Developing a Continuous Severity Scale for Macular Telangiectasia Type 2 Using Deep Learning and Implications for Disease Grading.

PURPOSE: Deep learning (DL) models have achieved state-of-the-art medical diagnosis classification accuracy. Current models are limited by discrete diagnosis labels, but could yield more information with diagnosis in a continuous scale. We developed a novel continuous severity scaling system for macular telangiectasia (MacTel) type 2 by combining a DL classification model with uniform manifold approximation and projection (UMAP). DESIGN: We used a DL network to learn a feature representation of MacTel severity from discrete severity labels and applied UMAP to embed this feature representation into 2 dimensions, thereby creating a continuous MacTel severity scale. PARTICIPANTS: A total of 2003 OCT volumes were analyzed from 1089 MacTel Project participants. METHODS: We trained a multiview DL classifier using multiple B-scans from OCT volumes to learn a previously published discrete 7-step MacTel severity scale. The classifiers' last feature layer was extracted as input for UMAP, which embedded these features into a continuous 2-dimensional manifold. The DL classifier was assessed in terms of test accuracy. Rank correlation for the continuous UMAP scale against the previously published scale was calculated. Additionally, the UMAP scale was assessed in the κ agreement against 5 clinical experts on 100 pairs of patient volumes. For each pair of patient volumes, clinical experts were asked to select the volume with more severe MacTel disease and to compare them against the UMAP scale. MAIN OUTCOME MEASURES: Classification accuracy for the DL classifier and κ agreement versus clinical experts for UMAP. RESULTS: The multiview DL classifier achieved top 1 accuracy of 63.3% (186/294) on held-out test OCT volumes. The UMAP metric showed a clear continuous gradation of MacTel severity with a Spearman rank correlation of 0.84 with the previously published scale. Furthermore, the continuous UMAP metric achieved κ agreements of 0.56 to 0.63 with 5 clinical experts, which was comparable with interobserver κ values. CONCLUSIONS: Our UMAP embedding generated a continuous MacTel severity scale, without requiring continuous training labels. This technique can be applied to other diseases and may lead to more accurate diagnosis, improved understanding of disease progression, and key imaging features for pathologic characteristics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).

Description of a patient cohort with Hereditary Sensory Neuropathy type 1 without retinal disease Macular Telangiectasia type 2 - implications for retinal screening in HSN1.

Pathogenic variants in the genes encoding serine palmitoyl transferase (SPTLC1 or SPTLC2) are the most common causes of the rare peripheral nerve disorder Hereditary Sensory Neuropathy Type 1 (HSN1). Macular telangiectasia type 2 (MacTel), a retinal disorder associated with disordered serine-glycine metabolism, has been described in some patients with HSN1. This study aims to further investigate this association in a cohort of people with HSN1. Fourteen patients with a clinically and genetically confirmed diagnosis of HSN1 from the National Hospital for Neurology and Neurosurgery (NHNN, University College London Hospitals NHS Foundation Trust, London, United Kingdom) were recruited to the MacTel Registry, between July 2018 and April 2019. Two additional patients were identified from the dataset of the international clinical registry study (www.lmri.net). Ocular examination included fundus autofluorescence, blue light and infrared reflectance, macular pigment optical density mapping and optical coherence tomography. Twelve patients had a pathogenic variant in the SPTLC1 gene, with p.Cys133Trp in 11 cases (92%) and p.Cys133Tyr in one case (8%). Four patients had a variant in the SPTLC2 gene. None of the patients showed clinical evidence of MacTel. The link between HSN1 and MacTel seems more complex than can solely be explained by the genetic variants. An extension of the spectrum of SPTLC1/2-related disease with phenotypic pleiotropy is proposed. HSN1 patients should be screened for visual symptoms and referred for specialist retinal screening, but the association of the two diseases is likely to be variable and remains unexplained.

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.

Macular Telangiectasia Type 2: Visual Acuity, Disease End Stage, and the MacTel Area: MacTel Project Report Number 8.

PURPOSE: To report the visual acuity measures from the macular telangiectasia type 2 (MacTel) registry and to investigate and describe phenotypic findings in eyes with substantial vision loss resulting from MacTel. DESIGN: Cross-sectional multicenter study. PARTICIPANTS: Participants in the MacTel Natural History Observation Registration Study. METHODS: Best-corrected visual acuity (BCVA) data, retinal imaging data, and clinical data were accessed from the MacTel Study databases in May 2019. MAIN OUTCOME MEASURES: Frequency distribution of BCVA and its relationship to age; morphologic changes in eyes with very late disease stages, defined by a BCVA of 20/200 or worse; average retinal thickness of macular subfields on OCT; and dimensions of the area affected by MacTel (i.e., the MacTel area). RESULTS: Best-corrected visual acuity was 20/50 or worse in 37.3% and 20/200 or worse in 3.8% of 4449 eyes of 2248 patients; 18.4% and 0.7% of all patients showed bilateral BCVA of 20/50 or worse and 20/200 or worse, respectively. Asymmetry between right and left eyes was present (median BCVA, 71 letters vs. 74 letters), a finding supported by more advanced morphologic changes in right eyes. Participant age correlated with BCVA, but the effect size was small. If a neovascularization or macular hole were present, bilateral occurrence was frequent (33% or 17%, respectively), and BCVA was better than 20/200 (79% or 78%, respectively) or 20/50 or better (26% or 13%, respectively). Eyes with advanced disease (BCVA, ≤20/200) showed the following characteristics: (1) atrophy of the foveal photoreceptor layer with or without associated subretinal fibrosis; (2) an affected area, termed MacTel area, limited to a horizontal diameter not exceeding the distance between the temporal optic disc margin and foveal center, and the vertical diameter not exceeding approximately 0.8 times this distance (exceptions were eyes with large active or inactive neovascular membranes); (3) reduced retinal thickness measures within the MacTel area; and (4) less frequent retinal greying and more frequent hyperpigmentations compared with eyes that have better BCVA. CONCLUSIONS: Severe vision loss is rare in MacTel and is related to photoreceptor atrophy in most people. Results indicate disease asymmetry with slightly worse vision and more advanced disease manifestation in right eyes. MacTel-related neurodegeneration does not spread beyond the limits of the MacTel area.

Novel biomarker of sphericity and cylindricity indices in volume-rendering optical coherence tomography angiography in normal and diabetic eyes: a preliminary study.

PURPOSE: Preliminary to evaluate geometric indices (vessel sphericity and cylindricity) for volume-rendered optical coherence tomography angiography (OCTA) in healthy and diabetic eyes. METHODS: Twenty-six eyes of 13 healthy subjects and 12 eyes of patients with central ischemic, non-proliferative diabetic retinopathy were included. OCTA volume and surface area of the foveal vessels were measured and compared to determine OCTA sphericity and cylindricity indices and surface efficiency (SE). RESULTS: The overall average OCTA volume in healthy was 0.49 ± 0.09 mm3 (standard deviation [SD]), compared to 0.44 ± 0.07 mm3 (SD) in the diabetic eyes (difference in means 0.06 mm3, p = 0.054). The overall average OCTA surface area in the healthy eyes was 87.731 ± 9.51 mm2 (SD), compared to 76.65 ± 13.67 mm2 (SD) in the diabetic eyes (difference in means 11.08 mm2, p = 0.021). In relation to total foveolar tissue volume, the proportion of blood vessels was 22% in healthy individuals and only 20% in diabetics. The difference between the groups was more pronounced with respect to the total OCTA surface area, with a decrease of 13% in diabetics. A diabetic eye was most likely using geometric vessel indices analysis if the sphericity value was ≥ 0.190, with a cylindricity factor of ≥ 0.001. Reproducibility of the method was good. CONCLUSIONS: A method for OCTA surface area and volume measurements was developed. The application of the novel OCTA sphericity and cylindricity indices could be suitable as temporal biomarker to characterize stable disease or disease progression and may contribute to a better understanding in the evolution of diabetic retinopathy.

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.

Postretinal Detachment Retinal Displacement: How Best to Detect It?

PURPOSE: The reported incidence of postretinal detachment (RD) macular displacement varies markedly (14-72%). This may in part be due to the imaging modalities used. We compared the ability of 2 types of fundus autofluorescence (FAF) imaging modalities to detect this phenomenon. METHODS: Prospective study of 70 eyes with macula-involving RDs. 8 weeks postoperatively, patients underwent FAF imaging with 2 machines: a confocal scanning laser ophthalmoscope (cSLO) and a digital fundus camera (FC). Images were graded for the presence of hyperautofluorescent RPE (retinal pigment epithelium) ghost vessels, indicative of retinal displacement, by 2 masked, independent graders. RESULTS: In total, 87.1% of FC images were gradable versus 88.6% of cSLO images. Retinal displacement was detectable in 61.4% of FC images versus 52.8% of cSLO images. Vessel shift often appeared more autofluorescent on FC imaging, but choroidal vessels were more visible. Cohen's agreement between the imaging modalities was 0.50, rated as moderate agreement. For both imaging modalities, the inter- and intragrader agreement was substantial, representing good test-retest reliability. CONCLUSIONS: Detection of post-RD retinal displacement was similar between FC and cSLO FAF imaging, with only moderate agreement between both modalities.

Stereoscopic Vision in Macular Telangiectasia Type 2.

PURPOSE: To investigate stereoscopic vision in patients with macular telangiectasia (MacTel) type 2 and correlate paracentral sensitivity loss to reduced stereoscopic function. METHODS: In a prospective single-center study, 50 patients with MacTel type 2 and 25 age-matched controls were investigated. Stereoscopic function was evaluated with Lang I, Titmus, and TNO tests. Sensitivity of the central 16° was tested using fundus-controlled perimetry (microperimetry). Functional loss was quantified as depth, size, and localization of scotomata. RESULTS: Both the Titmus and the TNO test revealed significantly reduced stereoscopic vision in patients compared to controls (p < 0.0001 for both). This applied even to patients with only relative or monocular paracentral scotoma. A strong correlation was observed for reduced stereoscopic vision with horizontal scotoma size and with the distance of scotomata from the foveal center. CONCLUSIONS: The results indicate that stereoscopic vision is impaired early in patients with MacTel type 2. A paracentral sensitivity loss, even if mild and limited to one eye, may considerably interfere with stereoscopic function despite normal visual acuity. Projection of paracentral scotomata within the patient's central visual field plays an important role in stereoscopic vision and should be considered when interpreting stereoscopic test results.

MACULAR TELANGIECTASIA TYPE 2: Quantitative Analysis of a Novel Phenotype and Implications for the Pathobiology of the Disease.

PURPOSE: To investigate retinal microcystoid spaces in macular telangiectasia type 2 with spectral domain optical coherence tomography. METHODS: Retrospective review of 135 patients enrolled in the MacTel Natural History Observation and Registry Study at Moorfields Eye Hospital, United Kingdom. One hundred seventy-two eyes from 86 patients who had a comparable scan protocol of at least 30 µm interval were included for analysis. Retinal microcystoid spaces were identified and segmented and metrics analyzed. RESULTS: From 172 eyes of 86 patients, microcystoid spaces were found in 11 eyes (6.4%) from 8 patients (9.3%). The mean number of microcystoid spaces per eye was 12.9 ± 18.2. Most were located in the inner nuclear layer. The inferonasal quadrant of the macula was the least commonly affected region. Microcystoid spaces were distributed entirely within the assumed macular telangiectasia area on blue light reflectance in all but 2 eyes (4 of 142 microcysts). The median diameter of the microcystoid spaces was 31 µm (range 15 µm-80 µm). CONCLUSION: Microcystoid spaces as a phenotype of macular telangiectasia should be considered in the differentials for microcystic edema. Understanding the pathogenesis of these lesions may provide further insight into the role of Müller cell dysfunction in this disorder.

CORRELATION OF CLINICAL AND STRUCTURAL PROGRESSION WITH VISUAL ACUITY LOSS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 6-The MacTel Research Group.

PURPOSE: To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity. METHODS: An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization. RESULTS: One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (-1.40 ± 0.14 letters, P < 0.001). CONCLUSION: Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.

EFFECT OF DARK ADAPTATION AND BLEACHING ON BLUE LIGHT REFLECTANCE IMAGING IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: In patients with macular telangiectasia Type 2, blue light reflectance imaging reveals an oval, parafoveal area in the macula that has increased reflectance compared with its surrounding. Here, we examine how dark adaptation and photobleaching can affect the blue light reflectance imaging pattern. METHODS: Prospective study of patients with macular telangiectasia enrolled in the MacTel Natural History Observation Study. After dark adaptation, a sequence of images was obtained with a confocal scanning laser ophthalmoscope at 488 nm. Change of reflectance patterns was analyzed over time. RESULTS: Eighteen eyes from 16 patients were analyzed. Initially, increased reflectivity in the parafoveal area resulted in higher gray values compared with the paramacular surrounding on blue light reflectance imaging. The difference between parafoveal and paramacular reflectance intensity decreased steadily during imaging, from 17.7 gray-value units (95% confidence interval: 12.1-23.2) down to 2.8 (95% confidence interval: -0.8 to 6.5) after around 30 seconds, and recovered after 5 minutes of dark adaptation. CONCLUSION: A bleaching effect was evident in our study. Understanding these changes is important for both diagnosis and assessment of blue light reflectance phenotype in patients with macular telangiectasia and could also provide further insights into the pathophysiology of this disease.

SCOTOMA CHARACTERISTICS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 7-The MacTel Research Group.

PURPOSE: To characterize scotomas in macular telangiectasia Type 2 (MacTel). METHODS: Five of the 27 centers performed microperimetry as part of the MacTel Natural History Observation Study. Data were analyzed in the Moorfields Eye Hospital Reading Centre. The number of stimuli under a threshold of 12, 10, 8, and <0 dB were counted (thresholding) and compared with one another. RESULTS: A total of 565 examinations were gradable, received from 632 eyes of 322 participants (age 61.1 ± 9.1 years, 62% females). The authors found absolute scotomas in 243 eyes (43%), 98% of these affected the temporal quadrant, and 99.5% were unifocal. Growth of absolute scotomas was limited to an extent of approximately 40 deg. Although transition from functionally unimpaired retina to absolute scotomas is generally steeply sloped, the larger a scotoma, the steeper it is. CONCLUSION: Scotoma features were consistent throughout a large MacTel cohort. The temporal quadrant was confirmed as predominantly affected, which might result from vascular or metabolic asymmetry. Functional loss did not exceed an area of 5° × 8° however advanced the disorder. Different MacTel phenotypes seem likely and point toward different types of progression; identifying these would improve planning for clinical trials and might lead to better understanding patient outcome.

LONGITUDINAL CORRELATION OF ELLIPSOID ZONE LOSS AND FUNCTIONAL LOSS IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To compare ellipsoid zone (EZ) loss and functional loss in macular telangiectasia (MacTel) type 2 longitudinally. METHODS: Prospective natural history study. Ellipsoid zone loss was measured in en-face images created from spectral domain optical coherence tomography. Functional loss was assessed by best-corrected visual acuity and microperimetry, counting the number of test points with impaired function. RESULTS: A total of 56 eyes of 31 participants were followed for 4.5 ± 1.2 years. Ellipsoid zone loss was 18,600 ± 3,917.3 pixel at baseline (≈0.59 mm) and increased 2,627.8 ± 427.9 pixel (≈0.08 mm) per year. Best-corrected visual acuity decreased 2.2 ± 0.9 letters per year. Change in EZ loss correlated significantly with change in relative and absolute scotomas (r = 0.62; P-value < 0.0001 and r = 0.72; P-value < 0.0001), but not with loss of best-corrected visual acuity. Functional loss showed a similar frequency of progression as EZ loss, but a higher rate of "regression," likely due to higher variability of the measurement, assuming a progressive neurodegenerative disease. CONCLUSION: The results of the authors support EZ loss as surrogate measure for visual function in MacTel type 2. Being objective, EZ loss might be considered more suitable than microperimetry as primary end point in future interventional trials.

ELECTROPHYSIOLOGICAL CHARACTERIZATION OF MACULAR TELANGIECTASIA TYPE 2 AND STRUCTURE-FUNCTION CORRELATION.

PURPOSE: To investigate the electrophysiological features of macular telangiectasia Type 2 and their relationship to structure as determined by optical coherence tomography imaging. METHODS: Forty-two eyes from 21 patients enrolled in the Macular Telangiectasia Natural History Observation Study were reviewed. All patients had full-field and pattern electroretinography (ERG; PERG) with some patients additionally having multifocal electroretinography (mfERG; N = 15) or electrooculography (N = 12). Multiple linear regression modeling assessed the relationship between the ellipsoid zone break size on optical coherence tomography and the central mfERG response. RESULTS: Full-field ERG and electrooculography were normal in all eyes. Six eyes (14%) from five patients had subnormal PERG P50 amplitudes. Twenty-two of 30 eyes (73%) had reduced central or paracentral stimulus on mfERG. There was a significant correlation between ellipsoid zone break size and both the P1 amplitude (R = 0.37, P = 0.002) and P1:N1 ratio (R = 0.32, P = 0.002) of the central response on mfERG. CONCLUSION: The electrophysiological findings in macular telangiectasia Type 2 are those of localized central dysfunction and are consistent with the structural data available from imaging and histologic studies. The ellipsoid zone break size correlates with mfERG reduction. The reduced mfERG P1:N1 ratio is consistent with inner retinal dysfunction.

In-vivo mapping of drusen by fundus autofluorescence and spectral-domain optical coherence tomography imaging.

PURPOSE: To determine fundus autofluorescence (FAF) signal variations and corresponding microstructural alterations on spectral-domain optical coherence tomography (SD-OCT) in areas of funduscopically visible drusen associated with age-related macular degeneration (AMD). METHODS: Thirty eyes from 22 patients with geographic atrophy (GA) secondary to AMD (median age 74, range 64-87 years), who had undergone retinal imaging including color fundus photography (CFP), FAF and SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) were retrospectively analyzed. In each eye, at least one druse (≥ 63 µm) in the perilesional zone of GA recorded on CFP was analyzed. Relative FAF intensities and alterations in SD-OCT bands at the site of each druse were evaluated. RESULTS: A total of 73 drusen were analyzed, which were associated with heterogeneous corresponding alterations on FAF and SD-OCT. The FAF signal was normal, increased, decreased or not evaluable in 32 (44 %), 27 (37 %), 12 (16 %), and 2 (3 %) drusen, respectively. Focal hyperreflectivity overlying drusen was most frequently spatially confined to increased FAF (present in 9 (33 %) of 27 drusen with increased FAF). Outer nuclear layer thinning and choroidal hyperreflectivity were associated with decreased FAF (present in 7 [58 %] of 12 and 6 [50 %] of 12 drusen with decreased FAF, respectively). CONCLUSIONS: The appearance of soft drusen on CFP does not allow for differentiation between preserved and markedly compromised outer retinal integrity, including incipient atrophy and focal neurosensory alterations of reflectivity overlying extracellular sub-retinal pigment epithelium (RPE) deposits. Multimodal imaging reveals a broad spectrum of microstructural changes, which may reflect different stages in the evolution of drusen.

VERY EARLY DISEASE MANIFESTATIONS OF MACULAR TELANGIECTASIA TYPE 2.

BACKGROUND: To report very early morphologic and functional alterations in patients with macular telangiectasia type 2. METHODS: Patients with asymmetric disease manifestations, in whom retinal alterations characteristic for macular telangiectasia type 2 were present in one but not in the apparently unaffected fellow eye, underwent multimodal imaging and functional testing (microperimetry, visual acuity, reading ability, Amsler test). RESULTS: Fellow eyes not allowing the diagnosis of macular telangiectasia type 2 based on hitherto diagnostic standards consistently showed a severely reduced directional cone reflectance (Stiles-Crawford effect). Optical coherence tomography revealed an asymmetric configuration of the foveal pit with focal temporal thinning most pronounced at 1° eccentricity. Topographically related, macular pigment optical density was reduced in a small wedge-shaped temporal paracentral sector, resulting in an increased signal on fundus autofluorescence and fluorescein angiography imaging. No functional deficits were detectable in fellow eyes. Haidinger brushes were perceived in the fellow eye but not in the affected index eye with pronounced loss of macular pigment. CONCLUSION: Specific morphologic alterations precede vascular alterations and functional deficits in macular telangiectasia type 2. The described alterations indicate a primarily degenerative process with a secondary retinal vascular phenotype, and may be helpful for early identification of patients and affected family members.

POOR LONG-TERM OUTCOME OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN NONPROLIFERATIVE MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To investigate long-term effects after intravitreal inhibition of vascular endothelial growth factor in nonproliferative macular telangiectasia type 2. METHODS: Nine patients with macular telangiectasia type 2 treated with 12 monthly intravitreal ranibizumab injections in 1 eye were investigated again after a mean follow-up of 6.0 ± 0.4 years. Functional assessment included best-corrected visual acuity and microperimetry testing. Morphologic investigations included optical coherence tomography imaging and fluorescein angiography. RESULTS: Mean visual acuity at baseline was similar in treated and control eyes (both 20/50; range: 20/32-20/125 in the treated eyes and 20/25-20/100 in the untreated eyes). None of the eyes had a neovascular membrane or a paracentral scotoma. At the last follow-up, more eyes of the treatment group had lost 2 or more lines on best-corrected visual acuity testing (4 vs. 1) and more eyes had developed an absolute paracentral scotoma (7 vs. 2). A secondary neovascular membrane had formed in four of the treated and in none of the untreated eyes. CONCLUSION: Vascular endothelial growth factor inhibition with monthly dosing over 1 year had no beneficial effect 5 years after cessation of therapy. The worse outcome in the treated eyes may be due to selection bias, small sample size, or a potential adverse effect of vascular endothelial growth factor inhibition in a degenerative, primarily nonvascular disease as macular telangiectasia type 2.

First symptoms and their age of onset in macular telangiectasia type 2.

PURPOSE: To investigate the first symptoms and their age of onset in a large cohort of patients with macular telangiectasia type 2. METHODS: Patients with the characteristic findings of macular telangiectasia type 2 were interviewed. Data collection also included a chart review to determine the delay of the correct diagnosis and visual function 10 years after the onset of first symptoms. RESULTS: Of 91 patients, 72 (79%) reported impaired reading ability as their first symptom, followed by metamorphopsia in 12%. The age of onset was most frequent (76%) in the sixth or seventh decade of life (50-69 years), and 58% of the patients were symptomatic before the age of 60 years. The median delay between first symptoms and the diagnosis of macular telangiectasia type 2 before the year 2005 was 7 years and has decreased to 1 year thereafter. Ten years after the onset of first symptoms, distance visual acuity of the better eye was ≥20/25 in 35% and ≤20/50 in 17%. CONCLUSION: Impaired reading ability was the most common initial visual disturbance of patients with macular telangiectasia type 2, starting generally between the age of 50 and 70 years. Knowledge of the presenting symptoms of macular telangiectasia type 2 together with recently identified characteristic morphologic alterations on retinal imaging will likely lead to earlier accurate diagnosis of this disease entity.