Evaluating Contrast Sensitivity in Early and Intermediate Age-Related Macular Degeneration With the Quick Contrast Sensitivity Function.

Purpose: The purpose of this study was to describe, validate, and compare the contrast sensitivity functions (CSFs) acquired with the novel quick CSF (qCSF) method from patients with early and intermediate age-related macular degeneration (eAMD and iAMD) and healthy controls. Methods: This is a cross-sectional analysis of contrast sensitivity (CS) and visual acuity (VA) baseline data from the prospective Multimodal Functional and Structural Visual System Characterization (MUMOVI) study. The qCSF testing was conducted with the manifold contrast vision meter (Adaptive Sensory Technology, San Diego, CA, USA). CS levels at spatial frequencies from 1 cycle per degree (CPD) to 18 CPD, the area underneath the logarithmic contrast sensitivity function (AULCSF), and contrast acuity (CA) were analyzed. The association of functional metrics with variables of interest was tested with linear models. Results: Ninety-four study eyes from 94 study patients were included in the analysis (13 patients with eAMD, 33 patients with iAMD, and 48 healthy controls). Significant differences between the eAMD and the iAMD model estimates were only found for CS at 1 CPD (t value = -2.9, P value = 0.006) and CS at 1.5 CPD (-2.7, 0.01). A specific association between smoking years and CS at 1 CPD (P = 0.02) and CS at 1.5 CPD (P = 0.03) could be described in patients with AMD. Conclusions: The qCSF testing allows the fast measurement of the whole CSF, enabling the integration into clinical routine. We showed that novel qCSF-derived metrics detect slight functional differences between AMD stages, which testing by Pelli-Robson charts or VA testing would miss. This study, therefore, yields novel qCSF-derived candidate metrics for therapeutic trials in AMD.

Comparison of Novel Volumetric Microperimetry Metrics in Intermediate Age-Related Macular Degeneration: PINNACLE Study Report 3.

Purpose: To investigate and compare novel volumetric microperimetry (MP)-derived metrics in intermediate age-related macular degeneration (iAMD), as current MP metrics show high variability and low sensitivity. Methods: This is a cross-sectional analysis of microperimetry baseline data from the multicenter, prospective PINNACLE study (ClinicalTrials.gov NCT04269304). The Visual Field Modeling and Analysis (VFMA) software and an open-source implementation (OSI) were applied to calculate MP-derived hill-of-vison (HOV) surface plots and the total volume (VTOT) beneath the plots. Bland-Altman plots were used for methodologic comparison, and the association of retinal sensitivity metrics with explanatory variables was tested with mixed-effects models. Results: In total, 247 eyes of 189 participants (75 ± 7.3 years) were included in the analysis. The VTOT output of VFMA and OSI exhibited a significant difference (P < 0.0001). VFMA yielded slightly higher coefficients of determination than OSI and mean sensitivity (MS) in univariable and multivariable modeling, for example, in association with low-luminance visual acuity (LLVA) (marginal R2/conditional R2: VFMA 0.171/0.771, OSI 0.162/0.765, MS 0.133/0.755). In the multivariable analysis, LLVA was the only demonstrable predictor of VFMA VTOT (t-value, P-value: -7.5, <0.001) and MS (-6.5, <0.001). Conclusions: The HOV-derived metric of VTOT exhibits favorable characteristics compared to MS in evaluating retinal sensitivity. The output of VFMA and OSI is not exactly interchangeable in this cross-sectional analysis. Longitudinal analysis is necessary to assess their performance in ability-to-detect change. Translational Relevance: This study explores new volumetric MP endpoints for future application in therapeutic trials in iAMD and reports specific characteristics of the available HOV software applications.

Exploring Healthy Retinal Aging with Deep Learning.

Purpose: To study the individual course of retinal changes caused by healthy aging using deep learning. Design: Retrospective analysis of a large data set of retinal OCT images. Participants: A total of 85 709 adults between the age of 40 and 75 years of whom OCT images were acquired in the scope of the UK Biobank population study. Methods: We created a counterfactual generative adversarial network (GAN), a type of neural network that learns from cross-sectional, retrospective data. It then synthesizes high-resolution counterfactual OCT images and longitudinal time series. These counterfactuals allow visualization and analysis of hypothetical scenarios in which certain characteristics of the imaged subject, such as age or sex, are altered, whereas other attributes, crucially the subject's identity and image acquisition settings, remain fixed. Main Outcome Measures: Using our counterfactual GAN, we investigated subject-specific changes in the retinal layer structure as a function of age and sex. In particular, we measured changes in the retinal nerve fiber layer (RNFL), combined ganglion cell layer plus inner plexiform layer (GCIPL), inner nuclear layer to the inner boundary of the retinal pigment epithelium (INL-RPE), and retinal pigment epithelium (RPE). Results: Our counterfactual GAN is able to smoothly visualize the individual course of retinal aging. Across all counterfactual images, the RNFL, GCIPL, INL-RPE, and RPE changed by -0.1 µm ± 0.1 µm, -0.5 µm ± 0.2 µm, -0.2 µm ± 0.1 µm, and 0.1 µm ± 0.1 µm, respectively, per decade of age. These results agree well with previous studies based on the same cohort from the UK Biobank population study. Beyond population-wide average measures, our counterfactual GAN allows us to explore whether the retinal layers of a given eye will increase in thickness, decrease in thickness, or stagnate as a subject ages. Conclusion: This study demonstrates how counterfactual GANs can aid research into retinal aging by generating high-resolution, high-fidelity OCT images, and longitudinal time series. Ultimately, we envision that they will enable clinical experts to derive and explore hypotheses for potential imaging biomarkers for healthy and pathologic aging that can be refined and tested in prospective clinical trials. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Cyclotorsion Measurement on Scanning Laser Ophthalmoscopy Imaging Compared With Fundus Photography in Patients With Fourth Nerve Palsy and Healthy Controls: CySLO-IV Study.

BACKGROUND: The purpose of the study is to evaluate the agreement of the foveopapillary angle (FPA) on conventional fundus photography (c-FPA) with the FPA on scanning laser ophthalmoscopy (SLO) imaging (SLO-FPA) in patients with fourth nerve palsy and healthy controls (HCs). METHODS: The FPA was measured in both eyes of 25 patients and 25 HCs in synedra View (c-FPA) and with the integrated algorithm of the Heidelberg Spectralis OCT (SLO-FPA). The primary endpoint was the agreement of both measurements. Furthermore, we evaluated the influence of the eye tracker, the influence of fixation on objective torsion, and the FPA cutoff between patients and HCs. RESULTS: The mean SLO-FPA in patients (6/25 acquired palsies) was 11.3 ± 3.6° and 6.4 ± 2.1° in HCs. The mean c-FPA was 11.4 ± 4.0° and 5.8 ± 2.2°, respectively. The Bland-Altman plot of c-FPA vs SLO-FPA in patients and HCs shows no systematic bias (mean of -0.28°). Limits of agreement were -6.58 and 6.02°. Using the eye tracker had no systematic effect. There was no evidence for an immediate shift of torsion with change of fixation (24/25 patients and 23/25 HCs). Discrimination between patients and HCs by the SLO-FPA is very good with an area under the curve = 0.92 (95% confidence interval: 0.84-0.99). CONCLUSIONS: SLO-FPA measurement allows convenient and consistent assessment of objective cyclotorsion. There was no systematic bias in the difference between SLO-FPA and traditional c-FPA; thus, SLO-FPA is a valuable alternative to the commonly used c-FPA. Using the eye tracker is recommended for proper centering of the ring scan.

Abnormal Connectivity and Brain Structure in Patients With Visual Snow.

OBJECTIVE: Visual snow (VS) is a distressing, life-impacting condition with persistent visual phenomena. VS patients show cerebral hypermetabolism within the visual cortex, resulting in altered neuronal excitability. We hypothesized to see disease-dependent alterations in functional connectivity and gray matter volume (GMV) in regions associated with visual perception. METHODS: Nineteen patients with VS and 16 sex- and age-matched controls were recruited. Functional magnetic resonance imaging (fMRI) was applied to examine resting-state functional connectivity (rsFC). Volume changes were assessed by means of voxel-based morphometry (VBM). Finally, we assessed associations between MRI indices and clinical parameters. RESULTS: Patients with VS showed hyperconnectivity between extrastriate visual and inferior temporal brain regions and also between prefrontal and parietal (angular cortex) brain regions (p < 0.05, corrected for age and migraine occurrence). In addition, patients showed increased GMV in the right lingual gyrus (p < 0.05 corrected). Symptom duration positively correlated with GMV in both lingual gyri (p < 0.01 corrected). CONCLUSION: This study found VS to be associated with both functional and structural changes in the early and higher visual cortex, as well as the temporal cortex. These brain regions are involved in visual processing, memory, spatial attention, and cognitive control. We conclude that VS is not just confined to the visual system and that both functional and structural changes arise in VS patients, be it as an epiphenomenon or a direct contributor to the pathomechanism of VS. These in vivo neuroimaging biomarkers may hold potential as objective outcome measures of this so far purely subjective condition.

Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy.

BACKGROUND: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. RESULTS: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. CONCLUSIONS: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone.

New Technologies for Outcome Measures in Glaucoma: Review by the European Vision Institute Special Interest Focus Group.

Glaucoma is the leading cause of irreversible blindness worldwide, with an increasing prevalence. The complexity of the disease has been a major challenge in moving the field forward with regard to both pathophysiological insight and treatment. In this context, discussing possible outcome measures in glaucoma trials is of utmost importance and clinical relevance. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "New Technologies for Outcome Measures in Retina and Glaucoma," addressing both functional and structural outcomes, as well as translational hot topics in glaucoma and retina research. In conjunction with the published literature, this review summarizes the meeting focusing on glaucoma.

New Technologies for Outcome Measures in Retinal Disease: Review from the European Vision Institute Special Interest Focus Group.

Novel diagnostic tools to measure retinal function and structure are rapidly being developed and introduced into clinical use. Opportunities exist to use these informative and robust measures as endpoints for clinical trials to determine efficacy and to monitor safety of therapeutic interventions. In order to inform researchers and clinician-scientists about these new diagnostic tools, a workshop was organized by the European Vision Institute. Invited speakers highlighted the recent advances in state-of-the-art technologies for outcome measures in the field of retina. This review highlights the workshop's presentations in the context of published literature.

Visual snow syndrome: a review on diagnosis, pathophysiology, and treatment.

PURPOSE OF REVIEW: Visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant bilateral whole-visual field flickering or pixelation. When associated with additional visual symptoms, it is referred to as visual snow syndrome. Its pathophysiology remains elusive. This review highlights the visual snow literature focusing on recent clinical studies that add to our understanding of its clinical picture, pathophysiology, and treatment. RECENT FINDINGS: Clinical characterization of visual snow syndrome is evolving, including a suggested modification of diagnostic criteria. Regarding pathophysiology, two recent studies tested the hypothesis of dysfunctional visual processing and occipital cortex hyperexcitability using electrophysiology. Likewise, advanced functional imaging shows promise to allow further insights into disease mechanisms. A retrospective study now provides Class IV evidence for a possible benefit of lamotrigine in a minority of patients. SUMMARY: Scientific understanding of visual snow syndrome is growing. Major challenges remain the subjective nature of the disease, its overlap with migraine, and the lack of quantifiable outcome measures, which are necessary for clinical trials. In that context, refined perceptual assessment, objective electrophysiological parameters, as well as advanced functional brain imaging studies, are promising tools in the pipeline.

Inter-Rater Reliability of Cyclotorsion Measurements Using Fundus Photography.

BACKGROUND: The foveo-papillary angle (FPA) on fundus photographs is the accepted standard for the measurement of ocular cyclotorsion. We assessed the inter-rater reliability of this method in healthy subjects and in patients with trochlear nerve palsies. PATIENTS AND METHODS: In this methodological study, fundus photographs of healthy subjects and of patients with trochlear nerve palsies were made with a fundus camera (Zeiss Fundus Camera FF 450 plus, Jena, Germany). Three independent observers measured the FPA on the fundus photographs of all subjects in synedra View (synedra View 16, Version 16.0.0.11, Innsbruck, Austria). RESULTS: One hundred and four eyes of 52 subjects (26 healthy controls and 26 patients) were assessed. The mean FPA of the healthy controls was 5.80 degrees (°) [± 0.44 standard error of the mean (SEM)] compared to 11.55° (± 0.80 SEM) for patients with trochlear nerve palsies. The inter-rater reliability of all measured FPAs showed an intraclass correlation coefficient (ICC) of 0.98 (95% CI 0.97 - 0.98). CONCLUSIONS: The inter-rater reliability of objective cyclotorsion measurements using fundus photographs was very high.

Multicenter reliability of semiautomatic retinal layer segmentation using OCT.

OBJECTIVE: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans. METHODS: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps. RESULTS: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers. CONCLUSIONS: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.

Amiodarone-associated Optic Neuropathy-A Clinical Criteria-based Diagnosis?

Amiodarone-associated optic neuropathy (AAON) is a controversial diagnosis with possible impact on vital cardiac therapy decisions. This retrospective case series aims for application of distinguishing features of AAON versus non-arteritic ischaemic optic neuropathy (NAION): Bilaterality, mode of onset, degree of optic nerve dysfunction, structure of uninvolved disc (unilateral cases), and systemic toxic effects. Applying these criteria to patients with disc swelling under amiodarone, the authors identified four unilateral disc swellings, one with NAION-typical features only and three with one or more NAION-atypical features. All three sequential and six bilateral cases showed one or more NAION-atypical features. The 12 cases highlight the persisting diagnostic dilemma arising from diversity of presentation, lack of plausible pathomechanism, and controversial existence of the entity itself.

Reliability of Cyclotorsion measurements using Scanning Laser Ophthalmoscopy imaging in healthy subjects: the CySLO study.

BACKGROUND/AIMS: To evaluate inter-rater and intra-rater reliability of objective cyclotorsion measurements obtained in healthy subjects using the Heidelberg Spectralis spectral domain-optical coherence tomography (SD-OCT) device. METHODS: In this prospective methodological study, 32 healthy subjects (14 men, 18 women; aged 21-64 years) were enrolled, 31 right eyes were examined and their foveo-papillary angles (FPAs) were measured. The retinal nerve fibre layer (RNFL) programme by Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) was used to measure cyclotorsion based on the in-built algorithm for the measurement of the FPA on the scanning laser ophthalmoscopy (SLO) image. Repeated scans of the fixating and non-fixating right eye without and with eye tracker each were obtained by three different examiners. RESULTS: The mean FPA measured overall by all three examiners was 6.6°±2.8°. The inter-rater reliability of the measured FPAs using the linear mixed effects model is estimated as rhointer=0.8803. The intra-rater reliability is estimated as rhointra=0.9589. CONCLUSIONS: Repeatability of objective cyclotorsion measurements within and between observers using the Heidelberg Spectralis OCT is very high. SD-OCT/SLO imaging is a reliable imaging technique to measure and study cyclotorsion. CLINICAL TRIAL NUMBER: NCT02631369, Results.

Natural history of primary paediatric optic nerve sheath meningioma: case series and review.

PURPOSE: To study the natural history, clinical and radiological characteristics of primary paediatric optic nerve sheath meningioma (PPONSM). METHODS: Retrospective study of eight paediatric patients who were treated between 1994 and 2016 at the University Hospital Zurich, Switzerland and the Royal Adelaide Hospital, Australia. Clinical records and imaging studies were reviewed. RESULTS: The mean age at presentation was 11 years (range: 6-17 years). There were six female patients and two male patients. 2/8 patients had associated neurofibromatosis type 2. Patients were followed up for 71-297 months (mean 156±70 months). 6/8 patients were observed through the course of their disease and 2/8 patients were treated with radiotherapy. 2/8 patients who were observed had minimal change in vision and did not experience tumour growth after long-term follow-up. CONCLUSIONS: This is the largest PPONSM case series with long-term data on patients treated conservatively. We highlight that a small subset of these tumours are indolent and can be managed using observation alone.

Enhanced Depth Imaging Optical Coherence Tomography of Optic Nerve Head Drusen: A Comparison of Cases with and without Visual Field Loss.

PURPOSE: Enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD OCT) has been recognized as the most sensitive tool to diagnose optic nerve head drusen (ONHD). The relationship between OCT characteristics and visual loss has not been well documented. This study compares EDI SD OCT-determined morphologic characteristics of drusen in eyes with or without visual field (VF) defects. DESIGN: Descriptive study of patients attending the neuro-ophthalmology service of Moorfields Eye Hospital between January 2013 and October 2014. SUBJECTS: Patients with diagnosed ONHD and EDI SD OCT imaging of the optic nerve head. METHODS: Eyes with and without VF defects were compared with regard to retinal nerve fiber layer (RNFL) thickness, drusen morphology, size, extent, visibility on funduscopy, ultrasound, and fundus autofluorescence. MAIN OUTCOME MEASURES: Difference in OCT characteristics of ONHD between patients with or without VF defects. RESULTS: Of 38 patients, 69 eyes with ONHD were included. Thirty-three eyes had a normal VF with average mean deviation (MD) -0.96 (±1.2) dB and pattern standard deviation (PSD) 1.6 (±0.3) dB (group I), and 36 eyes had VF defects with MD -13.7 (±10.4) dB and PSD 7.2 (±3.6) dB (group II). Mean global RNFL thickness was 62 (±20.9) µm in the latter group and 99.0 (±12.9) µm in group I. In group I, the predominant drusen type was peripapillary drusen, of variable size. In group II, most eyes had confluent (P < 0.02) and large (>500 µm; P < 0.003) drusen, and drusen were more commonly visible on funduscopy (P = 0.001), ultrasound (P = 0.013), and autofluorescence (P = 0.002). Differences between the 2 groups reached statistical significance in a clustered analysis. RNFL thinning and autofluorescence showed relative sparing of the temporal sector. Sixty-four percent of patients with a VF defect in 1 eye also had a VF defect in their fellow eye. CONCLUSIONS: Drusen size and drusen type as classified by OCT morphologic characteristics are significantly different in patients with or without VF defects. Confluent, large, and autofluorescent drusen were more commonly found in patients with VF defects. These findings may assist in clarifying how drusen give rise to visual loss, which is currently not known.

Malignant optic glioma - the spectrum of disease in a case series.

PURPOSE: Malignant optic glioma of adulthood is a rare, invasive neoplasm of the anterior visual pathway with 66 cases reported in the literature. It presents as anaplastic astrocytoma (WHO grade III) or glioblastoma (WHO grade IV). The present case series covers the spectrum of disease manifestations, discusses neuroradiological findings, and reviews the current literature. METHODS: Retrospective case series of five patients from three tertiary referral centers and literature review. RESULTS: Visual loss with or without pain was the presenting symptom in all patients (two women, three men). Two patients were initially misdiagnosed as optic neuritis, and one patient as atypical non-arteritic anterior ischemic optic neuropathy (NAION). A neoplastic disease was suspected in the two remaining patients. MRI features were iso- to hypointensity on T1-weighted native images, contrast enhancement, and hyperintensity on T2-weighted images. Biopsy was generally diagnostic; however, one patient required two biopsies for diagnosis. The series includes an exceptional case of intraocular tumor extension and vitreous spread. The disease was lethal within one to two years in all patients. CONCLUSIONS: Malignant optic glioma is a diagnostic challenge and remains a devastating and lethal disease. Advances in the understanding of tumor biology have yet failed to translate into effective treatment regimens.

Albino mice as an animal model for infantile nystagmus syndrome.

PURPOSE: Individuals with oculocutaneous albinism are predisposed to visual system abnormalities affecting the retina and retinofugal projections, which may lead to reduced visual acuity and Infantile Nystagmus Syndrome (INS). Due to absence of an established mammalian animal model, mechanisms underlying INS remain elusive. In this study, we screened wild-type mice of varying pigmentation for ocular motor abnormalities in order to identify a possible mouse model for INS. METHODS: Three albino mouse strains (CD1, BALB/c, DBA/1), and two normally pigmented strains (129S6, C57BL/6) were screened using infrared oculography. Varying visual stimuli (black or white background, stationary pattern, optokinetic, i.e., horizontally rotating pattern) were displayed to the full (fVF) or anterior visual field (aVF) of the restrained mouse. RESULTS: We found spontaneous nystagmus, specifically jerks and oscillations, in albino mice under all experimental conditions. Median eye velocity was between 0.8 and 3.4 deg/s, depending on the strain. In contrast, the eyes in pigmented mice were nearly stable with a median absolute eye velocity of below 0.4 deg/s. In albino mice, fVF optokinetic stimuli elicited an optokinetic response (OKR) in the correct direction, albeit with superimposed oscillations. However, aVF optokinetic stimuli evoked reversed OKR in these strains, a well known feature of INS. CONCLUSIONS: Based on our results, we endorse the investigated albino mouse strains as new animal models for INS.