Measuring Visual Fields in Children With Glaucoma Using a Portable Tablet.

Purpose: To compare perimetric outcomes of an iPad perimetry app (Melbourne Rapid Fields [MRF]) with those of the Humphrey Field Analyser (HFA) testing children with glaucoma. Methods: Sixteen children diagnosed and treated for glaucoma were recruited to evaluate their perimetric performance over two visits. At each visit, they undertook visual field assessment using the MRF application as well as the HFA. The HFA test was part of their usual clinical work up and a clinical assistant judged which test format (24-2 SITA standard or SITA fast) might be suited to the testing of that child. The primary outcome measure was the association and repeatability of mean deviation (MD) for the MRF and HFA tests, by way of regression, intraclass correlation coefficient and Bland-Altman analysis. Secondary measures were comparisons of pattern deviation indices, test times as well as an indication of participant test preference. Summary data show means ± standard deviation. Results: The age for our cohort was 7 to 15 years of age (mean, 10.0 ± 2.4 years of age). The MRF MD was in close concordance to HFA MD with an intraclass correlation coefficient of 0.91 (95% confidence interval, 0.82-0.95). Bland-Altman analysis found little bias (-0.6 dB) and a 95% coefficient of repeatability of 2.1 dB in eyes having a normal HFA MD. In eyes with glaucomatous visual field defects the 95% coefficient of repeatability at retest was much larger for both the MRF (10.5 dB) as well as for the HFA (10.0 dB). Average MRF test times (5.6 ± 1.2 minutes) were similar to SITA Fast (5.4 ± 1.9 minutes) with both being significantly faster than SITA standard (8.6 ± 1.4 minutes; P < 0.001). All children chose testing with the MRF as their preference. Conclusions: MRF correlated strongly with HFA and was preferred by the children over the HFA. MRF is suitable for perimetric evaluation of children with glaucoma. Translational Relevance: This study finds that an iPad based visual field test can be used with children having glaucoma to yield outcomes similar to SITA-fast. Children indicate a preference for such testing.

Diagnosing glaucoma in primary eye care and the role of Artificial Intelligence applications for reducing the prevalence of undetected glaucoma in Australia.

Glaucoma is the commonest cause of irreversible blindness worldwide, with over 70% of people affected remaining undiagnosed. Early detection is crucial for halting progressive visual impairment in glaucoma patients, as there is no cure available. This narrative review aims to: identify reasons for the significant under-diagnosis of glaucoma globally, particularly in Australia, elucidate the role of primary healthcare in glaucoma diagnosis using Australian healthcare as an example, and discuss how recent advances in artificial intelligence (AI) can be implemented to improve diagnostic outcomes. Glaucoma is a prevalent disease in ageing populations and can have improved visual outcomes through appropriate treatment, making it essential for general medical practice. In countries such as Australia, New Zealand, Canada, USA, and the UK, optometrists serve as the gatekeepers for primary eye care, and glaucoma detection often falls on their shoulders. However, there is significant variation in the capacity for glaucoma diagnosis among eye professionals. Automation with Artificial Intelligence (AI) analysis of optic nerve photos can help optometrists identify high-risk changes and mitigate the challenges of image interpretation rapidly and consistently. Despite its potential, there are significant barriers and challenges to address before AI can be deployed in primary healthcare settings, including external validation, high quality real-world implementation, protection of privacy and cybersecurity, and medico-legal implications. Overall, the incorporation of AI technology in primary healthcare has the potential to reduce the global prevalence of undiagnosed glaucoma cases by improving diagnostic accuracy and efficiency.

Retinal Vascular Measurements and Mortality Risk: Evidence From the UK Biobank Study.

Purpose: This study aimed to investigate the association between quantitative retinal vascular measurements and the risk of all-cause and premature mortality. Methods: In this population-based cohort study using the UK Biobank data, we employed the Retina-based Microvascular Health Assessment System to assess fundus images for image quality and extracted 392 retinal vascular measurements per fundus image. These measurements encompass six categories of vascular features: caliber, density, length, tortuosity, branching angle, and complexity. Univariate Cox regression models were used to identify potential indicators of mortality risk using data on all-cause and premature mortality from death registries. Multivariate Cox regression models were then used to test these associations while controlling for confounding factors. Results: The final analysis included 66,415 participants. After adjusting for demographic, health, and lifestyle factors and genetic risk score, 18 and 10 retinal vascular measurements were significantly associated with all-cause mortality and premature mortality, respectively. In the fully adjusted model, the following measurements of different vascular features were significantly associated with all-cause mortality and premature mortality: arterial bifurcation density (branching angle), number of arterial segments (complexity), interquartile range and median absolute deviation of arterial curve angle (tortuosity), mean and median values of mean pixel widths of all arterial segments in each image (caliber), skeleton density of arteries in macular area (density), and minimum venular arc length (length). Conclusions: The study revealed 18 retinal vascular measurements significantly associated with all-cause mortality and 10 associated with premature mortality. Those identified parameters should be further studied for biological mechanisms connecting them to increased mortality risk. Translational Relevance: This study identifies retinal biomarkers for increased mortality risk and provides novel targets for investigating the underlying biological mechanisms.

A Systematic Review and Meta-Analysis of Applying Deep Learning in the Prediction of the Risk of Cardiovascular Diseases From Retinal Images.

Purpose: The purpose of this study was to perform a systematic review and meta-analysis to synthesize evidence from studies using deep learning (DL) to predict cardiovascular disease (CVD) risk from retinal images. Methods: A systematic literature search was performed in MEDLINE, Scopus, and Web of Science up to June 2022. We extracted data pertaining to predicted outcomes, model development, and validation and model performance metrics. Included studies were graded using the Quality Assessment of Diagnostic Accuracies Studies 2 tool. Model performance was pooled across eligible studies using a random-effects meta-analysis model. Results: A total of 26 studies were included in the analysis. There were 42 CVD risk-related outcomes predicted from retinal images were identified, including 33 CVD risk factors, 4 cardiac imaging biomarkers, 2 CVD risk scores, the presence of CVD, and incident CVD. Three studies that aimed to predict the development of future CVD events reported an area under the receiver operating curve (AUROC) between 0.68 and 0.81. Models that used retinal images as input data had a pooled mean absolute error of 3.19 years (95% confidence interval [CI] = 2.95-3.43) for age prediction; a pooled AUROC of 0.96 (95% CI = 0.95-0.97) for gender classification; a pooled AUROC of 0.80 (95% CI = 0.73-0.86) for diabetes detection; and a pooled AUROC of 0.86 (95% CI = 0.81-0.92) for the detection of chronic kidney disease. We observed a high level of heterogeneity and variation in study designs. Conclusions: Although DL models appear to have reasonably good performance when it comes to predicting CVD risk, further work is necessary to evaluate the real-world applicability and predictive accuracy. Translational Relevance: DL-based CVD risk assessment from retinal images holds great promise to be translated to clinical practice as a novel approach for CVD risk assessment, given its simple, quick, and noninvasive nature.

Performance of a Smart Device over 12-Months for Home Monitoring of Patients with Intermediate Age-Related Macular Degeneration.

BACKGROUND: To determine the 12-month compliance with and retention of home monitoring (HM) with Melbourne Rapid Fields (MRFh) for patients with intermediate age-related macular degeneration (iAMD) and compare visual acuity (VA) and retinal sensitivity (RS) results to clinical measures. METHODS: Participants were recruited to a 12-month HM study with weekly testing of vision with MRFh. Inclusion criteria were a diagnosis of iAMD, understand English instructions, VA ≥ 20/40, and access to an iPad. Supervised in-clinic testing of high contrast VA (HVA, ETDRS), low-luminance VA (LLVA, ETDRS with ND2 filter), and RS (Macular Integrity Assessment, MAIA, and MRF in-clinic, MRFc) was conducted every 6-months. RESULTS: A total of 54 participants (67 ± 6.8 years) were enrolled. Compliance to weekly HM was 61% and study retention at 12-months was 50% of those with uptake (n = 46). No difference was observed between MRFc and MRFh across all RS and VA outcomes (p > 0.05). MRFh RS was higher than MAIA (29.1 vs. 27.1 dB, p < 0.001). MRFh HVA was not different from ETDRS (p = 0.08), but LLVA was 9 letters better (81.5 vs. 72.4 letters, p < 0.001). CONCLUSIONS: Over 12-months, MRFh yields a moderate level of compliance with (61%) and retention (50%) of weekly testing. Further studies are required to assess the ability of MRFh to detect early progression to nAMD.

Test Reliability and Compliance to a Twelve-Month Visual Field Telemedicine Study in Glaucoma Patients.

Background: Our primary aim is to quantify test reliability and compliance of glaucoma patients to a weekly visual field telemedicine (VFTM) schedule. A secondary aim is to determine concordance of the VFTM results to in-clinic outcomes. Methods: Participants with stable glaucoma in one eye were recruited for a 12 month VFTM trial using the Melbourne Rapid Fields (MRF-home, MRFh) iPad application. Participants attended routine 6 month clinical reviews and were tasked with weekly home monitoring with the MRFh over this period. We determined compliance to weekly VFTM (7 + 1 days) and test reliability (false positives (FPs) and fixation loss (FL) <33%). A secondary aim considered concordance to in-clinic measures of visual field (MRF-clinic (MRFc) and the Humphrey Field Analyzer (HFA)) in active participants (≥10 home examinations and 5 reliable HFA examinations). The linear trend in the MRFh mean deviation (MD) was compared to the HFA guided progression analysis (GPA) using Bland−Altman methods. Data are shown as the mean ± standard deviation. Results: Forty-seven participants with a mean age of 64 ± 14.6 years were recruited for the trial. The VFTM uptake was 85% and compliance to weekly home monitoring was 75% in the presence of weekly text reminders in the analysed group (n = 20). The analysed group was composed of test subjects with five reliable in-clinic HFA examinations (GPA analysis available) and who submitted a minimum of 10 MRFh examinations from home. Of the 757 home examinations returned, approximately two-thirds were reliable, which was significantly lower than the test reliability of the HFA in-clinic (MRFh: 65% vs. HFA: 85%, p < 0.001). The HFA-GPA analysis gave little bias from the MRFh slope (bias: 0.05 dB/yr, p > 0.05). Two eyes were found to have clinical progression during the 12 month period, and both were detected by VFTM. Conclusions: VFTM over 12 months returned good compliance (75%) to weekly testing with good concordance to in-clinic assays. VFTM is a viable option for monitoring patients with glaucoma for visual field progression in between clinical visits.

Vision and Visuomotor Performance Following Acute Ischemic Stroke.

BACKGROUND: As measurable sensory and motor deficits are key to the diagnosis of stroke, we investigated the value of objective tablet based vision and visuomotor capacity assessment in acute mild-moderate ischemic stroke (AIS) patients. METHODS: Sixty AIS patients (65 ± 14 years, 33 males) without pre-existing visual/neurological disorders and acuity better than 6/12 were tested at their bedside during the first week post-stroke and were compared to 40 controls (64 ± 11 years, 15 males). Visual field sensitivity, quantified as mean deviation (dB) and visual acuity (with and without luminance noise), were tested on MRFn (Melbourne Rapid Field-Neural) iPad application. Visuomotor capacity was assessed with the Lee-Ryan Eye-Hand Coordination (EHC) iPad application using a capacitive stylus for iPad held in the preferred hand.Time to trace 3 shapes and displacement errors (deviations of >3.5 mm from the shape) were recorded. Diagnostic capacity was considered with Receiver Operating Characteristics. Vision test outcomes were correlated with National Institutes of Health Stroke Scale (NIHSS) score at the admission. RESULTS: Of the 60 AIS patients, 58 grasped the iPad stylus in their preferred right hand even though 31 had left hemisphere lesions. Forty-one patients (68%) with better than 6/12 visual acuity (19 right, 19 left hemisphere and 3 multi-territorial lesions) returned significantly abnormal visual fields. The stroke group took significantly longer (AIS: 93.4 ± 60.1 s; Controls: 33.1 ± 11.5 s, p < 0.01) to complete EHC tracing and made larger displacements (AIS: 16,388 ± 36,367 mm; Controls: 2,620 ± 1,359 mm, p < 0.01) although both control and stroke groups made similar numbers of errors. EHC time was not significantly different between participants with R (n = 26, 84.3 ± 55.3 s) and L (n = 31, 101.3 ± 64.7 s) hemisphere lesions. NIHSS scores and EHC measures showed low correlations (Spearman R: -0.15, L: 0.17). ROC analysis of EHC and vision tests found high diagnostic specificity and sensitivity for a fail at EHC time, or visual field, or Acuity-in-noise (sensivity: 93%, specificity: 83%) that shows little relationship to NIHSS scores. CONCLUSIONS: EHC time and vision test outcomes provide an easy and rapid bedside measure that complements existing clinical assessments in AIS. The low correlation between visual function, NIHSS scores and lesion site offers an expanded clinical view of changes following stroke.

The Short-Term Compliance and Concordance to in Clinic Testing for Tablet-Based Home Monitoring in Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to determine the short-term compliance with regular home monitoring of macular retinal sensitivity (RS) in intermediate age-related macular degeneration (iAMD). Home-based outcomes were compared with in-clinic outcomes determined using (1) the same tablet device under supervision, and (2) the Macular Integrity Assessment (MaIA) microperimeter. DESIGN: Single-center longitudinal compliance and reliability study. METHODS: A total of 73 participants with iAMD were trained to perform macular field testing with the Melbourne Rapid Fields-macular (MRF-m) iPad application. Volunteers were asked to return 6 weekly tests from home, guided by audio instructions. We determined compliance with weekly testing and surveyed for factors that limited compliance. Test reliability (false positive, false negative) and RS were compared to in-clinic assays (MaIA). Data are given as mean ± SD or as median [quartile 1-3 range]. Group comparisons were achieved with bootstrap to define the 95% confidence limits. RESULTS: A total of 59 participants submitted 6 home examinations with a median intertest interval of 8.0 [7.0-17] days. Compliance with weekly testing (7 days ±24 hours) was 55%. The main barrier to compliance was information technology (IT) logistic reasons. Of 694 home examinations submitted, 96% were reliable (false-positive results <25%). The mean RS returned by the tablet was significantly higher (+3.2 dB, P < .05) compared to the MaIA. CONCLUSIONS: Home monitoring produces reliable results that differ from in-clinic tests because of test design. This should not affect self-monitoring once an at-home baseline is established, but these differences will affect comparisons with in-clinic outcomes. Reasonable compliance with weekly testing was achieved. Improved IT support might lead to better compliance.

Scaling the size of perimetric stimuli reduces variability and returns constant thresholds across the visual field.

The conventional stimulus for standard automated perimetry is fixed in size, giving elevated contrast thresholds and reduced test reliability in the periphery. Here, we test the hypothesis that appropriate scaling of the size of perimetric stimuli will return fixed thresholds and reduced variability across the visual field. We derived frequency-of-seeing (FOS) curves in five healthy subjects at central (3 degrees) and peripheral (27 degrees) locations with a method of constant stimuli (MOCS) using a desktop LCD display. FOS curves for a Goldmann III (GIII) stimulus were compared with those for size scaled spots. To consider clinical translation, we tested a further five healthy subjects (22-24 years) with the Melbourne Rapid Fields (MRF) tablet perimeter at several locations spanning 1 degree to 25 degrees from fixation, deriving FOS curves (MOCS) and also conducting repeated adaptive clinical thresholding to assess intra- and interobserver variability. We found that GIII contrast thresholds were significantly elevated in the periphery compared with the parafovea, with concomitant reduction of FOS slope. Using appropriately size scaled spots, threshold and slope differences between these locations were significantly reduced. FOS data collected with the tablet perimeter confirmed that size scaling confers broad equivalence of the shape of the FOS curve across the visual field. Repeated adaptive thresholding with size scaled stimuli gave relatively constant intra-observer variability across the visual field, which compares favorably with published normative data obtained with the GIII stimulus. The reduced variability will improve signal-to-noise ratio for correct classification of normal visual field test results, whereas the lower contrast thresholds yield greater dynamic range, which should improve the ability to reliably monitor moderate defects.

Retinal hyperspectral imaging in the 5xFAD mouse model of Alzheimer's disease.

Hyperspectral imaging of the retina has recently been posited as a potentially useful form of spectroscopy of amyloid-beta (Aß) protein in the eyes of those with Alzheimer's disease (AD). The concept of using the retina as a biomarker for AD is an attractive one, as current screening tools for AD are either expensive or inaccessible. Recent studies have investigated hyperspectral imaging in Aß models however these studies have been in younger mice. Here we characterised hyperspectral reflectance profile in 6 to 17 months old 5xFAD mice and compare this to Aß in isolated preparations. Hyperspectral imaging was conducted across two preparations of Aß using a custom built bench ophthalmoscope. In the in vitro condition, 1 mg of purified human Aß42 was solubilised and left to aggregate for 72 h. This soluble/insoluble Aß mixture was then imaged by suspending the solution at a pipette tip and compared against phosphate buffered saline (PBS) control (n = 10 ROIs / group). In the in vivo condition, a 5xFAD transgenic mouse model was used and retinae were imaged at the age of 6 (n = 9), 12 (n = 9) and 17 months (n = 8) with age matched wildtype littermates as control (n = 12, n = 13, n = 15 respectively). In the vitro condition, hyperspectral imaging of the solution showed greater reflectance compared with vehicle (p < 0.01), with the greatest differences occurring in the short visible spectrum (< 500 nm). In the in vivo preparation, 5xFAD showed greater hyperspectral reflectance at all ages (6, 12, 17 months, p < 0.01). These differences were noted most in the short wavelengths at younger ages, with an additional peak appearing at longer wavelengths (~ 550 nm) with advancing age. This study shows that the presence of Aß (soluble/insoluble mixture) can increase the hyperspectral reflectance profile in vitro as well as in vivo. Differences were evident in the short wavelength spectrum (< 500 nm) in vitro and were preserved when imaged through the ocular media in the in vivo conditions. With advancing age a second hump around ~ 550 nm became more apparent. Hyperspectral imaging of the retina does not require the use of contrast agents and is a potentially useful and non-invasive biomarker for AD.

Screening for Glaucomatous Visual Field Defects in Rural Australia with an iPad.

AIM AND OBJECTIVE: Developing improved methods for early detection of visual field defects is pivotal to reducing glaucoma-related vision loss. The Melbourne Rapid Fields screening module (MRF-S) is an iPad-based test, which allows suprathreshold screening with zone-based analysis to rapidly assess the risk of manifest glaucoma. The versatility of MRF-S has potential utility in rural areas and during infectious pandemics. This study evaluates the utility of MRF-S for detecting field defects in non-metropolitan settings. MATERIALS AND METHODS: This was a prospective, multicenter, cross-sectional validation study. Two hundred and fifty-two eyes of 142 participants were recruited from rural sites through two outreach eye services in Australia. Participants were tested using MRF-S and compared with a reference standard; either Zeiss Humphrey Field Analyzer or Haag-Streit Octopus performed at the same visit. Standardized questionnaires were used to assess user acceptability. Major outcome measures were the area under the curve (AUC) for detecting mild and moderate field defects defined by the reference tests, along with corresponding performance characteristics (sensitivity, specificity). RESULTS: The mean test duration for MRF-S was 1.88 minutes compared with 5.92 minutes for reference tests. The AUCs for mild and moderate field defects were 0.81 [95% confidence interval (CI): 0.75-0.87] and 0.87 (95% CI: 0.83-0.92), respectively, indicating very good diagnostic accuracy. Using a risk criterion of 55%, MRF-S identified moderate field defects with a sensitivity and specificity of 88.4 and 81.0%, respectively. CONCLUSION AND CLINICAL SIGNIFICANCE: The MRF-S iPad module can identify patients with mild and moderate field defects while delivering favorable user acceptability and short test duration. This has potential application within rural locations and amidst infectious pandemics. HOW TO CITE THIS ARTICLE: Chia MA, Trang E, Agar A, et al. Screening for Glaucomatous Visual Field Defects in Rural Australia with an iPad. J Curr Glaucoma Pract 2021;15(3):125-131.

Uptake, Persistence, and Performance of Weekly Home Monitoring of Visual Field in a Large Cohort of Patients With Glaucoma.

PURPOSE: This study examines the short-term uptake, compliance, and performance of a tablet device used for home monitoring of visual field (VF-Home) by glaucoma patients. DESIGN: Single-center, observational, longitudinal, compliance study. METHODS: Participants who were glaucoma suspects or had stable glaucoma in at least one eye were recruited during a regular clinic review. Baseline in-clinic visual field (VF) was recorded with the Humphrey Field Analyser (HFA, SITA standard) and repeated at 6 months. Participants were tasked with performing 6 VF examinations from home, at weekly intervals, using a loaned iPad tablet. Uptake was defined as returning at least 1 test from home. Reliability and global indices from VF-Home were compared to in-clinic outcomes. Data are shown as either mean ± [standard deviation] or median [quartile 1-3 range], and group comparisons were achieved with bootstrap. RESULTS: We recruited 186 eyes of 101 participants. VF-Home uptake was excellent, with 88% of participants successfully completing ≥1 home examination and 69% completing all 6 examinations. The median duration between tests was 7.0 [7.0-8.0] days. Barriers to uptake and compliance involved information technology (IT) logistical reasons, lack of motivation, or competing life demands. VF-Home gave greater fixation loss but a similar level of False Positives (FP) as the HFA. A high correlation was found for the mean defect between in-clinic and at-home outcomes (R = 0.85). CONCLUSIONS: VF-Home can return a high level of short-term compliance and results comparable to those found by in-clinic testing. IT logistical reasons and lack of motivation are barriers to uptake and compliance.

Safety and Efficacy of a Preservative-Free Artificial Tear Containing Carboxymethylcellulose and Hyaluronic Acid for Dry Eye Disease: A Randomized, Controlled, Multicenter 3-Month Study.

PURPOSE: To compare the efficacy and safety of an artificial tear combining the polymers carboxymethylcellulose (CMC) and hyaluronic acid (HA), to a formulation of CMC alone in subjects with dry eye. METHODS: A preservative-free artificial tear (CMC-HA) was compared with an existing artificial tear (CMC). Subjects with mild-to-severe signs and symptoms of dry eye were enrolled in this double-masked, randomized, multicenter trial, and dosed at least twice daily for 90 days, with follow-up visits at Days 7, 30, 60, and 90. Ocular Surface Disease Index (OSDI) was the primary outcome measure. Secondary outcome measures were tear break-up time (TBUT), ocular surface staining, Schirmer test with anesthesia, and visual analog scale (VAS) scores of dry eye symptom severity and formulation acceptability. Safety measures included adverse events, biomicroscopy, and visual acuity. RESULTS: A total of 460 subjects were enrolled across 45 sites (38 in Europe; 7 in Australia), of whom 454 were randomized to receive treatment. The per-protocol (PP) population consisted of 394 subjects, 364 (92.4%) of whom completed the study. In the PP population, the mean ± SD change from baseline in OSDI score at the primary timepoint, Day 90, was -16.9±17.5 for CMC-HA and -16.0±16.1 for CMC. CMC-HA was non-inferior to CMC based upon a confidence interval method. Both treatments significantly improved (P<0.001) OSDI, symptom VAS scores, TBUT, and ocular surface staining from baseline at all follow-up visits, with minimal differences between groups. Greater reduction of overall ocular pain/discomfort was reported in subjects using CMC-HA versus CMC (P=0.048). Approximately 10% of subjects in each group reported treatment-related adverse events of generally mild to moderate severity. CONCLUSION: The new CMC-HA formulation was effective and well tolerated, and demonstrates a greater potential for symptom relief compared with CMC. These data support implementation of this formula for the management of dry eye patients.

Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease is characterized by the aberrant deposition of protein in the brain and is the leading cause of dementia worldwide. Increasingly, there have been reports of the presence of these protein hallmarks in the retina. In this study, we assayed the retina of 5xFAD mice, a transgenic model of amyloid deposition known to exhibit dementia-like symptoms with age. Using OCT, we found that the retinal nerve fiber layer was thinner in 5xFAD at 6, 12, and 17 months of age compared with wild-type littermates, but the inner plexiform layer was thicker at 6 months old. Retinal function showed reduced ganglion cell responses to light in 5xFAD at 6, 12, and 17 months of age. This functional loss was observed in the outer retina at 17 months of age but not in younger mice. We showed using immunohistochemistry and ELISA that soluble and insoluble amyloid was present in the retina and brain at all ages. In conclusion, we report that amyloid is present in brain and retina of 5xFAD mice and that the pattern of neuronal dysfunction occurs in the inner retina at the early ages and progresses to encompass the outer retina with age. This implies that the inner retina is more sensitive to amyloid changes in early disease and that the outer retina is also affected with disease progression.

Acquired Visual Deficits Independent of Lesion Site in Acute Stroke.

Most clinical diagnoses of stroke are based on the persistence of symptoms relating to consciousness, language, visual-field loss, extraocular movement, neglect (visual), motor strength, and sensory loss following acute cerebral infarction. Yet despite the fact that most motor actions and cognition are driven by vision, functional vision per se is seldom tested rigorously during hospitalization. Hence we set out to determine the effects of acute stroke on functional vision, using an iPad application (Melbourne Rapid Field-Neural) that can be used to assess vision (visual acuity and visual field sensitivity) at the bedside or in the emergency ward in about 6 min per eye. Our convenience sample comprised 60 (29-88 years, 65 ± 14 years, 33 males) of 160 sequentially presenting first episode, acute (<7 days) ischemic stroke patients at Sunshine Hospital, Melbourne. One hundred patients were excluded due to existing eye disease, inadequate radiological confirmation, inability to comply with English directions or too ill to participate. Stroke cases were compared with 37 (29-85 years, 64 ± 12 years,14 males) similar-aged controls using a Mann-Whitney U-test. A significant loss in visual field sensitivity was measured in 68% of stroke cases (41/60, Mean Deviation: Stroke: -5.39 ± 6.26 dB, Control: 0.30 ± 0.60 dB, MWU = 246, p < 0.0001). Surprisingly, 44% (18/41) of these patients were unaware of their field loss. Although high contrast visual acuity was unaffected in most (55/60) patients, visual acuity-in-noise was reduced in 62% (37/60, Stroke: mean 6/12-2, log MAR 0.34 ± 0.21 vs. Control: mean 6/7·5-2, log MAR 0.14 ± 0.10; MWU = 470, p < 0.0001). Visual field defects were associated with all occipital, parietal and posterior cerebellar artery strokes while 9/15 middle cerebral artery lesions and 11 lesions in other brain regions were also associated with visual field defects. Our findings demonstrate that ~2/3 of acute first episode ischemic stroke patients experience acquired vision deficits, often unrelated to the confirmed lesion site. Our results also imply that visual dysfunction may be associated with a more generalized cerebral dysfunction while highlighting the need for bedside testing of vision for every stroke patient and demonstrating the translational clinical value of the "Melbourne Rapid Field- Neural" iPad application. Clinical Trial: http://www.ANZCTR.org.au/ACTRN12618001111268.aspx.

Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation.

Purpose: To test the hypothesis that the capacity for retinal ganglion cells to functionally recover from chronic IOP elevation is dependent on the duration of IOP elevation. Methods: IOP elevation was induced in one eye in anesthetized (isoflurane) adult C57BL6/J mice using a circumlimbal suture. Sutures were left in place for 8 and 16 weeks (n = 30 and 28). In two other groups the suture was cut after 8 and 12 weeks (n = 30 and 28), and ganglion cell function (electroretinography) and retinal structure (optical coherence tomography) were assessed 4 weeks later. Ganglion cell density was quantified by counting RBPMS (RNA-binding protein with multiple splicing)-stained cells. Results: With IOP elevation (∼10 mm Hg above baseline), ganglion cell function declined to 75% ± 8% at 8 weeks and 59% ± 4% at 16 weeks relative to contralateral control eyes. The retinal nerve fiber layer was thinner at 8 (84% ± 4%) and 16 weeks (83% ± 3%), without a significant difference in total retinal thickness. Ganglion cell function recovered with IOP normalization (suture removal) at week 8 (97% ± 7%), but not at week 12 (73% ± 6%). Ganglion cell loss was found in all groups (-8% to -13%). Conclusions: In the mouse circumlimbal suture model, 12 weeks of IOP elevation resulted in irreversible ganglion cell dysfunction, whereas retinal dysfunction was fully reversible after 8 weeks of IOP elevation.

An Electrophysiological Comparison of Contrast Response Functions in Younger and Older Adults, and Those With Glaucoma.

Purpose: Aging and glaucoma both result in contrast processing deficits. However, it is unclear the extent to which these functional deficits arise from retinal or post-retinal neuronal changes. This study aims to disentangle the effects of healthy human aging and glaucoma on retinal and post-retinal contrast processing using visual electrophysiology. Methods: Steady-state pattern electroretinograms (PERG) and pattern visual evoked potentials (PVEP) were simultaneously recorded across a range of contrasts (0%, 4%, 9%, 18%, 39%, 73%, 97%; 0.8° diameter checks, 31° diameter checkerboard) in 13 glaucoma patients (67 ± 6 years), 15 older (63 ± 8 years) and 14 younger adults (27 ± 3 years). PERG and PVEP contrast response functions were fit with a linear and saturating hyperbolic model, respectively. PERG and PVEP magnitude, timing (phase), and model fit parameters (slope, semi-saturation constant) were compared between groups. Results: PERG responses were reduced and delayed in older adults relative to younger adults, and further reduced and delayed in glaucoma patients across all contrasts. PVEP signals were also reduced and delayed in glaucoma patients, relative to age-similar (older) controls. However, despite having reduced PERG magnitudes, older adults did not demonstrate reduced PVEP magnitudes. Conclusions: Older adults with healthy vision demonstrate reduced magnitude and delayed timing in the PERG that is not reflected in the PVEP. In contrast, glaucoma produces functional deficits in both PERG and PVEP contrast response functions. Our results suggest that glaucomatous effects on contrast processing are not a simple extension of those that arise as part of the aging process.

Tear film inflammatory cytokine upregulation in contact lens discomfort.

PURPOSE: To investigate the ocular inflammatory response, using clinical and immunological techniques, in people experiencing contact lens (CL) discomfort. METHODS: This study involved 38 adults who were full-time, silicone-hydrogel CL wearers. Participants were categorized into groups based upon a validated CL dry-eye questionnaire (CLDEQ-8) (n = 17 'asymptomatic', CLDEQ-8 score <9; n = 21 'symptomatic', CLDEQ-8 score ≥13). Examinations were performed at two visits (one with, and one without, CL wear), separated by one-week. Testing included: tear osmolarity, ocular redness, tear stability, ocular surface staining, meibography, tear production and tear collection. Tear osmolarity was taken from the inferior-lateral and superior-lateral menisci. The 'Inferior-Superior Osmotic Difference', I-SOD, was the absolute osmolarity difference between these menisci. Concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-gamma, TNF-alpha) were assayed from basal tears using multiplex cytometric bead array. RESULTS: At baseline, there was no significant difference in key clinical signs between asymptomatic and symptomatic CL wearers (p > 0.05). The I-SOD was greater in symptomatic than asymptomatic CL wearers (23.1 ±â€¯2.6 versus 11.3 ±â€¯1.4 mOsmol/L, p = 0.001). People experiencing CL discomfort had higher tear IL-17A (122.6 ±â€¯23.7 versus 44.0 ±â€¯10.0 pg/mL, p = 0.02) and reduced tear stability (6.3 ±â€¯1.1 versus 10.4 ±â€¯1.6 s, p = 0.03) after several hours of CL wear. Tear IL-17A levels correlated with both the I-SOD (r = 0.43, p = 0.01) and CLDEQ-8 score (r = 0.40, p = 0.01). CONCLUSIONS: CL discomfort occurs in individuals having no clinical dry eye signs, and is associated with higher tear levels of the pro-inflammatory cytokine IL-17A. These findings support an association between the discomfort response and low-grade, ocular surface inflammation.

A Model of Glaucoma Induced by Circumlimbal Suture in Rats and Mice.

The circumlimbal suture is a technique for inducing experimental glaucoma in rodents by chronically elevating intraocular pressure (IOP), a well-known risk factor for glaucoma. This protocol demonstrates a step-by-step guide on this technique in Long Evans rats and C57BL/6 mice. Under general anesthesia, a "purse-string" suture is applied on the conjunctiva, around the equator and behind the limbus of the eye. The fellow eye serves as an untreated control. Over the duration of our study, which was a period of 8 weeks for rats and 12 weeks for mice, IOP remained elevated, as measured regularly by rebound tonometry in conscious animals without topical anesthesia. In both species, the sutured eyes showed electroretinogram features consistent with preferential inner retinal dysfunction. Optical coherence tomography showed selective thinning of the retinal nerve fiber layer. Histology of the rat retina in cross-section found reduced cell density in the ganglion cell layer, but no change in other cellular layers. Staining of flat-mounted mouse retinae with a ganglion cell specific marker (RBPMS) confirmed ganglion cell loss. The circumlimbal suture is a simple, minimally invasive and cost-effective way to induce ocular hypertension that leads to ganglion cell injury in both rats and mice.

Modulating Contact Lens Discomfort With Anti-Inflammatory Approaches: A Randomized Controlled Trial.

Purpose: To assess the efficacy of anti-inflammatory approaches, comprising a topical corticosteroid and omega-3 supplements, for modulating the inflammatory overlay associated with contact lens discomfort (CLD). Methods: This randomized controlled trial involved 72 adults with CLD, randomized (1:1:1:1) to one of the following: placebo (oral olive oil), oral fish oil (900 mg/d eicosapentaenoic acid [EPA] + 600 mg/d docosohexaenoic acid [DHA]), oral combined fish+flaxseed oils (900 mg/d EPA + 600 mg/d DHA + 900 mg/d alpha-linolenic acid), or omega-3 eye-drops (0.025% EPA + 0.0025% DHA four times per day [qid]) for 12 weeks, with visits at baseline, weeks 4 and 12. At week 12, participants who received placebo were assigned a low-potency corticosteroid (fluorometholone [FML] 0.1%, drops, three times per day [tid]) for 2 weeks (week 14). Results: Sixty-five participants completed the primary endpoint. At week 12, contact lens dry-eye questionnaire (CLDEQ-8) score was reduced from baseline with oral fish oil (-7.3 ± 0.8 units, n = 17, P < 0.05), compared with placebo (-3.5 ± 0.9 units, n = 16). FML produced significant reductions in tear IL-17A (-71.1 ± 14.3%, n = 12) and IL-6 (-47.6 ± 17.5%, n = 12, P < 0.05) relative to its baseline (week 12). At week 12, tear IL-17A levels were reduced from baseline in the oral fish oil (-63.2 ± 12.8%, n = 12, P < 0.05) and topical omega-3 (-76.2 ± 10.8%, n = 10, P < 0.05) groups, compared with placebo (-3.8 ± 12.7%, n = 12). Tear IL-6 was reduced with all omega-3 interventions, relative to placebo (P < 0.05) at week 12. Conclusions: CLD was attenuated by oral long-chain omega-3 supplementation for 12 weeks. Acute (2 week) topical corticosteroids and longer-term (12 week) omega-3 supplementation reduced tear levels of the proinflammatory cytokines IL-17A and IL-6, demonstrating parallels in modulating ocular inflammation with these approaches.