Risk of diabetic retinopathy and diabetic macular oedema with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in type 2 diabetes: a real-world data study from a global federated database.

AIMS/HYPOTHESIS: A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. METHODS: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. RESULTS: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). CONCLUSIONS/INTERPRETATION: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated  retinal imaging are required to determine the causal relationship with these therapies.

Cardiovascular Outcomes with Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Patients with Diabetes: A Real-World Data Analysis.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is commonly used intravitreally for diabetic proliferative retinopathy, but when used systemically for treating cancers, an excess of cardiovascular disease (CVD) events has been noted. The latter is of concern for people with diabetes, who are at higher risk of CVD. This study aims to explore the relationship between incident CVD and intravitreal anti-VEGF therapy in patients with diabetes, compared to other therapies, using a large real-world global federated dataset. METHODS: Data were analysed using TriNetX, a global electronic medical real-world ecosystem. The study included adults with diabetes and excluded those with a history of CVD prior to the time window of data extraction. Patients were categorised into two cohorts: anti-VEGF therapy or control cohort (laser or steroid therapies). The cohorts were 1:1 propensity score-matched for age, sex, ethnicity, body mass index, systolic blood pressure, HbA1c, and cardiovascular medications. Outcomes analysed at 1, 6 and 12 months were: (1) mortality; (2) acute myocardial infarction (MI); (3) cerebral infarction; and (4) heart failure. Relative risk analyses were performed using the built-in R statistical computing platform on TriNetX. RESULTS: In patients with diabetes (n = 2205; mean age 58.8 ± 15.8, Std diff 0.05; 56% male), anti-VEGF therapy was associated with a numerical but non-statistically significant increased CVD risk over 1, 6, and 12 months: Mortality over 1 month (RR 1; 95% CI 0.42, 2.40), 6 months (RR 1.46; 95% CI 0.72, 2.95) and 12 months (RR 1.41; 95% CI 0.88, 2.27). There was no excess of acute MI over 1 (RR n/a: not applicable; 0/0: 0 events in the anti-VEGF group/0 events in the control group), 6 and 12 months (RR n/a; 0/10 events); cerebral infarction over 1, 6 months (RR n/a; 0/0 events), and 12 months (RR n/a; 0/10); and heart failure over 1 month (RR n/a; 0/0 events), 6 months (RR 1; 95% CI 0.42, 2.40) and 12 months (RR 1; 95% CI 0.42, 2.34). CONCLUSIONS: There was no statistically significant risk of cardiovascular-related events in the short or medium term in patients with diabetes who received intravitreal anti-VEGF therapy, despite a small increase in the number of CVD events. Our study supports the real-world safety of intravitreal anti-VEGF therapy in patients with diabetes free of baseline CVD.

Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

A Case of Traumatic Submacular Hemorrhage Treated with tPA and Pneumatic Displacement.

This is a case of a 31-year-old female who presented to the emergency department at a London teaching hospital with a 24-h history of visual loss following an assault. The ophthalmological routine examination showed a submacular hemorrhage (SMH), and a computerized tomography scan demonstrated a displaced orbital floor fracture with inferior rectus entrapment and a medial wall fracture. To induce displacement of the SMH, intravitreal injection of 0.25 µg tissue plasminogen activator (tPA) was combined with 0.3 mL of intravitreal 100% perfluoropropane (C3F8) gas. At the 1-day follow-up, there was an inferotemporal displacement of the blood clot, and visual acuity improved from hand motions to 6/5 within 3 months. No complications occurred over 2 years of follow-up, with a final visual acuity of 6/5. This case shows us that intravitreal tPA and gas appear safe and effective as a treatment for traumatic SMHs. Furthermore, our results demonstrate that prompt treatment leads to favorable anatomical and functional outcomes.

Diagnosis, Classification, and Assessment of the Underlying Etiology of Uveitis by Artificial Intelligence: A Systematic Review.

Recent years have seen the emergence and application of artificial intelligence (AI) in diagnostic decision support systems. There are approximately 80 etiologies that can underly uveitis, some very rare, and AI may lend itself to their detection. This synthesis of the literature selected articles that focused on the use of AI in determining the diagnosis, classification, and underlying etiology of uveitis. The AI-based systems demonstrated relatively good performance, with a classification accuracy of 93-99% and a sensitivity of at least 80% for identifying the two most probable etiologies underlying uveitis. However, there were limitations to the evidence. Firstly, most data were collected retrospectively with missing data. Secondly, ophthalmic, demographic, clinical, and ancillary tests were not reliably integrated into the algorithms' dataset. Thirdly, patient numbers were small, which is problematic when aiming to discriminate rare and complex diagnoses. In conclusion, the data indicate that AI has potential as a diagnostic decision support system, but clinical applicability is not yet established. Future studies and technologies need to incorporate more comprehensive clinical data and larger patient populations. In time, these should improve AI-based diagnostic tools and help clinicians diagnose, classify, and manage patients with uveitis.

Effect of socioeconomic deprivation as determined by the English deprivation deciles on the progression of diabetic retinopathy and maculopathy: a multivariate case-control analysis of 88 910 patients attending a South-East London diabetic eye screening service.

PURPOSE: To determine associations between deprivation using the Index of Multiple Deprivation (IMD and individual IMD subdomains) with incident referable diabetic retinopathy/maculopathy (termed rDR). METHODS: Anonymised demographic and screening data collected by the South-East London Diabetic Eye Screening Programme were extracted from September 2013 to December 2019. Multivariable Cox proportional models were used to explore the association between the IMD, IMD subdomains and rDR. RESULTS: From 118 508 people with diabetes who attended during the study period, 88 910 (75%) were eligible. The mean (± SD) age was 59.6 (±14.7) years; 53.94% were male, 52.58% identified as white, 94.28% had type 2 diabetes and the average duration of diabetes was 5.81 (±6.9) years; rDR occurred in 7113 patients (8.00%). Known risk factors of younger age, Black ethnicity, type 2 diabetes, more severe baseline DR and diabetes duration conferred a higher risk of incident rDR. After adjusting for these known risk factors, the multivariable analysis did not show a significant association between IMD (decile 1 vs decile 10) and rDR (HR: 1.08, 95% CI: 0.87 to 1.34, p=0.511). However, high deprivation (decile 1) in three IMD subdomains was associated with rDR, namely living environment (HR: 1.64, 95% CI: 1.12 to 2.41, p=0.011), education skills (HR: 1.64, 95% CI: 1.12 to 2.41, p=0.011) and income (HR: 1.19, 95% CI: 1.02 to 1.38, p=0.024). CONCLUSION: IMD subdomains allow for the detection of associations between aspects of deprivation and rDR, which may be missed when using the aggregate IMD. The generalisation of these findings outside the UK population requires corroboration internationally.

A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration.

PURPOSE: Neovascular (wet) age-related macular degeneration (nAMD) is driven by VEGFs A, C, and D, which promote angiogenesis and vascular permeability. Intravitreal injections of anti-VEGF-A drugs are the standard of care, but these do not inhibit VEGF-C and D, which may explain why many patients fail to respond fully. This trial aimed to test the safety and efficacy of OPT-302, a biologic inhibitor of VEGF-C and D, in combination with the anti-VEGF-A inhibitor ranibizumab. DESIGN: Dose-ranging, phase 2b, randomized, double-masked, sham-controlled trial. PARTICIPANTS: Participants with treatment-naive nAMD were enrolled from 109 sites across Europe, Israel, and the United States. METHODS: Participants were randomized to 6, 4-weekly, intravitreal injections of 0.5 mg OPT-302, 2.0 mg OPT-302, or sham, plus intravitreal 0.5 mg ranibizumab. MAIN OUTCOME MEASURES: The primary outcome was mean change in ETDRS best-corrected visual acuity (BCVA) at 24 weeks. Secondary outcomes (comparing baseline with week 24) were the proportion of participants gaining or losing ≥ 15 ETDRS BCVA letters; area under the ETDRS BCVA over time curve; change in spectral-domain OCT (SD-OCT) central subfield thickness; and change in intraretinal fluid and subretinal fluid on SD-OCT. RESULTS: Of 366 participants recruited from December 1, 2017, to November 30, 2018, 122, 123, and 121 were randomized to 0.5 mg OPT-302, 2.0 mg OPT-302, and sham, respectively. Mean (± standard deviation) visual acuity gain in the 2.0 mg OPT-302 group was significantly superior to sham (+14.2 ± 11.61 vs. +10.8 ± 11.52 letters; P = 0.01). The 0.5 mg OPT-302 group was not significantly different than the sham group (+9.44 ± 11.32 letters; P = 0.83). Compared with sham, the secondary BCVA outcomes favored the 2.0 mg OPT-302 group, with structural outcomes favoring both OPT-302 dosage groups. Adverse events (AEs) were similar across groups, with 16 (13.3%), 7 (5.6%), and 10 (8.3%) participants in the lower-dose, higher-dose, and sham groups, respectively, developing at least 1 serious AE. Two unrelated deaths both occurred in the sham arm. CONCLUSIONS: Significantly superior vision gain was observed with OPT-302 2.0 mg combination therapy, versus standard of care, with favorable safety (ClinicalTrials.gov identifier: NCT03345082). FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The effect of ethnicity on anatomic success following macular hole surgery: a multicentre cohort study.

PURPOSE: The purpose is to assess the effect of ethnicity on surgical macular hole closure. METHODS: A retrospective cohort study was undertaken in five UK National Health Service Hospitals. We included all patients with known ethnicity undergoing vitrectomy, internal limiting membrane peel, and gas/oil tamponade for all stages of primary full-thickness macular hole (FTMH). The primary outcome was anatomic success, defined as FTMH closure with one operation. The secondary outcome was mean change in best-corrected visual acuity (BCVA) comparing baseline with final review. RESULTS: Of 334 operations, the ethnicity profile comprised 78.7% White patients, 11.7% Black patients, 8.1% Asian patients, and 1.5% in mixed/other ethnicities. Mean age was 69.7 years with 68.5% females. Overall, 280 (83.8%) had anatomic success. Anatomic failure occurred in 38.5% of Black patients versus 12.6% of White patients (relative risk: 1.788; 95% CI: 1.012 to 3.159; P = 0.045). Overall, baseline logarithm of the minimum angle of resolution BCVA improved by 0.34, from 0.95 (95% CI: 0.894 to 1.008) to 0.62 (95% CI: 0.556 to 0.676). Mean BCVA improved by 0.35 in White patients, 0.37 in Black patients, 0.23 in Asian patients, and 0.38 in mixed/other ethnicity (P = 0.689). Greater FTMH minimum linear diameter was associated with an increased risk of anatomic failure (relative risk: 1.004; 95% CI: 1.002 to 1.005; P < 0.0001), whereas better pre-operative BCVA (F [1,19] = 162.90; P < 0.0001) and anatomic success (F [1,19] = 97.69; P < 0.0001) were associated with greater BCVA improvement. Socio-economic status did not significantly influence anatomic success or BCVA change. CONCLUSIONS: Black ethnicity is associated with an approximately twofold greater risk of failed FTMH surgery. The reasons for this difference warrant further study.

Epimacular brachytherapy for previously treated neovascular age-related macular degeneration: month 36 results of the MERLOT randomised controlled trial.

BACKGROUND/AIM: To assess the long-term safety and efficacy of epimacular brachytherapy (EMB) for chronic, active, neovascular age-related macular degeneration (nAMD). METHODS: This pivotal, randomised, controlled surgical device trial recruited patients with chronic nAMD receiving intravitreal ranibizumab from 24 UK hospitals. Participants were randomised to either pars plana vitrectomy with 24 Gray EMB and pro re nata (PRN) ranibizumab (n=224) or PRN ranibizumab monotherapy (n=119). Although masking was not possible, masked clinicians assessed best-corrected visual acuity (BCVA) and imaging. After month 24, participants reverted to standard care, with either ranibizumab or aflibercept, returning for a month 36 study visit. RESULTS: Of 363 participants, 309 (85.1%) completed month 36. The number of injections was 12.1±8.1 in the EMB group versus 11.4±6.1 in the ranibizumab group (difference 0.7, 95% CI of difference -0.9 to 2.3, p=0.41) between months 1 and 36, and 3.6±3.3 (n=200) versus 3.9±2.7 (n=102) (difference -0.3, 95% CI of difference -1.0 to 0.4, p=0.43) between months 25 and 36 (standard care). Over 36 months, BCVA change was -19.7±18.5 letters in the EMB group and -4.8±12.5 in the ranibizumab group (difference -14.9, 95% CI of difference -18.5 to -11.2, p<0.0001). The month 36 BCVA of 20 EMB-treated participants with microvascular abnormalities (MVAs) at month 24 was similar to EMB-treated participants without MVAs (-21.8 vs -19.4 letters, p=0.65). CONCLUSION: EMB does not reduce the number of anti-vascular endothelial growth factor (VEGF) injections, either within or outside of a trial setting, and is associated with worse BCVA than anti-VEGF monotherapy. TRIAL REGISTRATION NUMBER: NCT01006538.

Multimodal testing reveals subclinical neurovascular dysfunction in prediabetes, challenging the diagnostic threshold of diabetes.

AIM: To explore if novel non-invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes. METHODS: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross-sectional analysis with optical coherence tomography angiography (OCT-A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC). RESULTS: Seventy-five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16-Td·s: 4.05 µV, 95% confidence interval [95% CI] 0.96-7.13) and high (32-Td·s: 5·20 µV, 95% CI 1.54-8.86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm2 , 95% CI 0.005-0.095) and deep (0.048 pixels/mm2 , 95% CI 0.003-0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32-Td·s (r = -0.256, p = 0.028), implicit time at 32-Td·s (r = 0.422, p < 0.001) and 16-Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = -0.238, p = 0.049) and deep (r = -0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = -0.293, p = 0.017), and ESC-hands (r = -0.244, p = 0.035) were observed. HOMA-IR was a predictor of CNFD (ß = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (ß = -5.02, 95% CI -10.01 to -0.05, p = 0.048). CONCLUSIONS: The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT-A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies.

Artificial Intelligence and Corneal Confocal Microscopy: The Start of a Beautiful Relationship.

Corneal confocal microscopy (CCM) is a rapid non-invasive in vivo ophthalmic imaging technique that images the cornea. Historically, it was utilised in the diagnosis and clinical management of corneal epithelial and stromal disorders. However, over the past 20 years, CCM has been increasingly used to image sub-basal small nerve fibres in a variety of peripheral neuropathies and central neurodegenerative diseases. CCM has been used to identify subclinical nerve damage and to predict the development of diabetic peripheral neuropathy (DPN). The complex structure of the corneal sub-basal nerve plexus can be readily analysed through nerve segmentation with manual or automated quantification of parameters such as corneal nerve fibre length (CNFL), nerve fibre density (CNFD), and nerve branch density (CNBD). Large quantities of 2D corneal nerve images lend themselves to the application of artificial intelligence (AI)-based deep learning algorithms (DLA). Indeed, DLA have demonstrated performance comparable to manual but superior to automated quantification of corneal nerve morphology. Recently, our end-to-end classification with a 3 class AI model demonstrated high sensitivity and specificity in differentiating healthy volunteers from people with and without peripheral neuropathy. We believe there is significant scope and need to apply AI to help differentiate between peripheral neuropathies and also central neurodegenerative disorders. AI has significant potential to enhance the diagnostic and prognostic utility of CCM in the management of both peripheral and central neurodegenerative diseases.

Automated image curation in diabetic retinopathy screening using deep learning.

Diabetic retinopathy (DR) screening images are heterogeneous and contain undesirable non-retinal, incorrect field and ungradable samples which require curation, a laborious task to perform manually. We developed and validated single and multi-output laterality, retinal presence, retinal field and gradability classification deep learning (DL) models for automated curation. The internal dataset comprised of 7743 images from DR screening (UK) with 1479 external test images (Portugal and Paraguay). Internal vs external multi-output laterality AUROC were right (0.994 vs 0.905), left (0.994 vs 0.911) and unidentifiable (0.996 vs 0.680). Retinal presence AUROC were (1.000 vs 1.000). Retinal field AUROC were macula (0.994 vs 0.955), nasal (0.995 vs 0.962) and other retinal field (0.997 vs 0.944). Gradability AUROC were (0.985 vs 0.918). DL effectively detects laterality, retinal presence, retinal field and gradability of DR screening images with generalisation between centres and populations. DL models could be used for automated image curation within DR screening.

The prevalence of retinopathy in prediabetes: A systematic review.

Diabetic retinopathy is a leading cause of vision loss globally. The current diagnostic thresholds for diabetes are still based on historic data correlating glycemic parameters with retinopathy; however, an excess prevalence of retinopathy has also been reported in prediabetes. We aimed to determine the reported prevalence of retinopathy in adults with prediabetes. We performed searches using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL, Google Scholar and the Cochrane databases from inception to August 1, 2020. We evaluated methodological quality and certainty of the evidence using a validated risk of bias tool and GRADE, respectively. Twenty-four studies (8,759 participants with prediabetes) were included after screening 5,155 abstracts and reviewing 98 full-text records. Nineteen studies (79%) reported population-based data. Retinopathy prevalence estimates ranged between 0.3-14.1% (median 7.1%, interquartile range 2.4-9.7%), with high variance in estimates due to differing screening methods, retinopathy grading protocols and study populations. We judged this as low-certainty evidence using GRADE, downgrading for risk of bias and inconsistency. From studies that compared both populations, post hoc analysis revealed a lower median retinopathy prevalence in normal glucose tolerance (3.2%, interquartile range 0.3-7.3%) than prediabetes (6.6%, interquartile range 1.9-9.8%). These data suggest an excess prevalence of retinopathy in prediabetes.

ASSOCIATIONS BETWEEN DYSGLYCEMIA, RETINAL NEURODEGENERATION, AND MICROALBUMINURIA IN PREDIABETES AND TYPE 2 DIABETES.

PURPOSE: To explore the association between retinal neurodegeneration and metabolic parameters in progressive dysglycemia. METHOD: A cross-sectional study was performed on 68 participants: normal glucose tolerance (n = 23), prediabetes (n = 25), and Type 2 diabetes without diabetic retinopathy (n = 20). Anthropometric assessment and laboratory sampling for HbA1c, fasting glucose, insulin, c-peptide, lipid profile, renal function, and albumin-to-creatinine ratio were conducted. Central and pericentral macular thicknesses on spectral domain optical coherence tomography were compared with systemic parameters. RESULTS: Baseline demographic characteristics were similar across all groups. Cuzick's trend test revealed progressive full-thickness macular thinning with increasing dysglycemia across all three groups (P = 0.015). The urinary albumin-to-creatinine ratio was significantly correlated with full-thickness superior (R = -0.435; P = 0.0002), inferior (R = -0.409; P = 0.0005), temporal (R = -0.429; P = 0.003), and nasal (R = -0.493; P < 0.0001) pericentral macular thinning, after post hoc Bonferroni adjustment. There was no association between macular thinning and waist circumference, body mass index, blood pressure, lipid profile, or insulin resistance. CONCLUSION: Progressive dysglycemia is associated with macular thinning before the onset of visible retinopathy and occurs alongside microalbuminuria. Retinal neurodegenerative changes may help identify those most at risk from dysglycemic end-organ damage.

Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial.

BACKGROUND: Neovascular (wet) age-related macular degeneration (AMD) can be associated with large submacular haemorrhage (SMH). The natural history of SMH is very poor, with typically marked and permanent loss of central vision in the affected eye. Practice surveys indicate varied management approaches including observation, intravitreal anti-vascular endothelial growth factor therapy, intravitreal gas to pneumatically displace SMH, intravitreal alteplase (tissue plasminogen activator, TPA) to dissolve the clot, subretinal TPA via vitrectomy, and varying combinations thereof. No large, published, randomised controlled trials have compared these management options. METHODS: TIGER is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomised controlled surgical trial. Eligible participants have large, fovea-involving SMH of no more than 15 days duration due to treatment-naïve or previously treated neovascular AMD, including idiopathic polypoidal choroidal vasculopathy and retinal angiomatous proliferation. A total of 210 participants are randomised in a 1:1 ratio to pars plana vitrectomy, off-label subretinal TPA up to 25 µg in 0.25 ml, intravitreal 20% sulfahexafluoride gas and intravitreal aflibercept, or intravitreal aflibercept monotherapy. Aflibercept 2 mg is administered to both groups monthly for 3 doses, then 2-monthly to month 12. The primary efficacy outcome is the proportion of participants with best-corrected visual acuity (BCVA) gain of ≥ 10 Early Treatment Diabetic Retinopathy (ETDRS) letters in the study eye at month 12. Secondary efficacy outcomes (at 6 and 12 months unless noted otherwise) are proportion of participants with a BCVA gain of ≥ 10 ETDRS letters at 6 months, mean ETDRS BCVA, Radner maximum reading speed, National Eye Institute 25-item Visual Function Questionnaire composite score, EQ-5D-5L with vision bolt-on score, Short Warwick and Edinburgh Mental Wellbeing score, scotoma size on Humphrey field analyser, and presence/absence of subfoveal fibrosis and/or atrophy and area of fibrosis/atrophy using independent reading centre multimodal image analysis (12 months only). Key safety outcomes are adverse events, serious adverse events, and important medical events, coded using the Medical Dictionary for Regulatory Activities Preferred Terms. DISCUSSION: The best management of SMH is unknown. TIGER aims to establish if the benefits of SMH surgery outweigh the risks, relative to aflibercept monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663750 ; EudraCT: 2020-004917-10.

Determining vitreous viscosity using fluorescence recovery after photobleaching.

PURPOSE: Vitreous humor is a complex biofluid whose composition determines its structure and function. Vitreous viscosity will affect the delivery, distribution, and half-life of intraocular drugs, and key physiological molecules. The central pig vitreous is thought to closely match human vitreous viscosity. Diffusion is inversely related to viscosity, and diffusion is of fundamental importance for all biochemical reactions. Fluorescence Recovery After Photobleaching (FRAP) may provide a novel means of measuring intravitreal diffusion that could be applied to drugs and physiological macromolecules. It would also provide information about vitreous viscosity, which is relevant to drug elimination, and delivery. METHODS: Vitreous viscosity and intravitreal macromolecular diffusion of fluorescently labelled macromolecules were investigated in porcine eyes using fluorescence recovery after photobleaching (FRAP). Fluorescein isothiocyanate conjugated (FITC) dextrans and ficolls of varying molecular weights (MWs), and FITC-bovine serum albumin (BSA) were employed using FRAP bleach areas of different diameters. RESULTS: The mean (±standard deviation) viscosity of porcine vitreous using dextran, ficoll and BSA were 3.54 ± 1.40, 2.86 ± 1.13 and 4.54 ± 0.13 cP respectively, with an average of 3.65 ± 0.60 cP. CONCLUSIONS: FRAP is a feasible and practical optical method to quantify the diffusion of macromolecules through vitreous.

Ocriplasmin for treatment of vitreomacular traction and macular hole: A systematic literature review and individual participant data meta-analysis of randomized, controlled, double-masked trials.

Ocriplasmin is used to treat vitreomacular traction (VMT), with or without full-thickness macular hole (MH). We systematically reviewed the evidence on ocriplasmin's effect on vitreomacular adhesion resolution (VMAR), MH closure, vitrectomy, and best-corrected visual acuity (BCVA) and investigated the effect of baseline covariates on outcome. We applied individual participant data meta-analyses to the entire population and to subgroups defined by MH or epiretinal membrane (ERM) presence. Safety data were pooled and tabulated. Five randomized controlled trials (1,067 participants) were included. Six months after treatment, ocriplasmin achieved higher rates of VMAR and MH closure versus control, lowered vitrectomy odds, and increased the likelihood of a ≥10-letter BCVA increase. VMAR rates were lower when ERM, broad VMA (> 1500 µm), diabetic retinopathy, or pseudophakia were present and higher in younger participants, women, and eyes with MHs. Ocriplasmin-treated participants experienced more short-term visual impairment that was not predictive of final BCVA, as well as vitreous floaters, photopsia, photophobia, eye pain, blurred vision, and dyschromatopsia. The most common serious adverse events for ocriplasmin and control, respectively, were MH progression (22.5%, 17.3%), new MH (1.5%, 3.4%) and retinal detachment (0.8%, 1.2%). Ocriplasmin promotes VMAR and MH closure. Transient visual phenomena are not uncommon.

The Effect of Intravitreal Ocriplasmin on Hue Discrimination.

SIGNIFICANCE: We report 13 patients who received ocriplasmin for symptomatic vitreomacular adhesion. Farnsworth-Munsell 100 (FM 100) hue test total error score (TES) increased from baseline to month 1, before recovering at year 1. Ocriplasmin may alter hue discrimination. PURPOSE: This study aimed to determine whether intravitreal ocriplasmin affects hue discrimination. METHODS: Thirteen patients with symptomatic vitreomacular adhesion received intravitreal ocriplasmin 125 µg. Patients underwent full ocular examination, optical coherence tomography, and FM 100 hue test at baseline, 1 week, 1 month, and 1 year. RESULTS: Mean age was 74.8 years. The median baseline FM 100 TES was similar in the injected and fellow eyes (272 vs. 252, respectively). Median TES in the injected eye increased from 272 to 348 at 1 week (median difference compared with baseline, +52.0; 98.8% confidence interval of difference, -64.0 to 184.0; P = .29), decreased to 324 at 1 month (median difference compared with baseline, -4.0; 98.8% confidence interval of difference, -44.0 to 256.0; P = .40), and decreased to 268 at 1 year (median difference compared with baseline, -108.0; 93.8% confidence interval of difference, -200.0 to 52.0; P = .19). Two patients (15.4%) had anatomic release of vitreomacular adhesion, occurring within 1 month of injection. CONCLUSIONS: Ocriplasmin may alter hue discrimination, but larger studies are required to provide sufficient power to detect or exclude a statistically significant effect. Longer follow-up is needed to determine the duration of any effect.