Intraocular immune response in human uveitis: time to look beyond animal models.

PURPOSE: To review the current and future approaches to investigating the intraocular immune response in human uveitis. DESIGN: Perspective METHODS: Review of currently available methods for investigating the immune response in ocular tissues and fluids in patients with intraocular inflammation/ uveitis. The advantages and disadvantages of human studies have been compared to those of animal models of uveitis. RESULTS: Animal models, while being excellent tools for mechanistic studies, do not replicate the clinical and immunological heterogeneity of human uveitis. Opportunities for immunological studies in human uveitis are mostly limited to histological studies, or sampling of intraocular fluids and peripheral blood. Histopathological studies can be enhanced by revisiting published historical data, tissue repositories or autopsy specimens. Intraocular fluids can be investigated by a variety of techniques. Among these, flow cytometry and single cell RNA sequencing (scRNAseq) provide single cell resolution. While the current technology is costly and labor-intensive, scRNAseq is less limited by the low cellular yield from intraocular fluids and allows unbiased immune profiling enabling discovery of new cellular subsets. Immunological phenotypes uncovered from human data can be further investigated in animal studies. CONCLUSION: The diversity of the intraocular immune response in uveitis patients remains challenging but can be studied by multiple techniques including histopathology, flow cytometry and scRNAseq. Human data can be combined with animal studies for translating uveitis research into novel therapies.

Treatment Outcomes of Intravitreal Aflibercept for Uveitic Macular Edema.

BACKGROUND/AIMS: To evaluate the efficacy of intravitreal aflibercept for UME (uveitic macular). METHODS: A retrospective review of records of patients that received aflibercept for UME from January 2017 to August 2022 was conducted. The primary outcomes were mean change in visual acuity (VA) and central subfield thickness (CST) 6 and 12 months from the start of aflibercept treatment. RESULTS: A total of 16 eyes of 12 patients were included. Indications for treatment included eyes that had previously demonstrated a history of elevated intraocular pressure secondary to a steroid response (n = 10) or a history of non-response or partial response to local corticosteroids (n = 6). Fifteen eyes (94%) demonstrated a reduction in CST after their initial injection. At 6-months, mean VA gain was 2.6 ± 7.7 letters (p = 0.24) from a mean VA of 67.8 ± 10.7 letters at baseline and mean CST improved by 97.6 ± 113.5 µm (p = 0.004) from 458.6 ± 123.1 µm at baseline. Fourteen eyes had 12-months of follow up and received a median of 4 injections over 12 visits. The mean VA at 12-months remained stable compared to baseline (mean change of -1.4 ± 12.5 letters (p = 0.87)) while the CST improved by a mean of 90.9 ± 114.6 µm (p = 0.053) compared to baseline. CONCLUSION: Intravitreal aflibercept injections resulted in reduced central subfield thickness at all time-points. It appears to be an effective treatment alternative for UME, particularly for patients who are not responsive to local corticosteroids or who have contraindications to corticosteroid treatment.

Herpes Zoster Chorioretinopathy: A Case Series.

PURPOSE: To report two patients with herpetic zoster panuveitis and chorioretinopathy with choroidal hypopigmentation. METHODS: Retrospective chart review of two patients. RESULTS: We report a series of two patients with a history of HZO with orbital inflammation and panuveitis, who developed patchy choroidal depigmentation consistent with a choroidopathy. The lesions were extensive and involved the posterior pole and mid-periphery in both cases. Both cases demonstrated scattered areas of ellipsoid zone loss, and fluorescein angiography showed corresponding late hyperfluorescence. OCTA in one case demonstrated flow voids at the level of choriocapillaris. CONCLUSIONS: Our series suggests that herpetic chorioretinopathy may be a relatively benign process that presents late and may involve large areas of the posterior choroid.

Ultrawide-field fluorescein angiography features in patients with anterior uveitis.

PURPOSE: To evaluate the utility of ultrawide-field fluorescein angiography (UWFFA) in patients with anterior uveitis by investigating the detection of retinal vascular leakage (RVL) and the subsequent implications on disease diagnosis and management. STUDY DESIGN/MATERIALS AND METHODS: Patients, who were referred to the National Eye Institute (NEI) for evaluation of anterior uveitis and underwent UWFFA imaging at the initial visit, were included in this study. The electronic medical records of eligible patients were reviewed. The UWFFA images were assessed for severity of retinal vascular leakage, presence of macular leakage, and optic disc leakage by a two-grader system, and intergrader agreement was calculated using the κ-value. Patients with altered diagnoses and management attributable to UWFFA results were noted. RESULTS: A total of 93 eyes of 63 patients were included in the study. Of 93 eyes, 31 (33.3%) eyes had RVL on UWFFA, with 26 (28.0%) eyes and 5 (5.4%) eyes showing mild and moderate-severe RVL, respectively. Twenty-five (26.9%) eyes showed macular leakage, and 7 (7.5%) eyes showed optic disc leakage. The κ-values ranged from 0.85 - 0.87 indicating excellent intergrader agreement. Of the 31 eyes with RVL, the diagnosis was changed to anterior/intermediate uveitis for 9 (29.0%) eyes and to panuveitis for 4 (12.9%) eyes. Systemic treatment was escalated in 5 patients. CONCLUSION: Our results suggest that UWFFA imaging is useful in detecting subclinical posterior involvement in patients with anterior uveitis. Moreover, UWFFA results in altered diagnosis and treatment approaches in a portion of patients.

Indocyanine Green Angiography of Optic Disc Granuloma in Ocular Sarcoidosis.

PURPOSE: To report novel indocyanine green angiography (ICG) findings of optic disc granulomas secondary to sarcoidosis. METHODS: Observational case report. RESULTS: A 36-year-old white male, who had previously been evaluated for birdshot chorioretinopathy and tested HLA-A29 negative, was referred for evaluation of choroidal lesions in both eyes. Fundus examination revealed ovoid choroidal lesions bilaterally in the posterior pole. Optical coherence tomography demonstrated bilateral focal choroidal elevations in the posterior pole and optic discs consistent with granulomas. ICG revealed diffuse choroidal hypocyanescent spots with late-phase focal hypercyanescence of the optic discs in both eyes corresponding to the granulomas. After three months of prednisone and immunomodulatory treatment, the granulomas improved and the optic disc hypercyanescence resolved. CONCLUSION: We describe a case of ocular sarcoidosis mimicking birdshot-like lesions, and ICG findings revealed late hypercyanescence, which resolved with treatment.

Treatment of Intermediate Uveitis-associated Retinal Vasoproliferative Tumors: A Case Series.

PURPOSE: To report the use of combination intravitreal pharmacotherapy using anti-vascular endothelial growth factor (VEGF) and short and long-term corticosteroid implants for the treatment of retinal vasoproliferative tumors (VPT) associated with intermediate uveitis. METHODS: Retrospective chart review of patients with VPT secondary to idiopathic intermediate uveitis that underwent combination intravitreal pharmacotherapy at a single center was performed. Multimodal imaging including ultrawide field color fundus photography, ultrawide field fluorescein angiography, and optical coherence tomography obtained before and after treatment were reviewed. RESULTS: Four eyes of 4 patients were treated with multiple injections of a combination of aflibercept, dexamethasone, and fluocinolone acetonide implants for VPT associated with intermediate uveitis. All 4 patients had improvement in visual acuity, intraocular inflammation, central macular thickness, and retinal vascular leakage, as well as regression of the VPT and reduction in lesion leakage on follow-up. CONCLUSION: Combination intravitreal anti-VEGF and corticosteroid implants may be a useful approach for the treatment of intermediate uveitis-associated VPTs and can lead to both functional and structural improvement.

Hypotony Maculopathy Associated With Extruded Fluocinolone Acetonide Intravitreal Implant.

This case report discusses a diagnosis of hypotony maculopathy associated with extrusion of a fluocinolone intravitreal implant in a patient who presented with painless, decreased vision in the right eye.

Bilateral Exudative Retinal Detachments and Panuveitis in a Patient with Multiple Myeloma.

PURPOSE: To report a case of bilateral exudative retinal detachments and panuveitis in a patient with multiple myeloma (MM). CASE REPORT: A 54-year-old patient with non-proliferative diabetic retinopathy was referred with blurred vision and scotomas in both eyes (OU). Three months prior to the onset of ocular symptoms, he was diagnosed with systemic MM and was receiving chemotherapy. Clinical examination revealed best-corrected visual acuities of 20/80 OU, rare anterior chamber cell, 2+ vitreous cell, diffuse intraretinal hemorrhages, and exudative retinal detachments (RD). Optical coherence tomography of the macula showed central subretinal fluid with cystic intraretinal fluid OU. The findings were consistent with panuveitis and exudative RD in the setting of MM. He reported symptomatic improvement after plasmapheresis and oral prednisone initiation. CONCLUSION: Extensive, bilateral exudative RD and panuveitis are rare but potentially sight-threatening findings in patients with MM.

Extensive Subretinal Fibrosis Associated with Pseudoxanthoma Elasticum.

PURPOSE: To report an unusual case of pseudoxanthoma elasticum (PXE) presenting with an inflammatory phenotype associated with atypical and rapidly progressive subretinal fibrosis. METHODS: Observational case report. RESULTS: A patient with a history of pseudoxanthoma elasticum presented with rapidly progressive subretinal fibrosis, particularly in the left eye, over the course of one year. The patient was noted at presentation to have intraocular inflammation, outer retinal attenuation, multifocal choroiditis-like lesions, and intraretinal fluid (in the absence of obvious clinical or angiographic signs of exudative CNVM). An ocular inflammatory phenotype was diagnosed, and the patient was treated with a combination of local steroids and systemic corticosteroids/immunomodulatory agents. After initiation of these agents, there was demonstrated functional and structural improvement, with partial outer retinal reconstitution, decreased intraretinal fluid, and lack of further progression of subretinal fibrosis. CONCLUSION: This report describes an inflammatory phenotype of PXE associated with severe and atypical subretinal fibrosis. This case expands upon the currently known spectrum of inflammatory phenotypes associated with PXE. Treatment with corticosteroids or immunomodulatory treatment should be considered in similar cases.

Central retinal vein occlusion associated with Bartonella henselae infection.

PURPOSE: To report the clinical features and treatment course of a case of central retinal vein occlusion (CRVO) as the initial sign of ocular Bartonella henselae (B. henselae) infection. OBSERVATION: A 36-year-old male was evaluated for unilateral vision loss. He denied prodromal symptoms but reported prior exposure to fleas. Best corrected visual acuity (BCVA) was 20/400 in the left eye. Clinical examination revealed a CRVO with atypical features including significant peripapillary exudates and peripheral vascular sheathing. Laboratory testing revealed elevated B. henselae IgG titers (1:512) with no abnormalities on hypercoagulability testing. The patient was treated with doxycycline and aflibercept with an excellent clinical response and improvement in BCVA to 20/25 in the left eye two months later. CONCLUSION: CRVO is a rare but sight-threatening complication of ocular bartonellosis and can be the presenting sign of infection, even in the absence of cat exposure or prodromal symptoms.

Histopathology and SARS-CoV-2 Cellular Localization in Eye Tissues of COVID-19 Autopsies.

Ophthalmic manifestations and tissue tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in association with coronavirus disease 2019 (COVID-19), but the pathology and cellular localization of SARS-CoV-2 are not well characterized. The objective of this study was to evaluate macroscopic and microscopic changes and investigate cellular localization of SARS-CoV-2 across ocular tissues at autopsy. Ocular tissues were obtained from 25 patients with COVID-19 at autopsy. SARS-CoV-2 nucleocapsid gene RNA was previously quantified by droplet digital PCR from one eye. Herein, contralateral eyes from 21 patients were fixed in formalin and subject to histopathologic examination. Sections of the droplet digital PCR-positive eyes from four other patients were evaluated by in situ hybridization to determine the cellular localization of SARS-CoV-2 spike gene RNA. Histopathologic abnormalities, including cytoid bodies, vascular changes, and retinal edema, with minimal or no inflammation in ocular tissues were observed in all 21 cases evaluated. In situ hybridization localized SARS-CoV-2 RNA to neuronal cells of the retinal inner and outer layers, ganglion cells, corneal epithelia, scleral fibroblasts, and oligodendrocytes of the optic nerve. In conclusion, a range of common histopathologic alterations were identified within ocular tissue, and SARS-CoV-2 RNA was localized to multiple cell types. Further studies will be required to determine whether the alterations observed were caused by SARS-CoV-2 infection, the host immune response, and/or preexisting comorbidities.

Antidrug Antibodies to Tumor Necrosis Factor α Inhibitors in Patients With Noninfectious Uveitis.

Importance: Tumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the association between ADAs and treatment response in patients with noninfectious uveitis (NIU) is not well understood. Objective: To assess the frequency of ADAs and their association with drug levels and clinical response in patients with NIU treated with adalimumab or infliximab. Design, Setting, and Participants: This retrospective cross-sectional study included patients diagnosed with NIU who received adalimumab or infliximab and underwent testing for serum drug level and ADAs at the National Eye Institute from September 2017 to July 2021. Exposures: Serum drug level testing with reflex testing for ADA levels was performed. Main Outcomes and Measures: The main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU. Results: Of 54 patients included in the study, 42 received adalimumab (mean [SD] age, 43.6 [19.6] years; 25 [59.5%] female) and 12 received infliximab (mean [SD] age, 42.7 [20.4] years; 7 [58.3%] male). In the adalimumab group, mean (SD) drug level was 9.72 (6.82) µg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients). Mean drug level was lower in those with ADAs compared with those without ADAs (mean [SD], 2.8 [2.6] µg/mL vs 13.6 [5.2] µg/mL; difference: 10.8 µg/mL; 95% CI, 8.3-13.2 µg/mL; P < .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (mean [SD], 11.0 [7.3] µg/mL vs 6.8 [4.5] µg/mL; difference: -4.2 µg/mL; 95% CI, -8.7 to 0.2 µg/mL; P = .06). Multivariable modeling showed that a 1-arbitrary unit increase in ADAs was associated with a -0.02 µg/mL (95% CI, -0.01 to -0.34 µg/mL) difference in mean drug level (P < .001). Favorable clinical response was associated with a threshold drug level above 2.7 µg/mL or an antibody level below 15.2 µg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) µg/mL, and no ADAs were detected. Conclusions and Relevance: In this study, 35.7% of adalimumab-treated patients with NIU had ADAs. The presence of ADAs was associated with lower drug levels, and higher ADA levels were associated with increased risk of TNFi treatment failure. Although limited by the retrospective design, our results suggest that therapeutic drug monitoring may be considered among patients experiencing therapy failure to help exclude ADAs as a potential cause of treatment failure.

Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy.

PURPOSE: We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy. DESIGN: Single-center observational case study. PARTICIPANTS: Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included. METHODS: Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing. MAIN OUTCOME MEASURES: Visual acuity, electrophysiology, fluorescein angiography, and OCT findings. RESULTS: Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33-5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography. CONCLUSIONS: Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Bilateral Acute Macular Neuroretinopathy after COVID-19 Vaccination and Infection.

PURPOSE: To describe a case of acute macular neuroretinopathy (AMN) in a patient with recent COVID-19 vaccination and infection who demonstrated atypical features on presentation. OBSERVATIONS: A 64-year-old woman presented with central vision loss in both eyes (OU). She had recently received the Moderna COVID-19 vaccine and rapidly developed systemic symptoms. Testing revealed COVID-19 infection. Visual acuities were 20/200 OU and near-infrared reflectance revealed hypo-reflective lesions in the maculae OU, optical coherence tomography (OCT) showed outer nuclear layer thinning and ellipsoid zone disruption OU, and OCT-angiography showed flow voids in the deep capillary plexus and choriocapillaris OU, all consistent with AMN. She was treated with oral prednisone with subsequent mild vision improvement and persistent scotomas. DISCUSSION: COVID-19 associated AMN can present with a more severe clinical presentation than classically seen in AMN. Ischemic and inflammatory changes due to COVID-19 infection may contribute to this more advanced presentation.

Impact of the COVID-19 pandemic on uveitis patient care.

BACKGROUND: The COVID-19 pandemic has significantly changed practice of medicine and patient care worldwide. The impact of the pandemic on patients with uveitis is unknown. We developed the COVID-19 Practice Patterns Study Group to evaluate the effect of the pandemic on uveitis patient care. METHODS: This is a multicentre, cross-sectional survey of uveitis specialists practising worldwide. A web-based survey was distributed through the mailing lists of international uveitis societies to assess modifications in patient care, and use of immunomodulatory therapies (IMTs),aswell as considerations regarding COVID-19 vaccination. RESULTS: A diverse group consisting of 187 uveitis specialists from six continents participated in this survey. Most of these experts noted a disruption in clinical management of patients, including clinic closures or decrease in volume, patients missing in-person visits due to the fear of infection and difficulties obtaining laboratory testing. Most participants initiated (66.8%) and continued (93.3%) IMTs based on clinical presentation and did not modify their use of immunosuppressives. In cases of reported exposure to COVID-19 infection, most participants (65.3%) recommended no change in IMTs. However, 73.0% of the respondents did recommend holding all or select IMTs in case of COVID-19 infection. COVID-19 vaccine was recommended universally by almost all the specialists and 52% stated that they would counsel patients regarding the decreased immunogenicity and effectiveness of the vaccine in immunocompromised patients. CONCLUSIONS: Uveitis patient care has changed significantly since the beginning of the pandemic. The recommendations will continue to evolve as new data on IMTs and vaccination become available.

Ocular symptoms in COVID-19 infection: a survey study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) systemic symptoms and sequelae have been studied extensively, but less is known about the characterization, duration, and long-term sequelae of ocular symptoms associated with COVID-19 infection. The purpose of this study was to analyze the frequency, spectrum, and duration of ocular symptoms in participants with COVID-19 infection treated in inpatient and outpatient settings. METHODS: A retrospective electronic survey was distributed to NIH employees and the public who reported testing positive for SARS-CoV-2. The anonymous survey collected information on demographics, past ocular history, systemic COVID-19 symptoms, and ocular symptoms. RESULTS: A total of 229 (21.9% male and 78.1% female, mean age 42.5 ± 13.9) survey responses were included. Ocular symptoms were reported by 165 participants with a mean of 2.31 ± 2.42 symptoms. The most commonly reported ocular symptoms were light sensitivity (31.0%), itchy eyes (24.9%), tearing (24.9%), eye redness (24.5%), and eye pain (24.5%). Participants with ocular symptoms had a higher number of systemic symptoms compared to participants without ocular symptoms (mean 9.17 ± 4.19 vs 6.22 ± 3.63; OR: 1.21; 95% CI: 1.11 - 1.32; p < 0.001). Ocular symptoms were more common in those who reported a past ocular history compared to those who did not (81.8% vs 67.1%; OR: 2.17; 95% CI: 1.08 - 4.37; p = 0.03). Additionally, the onset of ocular symptoms occurred most frequently at the same time as systemic symptoms (47.5%), and 21.8% reported symptoms lasting ≥ 14 days. CONCLUSIONS: Ocular surface-related symptoms are the most frequent ocular manifestations, and systemic disease severity is associated with the presence of ocular symptoms. Additionally, our results show that ocular symptoms can persist post-COVID-19 infection. Further work is needed to better understand ocular symptoms in COVID-19 and long-term sequelae.

Recurrent Multiple Evanescent White Dot Syndrome (MEWDS) Following First Dose and Booster of the mRNA-1273 COVID-19 Vaccine: Case Report and Review of Literature.

To report a rare case of a patient with two recurrent episodes of Multiple Evanescent White Dot Syndrome (MEWDS) associated with the second dose and second booster of the mRNA-1273 COVID-19 vaccine (Moderna), and to perform a literature review on COVID-19-vaccine-associated MEWDS. Case Report: A 31-year-old female was evaluated for a temporal scotoma and photopsias that started two weeks after the second dose of the Moderna COVID-19 vaccine. Dilated fundus findings were remarkable for unilateral, small whitish-yellow dots scattered around posterior pole of the left eye, consistent with a diagnosis of MEWDS. The symptoms resolved three months later without treatment. Approximately one year after the first vaccine, the patient received the second Moderna COVID-19 vaccine booster and experienced a recurrence of symptoms with an enlarged scotoma and similar examination findings. The patient was treated with a course of systemic corticosteroids with subsequent clinical improvement. Conclusion: Although uveitis following COVID-19 vaccines is rare, our case highlights a need for increased awareness amongst practitioners regarding COVID-19-vaccine-associated onset or recurrence of ocular inflammatory diseases.

Assessment of Retinal Changes Following Intravitreal Aflibercept in 2 Patients With Von Hippel-Lindau Disease-Related Retinal Capillary Hemangioblastoma.

This case report of 2 patients describes peripheral Von Hippel-Lindau disease associated with a series of aflibercept injections.

Isolated Optic Disc Granuloma as a Presenting Sign of Sarcoidosis.

PURPOSE: To report a case of an optic disc granuloma secondary to sarcoidosis in the absence of any systemic symptoms nor evident signs of intraocular inflammation at the time of presentation. METHODS: Retrospective case report. RESULTS: A 59-year-old Caucasian woman with previously unrevealing systemic work up was referred to the uveitis service for persistent optic disc edema of the right eye for over 1 year. Fundoscopic examination revealed an optic disc granuloma with associated hyper-reflectivity on OCT and high surface reflectivity with medium internal reflectivity on B-scan ultrasound. CT chest was negative, however, a PET scan demonstrated extensive FDG activity in the mediastinum and bilateral hilum, consistent with a diagnosis of sarcoidosis. CONCLUSION: Optic nerve head granulomas can rarely present as the only clinical sign of sarcoidosis. In these cases, additional imaging modalities may be needed to make the appropriate diagnosis.