pathogenesis of uveitis. Several studies have also shown that macrophages are major effectors of tissue damage in uveitis. Uveitis phenotypes can differ substantially, and most uveitis diseases are considered polygenic with complex inheritance patterns. This review attempts to present the current state of knowledge from in vitro and in vivo research on the role of genetics in the development and clinical course of uveitis. A review of the literature in the PubMed, MEDLINE, and Cochrane databases was conducted to identify clinical trials, comparative studies, case series, and case reports describing host genetic factors as well as immune imbalance which contribute to the development of uveitis. The search was limited to primary reports published in English with human subjects from 1990 to the present, yielding 3590 manuscripts. In addition, referenced articles from the initial searches were hand searched to identify additional relevant reports. After title and abstract selection, duplicate elimination, and manual search, 55 papers were selected for analysis and reviewed by the authors for inclusion in this review. Studies have demonstrated associations between various genetic factors and the development and clinical course of intraocular inflammatory conditions. Genes involved included genes expressing interleukins, chemokines, chemokine receptors, and tumor necrosis factor and genes involved in complement system. When considering the genetics of uveitis, common threads can be identified. Genome-wide scans and other genetic methods are becoming increasingly successful in identifying genetic loci and candidate genes in many inflammatory disorders that have a uveitic component. It will be important to test these findings as uveitis-specific genetic factors. Therefore, the burgeoning understanding of the human genome promises to result in new insight into the pathogenesis of uveitis.