Assessment of early and long-COVID related retinal neurodegeneration with optical coherence tomography.

PURPOSE: The aim of this study is to investigate short-term and long-term effects of coronovirus 19 disease (COVID-19) at inner and outer retinal layers of patients recovered from COVID-19 with Spectral Domain Optical Coherence Tomography (SD-OCT) and compare these to healthy subjects. METHODS: Twenty-seven patients recovered from COVID-19, and age- and gender-matched 27 healthy controls were included in this study. Macular and peripapillary retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL) and outer nuclear layer (ONL) were analyzed with SD-OCT 1 month (V1 visit) and 12 months (V2 visit) after negative result of reverse transcriptase-polymerase chain reaction test. RESULTS: Macular RNFL thickness in outer ring was thinner at V1 and V2 visits than healthy control (p = 0.049 and p = 0.005). Central and inferonasal quadrants of peripapillary RNFL thicknesses were reduced at V1 and V2 visits compared to controls (p = 0.001 and p = 0.024 for V1 visit; p = 0.001 and p = 0.006 for V2 visit). Thinning in ONL thickness in inner ring was observed at V1 and V2 visits than healthy subjects (p = 0.006 and p = 0.001). CONCLUSION: Subclinical localized changes in macular and peripapillary RNFL and outer nuclear layer were demonstrated in early and 12-months follow-up after COVID-19 recovery.

Effects of COVID-19 on Retinal and Choroidal Thickness by Optical Coherence Tomography.

PRCIS: The aim of our study was to evaluate the subclinical changes in the macula, retinal nerve fiber layer (RNFL), and choroidal thickness after coronavirus disease 2019 (COVID-19) infection using spectral domain optical coherence tomography. METHODS: Our study was prospectively designed and involved 170 eyes of 85 patients. Patients with polymerase chain reaction (PCR)-positive COVID-19 infection were examined in the ophthalmology clinic before and after infection were included. All included patients had mild COVID-19 with no hospitalization and no need for intubation. Control ophthalmic examination was repeated at least 6 months after PCR positivity. Macular and choroidal thickness and RNFL parameters were compared before and at least 6 months after PCR-positive COVID-19 infection using optical coherence tomography. RESULTS: When the mean macular thickness data were evaluated, a significant decrease was detected in the inner (mean difference, -3.37 µm; 95% CI: -6.09 to -0.65, P = 0.021) and outer (mean difference, -6.56 µm; 95% CI: -9.26 to -3.86, P < 0.001) temporal segments and the inner (mean difference, -3.39 µm; 95% CI: -5.46 to -1.32, P = 0.002) and outer (mean difference, -2.01 µm; 95% CI, -3.70 to -0.31, P = 0.018) su p erior segments in the post-COVID-19 measurements compared with pre-COVID-19 measurements. Similarly, on RNFL evaluation, some thinning was evident in the temporal superior (mean = 1.14 µm, P = 0.004) and temporal inferior (mean = 1.30 µm, P = 0.032) regions. All choroidal regions, including central, nasal 500 µm and 1500 µm and temporal 500 µm and 1500 µm, exhibited significant thinning ( P < 0.001). CONCLUSION: At least 6 months after mild COVID-19 infection, significant thinning was seen in the temporal and superior quadrants of the macula, the temporal superior and temporal inferior regions of the RNFL, and all measured areas of choroidal regions.

Evaluation of acute effects of pulmonary involvement and hypoxia on retina and choroid in coronavirus disease 2019: An optic coherence tomography study.

PURPOSE: We investigated the acute subclinical choroidal and retinal changes caused by Coronavirus Disease 2019 (COVID-19) in patients with and without pulmonary involvement, using spectral domain optic coherence tomography. METHODS: This prospective case-control study included COVID-19 patients: 50 with pulmonary involvement and 118 with non-pulmonary involvement. All patients were examined 1 month after recovering from COVID-19. The changes were followed using optic coherence tomography parameters such as choroidal and macular thickness and retinal nerve fibre layer and ganglion cell complex measurements. RESULTS: All choroidal thicknesses in the pulmonary involvement group were lower than in the non-pulmonary involvement group and the subfoveal choroidal thickness differed significantly (p=0.036). Although there were no significant differences between the central and average macular thicknesses in the two groups, they were slightly thicker in the pulmonary involvement group (p=0.152 and p=0.180, respectively). A significant decrease was detected in the pulmonary involvement group in all ganglion cell complex segments, except for the outer nasal inferior segment (p<0.05). In addition, a thinning tendency was observed in all retinal nerve fibre layer quadrants in the pulmonary involvement group compared to the non-pulmonary involvement group. CONCLUSION: In COVID-19 patients with pulmonary involvement, subclinical choroidal and retinal changes may occur due to hypoxia and ischemia in the acute period. These patients may be predisposed to ischemic retinal and optic nerve diseases in the future. Therefore, COVID-19 patients with pulmonary involvement should be followed for ophthalmological diseases.

The Comparison of Retinal Microvascular Findings in Acute COVID-19 and 1-Year after Hospital Discharge Assessed with Multimodal Imaging-A Prospective Longitudinal Cohort Study.

This study aimed to quantify possible long-term impairment of the retinal microcirculation and microvasculature by reassessing a cohort of patients with acute COVID-19 without other known comorbidities one year after their discharge from the hospital. Thirty patients in the acute phase of COVID-19 without known systemic comorbidities were enrolled in this prospective longitudinal cohort study. Fundus photography, SS-OCT, and SS-OCTA using swept-source OCT (SS-OCT, Topcon DRI OCT Triton; Topcon Corp., Tokyo, Japan) were performed in the COVID-19 unit and 1-year after hospital discharge. The cohort's median age was 60 years (range 28-65) and 18 (60%) were male. Mean vein diameter (MVD) significantly decreased over time, from 134.8 µm in the acute phase to 112.4 µm at a 1-year follow-up (p < 0.001). A significantly reduced retinal nerve fiber layer (RNFL) thickness was observed at follow-up in the inferior quadrant of the inner ring (mean diff. 0.80 95% CI 0.01-1.60, p = 0.047) and inferior (mean diff. 1.56 95% CI 0.50-2.61, p < 0.001), nasal (mean diff. 2.21 95% CI 1.16-3.27, p < 0.001), and superior (mean diff. 1.69 95% CI 0.63-2.74, p < 0.001) quadrants of the outer ring. There were no statistically significant differences between the groups regarding vessel density of the superior and deep capillary plexuses. The transient dilatation of the retinal vessels in the acute phase of COVID-19, as well as RNFL thickness changes, could become a biomarker of angiopathy in patients with severe COVID-19.

Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups.

PURPOSE: To assess safety of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). DESIGN: Phase 1 clinical trial. METHODS: Setting: single institution. PARTICIPANTS: Patients with G11778A LHON and chronic bilateral visual loss >12 months (group 1, n = 11), acute bilateral visual loss <12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8). INTERVENTION: unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. OUTCOME MEASURES: Best-corrected visual acuity (BCVA), adverse events, and vector antibody responses. Mean follow-up was 24 months (range, 12-36 months); BCVAs were compared with a published prospective natural history cohort with designated surrogate study and fellow eyes. RESULTS: Incident uveitis (8 of 28, 29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose: 5 of 7 (71%) higher-dose eyes vs 3 of 21 (14%) low-, medium-, or high-dose eyes (P < .001). Incident uveitis requiring treatment was associated with increased serum AAV2 neutralizing antibody titers (p=0.007) but not serum AAV2 polymerase chain reaction. Improvements of ≥15-letter BCVA occurred in some treated and fellow eyes of groups 1 and 2 and some surrogate study and fellow eyes of natural history subjects. All study eyes (BCVA ≥20/40) in group 3 lost ≥15 letters within the first year despite treatment. CONCLUSIONS: G11778A LHON gene therapy has a favorable safety profile. Our results suggest that if there is an efficacy effect, it is likely small and not dose related. Demonstration of efficacy requires randomization of patients to a group not receiving vector in either eye.

SARS-CoV-2 infects and replicates in photoreceptor and retinal ganglion cells of human retinal organoids.

Several studies have pointed to retinal involvement in COVID-19, yet many questions remain regarding the ability of SARS-CoV-2 to infect and replicate in retinal cells and its effects on the retina. Here, we have used human pluripotent stem cell-derived retinal organoids to study retinal infection by SARS-CoV-2. Indeed, SARS-CoV-2 can infect and replicate in retinal organoids, as it is shown to infect different retinal lineages, such as retinal ganglion cells and photoreceptors. SARS-CoV-2 infection of retinal organoids also induces the expression of several inflammatory genes, such as interleukin 33, a gene associated with acute COVID-19 and retinal degeneration. Finally, we show that the use of antibodies to block ACE2 significantly reduces SARS-CoV-2 infection of retinal organoids, indicating that SARS-CoV-2 infects retinal cells in an ACE2-dependent manner. These results suggest a retinal involvement in COVID-19 and emphasize the need to monitor retinal pathologies as potential sequelae of "long COVID."

A Pediatric COVID-19 Study: Retinal Nerve Fiber Layer, Ganglion Cell Layer, and Alterations in Choroidal Thickness in Swept-Source OCT Measurements.

PURPOSE: To investigate early covid measurements of central macular thickness (CMT), retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) thickness, and choroidal thickness (ChT) in children recovered from coronavirus disease 2019 (COVID-19). METHODS: This cross-sectional study was carried out 4 weeks after completed COVID-19 treatment. The diagnosis of the Alpha variant COVID-19 was made by the polymerase chain reaction test after prediagnosis with clinical, laboratory, and radiological findings. A total of 46 children were included in the study. Pediatric patients who received COVID-19 treatment comprised the COVID-19 group (24 children), and healthy children were enrolled in the control group (22 children). Only the right eyes of the participants were enrolled in the study. All pediatric patients in the COVID-19 group required hospitalization without the need for intubation. Swept-source optical coherence tomography (SS-OCT) was used to measure CMT, RNFL, and GCL thickness, and ChT measurements. RESULTS: The COVID-19 and control groups had similar mean values of visual acuity, intraocular pressure, spherical equivalent, axial length, and CMT (p > 0.05 for all). RNFL thickening, GCL, and choroidal thinning were observed in all SS-OCT measurements of COVID-19 children. However, RNFL thickening was significant only in the global and nasal peripapillary quadrants. GCL thinning was significant in the nasal/inferior sector (p < 0.002 for all). Some significant correlations were observed between the mean levels of inflammatory markers and OCT measurements (p < 0.002). CONCLUSION: This study may be among the first reports of SS-OCT examination of COVID-19 children. OCT measurements showed changes in retinal and ChT in the COVID-19 children as in adult patients.

LOW VULNERABILITY OF THE POSTERIOR EYE SEGMENT TO SARS-COV-2 INFECTION: Chorioretinal SARS-CoV-2 Vulnerability.

PURPOSE: Retinal manifestations have been described in COVID-19 patients, but it is unknown whether SARS-CoV-2, the causal agent in COVID-19, can directly infect posterior ocular tissues. Here, we investigate SARS-CoV-2 host factor gene expression levels and their distribution across retinal and choroidal cell types. METHODS: Query of single-cell RNA sequencing data from human retina and choroid. RESULTS: We find no relevant expression of two key genes involved in SARS-CoV-2 entry, ACE2 and TMPRSS2, in retinal cell types. By contrast, scarce expression levels could be detected in choroidal vascular cells. CONCLUSION: Given the current understanding of viral host cell entry, these findings suggest a low vulnerability of the posterior eye segment to SARS-CoV-2 with a potential weak spot in the vasculature, which could play a putative causative role in ocular lesions in COVID-19 patients. This may qualify the vasculature of the human posterior eye segment as an in vivo biomarker for life-threatening vascular occlusions in COVID-19 patients.

Posterior ocular structural and vascular alterations in severe COVID-19 patients.

PURPOSE: This study aimed to evaluate posterior ocular structural and vascular changes in severe coronavirus disease 2019 (COVID-19) patients. METHODS: This was an observational, prospective, and controlled study including 106 eyes of 53 severe COVID-19 patients, compared to after recovery and 106 eyes of 53 age- and gender-matched healthy controls. All subjects were previously healthy adults and were assessed using spectral domain optical coherence tomography (SD-OCT) and ImageJ software. Subfoveal over a 1500-µm span and macular over a 6000-µm span cross-sectional areas of the vascular, stromal, and total choroid were measured. RESULTS: Of the 53 included patients, 28 (52.8%) were male, and 25 (47.2%) were female, with a mean age of 50.2 ± 7.4 years. In the active period of the disease, compared to after recovery and healthy controls, the outer plexiform layer thickness showed a significant increase (p = 0.004), and mean choroidal thickness was significantly higher (p < 0.0001); however, choroidal vascularity was significantly lower (p < 0.0001). The stromal area to vascular area (S/V) ratio of the choroid was significantly increased (p < 0.0001). All quadrants of the peripapillary retinal nerve fiber layer (RNFL) thicknesses were significantly increased (for all, p < 0.05). The reflectivity of OCT echo of the choroid and peripapillary RNFL was significantly higher (p = 0.023, p < 0.0001, respectively). CONCLUSION: This study detected significant posterior ocular structural and vascular alterations in patients with severe COVID-19 infections. These findings may be associated with direct host-virus interaction or linked to an autoimmune process, vasculopathy, or viral-mediated inflammation.

SD-OCT assessment of macular and optic nerve alterations in patients recovered from COVID-19.

OBJECTIVE: To quantify microstructutal alterations in the macula and peripapillary retinal nerve fibre layer (RNFL) in patients recovered from coronavirus disease 2019 (COVID-19) using spectral domain optic coherence tomography (SD-OCT). DESIGN: Retrospective, observational. PARTICIPANTS: This comparative, cross-sectional study included patients who recovered from COVID-19 (Group 1) and age- and sex-matched normal controls (Group 2). METHODS: A comprehensive ophthalmic examination, including best-corrected visual acuity and biomicroscopic anterior and posterior segment examination was performed. SD-OCT analysis of the macula and peripapillary RNFL was obtained for each participant. In addition, patient demographics and comorbidities were recorded. RESULTS: 238 eyes of 122 subjects (Group 1: n = 63; Group 2: n = 59) were included. The incidence of coexisting comorbidity was higher in Group 1 (n = 26/63, 41.3%) compared with Group 2 (n = 12/59, 20.3%) (p = 0.013). The central foveal thickness (CFT) was significantly higher in Group 1 (271.0±26.8 µm) than Group 2 (263.2±22.0 µm) (p = 0.015). The average outer nuclear layer (ONL) thickness at central fovea in Group 1 (85.4±13.3 µm) was significantly thicker than that in Group 2 (81.4±15.2 µm) (p = 0.035). The mean peripapillary RNFL thickness of Group 1 (102.6±8.8 µm) and Group 2 (100.9±8.3 µm) were similar (p = 0.145). The mean choroidal thickness of groups at the fovea and at 1500 µm nasal and temporal to the fovea were not significantly different (p > 0.05 for all). CONCLUSION: Significant thickness alterations in individual retinal layers and CFT was detected in post-COVID-19 patients. The increase in CFT and ONL thickness might be attributed to direct infection or viral-induced inflammatory response of retina.

Retinal nerve fibre layer and ganglion cell layer changes in children who recovered from COVID-19: a cohort study.

OBJECTIVE: To investigate the optic nerve and macular parameters of children who recovered from COVID-19 compared with healthy children using optical coherence tomography (OCT). DESIGN: Cohort study. SETTING: Hospital Clinico San Carlos, Madrid. PATIENTS: Children between 6 and 18 years old who recovered from COVID-19 with laboratory-confirmed SARS-CoV-2 infection and historical controls were included. INTERVENTIONS: All patients underwent an ophthalmological examination, including macular and optic nerve OCT. Demographic data, medical history and COVID-19 symptoms were noted. MAIN OUTCOME MEASURES: Peripapillary retinal nerve fibre layer thickness, macular retinal nerve fibre layer thickness, macular ganglion cell layer thickness and retinal thickness. RESULTS: 90 patients were included: 29 children who recovered from COVID-19 and 61 controls. Patients with COVID-19 presented an increase in global peripapillary retinal nerve fibre layer thickness (mean difference 7.7; 95% CI 3.4 to 12.1), temporal superior (mean difference 11.0; 95% CI 3.3 to 18.6), temporal inferior (mean difference 15.6; 95% CI 6.5 to 24.7) and nasal (mean difference 9.8; 95% CI 2.9 to 16.7) sectors. Macular retinal nerve fibre layer analysis showed decreased thickness in the nasal outer (p=0.011) and temporal inner (p=0.036) sectors in patients with COVID-19, while macular ganglion cell layer thickness increased in these sectors (p=0.001 and p=0.015, respectively). No differences in retinal thickness were noted. CONCLUSIONS: Children with recent history of COVID-19 present significant changes in peripapillary and macular OCT analyses.

COVID-19: more than a respiratory virus, an optical coherence tomography study.

PURPOSE: The purpose of this study is to investigate anatomic and morphologic features of inner and outer retinal layers in patients recovered from COVID-19 with Spectral Domain Optical Coherence Tomography (SD-OCT), whether correlate with any symptoms during disease process. METHODS: 32 patients recovered from COVID-19 and age- and gender-matched 36 healthy controls were included in this cross-sectional study. Ganglion cell-inner plexiform layer, macular and peripapiller retinal nerve fiber layer (RNFL), inner nuclear layer (INL), outer nuclear layer (ONL), outer plexiform layer (OPL) and the outer retinal hyperreflective bands including external limiting membrane (ELM), ellipsoid zone (EZ) and interdigitation zone (IZ) were examined with SD-OCT. The differences of each retinal layers thickness among subgroup analysis of ocular pain and headache were also compared. RESULTS: Macular RNFL of inner and outer nasal and outer inferior quadrants were thinner in COVID-19 patients compared to healthy control group (p = 0.046, p = 0.014 and p = 0.016, respectively). Thinning in outer superior quadrant of GCIPL and INL quadrants were detected in patients with headache (p = 0.026 and p = 0.01). Superonasal and inferotemporal sectors of pRNFL were thinner in patients with ocular pain compared to patients without ocular pain (p = 0.024 and p = 0.015). Integrity of EZ, ELM and IZ was evaluated as continuous line and protected on each OCT scans. CONCLUSION: The study demonstrated convincing evidence that SARS-CoV-2 can affect the inner and outer retinal layers, with subclinical localized alterations, particularly in patients with headache and ocular pain symptoms during COVID-19 period.

Quantitative assessment of retinal changes in COVID-19 patients.

CLINICAL RELEVANCE: The SARS-COV 2 virus, which is responsible for the COVID-19 pandemic, acts on the angiotensin converting enzyme 2 (ACE-2) receptor in the host cell. Ocular effects may occur because of the ACE-2 receptor in the retina. BACKGROUND: To investigate the impact of COVID-19 on the retinal layers and optic disc parameters in previously confirmed COVID-19 patients using spectral domain optical coherence tomography (SD-OCT). METHODS: This study included 60 eyes of 60 subjects; 35 of them were in the COVID-19 group and the remaining 25 were in the control group. Patients with the diagnosis of COVID-19 that had a negative result after treatment were included in the study. Macular and peripapillary retinal nerve fiber layer (RNFL) thickness measurements, each retinal layer thickness of all participants were done 14-30 days after COVID-19 symptom onset, following the negative result of real time reverse transcriptase-polymerase chain reaction test using SD-OCT. RESULTS: The mean value of central macular thickness was significantly higher in the COVID-19 group than the control group (p = 0.02). The mean values of the ganglion cell layer and inner nuclear layer thickness in the COVID-19 group were significantly thinner than control group (p = 0.04 and p = 0.04, respectively). Even though mean RNFL thickness measurements in all sections in the COVID-19 group was thinner than controls, there were no significant differences between groups (p > 0.05 for all). CONCLUSION: In the early recovery phase, changes in the macula, ganglion cell layer and inner nuclear layer could be seen. These patients should be followed up closely for the recognition of new pathologies that could be seen in the late recovery phase.

Optic nerve and macular optical coherence tomography in recovered COVID-19 patients.

PURPOSE: To investigate the peripapillary retinal nerve fiber layer thickness (RNFLT), macular RNFLT, ganglion cell layer (GCL), and inner plexiform layer (IPL) thickness in recovered COVID-19 patients compared to controls. METHODS: Patients previously diagnosed with COVID-19 were included, while healthy patients formed the historic control group. All patients underwent an ophthalmological examination, including macular and optic nerve optical coherence tomography. In the case group, socio-demographic data, medical history, and neurological symptoms were collected. RESULTS: One hundred sixty patients were included; 90 recovered COVID-19 patients and 70 controls. COVID-19 patients presented increases in global RNFLT (mean difference 4.3; CI95% 0.8 to 7.7), nasal superior (mean difference 6.9; CI95% 0.4 to 13.4), and nasal inferior (mean difference 10.2; CI95% 2.4 to 18.1) sectors of peripapillary RNFLT. Macular RNFL showed decreases in COVID-19 patients in volume (mean difference -0.05; CI95% -0.08 to -0.02), superior inner (mean difference -1.4; CI95% -2.5 to -0.4), nasal inner (mean difference -1.1; CI95% -1.8 to -0.3), and nasal outer (mean difference -4.7; CI95% -7.0 to -2.4) quadrants. COVID-19 patients presented increased GCL thickness in volume (mean difference 0.04; CI95% 0.01 to 0.07), superior outer (mean difference 2.1; CI95% 0.8 to 3.3), nasal outer (mean difference 2.5; CI95% 1.1 to 4.0), and inferior outer (mean difference1.2; CI95% 0.1 to 2.4) quadrants. COVID-19 patients with anosmia and ageusia presented an increase in peripapillary RNFLT and macular GCL compared to patients without these symptoms. CONCLUSIONS: SARS-CoV-2 may affect the optic nerve and cause changes in the retinal layers once the infection has resolved.

Optic Nerve Head Parameters and Peripapillary Retinal Nerve Fiber Layer Thickness in Patients with Coronavirus Disease 2019.

PURPOSE: To quantify the optic nerve head (ONH) and peripapillary retinal nerve fiber layer (pRNFL) thickness in patients with Coronavirus Disease-2019 (COVID-19) and compare the measurements with a healthy control group. METHODS: In a comparative cross-sectional observational study, ONH and pRNFL thickness were evaluated in patients with a history of COVID-19, at least 2 weeks after recovery from the systemic disease, and compared with an age-matched, normal control group. RESULTS: Thirty COVID-19 patients along with 60 age- and gender-matched healthy controls were studied. Mean average pRNFL thickness was 105.0 ± 16.3 µm in the COVID-19 patients, compared to 99.0 ± 9.0 µm in the controls (p = .31). The pRNFL thicknesses in all sectors was higher in patients with a history of COVID-19; however, this did not reach statistical significance. Similarly, ONH parameters were not significantly different between the groups. CONCLUSION: Patients recovered from COVID-19 had unremarkable alterations in the peripapillary RNFL thickness. ABBREVIATIONS: ONH: Optic Nerve HeadRNFL: Retinal Nerve Fiber LayerSD-OCT: Spectral-Domain Optical Coherence TomographyCOVID-19: Coronavirus Disease 2019SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2CNS: Central Nervous SystemACE: Angiotensin-Converting EnzymeRT-PCR: Reverse Transcription-Polymerase Chain Reaction.