Large Phase Differences between L-Cone-and M-Cone- Driven Electroretinograms in Retinitis Pigmentosa

PURPOSE. To study the dynamics and interactions of the signals originating in the long-(L-) and middle (M)-wavelength-sensitive cone pathways in patients with retinitis pigmentosa (RP). METHODS. Twenty-six patients with RP and 29 normal subjects participated in the study. Electroretinographic (ERG) responses were measured to stimuli that modulated exclusively the L-or the M-cones or the two simultaneously (both in-phase and in counter-phase) with varying ratios of Lto M-cone contrasts. S-cones were not modulated. RESULTS. The data of the normal subjects and of the patients can be described by a model in which the amplitudes and the phases of the signals originating in the L-and M-cones are vector summed. In the RP patients, there was a general reduction in ERG sensitivity. The L-cone-driven ERG response was significantly delayed, whereas the M-cone-driven ERG response was phase advanced. CONCLUSIONS. Large dynamic differences between L-and M-cone-driven ERGs can be detected in RP. As a result, the interaction between the L-and M-cone systems, when modulated simultaneously at 30 Hz, is subtractive in RP patients and additive in normal subjects. Our data show that the use of only a standard white flicker ERG might lead to a misinterpretation of the mechanisms involved in retinal disorders, because the phases of different cone-driven responses are not considered. (Invest Ophthalmol Vis Sci. 2000;41:3225-3233) T he term retinitis pigmentosa (RP) is used for a group of progressive retinal diseases representing the most frequent retinal dystrophy with a prevalence of approximately 1:4000 and a frequency of heterozygotes of approximately 1:15. 1-3 Approximately 1.5 million people are affected around the world. 5-7 It has been shown that in early cases of RP the scotopic (rod) electroretinogram (ERG) is markedly reduced, whereas the photopic (cone) flash ERG is relatively normal. 8 The conedriven responses to 30-Hz white flicker have normal or reduced amplitudes, and they are usually delayed. 4,9 -12 To date, it is unresolved how changes in the different cones or their postreceptoral pathways contribute to these delays. There have been attempts to differentiate between the involvement of the three different cone systems in RP. RP patients exhibited reduced short (S-) wavelength-sensitive cone-driven ERGs; a subset of those patients showed significantly greater loss in the S-cone-driven ERG than in the mixed long (L)-and middle (M)-cone-driven ERG, We measured ERG responses to stimuli that either selectively modulated the L-or the M-cones or modulated the two simultaneously. Extensive data on normal subjects have been published recently. 14 RP patients showed generally larger ERG thresholds for nearly all combinations of L-and M-cone modulation. Surprisingly, the L-cone-driven ERG was very much delayed, whereas the M-cone-driven ERG was phase-advanced compared with normal observers. RP patients showed smaller ERG thresholds to counter-phase modulation than to in-phase modulation of the L-and M-cones, indicative of a subtractive interaction between the L-and M-cone-driven ERGs. This is probably caused by the increase in phase difference between the L-and M-cone-driven responses. (The term "L-and Mcone-driven ERGs" is used to refer to the responses originating in the L-and the M-cones, including the subsequent postreceptoral stages. The uncertainty about the exact cellular origins of the ERG does not influence the data interpretation.) METHODS Subjects Twenty-six patients (age range, 11-59 years) with different forms of RP (7 autosomal dominant RP, 1 autosomal recessive RP, 3 Usher II syndrome, 10 simplex RP, 1 X-linked RP [X-RP], and 4 carriers of X-RP) participated in the study. The diagnosis was based on history, symmetrical bilateral involvement, the typical alterations of the pigment epithelium layer, by visual field, and Ganzfeld electroretinography according to the ISCEV standard

A novel mutation in the Choroideremia gene in a Turkish family.

Choroideremia is an X-linked recessive genetic disorder caused by mutations in the CHM gene. It is a rare retinal dystrophy that manifests as nyctalopia and vision loss, progressing to blindness in later stages. We report a 21-year Turkish man who presented with nyctalopia for the past 4-5 years. His mother and maternal grandmother had similar, but less pronounced complaints. Fundus examination revealed pigmentary changes and retinal atrophy in both eyes. Optical coherence tomography showed outer retinal loss, with central island of preserved autofluorescence surrounded by absent autofluorescence on fundus autofluorescence examination. Goldmann visual fields were constricted. Microperimetry detected retinal sensitivity losses, and full-field electroretinogram demonstrated extinguished cone responses. Genetic analysis revealed a novel nonsense mutation in the CHM gene, namely p.E480X: c.1438G \u3eT. The mutation causes a premature stop codon in exon 12. This is the first report of a G1438T mutation resulting in an E480X premature stop in the CHM gene

Confocal Blue Reflectance Imaging in Type 2 Idiopathic Macular Telangiectasia

PURPOSE. To report the characteristics of confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia (type 2 IMT). METHODS. In a prospective observational cross-sectional study, both eyes of 33 patients with type 2 IMT were examined by means of fundus biomicroscopy, fundus photography, fluorescein angiography, and optical coherence tomography (OCT). Confocal blue reflectance (CBR) imaging was performed using a confocal scanning laser ophthalmoscope (HRA2; Heidelberg Engineering, Heidelberg, Germany). To compare the results derived from different imaging modalities, an analysis was performed using image analysis software (Heidelberg Eye Explorer; Heidelberg Engineering). RESULTS. CBR imaging revealed a parafoveal area of increased reflectance that was slightly larger than the area of hyperfluorescence in late-phase fluorescein angiography. The area usually encompassed an oval parafoveal area, but sectors could be spared. A parafoveal area of increased CBR was detected in 98% of eyes that showed angiographic evidence for type 2 IMT. CONCLUSIONS. CBR imaging is a new, noninvasive, and sensitive method that may contribute to differentiate type 2 IMT from other diseases. Abnormalities of macular pigment distribution and Miiller cell pathology may contribute to the phenomenon of increased CBR and thus the pathophysiology of type 2 IMT

Cynomolgus monkey's choroid reference database derived from hybrid deep learning optical coherence tomography segmentation.

Cynomolgus monkeys exhibit human-like features, such as a fovea, so they are often used in non-clinical research. Nevertheless, little is known about the natural variation of the choroidal thickness in relation to origin and sex. A combination of deep learning and a deterministic computer vision algorithm was applied for automatic segmentation of foveolar optical coherence tomography images in cynomolgus monkeys. The main evaluation parameters were choroidal thickness and surface area directed from the deepest point on OCT images within the fovea, marked as the nulla with regard to sex and origin. Reference choroid landmarks were set underneath the nulla and at 500 µm intervals laterally up to a distance of 2000 µm nasally and temporally, complemented by a sub-analysis of the central bouquet of cones. 203 animals contributed 374 eyes for a reference choroid database. The overall average central choroidal thickness was 193 µm with a coefficient of variation of 7.8%, and the overall mean surface area of the central bouquet temporally was 19,335 µm2 and nasally was 19,283 µm2. The choroidal thickness of the fovea appears relatively homogeneous between the sexes and the studied origins. However, considerable natural variation has been observed, which needs to be appreciated

Volume-rendered optical coherence tomography angiography during ocular interventions: Advocating for noninvasive intraoperative retinal perfusion monitoring.

We aimed to test for feasibility of volume-rendered optical coherence tomography angiography (OCTA) as a novel method for assessing/quantifying retinal vasculature during ocular procedures and to explore the potential for intraoperative use. Thirty patients undergoing periocular anaesthesia were enrolled, since published evidence suggests a reduction in ocular blood flow. Retinal perfusion was monitored based on planar OCTA image-derived data provided by a standard quantification algorithm and postprocessed/volume-rendered OCTA data using a custom software script. Overall, imaging procedures were successful, yet imaging artifacts occurred frequently. In interventional eyes, perfusion parameters decreased during anaesthesia. Planar image-derived and volume rendering-derived parameters were correlated. No correlation was found between perfusion parameters and a motion artifact score developed for this study, yet all perfusion parameters correlated with signal strength as displayed by the device. Concluding, volume-rendered OCTA allows for noninvasive three-dimensional retinal vasculature assessment/quantification in challenging surgical settings and appears generally feasible for intraoperative use

Reading Performance Is Reduced by Parafoveal Scotomas in Patients with Macular Telangiectasia Type 2

PURPOSE. Macular telangiectasia (MacTel) type 2 typically exhibits sharply demarcated parafoveal scotomas. In an investigation of their significance for reading performance, reading acuity and speed were measured and correlated with parafoveal sensitivity and fixation stability. METHODS. In this prospective controlled cross-sectional observational study, 49 eyes of 26 patients with MacTel type 2 were investigated. Twenty-four eyes of 14 age-matched normal subjects served as the control. Reading acuity and reading speed (in words per minute [wpm]) were assessed by Radner charts. Retinal sensitivity was measured using fundus controlled microperimetry (MP1; Nidek Technologies). Fixation stability was quantified by the bivariate contour ellipse area (BCEA). Multiple logistic regression analysis was used to delineate outcome predictors of reading acuity and speed. RESULTS. Mean reading speed was considerably reduced in patients (to 141 wpm; control speed, 190 wpm; P Ͻ 0.001) as was reading acuity (patients, 20/63; control subjects, 20/32; P Ͻ 0.001). Mean best corrected visual acuity (BCVA) was reduced in most eyes (patients, 20/50; control subjects, 20/20; P Ͻ 0.001). Mean BCEA was not reduced compared with that in the control subjects. BCVA reduction predicted reading acuity loss (P ϭ 0.02) and a decrease in maximum reading speed (P Ͻ 0.001). Parafoveal sensitivity loss resulted in decreased reading acuity (P ϭ 0.03) and reading speed reduction (P Ͻ 0.001). CONCLUSIONS. These findings indicate that parafoveal sensitivity loss in MacTel type 2 is associated with loss of reading performance despite stable central fixation. Reading performance appears to be a sensitive variable of functional impairment in MacTel type 2 and should therefore be considered an outcome measure in future interventional trials. (Invest Ophthalmol Vis Sci

Metadata-enhanced contrastive learning from retinal optical coherence tomography images

Supervised deep learning algorithms hold great potential to automate screening, monitoring and grading of medical images. However, training performant models has typically required vast quantities of labelled data, which is scarcely available in the medical domain. Self-supervised contrastive frameworks relax this dependency by first learning from unlabelled images. In this work we show that pretraining with two contrastive methods, SimCLR and BYOL, improves the utility of deep learning with regard to the clinical assessment of age-related macular degeneration (AMD). In experiments using two large clinical datasets containing 170,427 optical coherence tomography (OCT) images of 7,912 patients, we evaluate benefits attributed to pretraining across seven downstream tasks ranging from AMD stage and type classification to prediction of functional endpoints to segmentation of retinal layers, finding performance significantly increased in six out of seven tasks with fewer labels. However, standard contrastive frameworks have two known weaknesses that are detrimental to pretraining in the medical domain. Several of the image transformations used to create positive contrastive pairs are not applicable to greyscale medical scans. Furthermore, medical images often depict the same anatomical region and disease severity, resulting in numerous misleading negative pairs. To address these issues we develop a novel metadata-enhanced approach that exploits the rich set of inherently available patient information. To this end we employ records for patient identity, eye position (i.e. left or right) and time series data to indicate the typically unknowable set of inter-image contrastive relationships. By leveraging this often neglected information our metadata-enhanced contrastive pretraining leads to further benefits and outperforms conventional contrastive methods in five out of seven downstream tasks

Longitudinal Study of Optic Disk Perfusion and Retinal Structure in Leber's Hereditary Optic Neuropathy

Purpose: The purpose of this study was to evaluate optic disk perfusion and neural retinal structure in patients with subacute Leber's hereditary optic neuropathy (LHON) and LHON carriers, as compared with healthy controls. Methods: This study included 8 patients with LHON in the subacute stage, 10 asymptomatic carriers of a LHON-associated mitochondrial DNA mutation, and 40 controls. All subjects underwent measurement of the retinal nerve fiber layer (RNFL) thickness, the ganglion cell-inner plexiform layer (GCIPL) thickness using optical coherence tomography and optic disk microvascular perfusion (Mean Tissue [MT]) using laser speckle flowgraphy (LSFG). Patients were re-examined after a median interval of 3 months from the baseline visit. Results: LHON carriers had higher values of RNFL thickness, GCIPL thickness, and disk area than controls (P < 0.05), whereas MT was not different between the two groups (P = 0.936). Median MT and RNFL thickness were 32% and 15% higher in the early subacute stage of the disease than in controls (P < 0.001 and P = 0.001). MT declined below the values of controls during the late subacute stage (P = 0.024), whereas RNFL thickness declined later during the dynamic stage (P < 0.001). GCIPL thickness was lower in patients with LHON than in controls independently of the stage of the disease (P < 0.001). Conclusions: The high blood flow at the optic disk during the early subacute stage may be the consequence of vasodilation due to nitric oxide release as compensation to mitochondrial impairment. Optic disk perfusion as measured by LSFG is a promising biomarker for LHON diagnosis and monitoring as well as an objective outcome measure for assessing response to therapies