The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

OCTA Signal Quality Augmentation Using the Isometric Handgrip Test to Maximize Vascular Flow (SQUEEZE): A Randomized Crossover Trial.

Purpose: To determine if performing the isometric handgrip test (IHGT) can augment optical coherence tomography angiography (OCTA) vascular signal quality in eyes with macular abnormalities. Methods: A randomized, single-blinded crossover trial was conducted including 36 participants with macular abnormalities, randomized to undergo OCTA with or without the IHGT, then crossed over to the alternate "intervention" after 1 minute. The primary outcome was OCTA signal quality after 1 minute of squeezing at 50% maximum grip strength. Secondary outcomes were other measures of vascular flow and systemic blood pressure (BP), also regressed against person- and eye-level covariables. Results: Primary analysis of OCTA signal quality with versus without the IHGT was nonsignificant (P = 0.73). Nested analyses showed that the IHGT resulted in increased OCTA B-scan retinal vascular flow signal (2.95 [-1.64 to 7.55] Δ%, P < 0.05) and increased systolic BP, diastolic BP, pulse pressure, and mean arterial pressure (4.94 [0.41 to 9.47] to 12.38 [8.01 to 16.75] mm Hg, P < 0.05). OCTA signal quality and en face vessel density and perfusion changes were associated with sex, refraction, race/ethnicity, and right-hand IHGT use (P < 0.05). Greater increases in systolic and diastolic BP and mean arterial pressure were generally associated with right-hand IHGT use and greater maximum grip strength (P < 0.09). Conclusions: The IHGT can temporarily increase OCTA B-scan retinal vascular flow signal in participants with macular abnormalities. IHGT-induced changes to systemic BP appear to be linked to absolute (rather than relative) grip strength, implying that the IHGT may be ineffective with low grip strength. Further research in larger populations is warranted. Translational Relevance: This study provides early validation that the IHGT may augment OCTA output, which may lead to improved noninvasive detection of pathologic vascular changes.

Retinal sensitivity changes in early/intermediate AMD: a systematic review and meta-analysis of visual field testing under mesopic and scotopic lighting.

Visual fields under mesopic and scotopic lighting are increasingly being used for macular functional assessment. This review evaluates its statistical significance and clinical relevance, and the optimal testing protocol for early/intermediate age-related macular degeneration (AMD). PubMed and Embase were searched from inception to 14/05/2022. All quality assessments were performed according to GRADE guidelines. The primary outcome was global mean sensitivity (MS), further meta-analysed by: AMD classification scheme, device, test pattern, mesopic/scotopic lighting, stimuli size/chromaticity, pupil dilation, testing radius (area), background luminance, adaptation time, AMD severity, reticular pseudodrusen presence, and follow-up visit. From 1489 studies screened, 42 observational study results contributed to the primary meta-analysis. Supported by moderate GRADE certainty of the evidence, global MS was significantly reduced across all devices under mesopic and scotopic lighting with large effect size (-0.9 [-1.04, -0.75] Hedge's g, P < 0.0001). The device (P < 0.01) and lighting (P < 0.05) used were the only modifiable factors affecting global MS, whereby the mesopic MP-1 and MAIA produced the largest effect sizes and exceeded test-retest variabilities. Global MS was significantly affected by AMD severity (intermediate versus early AMD; -0.58 [-0.88, -0.29] Hedge's g or -2.55 [3.62, -1.47] MAIA-dB) and at follow-up visit (versus baseline; -0.62 [-0.84, -0.41] Hedge's g or -1.61[-2.69, -0.54] MAIA-dB). Magnitudes of retinal sensitivity changes in early/intermediate AMD are clinically relevant for the MP-1 and MAIA devices under mesopic lighting within the central 10° radius. Other factors including pupil dilation and dark adaptation did not significantly affect global MS in early/intermediate AMD.

Retinal vessel diameters in intermediate age-related macular degeneration using en face optical coherence tomography.

CLINICAL RELEVANCE: Clinical assessment of age-related macular degeneration (AMD) relies on biomarkers that do not necessarily reflect the contributions of vascular dysfunction. Validation of clinically accessible methods of measuring retinal vascular integrity could provide a more holistic understanding of AMD-related changes to facilitate appropriate care. BACKGROUND: There is conflicting evidence if retinal vessel calibre is significantly altered in the early stages of AMD. This study examined the outer and inner diameters of first order retinal vessels in intermediate AMD eyes using en face optical coherence tomography (OCT). METHODS: Retinal en face (6 × 6 mm) OCT images were examined in a single eye of participants with intermediate AMD (n = 46) versus normal macula (n = 43) for arterioles (all identifiable) and venules (40/46 and 39/43 identifiable). All participants were aged ≥50 years without diabetes mellitus, hypertension, or other systemic vascular disease. RESULTS: Intra- and inter-grader agreement was good-to-excellent for all en face OCT measurements of arteriole and venule diameters (intraclass correlation coefficient = 0.87 to 0.99). Arteriolar outer diameters (82.3 ± 19.8 µm vs 73.8 ± 16.1 µm; p < 0.05) and inner diameters (35.1 ± 8.4 µm vs 31.5 ± 8.1 µm; p < 0.05) were significantly greater in AMD eyes compared to normal eyes. Venular inner diameter was significantly greater (43.1 ± 9.5 µm vs 39.2 ± 10.1 µm; p < 0.05), but outer diameter remained unchanged (p = 0.17) in AMD eyes compared to normal eyes. CONCLUSION: Arteriolar dilation and altered venular inner diameter were observed in intermediate AMD eyes. These results support further investigation of vascular contributions to AMD in the early stages of disease, possibly using the en face OCT imaging modality.

Spatial Analysis Reveals Vascular Changes in Retinal and Choroidal Vessel Perfusion in Intermediate AMD With Reticular Pseudodrusen.

Purpose: To examine the effect of reticular pseudodrusen (RPD) on retinal and choroidal vessel perfusion (VP) topography in intermediate age-related macular degeneration (iAMD) using refined spatial analyses. Methods: This was a retrospective cross-sectional study of 120 individuals with 30 iAMDRPD, 60 iAMDno_RPD, and 30 normal eyes, propensity-score matched by age, sex, and presence of cardiovascular-related disease. VP of the superficial and deep retinal and choriocapillaris vascular slabs was assessed from 6 × 6-mm optical coherence tomography angiography (OCTA) scans divided into 126 × 126 grids, with adjustment for various person- and eye-level factors. Grid-wise VP differences (%) among the groups were spatially assessed according to analyses based on the Early Treatment for Diabetic Retinopathy Study (ETDRS), eccentricity (µm), and degree (°). Results: VP was significantly decreased between iAMDRPD and iAMDno_RPD, across all vascular slabs in various ETDRS sectors (up to -2.16%; 95% confidence interval, -2.99 to -1.34; P < 0.05). Eccentricity analyses revealed more complex patterns: a bisegmented relationship where VP in iAMDRPD eyes decreased linearly toward 1000 µm then returned toward similar values as iAMDno_RPD, plateauing around 2000 µm in the superficial and 3000 µm in the deep retina (R2 = 0.57-0.9; P < 0.001). Degree-based analysis further showed that the greatest VP differences in iAMDRPD eyes were commonly located superiorly and nasally across all vascular slabs (P < 0.05). Conclusions: RPD appears to compound the vascular impact of iAMD, displaying complex spatial patterns beyond the ETDRS sectors. This highlights the importance of considering spatial delineations for future work regarding the role of RPD and vascular dysfunction.

RPE Curvature Can Screen for Early and Intermediate AMD.

Purpose: Diagnosing AMD early optimizes clinical management. However, current diagnostic accuracy is limited by the subjectivity of qualitative diagnostic measures used in clinical practice. This study tests if RPE curvature could be an accurate, quantitative measure for AMD diagnosis. Methods: Consecutive patients without AMD or normal aging changes (n = 111), with normal aging changes (n = 107), early AMD (n = 102) and intermediate AMD (n = 114) were recruited. RPE curvature was calculated based on the sinuosity method of measuring river curvature in environmental science. RPE and Bruch's membrane were manually segmented from optical coherence tomography B-scans and then their lengths automatically extracted using customized MATLAB code. RPE sinuosity was calculated as a ratio of RPE to Bruch's membrane length. Diagnostic accuracy was determined from area under the receiver operator characteristic curve (aROC). Results: RPE sinuosity of foveal B-scans could distinguish any eyes with AMD (early or intermediate) from those without AMD (non-AMD or eyes with normal aging changes) with acceptable diagnostic accuracy (aROC = 0.775). Similarly, RPE sinuosity could identify intermediate AMD from all other groups (aROC = 0.871) and distinguish between early and intermediate AMD (aROC = 0.737). RPE sinuosity was significantly associated with known AMD lesions: reticular pseudodrusen (P < 0.0001) and drusen volume (P < 0.0001), but not physiological variables such as age, sex, and ethnicity. Conclusions: RPE sinuosity is a simple, robust, quantitative biomarker that is amenable to automation and could enhance screening of AMD.

OCT Prognostic Biomarkers for Progression to Late Age-related Macular Degeneration: A Systematic Review and Meta-analysis.

TOPIC: To evaluate which OCT prognostic biomarkers best predict the risk of progression from early/intermediate to late age-related macular degeneration (AMD). CLINICAL RELEVANCE: Among > 100 OCT prognostic biomarkers for AMD, it is unclear which are the most relevant for clinicians and researchers to focus on. This review evaluated which OCT biomarkers confer the greatest magnitude of prediction for progression to late AMD. METHODS: Study protocol was registered on PROSPERO (CRD42023400166). PubMed and Embase were searched from inception to March 2, 2023, and eligible studies assessed following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was any quantified risk of progression from treatment-naive early/intermediate AMD to late AMD, including hazard ratios (HRs), odds ratios (ORs), and standardized mean differences (at baseline, between eyes with versus without progression), subgrouped by each OCT biomarker. Further meta-analyses were subgrouped by progression to geographic atrophy or neovascularization. RESULTS: A total of 114 quantified OCT prognostic biomarkers were identified. With high GRADE certainty of evidence, the greatest magnitudes of prediction to late AMD belonged to: external limiting membrane abnormality (OR, 15.42 [7.63, 31.17]), ellipsoid zone abnormality (OR, 10.8 [4.58, 25.46]), interdigitation zone abnormality (OR, 7.68 [2.57, 23]), concurrent large drusen and reticular pseudodrusen (HR, 6.73 [1.35, 33.65], hyporeflective drusen cores (HR, 2.48 [1.8, 3.4]; OR 1.85 [1.29, 2.66]), intraretinal hyperreflective foci (IHRF; HR, 2.16 [0.92, 5.07]; OR 5.08 [3.26, 7.92]), and large drusen (HR, 2.01 [1.35, 2.99]); OR, 1.98 [1.27, 3.08]). There was greater risk of geographic atrophy for IHRF and hyporeflective drusen cores (P < 0.05), and neovascularization for ellipsoid zone abnormality (P < 0.05). Other OCT biomarkers such as drusenoid pigment epithelium detachment, shallow irregular retinal pigment epithelium elevations, and nascent geographic atrophy exhibited large magnitudes of risk but required further studies for validation. CONCLUSION: This review synthesizes the 6 most relevant OCT prognostic biomarkers for AMD with greater predictive ability than large drusen alone, for clinicians and researchers to focus on. Further study is required to validate other biomarkers with less than high certainty of evidence, and assess how the copresence of biomarkers may affect risks. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluating the clinical relevance and reliability of outer retinal band length on optical coherence tomography in retinal disease: a cross-sectional study.

OBJECTIVES: Hyper-reflective outer retinal band (HORB) disruptions are reported across a range of retinal disease, yet a reliable, easily implemented assessment method and thorough evaluation of their association to retinal disease is lacking. The purpose of the study was to assess the reliability of using magnitude estimation to evaluate HORB length and determine its association to visual acuity and retinal disease. DESIGN: Cross-sectional, retrospective study. SETTING: Patients attending a secondary eye care clinic in Sydney, Australia. PARTICIPANTS: 2039 unique consecutive patients were screened for inclusion between 2 November and 18 January 2021, and 600 were included in the study population. Patients were included if they were referred from primary care, presented for an initial, comprehensive eye examination during the study period, imaged with optical coherence tomography during their visit and over 18 years of age. PRIMARY OUTCOME: Reliability of HORB length estimations and associations to clinical outcomes. RESULTS: Intragrader (intraclass correlation coefficient, ICCfovea=0.81; ICCworst=0.91) and intergrader (ICCfovea=0.78-0.79; ICCworst=0.75-0.88) agreement of HORB length was good to excellent. HORB length was significantly associated with age (p<0.001, ß=-0.22 to -0.24) and refractive error (p<0.001, ß=0.12-0.16) at all B-scan locations. Visual acuity (p=0.001, ß=-0.13) was associated with the primary outcome for foveal B-scans and eccentricity (p=0.002, ß=-0.13) and device type (p=0.002, ß=0.13) for non-foveal B-scans. Glaucoma was associated with HORB length on univariate analysis (p=0.05-0.06, ß=-0.08); however, multivariate analysis revealed no significant association between HORB length and retinal disease. CONCLUSION: HORB length is reliably assessed using magnitude estimation and may be useful as a surrogate biomarker of visual acuity. Several factors affect HORB length estimations, which may contribute to the lack of association to retinal disease and highlights the need for covariable adjustment when examining HORB disruptions.

Development of a rabbit model of Adenosine triphosphate-induced monocular retinal degeneration for optimization of retinal prostheses.

Optimization of retinal prostheses requires preclinical animal models that mimic features of human retinal disease, have appropriate eye sizes to accommodate implantable arrays, and provide options for unilateral degeneration so as to enable a contralateral, within-animal control eye. In absence of a suitable non-human primate model and shortcomings of our previous feline model generated through intravitreal injections of Adenosine Triphosphate (ATP), we aimed in the present study to develop an ATP induced degeneration model in the rabbit. Six normally sighted Dutch rabbits were monocularly blinded with this technique. Subsequent retinal degeneration was assessed with optical coherence tomography, electroretinography, and histological assays. Overall, there was a 42% and 26% reduction in a-wave and oscillatory potential amplitudes in the electroretinograms respectively, along with a global decrease in retinal thickness, with increased variability. Qualitative inspection also revealed that there were variable levels of retinal degeneration and remodeling both within and between treated eyes, mimicking the disease heterogeneity observed in retinitis pigmentosa. These findings confirm that ATP can be utilized to unilaterally induce blinding in rabbits and, potentially present an ideal model for future cortical recording experiments aimed at optimizing vision restoration strategies.Clinical Relevance- A rapid, unilaterally induced model of retinal degeneration in an animal with low binocular overlap and large eyes will allow for clinically valid recordings of downstream cortical activity following retinal stimulation. Such a model would be highly beneficial for the optimization of clinically appropriate vision restoration approaches.

Spatial Cluster Patterns of Retinal Sensitivity Loss in Intermediate Age-Related Macular Degeneration Features.

Purpose: To examine spatial patterns of retinal sensitivity loss in the three key features of intermediate age-related macular degeneration (iAMD). Methods: One-hundred individuals (53 iAMD, 47 normal) underwent 10-2 mesopic microperimetry testing in one eye. Pointwise sensitivities (dB) were corrected for age, sex, iAMD status, and co-presence of co-localized key iAMD features: drusen load, pigmentary abnormalities, and reticular pseudodrusen (RPD). Clusters (labeled by ranks of magnitude C-2, C-1, C0) were derived from pointwise sensitivities and then assessed by quadrants and eccentricity/rings. Results: Two clusters of decreased sensitivities were evident in iAMD versus normal: C-2, -1.67 dB (95% CI (confidence intervals), -2.36 to -0.98; P < 0.0001); C-1, -0.93 dB (95% CI, -1.5 to -0.36; P < 0.01). One cluster of decreased sensitivity was independently associated each with increased drusen load (13.57 µm increase per -1 dB; P < 0.0001), pigmentary abnormalities (C-1: -2.23 dB; 95% CI, -3.36 to -1.1; P < 0.01), and RPD (C-1: -1.07 dB; 95% CI, -2 to -0.14; P < 0.01). Sensitivity loss in iAMD was biased toward the superior and central macula (P = 0.16 to <0.0001), aligning with structural distributions of features. However, sensitivity loss associated with drusen load also extended to the peripheral macula (P < 0.0001) with paracentral sparing, which was discordant with the central distribution of drusen. Conclusions: Drusen load, pigmentary abnormalities, and RPD are associated with patterns of retinal sensitivity loss commonly demonstrating superior and central bias. Results highlighted that a clinical focus on these three key iAMD features using structural measures alone does not capture the complex, spatial extent of vision-related functional impairment in iAMD. Translational Relevance: Defining the spatial patterns of retinal sensitivity loss in iAMD can facilitate a targeted visual field protocol for iAMD assessment.

Loss of Müller cell glutamine synthetase immunoreactivity is associated with neuronal changes in late-stage retinal degeneration.

Introduction: A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers. Methods: Aged Rd1 mice retinae (P150 - P536, n = minimum 5 per age) and control heterozygous rd1 mice retinae (P536, n = 5) were isolated, fixed and cryosectioned. Fluorescent immunolabeling of glutamine synthetase was performed and retinal areas quantified as having low glutamine synthetase immunoreactivity if proportion of labeled pixels in an area was less than two standard deviations of the mean of the total retina. Other Müller cell markers such as Sox9 and Glial fibrillary acidic protein along with neuronal cell markers Calbindin, Calretinin, recoverin, Protein kinase C-α, Glutamic acid decarboxylase 67, and Islet-1 were then quantified within areas of low and normal synthetase immunoreactivity. Results: Glutamine synthetase immunoreactivity was lost as a function of age in the rd1 mouse retina (P150 - P536). Immunoreactivity of other Müller cell markers, however, were unaffected suggesting Müller cells were still present in these low glutamine synthetase immunoreactive regions. Glutamine synthetase immunoreactivity loss affected specific neuronal populations: Type 2, Type 8 cone, and rod bipolar cells, as well as AII amacrine cells based on reduced recoverin, protein kinase Ca and parvalbumin immunoreactivity, respectively. The number of cell nuclei within regions of low glutamine synthetase immunoreactivity was also reduced suggesting possible neuronal loss rather than reduced cell marker immunoreactivity. Conclusion: These findings further support a strong interplay between glia-neuronal alterations in late-stage degeneration and highlight a need for future studies and consideration in intervention development.

Reticular Pseudodrusen Are Associated With More Advanced Para-Central Photoreceptor Degeneration in Intermediate Age-Related Macular Degeneration.

Purpose: The purpose of this study was to examine retinal topographical differences between intermediate age-related macular degeneration (iAMD) with reticular pseudodrusen (RPD) versus iAMD without RPD, using high-density optical coherence tomography (OCT) cluster analysis. Methods: Single eyes from 153 individuals (51 with iAMD+RPD, 51 with iAMD, and 51 healthy) were propensity-score matched by age, sex, and refraction. High-density OCT grid-wise (60 × 60 grids, each approximately 0.01 mm2 area) thicknesses were custom-extracted from macular cube scans, then compared between iAMD+RPD and iAMD eyes with correction for confounding factors. These "differences (µm)" were clustered and results de-convoluted to reveal mean difference (95% confidence interval [CI]) and topography of the inner retina (retinal nerve fiber, ganglion cell, inner plexiform, and inner nuclear layers) and outer retina (outer plexiform/Henle's fiber/outer nuclear layers, inner and outer segments, and retinal pigment epithelium-to-Bruch's membrane [RPE-BM]). Differences were also converted to Z-scores using normal data. Results: In iAMD+RPD compared to iAMD eyes, the inner retina was thicker (up to +5.89 [95% CI = +2.44 to +9.35] µm, P < 0.0001 to 0.05), the outer para-central retina was thinner (up to -3.21 [95% CI = -5.39 to -1.03] µm, P < 0.01 to 0.001), and the RPE-BM was thicker (+3.38 [95% CI = +1.05 to +5.71] µm, P < 0.05). The majority of effect sizes (Z-scores) were large (-3.13 to +1.91). Conclusions: OCT retinal topography differed across all retinal layers between iAMD eyes with versus without RPD. Greater para-central photoreceptor thinning in RPD eyes was suggestive of more advanced degeneration, whereas the significance of inner retinal thickening was unclear. In the future, quantitative evaluation of photoreceptor thicknesses may help clinicians monitor the potential deleterious effects of RPD on retinal integrity.

Multispectral pattern recognition measures change in drusen area in age-related macular degeneration with high congruency to expert graders.

Drusen are a hallmark lesion of age-related macular degeneration (AMD) and changes in their area and/or volume are strongly associated with disease progression. Assessment of longitudinal change in drusen size in clinical practice however is limited to a single commercial tool or manual inspection by clinicians. In this study we analysed change in drusen area in 33 eyes with intermediate AMD across two separate visits using a novel technique known as multispectral pattern recognition for en face retinal images from various imaging modalities (infrared (815 nm), fundus autofluorescence (488 nm) and green (532 nm) scanning laser ophthalmoscopy). We found 91% (30/33 eyes) agreement in the direction of drusen change for multispectral pattern recognition relative to expert graders who graded eyes as having drusen progression, regression or being stable. Multispectral pattern recognition showed 100% sensitivity (22/22 eyes) and 73% specificity (8/11 eyes). In comparison, we found only 70% (23/33 eyes) agreement in the direction of drusen change with a commercially available change analysis software, the Cirrus Advanced RPE Analysis relative to expert graders, with a sensitivity 64% (14/22 eyes) and specificity of 82% (9/11 eyes). Total drusen area or amount of change between visits had no significant effect on agreement. This suggests multispectral pattern recognition can quantify longitudinal change in drusen area from multimodal imaging with greater congruency to expert graders than a commercially available platform based on a single imaging modality. Considering the association of drusen area and disease progression, this method could aid clinical assessment and monitoring of AMD.

High-Density Optical Coherence Tomography Analysis Provides Insights Into Early/Intermediate Age-Related Macular Degeneration Retinal Layer Changes.

Purpose: To topographically map all of the thickness differences in individual retinal layers between early/intermediate age-related macular degeneration (AMDearly/AMDint) and normal eyes and to determine interlayer relationships. Methods: Ninety-six AMDtotal (48 AMDearly and 48 AMDint) and 96 normal eyes from 192 participants were propensity-score matched by age, sex, and refraction. Retrospective optical coherence tomography (OCT) macular cube scans were acquired, and high-density (60 × 60 0.01-mm2) grid thicknesses were custom extracted for comparison between AMDtotal and normal eyes corrected for confounding. Resultant "normal differences" underwent cluster, interlayer correlation, and dose-response analyses for the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle's fiber layer (ONL+HFL), inner and outer segment (IS/OS) thickness, and retinal pigment epithelium (RPE) to Bruch's membrane (BM) thickness. Results: AMDtotal inner retinal clusters demonstrated extensively thinned RNFL, GCL, IPL, and paracentral INL and thickened INL elsewhere, with normal difference means ranging from -8.13 µm (95% confidence interval [CI], -11.12 to -5.13) to 1.58 µm (95% CI, 1.07-2.09) (P < 0.0001 to P < 0.05). Outer retinal clusters displayed thinned paracentral OPL/ONL+HFL, central IS/OS, and peripheral RPE-BM and thickened central RPE-BM, with means ranging from -1.31 µm (95% CI, -2.06 to -0.55) to 2.99 µm (95% CI, 0.97-5.01] (P < 0.0001 to P <0.05). Effect sizes (-2.56 to 9.93 SD), cluster sizes, and eccentricity effects varied. All interlayer correlations were negligible to moderate regardless of AMD severity. Only the RPE-BM was partly thicker with greater AMD severity (up to 5.44 µm; 95% CI, 4.88-6.00; P < 0.01). Conclusions: From the early stage, AMD eyes demonstrate thickness differences compared to normal with unique topographies across all retinal layers. Poor interlayer correlations highlight that the outer retina inadequately reflects complete retinal health. The clinical importance of OCT assessment across all individual retinal layers in early/intermediate AMD requires further investigation.

Visualisation of peripheral retinal degenerations and anomalies with ocular imaging.

PURPOSE: Certain peripheral retinal degenerations pose a significant risk to vision and require prompt detection and management. Other historically "benign" peripheral lesions are being recognised as clinically significant due to their associations with ocular and systemic disorders. Assessment and documentation of these entities however can be difficult due to challenges in visualisation of the peripheral retina. This review addresses this by providing a series of clinical examples of these entities visualised with a variety of ocular imaging technologies. METHODS: A literature search was performed in Embase, Medline, and Google Scholar. We identified and analysed all papers referring to peripheral retinal degenerations and the peripheral retina, as well as reference lists of retrieved articles until August 2019. RESULTS: Using ocular imaging technologies including ultra-widefield imaging and peripheral optical coherence tomography, we comprehensively describe current evidence and knowledge of a number of peripheral retinal degenerations and anomalies including microcystoid, pavingstone, lattice, snail track, snowflake and reticular pigmentary degenerations, peripheral drusen, white without pressure, retinal holes and vitreoretinal tufts. A summary of these entities is also provided as a short and easily interpretable chairside guide to facilitate the translation of this evidence base into clinical practice. CONCLUSION: While ocular technologies are useful in visualising peripheral retinal degenerations, the current evidence is fragmented throughout the literature and there is a paucity of information on imaging of "benign" peripheral lesions. This review facilitates a multimodal imaging approach to evaluating peripheral lesions.

Ocular ischaemia: signs, symptoms, and clinical considerations for primary eye care practitioners.

Ischaemic stroke is a major disease burden as well as a leading cause of death. Early signs of ischaemic stroke can manifest in the eye, placing primary eyecare practitioners in an important position to identify patients at risk of ischaemic stroke and initiate suitable referral pathways. The vascular supply to the brain is reviewed with reference to vision including the various retinal signs and ocular symptoms associated with transient ischaemic attacks and ischaemic stroke. Using a range of clinical cases, the diverse clinical presentations of retinal embolic events, as well as other forms of vascular occlusion, are highlighted and the underlying pathophysiology is discussed. A succinct scheme for the assessment and management of ischaemic events for primary eye care practitioners is provided.

Should clinical automated perimetry be considered for routine functional assessment of early/intermediate age-related macular degeneration (AMD)? A systematic review of current literature.

PURPOSE: There is growing interest in functional testing for early/intermediate age-related macular degeneration (iAMD). However, systematic evaluation of existing clinical functional tests is lacking. This systematic review examines evidence for using clinical automated perimetry in routine assessment of early/iAMD. RECENT FINDINGS: PubMed, Web of Science Core Collection, and Embase were searched from inception to October 2020 to answer, is there evidence of visual field defects in early/iAMD, and if so, are early/iAMD visual field defects linked to real-world patient outcomes? Articles using clinical automated perimetry (commercially accessible and non-modified devices/protocols) were included. Microperimetry was excluded as this has yet to be incorporated into clinical guidelines. The primary outcome was global visual field indices including mean deviation (MD), pattern standard deviation (PSD), mean sensitivity (MS) and frequency of defects. The secondary outcome was any real-world patient outcome including quality of life and/or activities of daily living indices. Twenty-six studies were eligible for inclusion and all studies were observational. There was consistent evidence of worsened MD, PSD, MS and frequency of defects for early/iAMD compared to normal eyes under photopic, low-photopic and scotopic conditions. Meta-analysis of studies using standard automated perimetry (SAP) under photopic conditions revealed worsened MD (-1.52dB [-2.27, -0.78 dB]) and MS (-1.47dB [-2, -0.94 dB]) in early/iAMD compared to normal eyes, representing large statistical effect sizes but non-clinically meaningful reductions. There was insufficient data for meta-analyses regarding other clinical automated perimetry protocols. Only one study assessed a real-world patient outcome (on-road driving performance), with no significant link to visual field outcomes in early/iAMD. SUMMARY: Significant reduction of global visual field indices is present in early/iAMD, but not clinically meaningful using SAP under photopic conditions. Translational relevance of visual field outcomes to patient outcomes in early/iAMD remains unclear. Thus, SAP under photopic conditions is unlikely to be useful for routine assessment of early/iAMD.

Location-Specific Thickness Patterns in Intermediate Age-Related Macular Degeneration Reveals Anatomical Differences in Multiple Retinal Layers.

Purpose: To examine individual retinal layers' location-specific patterns of thicknesses in intermediate age-related macular degeneration (iAMD) using optical coherence tomography (OCT). Methods: OCT macular cube scans were retrospectively acquired from 84 iAMD eyes of 84 participants and 84 normal eyes of 84 participants propensity-score matched on age, sex, and spherical equivalent refraction. Thicknesses of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle's fiber layer (ONL+HFL), inner- and outer-segment layers (IS/OS), and retinal pigment epithelium to Bruch's membrane (RPE-BM) were calculated across an 8 × 8 grid (total 24° × 24° area). Location-specific analysis was performed using cluster(normal) and grid(iAMD)-to-cluster(normal) comparisons. Results: In iAMD versus normal eyes, the central RPE-BM was thickened (mean difference ± SEM up to 27.45% ± 7.48%, P < 0.001; up to 7.6 SD-from-normal), whereas there was thinned outer (OPL, ONL+HFL, and non-central RPE-BM, up to -6.76% ± 2.47%, P < 0.001; up to -1.6 SD-from-normal) and inner retina (GCL and IPL, up to -4.83% ± 1.56%, P < 0.01; up to -1.7 SD-from-normal) with eccentricity-based effects. Interlayer correlations were greater against the ONL+HFL (mean |r| ± SEM 0.19 ± 0.03, P = 0.14 to < 0.0001) than the RPE-BM (0.09 ± 0, P = 0.72 to < 0.0001). Conclusions: Location-specific analysis suggests altered retinal anatomy between iAMD and normal eyes. These data could direct clinical diagnosis and monitoring of AMD toward targeted locations.

Classifying Retinal Degeneration in Histological Sections Using Deep Learning.

Purpose: Artificial intelligence (AI) techniques are increasingly being used to classify retinal diseases. In this study we investigated the ability of a convolutional neural network (CNN) in categorizing histological images into different classes of retinal degeneration. Methods: Images were obtained from a chemically induced feline model of monocular retinal dystrophy and split into training and testing sets. The training set was graded for the level of retinal degeneration and used to train various CNN architectures. The testing set was evaluated through the best architecture and graded by six observers. Comparisons between model and observer classifications, and interobserver variability were measured. Finally, the effects of using less training images or images containing half the presentable context were investigated. Results: The best model gave weighted-F1 scores in the range 85% to 90%. Cohen kappa scores reached up to 0.86, indicating high agreement between the model and observers. Interobserver variability was consistent with the model-observer variability in the model's ability to match predictions with the observers. Image context restriction resulted in model performance reduction by up to 6% and at least one training set size resulted in a model performance reduction of 10% compared to the original size. Conclusions: Detecting the presence and severity of up to three classes of retinal degeneration in histological data can be reliably achieved with a deep learning classifier. Translational Relevance: This work lays the foundations for future AI models which could aid in the evaluation of more intricate changes occurring in retinal degeneration, particularly in other types of clinically derived image data.