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Amir Akhavanrezayat,1 Wataru Matsumiya,1,2 Prapatsorn Ongpalakorn,1 Hashem H Ghoraba,1 Chris Or,1 Hassan Khojasteh Jafari,1 Gunay Uludag Kirimli,1 Cigdem Yasar,1 Ngoc Trong Tuong Than,1 Irmak Karaca,1 Moosa Zaidi,1 Azadeh Mobasserian,1 Negin Yavari,1 Vahid Bazojoo,1 Yong Un Shin,1 Albert John Bromeo,1 Quan Dong Nguyen1 1Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; 2Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, JapanCorrespondence: Quan Dong Nguyen, Spencer Center for Vision Research, Byers Eye Institute at Stanford University, 2452 Watson Court, Suite 200, Palo Alto, CA, 94303, USA, Tel +1 650 723 9386, Email ndquan@stanford.eduPurpose: 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.Keywords: neurosarcoidosis, coccidioidomycosis, sarcoidosis, ocular involvement

Brandon Huy Pham,1 Gunay Uludag,2 Doan Luong Hien,2 Ngoc Trong Tuong Than,2 Jaclyn Joyce Hwang,2 Amir Akhavanrezayat,2 Wataru Matsumiya,2 Sherin Lajevardi,2 Jonathan Regenold,2 Muhammad Sohail Halim,2 Quan Dong Nguyen2 1Stanford University School of Medicine, Palo Alto, CA, USA; 2Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USACorrespondence: Quan Dong Nguyen, Spencer Center for Vision Research, Byers Eye Institute at Stanford, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA, Tel +1 650-725-7245, Email ndquan@stanford.eduPurpose: We describe the course of a patient diagnosed with birdshot chorioretinopathy (BSCR) in early adulthood and summarize clinical findings from similar BSCR patients reported in the literature.Observations: A 37-year-old male presented to our tertiary uveitis facility with bilateral ocular discomfort, hazy vision, and floaters. Ocular examination was notable for vitritis, optic disc edema, and ovoid hypopigmented chorioretinal lesions, visible on indocyanine green chorioangiography as multiple hypocyanescent spots in the intermediate phase. Full-field electroretinography and visual evoked potential showed global retinal dysfunction and optic nerve dysfunction. Laboratory evaluations were notable only for human leukocyte antigen (HLA)-A29 positivity. The patient was diagnosed with BSCR and started on oral prednisone and eventually managed with infliximab.Conclusions and Importance: BSCR can affect patients in early adulthood. Proper diagnostic work-up, including assessing HLA-A29 positivity, is needed to manage atypical cases.Keywords: birdshot chorioretinopathy, early adulthood, human leukocyte antigen (HLA)-A29

Chris Or,1 Sherin Lajevardi,1 Hashem Ghoraba,1 Jung Hyun Park,1 Neil Onghanseng,1,2 Muhammad Sohail Halim,1 Murat Hasanreisoglu,3 Muhammad Hassan,1 Gunay Uludag,1 Amir Akhavanrezayat,1 Quan Dong Nguyen1 1Department of Ophthalmology, Stanford University, Palo Alto, CA, USA; 2Department of Ophthalmology, Makati Medical Center, Manila, Philippines; 3Department of Ophthalmology, Koç University, School of Medicine, Istanbul, TurkeyCorrespondence: Quan Dong Nguyen, Spencer Center for Vision Research, Byers Eye Institute at Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA, Tel +1 650 725 7245, Email ndquan@stanford.eduPurpose: To describe the prevalence and characteristics of posterior segment manifestations in patients with HLA-B27-associated uveitis using wide field imaging.Methods: Medical records of patients diagnosed with HLA-B27-associated uveitis from a tertiary uveitis clinic were reviewed. Posterior segment involvements including but not limited to peripheral vasculitis, optic disc inflammation, and macula edema documented based on medical records and various imaging modalities including wide field fluorescein angiography and optical coherence tomography, were noted. Demographic characteristics, accompanied with systemic diseases as well as duration and chronicity of uveitis, were also evaluated. Patients with significant systemic and ocular comorbidities were excluded. Statistical analyses including chi-squared tests and paired t-tests were employed.Results: Of the 44 patients with HLA-B27 associated uveitis, 22 patients (50%) were noted to demonstrate posterior segment involvement. Disc leakage and peripheral vasculitis were the most common findings of posterior involvement. Those with anterior chamber inflammation were found to have a significantly increased risk of posterior involvement. Those with posterior involvement were also noted to have a statistically significant decreased visual acuity. No significant association was found between documented duration of disease and posterior segment involvement.Conclusion: The prevalence of posterior segment involvement in HLA-B27 associated uveitis is higher compared to previous reports when evaluated with wide angle imaging modalities. Careful examination of the posterior segment is required in patients with HLA-B27 associated uveitis.Keywords: HLA-B27, uveitis, retinal vasculitis, vitreous haze, vitreous cells, macular edema, anterior chamber cells, anterior chamber flare

Azadeh Mobasserian,1,&ast; Moosa Zaidi,1,&ast; Sohail Halim,1,2 Jaclyn Joyce Hwang,1 Jonathan Regenold,1 Amir Akhavanrezayat,1 Irmak Karaca,1,3 Hassan Khojasteh Jafari,1 Negin Yavari,1 Wataru Matsumiya,1,4 Cigdem Yasar,1,5 Ngoc Tuong Trong Than,1 Gunay Uludag,1 Diana Do,1 Hashem Ghoraba,1 Quan Dong Nguyen1 1Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; 2Ocular Imaging Research and Reading Center, Sunnyvale, CA, USA; 3Department of Ophthalmology, Ege University Faculty of Medicine, Izmir, Turkey; 4Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan; 5Department of Ophthalmology, Suleyman Demirel University, Faculty of Medicine, Isparta, Turkey&ast;These authors contributed equally to this workCorrespondence: Quan Dong Nguyen, Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA, Tel +1 650 725-7245, Fax +1 650 736-8232, Email ndquan@stanford.eduPurpose: 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.Keywords: electroretinogram, ERG, flicker ERG, pupil, magnitude, Diopsys

Hashem H Ghoraba, Amir Akhavanrezayat, Irmak Karaca, Negin Yavari, Sherin Lajevardi, Jaclyn Hwang, Jonathan Regenold, Wataru Matsumiya, Brandon Pham, Moosa Zaidi, Azadeh Mobasserian, Anthony Toan DongChau, Christopher Or, Cigdem Yasar, Kapil Mishra, Diana Do, Quan Dong Nguyen Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USACorrespondence: Quan Dong Nguyen, Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, USA, Tel +1 6507257245, Fax +1 6507368232, Email ndquan@stanford.eduAbstract: 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.Keywords: ocular gene therapy, gene therapy, viral vectors, ocular inflammation, review

Hashem H Ghoraba,1 Wataru Matsumiya,1,2 Hassan Khojasteh,1 Amir Akhavanrezayat,1 Irmak Karaca,1 Christopher Or,1 Negin Yavari,1 Sherin Lajevardi,1 Jaclyn Hwang,1 Cigdem Yasar,1 Diana Do,1 Quan Dong Nguyen1 1Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA; 2Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, JapanCorrespondence: Quan Dong Nguyen, Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, 2370 Watson Court, Suite 200, Palo Alto, CA, USA, Tel +16507257245, Fax +1 6507368232, Email ndquan@stanford.eduPurpose: 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.Keywords: pediatric uveitis, intravenous methylprednisolone, adverse events

Marie-France Forget,1 Sophie Del Degan,1 Julie Leblanc,1 Rita Tannous,1 Michaël Desjardins,2 Madeleine Durand,3,4 Thien Tuong Minh Vu,1,5 Quoc Dinh Nguyen,1,4 Philippe Desmarais1,5 1Department of Medicine, Division of Geriatrics, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada; 2Department of Medicine, Division of Infectious Disease, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada; 3Department of Medicine, Division of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada; 4Innovation Hub, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada; 5Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Québec, CanadaCorrespondence: Marie-France ForgetDepartment of Medicine, Division of Geriatrics, Centre Hospitalier de l’Université de Montréal, 1000 Rue Saint-Denis, Montréeal, Québec, H2X 0C1, CanadaTel + 1 514 890 8000Fax + 1-514-412-7953Email marie-france.forget@umontreal.caPurpose: The occurrence and predictors of delirium in older adults hospitalized for coronavirus disease 2019 (COVID-19) have not been well described. Highlighting the association with inflammatory markers may be useful for identifying delirium. This study aimed to determine the prevalence and incidence of delirium and explore its association with the C-reactive protein (CRP).Patients and Methods: This cohort study of adults aged 65 and older with a COVID-19 diagnosis took place at an academic healthcare institution between April and May 2020. COVID-19 was diagnosed by positive nasopharyngeal swab. Serum levels of CRP were collected as a marker of systemic inflammation. The primary outcome was the prevalence and incidence of delirium. Delirium was diagnosed primarily during a patient’s stay in hospital based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5). To ensure that no delirium diagnosis was missed during hospital stay, clinical records were reviewed by clinicians with geriatric medicine training for retrospective diagnoses.Results: A total of 127 patients aged 65 and older were hospitalized with a diagnosis of COVID-19. The median age was 82 years (IQR: 74– 88), with 54 (43%) females. Overall, delirium was present in 62 (49%) patients: manifestations of delirium were present on the first day of hospitalization in 53 of these cases (86%), while 9 cases (14%) developed delirium during hospitalization. After controlling for age and sex, the mean CRP value over the first 3 days since arrival was associated with a higher risk of delirium (OR 1.35; 95% CI: 1.01– 1.85) for every 50 mg/L increase.Conclusion: In this cohort of older adults hospitalized for COVID-19, delirium was highly prevalent. An early increase in CRP levels should raise suspicion about the occurrence of delirium and could improve its diagnosis.Keywords: delirium, COVID-19, SARS-CoV-2, older adults

Aniruddha Agarwal, William R Rhoades, Mostafa Hanout, Mohamed Kamel Soliman, Salman Sarwar, Mohammad Ali Sadiq, Yasir Jamal Sepah, Diana V Do, Quan Dong Nguyen Stanley M Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Abstract: Contemporary management of neovascular age-related macular degeneration (AMD) has evolved significantly over the last few years. The goal of treatment is shifting from merely salvaging vision to maintaining a high quality of life. There have been significant breakthroughs in the identification of viable drug targets and gene therapies. Imaging tools with near-histological precision have enhanced our knowledge about pathophysiological mechanisms that play a role in vision loss due to AMD. Visual, social, and vocational rehabilitation are all important treatment goals. In this review, evidence from landmark clinical trials is summarized to elucidate the optimum modern-day management of neovascular AMD. Therapeutic strategies currently under development, such as gene therapy and personalized medicine, are also described. Keywords: AMD, neovascular AMD, choroidal neovascular membrane, pharmacogenomics, VEGF, low-vision rehabilitation, gene therapy

Aniruddha Agarwal, Mohamed K Soliman, Yasir J Sepah, Diana V Do, Quan Dong Nguyen Ocular Imaging Research and Reading Center, Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, USA Abstract: Diabetes and its microvascular complications in patients poses a significant challenge and constitutes a major health problem. When it comes to manifestations in the eye, each case of diabetic retinopathy (DR) is unique, in terms of the phenotype, genotype, and, more importantly, the therapeutic response. It is therefore important to identify factors that distinguish one patient from another. Personalized therapy in DR is a new trend aimed at achieving maximum therapeutic response in patients by identifying genotypic and phenotypic factors that may result in less than optimal response to conventional therapy, and consequently, lead to poorer outcome. With advances in the identification of these genetic markers, such as gene polymorphisms and human leucocyte antigen associations, as well as development of drugs that can target their effects, the future of personalized medicine in DR is promising. In this comprehensive review, data from various studies have been analyzed to present what has been achieved in the field of pharmacogenomics thus far. An insight into future research is also provided. Keywords: personalized medicine, therapeutic variation, genomic markers, genotype, phenotype, VEGF mutation, polymorphism, linkage, mutation, responder

Robert J Barry,1 Quan Dong Nguyen,2 Richard W Lee,3 Philip I Murray,1 Alastair K Denniston1,4 1Academic Unit of Ophthalmology, Centre for Translational Inflammation, Research, University of Birmingham, UK; 2Stanley M Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA; 3Inflammation and Immunotherapy Theme, National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK; 4Department of Ophthalmology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation trust, Birmingham, UK Abstract: Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects. Keywords: clinical trials, immunomodulatory therapeutic agents, immunosuppression, inflammation, uvea

John D Sheppard Jr1, Quan Dong Nguyen2, Dale W Usner3, Timothy L Comstock3, for the Fluocinolone Acetonide Uveitis Study Group1Eastern Virginia Medical School, Norfolk, VA, USA; 2Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, MD, USA; 3Bausch and Lomb Incorporated, Rochester, NY, USAPurpose: To describe visual acuity (VA) and inflammation following cataract surgery in eyes with noninfectious posterior uveitis (NIPU) that were being treated with a fluocinolone acetonide (FA) intravitreal implant compared with those that were not.Design: Post hoc, subgroup analysis of data from a 3-year, dose-masked, randomized, multicenter trial evaluating the FA implant for the treatment of NIPU.Participants and controls: The subset of eyes that underwent cataract surgery during the 3-year trial. Eyes were either implanted with a 0.59- or a 2.1-mg FA implant, or, in the case of affected fellow eyes, received standard-of-care local treatment.Main outcome measures: VA, anterior and posterior chamber inflammation at 1 and 3 months after surgery, and rate of uveitis recurrence and serious postoperative ocular adverse events.Results: Of 278 patients enrolled in the main trial, 132/142 phakic implanted eyes and 39/186 phakic non-implanted eyes underwent cataract surgery. Mean improvement in VA was significantly greater in implanted than non-implanted eyes at 1 (P = 0.0047) and 3 months (P = 0.0015) postoperatively; significantly fewer anterior chamber cells were seen in implanted than non-implanted eyes at 1 (P = 0.0084) and 3 months (P = 0.0002). Severity of vitreous haze was less in implanted than non-implanted eyes at 3 months postoperatively (P = 0.0005). The postsurgical uveitis recurrence rate was lower in implanted than non-implanted eyes (26.5% vs 44.4%; P = 0.0433). Glaucoma was reported in 19.7% of implanted eyes and no non-implanted eyes (P = 0.0008) postoperatively.Conclusion: In this post hoc subgroup analysis, eyes with NIPU treated with the FA intravitreal implant demonstrated better vision and less intraocular inflammation following cataract surgery than non-implanted eyes. Recurrent uveitic inflammation did not appear to be triggered by cataract surgery. Glaucoma occurred more frequently in implanted eyes.Keywords: cataract surgery, posterior chamber inflammation, glaucoma, intraocular pressure, visual acuity, steroid implant