Assessment of Parafoveal Diabetic Macular Ischemia on Optical Coherence Tomography Angiography Images to Predict Diabetic Retinal Disease Progression and Visual Acuity Deterioration.

Importance: The presence of diabetic macular ischemia (DMI) on optical coherence tomography angiography (OCTA) images predicts diabetic retinal disease progression and visual acuity (VA) deterioration, suggesting an OCTA-based DMI evaluation can further enhance diabetic retinopathy (DR) management. Objective: To investigate whether an automated binary DMI algorithm using OCTA images provides prognostic value on DR progression, diabetic macular edema (DME) development, and VA deterioration in a cohort of patients with diabetes. Design, Setting, and Participants: In this cohort study, DMI assessment of superficial capillary plexus and deep capillary plexus OCTA images was performed by a previously developed deep learning algorithm. The presence of DMI was defined as images exhibiting disruption of fovea avascular zone with or without additional areas of capillary loss, while absence of DMI was defined as images presented with intact fovea avascular zone outline and normal distribution of vasculature. Patients with diabetes were recruited starting in July 2015 and were followed up for at least 4 years. Cox proportional hazards models were used to evaluate the association of the presence of DMI with DR progression, DME development, and VA deterioration. Analysis took place between June and December 2022. Main Outcomes and Measures: DR progression, DME development, and VA deterioration. Results: A total of 321 eyes from 178 patients were included for analysis (85 [47.75%] female; mean [SD] age, 63.39 [11.04] years). Over a median (IQR) follow-up of 50.41 (48.16-56.48) months, 105 eyes (32.71%) had DR progression, 33 eyes (10.28%) developed DME, and 68 eyes (21.18%) had VA deterioration. Presence of superficial capillary plexus-DMI (hazard ratio [HR], 2.69; 95% CI, 1.64-4.43; P < .001) and deep capillary plexus-DMI (HR, 3.21; 95% CI, 1.94-5.30; P < .001) at baseline were significantly associated with DR progression, whereas presence of deep capillary plexus-DMI was also associated with DME development (HR, 4.60; 95% CI, 1.15-8.20; P = .003) and VA deterioration (HR, 2.12; 95% CI, 1.01-5.22; P = .04) after adjusting for age, duration of diabetes, fasting glucose, glycated hemoglobin, mean arterial blood pressure, DR severity, ganglion cell-inner plexiform layer thickness, axial length, and smoking at baseline. Conclusions and Relevance: In this study, the presence of DMI on OCTA images demonstrates prognostic value for DR progression, DME development, and VA deterioration.

Response to 1-Year Fixed-Regimen Bevacizumab Therapy in Treatment-Naïve DME Patients: Assessment by OCT Angiography.

PURPOSE: To evaluate the effectiveness of intravitreal bevacizumab treatment in patients with diabetic macular edema (DME) by assessing retinal changes using optical coherence tomography angiography (OCT-A). METHODS: This prospective study was performed in patients with treatment-naïve DME. The eyes of patients were imaged using a swept-source OCT system with a scan area of 6 × 6 mm. The DME patients with a central macular thickness (CMT) of ≥300 µm received nine bevacizumab injections within 12 months. The demographic, systemic, and ocular parameters, including the best-corrected visual acuity (BCVA), CMT, microaneurysm (MA) count, and foveal avascular zone (FAZ) area in both superficial capillary plexus (SCP) and deep capillary plexus (DCP), as well as vessel density in SCP, were assessed in the patients. In addition, the response (good or poor) of the DME eyes to bevacizumab treatment and the final visual acuity (BCVA of 75 letters) were analyzed. RESULTS: Seventy-seven eyes of DME patients were subjected to the final analysis. Bevacizumab treatment reduced CMT from 425.06 µm (±77.15) to 350.25 µm (±82.04) and improved BCVA by about 8.61 letters (from 64.73 to 73.34) in the patients. The mean number of MAs in SCP decreased from 3.51 ± 2.07 to 2.31 ± 1.15 (p < 0.001) and in DCP from 17.12 ± 11.56 to 12.21 ± 6.99 (p < 0.001), whereas the area of FAZ increased in SCP from 328.22 ± 131.38 to 399.70 ± 156.98 (p < 0.001) and in DCP from 571.13 ± 396.01 to 665.89 ± 412.77 (p = 0.001). The final BCVA letter score and CMT were statistically significant in both poor and good responders, as well as in BCVA < 75 and BCVA ≥ 75 groups. CONCLUSION: The fixed-regimen intravitreal bevacizumab therapy was effective in treating DME. Apart from noninvasive visualization of microvascular damage, OCT-A showed limited usefulness in predicting treatment response. Although the study showed that the number of MAs was significantly reduced during treatment, which is an OCT-A predictor of a good response to bevacizumab treatment at a 12-month visit, commonly observed artifacts may reduce the usefulness of OCT-A.

Expression of Long Non-Coding RNA (lncRNA) SNHG5 in Patients with Refractory Diabetic Macular Edema and Its Regulatory Mechanism.

BACKGROUND The aim of this study was to assess use of lncRNAs as biomarkers in serum and aqueous humor of patients with diabetic macular edema (DME). MATERIAL AND METHODS Optical coherence tomography and fundus photography were used to analyze the retinal features of the patients. RT-qPCR was used to analyze the differential expression of lncRNA snhg5 in patients who have idiopathic macular hole (MH), DME, or refractory DME. The relationship between SNHG5 and the clinical characteristics of the patients was analyzed. The effect of SNHG5 on the hyperplasia and apoptosis of human retino-microvascular endothelial cells (HRMECs) and its mechanism were analyzed in vitro. RESULTS Patients with idiopathic MH developed retinal nerve epithelium rupture and retinal fundus thickening, and patients with DME or refractory DME showed significant macular edema with hemorrhaging. The refractory DME patients improved after treatment but still showed significant macular edema and multiple laser scarring. SNHG5 expression was not only low in the atrial fluid and plasma in DME patients, but also lower in the refractory DME group compared to the idiopathic MH patients. SNHG5 expression in the aqueous humor and plasma was negatively correlated with disease duration, body mass index, and levels of fasting blood glucose, glycated hemoglobin, proteinuria, and glycosuria. In the in vitro experiments, SNHG5 expression was significantly downregulated in high glucose-induced HMECs. After SNHG5 overexpression, cell proliferation, angiogenesis, and VEGF-A protein levels were distinctly downregulated. CONCLUSIONS SNHG5 correlates with the development of DME and is a potential target for therapy.

Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS: Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.

Assessment of Detailed Photoreceptor Structure and Retinal Sensitivity in Diabetic Macular Ischemia Using Adaptive Optics-OCT and Microperimetry.

Purpose: The purpose of this study was to assess density and morphology of cone photoreceptors (PRs) and corresponding retinal sensitivity in ischemic compared to nonischemic retinal capillary areas of diabetic eyes using adaptive optics optical coherence tomography (AO-OCT) and microperimetry (MP). Methods: In this cross-sectional, observational study five eyes of four patients (2 eyes with proliferative diabetic retinopathy (DR) and 3 eyes moderate nonproliferative DR) were included. PR morphology and density was manually assessed in AO-OCT en face images both at the axial position of the inner-segment outer segment (IS/OS) and cone outer segment tips (COSTs). Retinal sensitivity was determined by fundus-controlled microperimetry in corresponding areas (MP-3, Nidek). Results: In AO-OCT, areas affected by capillary nonperfusion showed severe alterations of cone PR morphology at IS/OS and COST compared to areas with intact capillary perfusion (84% and 87% vs. 9% and 8% of area affected for IS/OS and COST, respectively). Mean reduction of PR signal density in affected areas compared to those with intact superficial capillary plexus (SCP) and deep capillary plexus (DCP) perfusion of similar eccentricity was -38% at the level of IS/OS (P = 0.01) and -39% at the level of COST (P = 0.01). Mean retinal sensitivity was 10.8 ± 5.4 in areas affected by DCP nonperfusion and 28.2 ± 1.5 outside these areas (P < 0.001). Conclusions: Cone PR morphology and signal density are severely altered in areas of capillary nonperfusion. These structural changes are accompanied by a severe reduction of retinal sensitivity, indicating the importance of preventing impaired capillary circulation in patients with DR.

Understanding inherent image features in CNN-based assessment of diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness and affects millions of people throughout the world. Early detection and timely checkups are key to reduce the risk of blindness. Automated grading of DR is a cost-effective way to ensure early detection and timely checkups. Deep learning or more specifically convolutional neural network (CNN)-based methods produce state-of-the-art performance in DR detection. Whilst CNN based methods have been proposed, no comparisons have been done between the extracted image features and their clinical relevance. Here we first adopt a CNN visualization strategy to discover the inherent image features involved in the CNN's decision-making process. Then, we critically analyze those features with respect to commonly known pathologies namely microaneurysms, hemorrhages and exudates, and other ocular components. We also critically analyze different CNNs by considering what image features they pick up during learning to predict and justify their clinical relevance. The experiments are executed on publicly available fundus datasets (EyePACS and DIARETDB1) achieving an accuracy of 89 ~ 95% with AUC, sensitivity and specificity of respectively 95 ~ 98%, 74 ~ 86%, and 93 ~ 97%, for disease level grading of DR. Whilst different CNNs produce consistent classification results, the rate of picked-up image features disagreement between models could be as high as 70%.

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

BACKGROUND: Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. METHODS: In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. RESULTS: Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. CONCLUSIONS: Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.

Do Black and Asian individuals wait longer for treatment? A survival analysis investigating the effect of ethnicity on time-to-clinic and time-to-treatment for diabetic eye disease.

AIMS/HYPOTHESIS: This study explored the impact of ethnicity on time-to-clinic, time-to-treatment and rates of vision loss in people referred to hospital with diabetic eye disease. METHODS: A survival analysis was performed on all referrals from an inner-city diabetic eye screening programme to a tertiary hospital eye service between 1 October 2013 and 31 December 2017. Exclusion criteria were failure to attend hospital, distance visual acuity in both eyes too low to quantify with the Early Treatment Diabetic Retinopathy Study (ETDRS) letter chart and treatment received prior to referral. Demographic and screening grade data were collected at the point of referral. Small-area statistics and census data were used to calculate indices of multiple deprivation. The main outcome measures were time taken from the date of referral for an individual to achieve the following: (1) attend the first hospital clinic appointment; (2) receive the first macular laser, intravitreal anti-vascular endothelial growth factor injection or pan-retinal photocoagulation treatment, in either eye; and (3) lose at least ten ETDRS letters of distance visual acuity, in either eye. RESULTS: Of 2062 referrals, 1676 individuals were included. Mean age (± SD) was 57.6 ± 14.7 years, with 52% male sex and 86% with type 2 diabetes. The ethnicity profile was 52% Black, 30% White, 10% Asian and 9% mixed/other, with similar disease severity at the time of referral. Time-to-clinic was significantly longer for Asian people than for Black people (p = 0.03) or White people (p = 0.001). Time-to-treatment was significantly longer for Black people than for White people (p = 0.02). Social deprivation did not significantly influence time-to-treatment. There were no significant differences in the rates of vision loss between ethnic groups. CONCLUSIONS/INTERPRETATION: Black people wait longer for hospital eye treatment compared with their White counterparts. The reasons for this delay in treatment warrant further investigation.

Radiomics-based assessment of ultra-widefield leakage patterns and vessel network architecture in the PERMEATE study: insights into treatment durability.

AIM: To evaluate the potential of radiomics-based ultra-widefield fluorescein angiography (UWFA)-derived imaging biomarkers in retinal vascular disease for predicting therapeutic durability of intravitreal aflibercept injection (IAI). METHODS: The Peripheral and Macular Retinal Vascular Perfusion and Leakage Dynamics in Diabetic Macular Edema and Retinal Venous Occlusions During Intravitreal Aflibercept Injection (IAI) Treatment for Retinal Edema (PERMEATE) study prospectively evaluated quantitative UWFA dynamics in diabetic macular oedema or macular oedema secondary to retinal vascular occlusion. 27 treatment-naïve eyes were treated with 2 mg IAI q4 weeks for the first 6 months, and then administered q8 weeks. Morphological and graph-based attributes were used to model the spatial distribution of leakage areas, while tortuosity measures were used to model the vessel network disorder. Eyes were grouped based on functional tolerance of the first 8-week treatment interval challenge. 'Non-rebounders' (N=15) maintained/improved best-corrected visual acuity (BCVA) following the 8-week challenge. 'Rebounders' (N=12) exhibited worsened BVCA. The image biomarkers were used with a machine learning classifier to preliminarily evaluate their ability to predict BCVA stability. RESULTS: Two new UWFA image-derived biomarkers were identified and extracted. The cross-validated area under the receiver operating characteristic curve (AUC) was 0.77±0.14 using baseline leakage distribution features and 0.73±0.10 for the UWFA baseline tortuosity measures. Additionally, the change in vascular tortuosity between month 4 and baseline yielded an AUC of 0.73±0.08. Three baseline clinical features of letter score, macular volume and central subfield thickness yielded a corresponding AUC of 0.42±0.09. CONCLUSIONS: Two computer-extracted UWFA radiomics-based descriptors were identified as potential biomarkers for predicting treatment durability and tolerance of longer treatment intervals. Conventional treatment parameters were not significantly different between these same groups.

Global burden and gender disparity of vision loss associated with diabetes retinopathy.

PURPOSE: To assess the trend patterns and gender disparity in global burden of vision loss due to diabetic retinopathy (DR) by year, age, region and socioeconomic status using prevalence and years lived with disability (YLDs) from Global Burden of Disease (GBD) study 2017. METHODS: Prevalence and YLDs data of vision loss attributable to DR were extracted from GBD Study 2017 in 195 countries and territories. Socio-demographic Index (SDI) in 2017 was cited as indicators of socioeconomic status. Kruskal-Wallis test, Dunn's multiple comparisons and Pearson linear correlation were adopted to evaluate the gender disparity and association with socioeconomic levels. RESULTS: Globally, total age-standardized prevalence and YLDs rates of vision loss due to DR peaked around 2005, with prevalence rate of 58.98 [95% uncertainty interval (UI) 50.95-68.56] and YLDs rate of 5.00 (95% UI 3.51-6.84) per 100 000 population, respectively. The burden were expected to increase to 65.74 (95% UI 60.14-70.86) and 5.68 (95% UI 4.07-7.22) by 2050. The burden would increase according to our projection based on current epidemiological situation. However, gender disparity has existed since 1990 and been enlarging in recent years, with female being more heavily impacted. This pattern remained with ageing among different stages of vision impairments and varied through GBD super regions. Gender difference (females minus males) of age-standardized prevalence rates was positively related to SDI (r = 0.1661, p = 0.0203). Diabetes has become a more important risk over the past 3 decades among the leading causes of vision loss. CONCLUSIONS: The DR-related vision loss burden tended to increase under ageing population according to our projection with significant gender disparity. Public awareness of DR and gender sensitive health policy should be emphasized.

A personalised screening strategy for diabetic retinopathy: a cost-effectiveness perspective.

AIMS/HYPOTHESIS: In this study we examined the cost-effectiveness of three different screening strategies for diabetic retinopathy: using a personalised adaptive model, annual screening (fixed intervals), and the current Dutch guideline (stratified based on previous retinopathy grade). METHODS: For each individual, optimal diabetic retinopathy screening intervals were determined, using a validated risk prediction model. Observational data (1998-2017) from the Hoorn Diabetes Care System cohort of people with type 2 diabetes were used (n = 5514). The missing values of retinopathy grades were imputed using two scenarios of slow and fast sight-threatening retinopathy (STR) progression. By comparing the model-based screening intervals to observed time to develop STR, the number of delayed STR diagnoses was determined. Costs were calculated using the healthcare perspective and the societal perspective. Finally, outcomes and costs were compared for the different screening strategies. RESULTS: For the fast STR progression scenario, personalised screening resulted in 11.6% more delayed STR diagnoses and €11.4 less costs per patient compared to annual screening from a healthcare perspective. The personalised screening model performed better in terms of timely diagnosis of STR (8.8% less delayed STR diagnosis) but it was slightly more expensive (€1.8 per patient from a healthcare perspective) than the Dutch guideline strategy. CONCLUSIONS/INTERPRETATION: The personalised diabetic retinopathy screening model is more cost-effective than the Dutch guideline screening strategy. Although the personalised screening strategy was less effective, in terms of timely diagnosis of STR patients, than annual screening, the number of delayed STR diagnoses is low and the cost saving is considerable. With around one million people with type 2 diabetes in the Netherlands, implementing this personalised model could save €11.4 million per year compared with annual screening, at the cost of 658 delayed STR diagnoses with a maximum delayed time to diagnosis of 48 months.

Ranibizumabe para tratamento de Edema Macular Diabético (EMD) / Ranibizumab for the treatment of Diabetic Macular Edema (EMD)

INTRODUÇÃO: O EMD é a principal causa de perda visual observada na retinopatia diabética (RD), a qual é uma das principais complicações relacionadas à diabetes mellitus (DM). Caracteriza-se pelo espessamento do tecido da mácula, como resultado do extravasamento de líquido dos capilares sanguíneos ou a presença de exsudatos duros no centro da mácula. As principais terapias para o tratamento do EMD disponíveis no SUS são terapias a laser (fotocoagulação e pan-fotocoagulação), cirurgia vitrectomia e, conforme a recente incorporação, o antiangiogênico aflibercepte. PERGUNTA: O uso de ranibizumabe é eficaz e seguro como opção de anti-VEGF para o tratamento do edema macular diabético quando comparado aos tratamentos atualmente disponíveis no SUS (fotocoagulação a laser e aflibercepte)? EVIDÊNCIAS CIENTÍFICAS: Foram incluídos 12 estudos pelo demandante, sendo 3 revisões sistemáticas e 9 ensaios clínicos que avaliaram ranibizumabe. Foram também incluídas 2 metanálises que o demandante havia excluído de sua análise original. Todos os estudos primários compararam o ranibizumabe com o tratamento com o laser e apresentaram resultados significativos de superioridade de eficácia do ranibizumabe na melhora da acuidade visual em pacientes com EMD. As revisões sistemáticas que avaliaram o ranibizumabe com outros anti-VEGF mostraram que estes têm eficácia semelhantes, com alguns estudos sugerindo superioridade do aflibercepte como tratamento. Segundo resultados atualizados da metanálise de Virgilli e colaboradores, aflibercepte e ranibizumabe foram mais efetivos do que laser, melhorando a visão em 2 ou mais linhas depois de um ano de tratamento (alta qualidade). O risco relativo (RR) versus laser foi de 3,66 (IC95% 2,79 a 4,79) para aflibercepte e RR 2,76 (IC95% CI 2,12 a 3,59) para ranibizumabe. Pessoas com EMD em tratamento com ranibizumabe foram menos propensas a ganhar 3 ou mais linhas de acuidade visual em um ano comparado com aflibercepte - RR 0,75 (IC95% 0,60 a 0,94). Aflibercepte e ranibizumabe não diferiram com relação a eventos adversos graves sistêmicos. Outra metanálise em rede de Zhang e colaboradores mostrou que ranibizumabe teve melhores resultados que o aflibercepte na melhora do BCVA em 6 meses com odds ratio (OR) 7,01 (IC95% 2,56 a 11,39), mas o aflibercepte apresentou melhor eficácia aos 12 meses de tratamento com OR 8,19 (IC95% 5,07 a 11,96). Esses resultados demonstram que tanto o ranibizumabe quando o aflibercepte tem eficácia semelhante para o EMD. AVALIAÇÃO ECONÔMICA: A avaliação apresentada pelo demandante foi uma análise de custominimização utilizando como comparador o aflibercepte. Ranibizumabe é uma alternativa poupadora de recursos quando comparada ao aflibercepte para o tratamento de pacientes adultos com edema macular diabético (EMD). O custo total estimado com ranibizumabe para três anos de tratamento foi de R$ 18.171,48 e para o aflibercepte de R$ 21.629,11 proporcionando uma economia de aproximadamente 16% com o tratamento com ranibizumabe. A análise apresentada avaliou os custos de tratamento por paciente relacionados a aquisição, administração e acompanhamento e monitorização do tratamento. Porém não considerou gastos relacionados à segurança. Custos com complicações e eventos adversos podem impactar no resultado econômico do tratamento. Como não foram considerados esses custos, faltou avaliar esse parâmetro na análise de sensibilidade disponibilizada. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentária (AIO) apresentada incluiu a população estimada com RD com presença de EMD aplicando taxas de prevalência de 11,7% de acordo com estudo realizado no Brasil. O cenário proposto com ranibizumabe projetado para tratamento anual chega a R$ 79.266.917,64 no ano 1 e estima-se R$ 181.283.719,49 no ano 5 em relação ao aflibercepte que teve o valor estimado em R$ 69.312.302,72 para o primeiro ano de incorporação e de R$ 154.658.419,96 para o quinto ano. A AIO demonstrou que a incorporação de ranibizumabe como uma alternativa de tratamento para EMD além do aflibercepte pode promover uma economia de recursos de até R$ 104,1 milhões ao longo de cinco anos considerando uma difusão de mercado de 50%. Em todos os cenários avaliados pela análise de sensibilidade observou-se a geração de economia devido a incorporação de ranibizumabe para EMD no SUS. O modelo possui algumas limitações na análise, como incerteza no tamanho da cota de mercado do ranibizumabe (considerada em 50%), incerteza de que ocorrerá indicação terapêutica apenas para pacientes com espessamento de retina maior que 400 micrometros , incerteza da origem dos valores da taxa de difusão apresentadas o que pode comprometer os resultados. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As buscas encontraram dois medicamentos novos no horizonte para tratamento do EMD, Brolucizumabe (inibidor de VEGF-A) e Faricizumabe (inibidor VEGF-A e inibidor de ligante de angiopoietina-2) em estudo clínico de fase 3 em andamento. Ainda foram encontrados biossimilares do aflibercepte e ranibizumabe. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Pelo exposto, a Conitec, em sua 86ª reunião ordinária, nos dias 04 e 05 de março de 2020, recomendou-se que o tema fosse levado em consulta pública com recomendação preliminar favorável a incorporação no SUS do Ranibizumabe para o tratamento de pacientes adultos com edema macular diabético (EMD). CONSULTA PÚBLICA: O relatório de recomendação inicial da Conitec foi disponibilizado para contribuições por meio da consulta pública nº 16/2020 entre os dias 30/03/2020 e 20/04/2020. Foram recebidas 978 contribuições, sendo 156 contribuições de cunho técnico-científico e 822 contribuições de experiência pessoal ou opinião. Destas 95,5% e 92,3% concordavam com a recomendação preliminar da Conitec, respectivamente. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 89ª reunião ordinária, no dia 05/08/2020, deliberaram, por unanimidade, recomendar a incorporação do ranibizumabe para o tratamento do edema macular diabético, conforme protocolo do Ministério da Saúde e assistência oftalmológica no SUS. DECISÃO: Incorporar o ranibizumabe para tratamento de Edema Macular Diabético (EMD), no âmbito do Sistema Único de Saúde - SUS, conforme protocolo do Ministério da Saúde e a assistência oftalmológica no SUS, conforme Portaria n° 39, publicada no Diário Oficial da União n° 181, seção 1, página 235, em 21 de setembro de 2020.

Validating a low-cost laser speckle contrast imaging system as a quantitative tool for assessing retinal vascular function.

The ability to monitor progression of retinal vascular diseases like diabetic retinopathy in small animal models is often complicated by their failure to develop the end-stage complications which characterize the human phenotypes in disease. Interestingly, as micro-vascular dysfunction typically precedes the onset of retinal vascular and even some neurodegenerative diseases, the ability to visualize and quantify hemodynamic changes (e.g. decreased flow or occlusion) in retinal vessels may serve as a useful diagnostic indicator of disease progression and as a therapeutic outcome measure in response to treatment. Nevertheless, the ability to precisely and accurately quantify retinal hemodynamics remains an unmet challenge in ophthalmic research. Herein we demonstrate the ability to modify a commercial fundus camera into a low-cost laser speckle contrast imaging (LSCI) system for contrast-free and non-invasive quantification of relative changes to retinal hemodynamics over a wide field-of-view in a rodent model.

Screening for diabetic retinopathy: new perspectives and challenges.

Although the prevalence of all stages of diabetic retinopathy has been declining since 1980 in populations with improved diabetes control, the crude prevalence of visual impairment and blindness caused by diabetic retinopathy worldwide increased between 1990 and 2015, largely because of the increasing prevalence of type 2 diabetes, particularly in low-income and middle-income countries. Screening for diabetic retinopathy is essential to detect referable cases that need timely full ophthalmic examination and treatment to avoid permanent visual loss. In the past few years, personalised screening intervals that take into account several risk factors have been proposed, with good cost-effectiveness ratios. However, resources for nationwide screening programmes are scarce in many countries. New technologies, such as scanning confocal ophthalmology with ultrawide field imaging and handheld mobile devices, teleophthalmology for remote grading, and artificial intelligence for automated detection and classification of diabetic retinopathy, are changing screening strategies and improving cost-effectiveness. Additionally, emerging evidence suggests that retinal imaging could be useful for identifying individuals at risk of cardiovascular disease or cognitive impairment, which could expand the role of diabetic retinopathy screening beyond the prevention of sight-threatening disease.

Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Among eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity (VA), randomized clinical trial results showed no difference in VA loss between initial observation plus aflibercept only if VA decreased, initial focal/grid laser plus aflibercept only if VA decreased, or prompt aflibercept. Understanding the initial observation approach is relevant to patient management. Objective: To assess the DRCR Retina Network protocol-defined approach and outcomes of initial observation with aflibercept only if VA worsened. Design, Setting, and Participants: This was a post hoc secondary analyses of a randomized clinical trial of the DRCR Retina Network Protocol V that included 91 US and Canadian sites from November 2013 to September 2018. Participants were adults (n = 236) with type 1 or 2 diabetes, 1 study eye with CI-DME, and VA letter score at least 79 (Snellen equivalent, 20/25 or better) assigned to initial observation. Data were analyzed from March 2019 to November 2019. Interventions: Initial observation and follow-up with aflibercept only for VA loss of at least 10 letters from baseline at 1 visit or 5 to 9 letters at 2 consecutive visits. Follow-up occurred at 8 weeks and then every 16 weeks unless VA or optical coherence tomography central subfield thickness worsened. Main Outcomes and Measures: Whether individuals received aflibercept. Results: Among 236 eyes in 236 individuals (149 [63%] male; median age, 60 years [interquartile range, 53-67 years]) randomly assigned to initial observation, 80 (34%) were treated with aflibercept during 2 years of follow-up. At 2 years, the median VA letter score was 86.0 (interquartile range, 89.0-81.0; median Snellen equivalent, 20/20 [20/16-20/25]). Receipt of aflibercept was more likely in eyes with baseline central subfield thickness at least 300 µm (Zeiss-Stratus equivalent) vs less than 300 µm (45% vs 26%; hazard ratio [HR], 1.98 [95% CI, 1.26-3.13], continuous P = .005), moderately severe nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study retinopathy severity level 47) and above vs moderate nonproliferative diabetic retinopathy (retinopathy severity level 43) and below (51% vs 27%; HR, 2.22 [95% CI, 1.42-3.47], ordinal P < .001), and among participants whose nonstudy eye received DME treatment within 4 months of randomization vs not (52% vs 25%; HR, 2.55 [95% CI, 1.64-3.99], P < .001). Conclusions and Relevance: Most eyes managed with initial observation plus aflibercept only if VA worsened maintained good vision at 2 years and did not require aflibercept for VA loss. However, the eyes in the trial were approximately twice as likely to receive aflibercept for VA loss if they had greater baseline central subfield thickness, worse diabetic retinopathy severity level, or a nonstudy eye receiving treatment for DME. Trial Registration: ClinicalTrials.gov Identifier: NCT01909791.

Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment.

Introduction: Plasma kallikrein is a  mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden associated with frequent dosing, there is still considerable need for VEGF-independent targeted pathways.Areas covered: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clinical studies of plasma kallikrein pathway modulation for DME, which have been associated with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development.Expert opinion: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anatomic results in early clinical trials. Given the large unmet need in DME treatment, further studies are warranted.

A novel method for electroretinogram assessment in patients with central retinal vein occlusion.

PURPOSE: Central retinal vein occlusion (CRVO) is the second most common retinal vascular disorder after diabetic retinopathy that affects the eyes. We propose a method for distinction of normal and central CRVO eyes based on electroretinogram (ERG). METHODS: Seventeen patients with CRVO in one eye were analyzed. Their ERG signals were collected in six different stimuli, including four records in the darkness (dark-adapted 0.01, dark-adapted 3.0, dark-adapted oscillatory potentials, and dark-adapted 10) and two records in brightness (light-adapted 3.0 and light-adapted 30 Hz flicker). Nonlinear features such as Hurst exponent (HE) and approximate entropy (ApEn) were extracted from healthy and CRVO eyes. Finally, a parabolic mapping and two criteria (theta angle and the density of points) were proposed to distinguish the groups. RESULTS: For ApEn, the P values of dark-adapted 3.0 oscillatory (P = 0.0433) and flicker (P = 0.0425) confirmed significant differences between the groups. For HE, the P values of dark-adapted 3.0 oscillatory (P = 0.0421) and flicker 30 Hz (P = 0.0402) confirmed differences between the healthy and CRVO groups. The P values of theta angle for dark-adapted 3.0 (P = 0.0199), dark-adapted oscillatory (P = 0.0265), dark-adapted 10.0 (P = 0.0166), light-adapted 3.0 (P = 0.0411), and flicker (P = 0.0361) showed significant differences. Using the density criterion, the statistical test demonstrated a significant difference between the groups in dark-adapted 3 (P = 0.0038), dark-adapted oscillatory (P = 0.0102), dark-adapted 10.0 (P = 0.0071), light-adapted 3.0 (P = 0.0319), and flicker 30 Hz (P = 0.0076). CONCLUSION: The proposed features have made it possible to distinguish between healthy and CRVO eyes. This method could be helpful in some cases with no definite diagnosis or to estimate the severity of CRVO.

Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants.

One of the tissues of the central nervous system most affected by diabetes is the retina. Despite a growing understanding of the biochemical processes involved in glucose toxicity, little is known about the physiological consequences of chronic high glucose (HG) on individual neurons and neuronal circuits. Electroretinogram recordings suggest that retinal bipolar cells (BCs), which filter and transmit photoreceptor output to the inner retina, are among the first cells affected by diabetic conditions, and may therefore serve as sensitive early biomarkers for incipient neuronal damage caused in diabetes. Here, we comparatively assessed retinal integrity, calcium responses, and the electrophysiological profiles of specific BC types of mouse and rat organotypic retinal explants after 1 to 3 weeks in tissue culture, under moderate glucose (MG) and HG conditions. While the retinal layers of both rodent species displayed a progressively reduced thickness in culture, BCs retained their electrophysiological profiles and remained morphologically identifiable for up to 2 weeks. Responses to glutamate and endogenous inhibitory responses were routinely observed, indicating that the retinal circuitry remained intact during this period. Significant physiological differences between MG and HG conditions were evident in calcium signals and in the time course of responses to glutamate, but the voltage-gated current profiles of BCs displayed only minor variations. Overall, rat retina appeared slightly more sensitive to HG levels compared with mouse. In conclusion, electrophysiological analysis of neuronal function in rodent retinal explants is useful for the study of early damage due to HG neurotoxicity.

Psychological, social and everyday visual impact of diabetic macular oedema and diabetic retinopathy: a systematic review.

AIMS: To synthesize the evidence on the impact of diabetic retinopathy and diabetic macular oedema from the patient perspective. METHODS: A systematic literature review was conducted using MEDLINE Complete, PsycINFO, EMBASE and AMED. We included articles investigating the impact of the condition on quality of life, symptoms, visual functioning, activities of daily living, well-being, social functioning, and financial status. The studies evaluated were observational, including cross-sectional, prospective cohort and retrospective cohort designs. Outcome data were extracted and synthesized. RESULTS: Searches yielded 5114 publications. After screening, 85 studies were included, measuring the following outcomes: visual functioning (n=46); quality of life (n=22); well-being (n=16); functional status (n=5); work (n=4); and visual task performance (n=2). Diabetic retinopathy has a considerable impact on visual functioning and this is greater in people with greater disease severity. Diabetic retinopathy significantly limits activities including working, driving, walking and reading, and has the potential to have a negative impact on psychological well-being. CONCLUSIONS: Diabetic retinopathy is associated with poor self-reported visual functioning, well-being, and health-related quality of life. Ability to perform basic everyday tasks appears to diminish with disease severity. Some studies suggest impaired mobility and problems with work, but there are gaps in this evidence.