21q22 contains several dosage sensitive genes that are important in neurocognitive development. Determining impacts of gene dosage alterations in this region can be useful in establishing contributions of these genes to human development and disease. We describe a 15-month-old girl with a 1,140 kb homozygous deletion in the Down Syndrome Critical Region at 21q22.2 including 4 genes; B3GALT5, IGSF5, PCP4, DSCAM, and a microRNA (MIR4760). Clinical singleton genome sequencing did not report any candidate gene variants for the patient's phenotype. She presented with hypotonia, global developmental delay, cortical visual impairment, and mild facial dysmorphism. Ophthalmological exam was suggestive of retinopathy. We propose that the absence of DSCAM and PCP4 may contribute to the patient's neurological and retinal phenotype, while the role of absent B3GALT5 and IGSF5 in her presentation remain unclear at this time.

Mouse Müller cells, considered as dormant retinal progenitors, often respond to retinal injury by undergoing reactive gliosis rather than displaying neural regenerative responses. Tumor necrosis factor alpha (TNFα) is a key cytokines induced after injury and implicated in mediating inflammatory and neural regenerative responses in zebrafish. To investigate the involvement of TNFα in mouse retinal injury, adult C57BL/6J mice were subjected to light damage for 14 consecutive days. TNFα was elevated in the retina of mice exposed to light damage, which induced Müller cell proliferation in vitro. Affymetrix microarray showed that, in Müller cells, TNFα induces up-regulation of inflammatory and proliferation-related genes, including NFKB2, leukemia inhibitory factor, interleukin-6, janus kinase (Jak) 1, Jak2, signal transducer and activator of transcription (Stat) 1, Stat2, mitogen-activated protein kinase (MAPK) 7, and MAP4K4 but down-regulation of neuroprogenitor genes, including Sox9, Ascl1, Wnt2 and Hes1. Blocking the Jak/Stat and MAPK pathways attenuated TNFα-induced Müller cell proliferation. These results suggest that TNFα may drive the proliferation and inflammatory response, rather than the neural regenerative potential, of mouse Müller cells.

PURPOSE: An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD). DESIGN: A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328). PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes). METHODS: The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by ≥2 readers, then adjudicated by the SRC as a group. MAIN OUTCOME MEASURES: Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset. RESULTS: Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%. CONCLUSIONS: This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD.

Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease. Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired. Design, Setting, and Participants: A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020. Main Outcomes and Measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension. Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, β = -3.06; P = .007; outer inferior quadrant, β = -2.60; P = .02), outer plexiform layer (outer superior quadrant, β = -3.44; P = .03), and outer nuclear layer (central quadrant, β = -8.61; P = .03; inner nasal quadrant, β = -8.39; P = .04; inner temporal quadrant, β = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied. Conclusions and Relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.

AIMS/HYPOTHESIS: Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR. METHODS: We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration. RESULTS: We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024). CONCLUSIONS/INTERPRETATION: These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR. Graphical abstract.

PURPOSE: To describe a surgical approach for the resection of schwannomas occurring in the medial aspect of the orbit and to review a series of patients who underwent this novel technique. METHODS: This retrospective, non-comparative case series presents the surgical technique and outcomes of patients who underwent removal of a medial orbital schwannoma via an endoscopic endonasal approach combined with a small-incision medial orbitotomy by a team of two surgeons (BSB and SKF). Patient demographics, pre- and post-operative clinical examination findings, visual field testing, and radiographic studies were reviewed. Operative reports were reviewed for technical details and complications. RESULTS: The patients included a 12 year-old male, 73 year-old female and 8 year-old male. Indications for surgery included: decreased visual acuity, diplopia, proptosis and Humphrey visual field (HVF) deficit, in the presence of a medial orbital biopsy-proven schwannoma. The surgical approach in all three patients was primarily endoscopic endonasal. Additionally, two had transcaruncular orbitotomies and one had a small-incision medial lid crease orbitotomy to assist with lateral tumor dissection. Tumor resection was complete in one case and near-total in two cases. There were no intra-operative surgical complications. Average resected specimen volume was 3.41 cm3 ± 2.20. All patients had post-operative improvement in visual acuity (VA) and proptosis. Post-operative follow-up intervals were 27.5 months, 12.3 months and 3.5 months, respectively. CONCLUSION: Resection of orbital schwannomas using an endoscopic endonasal approach with small-incision medial transorbital assistance is a safe and effective option for a multidisciplinary surgical team.

PURPOSE: To report a case series of patients with treatment-resistant Acanthamoeba keratitis (AK) using oral miltefosine, often as salvage therapy. DESIGN: Descriptive, retrospective multicenter case series. METHODS: We reviewed 15 patients with AK unresponsive to therapy who were subsequently given adjuvant systemic miltefosine between 2011 and 2017. The main outcome measures were resolution of infection, final visual acuity, tolerance of miltefosine, and clinical course of disease. RESULTS: All patients were treated with biguanides and/or diamidines or azoles without resolution of disease before starting miltefosine. Eleven of 15 patients retained count fingers or better vision, and all were considered disease free at last follow-up. Eleven of 15 patients had worsening inflammation with miltefosine, with 10 of them improving with steroids. Six patients received multiple courses of miltefosine. Most tolerated oral miltefosine well, with mild gastrointestinal symptoms as the most common systemic side effect. CONCLUSIONS: Oral miltefosine is a generally well-tolerated treatment adjuvant in patients with refractory AK. The clinician should be prepared for a steroid-responsive inflammatory response frequently encountered during the treatment course.