Supplemental Digital Content is Available in the Text.Cases of retinopathy of unknown origin were investigated using an inherited retinal disease gene panel. In unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy cases, no clear genetic causes could be demonstrated. However, 20% of suspected nonparaneoplastic autoimmune retinopathy cases seemed to be inherited retinal disease. Purpose:Evaluating the presence of class 3, 4, and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO).Methods:Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmologic history, complete ophthalmologic examination, antiretinal antibodies, and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: nonparaneoplastic autoimmune retinopathy, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy.Results:The authors included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20-68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, two also demonstrated class 5 variants in other IRD genes. The remaining five patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) nonparaneoplastic autoimmune retinopathy patient in the RUO cohort. When considering the nonparaneoplastic autoimmune retinopathy subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved.Conclusion:Every suspected nonparaneoplastic autoimmune retinopathy patient should benefit from gene panel testing to not overlook undiagnosed IRDs. By contrast, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy subpopulations did not benefit from genetic testing in this study.

Purpose To evaluate F-18-fluorodeoxyglucose Positron Emission Tomography/ultra low dose Computed Tomography (F-18-FDG PET/ ULD CT) in the work-up of pediatric uveitis. Methods Retrospective study of 12 children followed for uveitis who underwent whole body F-18-FDG PET/ULD CT between 2011 and 2019. Results The average age of the patients was 11 years. A total of 100% of patients presented with bilateral uveitis, 50% had panuveitis and 92% had various choroidal involvement. Relevant information for diagnosis was provided in four patients. 5/12 had an abnormal 18F-FDG uptake. Of these, three patients had pathognomonic images of active granulomatous diseases. Three patients underwent PET CT-guided biopsies of which two were positive for sarcoidosis. Conclusion F-18-FDG PET/CT provided important information for final diagnosis in approximately 30% (4/12) of pediatric patients with bilateral uveitis. Whole body FDG PET/ULD CT can contribute to the final diagnosis thanks to pathognomonic image of active granulomatous disease and/or by indicating metabolically active site of biopsy that would not be visualized in thorax CT.

Background The c.2299delG mutation is prevalent and accounts for 24.5% USH2A pathogenic variants, with promising prospects for customized gene therapy. Materials and Methods We compared the ocular and auditory phenotypes in a retrospective cohort of 169 Usher type 2 patients, with and without the c.2299delG allele, including visual acuity, slit-lamp examination, optical coherence tomography, kinetic perimetry, and audiometric assessment to define the hearing disability. Statistical methods used were covariate balancing propensity score and adjusted survival curves log-rank test for the analysis of visual acuity. Results We compare 54 Usher patients (31%) carrying at least one c.2299delG allele to 109 patients without this variant. The mean ages at onset of night blindness (14 years) and onset of peripheral vision deficiency (24 years) were similar in both groups, as was the severity of hearing loss (p = 0.731), even in homozygotes (p = 0.136). Based on the covariate balancing propensity score, the c.2299delG carrier patients developed cataract and reached a BCVA of 20/63 earlier than patients without this mutation (mean age 36 versus 42 y.o.; and 52.2 versus 55.1 y.o., respectively). Using adjusted survival curves and a log-rank test based on inverse probability weighting, patients with the c.2299delG variant reach blindness (BCVA <20/400) at 42.3 years old instead of 79.8 years for other USH2A pathogenic variants. Conclusions We conclude that c.2299delG is associated with a more severe phenotype of the Usher type 2, in homozygotes and in compound heterozygotes.

Recent advances in ocular gene and cellular therapy rely on precisely controlled subretinal delivery. Due to its inherent limitations, manual delivery can lead to iatrogenic damage to the retina, the retinal pigment epithelium, favor reflux into the vitreous cavity. In addition, it suffers from lack of standardization, variability in delivery and the need to maintain proficiency. With or without surgical damage, an eye challenged with an exogenous viral vector or transplanted cells will illicit an immune response. Understanding how such a response manifests itself and to what extent immune privilege protects the eye from a reaction can help in anticipating short- and long-term consequences. Avoidance of spillover from areas of immune privilege to areas which either lack or have less protection should be part of any mitigation strategy. In that regard, robotic technology can provide reproducible, standardized delivery which is not dependent on speed of injection. The advantages of microprecision medical robotic technology for precise targeted deliveries are discussed.

PURPOSE: To determine classification criteria for varicella zoster virus (VZV) anterior uveitis. DESIGN: Machine learning of cases with VZV anterior uveitis and 8 other anterior uveitides. METHODS: Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set. RESULTS: One thousand eighty-three cases of anterior uveitides, including 123 cases of VZV anterior uveitis, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for VZV anterior uveitis included unilateral anterior uveitis with either (1) positive aqueous humor polymerase chain reaction assay for VZV; (2) sectoral iris atrophy in a patient >= 60 years of age; or (3) concurrent or recent dermatomal herpes zoster. The misclassification rates for VZV anterior uveitis were 0.9% in the training set and 0% in the validation set, respectively. CONCLUSIONS: The criteria for VZV anterior uveitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational re-search. ((C) 2021 Elsevier Inc. All rights reserved.)

An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.

PURPOSE:To present a case of frosted branch periphlebitis in a young Armenian patient with familial Mediterranean fever.METHODS:Case report.RESULTS:A 37-year-old man presented with a unilateral decreased visual acuity and floaters for 4 days on the left eye (LE). Visual acuity was 20/20 in the right eye (RE) and 20/28 in the LE. Anterior segment and fundus examinations of the RE were normal. Slit-lamp examination of LE revealed a mild nongranulomatous anterior uveitis and vitritis. Intraocular pressure was 19 mmHg in the RE and 12 mmHg in the LE. Fundoscopy of the LE showed typical appearance of frosted branch periphlebitis with perivascular sheathing of the retinal veins and scattered retinal hemorrhages. Fluorescein angiography of the RE was normal. The LE showed optic disk and segmented vascular staining without macular leakage. Optical coherence tomography of the RE was normal; LE demonstrated a localized macular thickening and few intraretinal cysts. The detailed ophthalmologic history was negative. The general history and workup were significant for familial Mediterranean fever and a positive lupus anticoagulant. One week later, the fundus findings worsened with a severe decrease of visual acuity of the LE to 20/200. A single intravitreal (IVT) injection of bevacizumab was performed. Three weeks after injection, fundus findings progressively improved with a decrease of the macular thickening and an improvement of the visual acuity to 20/25. Clinical improvement continued up to the last visit (19 weeks after the injection) with a visual acuity that reached back 20/20 with no signs of active inflammation.CONCLUSION:This case demonstrates a possible association between unilateral frosted branch periphlebitis and familial Mediterranean fever.

Background Blood-retinal barrier cells are known to exhibit a massive phenotypic change during experimental autoimmune uveitis (EAU) development. In an attempt to investigate the mechanisms of blood-retinal barrier (BRB) breakdown at a global level, we studied the gene regulation of total retinal cells and retinal endothelial cells during non-infectious uveitis. Methods Retinal endothelial cells were isolated by flow cytometry either in Tie2-GFP mice (CD31 + CD45 − GFP + cells), or in wild type C57BL/6 mice (CD31 + CD45 − endoglin + cells). EAU was induced in C57BL/6 mice by adoptive transfer of IRBP1–20-specific T cells. Total retinal cells and retinal endothelial cells from naïve and EAU mice were sorted and their gene expression compared by RNA-Seq. Protein expression of selected genes was validated by immunofluorescence on retinal wholemounts and cryosections and by flow cytometry. Results Retinal endothelial cell sorting in wild type C57BL/6 mice was validated by comparative transcriptome analysis with retinal endothelial cells sorted from Tie2-GFP mice, which express GFP under the control of the endothelial-specific receptor tyrosine kinase promoter Tie2. RNA-Seq analysis of total retinal cells mainly brought to light upregulation of genes involved in antigen presentation and T cell activation during EAU. Specific transcriptome analysis of retinal endothelial cells allowed us to identify 82 genes modulated in retinal endothelial cells during EAU development. Protein expression of 5 of those genes (serpina3n, lcn2, ackr1, lrg1 and lamc3) was validated at the level of inner BRB cells. Conclusion Those data not only confirm the involvement of known pathogenic molecules but further provide a list of new candidate genes and pathways possibly implicated in inner BRB breakdown during non-infectious posterior uveitis.

Sharanaya Abraham, Massimo Accorinti, Aniruddha Agarwal, Mamta Agarwal, Manisha Agarwal, Ashutosh Aggarwal, Kanika Aggarwal, Mukesh Agrawal, Rupesh Agrawal, Yonka Akova, Hassan Al-Dhibi, Radgonde Amer, Sofia Androudi, Fernando Arevalo, Fatma Asyari, Manohar Babu Balasundaram, Kalpana Babu Murthy, Edoardo Baglivo, Alay Banker, Reema Bansal, Talin Barisani-Asenbauer, Soumyava Basu, Digamber Behera, Jyotirmay Biswas, Bahram Bodaghi, Ester Carreño, Laure Caspers, Soon Phaik Chee, Romi Chhabra, Luca Cimino, Luz Elena Concha del Rio, Emmett T. Cunninghm, Andrè Luiz Land Curi, Dipankar Das, Janet Davis, Simona Degli Esposti, Marc DeSmet, Ekaterina Denisova, Alastair K. Denniston, Marie-Hélène Errera, Alejandro Fonollosa, Sudha Ganesh, Justus G. Garweg, Amala George, Debra A. Goldstein, Julio J González-López, Yan Guex Crosier, Dinesh Visva Gunasekeran, Amod Gupta Vishali Gupta, Avinash Gurbaxani, Zohar Habot-Wilner, Arnd Heilingenhaus, Carl P. Herbort Su Ling Ho, Alessandro Invernizzi, Hazlita M. Isa, Shah Md. Islam, Douglas A. Jabs, Nicholas Jones, Deeksha Katoch, Aera Kee, John H. Kempen Moncef Khairallah, Amit Khosla, Onn Min Kon, Michal Kramer, Lucia Kuffova, Amitabh Kumar, Atul Kumar, Rina La Distia Nora, Richard Lee, Careen Lowder, Saurabh Luthra, Sarakshi Mahajan, Padmamalini Mahendradas, Dorine Makhoul, Shahana Mazumdar, Peter McCluskey, Salil Mehta, Elisabetta Miserocchi, Manabu Mochizuki, Oli S. Mohamed, Bruttendu Moharana Cristina Muccioli, Marion R. Munk, Somasheila Murthy, Sengal Nadarajah Shishir Narain, Heloisa Nascimento, Piergiorgio Neri, Myhanh Nguyen, Quan Dong Nguyen, Annabelle A. Okada, Pinar Ozdal, Yilmaz Ozyazgan, Carlos Pavesio, Alan Palestine, Francesco Pichi, Dhananjay Raje, S.R. Rathinam, Andres Rousselot, Ariel Schlaen, Shobha Sehgal, H. Nida Sen, Aman Sharma, Kusum Sharma, Samir S. Shoughy, Nirbhai Singh, Ramandeep Singh, Justine R. Smith Masoud Soheilian, Sudharshan Sridharan, Anastasia Tasiopoulou Christoph Tappeiner, Stephen Teoh, Ilaria Testi, Jennifer E. Thorne, Maria Sofia Tognon, Ilknur Tugal-Tutkun, Mudit Tyagi, Harvey Uy, Daniel Vitor Vasconcelos Santos, Ruchi VALA, Natasa Vidovic Valentincic, Mark Westcott, Joyce Hisae Yamamoto, Ryoji Yanai, Peizeng Yang, Bety Yanez Alvarez, Yew Sen Yuen Rahman Zahedur, Manfred Zierhut

Purpose: To evaluate the effect of tumor necrosis factor (TNF) inhibitor therapy on ocular relapses in patients with Susac syndrome. Methods: Multicenter retrospective cohort study of patients diagnosed with Susac syndrome according to classical clinical criteria. We evaluated the disease activity before and after introduction of anti-TNF therapy and its value as a steroid-sparing agent. Results: Five patients were included. All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in three patients, and adalimumab was started in two patients. Patients had on average 5 ocular relapses during a mean follow-up time of 2.59 years before introducing a TNF inhibitor, corresponding with on average 1.93 relapses per year. After the introduction of an anti-TNF agent, this number was reduced by factor 5.51 to an average of 0.35 relapses per year for a mean follow-up of 2.86 years (P = 0.10). Before anti-TNF introduction ocular relapses occurred at a mean daily dose of 34 mg of prednisone, whereas with anti-TNF treatment, corticosteroid administration could be completely stopped in four patients with one patient still needing 5 mg daily (P = 0.10). Infliximab and adalimumab generally were well tolerated, and no serious adverse events were reported. Conclusion: Although not statistically significant, our results suggest that anti-TNF therapy can be a valuable option for the treatment of ocular Susac syndrome and may especially be considered in those patients unresponsive to more conventional immunosuppressive treatment.

Purpose: To evaluate neurosyphilis cerebrospinal fluid (CSF) findings and initial ophthalmic manifestations in patients with syphilitic uveitis.Methods: We retrospectively reviewed the records of CSF analysis of 14 patients with syphilitic uveitis with treponemal analysis - chemiluminescent immunoassay and TPHA- and non-treponemal analysis - Rapid Plasma Reagin test - RPR.Results: 86% were males and 43% HIV+. Ocular signs of syphilis lead to the diagnosis of syphilis in 78% of patients. Typical syphilitic uveitis presentations included: acute syphilitic posterior placoid chorioretinitis (50% of patients), retinitis (21% of patients) and punctate inner retinitis (7% of patients). 57% of patients had definite neurosyphilis by the CDC criteria, while 71% had CSF abnormalities suggestive of central nervous system involvement.Conclusion: Based on international guidelines, the frequent CSF abnormalities found in syphilitic uveitis patient supports the diagnosis of neurosyphilis in a majority of patients.

Corneal ulcer, especially in the context of neurotrophic keratopathy is a potentially challenging and sight threatening condition. We present a case of refractory post-surgical ulcer with decreased corneal sensitivity, successfully treated with RGTA (Cacicol ® ). A 95 years-old man underwent eyelid surgery for basocellular carcinoma. Because of a secondary eyelid malocclusion, a band keratopathy developed, leading visual acuity to 3/10. Two EDTA scratching surgeries were performed in order to improve vision. But six weeks after the last surgery, a partial loss of sensitivity associated with an epithelial defect (1.5 mm*2.5 mm) and deep stromal ulcer (with stromal edema all around and temporal neovascularization) was still present despite an intensive treatment with artificial tears, vitamine A ointment, antibiotic drops, 24-hr bandage with a topical antibiotic cream: oxytetracyclin- polymyxin and hydrocortisone (Terracortril ® ). For this refractory corneal ulcer with neurotrophic keratitis, we then decided to stop this treatment and to replace it by RGTA 1*/48 hr and artificial tears 5*/day. While it did not respond to previous topical treatments for six weeks, this post-surgical ulcer with decreased corneal sensitivity and exposed cornea, responded quickly to RGTA drops. After one week, the size of the ulcer was a fifth from its original size. It took fifteen days to completely close the ulcer. The healing of corneal ulcers especially when the corneal sensitivity is involved with a consequent neurotrophic keratitis is a challenge. Several steps are necessary: to stop topical toxic treatment, to find and to treat causes of the ulcer and then apply and alternative treatment. In some cases, RGTA drops can quickly help.

Uveitis is reported to be related to tuberculosis in 0.2–20% of cases. This large range reflects prevalence variations of tuberculosis around the globe as well as differences in diagnostic criteria. In addition, patients with noninfectious uveitis are frequently treated by immunomodulatory drugs and are thus at risk of TB reactivation. Search for tuberculosis infection is thus an important aspect in the work-up of patients with uveitis, even in low prevalence area. In the work up of such patients, the first question to ask is whether the patient has been infected by mycobacterium tuberculosis or not. The second question is to determine whether the uveitis is due or linked to this mycobacterial infection or not. Classical tuberculosis screening tools are used to answer the first question (TST, IGRA and chest X ray). The answer to the second question is much more challenging and will require the exclusion of other causes, to consider epidemiological data and clinical signs, polymerase chain reaction (PCR) on ocular fluids and therapeutically treatment trial. Disease prevalence will greatly influence all proposed tests and the final diagnosis. Tuberculosis prevalence in Western countries has progressively decreased during the twentieth century but remains elevated in cities with large migrating populations and drug addicts, with an increase of ultra-resistant cases. All those data must be carefully analyzed in order to collect enough evidences supporting tuberculosis uveitis before the initiation of a treatment with potential serious side and adapt the treatment to the increasing resistance.

Background Syphilitic uveitis is re-emerging alongside the systemic infection. In July 2017, an international group of uveitis-specialised ophthalmologists formed the International Ocular Syphilis Study Group to define current practice patterns. Methods 103 Study Group members based in 35 countries completed a 25-item questionnaire focused on case load, clinical presentations, use and interpretation of investigations, treatment and clinical indicators of poor prognosis. Results Members managed a mean of 6.1 patients with syphilitic uveitis in clinics that averaged 707 annual cases of uveitis (0.9%); 53.2% reported increasing numbers over the past decade. Patients presented to more members (40.2%) during secondary syphilis. Uveitis was usually posterior (60.8%) or pan (22.5%); complications included optic neuropathy, macular oedema and posterior synechiae. All members diagnosed syphilitic uveitis using serological tests (simultaneous or sequential testing algorithms), and 97.0% routinely checked for HIV co-infection. Cerebrospinal fluid (CSF) analysis was ordered by 90.2% of members, and 92.7% took uveitis plus Venereal Disease Research Laboratory test (VDRL) or fluorescent treponemal antibody absorption test (FTA-ABS) to indicate neurosyphilis. Patients were commonly co-managed with infectious disease physicians, and treated with penicillin for at least 10–14 days, plus corticosteroid. Features predicting poor outcome included optic neuropathy (86.3%) and initial misdiagnosis (63.7%). Reasons for delayed diagnosis were often practitioner-related. 82.5% of members tested every patient they managed with uveitis for syphilis. Conclusion This comprehensive report by an international group of uveitis-specialised ophthalmologists provides a current approach for the management of syphilitic uveitis.

Acanthamoeba keratitis (AK) is a sight-threatening infection classically linked to contact lens wear. Starting as a non-specific unilateral epithelial irregularity like punctate or pseudo-dendritic lesions, AK can evolve to a ring-shaped stromal infiltrate with risk of corneal melting. Radial keratoneuritis may appear. Diagnosis relies on protozoan identification by culture with direct exam and PCR analysis. Acanthamoeba can also be demonstrated by in vivo confocal microscopy (IVCM). Early phase AK is treated with a combination of topical amoebicides. We report three atypical cases of suspected AK. Retrospective report of three women with unilateral atypical corneal lesions, two of them extending to the conjunctiva. Slit lamp photographs, corneal oct and confocal microscopy will be presented. Three patients, two women in their thirties and one in her sixties, consulted for chronic ocular discomfort unsuccessfully treated by topical antibiotics and corticosteroids for months to years. No history of contact lens wear or water exposure was reported. Two had visual acuity (VA) at 20/20 and one a variable VA for 4 years. Slit lamp examination showed an atypical superficial well delimitated linear lesion across cornea and conjunctiva. In all patients, successive examinations had revealed a moving and migrating character of the refractory lesions to topical antibiotics and corticosteroids. All had a rapid response to Polyhexamethylenebiguanide (PHMB) and propamidine (Brolene) and healed without stromal opacification in a few weeks. Although corneal scrapping cultures remained negative, two of them realized an IVCM with signs of AK and all responded rapidly and completely to amoebicide drops supporting the diagnosis of AK. These cases show a particularly atypical involvement of corneal and conjunctival refractory lesions responding very well to PHMB and Brolene suggesting an AK origin.

Purpose: To evaluate diagnostic methods and clinical signs of CMV anterior uveitis (AU), a rarely described entity in Europe. Methods: We included patients with clinical characteristics of CMV AU and positive PCR and/or Goldmann-Witmer coefficient (GWc) for CMV. Results: We report 21 patients with unilateral uveitis (100%) and signs of Posner-Schlossman syndrome (PSS) (n = 20, 95.2%), Fuchs uveitis syndrome (FUS) (n = 1, 4.7%), and endotheliitis (n = 4, 19,04%). PCR was positive in 15/21 (71.4%) and GWc in 8/9 patients (88.9%) in aqueous for CMV. GWc was the only positive test in 6/9 patients (66,6%). When PCR alone was performed (without GWc) in the first tap, repeated aqueous taps were needed, twice in five cases and thrice in one case. Conclusion: Combining PCR and GWc were very helpful to confirm the clinical diagnosis of CMV AU. In case of very high clinical suspicion and negative results, repeated tap seems to be recommended.

Cytomegalovirus (CMV) anterior uveitis is the most common ocular manifestation of CMV disease in immunocompetent individuals. It is thought to be due to a local reactivation of latent CMV and is usually unilateral. The acute form presents as Posner-Schlossman Syndrome, a recurrent hypertensive anterior uveitis with few granulomatous keratic precipitates. There are geographic differences in the chronic form of CMV anterior uveitis. Asian patients commonly present as Fuchs Uveitis Syndrome with diffuse stellate keratic precipitates, while the European patients present with a chronic hypertensive anterior uveitis with fewer keratic precipitates that are brownin color and located inferiorly. Characteristic features of CMV anterior uveitis include mild anterior chamber inflammation, elevated intraocular pressure, stromal iris atrophy. Synechiae, macular edema and retinitis are typically absent. CMV disease may also be associated with the development of corneal endotheliitis with a reduced endothelial cell count. Longterm complications include glaucomatous optic neuropathy and cataract formation.

Diagnosis of uveitis is often challenging, but can be easy in typical viral-induced anterior uveitis (VIAU). Associated symptoms and signs are an important source of information. Certain classical clinical features such as keratic precipitates (KPs) distribution, iris atrophy, elevated intraocular pressure (IOP), and unilaterality are commonly used to support the diagnosis of VIAU. However, many etiologies of anterior uveitis may to a certain extent mimic VIAU, especially the ones with unilateral granulomatous KPs and elevated IOP. This review begins with how the clinician can differentiate viral from nonviral anterior uveitis, and subsequently focuses on the key features which may aid in differentiating among the different viruses that cause VIAU.