The structure-function relationship between multifocal pupil perimetry and retinal nerve fibre layer in glaucoma.

BACKGROUND: Multifocal pupillographic objective perimetry (mfPOP) is a novel method for assessing functional change in diseases like glaucoma. Previous research has suggested that, in contrast to the pretectally-mediated melanopsin response of intrinsically photosensitive retinal ganglion cells, mfPOP responses to transient onset stimuli involve the extrastriate cortex, and thus the main visual pathway. We therefore investigate the correlation between peripapillary retinal nerve fibre layer (pRNFL) thickness and glaucomatous visual field changes detected using mfPOP. Parallel analyses are undertaken using white on white standard automated perimetry (SAP) for comparison. METHODS: Twenty-five glaucoma patients and 24 normal subjects were tested using SAP, 3 mfPOP variants, and optical coherence tomography (OCT). Arcuate clusters of the SAP and mfPOP deviations were weighted according to their contribution to published arcuate divisions of the retinal nerve fibre layer. Structure-function correlation coefficients (r) were computed between pRNFL clock-hour sector thickness measurements, and the local visual field sensitivities from both SAP and mfPOP. RESULTS: The strongest correlation was observed in the superior-superotemporal disc sector in patients with worst eye SAP MD < -12 dB: r = 0.93 for the mfPOP LumBal test (p < 0.001). Correlations across all disc-sectors were strongest in these same patients in both SAP and mfPOP: SAP r = 0.54, mfPOP LumBal r = 0.55 (p < 0.001). In patients with SAP MD ≥ -6 dB in both eyes, SAP correlations across all sectors were higher than mfPOP; mfPOP correlations however, were higher than SAP in more advanced disease, and in normal subjects. CONCLUSIONS: For both methods the largest correlations with pRNFL thickness corresponded to the inferior nasal field of more severely damaged eyes. Head-to-head comparison of mfPOP and SAP showed similar structure-function relationships. This agrees with our recent reports that mfPOP primarily stimulates the cortical drive to the pupils.

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.

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.

Rapid, non-contact multifocal visual assessment in multiple sclerosis.

OBJECTIVE: Previous work on temporally sparse multifocal methods suggests that the results are correlated with disability and progression in people with multiple sclerosis (PwMS). Here, we assess the diagnostic power of three cortically mediated sparse multifocal pupillographic objective perimetry (mfPOP) methods that quantified response-delay and light-sensitivity at up to 44 regions of both visual fields concurrently. METHODS: One high-spatial-resolution mfPOP method, P129, and two rapid medium-resolution methods, W12 and W20, were tested on 44 PwMS and controls. W12 and W20 took 82 s to test both visual fields concurrently, providing response delay and sensitivity at each field location, while P129 took 7 min. Diagnostic power was assessed using areas under the receiver operating characteristic (AUROC) curves and effect-size (Hedges' g). Linear models examined significance. Concurrent testing of both eyes permitted assessment of between-eye asymmetries. RESULTS: Per-region response delays and asymmetries achieved AUROCs of 86.6% ± 4.72% (mean ± SE) in relapsing-remitting MS, and 96.5% ± 2.30% in progressive MS. Performance increased with increasing disability scores, with even moderate EDSS 2 to 4.5 PwMS producing AUROCs of 82.1 to 89.8%, Hedge's g values up to 2.06, and p = 4.0e - 13. All tests performed well regardless of any history of optic neuritis. W12 and W20 performed as well or better than P129. CONCLUSION: Overall, the 82-s tests (W12 and W20) performed better than P129. The results suggest that mfPOP assesses a correlate of disease severity rather than a history of inflammation, and that it may be useful in the clinical management of PwMS.

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.

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.

Objective perimetry and progression of multiple sclerosis.

Introduction: We re-examined the per-region response amplitudes and delays obtained from multifocal pupillographic objective perimetry (mfPOP) after 10 years in 44 persons living with multiple sclerosis (PwMS), both to examine which parts of the visual field had progressed in terms of response properties and to examine if the baseline data could predict the overall progression of disease. Methods: Expanded Disability Status Scale (EDSS) scores were assessed in 2009 and 2019. Both eyes of each participant were concurrently tested at 44 locations/eye on both occasions. Several measures of clinical progression were examined, using logistic regression to determine the odds of progression. Results: At the second examination the 44 PwMS (31 females) were aged 61.0 ± 12.2 y. Mean EDSS had not changed significantly (3.69 ± 1.23 in 2009, 3.81 ± 2.00 in 2019). mfPOP delay increased progressively from inferior to superior regions of the visual fields while amplitudes demonstrated a temporal to nasal gradient. The mean of the 3 most delayed visual field regions was correlated with progression of MS by 2019 (p = 0.023). Logistic regression indicated a significant association between delay and odds of progression (p = 0.045): an individual with 3 regions at least 1 SD (40 ms) slower than the mean in 2009 had 2.05× (±SE: 1.43× to 2.95×) the odds of progression by 2019. A 1 SD shorter delay was associated with 2.05× lower odds of progression. Amplitude changes were not predictive of progression. Significance: mfPOP may provide a rapid, convenient method of monitoring and predicting MS progression.

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.

Response characteristics of objective perimetry in persons living with epilepsy.

PURPOSE: To investigate safety and visual-field changes in people with epilepsy undergoing multifocal Pupillographic Objective Perimetry (mfPOP). METHODS: 15 people with epilepsy and 15 controls underwent mfPOP in the context of routine clinical EEG testing. Safety measures comprised the proportion of participants developing an aura or seizure, a photoparoxysmal response, or increased epileptiform activity on their EEG during mfPOP. Pupil responses were obtained concurrently from 44 regions/field of each eye. Changes in standardised amplitude of constriction and time-to-peak were compared between people with generalised and focal epilepsy, and controls. RESULTS: No participant developed an epileptic aura or clinical seizure during (or after) testing. One participant demonstrated EEG evidence of a focal subclinical seizure which began before mfPOP testing and continued unchanged during testing. Regional field sensitivities were increased in people with generalised epilepsy (+3.80 ± 1.43 dB compared to controls) but were reduced in individuals taking antiepileptic medication (-4.04 ± 1.74 dB). An extra delay of 24.9 ± 10.2 ms was seen in the time-to-peak of the responses in people with focal epilepsy. Based on receiver-operating characteristic analyses, discrimination of people with epilepsy from controls was greatest when using the 4 to 10 most abnormal visual field regions of each eye (%AUC 77.3 ± 9.70). SIGNIFICANCE: In the absence of any safety signal, mfPOP appears harmless in people with epilepsy. The observed abnormalities in per-region sensitives and delays suggest that mfPOP may provide significant new insights into the study of epilepsy.

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.

An Objective Perimetry Study of Central Versus Peripheral Sensitivities and Delays in Age-Related Macular Degeneration.

Purpose: The purpose of this study was to compare central versus peripheral retinal sensitivities and delays in neovascular age-related macular degeneration (nAMD) using US Food and Drug Administration (FDA)-cleared multifocal pupillographic objective perimetry (mfPOP). Methods: We recruited 18 patients with nAMD and commenced Pro re nata intravitreal anti- vascular endothelial growth factor (VEGF) injection. We compared macular (±15 degrees) and wide-field (±30 degrees) mfPOP variants. We examined temporal correlations between treated and untreated fellow eyes. We fitted linear models to selected treatment patterns, and compared the ability of central versus peripheral responses to predict the need for treatment. Results: Central sensitivity decreased by -2.23 ± 0.051 dB/month (P < 0.0002) in treated eyes, and -0.17 ± 0.07 dB/month (P = 0.033) in untreated eyes. Treated eyes showed quicker central responses by 13.08 ± 3.77 ms than untreated eyes (P = 0.001). Based on peripheral responses, we identified two eye-types. Among positive-eyes peripheral sensitivity increased by 9.88 ± 4.41 dB (P = 0.042) before treatment; delays increased by 3.49 ± 1.75 ms/month (P = 0.049). For negative-eyes peripheral delays were shorter a month before treatment by 9.38 ± 3.59 ms (P = 0.013). Correlations between treatment and peripheral sensitivities or delays peaked at 1 to 2 months post-treatment. Peripheral data significantly determined treatment frequency and final acuity (all P < 0.044). Conclusions: Peripheral macular function of treated and untreated eyes divided eyes into positive and negative groups. Those peripheral responses determined outcomes; changes preceding active disease by 1 to 3 months. Overall, mfPOP may provide potential biomarkers to assist nAMD management. Translational Relevance: Objective perimetry may identify the requirement for treatment in nAMD that accords with the decision of a skilled clinician based on optical coherence tomography (OCT) and clinical findings.

Comparing Objective Perimetry, Matrix Perimetry, and Regional Retinal Thickness in Mild Diabetic Macular Edema.

Purpose: To compare per-region macular sensitivity and delay from objective perimetry with Matrix perimetry and retinal thickness in mild diabetic macular edema (DMO). Methods: Thirty-three patients with type 2 diabetes (T2D) aged 59.2 ± 10.5 years participated in a longitudinal study. Macular thickness, sensitivities and delays from the objectiveFIELD Analyzer (OFA), and Matrix perimeter sensitivities were mapped onto a common spatial layout to compute per-region correlations between structure/function measures. A generalized linear mixed-effects logistic regression model determined which variables contributed to clinical diagnosis of DMO. Results: For OFA, the mean sensitivity differences compared with normal in patients with T2D were negative and the mean delay differences positive, indicating lowered sensitivities and prolonged delays, both increasing with diabetes duration. Shorter diabetes duration could produce either localized peripheral hypersensitivities or shorter delays. Functional change could occur when retinal thickness was stable. Peripheral macular thickness correlated with central and peripheral OFA sensitivity and delay, all P < 0.0012 in DMO and a median of P = 0.001 without DMO; this was not true for Matrix sensitivities. The logistic model determined that peripheral thickness, OFA sensitivity (P = 0.043), and time in the study (P = 0.001) contribute independently to the odds of DMO versus no DMO. Conclusions: Mean sensitivities decreased and mean delays increased with duration of diabetes. Peripheral macular thickness correlated significantly with central and peripheral macular OFA sensitivity and delay. Peripheral macular thickness and functional measures may provide sensitive prognostic data. Translational Relevance: Functional loss can precede structural change in DMO, so including such functional assessment for deciding on treatment may be beneficial.

Assessing migraine patients with multifocal pupillographic objective perimetry.

BACKGROUND: To establish the effects of stimulating intrinsically-photosensitive retinal ganglion cells (ipRGCs) on migraine severity, and to determine if migraine produces objectively-measured visual field defects. METHODS: A randomized, open labelled, crossover study tested migraineurs and normal controls using multifocal pupillographic objective perimetry (mfPOP) with 44 test-regions/eye. A slow blue protocol (BP) stimulated ipRGCs, and a fast yellow protocol (YP) stimulated luminance channels. Migraine diaries assessed migraine severity. Per-region responses were analyzed according to response amplitude and time-to-peak. RESULTS: Thirty-eight migraineurs (42.0 ± 16.5 years, 23 females) and 24 normal controls (39.2 ± 15.2 years, 14 females) were tested. The proportion of subjects developing a migraine did not differ after either protocol, either during the 1st day (odds ratio 1.0; 95% confidence interval 0.2-4.4, p = 0.48) or during the first 3 days after testing (odds ratio 0.8; 95% confidence interval 0.3-2.1, p = 0.68). Migraine days/week did not increase following testing with either protocol in comparison to the baseline week (1.4 ± 1.6 pre-testing (mean ± SD), 1.3 ± 1.4 post-BP, and 1.3 ± 1.2 post-YP; p = 0.96), neither did other measures of severity. Migraine occurring up to 2 weeks before testing significantly lowered amplitudes, - 0.64 ± 0.14 dB (mean ± SE), while triptan use increased amplitudes by 0.45 ± 0.10 dB, both at p < 0.001. CONCLUSIONS: Stimulating ipRGCs did not affect migraine occurrence or severity. Pupillary response characteristics were influenced by the occurrence of a recent migraine attack and a history of triptan use.

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.

Comparing multifocal pupillographic objective perimetry (mfPOP) and multifocal visual evoked potentials (mfVEP) in retinal diseases.

Multifocal pupillographic objective perimetry (mfPOP) shows regions of slight hypersensitivity away from retinal regions damaged by diabetes or age-related macular degeneration (AMD). This study examines if such results also appear in multifocal visual evoked potentials (mfVEPs) recorded on the same day in the same patients. The pupil control system receives input from the extra-striate cortex, so we also examined evidence for such input. We recruited subjects with early type 2 diabetes (T2D) with no retinopathy, and patients with unilateral exudative AMD. Population average responses of the diabetes patients, and the normal fellow eyes of AMD patients, showed multiple regions of significant hypersensitivity (p < 0.05) on both mfPOP and mfVEPs. For mfVEPs the occipital electrodes showed fewer hypersensitive regions than the surrounding electrodes. More advanced AMD showed regions of suppression becoming centrally concentrated in the exudative AMD areas. Thus, mfVEP electrodes biased towards extra-striate cortical responses (surround electrodes) appeared to show similar hypersensitive visual field locations to mfPOP in early stage diabetic and AMD damage. Our findings suggest that hypersensitive regions may be a potential biomarker for future development of AMD or non-proliferative diabetic retinopathy, and may be more informative than visual acuity which remains largely undisturbed during early disease.

Blue Multifocal Pupillographic Objective Perimetry in Glaucoma.

PURPOSE: This study investigated multifocal pupillographic objective perimetry (mfPOP) stimuli that target the intrinsic photosensitivity of melanopsin retinal ganglion cells. The diagnostic potential for glaucoma is compared between stimuli biased toward either cone input to these cells or their melanopsin response. METHODS: Nineteen glaucoma patients and 24 normal subjects were tested using mfPOP stimulus protocols with either 33-ms yellow or 750-ms blue stimuli. Subjects' color discrimination was assessed using the Farnsworth 100-hue test. Pupillary responses were measured, and mixed-effects regression was used to quantify results. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) analysis. RESULTS: The mean reduction in moderate to severe glaucoma pupil responses using blue mfPOP stimuli was larger but more variable than that of the shorter yellow stimuli (blue: -1.32 dB [t(40) = -2.29; P = 0.027]; yellow: -0.93 dB [t(40) = -3.13; P = 0.003]). Color discrimination decreased significantly with age and glaucoma, with type III blue-yellow anomalies dominating. ROC analysis revealed similar diagnostic accuracies (AUC for eyes classified as moderate to severe; blue: 81.7%, yellow: 83.7). Slightly higher sensitivity and specificity were obtained using blue stimuli in mild disease (AUCs blue: 71.1, cf. yellow: 67.7), although this difference was not significant. CONCLUSIONS: In moderate to severe glaucoma, diagnostic accuracy of yellow and blue was similar, but blue stimuli showed limited ability to resolve scotomas. Blue mfPOP stimuli, however, may have advantages over yellow in detecting early glaucoma.

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.

Luminance and colour variant pupil perimetry in glaucoma.

BACKGROUND: This study investigated the diagnostic utility for glaucoma of multifocal pupillographic objective perimetry stimuli targeting different components of the pupillary response: cortically derived colour responses and subcortical luminance responses. DESIGN: Observational cross-sectional study undertaken at the Australian National University. PARTICIPANTS: Thirty-five eyes of 24 glaucoma subjects and 46 eyes of 23 normal subjects. METHODS: Subjects were tested with three multifocal pupillographic objective perimetry stimulus variants. The luminance-only variant (YYbal) utilized yellow stimuli on a yellow background; mixed colour and luminance protocols utilized green stimuli on a red background (RGbal, RG). Stimuli of 33 ms duration were presented at mean intervals of 4 s/region. MAIN OUTCOME MEASURES: Pupil constriction amplitude and time to peak. Area under the receiver operating characteristic curve was the main measure of sensitivity and specificity for glaucoma. RESULTS: Colour and luminance protocols were more accurate at differentiating glaucoma subjects from normal subjects than the luminance-only protocol, and produced the largest reductions in amplitudes. This type of protocol also produced the highest overall sensitivity and specificity for glaucoma (receiver operating characteristic % area under the curve: severe, 100%; moderate, 94.4%; mild, 71.0%). Pattern deviations tended to produce higher area under the receiver operating characteristic curves in eyes classified as mild. Significant differences in the means of the six worst amplitude deviations were observed between normal and severe glaucoma subjects only. CONCLUSIONS: Stimuli targeting both cortical pupillary colour response and subcortical pupillary luminance response components produced higher diagnostic accuracy than stimuli targeting subcortical pupillary luminance responses alone. Inclusion of constriction latencies further improved accuracy.

High- versus low-density multifocal pupillographic objective perimetry in glaucoma.

BACKGROUND: Multifocal pupillographic objective perimetry was compared using 24 and 44 regions per visual field. DESIGN: Experimental design in a university setting. PARTICIPANTS: Twenty-seven normal control and 36 age-matched glaucoma patients. METHODS: The four test variants differed in the mean interval between stimuli: 4, 1 or 0.25 s; and the number of visual field regions tested within the central 60 degrees: 24 or 44. All subjects had their diagnostic status confirmed by optical coherence tomography, two forms of perimetry and slit-lamp biomicroscopy. Both eyes were measured concurrently in 2.73 ± 0.45 min/eye (mean ± standard deviation), and tests were repeated about 2 weeks apart. MAIN OUTCOME MEASURES: The main outcome measures were: (i) mean change in light sensitivity due glaucoma; and (ii) areas under Receiver Operator Characteristic plots for detecting glaucoma. RESULTS: For all four variants, consensual responses, female gender and age produced small but significant sensitivity differences, and sensitivity declined with age by ≤-0.27 dB/decade (all P < 0.0003). The best diagnostic accuracy (area under curve 93.2 ± 3.89%) was produced by the one-presentation/s 44-region protocol. Across the four protocols, the effect of repeat testing was small (all methods ≤0.15 dB). CONCLUSIONS: Presentation rate had little effect, but increasing the tested density from 24 to 44 regions/field improved diagnostic power. Given that multifocal pupillographic objective perimetry also provides information on response delay and afferent versus efferent defects at every visual field region, it may be a useful adjunct to perimetry.