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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.Single-center longitudinal compliance and reliability study.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.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 results25%). The mean RS returned by the tablet was significantly higher (+3.2 dB, P.05) compared to the MaIA.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.

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.

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.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).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.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.Chia MA, Trang E, Agar A

To investigate the ocular inflammatory response, using clinical and immunological techniques, in people experiencing contact lens (CL) discomfort.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 score9; 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.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 ± 2.6 versus 11.3 ± 1.4 mOsmol/L, p = 0.001). People experiencing CL discomfort had higher tear IL-17A (122.6 ± 23.7 versus 44.0 ± 10.0 pg/mL, p = 0.02) and reduced tear stability (6.3 ± 1.1 versus 10.4 ± 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).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.

Hyperspectral imaging of the retina has recently been posited as a potentially useful form of spectroscopy of amyloid-beta (Aβ) 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 Aβ 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 Aβ in isolated preparations. Hyperspectral imaging was conducted across two preparations of Aβ using a custom built bench ophthalmoscope. In the in vitro condition, 1 mg of purified human Aβ42 was solubilised and left to aggregate for 72 h. This soluble/insoluble Aβ 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 p

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.

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.

Purpose Recent developments in electronic technology are making it possible to home monitor the sensitivity of the central visual field using portable devices. We used simulations to investigate whether the higher test frequency afforded by home monitoring improves the early detection of rapid visual field loss in glaucoma and how any benefits might be affected by imperfect compliance or increased variability in the home-monitoring test. Design Computer simulation, with parameter selection confirmed with a cohort study. Participants A total of 43 patients with treated glaucoma (both open-angle and closed-angle), ocular hypertension or glaucoma suspects (mean age, 71 years; range, 37–89 years), were followed in the cohort study. Methods We simulated series (n = 100 000) of visual fields for patients with stable glaucoma and patients with progressing glaucoma for 2 in-clinic (yearly and 6-monthly) and 3 home-monitoring (monthly, fortnightly, and weekly) schedules, each running over a 5-year period. Various percentages of home-monitored fields were omitted at random to simulate reduced compliance, and the variability of the home monitored fields also was manipulated. We used previously published variability characteristics for perimetry and confirmed their appropriateness for a home-monitoring device by measuring the device's retest variability at 2 months in a cohort of 43 patients. The criterion for flagging progression in our simulation was a significant slope of the ordinary least squares regression of a simulated patient's mean deviation (MD) data. Main Outcome Measures The sensitivity for identifying rapid visual field loss (−2 decibels [dB]/year loss of MD). Results Although a sensitivity of 0.8 for rapid field loss was achieved after 2.5 years of 6-monthly testing in the clinic, weekly home monitoring achieved this by 0.9 years despite moderate test compliance of 63%. The improved performance of weekly home monitoring over 6-monthly clinical testing was retained even when home monitoring was assumed to produce more variable test results or be associated with low patient compliance. Conclusions Detecting rapid visual field progression may be improved using a home-monitoring strategy, even when compliance is imperfect. The cost-benefit of such an approach is yet to be demonstrated, however.

Background Several visual tasks have been proposed as indirect assays of the balance between cortical inhibition and excitation in migraine. This study aimed to determine whether daily measurement of performance on such tasks can reveal perceptual changes in the build up to migraine events. Methods Visual performance was measured daily at home in 16 non-headache controls and 18 individuals with migraine using a testing protocol on a portable tablet device. Observers performed two tasks: luminance increment detection in spatial luminance noise and centre surround contrast suppression. Results Luminance thresholds were reduced in migraine compared to control groups ( p Conclusions Daily portable testing of vision enabled insight into perceptual performance in the lead up to migraine events, a time point that is typically difficult to capture experimentally. Perceptual surround suppression of contrast fluctuates during the migraine cycle, supporting the utility of this measure as an indirect, non-invasive assay of the balance between cortical inhibition and excitation.

The retina is an easily accessible out-pouching of the central nervous system (CNS) and thus lends itself to being a biomarker of the brain. More specifically, the presence of neuronal, vascular and blood-neural barrier parallels in the eye and brain coupled with fast and inexpensive methods to quantify retinal changes make ocular biomarkers an attractive option. This includes its utility as a biomarker for a number of cerebrovascular diseases as well as a drug pharmacology and safety biomarker for the CNS. It is a rapidly emerging field, with some areas well established, such as stroke risk and multiple sclerosis, whereas others are still in development (Alzheimer's, Parkinson's, psychological disease and cortical diabetic dysfunction). The current applications and future potential of retinal biomarkers, including potential ways to improve their sensitivity and specificity are discussed. This review summarises the existing literature and provides a perspective on the strength of current retinal biomarkers and their future potential.

To assess the efficacy of 2 forms of oral long-chain omega-3 (ω-3) essential fatty acid (EFA) supplements, phospholipid (krill oil) and triacylglyceride (fish oil), for treating dry eye disease (DED).Randomized, double-masked, placebo-controlled clinical trial.This study was conducted at a single site and involved 60 participants with mild to moderate DED who were randomized (1:1:1) to 1 of 3 groups: placebo (olive oil), krill oil, or fish oil supplements.Participants received 1 of the 3 interventions: placebo (olive oil 1500 mg/day), krill oil (945 mg/day eicosapentaenoic acid [EPA], + 510 mg/day docosahexaenoic acid [DHA]), or fish oil (1000 mg/day EPA + 500 mg/day DHA) for 90 days, with monthly study visits.Primary outcome measures were mean change in (1) tear osmolarity and (2) DED symptoms (Ocular Surface Disease Index [OSDI] score) between days 1 and 90. Secondary outcomes included mean change in key clinical signs (tear stability, tear production, ocular surface staining, bulbar and limbal redness, tear volume, anterior blepharitis, meibomian gland capping) and tear inflammatory cytokine levels.In total, 54 participants completed the study. At day 90, tear osmolarity was reduced from baseline with both krill oil (mean ± standard error of the mean: -18.6±4.5 mOsmol/l; n = 18; P0.001) and fish oil (-19.8±3.9 mOsmol/l; n = 19; P0.001) supplements, compared with placebo (-1.5±4.4 mOsmol/l; n = 17). OSDI score was significantly reduced at day 90 relative to baseline in the krill oil group only, compared with placebo (-18.6±2.4 vs. -10.5±3.3; P = 0.02). At day 90, there were also relative improvements in tear breakup time and ocular bulbar redness, compared with placebo, for both forms of ω-3 EFAs. Basal tear levels of the proinflammatory cytokine interleukin 17A were significantly reduced in the krill oil group, compared with placebo, at day 90 (-27.1±10.9 vs. 46.5±30.4 pg/ml; P = 0.02).A moderate daily dose of both forms of long-chain ω-3 EFAs, for 3 months, resulted in reduced tear osmolarity and increased tear stability in people with DED. Omega-3 EFAs in a predominantly phospholipid form (krill oil) may confer additional therapeutic benefit, with improvements in DED symptoms and lower basal tear levels of interleukin 17A, relative to placebo.

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.

Introduction: This study considers changes in vision from acute phase of ischemic stroke to 3-6 months post ischemic stroke. Methods: We tested Fifty ischemic stroke patients (age 32-95) within a week (mean:day3) of admission to Sunshine Hospital at the bed side using an iPad tablet, between July to December, 2017.We excluded: existing eye disease (twenty), cannot comprehend test (four) and unreliable testing (five).Testing was performed using the Melbourne Rapid Field (MRF-neural) Application for Visual Acuity, Visual Acuity in Noise and Visual Fields. The Eye-Hand co-ordination (EHC) was evaluated with timing of completing a tracking task generated by the iPad (UNSW L-R Eye Hand Coordination Application). The MRF-neural assays high contrast acuity (Landolt C optotype) and acuity targets immersed in luminance noise. It presents a modified 24-2 pattern (20 deg eccentricity and 4 foveal spots) for visual field testing. The results of the stroke group were compared to 30 age similar normal volunteers (controls). All participants provided written consent.These tests were repeated in cases who had abnormality 3-6 months later to determine long-term change or recovery. Results: During the acute phase, most stroke cases have normal high contrast visual acuity (p=0.11) but 46% return reduced acuity-in-noise (p95%) identifies 47 (94%) ischemic stroke cases as having abnormal visual capacity. At follow up: improvement was found in 73% cases for acuity in noise, 53% cases with visual field loss and 20% of cases with prolonged EHC. In 2 patients (13%) EHC was normal during the acute phase but showed deterioration over the recovery. Conclusion: Acute stroke cases (94%) have some form of vision abnormality on admission to hospital, despite near normal high contrast acuity. After 3-6 months, acuity-in-noise and visual fields normalize in the majority of cases but EHC shows variable outcomes.

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.

Glaucoma is a neurodegenerative disease, characterized by the progressive death of retinal ganglion cells. Elevated intraocular pressure (IOP) is known to be an important risk factor for glaucoma; however, it is not the only force acting on the optic nerve. Intracranial pressure (ICP) also exerts an effect on the optic nerve head, effectively opposing the force applied by IOP. Indeed, this balance of forces creates a pressure gradient (or the translaminar pressure gradient) across the optic nerve head [1]. Increasingly it is thought that the pressure difference between IOP and ICP, the translaminar pressure (TLP), may be critical for the integrity of the retina and optic nerve [2], and thus ICP may be an important risk factor for glaucoma [2–6].

Migraine is a common and debilitating primary headache disorder that affects 10-15% of the general population, particularly people of working age. Migraine is relevant to providers of clinical eye-care because migraine attacks are associated with a range of visual sensory symptoms, and because of growing evidence that the results of standard tests of visual function necessary for the diagnosis and monitoring of glaucoma (visual fields, electrophysiology, ocular imaging) can be abnormal due to migraine. These abnormalities are measureable in-between migraine events (the interictal period), despite patients being asymptomatic and otherwise healthy. This picture is further complicated by epidemiological data that suggests an increased prevalence of migraine in patients with glaucoma, particularly in patients with normal tension glaucoma. We discuss how migraine, as a co-morbidity, can confound the results and interpretation of clinical tests that form part of contemporary glaucoma evaluation, and provide practical evidence-based recommendations for the clinical testing and management of patients with migraine who attend eye-care settings.

PURPOSE The aim of this study was to compare the self-reported clinical practice behaviours of optometrists in Australia and the United Kingdom (UK) with respect to the diagnosis and management of dry eye disease (DED). We also sought to examine whether the reported practices of clinicians in each region were consistent with current evidence-based recommendations for DED. METHODS An online survey was distributed to optometrists (Australia, n = 654; UK, n = 1006). Respondents provided information about practice modality, years of optometric experience, preferred diagnostic and management strategies (stratified by DED severity) and the information/evidence base used to guide patient care. RESULTS A total of 317 completed surveys were received (response rates, Australia: 21%, UK: 17%). Optometrists in both regions demonstrated similarly strong knowledge of tear film assessment and adopted both subjective and objective techniques to diagnose DED. Patient symptoms were considered the most important, valuable and commonly performed assessment by both Australian and UK respondents. UK practitioners valued and utilised conjunctival signs and tear meniscus height assessments more than Australian optometrists (p < 0.05), who placed relatively greater emphasis on sodium fluorescein tear break-up time to diagnose DED (p < 0.05). Clinicians in both locations tailored DED therapy to severity. While practitioners in both regions predominantly managed mild DED with eyelid hygiene and tear supplementation, Australian optometrists indicated prescribing topical corticosteroid therapy significantly more often than UK practitioners for moderate (14% vs 6%) and severe (52% vs 8%) disease (p < 0.05). The major source of information used to guide practitioners' dry eye management practices was continuing education conferences. CONCLUSIONS This study highlights a range of parallels and divergences in dry eye clinical practice between Australian and UK optometrists. Our data identify both areas of strength in the adoption of evidence-based practice, as well as some potential to improve international translation of dry eye research evidence into practice.

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.

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.

PURPOSE: To establish the medium-term repeatability of the iPad perimetry app Melbourne Rapid Fields (MRF) compared to Humphrey Field Analyzer (HFA) 24-2 SITA-standard and SITA-fast programs. DESIGN: Multicenter longitudinal observational clinical study. METHODS: Sixty patients (stable glaucoma/ocular hypertension/glaucoma suspects) were recruited into a 6-month longitudinal clinical study with visits planned at baseline and at 2, 4, and 6 months. At each visit patients undertook visual field assessment using the MRF perimetry application and either HFA SITA-fast (n = 21) or SITA-standard (n = 39). The primary outcome measure was the association and repeatability of mean deviation (MD) for the MRF and HFA tests. Secondary measures were the point-wise threshold and repeatability for each test, as well as test time. RESULTS: MRF was similar to SITA-fast in speed and significantly faster than SITA-standard (MRF 4.6 ± 0.1 minutes vs SITA-fast 4.3 ± 0.2 minutes vs SITA-standard 6.2 ± 0.1 minutes, P < .001). Intraclass correlation coefficients (ICC) between MRF and SITA-fast for MD at the 4 visits ranged from 0.71 to 0.88. ICC values between MRF and SITA-standard for MD ranged from 0.81 to 0.90. Repeatability of MRF MD outcomes was excellent, with ICC for baseline and the 6-month visit being 0.98 (95% confidence interval: 0.96-0.99). In comparison, ICC at 6-month retest for SITA-fast was 0.95 and SITA-standard 0.93. Fewer points changed with the MRF, although for those that did, the MRF gave greater point-wise variability than did the SITA tests. CONCLUSIONS: MRF correlated strongly with HFA across 4 visits over a 6-month period, and has good test-retest reliability. MRF is suitable for monitoring visual fields in settings where conventional perimetry is not readily accessible.

Purpose We consider whether quantification of ocular bulbar redness, using image processing of relative Red-channel activity (Red-value), can be applied to a clinical sample and how this approach compares to an automated bulbar redness grading technique (Oculus Keratograph 5M, R-scan). Methods Red-values from dry eye patients (n = 25) were determined using image processing of digital photographs over the nasal bulbar conjunctiva. Red-values were compared with subjective grades from six clinicians who graded the images using the IER scale. We considered the level of agreement between the Red-value and automated bulbar redness scores from the commercial instrument (R-scan). Scoring variability for each technique was assessed using the geometric coefficient of variation (gCoV, %). Agreement between techniques was considered with Bland-Altman analyses. Results Red-values showed a strong linear relationship (R2 = 0.99) to the R-scan. The Red-value had least variability (gCoV = 0.97%, 95% CI: 0.76–1.35%). The IER grade showed a linear relationship with Red-value (R2 = 0.99), bound by a floor effect; it did not discriminate changes in redness below a threshold of 1.75 units (Red-value = 33.0%), after which it paralleled the redness returned by the R-scan. Intra-method variability for the redness returned by the R-scan (gCoV = 9.84%, 95% CI: 7.60–13.94%) and IER grades (gCoV = 7.30%, 95% CI: 1.73–10.31%) was similar (p > 0.05). Bland-Altman analysis showed the R-scan was consistently biased towards lower absolute redness scores than the IER. Conclusions Digital imaging processing, using relative Red-channel activity, was the least variable of the three techniques. The R-scan and IER showed similar intra-observer variability. The linear relationship between R-scan and Red-value suggests that the R-scan could be derived using similar methods.

Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or “wet”) form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

To consider whether imaging retinal vasculature may be used as a marker for cortical vessels, we compared fluorescein angiography flow dynamics before and after pharmacological disruption of blood-neural barriers. Sodium fluorescein (1%, 200 μl/kg) was intravenously delivered in anesthetized adult Long Evans rats (n = 44, brain = 18, retina = 26). In the brain cohort, a cranial window was created to allow direct visualization of surface cortical vessels. Video fluorescein angiography was captured using a rodent retinal camera at 30 frames/second and fluorescence intensity profiles were evaluated for the time to reach 50% brightness (half-rise), 50% decay (half-fall), and the plateau level of remnant fluorescence (offset, %). Cortical vessels fluoresced earlier (artery half-rise: 5.6 ± 0.2 s) and decayed faster (half-fall: 10.3 ± 0.2 s) compared to retinal vasculature. Cortical vessels also had a considerably higher offset, particularly in the capillaries/extravascular space (41.4 ± 2.7%) whereas pigment in the retina reduces such residual fluorescence. In a sub-cohort of animals, sodium deoxycholate (DOC, 0.06 M dissolved in sterile saline, 1 mL) was delivered intravenously to cause simultaneous disruption of the blood-brain and blood-retinal barriers. A separate group received saline as vehicle control. Fluorescein angiography was re-measured at 6 and 24 h after drug infusion and evaluated by comparing flow dynamics to the upper quartile (75%) of the control group. Retinal vasculature was more sensitive to DOC-induced disruption with a higher fluorescence offset at 6 h (47.3 ± 10.6%). A delayed effect was seen in cortical vessels with a higher offset evident only at 24 h (65.6 ± 10.1%). Here we have developed a method to quantitatively compare fluorescein angiography dynamics in the retina and superficial cortical vessels. Our results show that systemic disruption of blood-neural barriers causes vascular leakage in both tissues but earlier in the retina suggesting that pharmacological blood-neural barrier disruption may be detected earlier in the eye than in cortical vasculature.

Purpose To assess ocular blood flow responses to acute IOP stress following 4 weeks of chronic IOP elevation in streptozotocin (STZ)-induced diabetic and control rats. We hypothesise that chronic IOP elevation for 4 weeks will further impair blood flow regulation in STZ-induced diabetic rats eyes. Methods Two weeks following citrate buffer or STZ-injections chronic IOP elevation was induced in Long Evans rats via fortnightly intracameral injections of microspheres (15 μm) suspended in 5% polyethylene glycol. IOP was monitored daily. Electroretinography (ERG, −6.79–2.07 log cd s m−2) was undertaken at Week 4 to compare photoreceptor (RmPIII), ON-bipolar cell (Vmax) and ganglion cell dominant ERG [scotopic threshold response (STR)] components. 4 weeks post-chronic IOP induction, ocular blood flow (laser Doppler flowmetry) was measured in response to acute IOP challenge (10–100 mmHg, in 5 mmHg steps, each 3 min). Results Four weeks of chronic IOP (mean ± S.E.M., citrate: 24.0 ± 0.3 to 30.7 ± 1.3 and STZ-diabetes: 24.2 ± 0.2 to 31.1 ± 1.2 mmHg) was associated with reduced photoreceptor amplitude in both groups (−25.3 ± 2.2% and −17.2 ± 3.0%, respectively). STZ-diabetic eyes showed reduced photoreceptor sensitivity (citrate: 0.5 ± 1.8%, STZ-diabetic: −8.1 ± 2.4%). Paradoxically ON-bipolar cell sensitivity was increased, particularly in citrate control eyes (citrate: 166.8 ± 25.9%, STZ-diabetic: 64.8 ± 18.7%). The ganglion cell dominant STR was not significantly reduced in STZ-diabetic rats. Using acute IOP elevation to probe autoregulation, we show that STZ-diabetes impaired autoregulation compared with citrate control animals. The combination of STZ-diabetes and chronic IOP elevation further impaired autoregulation. Conclusions STZ-diabetes and chronic IOP elevation appear to be additive risk factors for impairment of ocular blood flow autoregulation.

Background A novel, ultra-low energy nanosecond laser (retinal rejuvenation therapy) has been developed with the aim to slow progression of early age-related macular degeneration (AMD). The safety, changes in fundus characteristics and macular function in a cohort of participants with bilateral intermediate AMD are reported. Design Prospective non-randomised, pilot intervention study. Participants or Samples Subjects with bilateral intermediate AMD (n = 50, aged 50–75 years). Methods Ultra-low energy laser pulses applied in 12 spots around the macula of one eye (0.15–0.45 mJ), using 400 μm diameter spot, 3 nanosecond pulse length, 532 nm wavelength and energy titrated to each patient. Main Outcome Measures Best corrected visual acuity, drusen area and macular sensitivity (flicker perimetry) at baseline and at 3, 6 and 12 months post-laser. Results Treatment was painless with no clinically visible lesions. No participant developed choroidal neovascularization, while two with thin central retinal thickness at baseline developed atrophy at 12-month follow up. Drusen area was reduced in 44% of treated eyes and 22% of untreated fellow eyes, with changes in drusen and function not being coincident. Improvement in flicker threshold within the central 3° was observed in both the treated and untreated fellow eyes at 3 months post-laser. Of the 11 eyes at greatest risk of progression (flicker defect >15 dB), seven improved sufficiently to be taken out of this high-risk category. Conclusions A single unilateral application of nanosecond laser to the macula produced bilateral improvements in macula appearance and function. The nanosecond retinal rejuvenation therapy laser warrants ongoing evaluation as an early intervention for AMD.

Purpose: In between migraine attacks, some people show visual field defects that are worse when measured closer to the end of a migraine event. In this cohort study, we consider whether electrophysiological responses correlate with visual field performance at different times post-migraine, and explore evidence for cortical versus retinal origin. Methods: Twenty-six non-headache controls and 17 people with migraine performed three types of perimetry (static, flicker and blue-on-yellow) to assess different aspects of visual function at two visits conducted at different durations post-migraine. On the same days, the pattern electroretinogram (PERG) and visual evoked response (PVER) were recorded. Results: Migraine participants showed persistent, interictal, localised visual field loss, with greater deficits at the visit nearer to migraine offset. Spatial patterns of visual field defect consistent with retinal and cortical dysfunction were identified. The PERG was normal, whereas the PVER abnormality found did not change with time post-migraine and did not correlate with abnormal visual field performance. Conclusions: Dysfunction on clinical tests of vision is common in between migraine attacks; however, the nature of the defect varies between individuals and can change with time. People with migraine show markers of both retinal and/or cortical dysfunction. Abnormal visual field sensitivity does not predict abnormality on electrophysiological testing.

The rd1 mouse is a well-established animal model for human retinitis pigmentosa (RP). We used electroretinography (ERG) to evaluate retinal function and postembedding immunocytochemistry to determine the changes in cellular amino acid expression in the normal (C57Bl6) and degenerating mouse retina (rd1), as a function of age during development and the onset of degeneration. In the normal mouse retina, photoreceptoral and post-photoreceptoral ERG responses improved simultaneously from eye-opening until adult levels were achieved at approximately postnatal day (P) 30. Maturation of amino acid neurochemistry preceded the development of retinal function in the normal retina. Amino acid levels increased immediately from birth and reached stable levels by eye-opening. In contrast, in the rd1 mouse, both rod and cone pathway function rapidly reduced from eye-opening and by P21 became undetectable. Interestingly, at P18 cone responses were still comparable between the normal and degenerating retina. Before eye opening, the pattern of amino acid immunoreactivity in the rd1 retina was similar to the normal retina. Alterations in neurochemistry were observed after the onset of rod photoreceptor cell death. The most obvious change was the reduction in neurotransmitter immunoreactivity within the synaptic layers and some cell classes of the rd1 retina. Reduction of glutamine and glutamate was observed in Müller cells before established gliosis markers. Overall, these results suggest the rapid maturation of neurochemistry by eye opening followed by functional maturation by P30 in the normal retina. The dystrophic retina displays similar neurochemistry to control retina before eye opening but a subsequent decline.

Aim: Dietary deficiencies in o-3 polyunsaturated fatty acids are known to effect retinal function including retinal ganglion cell (RGC) activity, which may have implications for glaucoma. In this study we consider retinal function after dietary manipulation and intraocular pressure (IOP) stress designed to compromise RGCs. Methods: Sprague-Dawley dams were fed either o-3 sufficient (o-3 + , n = 15) or deficient (o-3 � , n = 16) diets 5 weeks before conception with pups subsequently weaned onto their mothers diets. At 20 weeks of age, acute IOP elevation was induced repeatedly through anterior chamber cannulation to 70 mm Hg for 1 hour on 3 separate occasions separated by 1 week. Electroretinograms were recorded 1 week after each IOP elevation to assay the photoreceptors (PIII), ON-bipolar cells (PII), and ganglion/ amacrine cells (STR). Results: Repeat IOP insult results in a specific RGC dysfunction (pSTR � 14.5%, P < 0.035) as does o-3 deficiency (� 26.4%, P < 0.01). However, the combination of both causes an even larger RGC functional loss (� 40.1%, P < 0.001) than does either diet or IOP insult in isolation (P < 0.001). Conclusions: Both o-3 deficiency and repeat acute IOP insult cause RGC dysfunction and the combination of these factors results in a cumulative effect. Our data indicate that sufficient dietary o-3 improves RGC function making it less susceptible to IOP insult.

The most dominant feature of the electroretinogram, the b-wave, is thought to reflect ON-bipolar cell responses. However, a number of studies suggest that the b-wave is made up of several components. We consider the composition of the rat b-wave by subtracting corneal negative components obtained using intravitreal application of pharmacological agents to remove postreceptoral responses. By analyzing the intensity-response characteristic of the PII across a range of fixed times during and after a light step, we find that the rat isolated PII has 2 components. The first has fast rise and decay characteristics with a low sensitivity to light. GABAc-mediated inhibitory pathways enhance this transient-ON component to manifest increased and deceased sensitivity to light at shorter (

Purpose: To assess whether tear hyperosmolarity, being diagnostic of dry eye disease (DED), is associated with specific alterations to the cytokine content of human tears that may provide a biomarker for DED. Methods: In this prospective, cross-sectional, clinical study, participants (n = 77) were recruited from a single clinical site and categorized into groups based upon tear osmolarity status (n = 62 hyperosmolar, n = 15 normo-osmolar). Comprehensive anterior eye clinical assessments were undertaken. Concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α) in basal tears were assayed using multiplex cytometric bead array. The main outcome measure was difference in cytokine concentration between groups. Group comparisons were undertaken using 2-tailed t-tests. Cohen's effect size was calculated for each finding. Spearman correlations between cytokine concentrations, clinical symptoms, and clinical parameters of DED were calculated. Results: Tear hyperosmolarity was specifically associated with increased tear IFN-γ levels (13.3 ± 2.0 vs. 4.4 ± 1.4 pg/mL, P = 0.03). Cohen's effect size was large (0.8) for changes to tear IFN-γ levels. Significant correlations were observed between IFN-γ concentration and each of: tear osmolarity (r = 0.34; P = 0.007), total ocular surface staining (r = 0.56, P < 0.0001), and Schirmer test score (r = -0.33, P = 0.003). Conclusions: Tear hyperosmolarity is specifically associated with higher levels of the proinflammatory cytokine IFN-γ, which correlate with key clinical parameters of DED. The calculated effect size (0.8) suggests that this assay has diagnostic power as a biomarker for evaporative DED.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area.

Purpose This pilot study considered whether intraocular pressure (IOP) lowering could reverse ganglion cell dysfunction in a rat model of chronic ocular hypertension. Methods A circumlimbal suture was applied in one eye to induce ocular hypertension (n = 7) in Long-Evans rats. The contralateral eye served as an untreated control. After 8 weeks of IOP elevation the suture was removed to lower IOP for the remaining 7 weeks. Electroretinogram (ERG) and optical coherence tomography (OCT) were measured at baseline, 2, 4, 8, 12 and 15 weeks. Retinae were collected for histology at week 15. Results In sutured eyes, IOP was elevated by 7–11 mmHg above control eyes (12 ± 0.2 mmHg [standard error of the mean]). Eight weeks of chronic IOP elevation resulted in a reduction of the ganglion cell mediated positive Scotopic Threshold Response (pSTR, −25 ± 7% of baseline), as well as smaller photoreceptor (−7 ± 4%) and bipolar cell mediated responses (−6 ± 5%). After suture removal, IOP recovered to normal. By 15 weeks the a-wave (0 ± 6%), b-wave (−2 ± 6%) and pSTR had recovered back to baseline (from −25 ± 7% to −4 ± 6%). The retinal nerve fiber layer was thinned by −9 ± 3% at week 8 and showed no further decline at week 15 (−10 ± 2%). Cell numbers in the ganglion cell layer were similar between suture removal and control eyes at week 15 (3543 ± 478 vs 4057 ± 476 cells mm−2). Conclusions The circumlimbal suture model might be a useful platform to study the reversibility of neuronal dysfunction from chronic IOP challenge.

The full-field electroretinogram (ERG) and visual evoked potential (VEP) are useful tools to assess retinal and visual pathway integrity in both laboratory and clinical settings. Currently, preclinical ERG and VEP measurements are performed with anesthesia to ensure stable electrode placements. However, the very presence of anesthesia has been shown to contaminate normal physiological responses. To overcome these anesthesia confounds, we develop a novel platform to assay ERG and VEP in conscious rats. Electrodes are surgically implanted sub-conjunctivally on the eye to assay the ERG and epidurally over the visual cortex to measure the VEP. A range of amplitude and sensitivity/timing parameters are assayed for both the ERG and VEP at increasing luminous energies. The ERG and VEP signals are shown to be stable and repeatable for at least 4 weeks post surgical implantation. This ability to record ERG and VEP signals without anesthesia confounds in the preclinical setting should provide superior translation to clinical data.

PURPOSE: To describe a tangent perimeter developed on an Apple iPad (Melbourne Rapid Field, MRF). METHODS: The MRF assays 66 locations over 28° × 18° by having the patient vary fixation. Spot size and background luminance are paired to yield constant thresholds across the field. Spot locations were selected after analysis of 360 patient records. The capacity of the MRF to detect defects was verified in five participants (age 22-28 years) by simulating four common losses: central, arcuate, quadrant, and hemianopia. We also consider the effect of: myosis, blur (+3 DS), viewing distance (25-75 cm), ambient light (4-600 lux), and retest repeatability (1-week apart) on thresholds. Group means [SEM] are compared by Student's t-test and repeatability returned from Bland-Altman analysis. RESULTS: We found a 5 cd.m-2 background replicates the Weber fraction produced by a Humphrey spot shown at 35 dB. Our variable size gives constant thresholds (29.6 [0.2] dB) across all locations. Altering viewing distance (25 cm = 29.8 [0.9] dB; 75 cm = 28.9 [0.6] dB) and ambient lighting (4 lux, 29.8 [0.8] dB; 600 lux, 29.5 [1.0] dB) did not affect threshold although screen reflections must be avoided. Myosis (-1.2 dB) and blur (-1.5 dB) will reduce sensitivity (P < 0.05). Simulated defects with a mean defect (MD) of -3.3 dB are detected by the MRF. The Coefficient of repeatability was 9.6% (SD ∼2.9 dB) in normal regions and 48.1% (SD ∼8.0 dB) in areas of simulated scotoma. CONCLUSIONS: Tablet technology can return efficient and reliable thresholds to 30° as a tangent perimeter. TRANSLATIONAL RELEVANCE: The MRF will allow testing at a bedside, at home, in rural or remote areas, or where equipment cannot be financed.

We consider whether pre-existing streptozotocin induced hyperglycemia in rats affects the ability of the eye to cope with a single episode of acute intraocular pressure (IOP) elevation.Electroretinogram (ERG) responses were measured (-6.08 to 1.92 log cd.s.m(-2)) in anaesthetized (60:5 mg/kg ketamine:xylazine) dark-adapted (12 h) adult Sprague-Dawley rats 1 week after a single acute IOP elevation to 70 mmHg for 60 min. This was undertaken in rats treated 11 weeks earlier with streptozotocin (STZ, n = 12, 50 mg/kg at 6 weeks of age) or citrate buffer (n = 12). ERG responses were analyzed to derive an index of photoreceptor (a-wave), ON-bipolar (b-wave), amacrine (oscillatory potentials) and inner retinal (positive scotopic threshold response, pSTR) function.One week following acute IOP elevation there was a significant reduction of the ganglion cell pSTR (-35 ± 11 %, P = 0.0161) in STZ-injected animals. In contrast the pSTR in citrate-injected animals was not significant changed (+16 ± 14 %). The negative component of the STR was unaffected by IOP elevation in either citrate or STZ-treated groups. Photoreceptoral (a-wave, citrate-control +4 ± 3 %, STZ +4 ± 5 %) and ON-bipolar cell (b-wave, control +4 ± 3 %, STZ +4 ± 5 %) mediated responses were not significantly affected by IOP elevation in either citrate- or STZ-injected rats. Finally, oscillatory potentials (citrate-control +8 ± 23 %, STZ +1 ± 17 %) were not reduced 1 week after IOP challenge.The ganglion cell dominated pSTR was reduced following a single episode of IOP elevation in STZ diabetic, but not control rats. These data indicate that hyperglycemia renders the inner retina more susceptible to IOP elevation.

© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland

Purpose: To evaluate the clinical effects of using fixed (four times daily [QID]) versus as-needed (PRN) dosing of an artificial tear product (polyethylene glycol/propylene glycol [PEG/PG]; Systane Ultra) in individuals with dry eye disease. Methods: In this prospective, multicenter, observer-masked, active-control, parallel-group trial, participants were randomized (1:2 allocation) to receive 1 drop of PEG/PG QID (n = 34) or PRN (n = 63) for 28 days. The primary endpoint was change from baseline in the total ocular surface staining (TOSS) score (according to the Oxford scale) at day 28. Results: At day 28, the change from baseline in least squares mean (LSM) TOSS scores for QID and PRN groups were -1.19 and -0.94, respectively (treatment difference [TD]: -0.26; 95% confidence interval [CI]: -∞ to 0.21; P = 0.184); superiority of QID versus PRN dosing was not established, as the upper limit of one-sided 95% CI for TD was not

Purpose: Elevated intraocular pressure (IOP) is the major modifiable risk factor for the sight-threatening eye disease, glaucoma. We investigated whether oral omega-3 supplements affect IOP in normotensive adults. Methods: We undertook a pooled analysis of data from two double-masked, placebo-controlled randomized trials (Australian New Zealand Clinical Trials Registry, ACTRN12614001019695, ACTRN12615000173594) that investigated the efficacy and safety of oral omega-3 supplementation for treating ocular surface inflammation. Recruitment involved adults (n = 105) with IOP

To determine the visual adaptation and retinal eccentricity profiles for red flickering and static test stimuli and report a clinical implementation of these stimuli in visual perimetry.The adaptation profile for red-on-white perimetry stimuli was measured using a threshold vs. intensity (TvI) paradigm at 0 degree and 12 degrees eccentricity and by comparing the eccentricity-related sensitivity change for red and white, static, and flickering targets in young normal trichromats (n = 5) and a group of dichromats (n = 5). A group of older normal control observers (n = 30) were tested and retinal disease was evaluated in persons having age-related maculopathy (n = 35) and diabetes (n = 12).Adaptation and eccentricity profiles indicate red static and flickering targets are detected by two mechanisms in the paramacular region, and a single mechanism for5 degrees eccentricity. The group data for the older normal observers has a high level of inter-observer variability with a generalized reduction in sensitivity across the entire visual field. Group data for the participants with age-related maculopathy show reduced sensitivities that were pronounced in the central retina. The group data for the diabetic observers showed sensitivities that were reduced at all eccentricities. The disease-related sensitivity decline was more apparent with red than white stimuli.The adaptation profile and change in sensitivity with retinal eccentricity for the red-on-white perimetric stimuli are consistent with two detection processes. In the macula, the putative detection mechanism is color-opponent with static targets and non-opponent with flickering targets. At peripheral field locations, the putative detection mechanism is non-opponent for both static and flicker targets. The long-wavelength stimuli are less affected by the preretinal absorption common to aging. Red-on-white static and flicker perimetry may be useful for monitoring retinal disease, revealing greater abnormalities compared with conventional white-on-white perimetry, especially in the macula where two detection mechanisms are found.

We characterised the dynamics in the oscillatory potentials (OPs) of the rat electroretinogram (ERG) using a continuous complex Morlet wavelet transform. Dark-adapted (>12h) full field ERG responses were recorded from five anaesthetized (ketamine:xylazine, 60:5mg/kg) adult Long-Evans rats (10-12weeks). Five responses were obtained for brief LED flashes (1-4ms) in a ganzfeld at exposures ranging from -4.2 to 1.58logcdsm(-2). Signals were recorded across a bandwidth of 0.3-1kHz and digitized at 10kHz. Morlet wavelets with frequencies between 50 and 250Hz were correlated with raw ERG signals at 1ms intervals. The amplitude of the correlation at each time and frequency was given by the modulus of the complex wavelet response. Candidate OPs were identified as local peaks within 10% of the maximum amplitude. As flash exposure increased, the amplitude of the OP response increased, the peak OP occurred earlier, and the peak OP frequency increased. OPs at brighter flashes clustered into two groups, peaking at 50ms in the 70 and 130Hz band for moderate intensities, and peaking at 20ms in the 70Hz band and 50ms in the 120Hz band for the highest intensities (>0logcdsm(-2)). These dynamics agree with physiological, pharmacological and clinical studies that suggest several distinct neural mechanisms contribute to OPs. Wavelet analysis reveals important dynamics in OP data that are not evident with traditional analytical approaches.

We investigated the effect of receptor blockade induced by an angiotensin II type-1 receptor antagonist (AT(1)-RB) on glial and vascular changes in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity (ROP). OIR was induced in Sprague-Dawley rats by exposure to 80% oxygen from postnatal (P) days 0-11, followed by 7 days in room air. Control animals were in room air for the entire duration. One cohort of OIR and control pups received the AT(1)-RB valsartan (40 mg/kg/day intraperitoneal) from P11 to P18. The vascular response was examined immunocytochemically using retinal wholemounts and vertical sections labeled with endothelial (Isolectin-B4) and pericyte (NG2, desmin) markers. Glial cell changes were assessed by measuring cell numbers and immunoreactivity (S100beta, connexin-26, and glial fibrillary acidic protein). OIR resulted in extensive intravitreal neovascularization and under-development of the outer vascular plexus. Pericyte numbers were not significantly affected in OIR, although pericyte-endothelial (desmin-IB4) interactions were impaired. Peripheral astrocyte degeneration occurred between P11 and P13 with prominent Müller cell reactivity at P18. Valsartan imparted a protective effect on glia and blood vessels in OIR. At P18, valsartan-treated OIR retinae showed significantly greater astrocyte survival, improved revascularization of the retina, and reduced preretinal neovascularization and Müller cell reactivity. This study identifies a glio-vascular protective effect with AT(1)-RB in OIR.

Objective To record intraocular pressure (IOP) of three different dog breeds following administration of one drop of 1% tropicamide. Animals Three dog breeds – Golden Retrievers ( n = 20), Siberian Huskies ( n = 20) and Cocker Spaniels ( n = 36) – were studied. Procedure IOPs were measured using a Tonopen following corneal anesthesia with a single drop of 0.5% proxymetacaine. A drop of 0.5% tropicamide was then administered bilaterally and a second IOP measurement was taken 30 min later (postdilation). The difference between the two measurements was considered as the effect of mydriasis on IOP. Results Dogs had an average IOP of 14.9 ± 3.2 mmHg, with 95% confidence limits ranging from 8 to 22 mmHg. There were significant differences between breeds ( P < 0.006) with Siberian Huskies having higher IOPs (17.2 ± 3.7 mmHg) than the other breeds (Spaniels: 14.2 ± 2.8 mmHg, P < 0.01; Retrievers: 14 ± 1.9 mmHg, P < 0.001). The majority (60%) of dogs displayed 5 mmHg or less in IOP change postmydriasis. Siberian Huskies showed the highest IOP levels, and also had the greatest variability with dilation. Conclusions and clinical relevance Interbreed variability in effect of tropicamide of canine IOP is evident.

Studies of retinal ischemia/reperfusion indicate a disparity between the anatomical and functional results; while a large number of rod bipolar cells remain postischemia, there is a significant reduction in the amplitude of the scotopic b-wave of the electroretinogram (ERG). We investigated the alterations in photoreceptor-bipolar cell signaling following ischemia/reperfusion and suggest a mechanism for the decrease in b-wave amplitude. A cation channel probe (agmatine, 1-amino-4-guanidobutane, AGB) was used to assess cellular ion channel activity in neurochemically identified cells secondary to endogenous glutamate release or pharmacological manipulations. By applying the "neurochemical truth point" principle (Sun et al. [2007a] J Comp Neurol, this issue), we have been able to confirm the loss of specific subpopulations of neurons. ERG was used to assess gross retinal function, with parameters of the ERG model providing insight into changes in the phototransduction cascade and sensitivity of postreceptoral glutamate receptors. Following ischemia/reperfusion, rod bipolar cells maintained 2-amino-4-phosphonobutyric acid-responsive metabotropic glutamate receptors and displayed no change in sensitivity to flashes of light as assessed by ERG. Therefore, the loss in b-wave amplitude is likely due to alterations in photoreceptoral glutamate release detected as a change in postsynaptic AGB permeation into rod bipolar cells. Bipolar cell to amacrine cell signaling was also altered. The robust AGB entry into cholinergic amacrine cells was virtually absent in retinas that had undergone ischemia/reperfusion but remained in the AII amacrine cells. Such results suggest a loss of glutamate receptors and/or a change in receptor subunit expression in subpopulations of inner retinal neurons. Although many cells retain their characteristic neurochemical labeling following ischemia/reperfusion, caution should be used when assuming cells participate in functional retinal circuits based solely on the persistence of neurochemical labeling.

PURPOSE To induce chronic intraocular pressure (IOP) elevation in rat eyes by circumlimbal suture. METHODS Anesthetized (isoflurane) Long-Evans rats underwent unilateral circumlimbal suture implantation while the fellow eyes served as untreated controls (n = 15). A sham group (n = 8) received the same procedure except that the suture was loosely tied. Intraocular pressure, electroretinography (ERG), and optical coherence tomography (OCT) were monitored for 15 weeks, after which retinal histology and immunofluorescence staining for glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (Iba-1) were undertaken. RESULTS Both IOP and ERG remained unaltered in the sham and all control eyes over 15 weeks. In the ocular hypertensive eye, IOP spiked from 17 ± 1 to 58 ± 3 mm Hg immediately after suture application, recovering to 32 ± 2 mm Hg by 24 hours, and remained elevated by 7 to 10 mm Hg above baseline for 15 weeks. At week 2, there was a small reduction of ERG components involving the photoreceptor a-wave, bipolar cell b-wave, and ganglion cell-mediated scotopic threshold response (pSTR). The reduction in a- and b-wave remained stable, while the pSTR became more affected from week 8 onward (P < 0.05). By week 12, there was progressive retinal nerve fiber layer (RNFL) thinning. At week 15, GFAP expression was upregulated in inner retina and on Muller cells. The ganglion cell dysfunction was associated with RNFL thinning and cell loss in the ganglion cell layer. CONCLUSIONS Circumlimbal suture provides a simple and cost-effective way to induce mild chronic ocular hypertension in rat eyes. This model produces preferential ganglion cell dysfunction and RNFL reduction.

Extracellular ATP mediates fast excitatory neurotransmission in many regions of the central nervous system through activation of P2X receptors. Although several P2X receptor subunits have been identified in the mammalian retina, little is known about the functional role of these receptors in retinal signalling. The purpose of the present study was to investigate whether purinergic P2X7 receptors are involved in outer retinal processing by assessing receptor localization, degradation of extracellular ATP and the effect of functional activation of P2X7 receptors on the electroretinogram (ERG). Using light and electron microscopy, we demonstrated that P2X7 receptors are expressed postsynaptically on horizontal cell processes as well as presynaptically on photoreceptor synaptic terminals in both the rat and marmoset retina. Using an enzyme cytochemical method, we showed that ecto-ATPases are active in the outer plexiform layer of the rat retina, providing a mechanism by which purinergic synaptic transmission can be rapidly terminated. Finally, we evaluated the role of P2X7 receptors in retinal function by assessing changes to the ERG response of rats after intravitreal delivery of the P2X7 receptor agonist benzoyl benzoyl ATP (BzATP). Intravitreal injection of BzATP resulted in a sustained increase (up to 58%) in the amplitude of the photoreceptor-derived a-wave of the ERG. In contrast, BzATP caused a transient reduction in the rod- and cone-derived postreceptoral responses. These results provide three lines of evidence for the involvement of extracellular purines in outer retinal processing.

We develop the logic for a stimulus that can evaluate cone-dependent spatial summation and detail the modelling and interpretation of thresholds obtained with this stimulus. Fifteen observers participated, including two young normals tested extensively in control experiments, and a clinical trial based on four observers with age-related macular degeneration (AMD), four age-similar controls and five young observers. Monocular spatial summation functions were measured with contrast-modulated Gabor targets that approximated the optimal visual contrast detector. Thresholds were returned from a yes/no adaptive psychophysical algorithm. By fine titration along the size domain it was demonstrated that the spatial summation of normal observers can be adequately described by a two-component model. A reduced set of variables are proposed for clinical applications and the model was applied to data derived using these variables in persons with AMD and age-similar controls. We do not find a significant age-related loss of contrast sensitivity in our normal group. On the other hand, persons with early AMD exhibited a 0.41 log unit loss of sensitivity (P=0.04) from age-similar controls, without any change in their maximum summation area (Amax). The nature of the spatial summation is consistent with the interpretation that early AMD produces a decrease in cone input to post-receptoral mechanisms in the absence of neural remodelling.

We demonstrate that cathode-ray-tube (CRT) monitors commonly used as stimulus generators in visual neuroscience produce signal artefacts. This arises from two factors, one being the finite time needed for the raster scan of the CRT to cross the receptive field being stimulated, and the other being the restraint imposed by the impulse response of the phosphor itself. Together these factors result in smearing or blurring that manifests as high frequency noise, distorting the desired signal applied by the investigator. Our analysis identifies those conditions that promote these artefacts and we describe methods for their minimisation. We suggest that a monitor frame rate/=100 Hz provides a reasonable trade-off between refresh and the generators of high frequency noise.