Comparing 2-dimensional macular pigment optical density with objective and subjective perimetry and visual acuity in age-related macular degeneration.

PURPOSE: To compare diagnostic power for different severities of age-related macular degeneration (AMD) of two-dimensional macular pigment optical densities (2D-MPOD) and spatially matched objective perimetry, with standard perimetry and best-corrected visual acuity (BCVA). METHODS: The ObjectiveField Analyser (OFA) provided objective perimetry, and a Heidelberg Spectralis optical coherence tomography (OCT) measured 2D-MPOD in AMD patients, both completed twice over 0.99 ± 0.16 years. From each 2D-MPOD image, we extracted 20 regions/macula, matched to the 20 OFA stimuli/macula. For each region, we calculated 7 measures from the 2D-MPOD pixel values and correlated those with OFA sensitivities and delays. We quantified 2D-MPOD changes, the ability of 2D-MPOD and OFA to discriminate AMD stages, and the discriminatory power of Matrix perimetry and BCVA using percentage area under receiver operator characteristic plots (%AUROC). RESULTS: In 58 eyes of 29 subjects (71.6 ± 6.3 years, 22 females), we found significant correlations between 2D-MPOD and OFA sensitivities for Age-Related Eye Disease Studies (AREDS)-3 and AREDS-4 severities. Delays showed significant correlations with AREDS-2. For AREDS-4, correlations extended across all eccentricities. Regression associated with the Bland-Altman plots showed significant changes in 2D-MPOD over the study period, especially variability measures. MPOD per-region medians discriminated AREDS-1 from AREDS-3 eyes at a %AUROC of 80.0 ± 6.3%, outperforming OFA, Matrix perimetry, and BCVA. CONCLUSIONS: MPOD changes correlated with central functional changes and significant correlations extended peripherally in later-stage AMD. Good diagnostic power for earlier-stage AMD and significant change over the study suggest that 2D-MPOD and OFA may provide effective biomarkers.

Multifocal pupillographic objective perimetry for assessment of early diabetic retinopathy and generalised diabetes-related tissue injury in persons with type 1 diabetes.

BACKGROUND: To examine the potential utility of five multifocal pupillographic objective perimetry (mfPOP) protocols, in the assessment of early diabetic retinopathy (DR) and generalised diabetes-related tissue injury in subjects with type 1 diabetes (T1D). METHODS: Twenty-five T1D subjects (age 41.8 ± 12.1 (SD) years, 13 male) with either no DR (n = 13) or non-proliferative DR (n = 12), and 23 age and gender-matched control subjects (age 39.7 ± 12.9 years, 9 male) were examined by mfPOP using five different stimulus methods differing in visual field eccentricity (central 30° and 60°), and colour (blue, yellow or green test-stimuli presented on, respectively, a blue, yellow or red background), each assessing 44 test-locations per eye. In the T1D subjects, we assessed 16 metabolic status and diabetes complications variables. These were summarised as three principal component analysis (PCA) factors. DR severity was assessed using Early Treatment of Diabetic Retinopathy Study (ETDRS) scores. Area under the curve (AUC) from receiver operator characteristic analyses quantified the diagnostic power of mfPOP response sensitivity and delay deviations for differentiating: (i) T1D subjects from control subjects, (ii) T1D subjects according to three levels of the identified PCA-factors from control subjects, and (iii) TID subjects with from those without non-proliferative DR. RESULTS: The two largest PCA-factors describing the T1D subjects were associated with metabolic variables (e.g. body mass index, HbA1c), and tissue-injury variables (e.g. serum creatinine, vibration perception). Linear models showed that mfPOP per-region response delays were more strongly associated than sensitivities with the metabolic PCA-factor and ETDRS scores. Combined mfPOP amplitude and delay measures produced AUCs of 90.4 ± 8.9% (mean ± SE) for discriminating T1D subjects with DR from control subjects, and T1D subjects with DR from those without of 85.9 ± 8.8%. The yellow and green stimuli performed better than blue on most measures. CONCLUSIONS/INTERPRETATION: In T1D subjects, mfPOP testing was able to identify localised visual field functional abnormalities (retinal/neural reflex) in the absence or presence of mild DR. mfPOP responses were also associated with T1D metabolic status, but less so with early stages of non-ophthalmic diabetes complications.

Relationships between retinal structure and function and vision-related quality of life measures in advanced age-related macular degeneration.

PURPOSE: To evaluate the association between ophthalmic structure/function measures and five standardized quality of life (QoL) instruments, in patients with advanced age-related macular degeneration (AMD). METHODS: We examined 20 AMD patients (ages 66-93 years) recruited from the Canberra Hospital Ophthalmology Department. Visual function measures included low and high contrast visual acuity (LCVA and HCVA) and measures from 10-2 Matrix visual fields (VF). Optical coherence tomography (OCT) quantified central retinal thickness (CRT), average macular thickness (AT), and retinal nerve fibre layer thickness (RNFL). The QoL instruments were the macular degeneration-related quality of life (MacDQoL), the National Eye Institute Visual Functioning Questionnaire (VFQ), its two face-recognition questions (A6 and 11), and the Geriatric Depression Scale (GDS). Pearson correlations, Canonical Correlation Analysis (CCA), and cross-validated stepwise-regression were used to examine the relationships between structure/function measures and the QoL instruments. RESULTS: The selected models for the five instruments had R2 ranging from 0.65 ± 0.12 to 0.90 ± 0.05 (mean ± SD) and median F-statistics > 188. HCVA was strongly associated with all QoL except the GDS, for which CRT, AT and RNFL figured highly. RNFL was most important for MacDQoL, and 2nd for VFQ question-A6. Centrally weighted VF measures were rarely selected but global VF measures were common, especially for the overall NEI-VFQ questionnaire. CCA revealed that the structure/function measures and QoL instruments contained 2 statistically independent mechanisms. CONCLUSIONS: In patients with advanced AMD, CRT and HCVA were strong determinants of QoL instruments in AMD patients.

Recovery dynamics of multifocal pupillographic objective perimetry from tropicamide dilation.

PURPOSE: To study the pupillary system by combining mydriasis and multifocal pupillographic objective perimetry (mfPOP). In particular, we explored how the dynamics of recovery differ for concurrently measured direct and consensual sensitivity, response delay, and signal-to-noise ratios (SNRs) for binocular mydriasis. METHODS: We recruited 26 normal participants, all with brown irides. The dichoptic mfPOP stimuli concurrently assessed 44-region/eye and both pupils. Two pre-dilation tests were followed by pairs of repeated tests at 1, 2, 4, 6, 8, 12, 24, and 48 h following dilation of both pupils with 1% tropicamide. Three subjects were retested with only the right pupil dilated. Linear models determined the independent effects of mydriasis upon the per-region and pupil measures over time. RESULTS: Post-dilation, the per-region delays initially decreased by 16.3 ± 6.02 ms (mean ± SE) (p < 0.0001, cf. baseline of 471.1 ± 4.36 ms), then increased to slower than baseline by 17.42 ± 5.57 ms after 4 h (p < 0.002), recovering to baseline at 8 h. By comparison, per-region sensitivities (constriction amplitudes) were still reduced by - 6.20 ± 0.70 µm at 8 h (p < 0.0001, cf. baseline of 21.1 ± 0.55 µm), recovered at 24 h, but rebounded at 48 h (p = 0.005). The SNRs for sensitivities and delays both recovered by 8-12 h. Across all the data, sensitivities reduced by 2.67 ± 0.25 µm/decade of age, and delay increased by 15.4 ± 1.98 ms/decade (both p < 0.00001). Data from 3 of the 26 subjects who repeated the testing for monocular dilation found that consensual response sensitivities were larger than direct for 8 h (p < 0.018). CONCLUSIONS: The per-region sensitivities were affected for longer than SNRs or delays. Strong early SNRs indicated proportionately lower pupil noise for larger pupil diameters. Following mydriasis with tropicamide 1%, the constriction amplitude measurements with mfPOP should be considered only after 48 h, but time-to-peak can be measured after 8-12 h.

Caricaturing can improve facial expression recognition in low-resolution images and age-related macular degeneration.

Previous studies of age-related macular degeneration (AMD) report impaired facial expression recognition even with enlarged face images. Here, we test potential benefits of caricaturing (exaggerating how the expression's shape differs from neutral) as an image enhancement procedure targeted at mid- to high-level cortical vision. Experiment 1 provides proof-of-concept using normal vision observers shown blurred images as a partial simulation of AMD. Caricaturing significantly improved expression recognition (happy, sad, anger, disgust, fear, surprise) by ∼4%-5% across young adults and older adults (mean age 73 years); two different severities of blur; high, medium, and low intensity of the original expression; and all intermediate accuracy levels (impaired but still above chance). Experiment 2 tested AMD patients, running 19 eyes monocularly (from 12 patients, 67-94 years) covering a wide range of vision loss (acuities 6/7.5 to poorer than 6/360). With faces pre-enlarged, recognition approached ceiling and was only slightly worse than matched controls for high- and medium-intensity expressions. For low-intensity expressions, recognition of veridical expressions remained impaired and was significantly improved with caricaturing across all levels of vision loss by 5.8%. Overall, caricaturing benefits emerged when improvement was most needed, that is, when initial recognition of uncaricatured expressions was impaired.

Multifocal pupillography in early age-related macular degeneration.

PURPOSE: To investigate the potential of multifocal pupillographic objective perimetry to assess changes in retinal function with clinical severity of age-related macular degeneration (AMD). METHODS: Pupil responses were recorded from 40 subjects with AMD and 23 normal control subjects (mean ± SD age, 71.3 ± 5.1 years). Age-related macular degeneration subjects were classified according to the Age-Related Eye Disease Study (AREDS) classification system and allocated into one of four AMD severity groups. Three multifocal pupillographic objective perimetry stimulus variants that were identical in luminance but varied in spatiotemporal sequence were used. In one of the three protocols, stimuli were presented with a pedestal flicker for 266 milliseconds at 15 Hz. RESULTS: On average, response amplitudes demonstrated a significant change in sensitivity with progression from early-stage (0.32 ± 0.08 dB, t = 3.88) to late-stage (-1.60 ± 0.12 dB, t = -12.7) age-related macular degeneration. Response delays followed a similar trend with the longest delays in AREDS4 (57.2 ± 1.9 milliseconds, t = 29.5). Ring analysis identified the largest mean effect on responses within the central 6 degrees of fixation. The NewStimuli protocol achieved the best diagnostic accuracy across all severity groups with area under the curve values of 0.85 ± 0.066 (AREDS1), 0.908 ± 0.085 (AREDS2), 0.929 ± 0.040 (AREDS3), and 1.0 ± 0.0 (AREDS4). CONCLUSIONS: The mean effect of AMD on contraction amplitudes and response delays reflected the severity of disease, and the NewStimuli protocol achieved good diagnostic accuracy across all AMD severity groups. Multifocal pupillographic objective perimetry may potentially be a useful method in monitoring progression of AMD and assessing change in retinal function with novel interventions in early AMD. Longitudinal studies are required to identify biomarkers that predict eyes at risk of progression.

Visual Field Tests: A Narrative Review of Different Perimetric Methods.

Visual field (VF) testing dates back to fifth century B.C. It plays a pivotal role in the diagnosis, management, and prognosis of retinal and neurological diseases. This review summarizes each of the different VF tests and perimetric methods, including the advantages and disadvantages and adherence to the desired standard diagnostic criteria. The review targets beginners and eye care professionals and includes history and evolution, qualitative and quantitative tests, and subjective and objective perimetric methods. VF testing methods have evolved in terms of technique, precision, user-friendliness, and accuracy. Consequently, some earlier perimetric techniques, often still effective, are not used or have been forgotten. Newer technologies may not always be advantageous because of higher costs, and they may not achieve the desired sensitivity and specificity. VF testing is most often used in glaucoma and neurological diseases, but new objective methods that also measure response latencies are emerging for the management of retinal diseases. Given the varied perimetric methods available, clinicians are advised to select appropriate methods to suit their needs and target disease and to decide on applying simple vs. complex tests or between using subjective and objective methods. Newer, rapid, non-contact, objective methods may provide improved patient satisfaction and allow for the testing of children and the infirm.

Retinal Function in Young Adults Following Topical Application of Levodopa to the Eye.

Purpose: Levodopa has been investigated as a therapeutic solution for ocular disorders involving dysregulation of the dopaminergic system, especially in the context of myopia. However, given the critical role dopamine plays in normal vision, this phase I trial examined whether levodopa/carbidopa eye drops induce any regional changes in retinal structure and function. Methods: Twenty-nine healthy male subjects 18 to 30 years of age were randomly assigned to receive either a low (1.4/0.34 µmoles/day, n = 14) or high (2.7/0.68 µmoles/day, n = 15) dose of levodopa/carbidopa eye drops in 1 eye for 28 consecutive days. A placebo solution was applied to all fellow eyes. Measures included visual acuity, regional frequency doubling perimetry, regional multifocal electroretinogram (mfERG) and optical coherence tomography (retinal thickness). Outcome measures were undertaken at baseline, end-of-treatment (4 weeks), and at a follow-up (4 months post-treatment). Results: For low dose treated eyes, regional analysis showed a small, statistically significant change in mfERG recordings (increase in ring 5 amplitude in low dose treated eyes, P < 0.05) and the retinal thickness map (localized retinal thinning in low dose treated eyes, P < 0.05). These changes were not clinically significant. No significant changes were observed in high dose treated eyes. Pharmacokinetic analysis (rabbits) demonstrated that levodopa was not detectable within blood and peaked within the eye at 15 to 30 minutes (and eliminated within 4 hours). Conclusions: No clinically significant effects of levodopa/carbidopa eye drops were found with regard to normal retinal structure and function following short-term use. Translational Relevance: This study further demonstrates the safety of topical levodopa, which may support its use in the treatment of ocular disorders in which the dopamine system is dysregulated.

Early diabetic eye damage: Comparing detection methods using diagnostic power.

It is now clear that retinal neuropathy precedes classical microvascular retinopathy in diabetes. Therefore, tests that underpin useful new endpoints must provide high diagnostic power well before the onset of moderate diabetic retinopathy. Hence, we compare detection methods of early diabetic eye damage. We reviewed data from a range of functional and structural studies of early diabetic eye disease and computed standardized effect size as a measure of diagnostic power, allowing the studies to be compared quantitatively. We then derived minimum performance criteria for tests to provide useful clinical endpoints. This included the criteria that tests should be rapid and easy so that children with type 1 diabetes can be followed into adulthood with the same tests. We also defined attributes that lend test data to further improve performance using Machine/Deep Learning. Data from a new form of objective perimetry suggested that the criteria are achievable.

Diagnostic Power and Reproducibility of Objective Perimetry in Glaucoma.

PRCIS: An objective perimetry method provides four 30-2 style reports in 8 minutes. These comprise sensitivity and delay reports for both eyes. A combined report format shows comparable diagnostic power to two forms of automated perimetry. PURPOSE: To compare objective perimetry with two forms of standard automated perimetry (SAP) in glaucoma. METHODS: The study cohort contained 40 persons with glaucoma (PwG) and 94 normal control subjects. The PwG had both perimetric and pre-perimetric eyes. Multifocal pupillographic objective perimetry was performed with the objectiveField Analyser® (OFA®), which independently assesses the visual fields of both eyes concurrently. Its OFA30 test assessed the central ±30°, and the OFA15 test assessed the central ±15°, both providing 30-2 style reports. The OFA tests were repeated two weeks apart to assess test-retest variability (TRV). OFA was compared with Matrix and HFA-SITA fast 24-2 threshold testing. Diagnostic power was quantified as area under receiver operating characteristic curves (AUROC). Test durations, Mean Defects and Pattern Standard Deviations of the 4 tests were compared. RESULTS: At a median of 4.09±0.02 minutes/eye the OFA tests were quicker than SAP (all P≤0.0001), 2 minutes/eye if OFA per-region sensitivities and delays are considered separately. The %AUROCs for OFA, Matrix and HFA were not significantly different, averaging 93±3% (mean±SD) in perimetric eyes, and 73±6% in pre-perimetric eyes. For moderate to severe fields OFA TRV was less than published results for SAP. OFA30 mean defects were significantly correlated between repeats (r=0.91), and with OFA15 (r=0.93, both P<0.0001). CONCLUSIONS: OFA provides extra functional measures in the form of per-region delays, and between-eye asymmetries. Both the OFA wide-field and macular tests provided comparable diagnostic power to SAP and better TRV in damaged eyes.

Dichoptic multifocal visual evoked potentials identify local retinal dysfunction in age-related macular degeneration.

PURPOSE: To evaluate the ability of multifocal visual evoked potentials (mfVEPs) to identify functional loss in patients with early and exudative age-related macular degeneration (AMD). A dichoptic multifocal stimulus presentation was employed to investigate the regional effects of AMD and the potential diagnostic utility in macular disease. METHODS: MfVEP responses were recorded from 19 unilateral exudative AMD patients with non-exudative (n = 15) or normal (n = 4) presentations in the fellow eye and 28 age-matched controls. Root mean square (RMS) waveforms were pooled across selected EEG channels to produce global field RMS (gfRMS) waveforms. GfRMS amplitudes and response delays were analysed by multivariate linear models, and diagnostic capacity was measured using areas under the curve (AUC) of receiver operator characteristic plots. RESULTS: The mean gfRMS amplitude of the exudative eye of AMD patients was significantly reduced compared with the controls (-2.03 ± 0.08 dB, t = -12.9). Fellow non-exudative AMD eyes were less effected but still significantly reduced (-0.84 ± 0.07 dB, t = -11.5). No significant difference in mean gfRMS delay of AMD eyes across the central 46° was observed. AUC values of 100 ± 0.0% (mean ± SE) for exudative and 79.7 ± 6.5% for non-exudative eyes were obtained for response amplitudes. CONCLUSION: The study demonstrated that mfVEP identified retinal dysfunction in both exudative AMD and fellow non-exudative AMD eyes, but mostly affecting the macular field. The reduced testing duration and good diagnostic accuracy suggest that dichoptic mfVEPs may be a sensitive tool for monitoring progression in AMD.

Multifocal pupillography identifies retinal dysfunction in early age-related macular degeneration.

BACKGROUND: Early age-related macular degeneration (AMD) is common among the elderly. While only a small number progress to sight-threatening stages of AMD, identifying prognostic functional markers remains paramount. Here, we objectively evaluate retinal function in patients with large drusen by multifocal pupillographic objective perimetry (mfPOP). Different temporal presentation rates and luminances were compared to optimize parameters for high signal to noise ratios (SNR) and diagnosticity for early AMD. METHODS: Pupil responses were recorded from 19 early AMD patients (30 eyes) and 29 age-matched control subjects. We compared a luminance-balanced stimulus ensemble and two unbalanced stimulus variants, each consisting of 44 independent stimulus regions per eye extending from fixation to 15˚ eccentricity. Video cameras recorded pupil responses for each eye under infrared illumination. The amplitudes and delays of the peak responses were analysed by multivariate linear models. The diagnostic accuracy of the stimulus variants was compared using areas under the curve (AUC) of receiver operator characteristic (ROC) plots. RESULTS: Early AMD eyes differed significantly from normal in their mean constriction amplitudes (-2.22 ± 0.15 dB, t = -14.8) and delays (17.92 ± 1.2 ms, t = 14.9). The brightest stimulus ensembles produced the highest median SNRs of 3.45 z-score units; however, the balanced method was found to be the most diagnostic. AUC values of 0.95 ± 0.03 (mean ± SE) for early AMD were obtained when the asymmetry of response amplitudes between eyes was considered. CONCLUSIONS: The mfPOP responses of early AMD eyes showed significant abnormality in response amplitudes and peak time. The ROC AUCs of 95 % suggest that mfPOP is a sensitive tool for detecting early abnormalities in AMD and longitudinal studies measuring progression of retinal dysfunction are warranted.

The experience of visual art for people living with mild-to-moderate vision loss.

BACKGROUND: Visual art can enhance wellbeing and quality-of-life; however, the experience of visual art for people with mild-to-moderate vision loss has not been examined. METHODS: Eight participants (6 females, 2 males; Mean age = 81 years, SD = 7.9, range 70-91 years; 4 with mild vision loss and 4 with moderate vision loss based on binocular visual acuity) completed a mixed-methods study comprising: a semi-structured interview on visual art experience; an eye examination; and questionnaires about visual functioning and quality-of-life. RESULTS: Various themes were identified: visual perception of art (e.g. altered colours, visual distortions, etc.), viewing conditions, elements of art, personal preference, deriving meaning, appreciation of art, impact of impaired visual perception, and social aspects of art. CONCLUSIONS: The overall experience of art is influenced by how an individual sees, perceives, and makes meaning from art. Even mild vision loss can impair this experience and impact emotional and social wellbeing.

Discriminating early-stage diabetic retinopathy with subjective and objective perimetry.

Introduction: To prevent progression of early-stage diabetic retinopathy, we need functional tests that can distinguish multiple levels of neural damage before classical vasculopathy. To that end, we compared multifocal pupillographic objective perimetry (mfPOP), and two types of subjective automated perimetry (SAP), in persons with type 2 diabetes (PwT2D) with either no retinopathy (noDR) or mild to-moderate non-proliferative retinopathy (mmDR). Methods: Both eyes were assessed by two mfPOP test methods that present stimuli within either the central ±15° (OFA15) or ±30° (OFA30), each producing per-region sensitivities and response delays. The SAP tests were 24-2 Short Wavelength Automated Perimetry and 24-2 Matrix perimetry. Results: Five of eight mfPOP global indices were significantly different between noDR and mmDR eyes, but none of the equivalent measures differed for SAP. Per-region mfPOP identified significant hypersensitivity and longer delays in the peripheral visual field, verifying earlier findings. Diagnostic power for discrimination of noDR vs. mmDR, and normal controls vs. PwT2D, was much higher for mfPOP than SAP. The mfPOP per-region delays provided the best discrimination. The presence of localized rather than global changes in delay ruled out iris neuropathy as a major factor. Discussion: mfPOP response delays may provide new surrogate endpoints for studies of interventions for early-stage diabetic eye damage.

Objective perimetry identifies regional functional progression and recovery in mild Diabetic Macular Oedema.

PURPOSE: Retinal function beyond foveal vision is not routinely examined in the clinical screening and management of diabetic retinopathy although growing evidence suggests it may precede structural changes. In this study we compare optical coherence tomography (OCT) based macular structure with function measured objectively with the ObjectiveFIELD Analyzer (OFA), and with Matrix perimetry. We did that longitudinally in Type 2 diabetes (T2D) patients with mild Diabetic Macular Oedema (DMO) with good vision and a similar number of T2D patients without DMO, to evaluate changes in retinal function more peripherally over the natural course of retinopathy. METHODS: Both eyes of 16 T2D patients (65.0 ± 10.1, 10 females), 10 with baseline DMO, were followed for up longitudinally for 27 months providing 94 data sets. Vasculopathy was assessed by fundus photography. Retinopathy was graded using to Early Treatment of Diabetic Retinopathy Study (ETDRS) guidelines. Posterior-pole OCT quantified a 64-region/eye thickness grid. Retinal function was measured with 10-2 Matrix perimetry, and the FDA-cleared OFA. Two multifocal pupillographic objective perimetry (mfPOP) variants presented 44 stimuli/eye within either the central 30° or 60° of the visual field, providing sensitivities and delays for each test-region. OCT, Matrix and 30° OFA data were mapped to a common 44 region/eye grid allowing change over time to be compared at the same retinal regions. RESULTS: In eyes that presented with DMO at baseline, mean retinal thickness reduced from 237 ± 25 µm to 234.2 ± 26.7 µm, while the initially non-DMO eyes significantly increased their mean thickness from 250.7 ± 24.4 µm to 255.7 ± 20.6 µm (both p<0.05). Eyes that reduced in retinal thickness over time recovered to more normal OFA sensitivities and delays (all p<0.021). Matrix perimetry quantified fewer regions that changed significantly over the 27 months, mostly presenting in the central 8 degrees. CONCLUSIONS: Changes in retinal function measured by OFA possibly offer greater power to monitor DMO over time than Matrix perimetry data.

Clustered Volleys Stimulus Presentation for Multifocal Objective Perimetry.

PURPOSE: Multifocal pupillographic objective perimetry (mfPOP) is being developed as an alternative to subjective threshold perimetry for the management of visual and neurological disorders. Here, we evaluate, in normal subjects, differences in signal quality between the original mfPOP method of spatially sparse Continuous stimulus presentation and the new Clustered Volleys (CVs) method. We hypothesized that the CVs method would lead to increased signal-to-noise ratios (SNRs) over the original method due to the stabilization of gain within the pupillary system. METHODS: Data were collected from six separate studies where otherwise-identical pairs of mfPOP tests using either the original Continuous stimulus presentation method or the new CVs method were undertaken; 440 6-minute tests from 96 normal subjects of varying ages were included. Per-region SNRs were compared between the two methods. RESULTS: Mean SNRs for the CVs mfPOP variants were between 35% and 57% larger than the original Continuous mfPOP variants (P < 0.001 in five of six studies). Similarly, the goodness-of-fit measure (r2) demonstrated large and significant fold increases of between 2.3× and 3.4× over the original method (all P < 0.001). Significant improvements in SNRs were present in all of the 88 test regions (44/eye), ranging between 8.4% and 93.7%; mean SNRs were significantly larger in 98% of test subjects. CONCLUSIONS: The CVs mfPOP stimulus presentation method produced substantial increases in signal quality over the original method. This is likely due to the stabilization of pupillary gain during stimulus presentation. TRANSLATIONAL RELEVANCE: These improvements increase diagnostic accuracy and have enabled shorter, 80-second mfPOP tests to be developed.

The safety and tolerability of levodopa eye drops for the treatment of ocular disorders: A randomized first-in-human study.

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first-in-human study reports on the safety profile of a novel dopamine-based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first-in-human, monocenter, placebo-controlled, double-blind, paired-eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18-30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [µmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [µmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4-week trial, and after a 4-month follow-up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non-ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age-related macular degeneration) in which levodopa has been identified as a potential clinical intervention.

Rapid Objective Testing of Visual Function Matched to the ETDRS Grid and Its Diagnostic Power in Age-Related Macular Degeneration.

Purpose: To study the power of an 80-second multifocal pupillographic objective perimetry (mfPOP) test tailored to the ETDRS grid to diagnose age-related macular degeneration (AMD) by Age-Related Eye Disease Study (AREDS) severity grade. Design: Evaluation of a diagnostic technology. Methods: We compared diagnostic power of acuity, ETDRS grid retinal thickness data, new 80-second M18 mfPOP test, and two wider-field 6-minute mfPOP tests (Macular-P131, Widefield-P129). The M18 stimuli match the size and shape of bifurcated ETDRS grid regions, allowing easy structure-function comparisons. M18, P129, and P131 stimuli test both eyes concurrently. We recruited 34 patients with early-stage AMD with a mean ± standard deviation (SD) age of 72.6 ± 7.06 years. The M18 and P129 plus P131 stimuli had 26 and 51 control participants, respectively with mean ± SD ages of 73.1 ± 8.17 years and 72.1 ± 5.83 years, respectively. Multifocal pupillographic objective perimetry testing used the Food and Drug Administration-cleared Objective FIELD Analyzer (OFA; Konan Medical USA). Main Outcome Measures: Percentage area under the receiver operator characteristic curve (AUC) and Hedge's g effect size. Results: Acuity and OCT ETDRS grid thickness and volume produced reasonable diagnostic power (percentage AUC) for AREDS grade 4 eyes at 83.9 ± 9.98% and 90.2 ± 6.32% (mean ± standard error), respectively, but not for eyes with less severe disease. By contrast, M18 stimuli produced percentage AUCs from 72.8 ± 6.65% (AREDS grade 2) to 92.9 ± 3.93% (AREDS grade 4), and 82.9 ± 3.71% for all eyes. Hedge's g effect sizes ranged from 0.84 to 2.32 (large to huge). Percentage AUC for P131 stimuli performed similarly and for P129 performed somewhat less well. Conclusions: The rapid and objective M18 test provided diagnostic power comparable with that of wider-field 6-minute mfPOP tests. Unlike acuity or OCT ETDRS grid data, OFA tests produced reasonable diagnostic power in AREDS grade 1 to 3 eyes.

Multifocal pupillographic assessment of age-related macular degeneration.

PURPOSE: To investigate retinal function in subjects with unilateral exudative age-related macular degeneration (AMD) using multifocal pupillographic objective perimetry (mfPOP) and to assess the diagnostic accuracy of this technique. METHODS: We tested each of 20 exudative AMD patients and 20 control subjects with 4 different mfPOP stimulus variants. Multifocal stimuli consisting of 24 or 44 independent stimulus regions per eye extending from fixation to 15° eccentricity were presented dichoptically. The aperiodic stimuli were presented at 1 or 4 s mean intervals. Video cameras recorded pupil responses under infrared illumination. Test duration consisted of 8 segments of 30 s. Stimuli were presented at a luminance of 250 cd/m and a background of 10 cd/m. Peak regional contraction amplitudes, time to peaks, and a linear combination of these were used to produce receiver operator characteristic (ROC) curves to measure the diagnostic accuracy of this method. RESULTS: Mean constriction amplitudes of exudative AMD subjects were decreased by 0.77 ± 0.15 dB (p < 5 × 10). Stimulus ensembles with 44 regions and faster presentation rates produced the largest effect on response sizes (t = 3.63; p < 0.0002). When comparing the control eyes to exudative AMD eyes, the area under the curve of ROC plots was 0.96 ± 0.03 (mean ± SE). This was achieved for asymmetry analysis of the difference in response amplitudes obtained from the two eyes at each point in the visual field. CONCLUSIONS: The mean effect of exudative AMD on contraction amplitudes reflected the severity of disease, and ROC analysis from amplitude deviations improved the sensitivity of detection of exudative AMD. A longitudinal investigation into the mfPOP responses of patients with non-exudative AMD may detect and classify visual fields with poor prognosis.