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    Research update: 527

    The latest research highlights for 14 February 2022.

    Issue 527


    Genetics of reticular pseudodrusen in age-related macular degeneration.

    Trends in Genetics. 2022 Jan 26

    Farashi S, Ansell BRE, Wu Z, Abbott CJ, Pébay A, Fletcher EL, Guymer RH, Bahlo M.

    Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.

    DOI: 10.1016/j.tig.2022.01.003


    Mental Status and Feasibility of an Intravitreal Ranibizumab Treat-and-Extend Regimen in Patients with Neovascular Age-Related Macular Degeneration.

    Advances in Therapy. 2022 Feb 3.

    Kato A, Yasukawa T, Sugita I, Yoshida M, Nozaki M, Hirano Y, Kondo J, Abe T, Sugita K, Okita T, Morita H, Takase N, Ogura Y.

    Introduction: Anti-vascular endothelial growth factor (VEGF) therapy is the first-choice treatment for neovascular age-related macular degeneration (nvAMD); however, patients often are burdened physically, financially, and mentally. We investigated the relationship between mental status and feasibility of an intravitreal ranibizumab treat-and-extend (TAE) regimen for nvAMD.

    Methods: In this prospective, multicenter study, 75 patients with nvAMD received ranibizumab intravitreally in a TAE regimen. After two monthly injections, the injection intervals were extended step-by-step to 6, 8, 12, and 16 weeks in eyes with dry maculas on optical coherence tomography (OCT) and, if exudation persisted or relapsed, shortened by one step. The best corrected visual acuity (BCVA) measurement and OCT were performed at baseline and on the same days of the scheduled injections. At baseline, all patients completed a survey, the Hospital Anxiety and Depression Scale (HADS), regarding mental burden. At week 52, patients on the TAE regimen for 1 year completed the HADS and a questionnaire designated to assess treatment-associated mental status.

    Results: Fifty-one patients (68%) completed the 1-year TAE regimen; 24 eyes (32%) discontinued the TAE regimen because of the rescue treatment, difficulty in completing clinical visits, or financial burden. In 51 eyes on the TAE regimen for 1 year, the mean BCVAs improved from 64.3 letters at baseline to 71.6 letters at week 52. The mean anxiety and depression scores on HADS decreased significantly (p < 0.01) after the 1-year treatment. Women tended to have higher anxiety scores, possibly associated with fear of injection and recurrence, while some men had higher depression scores potentially associated with financial burden, difficulty in completing clinical visits, and subsequent interruption of the TAE regimen especially in eyes with low treatment efficacy.

    Conclusions: A TAE regimen of intravitreal ranibizumab injections preserves vision in eyes with nvAMD and reduces mental burden associated with disease relapse.

    DOI: 10.1007/s12325-022-02052-1


    Association of neovascular age-related macular degeneration with migraine

    Scientific Reports12, Article number: 1792 (2022)

    Tung-Mei Kuang, Sudha Xirasagar, Yi-Wei Kao, Jau-Der Ho, Herng-Ching Lin.

    Abstract: Patients with early onset vascular pathology have been reported to manifest neovascular age-related macular degeneration (AMD). While the blood vessels involved in pathogenesis of migraine remains controversial, it is generally accepted that a major contributor is blood vessel pathology.

    This study aimed to examine the association between migraine and AMD using a nationwide population-based dataset. Retrospective claims data were collected from the Taiwan National Health Insurance Research Database.

    We identified 20,333 patients diagnosed with neovascular AMD (cases), and we selected 81,332 propensity score-matched controls from the remaining beneficiaries in Taiwan’s National Health Insurance system. We used Chi-square tests to explore differences in the prevalence of migraine prior to the index date between cases and controls. We performed multiple logistic regressions to estimate the odds of prior migraine among neovascular AMD patients vs. controls after adjusting for age, sex, monthly income, geographic location, residential urbanization level, hyperlipidemia, diabetes, coronary heart disease, hypertension, and previous cataract surgery.

    A total of 5184 of sample patients (5.1%) had a migraine claim before the index date; 1215 (6.1%) among cases and 3969 (4.9%) among controls (p < 0.001), with an unadjusted OR of 1.239 (95% CI 1.160~1.324, p < 0.001) for prior migraine among cases relative to controls. Furthermore, the adjusted OR was 1.201 (95% CI 1.123~1.284; p < 0.001) for AMD cases relative to controls.

    The study offers population-based evidence that persons with migraine have 20% higher risk of subsequently being diagnosed with neovascular AMD.

    DOI: 10.1038/s41598-022-05638-5


    Metformin and risk of age-related macular degeneration in individuals with type 2 diabetes: a retrospective cohort study.

    British Journal of Ophthalmology 2022 Feb 3

    Gokhale KM, Adderley NJ, Subramanian, Lee WH, Han D, Coker J, Braithwaite T, Denniston AK, Keane PA, Nirantharakumar K.

    Background: Age-related macular degeneration (AMD) in its late stages is a leading cause of sight loss in developed countries. Some previous studies have suggested that metformin may be associated with a reduced risk of developing AMD, but the evidence is inconclusive. AIMS: To explore the relationship between metformin use and development of AMD among patients with type 2 diabetes in the UK.

    Methods: A large, population-based retrospective open cohort study with a time-dependent exposure design was carried out using IQVIA Medical Research Data, 1995-2019. Patients aged ≥40 with diagnosed type 2 diabetes were included.The exposed group was those prescribed metformin (with or without any other antidiabetic medications); the comparator (unexposed) group was those prescribed other antidiabetic medications only. The exposure status was treated as time varying, collected at 3-monthly time intervals.Extended Cox proportional hazards regression was used to calculate the adjusted HRs for development of the outcome, newly diagnosed AMD.

    Results: A total of 173 689 patients, 57% men, mean (SD) age 62.8 (11.6) years, with incident type 2 diabetes and a record of one or more antidiabetic medications were included in the study. Median follow-up was 4.8 (IQR 2.3-8.3, range 0.5-23.8) years. 3111 (1.8%) patients developed AMD. The adjusted HR for diagnosis of AMD was 1.02 (95% CI 0.92 to 1.12) in patients prescribed metformin (with or without other antidiabetic medications) compared with those prescribed any other antidiabetic medication only.

    Conclusions: We found no evidence that metformin was associated with risk of AMD in primary care patients requiring treatment for type 2 diabetes.

    DOI: 10.1136/bjophthalmol-2021-319641

    Comparison of agents using higher dose anti-VEGF therapy for treatment-resistant neovascular age-related macular degeneration.

    Graefes Archive for Clinical and Experimental Ophthalmology 2022 Jan 29.

    Broadhead GK, Keenan TDL, Chew EY, Wiley HE, Cukras CA.

    Purpose: To explore the comparative efficacy and safety of higher dose intravitreal bevacizumab, ranibizumab, or aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD).

    Methods: Retrospective analysis of 37 eyes of 35 patients with treatment-resistant nAMD divided into 3 cohorts based on high-dose treatment received: 3 mg aflibercept, 0.75 mg or 1.0 mg ranibizumab, and 1.8 mg or 2.5 mg bevacizumab. The eyes were analyzed at standardized time points up to 48 months. Included eyes demonstrated active nAMD with persistent exudation on imaging for at least 6 months with at least 4 anti-VEGF injections during this time. Outcomes included change in visual acuity (VA), central retinal thickness (CRT), intraocular pressure (IOP), retinal morphology, adverse event occurrence, and yearly intravitreal injection (IVI) rate.

    Results: There was no significant difference in VA or IOP change compared to the initiation of high-dose treatment for any agent or comparing between agents at any time point (p > 0.05). CRT improved at month 1, 3, 6, and 12 with all 3 agents (p < 0.05 for all) with a greater CRT reduction seen for ranibizumab than aflibercept at month 6 (p < 0.05), although baseline CRT was greater in the ranibizumab group than the aflibercept group (p < 0.05). Mean absolute CRT was similar at month 6 for all agents (p > 0.05). IVI rates pre- and post-conversion to higher-dose therapy were similar (1 injection per 5.7-6.4 weeks). Mean follow-up was 22.8 months.

    Conclusions: Higher dose therapy may achieve improved anatomic outcomes and maintain vision, but frequent injections are required to achieve this. There was no detected difference in efficacy or safety between agents.

    DOI: 10.1007/s00417-021-05547-9

    Factors associated with the response to fluocinolone acetonide 0.19mg in diabetic macular oedema evaluated as the area-under-the-curve.

    Eye (London). 2022 Jan 30

    Cicinelli MV, Rabiolo A, Capone L, Di Biase C, Lattanzio R, Bandello F.

    Objectives: The area-under-the-curve (AUC) measures the average drug effect over time. We investigated the impact of baseline clinical and optical coherence tomography (OCT) factors on the response to fluocinolone acetonide (FAc) 0.19 mg implant in patients with diabetic macular oedema (DMO) as the AUC over 36 months.

    Methods: Retrospective study of DMO eyes undergoing FAc with follow-up from 12 to 36 months. The AUC of the best-corrected visual acuity (BCVA) and the central macular thickness (CMT) were calculated with the trapezoidal rule. Demographic and clinical data at the time of FAc administration were collected, and associations with BCVA and CMT changes were investigated with linear mixed models.

    Results: Eighty-nine eyes of 63 patients were enroled; median follow-up was 26 months. Mean±standard deviation (SD) AUCBCVA and AUCCMT after FAc injection were 0.24 ± 0.17 LogMAR/month and 179.6 ± 54.3 μm/month, respectively. Worse baseline BCVA (β = 0.30 LogMAR/month, p < 0.001), higher AUCCMT after FAc administration (β = 0.08 LogMAR/month, p < 0.001), diagnosis of type 1 diabetes (β = -0.04 LogMAR/month, p = 0.04), and absent ELM/EZ layers (β = 0.06 LogMAR/month, p = 0.01) were associated with worse vision over time (higher AUCBCVA). Eyes with higher CMT at baseline (β = 9.61 μm/month, p < 0.001) and those with tractional DMO (β = 24.7 μm/month, p = 0.01) had worse anatomic outcomes (higher AUCCMT). The need for additional treatments after FAc was also associated with higher AUCCMT (β = 33.9 μm/month, p = 0.001).

    Conclusions: Baseline better visual acuity, lower macular thickness, and photoreceptors’ layers integrity are associated with better functional response to FAc in DMO. Eyes with severe DMO at the time of implant or tractional oedema have worse anatomic response. These findings might guide clinicians in a more informed decisional algorithm in treating DMO.

    DOI: 10.1038/s41433-021-01921-3.


    Non-invasive testing for early detection of neovascular macular degeneration in unaffected second eyes of older adults: EDNA diagnostic accuracy study

    Health Technology Assessment 2022 Jan 26.

    Katie Banister, Jonathan A Cook, Graham Scotland, Augusto Azuara-Blanco, Beatriz Goulão, Heinrich Heimann, Rodolfo Hernández, Ruth Hogg, Charlotte Kennedy, Sobha Sivaprasad, Craig Ramsay, Usha Chakravarthy

    Background: Neovascular age-related macular degeneration is a leading cause of sight loss, and early detection and treatment is important. For patients with neovascular age-related macular degeneration in one eye, it is usual practice to monitor the unaffected eye. The test used to diagnose neovascular age-related macular degeneration, fundus fluorescein angiography, is an invasive test. Non-invasive tests are available, but their diagnostic accuracy is unclear.

    Objectives: The primary objective was to determine the diagnostic monitoring performance of tests for neovascular age-related macular degeneration in the second eye of patients with unilateral neovascular age-related macular degeneration. The secondary objectives were the cost-effectiveness of tests and to identify predictive factors of developing neovascular age-related macular degeneration.

    Design: This was a multicentre, prospective, cohort, comparative diagnostic accuracy study in a monitoring setting for up to 3 years. A Cox regression risk prediction model and a Markov microsimulation model comparing cost-effectiveness of the index tests over 25 years were used.

    Setting: This took place in hospital eye services.

    Participants: Participants were adults (aged 50-95 years) with newly diagnosed (within the previous 6 weeks) neovascular age-related macular degeneration in one eye and an unaffected second (study) eye who were attending for treatment injections in the first eye and who had a study eye baseline visual acuity of ≥ 68 Early Treatment Diabetic Retinopathy Study letters.

    Interventions: The index tests were Amsler chart (completed by participants), fundus clinical examination, optical coherence tomography, self-reported vision assessment (completed by participants) and visual acuity. The reference standard was fundus fluorescein angiography.

    Main outcome measures: The main outcome measures were sensitivity and specificity; the performance of the risk predictor model; and costs and quality-adjusted life-years.

    Results: In total, 552 out of 578 patients who consented from 24 NHS hospitals (n = 16 ineligible; n = 10 withdrew consent) took part. The mean age of the patients was 77.4 years (standard deviation 7.7 years) and 57.2% were female. For the primary analysis, 464 patients underwent follow-up fundus fluorescein angiography and 120 developed neovascular age-related macular degeneration on fundus fluorescein angiography. The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)], fundus clinical examination [53.8 (44.8 to 62.5); 97.6 (95.3 to 98.9)], Amsler [33.7 (25.1 to 43.5); 81.4 (76.4 to 85.5)], visual acuity [30.0 (22.5 to 38.7); 66.3 (61.0 to 71.1)] and self-reported vision [4.2 (1.6 to 9.8); 97.0 (94.6 to 98.5)]. Optical coherence tomography had the highest sensitivity across all secondary analyses. The final prediction model for neovascular age-related macular degeneration in the non-affected eye included smoking status, family history of neovascular age-related macular degeneration, the presence of nodular drusen with or without reticular pseudodrusen, and the presence of pigmentary abnormalities [c-statistic 0.66 (95% confidence interval 0.62 to 0.71)]. Optical coherence tomography monitoring generated the greatest quality-adjusted life-years gained per patient (optical coherence tomography, 5.830; fundus clinical examination, 5.787; Amsler chart, 5.736, self-reported vision, 5.630; and visual acuity, 5.600) for the lowest health-care and social care costs (optical coherence tomography, £19,406; fundus clinical examination, £19,649; Amsler chart, £19,751; self-reported vision, £20,198; and visual acuity, £20,444) over the lifetime of the simulated cohort. Optical coherence tomography dominated the other tests or had an incremental cost-effectiveness ratio below the accepted cost-effectiveness thresholds (£20,000) across the scenarios explored.

    Limitations: The diagnostic performance may be different in an unselected population without any history of neovascular age-related macular degeneration; the prediction model did not include genetic profile data, which might have improved the discriminatory performance.

    Conclusions: Optical coherence tomography was the most accurate in diagnosing conversion to neovascular age-related macular degeneration in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Economic modelling suggests that optical coherence tomography monitoring is cost-effective and leads to earlier diagnosis of and treatment for neovascular age-related macular degeneration in the second eye of patients being treated for neovascular age-related macular degeneration in their first eye.

    Future work: Future works should investigate the role of home monitoring, improved risk prediction models and impact on long-term visual outcomes.

    DOI: 10.3310/VLFL1739


    Progression of Age-Related Macular Degeneration Among Individuals Homozygous for Risk Alleles on Chromosome 1 (CFH-CFHR5) or Chromosome 10 (ARMS2/HTRA1) or Both

    JAMA Ophthalmology. 2022 Feb 3.

    Steffen Schmitz-Valckenberg, Monika Fleckenstein, Moussa A Zouache, Maximilian Pfau, Christian Pappas, Jill L Hageman, Elvira Agrón, Claire Malley, Tiarnan D L Keenan, Emily Y Chew, Gregory S Hageman.

    Importance: Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized.

    Objective: To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss.

    Design, Setting & Participants: This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy.

    Main Outcomes & Measures: Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines.

    Results: In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years).

    Conclusions & Relevance: These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials.
    DOI: 10.1001/jamaophthalmol.2021.6072