Comparison of Full-Field Stimulus Threshold Measurements in Patients With Retinitis Pigmentosa and Healthy Subjects With Dilated and Nondilated Pupil.

Purpose: The common protocol of full-field stimulus threshold (FST) testing recommends pupil dilation. The aim of this study is to investigate the difference between FST measurements with dilated and nondilated pupils in healthy subjects and patients with retinitis pigmentosa (RP). Methods: Twenty healthy subjects and 20 RP patients were selected. One pupil of each subject was dilated; the other eye was measured in physiological width of the pupil. The FST was conducted using Diagnosys Espion E2/E3 with white, blue, and red stimuli. Statistical analysis was conducted with a mixed-model analysis of variance and a paired t-test. Results: The statistical analysis revealed a significant difference between measurements of dilated and nondilated pupils with the following: blue stimuli for all subjects and groups except those with highly progressed RP; white stimuli for all tested subjects in total, for RP patients with better-preserved visual field (VF), and rod-mediated FST response; and red stimuli for RP patients with better-preserved VF and rod-mediated FST response. On average, the difference between the FST values for RP patients were -3.2 ± 3 dB for blue, -2.3 ± 2.9 dB for white, and -0.83 ± 3 dB for red stimuli. The correlation between the FST values of dilated and nondilated pupils with all three stimuli was linear. Conclusions: Current recommendations are to perform FST with dilated pupils. However, based on this study's findings, pupil dilation can be omitted for clinical diagnostics or rough follow-ups. Translational Relevance: Our data provide useful information for the clinical use of FST.

Chorioretinal Atrophy Growth After Voretigene Neparvovec Retinotopically Is Connected to Retinal Functional Rescue.

Purpose: Chorioretinal atrophy growth after voretigene neparvovec has been reported recently with its positive correlation with successful treatment. This finding raised the question on long-term effects and the etiology of the chorioretinal atrophy. Methods: Using local retinal functional diagnostics, we tested whether the atrophy growth is connected to the initial local functional improvement after the therapy. Results: The results describe factors predicting the development of atrophy. First, the atrophy emerges after approximately 3 months in an area with local functional rescue before. The areas of the greatest gain in the number of functionally rescued rods are prone to be the initial spots of atrophy growth in almost one-half of the cases and the retinotopy corresponds with the area of a high number of post-treatment functioning rods. Second, the dark-adapted perimetry shows that the atrophy growth is in the area with functioning rescued rods. However, the rods with the greatest sensitivity gain are not the parts of the growing atrophy in the first 2 years after intervention. This preservation of rods with the greatest sensitivity seems to explain the excellent profile of rods rescue over the long term measured by full-field stimulus threshold and reported earlier. Conclusions: A disbalance between the increase of functional rods and their threshold shortly after treatment could be an indicator for a metabolic origin of chorioretinal atrophy after voretigene neparvovec. Translational Relevance: A basic understanding of the photoreceptor rescue aspects after gene therapy can demonstrate a metabolic causal influence of the efficacy on the development of side effects, such as chorioretinal atrophy.

Multi-luminance mobility testing after gene therapy in the context of retinal functional diagnostics.

BACKGROUND: Voretigene neparvovec (Luxturna®) is the first approved gene therapy for RPE65-linked Leber congenital amaurosis (LCA). Though individual effects are highly variable, most recipients report improved vision in everyday life. To describe such effects, visual navigation tests are now frequently used in clinical trials. However, it is still unclear how their results should be interpreted compared to conventional parameters of visual function. METHODS: Seven LCA patients underwent a multi-luminance visual navigation test (Ora-VNCTM) before and 3 months after receiving Luxturna gene therapy. Their performance was rated based on the luminance level at which they passed the course. Differences between the first and second test were correlated to changes in visual acuity, full-field stimulus thresholds, chromatic pupil campimetry, and dark-adapted perimetry. RESULTS: A few patients displayed notable improvements in conventional measures of visual function whereas patients with advanced retinal degeneration showed no relevant changes. Independent of these results, almost all participants improved in the visual navigation task by one or more levels. The improvement in the mobility test was best correlated to the change in full-field stimulus thresholds. Other measures of visual functions showed no clear correlation with visual navigation. DISCUSSION: In patients who passed the test's more difficult levels, improved visual navigation can be attributed to the reactivation of rods. However, the performance of patients with low vision seemed to depend much more on confounding factors in the easier levels. In sum, such tests might only be meaningful for patients with better preserved visual functions.

A morphometric analysis of the retinal arterioles with adaptive optics imaging in RPE65-associated retinal dystrophy after treatment with voretigene neparvovec.

PURPOSE: To investigate the changes in retinal arterial architecture after treatment with voretigene neparvovec in patients with retinal dystrophy caused by bi-allelic mutations in the RPE65 gene. METHODS: Sixteen eyes treated with voretigene neparvovec at the University Eye Clinic in Tuebingen, Germany, underwent adaptive optics ophthalmoscopy (AO) imaging at baseline and 2 weeks, 1, 3, 6 and 12 months after treatment. Follow-up was performed in six eyes of four patients. For each eye, five different positions at arterial vessels were selected and the wall-to-lumen ratio (WLR), the lumen diameter (LD) and the wall cross-sectional area (WCSA) were measured by the manufacturer's software over the observational period. RESULTS: Vast retinal atrophy dominated all gained AO images. WLR fluctuated in the observation period without statistically significant change. LD and WCSA changed significantly after 2 weeks from the baseline examination and returned to values similar to baseline thereafter. There were no signs of inflammation such as macrophages or perivascular accumulated fluid visible. CONCLUSION: AO imaging of the retinal vessels in RPE65-associated retinal dystrophies (IRD) is challenging. There was no change in the retinal arterial vasculature over the observation period of 12 months that would indicate inflammatory changes. Decrease of the LD and WCSA shortly after treatment might be caused by the perioperative prednisolone intake. AO of retinal vessels can be used as a diagnostic module to complement monitoring the disease and effects of genetic treatments if the acquisition is possible in selected cases.

Rod and Cone Function Measured Objectively by Chromatic Pupil Campimetry Show a Different Preservation Between Distinct Genotypes in Retinitis Pigmentosa.

Purpose: Verifying whether specific genotypes causing retinitis pigmentosa (RP) show differences in the preservation of rod and cone function measured by chromatic pupil campimetry (CPC). Methods: Sixty-three RP eyes (37 male, 14-58 years) were measured using CPC with specific photopic and scotopic protocols, and the relative maximal constriction amplitudes and latencies to constriction onset were analyzed per genotype (RP due to variants in EYS, n = 14; PDE6A, n = 10; RPE65, n = 15; USH2A, n = 10; and RPGR, n = 14). Correlation analyses between the pupillary responses were performed with age, full-field stimulus threshold (FST), and optical coherence tomography (OCT) for cones and rods, respectively, to the genotype. Results: Pupillary responses were most severely reduced in RPE65-RP. Patients with disease-associated variants in EYS and USH2A were accompanied with better-preserved rod function compared with the other subgroups, reaching statistical significance between EYS and RPE65. Cone function was statistically significantly correlated with age in USH2A-RP with an annual decline of 2.4%. Correlations of pupillary responses were found with FST but barely with the ellipsoid zone area in OCT. Latency was significantly more prolonged in RPE65-RP compared with the other genotypes for cones. Conclusions: Rod and cone function measured objectively by CPC showed a different preservation between genotypes in RP. However, heterogeneity inside the same genotype was present. CPC data correlated with FST, but structural OCT parameters seem to be limited indicators for photoreceptor function in RP. Prolonged time dynamics for cones in RPE65 mutations suggest an impact on cone processing and might provide additional information in the evaluation of therapy effects.

Photoreceptor-Specific Temporal Contrast Sensitivities in RP1L1-Associated Occult Macular Dystrophy.

Purpose: The purpose of this study was to compare L-, M-, S-cone-, and rod-driven temporal contrast sensitivities (tCS) in patients with RP1L1-associated autosomal-dominant occult macular dystrophy (OMD), and to investigate how photoreceptor degeneration determines which post-receptoral channels dominate perception. Methods: Photoreceptor isolating stimuli were created with the silent substitution technique. Photoreceptor-selective tCS deviations (D L-cone/M-cone/S-cone/Rod) were obtained as a function of temporal frequency with identical retinal adaptation, by subtracting tCS from age-corrected normal values. A linear-mixed effects model was used for analysis. Results: Eleven genetically confirmed patients were included (7 women, 5 men; age = 52.27 ± 14.44 years). Overall, L- and M-cone-driven sensitivity deviations (DL-cone and DM-cone) were more negative than DS-cone; DRod was normal at frequencies between 8 and 12 Hz in all subjects. Rod-driven tCS functions allowed identification of two subgroups of patients: one with band-pass properties and one with low-pass properties, suggesting dominance of different post-receptoral filters. The same filtering properties were observed in L-cone-driven tCS functions. Furthermore, the two subgroups also differed in clinical parameters (spherical equivalent, BCVA, perimetry, and ocular coherence tomography (OCT) reflectivity of the ellipsoid zone relative to the RPE). Conclusions: OMD was characterized predominantly by deterioration of L- and M-cone-cone driven function in the perifovea. Rod-driven functions were normal. Differences in the photoreceptor signals were further modified by postreceptoral filters.

Full-field Scotopic Threshold Improvement after Voretigene Neparvovec-rzyl Treatment Correlates with Chorioretinal Atrophy.

PURPOSE: To analyze demographic and ophthalmic data in patients with and without chorioretinal atrophy after voretigene neparvovec-rzyl (VN) to identify possible causes for this phenomenon. DESIGN: Retrospective cohort study with longitudinal follow-up. PARTICIPANTS: A total of 71 eyes of 38 patients aged 2 to 44 years with RPE65-mediated retinal dystrophy treated with VN across 2 large gene therapy centers in the United States and Germany. METHODS: Patients treated with VN who developed atrophy were compared with those who did not. MAIN OUTCOME MEASURES: Gender, age, surgical center, spherical equivalent refraction, best-corrected visual acuity (BCVA), baseline full-field scotopic threshold testing (FST), and posttreatment change in FST. RESULTS: A total of 20 eyes of 12 patients developed atrophy after treatment with VN (28% of all eyes). There was no significant difference in gender, age, surgical center, or spherical equivalent refraction between the atrophy group and the no atrophy group. However, patients between school age and young adulthood were predominantly affected, whereas the youngest and the oldest patients did not develop atrophy. Baseline BCVA was better in patients who developed atrophy than those who did not (P = 0.006). The postoperative improvement in FST at 1 month was significantly higher in the atrophy group than in the no atrophy group (P = 0.0005), and this difference remained statistically significant at 1 year (P = 0.0001). There was no correlation to baseline FST, to inflammation, or to which eye was treated first. CONCLUSIONS: The degree of FST improvement after VN appears to be strongly correlated with the development of VN-related chorioretinal atrophy. This finding raises the possibility that atrophy may develop as a toxic or metabolic sequela of vector-mediated RPE65 expression. In light of the expanding number of retinal gene therapy clinical trials, this complication warrants further study because it may not be limited to VN. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Central retina plays a decisive role in the suppression of pupillary escape.

PURPOSE: To explore the pupil redilation during persistent light exposure (pupillary escape phenomenon) at the macula and periphery with monochromatic light stimuli. METHODS: Forty healthy subjects aged 18-64 years (24 females) were examined by chromatic pupil campimetry (CPC) using red and blue 4-s stimuli of 10° radius at the center and 20°-peripheral locations one per quadrant. One glaucoma patient and one achromatopsia patient served as disease models. For statistical analyses, linear mixed-effects models were performed followed by post hoc t-tests. RESULTS: A distinct pupillary escape could be demonstrated peripherally (blue 0.099%*s, red 0.153%*s); at the central healthy retina, there was no relevant escape, neither for blue nor red stimulation. Comparing central versus peripheral stimulation revealed highly significant differences in the escape (difference blue 0.100 ± 0.013, red 0.144 ± 0.013, < 0.0001, respectively). In the periphery, the escape was significantly more pronounced for red compared with blue stimulation (difference 0.054 ± 0.013; p = 0.0001). Enhanced pupillary escape outside of the 95% confidence interval of the linear mixed-effects model of the healthy population could be exemplarily shown in a patient with glaucomatous ganglion cell damage. In the achromatopsia example, no relevant escape was found for blue stimulation, but for red stimulation in the periphery in a comparable range to healthy controls. CONCLUSION: The results emphasize that an intact inner retinal network of nerve fibers arising from the central macular region is necessary for maintaining pupillary constriction during a bright 4-s light stimulus and preventing increase of pupillary escape. Increasing receptive field sizes towards the periphery on the level of retinal ganglion cells and less input from central 1:1 connections could be one of the driving mechanisms for pupillary escape.

Therapy with voretigene neparvovec. How to measure success?

Retinal gene supplementation therapy such as the first approved one, voretigene neparvovec, delivers a functioning copy of the missing gene enabling the protein transcription in retinal cells and restore visual functions. After gene supplementation for the genetic defect, a complex network of functional regeneration is the consequence, whereas the extent is very individualized. Diagnostic and functional testings that have been used routinely by ophthalmologists so far to define the correct diagnosis, cannot be applied in the new context of defining small, sometimes subtle changes in visual functions. New view on retinal diagnostics is needed to understand this processes that define safety and efficacy of the treatment. Not only does vision have many aspects that must be addressed by specific evaluations and imaging techniques, but objective readouts of local retinal function for rods and cones separately have been an unmet need until recently. A reliable test-retest variability is necessary in rare diseases such as inherited retinal dystrophies, because statistics are often not applicable due to a low number of participants. Methods for a reliable individual evaluation of the therapy success are needed. In this manuscript we present an elaboration on retinal diagnostics combining psychophysics (eg. full-field stimulus threshold or dark adapted perimetry) as well as objective measures for local retinal function (eg. photopic and scotopic chromatic pupil campimetry) and retinal imaging for a meaningful workflow to apply in evaluation of the individual success in patients receiving gene therapy for photoreceptor diseases.

Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec.

BACKGROUND/AIMS: Voretigene neparvovec (VN) is the first and only subretinal gene therapy approved by the Food and Drug Administration and European Medicines Agency. Real-world application has started in 2018 in patients with vision impairment due to biallelic retinal pigment epithelium (RPE) 65 mutation-associated inherited retinal degenerations. Herein, we evaluated the development of retinal atrophy within in a single-centre patient cohort treated with VN. METHODS: 13 eyes of eight patients treated with VN were retrospectively analysed for areas of retinal atrophy over a period of 6-24 months following surgery. Ultrawide field images were used to measure the area of atrophy. Fundus autofluorescence imaging is presented as an instrument for early detection of signs of retinal atrophy in these patients. RESULTS: Atrophic changes beyond the retinotomy site were observed in all eyes. Areas of atrophy developed within the area of detachment (bleb) in all eight patients and outside the bleb in three patients. Changes in autofluorescence preceded the development of retinal atrophy and were already evident 2 weeks after surgery in the majority of patients. The areas of atrophy increase with time and progression continued over year 1. Functional outcomes remained stable (VA, FST, visual field). CONCLUSION: Subretinal injection of VN can lead to RPE atrophy with consequent photoreceptor loss in and outside of the bleb area. Fundus autofluorescence is an important tool to monitor atrophic changes in patients after gene therapy. Interestingly, while areas of atrophy also included central areas, the functional benefits of the treatment did not appear to be affected and remained stable.

Frequency-dependent retinal responsiveness to sinusoidal electrical stimulation in achromatopsia.

Recently, we proposed a method to assess cell-specific retinal functions based on the frequency-dependent responses to sinusoidal transcorneal electrostimulation. In this study, we evaluated the alterations in responsiveness in achromatopsia patients to explore the frequency-selectivity of photoreceptors. The electrical stimulation was applied to one eye of genetically confirmed achromatopsia patients via corneal electrodes. The stimulus was composed of amplitude-modulated sine waves with variable carrier frequencies (4-30 Hz) and a steady low-frequency envelope. The retinal responsiveness across the spectrum was calculated based on the velocity and the synchronicity of the electrically evoked pupillary oscillations. Achromats displayed a characteristic peak in responsiveness in the 6-10 Hz range. In contrast, stimulus frequencies above 16 Hz elicited only weak pupil responses and weak phosphenes. Compared to the tuning curve of the healthy retina, responses to low-frequency stimulation appear to reflect mainly rod activation while higher frequencies seem to activate cones. The possibility to examine cell-specific retinal functions independently from their responses to light may improve our understanding of the structural changes in the retina induced by gene therapy.

Cell-specific electrical stimulation of human retinal neurons assessed by pupillary response dynamics in vivo.

Studies on the electrical excitability of retinal neurons show that photoreceptors and other cell types can be selectively activated by distinct stimulation frequencies in vitro. Yet, this principle still needs to be validated in humans in vivo. As a first step, this study explored the frequency preferences of human rods by means of transcorneal electrostimulation (TES), using the electrically-elicited pupillary responses (EEPRs) as an objective readout. The stimulation paradigm contained a 1.2 Hz sinusoidal envelope, which was superimposed on variable carrier frequencies (4-30 Hz). These currents were delivered to one of the participant's eyes via a corneal electrode and consensual pupillary reactions were recorded from the contralateral eye. The responsiveness of the retina at each frequency was assessed based on the EEPR dynamics. Differences between healthy participants and patients with retinitis pigmentosa were evaluated to identify the preferred frequency range of rods. The responsiveness of healthy individuals revealed a clear peak around 6-8 Hz. In contrast, the pupillary responses of patients were significantly reduced in the lower frequency range. These findings suggest that the responses in this frequency bin were selectively mediated by rods. This work provides evidence that different retinal cell types can be selectively activated via TES in vivo, and that this effect can be captured noninvasively using EEPRs. This knowledge may be exploited for the diagnostics and therapy of retinal diseases, e.g., to design cell-specific functional tests for the degenerating retina, or to optimize stimulation paradigms which are currently used by retinal prostheses.

Evaluation of Local Rod and Cone Function in Stargardt Disease.

Purpose: In this study, chromatic pupil campimetry (CPC) was used to map local functional degenerative changes of cones and rods in Stargardt disease (STGD1). Methods: 19 patients (age 36 ± 8 years; 12 males) with genetically confirmed ABCA4 mutations and a clinical diagnosis of STGD1 and 12 age-matched controls (age 37 ± 11 years; 2 males) underwent scotopic (rod-favoring) and photopic (cone-favoring) CPC. CPC evaluates the local retinal function in the central 30° visual field via analysis of the pupil constriction to local stimuli in a gaze-corrected manner. Results: Scotopic CPC revealed that the rod function of patients with STGD1 inside the 30° visual field was not impaired when compared with age-matched controls. However, a statistically significant faster pupil response onset time (∼ 40 ms) was observed in the measured area. Photopic CPC showed a significant reduction of the central cone function up to 6°, with a minor, non-significant reduction beyond this eccentricity. The time dynamic of the pupillary response in photopic CPC did not reveal differences between STGD1 and controls. Conclusions: The functional analysis of the macular region in STGD1 disease indicates reduced central cone function, corresponding to photoreceptor degeneration. In contrast, the rod function in the central area was not affected. Nevertheless, some alteration of the time dynamics in the rod system was observed indicating a complex effect of cone degeneration on the functional performance of the rod system. Our results should be considered when interpreting safety and efficacy in interventional trials of STGD1.

Effect of central and peripheral cone- and rod-specific stimulation on the pupillary light reflex.

PURPOSE: To assess the effect of central and peripheral stimulation on the pupillary light reflex. The aim was to detect possible differences between cone- and rod-driven reactions. METHODS: Relative maximal pupil constriction amplitude (relMCA) and latency to constriction onset (latency) to cone- and rod-specific stimuli of 30 healthy participants (24 ± 5 years (standard deviation)) were measured using chromatic pupil campimetry. Cone- and rod-specific stimuli had different intensities and wavelengths according to the Standards in Pupillography. Five filled circles with radii of 3°, 5°, 10°, 20° and 40° and four rings with a constant outer radius of 40° and inner radii of 3°, 5°, 10° and 20° were used as stimuli. RESULTS: For cone-and rod-specific stimuli, relMCA increased with the stimulus area for both, circles and rings. However, increasing the area of a cone-specific ring by minimizing its inner radius with constant outer radius increased relMCA significantly stronger than the same did for a rod-specific ring. For cones and rods, a circle stimulus with a radius of 40° created a lower relMCA than the summation of the relMCAs to the corresponding ring and circle stimuli which combined create a 40° circle-stimulus. Latency was longer for rods than for cones. It decreased with increasing stimulus area for circle stimuli while it stayed nearly constant with increasing ring stimulus area for cone- and rod-specific stimuli. CONCLUSION: The effect of central stimulation on relMCA is more dominant for cone-specific stimuli than for rod-specific stimuli while latency dynamics are similar for both conditions.

How lesions at different locations along the visual pathway influence pupillary reactions to chromatic stimuli.

PURPOSE: To examine systematically how prechiasmal, chiasmal, and postchiasmal lesions along the visual pathway affect the respective pupillary responses to specific local monochromatic stimuli. METHODS: Chromatic pupil campimetry (CPC) was performed in three patient groups (10 subjects with status after anterior ischemic optic neuropathy, 6 with chiasmal lesions, and 12 with optic tract or occipital lobe lesions (tumor, ischemia)) using red, low-intensity red, and blue local stimuli within the central 30° visual field. Affected areas - as determined by visual field defects revealed using conventional static perimetry - were compared with non-affected areas. Outcome parameters were the relative maximal constriction amplitude (relMCA) and the latency to constriction onset of the pupillary responses. RESULTS: A statistically significant relMCA reduction was observed in the affected areas of postchiasmal lesions with red (p = 0.004) and low-intensity red stimulation (p = 0.001). RelMCA reduction in the affected areas seemed more pronounced for low-intensity red stimulation (46.5% mean reduction compared to non-affected areas; 36% for red stimulation), however statistically not significant. In prechiasmal lesions, a statistically significant latency prolongation could be demonstrated in the affected areas with low-intensity red stimulation (p = 0.015). CONCLUSION: Our results indicate that the choice of stimulus characteristics is relevant in detecting defects in the pupillary pathway of impairment along the visual pathway, favoring red stimuli of low intensity over blue stimuli. Such knowledge opens the door for further fundamental research in pupillary pathways and is important for future clinical application of pupillography in neuro-ophthalmologic patients.

Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec.

BACKGROUND: Voretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue. METHODS: Seven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations have been treated with voretigene neparvovec. The clinical examinations included visual acuity testing, dark-adapted full-field stimulus threshold (FST), dark-adapted chromatic perimeter (DAC) with a 30-degree grid, and a 30 degrees grid scotopic and photopic chromatic pupil campimetry (CPC). All evaluations and spectral domain optical coherence tomography were performed at baseline, 1 month and 3 months. RESULTS: All except the oldest patient had a measurable improvement of the rod function assessed via FST, DAC or scotopic CPC at 1 month. The visual acuity improved slightly or remained stable in all eyes. A cone function improvement as measured by photopic CPC was observed in three eyes. The gain of the dark-adapted threshold with blue FST and the DAC stimuli (cyan) average correlated strongly with age (R2>0.7). The pupil response improvement in the scotopic CPC correlated with the baseline local retinal volume (R2=0.5). CONCLUSIONS: The presented protocols allow evaluating the individual spatial and temporal effects of gene therapy effects. Additionally, we explored parameters that correlated with the success of the therapy. CPC and DAC present new and fast ways to assess functional changes in retinotopic maps of rod and cone function, measuring complementary aspects of retinal function.

Oscillatory Potentials in Achromatopsia as a Tool for Understanding Cone Retinal Functions.

Achromatopsia (ACHM) is an inherited autosomal recessive disease lacking cone photoreceptors functions. In this study, we characterize the time-frequency representation of the full-field electroretinogram (ffERG) component oscillatory potentials (OPs), to investigate the connections between photoreceptors and the inner retinal network using ACHM as a model. Time-frequency characterization of OPs was extracted from 52 controls and 41 achromat individuals. The stimulation via ffERG was delivered under dark-adaptation (DA, 3.0 and 10.0 cd·s·m-2) to assess mixed rod-cone responses. The ffERG signal was subsequently analyzed using a continuous complex Morlet transform. Time-frequency maps of both DA conditions show the characterization of OPs, disclosing in both groups two distinct time-frequency windows (~70-100 Hz and >100 Hz) within 50 ms. Our main result indicates a significant cluster (p < 0.05) in both conditions of reduced relative power (dB) in ACHM people compared to controls, mainly at the time-frequency window >100 Hz. These results suggest that the strongly reduced but not absent activity of OPs above 100 Hz is mostly driven by cones and only in small part by rods. Thus, the lack of cone modulation of OPs gives important insights into interactions between photoreceptors and the inner retinal network and can be used as a biomarker for monitoring cone connection to the inner retina.

Clinical Protocols for the Evaluation of Rod Function.

This work presents a quick clinical protocol for dark-adapted chromatic (DAC) perimetry as well as a novel clinical tool, scotopic chromatic pupil campimetry (CPC). The goal of the study was to explore the applicability of these methods in a clinical setting, their test-retest repeatability, and the congruence of the results. Local rod sensitivity was assessed at 36 locations within 30° eccentricity of the visual field in 15 healthy subjects (mean age 43 ± 16 years; 7 females and 8 males) with DAC perimetry (red and cyan stimuli) and CPC 2 times in repeated measurements. The duration of individual measurements was 370 ± 5 s for CPC and 366 ± 62 s for DAC perimetry. The intraclass correlation (ICC) coefficient was 0.53 for DAC perimetry cyan stimuli, 0.67 for red stimuli, and 0.93 for CPC. However, the spatial resolution of CPC was substantially smaller than in DAC perimetry. We did not find a correlation of DAC perimetry and CPC measurements on the global or the local level. In comparison to DAC perimetry, CPC shows a superior intervisit repeatability in detecting functional changes in the rod population in an objective way with lower spatial resolution. Our results also indicate that these 2 methods measure the rod function in different ways and could thus constitute complementary scotopic functional diagnostics.

Chromatic Pupil Campimetry Reveals Functional Defects in Exudative Age-Related Macular Degeneration with Differences Related to Disease Activity.

Purpose: The purpose of this study was to use chromatic pupil campimetry (CPC) for an objective evaluation of local retinal function in exudative age-related macular degeneration (AMD) and to assess disease activity. Methods: Gaze-controlled CPC was performed in 19 subjects with optical coherence tomography-confirmed exudative AMD (75 ± 4 years; 11 women) and the results compared with those of an age-matched control group (n = 11; 72 ± 6 years; 8 women). Local retinal function was evaluated by measuring pupil responses to 3° red stimuli (60 cd/m2, 1 second) at 41 positions covering 30° of the central visual field on a dim blue background (test duration 6 minutes). Primary outcome parameters were relative maximal pupil constriction amplitude (% from baseline) and latency to constriction onset. Results: Pupil constriction amplitudes were significantly reduced in the macular region, and especially in the fovea in AMD (16% ± 4.7%; mean ± standard deviation), compared with the control group (24% ± 6%; P = 0.00036). Receiver operating characteristic values were 0.84 for the constriction amplitude in the fovea, and 0.9 for the steepness angle between periphery and center. Mean latency to constriction onset in the fovea in AMD was significantly longer (333 ± 53 ms; normals 273 ± 59 ms, P = 0.0072), and particularly in the active compared with the inactive status of exudative AMD (P = 0.01). Conclusions: CPC detected functional changes in exudative AMD with high sensitivity. Time dynamics of active exudative AMD differed from disease inactivity. Translational Relevance: With the combination of short recording time, objectiveness of the measurement and gaze-correction for fixation problems, this method presents a suitable complement to the currently used clinical functional tests of the macula.