Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy.

OBJECTIVE: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. DESIGN: Cross sectional descriptive study from December 2021 to December 2022. PARTICIPANTS: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. METHODS: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (µm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. RESULTS: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 µm (range, 217-488 µm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18-1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9-6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. CONCLUSIONS: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dark Adaptometry and Optical Coherence Tomography Angiography in Huntington Disease.

Purpose: Huntington's Disease (HD) is a fully penetrant neurodegenerative disease leading to cognitive and motor disturbances. The retina may serve as a structural and functional extension of the central nervous system to identify biomarkers of HD using noninvasive imaging technology such as optical coherence tomography angiography (OCTA) and dark adaptometry. Methods: This case-control study included 12 HD participants (24 eyes) recruited from the Huntington's Disease Society of America Center of Excellence at Washington University in St. Louis along with 16 control participants (31 eyes). Disease-positive participants underwent imaging testing of retinal capillary density and foveal avascular zone utilizing OCTA along with dark adaptometry testing. Data were collected from November 2020 to February 2022. Results: Individuals with HD had a lower mean age-adjusted superficial foveal capillary density and a higher mean deep foveal capillary density compared to control subjects. There was no significant difference in the mean foveal avascular zone or in dark adaptometry testing between the two groups. Conclusion: This study suggests that changes in retinal biomarkers may exist in patients with HD and that additional investigations using multimodal techniques are warranted.

Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration.

Purpose: Choroidal neovascularization (CNV) accounts for the majority of severe vision loss in neovascular age-related macular degeneration (AMD). Despite therapies that target VEGF, patients are often under-responsive, require frequent eye injections to control disease, and eventually lose some vision despite chronic therapy implicating a multifactorial etiology in treatment response. Genetic studies implicate systemic immunity in AMD and systemic immune cells accumulate within CNV lesions, yet a role for these cells in anti-VEGF response remains undetermined. The purpose of this study was to identify transcriptional signatures of circulating immune cells that are associated with high anti-VEGF treatment burden. Design: Experimental pilot study. Participants: Patients with neovascular AMD seen at Washington University School of Medicine in St. Louis and BJC Health System. Methods: We profiled by single cell RNA sequencing the peripheral blood mononuclear cells of 27 treatment-experienced patients with wet AMD. We stratified this cohort into 2 groups with low and high treatment burden (≤ 5 or ≥ 6 injections in the past 12 months, respectively). Main Outcome Measures: Identification of immune cells associated with high treatment burden. Results: Gene expression signature of CD16+ monocytes may be associated with high treatment burden. Conclusions: These studies delineate potential signatures of circulating immune cells that may be associated with high treatment burden in neovascular AMD, potentially informing the development of diagnostic predictors of anti-VEGF response and new precision medicine-based approaches to complement anti-VEGF therapies. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Targeting cell-type-specific, choroid-peripheral immune signaling to treat age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness featuring pathogenic neovascularization of the choroidal vasculature (CNV). Although systemic immunity plays a role in AMD, the ocular signals that recruit and activate immune cells remain poorly defined. Using single-cell RNA sequencing, we prospectively profile peripheral blood mononuclear cells from 65 individuals including AMD and controls, which we integrate with existing choroid data. We generate a network of choroid-peripheral immune interactions dysregulated in AMD, including known AMD-relevant gene vascular endothelial growth factor (VEGF) receptor 2. Additionally, we find CYR61 is upregulated in choroidal veins and may signal to circulating monocytes. In mice, we validate that CYR61 is abundant in endothelial cells within CNV lesions neighboring monocyte-derived macrophages. Mechanistically, CYR61 activates macrophage anti-angiogenic gene expression, and ocular Cyr61 knockdown increases murine CNV size, indicating CYR61 inhibits CNV. This study highlights the potential of multi-tissue human datasets to identify disease-relevant and potentially therapeutically modifiable targets.

Association of Systemic Lupus Erythematosus Disease Activity With Choroidal Thickness.

OBJECTIVE: To determine the association between disease activity and choroidal thickness in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a cohort study of 24 SLE patients and 13 healthy controls recruited at Washington University School of Medicine between June 2019 and November 2021. SLE disease activity was assessed using the SLE Disease Activity Index-2000 Responder Index-50 (S2K RI-50). Patients were divided into four groups: high disease activity/no lupus nephritis (HDA/no LN; S2K RI-50 > 4), HDA/active LN (HDA/active LN; S2K RI-50 > 4), low disease activity/inactive LN (LDA/inactive LN; S2K RI-50 ≤ 4), and LDA/no LN (LDA/no LN; S2K RI-50 ≤ 4). LDA/no LN patients were age-, sex-, and race-matched to healthy controls and patients in other SLE groups. Choroidal thickness of the right eye was measured blinded to disease activity on a horizontal section through the fovea on optical coherence tomography images taken within a week of disease assessment. RESULTS: Patients with HDA had choroidal thickening compared with matched patients with LDA. After controlling for multiplicity, choroidal thinning remained statistically significant at 1000 µm nasal to the fovea (308 ± 68 vs 228 ± 64 µm, p = 0.001). Choroidal thickness was not different between LDA/no LN and LDA/inactive LN or healthy controls. CONCLUSION: HDA in patient with SLE is associated with increased choroidal thickness whereas comorbid inactive LN did not affect choroidal thickness. Additional studies in a larger longitudinal cohort are needed to study whether choroidal thickness may be used as a noninvasive, adjunctive measure for disease activity in SLE.

The spectrum of COVID-19-associated chorioretinal vasculopathy.

Purpose: Although conjunctivitis represents the most common ocular manifestation of COVID-19 infection, sight-threatening retinal involvement has been reported. Herein, we report and characterize with multimodal retinal imaging 5 cases of acute vision loss secondary to presumed chorioretinal vasculopathy temporally associated with COVID-19 infection with varying severity, visual morbidity, and treatment response, and review the available literature on the association between COVID-19 infection and retinal microvascular changes. Design: Observational case series and literature review. Methods: Multicenter case series of 5 patients who presented to academic centers and private offices with acute vision loss temporally associated with COVID-19 infection. A review of the literature was conducted using online databases. Results: 10 eyes of 5 patients, 3 men and 2 women, with a mean age of 30.8 years (median 33, range 16-44) were described. All patients had a recently preceding episode of COVID-19, with symptomatology ranging from mild infection to life-threatening encephalopathy. Treatment for their retinal disease included topical, oral, intravitreal, and intravenous steroids, steroid-sparing immunosuppression, retinal photocoagulation, antivirals, and antiplatelet and anticoagulant agents. Treatment response and visual recovery ranged from complete recovery of baseline acuity to permanent vision loss and need for chronic immunosuppression. Conclusions and Importance: Clinicians should be mindful of the potential for vision-threatening retinal involvement after COVID-19 infection. If found, treatment with both anti-inflammatory therapy and anticoagulation should be considered, in addition to close monitoring, as some patients with this spectrum of disease may require chronic immune suppression and/or anti-VEGF therapy.

Ocular Manifestations of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by intestinal inflammation; however, it is also known to have extraintestinal manifestations. Ocular manifestations of IBD include keratopathy, episcleritis, scleritis, and uveitis and are among the most common extraintestinal manifestations. These diseases can lead to significant ocular morbidity if unrecognized and left untreated. A review of the literature was performed on PubMed and is summarized and critically appraised in this article with the aim being to describe the varying ocular manifestations of IBD and outlining their treatments. Ultimately, a framework is provided to investigate ocular symptoms in patients with IBD. An ocular review of systems is also provided as a tool to equip gastroenterologists and internal medicine physicians to be able to recognize and triage ocular complaints appropriately.

Optical Coherence Tomography Angiography: A Window into Central Nervous System Neurodegeneration.

Optical coherence tomography angiography (OCT-A) allows noninvasive visualization of intraocular tissues with high resolution. Recently, an innovative use of this technology in studying neurodegenerative diseases has emerged with the neurosensory retina as a unique window into deeper brain tissues. Here, we discuss its role in identifying biomarkers of neurodegenerative diseases.

Effects of image brightness and contrast dynamic altering stimuli (DAS) when viewing video content on ocular blood flow.

BACKGROUND/AIM: Blood flow deficiencies of the retinal and retrobulbar circulations have been previously reported in open-angle glaucoma (OAG) and other eye diseases. Herein we investigated the effects of image brightness and contrast dynamic altering stimuli (DAS) when viewing a video content on ocular blood flow, intraocular pressure (IOP) and ocular perfusion pressure (OPP) in OAG and healthy subjects. METHODS: Thirty-five subjects, 25 with OAG (mild to moderate) and 10 healthy controls, were evaluated for blood pressure, IOP, OPP and retinal capillary blood flow before, immediately after, 30 min after and 60 min after using ReviView (a dichoptic video goggles device), which stimulates one eye with a DAS video image that is brighter and with greater contrast than the fellow eye (duration of exposure 30 min). Differences between each subject's eyes and between OAG and healthy subjects were evaluated using repeated-measures analysis of variance with p<0.05 considered statistically significant. RESULTS: All subjects demonstrated a significant increase in OPP in both eyes immediately following viewing. In all DAS eyes, retinal capillary blood flow rose immediately after stimulation and remained elevated for an hour postviewing. Viewing DAS increased retinal blood flow compared with control eyes (p=0.0014, 0.0135 superiorly and p=0.0094, 0.0001 inferiorly, at 30 and 60 min, respectively). OAG eyes had a significant reduction in the number of dormant retinal capillaries (p=0.0174), while healthy eyes demonstrated a larger increase in retinal capillary blood flow (p=0.0006 and p=0.0093 at 60 min, superior and inferior, respectively) following DAS viewing. CONCLUSION: Viewing DAS video for 30 min using ReviView increased retina blood flow both in healthy subjects and in patients with OAG. TRIAL REGISTRATION NUMBER: NCT02959593.

Optical coherence tomography angiography: an overview of the technology and an assessment of applications for clinical research.

In recent years, ophthalmology has experienced significant developments with respect to imaging modalities. Optical coherence tomography angiography is one such technology that seeks to improve diagnostics for retinal diseases. Using standard structural ocular coherence tomography hardware, optical coherence tomography angiography demonstrates the ability to non-invasively visualise the vasculature in the retina and the choroid with high resolution, allowing greater insight into retinal vascular pathologies. In addition, retinal and choroidal vessel density and blood flow can be quantified, offering potential to assist in the diagnosis of a variety of retinal diseases. To date, numerous retinal diseases, such as open-angle glaucoma, have been found to possess a vascular component. Specifically, ischaemia of the optic nerve head and lamina cribrosa has been theorised as a causative factor in ganglion cell death; however, confirmation of this mechanism has been prohibited by the limitations of currently existing imaging modalities. Optical coherence tomography angiography provides clear imaging of these regions and the possibility to elucidate further understanding of vascular factors that contribute to glaucoma development and progression. Furthermore, this imaging modality may provide insight to neural pathologies with vascular components such as Alzheimer's disease. Herein, the authors discuss the theory of operation for optical coherence tomography angiography and the current findings from pilot studies with a focus on open-angle glaucoma. In addition, speculation is offered for future applications of the technology to study other diseases with microvascular contributions.