Multimodal Retinal Imaging in Patients with Diabetes Mellitus and Association with Cerebrovascular Disease.

INTRODUCTION: This study aimed to evaluate the association between macular optical coherence tomography angiography (OCT-A) metrics, characteristics of ultrawide field (UWF) imaging, and cerebrovascular disease in patients with diabetes mellitus (DM) with different stages of diabetic retinopathy (DR). METHODS: 516 eyes of 258 DM patients were enrolled in two centers (Milan and Belfast). UWF color fundus photos (CFPs) were obtained with Optos California (Optos, PLC) and graded for both DR severity and predominantly peripheral lesions presence (>50% of CFP lesions) by two independent graders. OCT-A (3 × 3 mm), available in 252 eyes of 136 patients, was used to determine perimeter, area, and circularity index of the foveal avascular zone and vessel density (VD); perfusion density (PD); fractal dimension on superficial, intermediate (ICP), and deep capillary plexuses; flow voids (FVs) in the choriocapillaris. RESULTS: Out of 516 eyes, 108 eyes (20.9%) had no DR, and 6 eyes were not gradable. The remaining 402 eyes were as follows: 10.3% (53) had mild nonproliferative DR (NPDR), 38.2% (197) had moderate NPDR, 11.8% (61) had severe NPDR, and 17.6% (91) had proliferative DR. A worse DR stage was associated with a history of stroke (p = 0.044). Logistic regression analysis after taking into account sex, type of DM, age, DM duration, and OCT-A variables found that PD and VD on ICP were significantly associated with presence of stroke and DR severity. CONCLUSION: OCT-A metrics show an association with the presence of cerebrovascular complications, providing potentially useful parameters to estimate vascular risk in patients with DM.

Retinal vascular occlusion and SARS-CoV-2 vaccination.

PURPOSE: To assess the clinical and retinal imaging features of patients in whom retinal vascular occlusion (VO) had developed in temporal associations with COVID-19 vaccination. METHODS: In this retrospective case series, all consecutive adult patients with new onset VO within 6 weeks of vaccination against COVID-19 were included in the study between May 1 and October 31, 2021. All patients had a systemic medical health assessment, full ophthalmic evaluation, and complete fundus imaging. RESULTS: Fifteen eyes of VO (14 patients) after COVID-19 vaccinations were identified. The median time between vaccination and symptoms onset was 14 days (range 7-42 days). The mean best-corrected visual acuity (BCVA) was 20/55 with a range of 20/20 to 20/200. Eleven of 15 eyes (73.3%) had visual acuity improvement after intravitreal treatment at 60-90 days (range, 45-105 days) from the presentation. Four of 5 cases without systemic risk factors for VO had a mean BCVA > 20/32 at presentation and > 20/25 at the latest evaluation. Between May 1 and October 31, 2021, a temporal association was found between the 15 reported cases and COVID-19 vaccination out of a total of 29 VO (p = 0.05). The incidence of VO was higher in the considered period compared to the equivalent 6-month period in 2019 (1.17% vs 0.52%, respectively; p = 0.0134). CONCLUSIONS: Retinal vascular occlusion with different grades of severity are reported in temporal association with COVID-19 vaccination. The exact pathogenic mechanism needs to be further studied. No certain causal relationship can be established from this case series.

Exploring Patient Demographics and Presence of Retinal Vascular Disease in Paracentral Acute Middle Maculopathy.

PURPOSE: To investigate the sociodemographic profile, the association with retinal vascular diseases (RVD) and systemic comorbidities, and visual outcomes of patients with paracentral acute middle maculopathy (PAMM) in a large, ethnically diverse single-center cohort. DESIGN: Retrospective cohort study. METHODS: Electronic health record query for all patients presenting with PAMM at Moorfields Eye Hospital, London, was completed. Detailed demographic, clinical, and systemic information were collected and analyzed. RESULTS: A total of 78 eyes of 78 patients with confirmed PAMM were included in the study. Forty patients (51.3%) presented with no RVD, 20 patients (25.6%) with retinal vein occlusion (RVO), 16 patients (20.5%) with retinal artery occlusion (RAO), and 2 patients (2.6%) with concomitant RAO and RVO. Patients with PAMM+RAO were older than those with RVO (P = .02) and more likely to have a history of major adverse cardiovascular events (MACE) (P = .01), with a significantly worse presenting best corrected visual acuity (BCVA) (20/50) compared to patients with RVO (P = .02) and no RVD (P < .001). Individuals with isolated PAMM had a significantly higher prevalence of previous MACE (P = .04) and sickle cell disease (SCD) (P = .04) compared to those with RVO. At the last follow-up, 64 patients (85.3%) had a good BCVA (>20/32). CONCLUSIONS: The significant association of PAMM with RVD supports the hypothesis of an ischemic etiology. Individuals with isolated PAMM had a higher prevalence of MACE and SCD. Thus, it is important to prompt immediate referral for a comprehensive systemic evaluation. Across the whole cohort, PAMM was associated with good BCVA improvement during follow-up, indicating a good visual prognosis.

Clinical Features Related to OCT Angiography Artifacts in Patients with Diabetic Macular Edema.

PURPOSE: To investigate the frequency and type of artifacts on OCT angiography (OCTA) images and the relationship with clinical features in eyes with diabetic macular edema (DME). DESIGN: Retrospective, cross-sectional comparative study. SUBJECTS: One hundred ninety-two eyes of 140 patients with DME were included. METHODS: Medical records, OCT and OCTA images (Spectralis), and ultrawidefield color fundus photographs (Optos plc) were evaluated. MAIN OUTCOME MEASURES: The frequency of artifact types (segmentation, motion, projection artifact, and low signal) was determined. The relationships between artifact types and clinical features such as best-corrected visual acuity (BCVA), mean central retinal thickness (CRT), foveal avascular zone (FAZ) area, perimeter, circularity index, perfusion density (PD), vessel density (VD), fractal dimension (FD) in the superficial capillary plexus, intermediate capillary plexus (ICP), and deep capillary plexus (DCP), flow voids (FVs) in the choriocapillaris, presence of hard exudate (HE), and cataract were determined. RESULTS: The mean age was 71.6 ± 11.4 years, and 86 (61.4%) out of 140 were men. Artifacts were present in 63 (32.8%) of 192 eyes. Twenty-nine (15.1%) eyes had segmentation artifacts, 12 (6.3%) had motion artifacts, 11 (5.7%) had projection artifacts, and 18 (9.4%) had low signal. Best-corrected visual acuity, PD, VD, and FD in ICP and DCP were significantly lower; and CRT, FAZ area and perimeter in ICP and DCP, and presence of cystoid macular edema, HE, and cataract were higher in eyes with artifacts versus eyes without artifacts (P < 0.05 for each). Multivariate linear regression analysis showed a significant association between segmentation artifacts and decreased BCVA (odds ratio [OR], 5.277; P = 0.02), increased CRT (OR, 1.015; P < 0.001), increased area of FAZ in DCP (OR, 6.625; P = 0.02), and increased perimeter of FAZ in DCP (OR, 1.775; P < 0.04); there was also a significant association between projection artifacts and presence of HE (OR, 2.017; P = 0.02) and between motion artifacts and presence of cataract (OR, 4.102; P = 0.01). CONCLUSIONS: OCT angiography artifacts were present in one third of DME eyes, with segmentation artifacts being the most frequent type. Determining OCTA artifacts is crucial to ensure accurate clinical evaluation. These data could help in developing more standardized clinical protocols for image acquisition and interpretation used in clinical practice and research. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A gender-based analysis of retinal microvascular alterations in patients with diabetes mellitus using OCT angiography.

PURPOSE: To assess the difference in microvascular changes between males and females with diabetes mellitus (DM) without diabetic retinopathy (NoDR) and with mild-to-moderate non-proliferative diabetic retinopathy (NPDR) using Optical Coherence Tomography Angiography (OCT-A). DESIGN: Retrospective cross-sectional study. METHODS: 267 DM patients, 133 females (49.81 %), 111 with NoDR (41.57 %) and 156 NPDR (58.43 %) were included. Foveal-centered 3 × 3 mm OCT-A images corresponding to the superficial (SCP), intermediate (ICP) and deep capillary plexus (DCP), and full retinal (RET) slab were used for analysis. For each slab, FAZ area, perimeter, and circularity index (CI) were determined, following manual delineation of the FAZ; perfusion (PD) and vessel density (VD), fractal dimension (FD), vessel length density (VLD), geometric perfusion deficits (GPD) were also computed. Flow voids (FV) were determined in the choriocapillaris plexus; and perfused capillary density (PCD) in the RET slab. RESULTS: Females showed larger FAZ CI in SCP and greater FAZ area and perimeter than males in NPDR group. Males had higher central macular thickness than females in NPDR group. All density metrics at the level of ICP and DCP were affected in the NPDR group with no gender differences. Of note, the same significant findings were found in type 1 DM patients, and not in type 2 DM patients. CONCLUSIONS: Our OCT-A findings suggest significant microvascular changes in females with NPDR compared to males, but no such differences in patients without DR. Therefore, gender-related vascular alterations might be present in early stages of DR with potential role.

Paracentral acute middle maculopathy and risk of cardiovascular disease, stroke, and death: a longitudinal study.

PURPOSE: To evaluate the risk of acute cardiovascular events (CVE), including cardiovascular diseases, cerebrovascular diseases, and all-cause mortality in patients with paracentral acute middle maculopathy (PAMM). DESIGN: Retrospective cohort study METHODS: We studied 43 individuals with optical coherence tomography -documented PAMM attending Moorfields Eye Hospital between January 2014 and June 2021. We excluded patients with preceding (< 2 years) major adverse cardiac events. We stratified patients by age (<50 years & ≥50 years) and whether associated with retinal vascular diseases (RVD) or isolated (iPAMM). We assessed risk factors, clinical characteristics, and visual prognosis of the patients. CVE risk was estimated using Kaplan-Meier curves, the log-rank test, and Cox proportional hazards regression. RESULTS: In young patients with iPAMM patients (n=12), underlying predisposing factors included six (50%) sickle cell disease and five (41.6%) others, including breakthrough bleeding in pregnancy, migraine, genetic cardiomyopathy, amphetamine use; among those with PAMM+RVD (n=12) one (9%) had a vascular disorder, and four (44.4%) oral contraceptive use. In the older group of 20 patients, 15 (75%) had at least one coronary risk factor. During a median follow-up of 14 months (range 12-54), older subjects with iPAMM had a higher risk of developing CVE than those with PAMM+RVD (p<0.001). Notably, iPAMM displayed a significantly earlier peak in peri-PAMM CVE risk compared to PAMM+RVD (median: 1 month, range 1-40 months vs. 36 months, range 12-54 months). Relative to those with PAMM+RVD, risk of CVE was significantly higher in patients with iPAMM, adjusted for age and sex (hazard ratio: 6.37, 95% Confidence Interval 1.68-24.14, p=0.017). No young patients experienced adverse CVE. At baseline, older iPAMM patients mean best corrected visual acuity of 0.7 (0-1.8) LogMAR, which improved significantly to 0.2 (0-1.30) LogMAR at the latest visit (p=0.033). CONCLUSION: Young individuals with iPAMM have a higher prevalence of predisposing factors compared to those presenting with combined PAMM+RVD. Older patients with iPAMM had a higher risk of CVE than those with PAMM+RVD, especially in the peri-onset timeframe. This suggests the need for a prompt cardiovascular assessment to rule out systemic etiologies and optimize cardiovascular risk factors, in addition to ongoing ophthalmology input.

Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children.

The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington's disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.

Digital innovations for retinal care in diabetic retinopathy.

AIM: The purpose of this review is to examine the applications of novel digital technology domains for the screening and management of patients with diabetic retinopathy (DR). METHODS: A PubMed engine search was performed, using the terms "Telemedicine", "Digital health", "Telehealth", "Telescreening", "Artificial intelligence", "Deep learning", "Smartphone", "Triage", "Screening", "Home-based", "Monitoring", "Ophthalmology", "Diabetes", "Diabetic Retinopathy", "Retinal imaging". Full-text English language studies from January 1, 2010, to February 1, 2022, and reference lists were considered for the conceptual framework of this review. RESULTS: Diabetes mellitus and its eye complications, including DR, are particularly well suited to digital technologies, providing an ideal model for telehealth initiatives and real-world applications. The current development in the adoption of telemedicine, artificial intelligence and remote monitoring as an alternative to or in addition to traditional forms of care will be discussed. CONCLUSIONS: Advances in digital health have created an ecosystem ripe for telemedicine in the field of DR to thrive. Stakeholders and policymakers should adopt a participatory approach to ensure sustained implementation of these technologies after the COVID-19 pandemic. This article belongs to the Topical Collection "Diabetic Eye Disease", managed by Giuseppe Querques.

Mesenchymal stem and non-stem cell surgery, rescue, and regeneration in glaucomatous optic neuropathy.

BACKGROUND: Glaucomatous optic neuropathy (GON) is an anatomofunctional impairment of the optic nerve triggered by glaucoma. Recently, growth factors (GFs) have been shown to produce retinal neuroenhancement. The suprachoroidal autograft of mesenchymal stem cells (MSCs) by the Limoli retinal restoration technique (LRRT) has proven to achieve retinal neuroenhancement by producing GF directly into the choroidal space. This retrospectively registered clinical study investigated the visual function changes in patients with GON treated with LRRT. METHODS: Twenty-five patients (35 eyes) with GON in progressive disease conditions were included in the study. Each patient underwent a comprehensive ocular examination, including the analysis of best corrected visual acuity (BCVA) for far and near visus, sensitivity by Maia microperimetry, and the study of the spectral domain-optical coherence tomography (SD-OCT). The patients were divided into two groups: a control group, consisting of 21 eyes (average age 72.2 years, range 50-83), and an LRRT group, consisting of 14 eyes (average age 67.4, range 50-84). RESULTS: After 6 months, the BCVA, close-up visus, and microperimetric sensitivity significantly improved in the LRRT-treated group (p<0.05), whereas the mean increases were not statistically significant in controls (p>0.5). CONCLUSIONS: Patients with GON treated with LRRT showed a significant increase in visual performance (VP) both in BCVA and sensitivity and an improvement of residual close-up visus, in the comparison between the LRRT results and the control group. Further studies will be needed to establish the actual significance of the reported findings.

Antioxidant and Biological Properties of Mesenchymal Cells Used for Therapy in Retinitis Pigmentosa.

Both tissue repair and regeneration are a priority in regenerative medicine. Retinitis pigmentosa (RP), a complex retinal disease characterized by the progressive loss of impaired photoreceptors, is currently lacking effective therapies: this represents one of the greatest challenges in the field of ophthalmological research. Although this inherited retinal dystrophy is still an incurable genetic disease, the oxidative damage is an important pathogenetic element that may represent a viable target of therapy. In this review, we summarize the current neuroscientific evidence regarding the effectiveness of cell therapies in RP, especially those based on mesenchymal cells, and we focus on their therapeutic action: limitation of both oxidative stress and apoptotic processes triggered by the disease and promotion of cell survival. Cell therapy could therefore represent a feasible therapeutic option in RP.

Mesenchymal stem cell surgery, rescue and regeneration in retinitis pigmentosa: clinical and rehabilitative prognostic aspects.

PURPOSE: To assess whether treatment with the Limoli Retinal Restoration Technique (LRRT) can be performed in patients with retinitis pigmentosa (RP), grafting the autologous cells in a deep scleral pocket above the choroid of each eye to exert their beneficial effect on the residual retinal cells. METHODS: The patients were subjected to a complete ophthalmological examination, including best corrected visual acuity (BCVA), close-up visus measurements, spectral domain-optical coherence tomography (SD-OCT), microperimetry (MY), and electroretinography (ERG). Furthermore, the complete ophthalmological examination was carried out at baseline (T0) and at 6 months (T180) after surgery. The Shapiro-Wilk test was used to assess the normality of distribution of the investigated parameters. A mixed linear regression model was used to analyse the difference in all the studied parameters at T0 and T180, and to compare the mean change between the two groups. All statistical analyses were performed with STATA 14.0 (Collage Station, Texas, USA). RESULTS: LRRT treatment was performed in 34 eyes of 25 RP patients recruited for the study. The eyes were classified in two groups on the basis of foveal thickness (FT) assessed by SD-OCT: 14 eyes in Group A (FT≤190µm) and the remaining 20 ones in Group B (FT > 190µm). Although it had not reached the statistical significance, Group B showed a better improvement in BCVA, residual close-up visus and sensitivity than Group A. CONCLUSIONS: Previous studies have described the role of LRRT in slowing down retinal degenerative diseases. Consequently, this surgical procedure could improve the clinical and rehabilitative prognostic parameters in RP patients. On the other hand, further clinical research and studies with longer follow-up will be needed to evaluate its efficacy.

Stem Cell Surgery and Growth Factors in Retinitis Pigmentosa Patients: Pilot Study after Literature Review.

To evaluate whether grafting of autologous mesenchymal cells, adipose-derived stem cells, and platelet-rich plasma into the supracoroideal space by surgical treatment with the Limoli retinal restoration technique (LRRT) can exert a beneficial effect in retinitis pigmentosa (RP) patients. Twenty-one eyes underwent surgery and were divided based on retinal foveal thickness (FT) ≤ 190 or > 190 µm into group A-FT and group B-FT, respectively. The specific LRRT triad was grafted in a deep scleral pocket above the choroid of each eye. At 6-month follow-up, group B showed a non-significant improvement in residual close-up visus and sensitivity at microperimetry compared to group A. After an in-depth review of molecular biology studies concerning degenerative phenomena underlying the etiopathogenesis of retinitis pigmentosa (RP), it was concluded that further research is needed on tapeto-retinal degenerations, both from a clinical and molecular point of view, to obtain better functional results. In particular, it is necessary to increase the number of patients, extend observation timeframes, and treat subjects in the presence of still trophic retinal tissue to allow adequate biochemical and functional catering.

Regenerative Therapy by Suprachoroidal Cell Autograft in Dry Age-related Macular Degeneration: Preliminary In Vivo Report.

This study is aimed at examining whether a suprachoroidal graft of autologous cells can improve best corrected visual acuity (BCVA) and responses to microperimetry (MY) in eyes affected by dry Age-related Macular Degeneration (AMD) over time through the production and secretion of growth factors (GFs) on surrounding tissue. Patients were randomly assigned to each study group. All patients were diagnosed with dry AMD and with BCVA equal to or greater than 1 logarithm of the minimum angle of resolution (logMAR). A suprachoroidal autologous graft by Limoli Retinal Restoration Technique (LRRT) was carried out on group A, which included 11 eyes from 11 patients. The technique was performed by implanting adipocytes, adipose-derived stem cells obtained from the stromal vascular fraction, and platelets from platelet-rich plasma in the suprachoroidal space. Conversely, group B, including 14 eyes of 14 patients, was used as a control group. For each patient, diagnosis was verified by confocal scanning laser ophthalmoscope and spectral domain-optical coherence tomography (SD-OCT). In group A, BCVA improved by 0.581 to 0.504 at 90 days and to 0.376 logMAR at 180 days (+32.20%) postoperatively. Furthermore, MY test increased by 11.44 dB to 12.59 dB at 180 days. The different cell types grafted behind the choroid were able to ensure constant GF secretion in the choroidal flow. Consequently, the results indicate that visual acuity (VA) in the grafted group can increase more than in the control group after six months.

Cell surgery and growth factors in dry age-related macular degeneration: visual prognosis and morphological study.

BACKGROUND: The aim of this research was to study the overall restoration effect on residual retinal cells through surgically grafted autologous cells onto the surrounding tissue, choroid and retina in order to produce a constant secretion of growth factors (GFs) in dry age-related macular degeneration (AMD) patients. RESULTS: 6 months after surgery, several values were statistically significant in the group with higher RTA. Also patient compliance analysis (PCA) in relation to functional change perception appeared to be very good. METHODS: Thirty-six eyes of 25 patients (range 64-84 years of age) affected by dry AMD were included in study, and divided in two groups by spectral domain-optical coherence tomography (SD-OCT): group A with retinal thickness average (RTA) less than 250 microns (µm) and group B with RTA equal to or more than 250 µm. Adipocytes, adipose-derived stem cells from the stromal-vascular fraction, and platelets from platelet-rich plasma were implanted in the suprachoroidal space. Particularly, the following parameters were evaluated: best corrected visual acuity (BCVA) for far and near distance, retinal thickness maps, scotopic and photopic electroretinogram (ERG), and microperimetry (MY). All statistical analyses were performed with STATA 14.0 (Collage Station, Texas, USA). CONCLUSIONS: The available set of GFs allowed biological retinal neuroenhancement. After 6 months it improved visual performance (VP), but the increase was better if RTA recorded by OCT was higher, probably in relation to the presence of areas with greater cellularity.

Preliminary study on electrophysiological changes after cellular autograft in age-related macular degeneration.

Evolving atrophic macular degeneration represents at least 80% of all macular degenerations and is currently without a standardized care. Autologous fat transplantation efficacy was demonstrated by several studies, as these cells are able to produce growth factors. The aim of the work was to demonstrate possible therapeutic effect of the joined suprachoroidal graft of adipocytes, adipose-derived stem cells (ADSCs) in stromal vascular fractions (SVFs) of adipose tissue, and platelet-rich plasma (PRP). Twelve eyes in 12 dry age-related macular degeneration (AMD) patients, aged 71.25 (SD ± 6.8) between 62 and 80 years, were analyzed. A complete ocular evaluation was performed using best corrected visual acuity (BCVA), retinographic analysis, spectral-domain optical coherence tomography, microperimetry, computerized visual field, and standard electroretinogram (ERG). Each eye received a cell in graft between choroid and sclera of mature fat cells and ADSCs in SVF enriched with PRP by means of the variant second Limoli (Limoli retinal restoration technique [LRRT]). In order to test if the differences pre- and post-treatment were significant, the Wilcoxon signed-rank test has been performed. Adverse effects were not reported in the patients. After surgery with LRRT, the most significant increase in the ERG values was recorded by scotopic rod-ERG (answer coming from the rods), from 41.26 to 60.83 µV with an average increase of 47.44% highly significant (P < 0.05). Moderately significant was the one recorded by scotopic maximal ERG (answer coming from the rods and cones), from 112.22 to 129.68 µV with an average increase of 15.56% (P < 0.1). Cell-mediated therapy based on growth factors used appears interesting because it can improve the retinal functionality responses in the short term. The ERG could, therefore, be used to monitor the effect of cell-mediated regenerative therapies.