Relative Ellipsoid Zone Reflectivity in Macular Telangiectasia Type 2.

Purpose: The relative ellipsoid zone reflectivity (rEZR) has been proposed as an innovative biomarker for photoreceptor integrity. This study evaluates the rEZR in macular telangiectasia type 2 (MacTel) eyes of different disease stages. Methods: The mean rEZR (ratio ellipsoid zone [EZ]/external limiting membrane [ELM] reflectivity [arbitrary units {AUs}], grey level range = 0-1) was analyzed for an entire spectral domain optical coherence tomography volume scan (global) and for each subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid (topographic) in patients with MacTel and controls. MacTel disease severity was classified according to Gass and Blodi. Results: Linear mixed-model analysis of 145 eyes of 74 patients and 50 eyes of 25 controls revealed globally lower, yet not statistically significant, rEZR values in MacTel eyes. Topographically, most pronounced decreases were found in stages 3 and 4/5 for the temporal inner (coefficient estimates [CEs] = -25.4 [-38.2; -12.6] and -34.1 [-48.7; -19.6] AU, both: P < 0.001), the inferior inner (-29.9 [-44.6; -15.6] and -35.3 [-52.1; -18.5] AU, both: P < 0.001), the nasal inner (-21.5 [-35.52; -7.4] and -31.6 [-47.6; -15.6] AU, P = 0,003 and P < 0.001), and in the superior inner subfield of stage 4/5 (-25.0 [-42.0; -7.9] AU, P = 0.004). Conclusions: The rEZR showed association with disease severity and the predilection area of MacTel. Given the current understanding of the pathophysiological concept of MacTel, these findings underscore the value of the rEZR as a potential novel biomarker for outer retinal integrity. Longitudinal studies are demanded to better characterize its value as a biomarker for early photoreceptor alterations and disease progression in MacTel.

iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function.

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.

Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease.

OBJECTIVES: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. METHODS: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants. RESULTS: MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and glycine restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. CONCLUSIONS: These results highlight metabolic distinctions between MacTel and HSAN1, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches for these two neurodegenerative diseases.

Tamoxifen Retinopathy and Macular Telangiectasia Type 2: Similarities and Differences on Multimodal Retinal Imaging.

PURPOSE: Tamoxifen-induced retinopathy (TR) and macular telangiectasia type 2 (MacTel) share a highly similar retinal phenotype. In this study, we aimed to evaluate differences and similarities that may point toward underlying mechanisms linking both disease entities. DESIGN: Retrospective, cross sectional study. SUBJECTS: Patients diagnosed with MacTel or TR. METHODS: Patients underwent multimodal retinal imaging, including color fundus photography, spectral-domain OCT, fundus autofluorescence, fluorescein angiography, and OCT angiography (if available). Age, age of onset, best-corrected visual acuity, and bilaterality of changes were evaluated. Patients' eyes were graded for different morphologic characteristics by 4 experienced graders. MAIN OUTCOME MEASURES: Phenotypical characterization and comparison of frequencies of retinal characteristics of TR and MacTel on multimodal imaging. RESULTS: Twenty-eight eyes of 14 patients with TR and 118 eyes of 59 patients with MacTel were included. Age, age of onset, and best-corrected visual acuity were similar in both cohorts. All but 1 patient showed bilateral changes. In patients with MacTel, neurodegenerative changes and vascular alterations were equally present, whereas in patients with TR, neurodegenerative changes usually prevailed. Predilection sites within the central retina differed between the 2 diseases: most findings in patients with TR were limited to the foveal center, whereas changes in patients with MacTel were present throughout a slightly larger region ("MacTel area"), with an epicenter temporal to the foveal center. Distinct morphologic features included the distribution of retinal crystals, the size and position of ellipsoid zone breaks, and the presence of hyperreflective changes on OCT images. Focal hyperpigmentation and neovascular membranes were only present in eyes with MacTel. CONCLUSIONS: Macular telangiectasia and TR share a highly similar retinal phenotype, especially in early disease stages. Subtle differences on multimodal retinal images may help distinguish between these 2 disease entities. Our findings indicate the involvement of Müller cells in both diseases, which may explain the observed phenotypic characteristics and similarities.

Morphological characteristics preceding exudative neovascularisation secondary to macular telangiectasia type 2.

AIMS: To identify morphological characteristics preceding the development of exudative neovascularisation secondary to Macular Telangiectasia type 2 (MacTel) using multimodal retinal imaging. METHODS: In this retrospective study, eyes with a minimum observation period of 6 months prior to the de novo diagnosis of an exudative neovascularisation secondary to MacTel were analysed. Morphological changes preceding the formation of neovascularisation were evaluated using colour fundus photography, infrared imaging, fluorescein angiography, macular pigment measurement and optical coherence tomography (OCT). OCT-angiography (OCT-A) images were additionally available in a subset of patients. RESULTS: Twenty eyes from 20 patients were examined over a median period of 17 months (range: 6-100 months). Eyes were characterised by an accelerated progression of ellipsoid zone loss (median of 0.013 mm2/month), increased thickness of the temporal parafovea and hyper-reflective lesions on OCT. The latter underwent morphological changes preceding the development of exudative neovascularisation, including an increase in size and density, and expansion to outer retinal layers and the retinal pigment epithelium. All eyes showed a foveal depletion of macular pigment. On OCT-A, a focal increase in blood flow was observed at the level of the outer retina/choriocapillaris, and retinal-retinal and retinal-choroidal anastomoses preceded the formation of exudative neovascularisation. CONCLUSIONS: Multimodal imaging allows the identification of prognostic morphological features preceding the formation of exudative neovascularisation in MacTel. Eyes exhibiting these characteristics should be monitored closely and patients should be alert for emergent symptoms in order to detect and treat neovascularisation early and, thereby, prevent irreversible visual loss.

Functional Relevance of Hyper-Reflectivity in Macular Telangiectasia Type 2.

Purpose: The purpose of this study was to quantify hyper-reflective lesions on en face optical coherence tomography (OCT) and study its functional relevance in macular telangiectasia type 2 (MacTel). Design: This was a retrospective, cross-sectional cohort study. Methods: Baseline image and functional data from participants of a phase II clinical trial (NCT01949324) that studied the effect of Ciliary Neurotrophic Factor in patients with MacTel were analyzed. The projection of hyper-reflectivity within different layers on OCT was used to generate an en face view and measure the en face size of hyper-reflectivity. Ellipsoid zone (EZ)-loss was additionally evaluated, and en face images were superimposed onto microperimetry sensitivity maps, allowing to estimate mean retinal sensitivity within areas displaying hyper-reflectivity and EZ-loss, respectively. Best-corrected visual acuity (BCVA) and reading speed were also analyzed. Results: Fifty-two eyes from 52 patients were analyzed. Hyper-reflectivity was present in 32 eyes (62%), and EZ-loss in 50 (96%) eyes. Mean lesion size was 0.11 mm² (range = 0.01-0.26) for hyper-reflectivity and 0.51 mm² (range = 0.02-1.34) for EZ-loss, and lesion sizes correlated strongly (Spearman r = 0.79, P < 0.001). Although both hyper-reflectivity and EZ-loss were associated with a significant decrease in retinal sensitivity, mean sensitivity thresholds differed significantly between lesions (0.9 dB vs. 16.3 dB; P < 0.001), indicating an almost complete loss of sensitivity in hyper-reflective areas. No correlations were found between the size of hyper-reflectivity and BCVA (r = 0.09) or reading speed (r = -0.17). Conclusions: En face OCT can be used to quantify the area of hyper-reflective lesions in MacTel. Hyper-reflectivity in MacTel is associated with severe functional impairment, leading to an almost complete loss of retinal sensitivity as observed on microperimetry.

HYPERREFLECTIVITY ON OPTICAL COHERENCE TOMOGRAPHY IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To define, characterize, and classify hyperreflectivity on optical coherence tomography and report its prevalence in macular telangiectasia Type 2. METHODS: In a primary cross-sectional analysis, multimodal imaging data were retrospectively analyzed. The definition of hyperreflectivity and neovascularization on optical coherence tomography followed optical coherence tomography angiography-based criteria. Eyes were graded for the presence of hyperreflectivity and neovascularization and further categorized into three classes based on position and extent of hyperreflectivity. In a secondary analysis, eyes were reviewed for ≥24 months using optical coherence tomography imaging. RESULTS: Three hundred and twenty-two eyes from 161 patients were analyzed in the cross-sectional analysis. Hyperreflectivity was found in 177 (55%) and neovascular membranes in 49 (15%) eyes. Hyperreflectivity correlated significantly with parameters indicative of disease progression. In the longitudinal analysis, 206 eyes from 103 patients were reviewed over a mean of 35.6 months. 17/86 eyes (20%) showed a de novo development of hyperreflectivity. 8/29 eyes (28%) with preexistent intraretinal hyperreflectivity developed outer retinal hyperreflectivity. A high proportion of eyes with outer retinal hyperreflectivity (17/52 [33%]) developed neovascular membranes. CONCLUSION: Hyperreflectivity represents a common finding in macular telangiectasia Type 2 but lacks a uniform definition. We propose a hyperreflectivity grading scale that may help to estimate disease progression and identify eyes at risk for developing neovascular membranes.

Optical coherence tomography-angiography for monitoring neovascularisations in macular telangiectasia type 2.

PURPOSE: To evaluate the utility of optical coherence tomography-angiography (OCT-A) for monitoring activity, progression and response to therapy of neovascularisations (NVs) secondary to macular telangiectasia type 2 (MacTel). METHODS: In a retrospective analysis, eyes with NVs secondary to MacTel were reviewed over a period of ≥8 months. Examinations at monthly intervals included visual acuity testing, dilated funduscopy, spectral domain-OCT and OCT-A. Eyes were treated with intravitreal VEGF (vascular endothelial growth factor)-inhibitors following a pro-re-nata (PRN) regime, and treatment decisions were based on morphological signs of activity as determined by B-scan OCT and funduscopy. Signs of neovascular activity were defined as an increase in retinal thickness, presence/increase of intraretinal/subretinal fluid and haemorrhages. RESULTS: A total of 19 eyes from 17 patients were analysed. Patients were evaluated over a mean period of 13.4 months (range: 8.9 to 24.2). OCT-A permitted the monitoring of both treatment effects (regression) and progression (growth) of NVs, but not neovascular activity. The growth of neovascular vessels was detectable in OCT-A before signs of activity occurred on OCT. NVs showed a progressive growth over time despite PRN-treatment and preferentially grew and extended within areas characterised by a focal reduction of choriocapillaris perfusion. CONCLUSIONS: The results indicate that OCT-A represents a useful imaging modality for monitoring NV-progression and treatment effects in MacTel. We demonstrate its advantages over conventional B-scan OCT imaging, including an earlier detection of NV-progression, and propose an adjustment of the current OCT-controlled PRN treatment regime in order to prevent NV-progression and subsequent functional loss in neovascular MacTel.

Right-angled vessels in macular telangiectasia type 2.

PURPOSE: To evaluate the role of right-angled vessels (RAVs) during disease progression in macular telangiectasia type 2 (MacTel). METHODS: In this study, 100 eyes of 52 patients and 52 eyes of 26 age-related controls were examined using fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT angiography (OCT-A) and fundus fluorescein angiography (FFA). Two masked readers graded fundus photographs of patients' eyes into five disease stages according to Gass and Blodi, and evaluated all eyes for the presence of RAVs. If RAVs were present, their course and origin (arterial vs venous) was evaluated with OCT-A and FFA, respectively. Additionally, we looked for morphological correlates of these vessels on SD-OCT scans. Neovascular eyes were analysed for the presence of RAVs and for morphological changes on formation of neovascularisations (NVs). RESULTS: In OCT-A, RAVs were already detectable in eyes with early stages (1 to 2), could be tracked from superficial to outer retinal layers and were shown to form anastomoses in the outer retina with disease progression. These vessels were of both arterial and venous origin as shown by early phase FFA. Dilated capillaries and RAVs in OCT-A corresponded to hyper-reflective alterations of the outer retina on SD-OCT scans. In 19/19 eyes, NVs were associated with the presence of RAVs, and RAVs were shown to directly connect to neovascular complexes and to undergo morphological changes upon NV formation. CONCLUSIONS: The results emphasise the role of RAVs during disease progression from an early stage on and demonstrate their involvement in the development of secondary NVs in MacTel.

WITHDRAWN: Hyper-reflectivity on optical coherence tomography in macular telangiectasia type 2.

Ahead of Print article withdrawn by publisher.

DARK ADAPTATION IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To evaluate dark adaptation (DA) in patients with macular telangiectasia Type 2 (MacTel). METHODS: After a local photobleach (4 × 4° size, 83% bleach), DA was measured using a test stimulus (2° diameter) projected at 5° eccentricity horizontal from the foveal center within the temporal parafovea. Cone plateau, rod intercept time, and rod recovery rate (S2) were calculated from the resulting DA curves. Findings were correlated with disease stages (according to Gass and Blodi), the area of ellipsoid zone loss in optical coherence tomography, and macular pigment loss ("MP-Classes 1-3"). RESULTS: Fifty-nine eyes of 59 patients were compared with 18 eyes of 18 healthy controls. Dark adaptation was significantly impaired in patients with MacTel. Although differences were most pronounced for parameters indicating rod-mediated recovery, cone-mediated recovery was also decreased, yet to a lesser extent. Dark adaptation parameters were only weakly associated with disease stages and ellipsoid zone loss. A better association was found between rod-mediated recovery (S2 and rod intercept time) and macular pigment loss (Kendall's tau for rod intercept time: 0.69 and S2: -0.51; both P < 0.0001). CONCLUSION: Dark adaptation is significantly impaired in patients with MacTel. Our results indicate an association of reduced macular pigment and rod dysfunction in MacTel.

Binocular Inhibition of Reading in Macular Telangiectasia Type 2.

Purpose: To assess the presence of binocular gain in macular telangiectasia type 2 (MacTel) and its correlation to paracentral scotomas. Methods: Sixty-eight patients with MacTel were consecutively recruited for a cross-sectional analysis. Best-corrected visual acuity (BCVA), reading acuity, and reading speed were tested monocularly and binocularly. Macular retinal sensitivity was examined with fundus-controlled perimetry (microperimetry). Scotomas were quantified by their size, their depth, and their proximity to the fovea. Results: Binocular reading speed and acuity were lower than monocular reading speed and acuity in the functionally better eye (142 vs. 159 words per minute and 0.43 vs. 0.28 log reading acuity determination, P < 0.001). Magnitude of binocular inhibition of reading speed was correlated to the degree of interocular functional difference (R2 = 0.61, P < 0.001). This correlation was not found for reading acuity or BCVA (R2 < 0.03). Binocular reading speed was negatively correlated to size of right and left eye scotomas, with bigger effect size for left eye scotomas. The magnitude of binocular inhibition was correlated to size of left eye scotomas, but not of right eye scotomas. When both eyes had similar scotoma characteristics, the right eye was more frequently the better reading eye. Conclusions: We provide evidence for the presence of binocular inhibition of reading performance in MacTel, likely due to binocular rivalry. This may result from the characteristic paracentral scotomas in noncorresponding retinal fields and, in particular, a disruptive projection of scotomas in reading direction arising from the left eyes. Patients may benefit from occluding one eye while reading.

Quantification of Retinal and Choriocapillaris Perfusion in Different Stages of Macular Telangiectasia Type 2.

Purpose: To quantify the retinal and choriocapillaris perfusion in different disease stages of macular telangiectasia type 2 (MacTel) using optical coherence tomography-angiography (OCT-A). Methods: We examined 76 eyes of 76 patients and 24 eyes of 24 age-related controls. Participants underwent multimodal imaging, including OCT and OCT-A. Patients' eyes were divided into three groups considering predefined criteria from funduscopy, OCT, and fluorescein angiography, thus reflecting the disease severity ("early," "advanced," and "neovascular"). Quantitative analyses of vessel density (VD), skeleton density (SD), and fractal dimension (FD) were conducted in the superficial and deep retinal plexus and in the avascular layer. The choriocapillaris was analyzed for mean signal intensity and percentage of nondetectable perfused choriocapillaris-area (PNPA). Results: The deep retinal plexus showed a progressive decrease of mean VD, SD, and FD in the temporal parafovea in all disease stages. In the superficial layer, VD, SD, and FD were significantly decreased in the temporal parafovea of advanced and neovascular stages, while these parameters did not differ from controls in early stages. In MacTel, signals of blood flow were also detectable at the level of the avascular layer and showed a significant increase with disease progression. The choriocapillaris in MacTel showed a significant increase of mean PNPA and a decrease of mean signal intensity in comparison to controls. These findings were consistent in all disease stages. Conclusions: Quantitative OCT-A data show a progressive rarefication of the retinal microvasculature in MacTel. We propose an altered choriocapillaris perfusion as a possibly early alteration of the disease.

Dark-Adapted Two-Color Fundus-Controlled Perimetry in Macular Telangiectasia Type 2.

Purpose: Macular telangiectasia type 2 (MacTel) is a bilateral neurodegenerative disorder of the central macula. Previous findings indicated more functional impairment in low light conditions. We sought to further characterize retinal dysfunction using dark-adapted two-color fundus-controlled perimetry ("scotopic microperimetry"). Methods: Participants of the MacTel Natural History Observation Registry study and age-matched healthy controls underwent retinal imaging including dual wavelength autofluorescence macular pigment optical density (MPOD) measurement. Retinal sensitivity was assessed with scotopic microperimetry using cyan (505 nm) and red (627 nm). Disease was graded into classes of MPOD loss (0 to 3). For perimetry analysis, the differences of the mean sensitivities (MacTel minus controls) were compared at each test location and the results were aggregated to global indices. Results: Thirty-four eyes (19 patients, mean age 62.2 years) were compared with 25 eyes (25 controls, mean age 61.5 years). Both cyan and red sensitivity were lower in MacTel. This was more pronounced at one- and three-degree eccentricity. Eyes with MPOD class 0 did not exhibit a functional deficit. Class 1 had impaired cyan, but normal red sensitivity. Class 2 and 3 behaved similarly and had impaired cyan and red sensitivity with a relatively higher cyan impairment. Conclusions: Rods might be compromised to a greater extent than cones. Linking to previous studies, our results might also hint toward (postreceptoral) dysfunction of the cone system in very early disease stages. Macular pigment loss and global perimetry indices seemed to reflect functional impairment and might be useful as adjunct measures for disease progression.

Estimating Retinal Sensitivity Using Optical Coherence Tomography With Deep-Learning Algorithms in Macular Telangiectasia Type 2.

Importance: As currently used, microperimetry is a burdensome clinical testing modality for testing retinal sensitivity requiring long testing times and trained technicians. Objective: To create a deep-learning network that could directly estimate function from structure de novo to provide an en face high-resolution map of estimated retinal sensitivity. Design, Setting, and Participants: A cross-sectional imaging study using data collected between January 1, 2016, and November 30, 2017, from the Natural History Observation and Registry of macular telangiectasia type 2 (MacTel) evaluated 38 participants with confirmed MacTel from 2 centers. Main Outcomes and Measures: Mean absolute error of estimated compared with observed retinal sensitivity. Observed retinal sensitivity was obtained with fundus-controlled perimetry (microperimetry). Estimates of retinal sensitivity were made with deep-learning models that learned on superpositions of high-resolution optical coherence tomography (OCT) scans and microperimetry results. Those predictions were used to create high-density en face sensitivity maps of the macula. Training, validation, and test sets were segregated at the patient level. Results: A total of 2499 microperimetry sensitivities were mapped onto 1708 OCT B-scans from 63 eyes of 38 patients (mean [SD] age, 74.3 [9.7] years; 15 men [39.5%]). The numbers of examples for our algorithm were 67 899 (103 053 after data augmentation) for training, 1695 for validation, and 1212 for testing. Mean absolute error results were 4.51 dB (95% CI, 4.36-4.65 dB) when using linear regression and 3.66 dB (95% CI, 3.53-3.78 dB) when using the LeNet model. Using a 49.9 million-variable deep-learning model, a mean absolute error of 3.36 dB (95% CI, 3.25-3.48 dB) of retinal sensitivity for validation and test was achieved. Correlation showed a high degree of agreement (Pearson correlation r = 0.78). By paired Wilcoxon rank sum test, our model significantly outperformed these 2 baseline models (P < .001). Conclusions and Relevance: High-resolution en face maps of estimated retinal sensitivities were created in eyes with MacTel. The maps were of unequalled resolution compared with microperimetry and were able to correctly delineate functionally healthy and impaired retina. This model may be useful to monitor structural and functional disease progression and has potential as an objective surrogate outcome measure in investigational trials.