Importance of Baseline Fluorescein Angiography for Patients Presenting to Tertiary Uveitis Clinic.

PURPOSE: To ascertain whether the use of ultra-wide-field fluorescein angiography (UWFFA) at baseline visit alters the assessment of disease activity and localization, as well as the management of patients presenting to a tertiary uveitis clinic. DESIGN: Retrospective comparison of diagnostic approaches. METHODS: Baseline visits of 158 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were evaluated by three uveitis-trained ophthalmologists (I.K., A.B., and H.G.). Each eye had undergone clinical examination along with ultra-wide-field fundus photography (UWFFP) (Optos Plc, Dunfermline, Scotland, UK), spectral-domain optical coherence tomography (SD-OCT, Spectralis Heidelberg, Heidelberg Engineering, Heidelberg, Germany) and UWFFA (Optos Plc, Dunfermline, Scotland, UK) at the baseline visit. Investigators were asked to successively determine disease activity, localization of disease (anterior, posterior or both), and management decisions based on clinical examination and UWFFP and SD-OCT (Set 1) and Set 1 plus UWFFA (Set 2). The primary outcome was the percentage of eyes whose management changed based on the availability of UWFFA, compared with Set 1. RESULTS: The mean age of the patients was 46.9±22.4 (range, 7-96) and 91 (57.6%) were female. With Set 1 alone, 138 (55.2%) eyes were found to have active disease; localization was anterior in 58 (42.0%) eyes, posterior in 53 (38.4%) eyes and anterior + posterior in 27 (19.6%) eyes. With Set 2, 169 eyes of 107 patients had active anterior, posterior or pan-uveitis. In comparison with Set 1, assessment with Set 2 identified additional 31 (18.3%) eyes with active disease (p=0.006), and additional 31 (18.3%) eyes having disease in both anterior + posterior segments (p<0.001). Regarding the primary outcome, management was changed in 68 (27.4%) eyes in Set 2, compared to Set 1. CONCLUSION: Baseline UWFFA may alter assessment of disease activity, localization, and management decisions compared to clinical examination with only UWFFP and SD-OCT for eyes with uveitis. Thus, UWFFA may be considered as an essential tool in the evaluation of uveitis patients at the baseline visit.

Risk factors for development of anti-adalimumab antibodies in non-infectious uveitis.

Purpose: To evaluate risk factors associated with development of anti-adalimumab antibodies (AAA) in patients with non-infectious uveitis treated with adalimumab. Methods: A retrospective, cross-sectional, case-control study was done evaluating patients with non-infectious uveitis treated with adalimumab for at least 12 months and have undergone testing for AAA levels. Demographics, clinical characteristics, grading of ocular inflammation, and previous and concomitant immunomodulatory therapy were assessed. Univariate and multivariate analysis were done to estimate odds ratio (OR) with 95% confidence intervals for the various risk factors. Results: A total of 31 patients were included in the analysis, in which 12 patients who tested positive (Group 1) were matched with 19 patients who tested negative for AAA (Group 2). The groups differed significantly in terms of sex (female) (91.7% vs 52.6%, p = 0.046), presence of systemic disease (91.7% vs 42.1%, p = 0.008), and presence of anterior chamber inflammation at baseline (100% vs 63.2%, p = 0.026). A history of interruption in anti-TNF therapy prior to starting or restarting adalimumab was found to have an increased odds for development of AAA (OR 16.89 [2.92, 107.11], p = 0.008), as well as flare-ups (reactivation of disease) during adalimumab therapy (OR 6.77 [1.80, 61.80], p = 0.027). Weekly dosing of adalimumab was shown to decrease odds of AAA development (OR 0.34 [0.02, 0.70], p = 0.040), while concomitant anti-metabolite therapy was not shown to be a statistically significant protective factor (OR 2.22 [0.50, 9.96], p = 0.148). Conclusions: History of interruption in anti-TNF therapy and flare during adalimumab were associated with development of AAA, while weekly dosing of adalimumab was protective against AAA. Identification of those with higher risk of developing AAA may guide in clinical decision making to optimize management for these patients.

Intravenous cyclophosphamide therapy for patients with severe ocular inflammatory diseases who failed other immunomodulatory therapies.

BACKGROUND: Ocular inflammatory diseases, including scleritis and uveitis, have been widely treated with immunomodulatory therapies (IMTs) as a steroid-sparing approach. Such strategy includes conventional therapies (antimetabolites, alkylating agents, and calcineurin inhibitors) as well as biologic agents like adalimumab, infliximab, rituximab, and tocilizumab. Cyclophosphamide (CP) is an alkylating agent and mainly inhibits the functioning of both T and B cells. Though known to have potential adverse events, including bone marrow suppression, hemorrhagic cystitis, and sterility, CP has been shown to be efficacious, especially in recalcitrant cases and when used intravenous (IV) for a limited period. MAIN FINDINGS: We conducted a retrospective case-series to assess the safety and efficacy of CP therapy for patients with severe ocular inflammatory diseases who failed other IMTs. Medical records of 1295 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were reviewed. Seven patients (10 eyes) who received CP therapy for ocular inflammatory diseases with at least one year of follow-up were included. The mean age of the patients (4 males, 3 females) was 61.6 ± 14.9 (43.0-89.0) years. Clinical diagnoses included necrotizing scleritis (5 eyes), peripheral ulcerative keratitis (2 eyes), orbital pseudotumor (1 eye), HLA-B27 associated panuveitis and retinal vasculitis (2 eyes). Ocular disease was idiopathic in 3 patients, and was associated with rheumatoid arthritis, IgG-4 sclerosing disease, dermatomyositis, and ankylosing spondylitis in 1 patient each. All the patients had history of previous IMT use including methotrexate (5), mycophenolate mofetil (3), azathioprine (1), tacrolimus (1), adalimumab (2), infliximab (4), and rituximab (1). The mean follow-up time was 34.4 ± 11.0 (13-45) months, and mean duration of CP therapy was 11.9 ± 8.8 (5-28) months. Remission was achieved in 5 patients (71.4%). Four patients (57.1%) experienced transient leukopenia (white blood cell count < 4000/mL). SHORT CONCLUSION: CP therapy can be considered a potentially effective and relatively safe therapeutic option for patients with severe ocular inflammatory diseases who failed other IMTs including biologics (TNFa and CD20 inhibitors).

Challenges for further successful development of tumor necrosis factor targeting therapies for uveitis.

INTRODUCTION: Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract and is one of the leading causes of vision impairment. In developed countries, noninfectious uveitis (NIU) represents most cases and is challenging to treat due to its severity, chronicity, and high recurrence rates. The advent of anti-tumor necrosis factor-α (anti-TNF-α) agents have dramatically improved outcomes and changed treatment paradigms in NIU. AREAS COVERED: The index article summarizes the present experience of anti-TNF-α agents in NIU pharmacotherapy and highlights the barriers to further research and development of anti-TNF-α agents for uveitis. Common challenges faced in NIU clinical drugs trials, specific difficulties in anti-TNF-α drug development, and promising competitor drug candidates are discussed and evaluated. EXPERT OPINION: Anti-TNF-α agents have revolutionized NIU pharmacotherapy and greatly improved outcomes with good safety profiles. The great success of systemic infliximab and adalimumab in NIU treatment has resulted in little impetus for further development of this class of medication. Attempts have been made to deliver anti-TNF-α agents intravitreally but that has not been successful thus far. With expiring patents, competition from biosimilars and newer, novel molecules, it may not be viable to continue pursuing anti-TNF-α drug development.

The Role of Corticosteroids and Immunomodulatory Therapy in the Management of Infectious Uveitis.

PURPOSE: The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis. METHOD: Narrative literature review. RESULTS: Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids. CONCLUSION: There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.

Ocular manifestations and clinical outcomes in Tubulointerstitial Nephritis and Uveitis Syndrome (TINU).

PURPOSE: To describe the various ocular clinical features and visual outcomes in Tubulointerstitial Nephritis and Uveitis Syndrome (TINU). METHODS: The medical records of 13 patients (26 eyes) diagnosed with TINU were reviewed. RESULTS: Twenty-six (26) eyes of 13 patients with TINU were reviewed in this study. The median age at onset of uveitis was 14 (range, 9-45). Eight (61.5%) subjects were female. The median follow-up of patients was 30 months (range, 6-89 months). Posterior segment findings were seen in 18 eyes of 9 patients (69.2%). The most common posterior findings were optic nerve head inflammation (16 eyes, 88.8%) and retinal vasculitis (13 eyes, 72.2%). Other posterior findings included vitritis (8 eyes, 44.4%), macular edema (6 eyes, 33.3%), snowball (4 eyes, 22.2%), and chorioretinal lesions (2 eye, 11.1%). Eight patients had fluorescein angiography (FA) data available and most eyes had retinal capillary leakage (13 eyes, 81.2%) followed by optic disc staining/leakage (12 eyes, 75%). Twelve (12) patients (92.3%) were treated with immunomodulatory treatment (IMT) and/or biologics. Five patients (%38.4) required biologics to control intraocular inflammation. CONCLUSION: Posterior segment involvement may be common in patients with TINU syndrome. FA provides significant information for detecting posterior segment involvement and disease activity in TINU. The majority of patients required systemic treatment in order to control intraocular inflammation and prevent relapses.

Ocular Ischemic Syndrome in the Setting of Normal Carotid Duplex Ultrasound.

PURPOSE: To describe two cases of ocular ischemic syndrome (OIS) that were initially ruled out due to a negative carotid duplex ultrasound (DUS) but eventually confirmed by angiography studies. METHODS: Case series. RESULTS: Case 1: A 67-year-old female presented with symptoms suggestive of OIS, but carotid DUS was negative, and the patient was diagnosed with occlusive retinal vasculitis due to retinal non-perfusion and vascular leakage on fluorescein angiography (FA). Immunosuppressive therapy was initiated but her symptoms did not improve. Computerized tomography angiography (CTA) was significant for severe osteal stenosis of the aortic arch vessels. Left common carotid angioplasty and stenting resulted in complete resolution of the symptoms and vascular leakage of the left eye. Case 2: A 41-year-old male with cryoglobulinemia-associated vasculitis complained of symptoms consistent with OIS, which was initially ruled out through a negative carotid DUS. FA revealed delayed arterial filling with poor retinal perfusion. Magnetic resonance angiography (MRA) revealed ophthalmic artery stenosis which was attributed to the underlying systemic vasculitis. CONCLUSION: CTA or MRA should be performed to rule out OIS if DUS is negative in the setting of high clinical suspicion. Carotid ostial and ophthalmic artery stenoses are rare but possible causes of OIS.

Structural and Functional Changes in Non-Paraneoplastic Autoimmune Retinopathy.

BACKGROUND: To describe longitudinal changes in patients with non-paraneoplastic autoimmune retinopathy (npAIR) by utilizing different diagnostic modalities/tests. METHODS: The index study is a retrospective longitudinal review of sixteen eyes of eight patients from a tertiary care eye hospital diagnosed with npAIR. Multiple diagnostic modalities such as wide-angle fundus photography (WAFP), WA fundus autofluorescence (WAFAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann visual field (GVF) perimetry, microperimetry (MP), electrophysiologic testing, and adaptive optics scanning laser ophthalmoscopy (AOSLO) were reviewed and analyzed. RESULTS: At the baseline visits, anomalies were detected by multimodal diagnostic tests on all patients. Subjects were followed up for a median duration of 11.5 [3.0-18.7] months. Structural changes at the baseline were detected in 14 of 16 (87.5%) eyes on WAFP and WAFAF and 13 of 16 (81.2%) eyes on SD-OCT. Eight of the ten (80%) eyes that underwent AOSLO imaging depicted structural changes. Functional changes were detected in 14 of 16 (87.5%) eyes on GVF, 15 of 16 (93.7%) eyes on MP, and 11 of 16 (68.7%) eyes on full-field electroretinogram (ff-ERG). Multifocal electroretinogram (mf-ERG) and visual evoked potential (VEP) tests were performed in 14 eyes, of which 12 (85.7%) and 14 (100%) of the eyes demonstrated functional abnormalities, respectively, at baseline. Compared to all the other structural diagnostic tools, AOSLO had a better ability to demonstrate deterioration in retinal microstructures occurring at follow-ups. Functional deterioration at follow-up was detected on GVF in 8 of 10 (80%) eyes, mf-ERG in 4 of 8 (50%) eyes, and MP in 7 of 16 (43.7%) eyes. The ff-ERG and VEP were stable in the majority of cases at follow-up. CONCLUSIONS: The utilization of multimodal imaging/tests in the diagnosing and monitoring of npAIR patients can aid in identifying anomalous changes over time. Analysis of both the anatomical and functional aspects by these devices can be supportive of detecting the changes early in such patients. AOSLO shows promise as it enables the capture of high-resolution images demonstrating quantifiable changes to retinal microstructure.

Pars plana vitrectomy with internal limiting membrane flap versus pars plana vitrectomy with conventional internal limiting membrane peeling for large macular hole.

BACKGROUND: Macular hole (MH) is a full-thickness defect in the central portion of the retina that causes loss of central vision. According to the usual definition, a large MH has a diameter greater than 400 µm at the narrowest point. For closure of MH, there is evidence that pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling achieves better anatomical outcomes than standard PPV. PPV with ILM peeling is currently the standard of care for MH management; however, the failure rate of this technique is higher for large MHs than for smaller MHs. Some studies have shown that the inverted ILM flap technique is superior to conventional ILM peeling for the management of large MHs. OBJECTIVES: To evaluate the clinical effectiveness and safety of pars plana vitrectomy with the inverted internal limiting membrane flap technique versus pars plana vitrectomy with conventional internal limiting membrane peeling for treating large macular holes, including idiopathic, traumatic, and myopic macular holes. SEARCH METHODS: The Cochrane Eyes and Vision Information Specialist searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries on 12 December 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated PPV with ILM peeling versus PPV with inverted ILM flap for treatment of large MHs (with a basal diameter greater than 400 µm at the narrowest point measured by optical coherence tomography) of any type (idiopathic, traumatic, or myopic). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane and assessed the certainty of the body of evidence using GRADE. MAIN RESULTS: We included four RCTs (285 eyes of 275 participants; range per study 24 to 91 eyes). Most participants were women (63%), and of older age (range of means 59.4 to 66 years). Three RCTs were single-center trials, and the same surgeon performed all surgeries in two RCTs (the third single-center RCT did not report the number of surgeons). One RCT was a multicenter trial (three sites), and four surgeons performed all surgeries. Two RCTs took place in India, one in Poland, and one in Mexico. Maximum follow-up ranged from three months (2 RCTs) to 12 months (1 RCT). No RCTs reported conflicts of interest or disclosed financial support. All four RCTs enrolled people with large idiopathic MHs and compared conventional PPV with ILM peeling versus PPV with inverted ILM flap techniques. Variations in technique across the four RCTs were minimal. There was some heterogeneity in interventions: in two RCTs, all participants underwent combined cataract-PPV surgery, whereas in one RCT, some participants underwent cataract surgery after PPV (the fourth RCT did not mention cataract surgery). The critical outcomes for this review were mean best-corrected visual acuity (BCVA) and MH closure rates. All four RCTs provided data for meta-analyses of both critical outcomes. We assessed the risk of bias for both outcomes using the Cochrane risk of bias tool (RoB 2); there were some concerns for risk of bias associated with lack of masking of outcome assessors and selective reporting of outcomes in all RCTs. All RCTs reported postoperative BCVA values; only one RCT reported the change in BCVA from baseline. Based on evidence from the four RCTs, it is unclear if the inverted ILM flap technique compared with ILM peeling reduces (improves) postoperative BCVA measured on a logarithm of the minimum angle of resolution (logMAR) chart at one month (mean difference [MD] -0.08 logMAR, 95% confidence interval [CI] -0.20 to 0.05; P = 0.23, I2 = 65%; 4 studies, 254 eyes; very low-certainty evidence), but it may improve BCVA at three months or more (MD -0.17 logMAR, 95% CI -0.23 to -0.10; P < 0.001, I2 = 0%; 4 studies, 276 eyes; low-certainty evidence). PPV with an inverted ILM flap compared to PPV with ILM peeling probably increases the proportion of eyes achieving MH closure (risk ratio [RR] 1.10, 95% CI 1.02 to 1.18; P = 0.01, I2 = 0%; 4 studies, 276 eyes; moderate-certainty evidence) and type 1 MH closure (RR 1.31, 95% CI 1.03 to 1.66; P = 0.03, I² = 69%; 4 studies, 276 eyes; moderate-certainty evidence). One study reported that none of the 38 participants experienced postoperative retinal detachment. AUTHORS' CONCLUSIONS: We found low-certainty evidence from four small RCTs that PPV with the inverted ILM flap technique is superior to PPV with ILM peeling with respect to BCVA gains at three or more months after surgery. We also found moderate-certainty evidence that the inverted ILM flap technique achieves more overall and type 1 MH closures. There is a need for high-quality multicenter RCTs to ascertain whether the inverted ILM flap technique is superior to ILM peeling with regard to anatomical and functional outcomes. Investigators should use the standard logMAR charts when measuring BCVA to facilitate comparison across trials.

ASSOCIATION OF ORAL MONTELUKAST WITH REDUCED ODDS OF DEVELOPING EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: This study was conducted to evaluate the association of oral montelukast, selective antagonism for cysteinyl leukotriene receptor 1, with reduced odds of exudative age-related macular degeneration (exAMD) development. METHODS: This case-control study was conducted using institutional cohort finder tool, and included 1913 patients with exAMD (ICD: H35.32 and 362.52) and 1913 age- and gender-matched control subjects without exAMD. Subanalysis among 1913 exAMD and 324 nonexudative AMD was also conducted. RESULTS: A total of 47 (2.5%) exAMD cases were identified to have a history of oral montelukast use before exAMD diagnosis, compared with 84 (4.4%) controls. Montelukast usage was significantly associated with reduced odds of exAMD in the multivariable analysis (adjusted odds ratio [OR]: 0.50, 95% confidence interval: 0.31-0.80) and nonsteroidal anti-inflammatory drug usage (adjusted OR: 0.69). Caucasian race, history of smoking, and nonexudative macular degeneration in either eye were also found to have a significant relationship with increased odds of exAMD. In the subanalysis, montelukast usage showed significant association with reduced odds of developing exAMD from nonexudative AMD (adjusted OR: 0.53, 95% confidence interval: 0.29-0.97) and the presence of atopic disease (adjusted OR: 0.60). CONCLUSION: The study results suggested that oral montelukast is linked to reduced odds of exAMD development.

Six-month outcomes of infliximab and tocilizumab therapy in non-infectious retinal vasculitis.

PURPOSE: To evaluate the efficacy of infliximab (IFX, 5-10 mg/kg) (Group 1) and tocilizumab (TCZ, 4-8 mg/kg) (Group 2) infusions in non-infectious retinal vasculitis (RV) using Angiographic Scoring for the Uveitis Working Group fluorescein angiography (FA) scoring system. METHODS: Records of 14 patients (24 eyes) in Group 1 and 8 patients (11 eyes) in Group 2 were retrospectively evaluated to assess visual acuity (VA), anterior chamber cell and flare, vitreous haze, central subfield thickness (CST), and FA scoring at baseline and 6 months of follow-up. The measurements were employed to grade in each group. RESULTS: In Group 1 and 2, respectively, there was no underlying disease in 9 (60%) and 3 (42.9%) patients. Three (42.9%) patients in Group 2 had juvenile idiopathic arthritis (JIA) as the most common identified cause. Mean improvement in VA (log MAR) and CST were 0.04 ± 0.14 and 40.3 ± 78.5 µm in Group 1; 0.04 ± 0.09 and 47.3 ± 82.3 µm in Group 2, respectively. Mean FA scores were significantly reduced from 12.4 ± 5.2 and 11.6 ± 4.4 at baseline to 6.4 ± 5.0 and 5.8 ± 3.9 at 6-month in Group 1 and 2, respectively. In Group 2, 9 eyes of 6 patients (75%) had the history of IFX use prior to TCZ initiation. There was no significant safety concern requiring treatment discontinuation during the follow-up in either group. CONCLUSION: IFX and TCZ infusions showed statistically significant improvement of non-infectious RV as shown by ASUWOG FA Scoring System. TCZ, as well as IFX, appeared to be effective treatment options for non-infectious RV.

Electroretinographic findings in retinal vasculitis.

AIM: To describe and correlate electroretinographic responses with clinical and angiographic findings in retinal vasculitis (RV). METHODS: Medical records of patients with diagnosis of RV at a tertiary eye centre from December 2017 to May 2021 were reviewed. Cases in which fluorescein angiography (FFA) and full field electroretinography (ffERG) were done within 1 month were included. FFAs were graded according to the Angiography Scoring for Uveitis Working Group from 0 to 40, where 0 is normal. A novel ffERG grading system was implemented where individual waves were graded for timing and amplitude and general ffERG score was determined with 6 being a perfect score. RESULTS: 20 patients (34 eyes) were included. Mean age was 43.9±19.8 years; 70% were female. Median best-corrected visual acuity was 0.8 (0.08-1). Mean FFA score was 12.6±6.5. Median general ffERG score was 5 (0-6). 68% and 91% of eyes had responses with general ffERG scores ≥5 and 4, respectively. Flicker timing was most commonly affected.FFA scores weakly correlated with delayed photopic cone b-wave and flicker timing (p=0.03 and 0.016, respectively). Vitreous haze moderately correlated with delayed cone b-wave timing (p<0.001), delayed flicker timing (p=0.002) and weakly correlated with lower flicker amplitude (p=0.03). Underlying systemic disease was associated with poor ffERG responses. CONCLUSION: In this study, RV was not frequently associated with severe global retinal dysfunction Higher FFA scores, and vitreous haze grading were weakly, but significantly, correlated with cone-generated ffERG responses.

Neurosarcoidosis, Coccidioidomycosis, or Both!

Purpose: To report a case of neurosarcoidosis (NS) who was initially diagnosed as Coccidioidomycosis immitis (CI) infection. Observations: A 57-year-old diabetic man presented with sudden painless diminution of vision, metamorphopsia, and color vision deficits in the left eye (OS) for one month. His vision was 20/20 in the right eye (OD) and 20/40 OS. Ophthalmic examination revealed left relative afferent pupillary defect, blurred optic nerve margin, creamy chorioretinal infiltration around the optic disc, and mild macular edema. OD examination was non-revealing. Chest CT scan with contrast showed calcified mediastinal lymph nodes, but biopsy of the lymph nodes was normal. Brain and orbit MRI demonstrated soft tissue abnormality with enhancement in left orbital apex with involvement of the extraocular muscles. CSF culture was negative, but complement fixation had positive titer of 1:2 for CI. The patient was diagnosed with CI meningitis, and antifungal therapy was initiated. Slight visual and symptomatic improvement was observed, which was not completely satisfactory. Biopsy of extraocular orbital muscle five months later revealed non-caseating granulomatous inflammation, leading to initiation of prednisone trial therapy. Nine months later, the patient was referred to a tertiary center owing to persistence of optic disc edema OS. PET CT was consistent with a diagnosis of sarcoidosis. Antifungal treatment was discontinued, and oral prednisone with methotrexate was initiated. Subsequently, methotrexate was replaced by infliximab to further manage ocular inflammation and neurologic symptoms which was effective. Vision was 20/20 OD and 20/30 OS at the most recent visit. Conclusion and Importance: Signs and symptoms of neurosarcoidosis and coccidioidomycosis can be similar and deceiving. The index case underscores importance of considering appropriate differential diagnoses in patients with similar symptoms and signs who may respond to preliminary designated treatment but not to the optimal extent. Considering such possibility could assist clinicians in managing the patients timely and efficiently.

Efficacy and Safety of Tocilizumab in the Management of Non-Infectious Uveitis Failed with Conventional Immunomodulatory and Anti-TNFα Therapies.

PURPOSE: To determine the outcomes of intravenous (IV) tocilizumab (TCZ) in patients with non-infectious uveitis who failed with conventional immunomodulatory and anti-TNFα therapies. METHODS: Records of seven patients with non-infectious uveitis treated with monthly IV TCZ (4-10 mg/kg) or biweekly IV TCZ (8 mg/kg) were reviewed. Outcome measures were changes in visual acuity, anterior chamber cell and flare grade, vitreous haze, central subfield thickness (CST), and fluorescein angiography (FA) score. RESULTS: Ten eyes of seven patients received TCZ therapy. Median age of patients was 14 (range, 7-24) years. Median duration of TCZ therapy was 15 (range, 5-32) months. Mean CST reduced from 373 ± 101.0 µm to 298.2 ± 40.3 µm. Mean FA score reduced from 12.5 ± 4.3 to 3.6 ± 2.6. One patient developed elevated liver transaminases. CONCLUSION: IV TCZ is a potentially effective and safe therapeutic option for the management of refractory non-infectious uveitis.

Multifocal electroretinographic findings in angiographic macular leakage in the setting of intermediate, posterior, or panuveitis.

OBJECTIVE: To evaluate the functional implications of angiographic macular leakage without the presence of intraretinal fluid on optical coherence tomography (OCT) in eyes with intermediate, posterior, or panuveitis. METHODS: Retrospective study on patients with a diagnosis of intermediate, posterior, or panuveitis. Patients who had fluorescein angiography, OCT, and multifocal electroretinography (mfERG) within a predetermined time frame were included. Demographic and clinical data including types of ocular inflammation and best-corrected visual acuity (BCVA), in addition to OCT, fluorescein angiography, and mfERG data were collected. The study cohort was divided into 2 groups based on the presence of angiographic macular leakage and macular edema (ME): group 1 (no ME and no macular leakage) and group 2 (presence of macular leakage without ME). RESULTS: A total of 29 patients (43 eyes) were included in the study, with 13 patients (17 eyes) in group 1 and 16 patients (26 eyes) in group 2. No statistically significant differences in age, sex, anterior-chamber cells, lens status, vitreous cells, vitreous haze, BCVA, or mean central subfoveal thickness were found between groups 1 and 2. All mfERG values, including N1 and P1 response densities and timings for rings 1-5, did not show any statistically significant difference between group 1 and 2. No correlation was found between either BCVA or central subfoveal thickness and any of mfERG values for rings 1-3. CONCLUSIONS: In absence of ME, angiographic macular leakage in eyes with uveitis might not be associated with worse macular function when compared with eyes without angiographic macular leakage.

Effect of Pupil Size on Fixed-Luminance Flicker Full-Field Electroretinogram Magnitude.

Purpose: Diopsys® NOVA fixed-luminance flicker full-field electroretinogram (ffERG) device is a potential adjunct to conventional flicker ffERG testing for assessing cone cell function. Magnitude of measured electrical response is known to vary with pupil size in conventional ffERG testing. The index study characterizes the relationship between magnitude of measured electrical activity and pupil size, both pupil diameter and pupil area, for this device. Methods: Seventeen patients (34 eyes) with no known ocular diseases were enrolled in the study. Electrophysiologic function of cone cells was evaluated using fixed-luminance flicker ffERG before and after dilation. Linear regression models, with inter-eye correlations controlled as fixed-effects, were used to characterize the effect of pupil dilation on the magnitude of the measured responses. Results: Mean age of study patients was 33.5 (standard deviation 7.4 years), and 35.3% of the subjects were female. Mean value of electrical response magnitude was 10.07±2.79µV before dilation and 15.30±4.08µV after dilation. The correlations of ERG magnitude with pupil diameter and with pupil area were not significant for either dilated or undilated eyes considered separately but were highly significant (p<0.001) for dilated and undilated eyes considered in aggregate. ERG magnitude tended to increase by 1.08 µV for every 1 mm increase in pupillary diameter. Conclusion: An increase in pupil size, both pupil diameter and pupil area, is significantly associated with an increase in flicker ffERG magnitude recorded by the Diopsys device, suggesting that pupil size should be measured and considered when making clinical judgments based on the flicker ffERGs recorded by the device, and that pupil size-specific reference ranges could improve the clinical utility of the device.

C3 glomerulopathy associated with both hypertensive retinopathy and purtscher-like retinopathy.

Purpose: This article reports the case of a 21-year-old woman with both hypertensive retinopathy and Purtscher-like retinopathy in association with C3 glomerulopathy. Observations: The patient was referred for bilateral painless vision loss with posterior pole cotton wool spots, optic disc edema, and confluent retinal whitening suggesting a mixed picture of hypertensive retinopathy, with initial blood pressure 236/152, and Purtscher-like retinopathy. She was subsequently diagnosed with C3 glomerulopathy which likely caused her severe hypertension and which likely occurred alongside Purtscher-like retinopathy due to a shared pathogenesis of complement dysregulation. Follow up examination and imaging revealed gradual improvement in visual acuity, almost complete resolution of fundus exam abnormalities, improvement in macular nonperfusion, resolution of disc leakage and choroidal leakage, resolution of macular edema, and residual outer retinal hyperreflective foci in both eyes. Conclusion and importance: This case represents the first report of both Purtscher-like retinopathy and hypertensive retinopathy occurring in association with C3 glomerulopathy. It supports investigation of anti-complement therapy as a potential treatment for Purtscher-like retinopathy.

Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses.

Gene therapy has emerged as a research topic of choice in recent years. The eye in particular is one of few organs of the body for which gene therapy has received Food and Drug Administration approval, and it remains a field of great interest for gene therapy development. However, its associated immune and inflammatory reactions may render the treatment ineffective or harmful, which are of particular concern for the eyes due to their susceptibility to inflammation. The severity of immune and inflammatory reactions depends on the choice of vector and its route of administration. Furthermore, most preclinical and clinical studies have shown that the dose of vectors is correlated with the degree of humoral response and ocular inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Subretinal delivery produces a weaker humoral response than the intravitreal route. However, some studies have demonstrated that the subretinal delivery induces a stronger inflammatory reaction. On the other hand, several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors. When compared with the intravitreal route, suprachoroidal gene delivery has been shown to produce weaker humoral response. However, unlike the subretinal space, the suprachoroidal space is not known to have immune privilege status. Inflammatory reactions following ocular gene therapy are typically mild and most clinical and preclinical studies have shown that they can be controlled with topical, local or systemic steroids. However, severe inflammatory responses may occur and require aggressive management to avoid permanent vision loss. Further investigations are required to elucidate and expand our knowledge of inflammatory reactions, and their optimal management, following ocular gene therapy.

Safety of Intravenous Methylprednisolone in Refractory and Severe Pediatric Uveitis.

Purpose: To evaluate the safety of intravenous high-dose pulse methylprednisolone succinate (IVHDM) in the management of severe or refractory non-infectious pediatric uveitis. Methods: We reviewed all uveitis patients who were ≤16 years of age and who received IVHDM with a dose of ≥500 mg per day (1-3 days a month) for at least 3 months during their management at a tertiary care eye hospital. Results: Twenty pediatric patients with severe or refractory uveitis who received IVHDM were identified. Six patients received IVHDM either once, as a preoperative medication, or at a lower dose than 500 mg, and were excluded. The remaining 14 patients received IVHDM for at least 4 months. Age (mean±SD) was 11.9±2.4 years and 50% were female. Duration of treatment was 14.2±7.5 months. Thirteen patients received IVHDM in combination with other immunomodulatory therapy (IMT). Except for two outliers, IVHDM was given at a dose of 8-25 mg/kg per infusion. Three major adverse events (AEs) occurred in two patients: a single episode of bradycardia, compression fracture following minor trauma and adrenal insufficiency. The number of AEs (major and minor) strongly correlated with duration of treatment (p=0.004) and moderately correlated with the cumulative dose/weight (p=0.051). Weight gain was associated with the use of concomitant oral steroids and not with duration of treatment or cumulative dose. Conclusion: IVHDM may be a valid therapeutic option for aggressive/refractory pediatric uveitis. The reported AEs in this series can also be attributed to the concurrent IMT or the underlying disease itself.

Immunotherapy-induced retinopathy mimicking cancer associated retinopathy.

Purpose: To report a patient who developed a cancer associated retinopathy (CAR) like syndrome in the setting of pembrolizumab and lenvatinib combination therapy for metastatic endometrial carcinoma. Symptoms resolved with normalization of objective functional tests following cessation of medications. Observations: A 52-year-old female with history of endometrial carcinoma, managed with pembrolizumab infusions and daily oral lenvatinib treatment for 18 months, presented to a tertiary eye center with complaints of nyctalopia, photosensitivity and photopsia. Further investigations revealed a reduction in b-wave amplitude on full field ERG (ffERG), a mild color vision deficit, and positive antiretinal antibodies against carbonic anhydrase II, enolase and arrestin. A preliminary diagnosis of CAR was made. One month following diagnosis, the patient discontinued both lenvatinib and pembrolizumab and subsequently reported significant improvement in her eye symptoms and vision. Repeat ffERG had normalized with a robust b-wave, with an improvement noted on repeat color vision testing. A presumed diagnosis of immunotherapy-induced retinopathy was made, with clinical findings mimicking CAR. Conclusions and importance: Pembrolizumab and lenvatinib treatment may be associated with a reversible retinopathy, with presentation very similar to CAR.