MD Research News – Issue 425 – 14 June 2019

Drug treatment

Ophthalmologica. 2019 Jun 3:1-15.

Current outcomes of anti-VEGF therapy in the treatment of macular oedema secondary to branch retinal vein occlusions: a meta-analysis.

Spooner K, Hong T, Fraser-Bell S, Chang AA.

Purpose: The current body of evidence on the efficacy and safety of anti-VEGFs for macular oedema secondary to branch retinal vein occlusion (BRVO) is steadily growing as large clinical trials and observational studies are continually completed. The aim of this meta-analysis is to analyse anatomical and functional outcomes in response to anti-VEGF therapy using evidence generated from a pooled analysis of current clinical trials and observational studies.

Methods: The current meta-analysis includes treatment of BRVO with aflibercept, bevacizumab and ranibizumab from randomised controlled trials and observational studies. Inclusion criteria included peer-reviewed publications with at least a 12-month follow-up period. On literature review using multiple electronic databases (PubMed, Embase and Cochrane), 22 studies met the inclusion criteria. Baseline patient characteristics, study design, sample size and 12- and 24-month change in best corrected visual acuity (BCVA) and central foveal thickness (CFT) as measured on optical coherence tomography imaging were pooled in a meta-analysis. Data were then stratified by study design and anti-VEGF therapy in subgroup analyses.

Results: A total of 1,236 eyes from 22 studies were included in this meta-analysis. Mean baseline BCVA ranged from 66 ETDRS letters (20/50 Snellen equivalent) to 35 letters (20/200 Snellen). Mean baseline CFT ranged from 406.0 to 681.0 µm. Anti-VEGF treatment demonstrated an overall mean improvement in BCVA at 12 months of 14 letters (95% CI 12.0 to 16.2, p < 0.001) and CFT reduction of 228 µm (95% CI -278.9 to -176.1, p < 0.001). The BCVA gains at 12 months were maintained to month 24 with a mean gain of 12.5 letters (95% CI 6.3 to 18.8, p < 0.001), as well as reduction of CFT of 238 µm (95% CI -336.0 to -140.2, p < 0.001). No cases of endophthalmitis or glaucoma were reported in any study.

Conclusion: This meta-analysis confirms the comparable safety and efficacy of anti-VEGF therapies for patients with cystoid macular oedema secondary to BRVO. There is a need for randomised prospective comparative trials of anti-VEGF agents for BRVO.

PMID: 31158837 DOI: 10.1159/000497492

 

Ophthalmologica. 2019 Jun 4:1-8.

Intravitreal aflibercept for retinal angiomatous proliferation: results of a prospective case series at 96 weeks.

Browning AC, O'Brien JM, Vieira RV, Gupta R, Nenova K.

Introduction: Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (nAMD). Untreated, the lesions are thought to be aggressive and lead to a poor visual outcome. Despite some limitations, studies reporting the treatment of RAP lesions with the intravitreal anti-VEGF drugs ranibizumab and bevacizumab have demonstrated variable but generally favourable responses. More recently, aflibercept has been licensed for the treatment of nAMD and may offer some advantages over other agents. We present the visual and anatomical outcomes at 96 weeks of patients with RAP lesions who were treated with intravitreal aflibercept, according to the pivotal VIEW study nAMD treatment protocol.

Methods: This is a prospective study of treatment-naïve patients with Reading Centre-graded RAP lesions. The patients received aflibercept every 8 weeks, after 3 initial monthly injections, up to and including week 48. During weeks 52-96, patients received injections at least every 12 weeks, with monthly evaluations for interim injections if they fulfilled the retreatment criteria. At each visit, best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) central macular thickness (CMT) were measured.

Results: Forty-six patients reached study completion at week 96. Mean BCVA had improved by 6.0 (standard deviation [SD] 7.9) and 4.8 (SD 7.4) ETDRS letters at 52 (p = 0.003) and 96 (p = 0.02) weeks, respectively, from a baseline of 57.3 (SD 12.0) letters. At 52- and 96-week time points, 45/46 (98%) and 41/46 (89%) of patients, respectively, had maintained their vision (<15 letters of BCVA lost). At the 96-week time point, 13/46 (28%) of patients had gained ≥15 letters and also demonstrated a mean reduction in CMT of 162 μm (SD 106) (p = <0.0001), with 72% of maculae being fluid-free. Using univariate analysis, we found no significant difference between any of the visual outcome measures in this study and the pivotal VIEW study; the mean number of injections required and change in CMT were also similar.

Conclusions: In this study, we present the 96-week results, of the largest series to date, of patients treated prospectively with aflibercept for RAP using the VIEW protocol. We show that they benefited from treatment to a degree similar to those with type 1 and 2 nAMD.

PMID: 31163436 DOI: 10.1159/000500203

 

Ophthalmol Retina. 2019 Apr 5. pii: S2468-6530(19)30023-5.

Stereopsis after intravitreal ranibizumab injections for branch retinal vein occlusion.

Morikawa S, Okamoto F, Sugiura Y, Murakami T, Hiraoka T, Oshika T.

Purpose: To evaluate stereopsis before and after intravitreal ranibizumab (IVR) injections in patients with branch retinal vein occlusion (BRVO) and investigate the relationship between stereopsis and retinal microstructure.

Design: Prospective, observational, controlled study.

Participants: Thirty-two eyes of 32 patients undergoing IVR treatment for BRVO and 28 eyes of age-matched healthy control participants.

Methods: Stereopsis was measured using the Titmus stereo test (TST) and TNO stereo test before and 1, 2, 3, 4, 5, and 6 months after treatment.

Main Outcome Measures: Stereopsis, best-corrected visual acuity (BCVA), duration of disease, central retinal thickness, status of the external limiting membrane, ellipsoid zone, and external limiting membrane, and serous retinal detachment (SRD) after treatment.

Results: Treatment with IVR significantly improved the TST (P < 0.001) and TNO stereo test (P < 0.05) scores as well as BCVA (P < 0.001) and central retinal thickness (P < 0.005). Stereopsis after IVR injection in eyes with BRVO was significantly worse than that in healthy control participants (TST, P < 0.001; TNO stereo test, P < 0.001). The TST and TNO stereo test scores were correlated significantly with BCVA and the presence of SRD at baseline. After 6 months of treatment, an association of TST and TNO stereo test scores with BCVA and status of the external limiting membrane and ellipsoid zone was observed. Stereopsis after treatment showed a significant relationship with BCVA and presence of SRD at baseline.

Conclusions: Administration of IVR for BRVO improved early stereopsis, albeit not to a normal level. Presence of SRD and visual acuity were predictors of stereopsis after treatment in patients with BRVO.

PMID: 31155472 DOI: 10.1016/j.oret.2019.04.003

 

Ophthalmol Retina. 2019 Apr 11. pii: S2468-6530(18)30699-7.

Aflibercept-related sterile intraocular inflammation outcomes.

Greenberg JP, Belin P, Butler J, Feiler D, Mueller C, Tye A, Friedlander SM, Emerson GG, Ferrone PJ; Aflibercept Sterile Inflammation Research Group.

Purpose: A recent increase in sterile intraocular inflammation after aflibercept (EYLEA; Regeneron Pharmaceuticals, Inc, Tarrytown, NY) injection was reported to the American Society of Retina Specialists' Research and Safety in Therapeutics Committee. This study describes their clinical characteristics and outcomes.

Design: Case series.

Participants: Sixty-eight eyes of 66 patients (97% reported from May 2017 through February 2018).

Methods: Exclusion criteria were intravitreal antibiotic injection and follow-up of less than 7 days. Diagnosis was at each physician's discretion.

Main Outcome Measures: Presenting signs and symptoms, injection characteristics, management details, and visual outcomes.

Results: Mean time to presentation was 2.6 days (median, 2.0 days; range, 0-15 days). Symptoms included blurry vision (93%), floaters (60%), pain (44%), severe pain (6%), and photophobia (19%). Mean visual acuities before and after injection were 20/50 and 20/178, respectively. All patients showed intraocular inflammation: 24% with only vitritis, 16% with only anterior chamber reaction, and 60% with both. Less common findings included keratic precipitates (22%), corneal edema (13%), conjunctival injection (10%), chemosis (4%), hypopyon (4%), and fibrin (3%). Two patients were affected bilaterally. Treatment included topical steroids (93%), with 1% supplemented by oral steroids. Inflammation resolved in 79% at study completion (mean, 34 days; range, 7-105 days; 51% resolved by 1 month). This group's mean final visual acuity (VA) was 20/55, and 15% lost 2 lines or more. This vision loss was associated with shorter time to presentation (P < 0.0001), magnitude of decrease in presenting VA (P = 0.0004), presence of fibrin (P = 0.02), and trended toward receiving only observation (P = 0.10). There were no other presenting factors that significantly affected visual outcome. In patients with unresolved inflammation at the final visit, mean follow-up was 29 days, and mean final VA was 20/118. Overall, 26 aflibercept lots were involved.

Conclusions: This is the largest study of aflibercept-related sterile intraocular inflammation, and is the only large report to exclude eyes injected with intraocular antibiotics. Most patients presented early with decreased VA and intraocular inflammation, but without injection, hypopyon, fibrin, or severe pain. Final VA remained decreased in a significant minority of patients.

PMID: 31153850 DOI: 10.1016/j.oret.2019.04.006

 

Imaging

Ophthalmol Retina. 2019 Apr 18. pii: S2468-6530(18)30673-0.

Peripheral retinal lesions in eyes with age-related macular degeneration using ultra-widefield imaging: a systematic review with meta-analyses.

Forshaw TRJ, Minör ÅS, Subhi Y, Sørensen TL.

Topic: Age-related macular degeneration (AMD) is highly prevalent among the elderly. We systematically reviewed the literature to provide an overview of ultra-widefield imaging (UWFI) of peripheral retinal lesions in AMD.

Clinical Relevance: Information regarding retinal characteristics and prevalence of AMD is based mainly on studies using color photography of the central retina, where early and potentially severe manifestations of the disease are found. However, this approach has the effect of neglecting the periphery. Studies using UWFI provide new evidence to show that clinical features associated with AMD are not exclusive to the area of the macula.

Methods: Eligible studies had to detect lesions of the peripheral retina (based on the original definition of a standard macular grid, with the addition of 2 zones classed as peripheral) using UWFI in eyes with AMD. Ultra-widefield imaging included pseudocolor photography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography. Eligibility was restricted to human participants and studies written in English. We searched the bibliographic databases PubMed, the Cochrane Library, EMBASE, and the Web of Science on March 27, 2018. We calculated the prevalence of peripheral findings in eyes with AMD and performed similar meta-analyses on the healthy control group. A random-effects model was used because of possible study heterogeneity.

Results: Twelve studies were eligible for the review, which included 3261 or more eyes. Studies were clinic based, apart from 1 study that was a random population sample of individuals 62 years of age or older. Studies were cross-sectional in nature, apart from 1 case-control study. The peripheral lesions most commonly observed were drusen, atrophy, and changes to the retinal pigment epithelium. In eyes with AMD, peripheral lesions were found in 82.7% of eyes (confidence interval, 78.4%-86.7%) compared with 33.3% of healthy eyes (confidence interval, 28.3%-38.5%).

Conclusions: Peripheral changes were found to be highly prevalent in eyes with AMD, supporting the claim that the disease is panretinal and not macula only. The clinical significance of peripheral lesions in AMD remains incompletely understood, and therefore, further UWFI studies are recommended.

PMID: 31167730 DOI: 10.1016/j.oret.2019.04.014

 

PLoS One. 2019 Jun 4;14(6):e0217805.

Progression of subclinical choroidal neovascularization in age-related macular degeneration.

Heiferman MJ, Fawzi AA.

Purpose: To use optical coherence tomography angiography (OCTA) to study longitudinal subclinical choroidal neovascularization (CNV) changes and their correlation with progression to exudation in age-related macular degeneration (AMD).

Methods: This study included a total of 34 patients with unilateral neovascular AMD who were evaluated prospectively using OCTA to detect subclinical CNV in their fellow eye. Eyes with baseline subclinical CNV were followed with serial OCTA for a minimum of one year (15.2±3.27 months) to monitor the development of exudation.

Results: Of the 34 fellow eyes studied, five were found to have baseline subclinical CNV. One of the five cases of baseline subclinical CNV converted to exudative AMD during the follow up period. The average surface area of baseline subclinical CNV on OCTA was 0.131±0.096 mm2 which progressed to 0.136±0.104 mm2 at the final follow up (P = 0.539). Geographic atrophy grew at a rate of 0.82±1.20mm2/year in four eyes without subclinical CNV and 0.02mm2/year in one eye with subclinical CNV.

Conclusion & Importance: The rate of conversion to exudative AMD in eyes with subclinical CNV of 20% in our study is similar to previous reports and suggests the importance of vigilance in these eyes. The lower growth rate of geographic atrophy may suggest a protective effect of subclinical CNV that deserves further study.

PMID: 31163067 DOI: 10.1371/journal.pone.0217805

 

Ophthalmol Retina. 2019 Apr 12. pii: S2468-6530(18)30672-9.

Precursors and development of geographic atrophy with autofluorescence imaging: age-related eye disease study 2 report number 18.

Holmen IC, Aul B, Pak JW, Trane RM, Blodi B, Klein M, Clemons T, Chew E, Domalpally A;

Age-Related Eye Disease Study 2 Research Group.

Purpose: To describe the sequence of events leading to development of geographic atrophy (GA) in age-related macular degeneration with fundus autofluorescence (FAF) imaging.

Design: Post hoc analysis of FAF images from the Age-Related Eye Disease Study 2.

Participants: Fundus autofluorescence images of 120 eyes (109 patients) with incident GA and at least 2 years of preceding FAF images.

Methods: Images of incident GA were stacked and aligned over FAF images of preceding annual visits. The regions of retina where incident GA developed were assessed on prior years' FAF images. These regions, defined as precursor lesions, were classified into minimal change autofluorescence, predominant hypoautofluorescence (decreased autofluorescence), predominant hyperautofluorescence (increased autofluorescence), and mixed autofluorescence. The natural progression in precursor lesions leading to GA formation and their associations with incident GA size and GA enlargement rate were evaluated.

Main Outcome Measures: Incident GA area and enlargement rate and precursor pattern frequency.

Results: Incident GA had a mean area of 1.00 mm2 (range, 0.15-8.22 mm2) and an enlargement rate of 0.97 mm2/year (standard deviation, 1.66 mm2/year). Predominant hypoautofluorescence was the most common precursor lesion, increasing from 42% to 81% over 3 years before onset of GA. Almost 30% of eyes showed minimal change autofluorescence 3 years before GA. Among the other precursors, 70% progressed to predominant hypoautofluorescence before GA developed. The type of precursor lesions was not associated with incident GA area. Geographic atrophy evolving from minimal change autofluorescence precursor lesions was associated with faster GA enlargement rates compared with other precursor lesion classes.

Conclusions: Using image registration, we identified changes in autofluorescence images before the onset of GA. Decreased autofluorescence was the most common change, although minimal changes also were seen in one third of the images. Incident GA that arises from predominantly normal autofluorescence is associated with faster enlargement rates compared with GA arising from abnormal autofluorescence. Faster GA enlargement rates also were associated with incident GA size, area of surround abnormal autofluorescence, and presence of reticular pseudodrusen.

PMID: 31153849 DOI: 10.1016/j.oret.2019.04.011

 

Asia Pac J Ophthalmol (Phila). 2019 May 31.

Promising artificial intelligence-machine learning-deep learning algorithms in ophthalmology.

Balyen L, Peto T.

Abstract: The lifestyle of modern society has changed significantly with the emergence of artificial intelligence (AI), machine learning (ML), and deep learning (DL) technologies in recent years. Artificial intelligence is a multidimensional technology with various components such as advanced algorithms, ML and DL. Together, AI, ML, and DL are expected to provide automated devices to ophthalmologists for early diagnosis and timely treatment of ocular disorders in the near future. In fact, AI, ML, and DL have been used in ophthalmic setting to validate the diagnosis of diseases, read images, perform corneal topographic mapping and intraocular lens calculations. Diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma are the 3 most common causes of irreversible blindness on a global scale. Ophthalmic imaging provides a way to diagnose and objectively detect the progression of a number of pathologies including DR, AMD, glaucoma, and other ophthalmic disorders. There are 2 methods of imaging used as diagnostic methods in ophthalmic practice: fundus digital photography and optical coherence tomography (OCT). Of note, OCT has become the most widely used imaging modality in ophthalmology settings in the developed world. Changes in population demographics and lifestyle, extension of average lifespan, and the changing pattern of chronic diseases such as obesity, diabetes, DR, AMD, and glaucoma create a rising demand for such images. Furthermore, the limitation of availability of retina specialists and trained human graders is a major problem in many countries. Consequently, given the current population growth trends, it is inevitable that analyzing such images is time-consuming, costly, and prone to human error. Therefore, the detection and treatment of DR, AMD, glaucoma, and other ophthalmic disorders through unmanned automated applications system in the near future will be inevitable. We provide an overview of the potential impact of the current AI, ML, and DL methods and their applications on the early detection and treatment of DR, AMD, glaucoma, and other ophthalmic diseases.

PMID: 31149787 DOI: 10.22608/APO.2018479

 

Pathogenesis

Exp Eye Res. 2019 May 31. pii: S0014-4835(19)30262-3.

Increased serum proteins in non-exudative AMD retinas.

Schultz H, Song Y, Baumann BH, Kapphahn RJ, Montezuma SR, Ferrington DA, Dunaief JL.

Abstract: The blood retinal barrier (BRB) closely regulates the retinal microenvironment. Its compromise leads to the accumulation of retinal fluid containing potentially harmful plasma components. While eyes with non-exudative age-related macular degeneration (AMD) were previously felt to have an intact BRB, we propose that the BRB in non-exudative AMD eyes may be subclinically compromised, allowing entry of retina-toxic plasma proteins. We test this hypothesis by measuring retinal levels of abundant plasma proteins that should not cross the intact BRB. Two cohorts of frozen, post mortem neurosensory retinas were studied by Western analysis. One cohort from Alabama had 4 normal controls and 4 eyes with various forms of AMD. Another cohort from Minnesota had 5 intermediate AMD and 5 normals. Both cohorts were age/post mortem interval (PMI) matched. The non-exudative AMD retinas in the Alabama cohort had significantly higher levels of albumin and complement component 9 (C9) than normal controls. The positive control exudative AMD donor retina had higher levels of all but one serum protein. In both macular and peripheral neurosensory retina samples, intermediate AMD retinas in the Minnesota cohort had significantly higher levels of albumin, fibrinogen, IgG, and C9 than controls. Our results suggest that there may be moderate subclinical BRB leakage in non-exudative AMD. Potentially harmful plasma components including complement or iron could enter the neurosensory retina in AMD patients prior to advanced disease. Thus, therapies aiming to stabilize the BRB might have a role in the management of non-exudative AMD.

PMID: 31158383 DOI: 10.1016/j.exer.2019.05.026

 

Invest Ophthalmol Vis Sci. 2019 Jun 3;60(7):2481-2493.

Quantifying retinal pigment epithelium dysmorphia and loss of histologic autofluorescence in age-related macular degeneration.

Gambril JA, Sloan KR, Swain TA, Huisingh C, Zarubina AV, Messinger JD, Ach T, Curcio CA.

Purpose: Lipofuscin and melanolipofuscin organelles in retinal pigment epithelium (RPE) cells are signal sources for clinical fundus autofluorescence (AF). To elucidate the subcellular basis of AF imaging, we identified, characterized, and quantified the frequency of RPE morphology and AF phenotypes in donor eyes with age-related macular degeneration (AMD).

Methods: In 25 RPE-Bruch's membrane flat mounts from 25 eyes, we analyzed 0.4-μm z-stack epifluorescence images of RPE stained with phalloidin for actin cytoskeleton. Using a custom ImageJ plugin, we classified cells selected in a systematic unbiased fashion in six phenotypes representing increasing degrees of pathology. For each cell, area, AF intensity, and number of Voronoi neighbors were compared with phenotype 1 (uniform AF, polygonal morphology) via generalized estimating equations. We also analyzed each cell's neighborhood.

Results: In 29,323 cells, compared with phenotype 1, all other phenotypes, in order of increasing pathology, had significantly larger area, reduced AF, and more variable number of neighbors. Neighborhood area and AF showed similar, but subtler, trends. Cells with highly autofluorescent granule aggregates are no more autofluorescent than others and are in fact lower overall in AF. Pre-aggregates were found in phenotype 1. Phenotype 2, which exhibited degranulation despite normal cytoskeleton, was the most numerous nonhealthy phenotype (16.23%).

Conclusions: Despite aggregation of granules that created hyperAF aggregates within cells, overall AF on a per cell basis decreased with increasing severity of dysmorphia (abnormal shape). Data motivate further development of subcellular resolution in clinical fundus AF imaging and inform an ongoing reexamination of the role of lipofuscin in AMD.

PMID: 31173079 DOI: 10.1167/iovs.19-26949

 

Genetics & gene therapy

Drug Discov Today. 2019 Jun 4. pii: S1359-6446(18)30472-0.

Ocular gene therapies in clinical practice: viral vectors and non-viral alternatives.

Bordet T, Behar-Cohen F.

Abstract: Ocular gene therapy has entered into clinical practice. Although viral vectors are currently the best option to replace and/or correct genes, the optimal method to deliver these treatments to the retinal pigment epithelial (RPE) cells and/or photoreceptor cells remains to be improved to increase transduction efficacy and reduce iatrogenic risks. Beyond viral-mediated gene replacement therapies, nonviral gene delivery approaches offer the promise of sustained fine-tuned expression of secreted therapeutic proteins that can be adapted to the evolving stage of the disease course and can address more common nongenetic retinal diseases, such as age-related macular degeneration (AMD). Here, we review current gene therapy strategies for ocular diseases, with a focus on clinical stage products.

PMID: 31173914 DOI: 10.1016/j.drudis.2019.05.038