ASSOCIATIONS BETWEEN AUTOFLUORESCENCE ABNORMALITIES AND VISUAL ACUITY IN IDIOPATHIC MACULAR TELANGIECTASIA TYPE 2 MacTel Project Report Number 5 KONSTANTINOS BALASKAS, MD,*†‡ IRENE LEUNG, PHD,† FERENC B. SALLO, PHD,†§ TRACI E. CLEMONS, PHD,¶ ALAN C. BIRD, PHD,** TUNDE PETO, PHD,†† ON BEHALF OF THE MACTEL PROJECT STUDY GROUP Purpose: The aim of this study was to determine whether typical abnormalities seen on autofluorescence (AF) imaging in patients with macular telangiectasia (MacTel) type 2 are correlated with visual acuity at presentation and with progression of visual loss over a 2-year follow-up period. Methods: A subgroup of 218 patients (413 eyes) enrolled in the MacTel study that underwent AF imaging was included in the present study. Images were graded at the Moorfields Eye Hospital Reading Center. Recorded AF abnormalities at baseline and at 2 years included the presence of increased AF because of loss of masking at the central macula, localized decreased AF at the end of a retinal vessel, and large area of decreased AF. Best-corrected visual acuity was measured using the Early Treatment for Diabetic Retinopathy chart at baseline and after 2 years. Statistical associations were sought by means of a generalized linear model. Results: Presence of increased macular AF (P = 0.004), a large area of decreased AF (P , 0.001), or decreased AF at the end of a retinal vessel (P , 0.001) at baseline were significantly associated with worse best-corrected visual acuity. Presence of increased macular AF (P , 0.001) or of localized decreased AF at the end of a retinal vessel (P , 0.001) and the absence of a large area of decreased AF (P , 0.001) were predictive of a subtle but significant drop in best-corrected visual acuity at 2 years. Conclusions: Increased central AF at baseline heralds worse best-corrected visual acuity and predicts further subtle visual loss in a period of 2 years, which, however, does not stand out from the overall slowly progressive natural history of the disease. RETINA 34:1630–1636, 2014

H

the retinal pigment epithelium layer.8 Pathologic processes associated with MacTel within the retinal layers in the path of the autofluorescent light alter its visibility. The depletion of luteal pigment characteristic of MacTel may lead to a “window defect” appearing as increased autofluorescence (AF) within 1 disk diameter of the foveal center.9,10 Plaques in the mid-retina containing brown pigment block normal AF and may appear as large areas of decreased AF. These plaques typically involve blood vessels (veins or venules) and appear initially temporal to the foveal center as a “localized decrease of AF at a vessel.” Although AF imaging is quite widely available, information about the functional significance of AF signs of MacTel is sparse.11

istorically idiopathic macular telangiectasia (MacTel) type 2 has been considered a disease of the retinal vasculature. However, some of the characteristic changes described by Gass and Blodi1 already 40 years ago, namely the presence of crystals and retinal opacification, appeared inconsistent with the prevailing pathogenetic model, suggesting a primarily vascular disease. Over the last few years, it has become evident that photoreceptor loss is integral to disease and it may now be considered a disorder of neuroglial origin.2–6 Autofluorescence imaging at 488 nm demonstrates a number of characteristic changes in MacTel type 2.7 Autofluorescent light at this excitation wavelength emanates mainly from components of lipofuscin in 1630

AUTOFLUORESCENCE AND VISUAL ACUITY IN MACTEL 2  BALASKAS ET AL

The high variability of psychophysical testing renders the verification of functional deterioration difficult in a slowly progressive disease, such as MacTel type 2. Objective surrogate markers, such as the ones derived from image analysis, may serve to indicate functional deterioration. Since not all structural alterations over time are functionally meaningful, surrogate markers, such as AF patterns, need to be validated against true clinical endpoints. The purpose of the present work stemming from the MacTel Project was to describe the association between visual acuity and AF features in MacTel type 2 at baseline and after 2 years of followup. It is thus attempted to assess whether functional significance can be ascribed to the AF patterns encountered in MacTel and whether these can serve as clinically meaningful markers of disease progression. Methods Patients were selected from the cohort of the MacTel Project’s Natural History Study, a multi-center, prospective, longitudinal observational study of the disease phenotype, currently involving 27 research centers worldwide.12 The study protocol adheres to the tenets of the Declaration of Helsinki and was approved by the institutional ethics committee of each participating center. Written informed consent was obtained from each participant after explanation of the nature of the study. The main inclusion and exclusion criteria as well as data collection strategies for the study have been published previously.12 By December 31, 2011, a total of 554 participants were enrolled. Participants are followed annually by a full ophthalmologic examination comprising of functional tests (best-corrected visual acuity [BCVA] and where available microperimetry) and multimodal fundus photographic imaging, including From the *Medical Retina Service, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; †Department of Research and Development, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; ‡Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; §UCL Institute of Ophthalmology, London, United Kingdom; ¶The EMMES Corporation, Rockville, Maryland; **Inherited Eye Disease, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; and ††NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom. Supported by the Lowy Medical Research Institute and the National Institute for Health Research. None of the authors have any financial/conflicting interests to disclose. The list of all Participating Principal Investigators and Centers in the MacTel Study can be found in the Appendix. Reprint requests: Konstantinos Balaskas, MD, Department of Research and Development, Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London EC1V 2PD, United Kingdom; e-mail: konstantinos.balaskas@moorfields.nhs.uk

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color fundus, fluorescein angiography, and AF images. Best-corrected visual acuity is measured according to the Early Treatment Diabetic Retinopathy Study protocol.13 In our current analysis, we focus on features of MacTel type 2 in AF images. Patients with available AF imaging of gradable quality and at least 2 years of follow-up were included. AF images were only taken at sites where the appropriate equipment is available and the AF protocol certification procedure was used to ensure that the images were of the required quality. AF images were obtained before fluorescein angiography. Pupils were fully dilated and the participant was comfortably seated as for routine AF imaging. Focus on the retinal plane was ascertained in the reflection and red-free mode. Requirements were that the whole macular area be visible with the optic disc and the arcades at the edge of the image. Between 10 and 15 good quality images per participant were acquired and then aligned and averaged with the analysis software to achieve a single good quality AF image of each macula. AF images were acquired using Heidelberg Retinal Angiograph 2 or Spectralis scanning laser ophthalmoscope devices (Heidelberg Engineering, Heidelberg, Germany). Few AF images (12 patients at 2 sites) were acquired digitally using Topcon TRC-50DX fundus cameras equipped with a Spaide AF filter system (Topcon Medical Systems, Inc, Tokyo, Japan). The central 6,000-mm area of the macular region (as defined by the International Classification for AMD grading grid14) in AF images was graded for the presence of increased central AF (within 1000 mm of the foveal center), defined as the presence of a higher grayscale value clearly detectable to the human eye that may or may not involve the foveal center (Figure 1, A and B) and for the presence of areas of decreased AF that may be minor patches at the end of a retinal vessel or more extensive, involving larger areas (larger than approximately 500 mm in diameter; Figure 2, A and B). The two categories of decreased AF are mutually exclusive. Autofluorescence images from 25 sites within the study were analyzed. Grading was performed independently by two certified graders (I.L., T.P.) masked to the identity and clinical data of the patients. Gradings were compared and a final copy was created by adjudication (T.P., A.C.B.). Any statistically significant change in visual acuity was deemed as clinically relevant for the purposes of this study, given the slowly progressive natural history of the disease. To describe the association of MacTel type 2 AF features with visual acuity, a generalized linear model was used incorporating generalized estimation equations to account for the correlation between eyes. P , 0.05 was accepted as statistically significant, given the exploratory nature of these analyses. Descriptive statistics are

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2014  VOLUME 34  NUMBER 8

Fig. 1. A and B. Examples of the typical pattern of increased macular AF in MacTel type 2.

expressed in terms of means (standard deviation/ standard error) or proportions. All analyses were conducted using commercially available statistical software (SAS version 9.2; SAS Institute, Cary, NC).

Results Of the 554 participants enrolled in the MacTel Natural History Study, 218 had 2 years of AF images and corresponding visual acuity data available. Table 1 provides a summary of the baseline characteristics of the 218 patients included in this report. The mean time between disease diagnosis and enrollment into the study was 2.6 ± 3.9 years. Approximately, half of the patients were enrolled around the time of their MacTel diagnosis while 18% were enrolled 5 or more years after their initial diagnosis. Of the 218 patients, 23 (11%) had

Fig. 2. A. Example of a large central area of decreased AF corresponding to a pigmentary plaque obscuring underlying AF of the retinal pigment epithelium. B. Example of decreased AF at the end of a retinal vessel corresponding to localized pigmentary migration.

1 eye treated for MacTel type 2. These treated eyes are excluded from the analyses, resulting in a total of 413 eyes included in the analyses to follow. Visual acuity at baseline and at 2 years for the 413 eyes is provided in Table 2. Mean visual acuity at baseline was 71.7 ± 0.9 letters dropping to 69.5 ± 0.9 letters at 24 months. Newly diagnosed participants’ mean BCVA acuity was 73.1 ± 1.0 letters compared with 63.8 ± 1.8 letters for participants with 5 or more years between diagnosis and enrollment. Mean change in BCVA between baseline and 2 years was −2.2 ± 0.6 letters (P , 0.001). Table 3 provides a summary of the associations between baseline BCVA and MacTel type 2 features identified on AF imaging. The typical MacTel type 2 AF pattern of increased central AF was present in 77% of the 413 MacTel type 2 eyes at baseline. The presence of localized decrease in AF at the end of a retinal

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AUTOFLUORESCENCE AND VISUAL ACUITY IN MACTEL 2  BALASKAS ET AL Table 1. Participant Characteristics (N = 218) Characteristic Age (years) at enrollment Mean (SD), years Age (years) at enrollment, N (%) ,50 50–59 60–69 $70 Gender, N (%) Male Female Time from diagnosis to MacTel study enrollment Mean (SD), years Time from diagnosis to MacTel study enrollment Newly diagnosed ,2 years ,5 years $5 years

60.3 (8.9) 23 74 91 30

(10) (34) (42) (14)

85 (39) 133 (61) 2.6 (3.9) 99 47 32 40

visual acuity at 2 years. Visual acuity decreased significantly by 1.7 ± 0.6 letters (P , 0.001) for eyes with the typical MacTel type 2 AF pattern at baseline. Visual acuity decreased, but not significantly, for those eyes without the pattern by 0.9 ± 1.0 letters. Bestcorrected visual acuity loss did not meet statistical significance for eyes with a large area of decreased AF either with or without center involvement. Finally, the mean change in visual acuity at 2 years for eyes with localized decreased AF at the end of a retinal vessel was −2.1 ± 0.8, and this feature was significantly associated with a decrease in visual acuity at 2 years (P , 0.001). Worthy of note, between-group comparisons of changes in BCVA after 2 years were in all cases statistically nonsignificant.

(45) (22) (15) (18)

vessel, usually associated with the presence of a small pigment plaque, was observed in 33% of eyes. Approximately 6% of eyes presented with a large area of decreased AF (2% with and 4% without center involvement), indicative of central pigment plaque. Mean visual acuity of eyes with the typical MacTel type 2 AF pattern was significantly lower compared with eyes without the pattern (66.5 ± 1.1 letters vs. 71.4 ± 1.6 letters, P = 0.004). Furthermore, mean visual acuity was lower for eyes with a large area of decreased AF either with (51.4 ± 4.4; P , 0.001) or without (54.2 ± 5.5; P = 0.01) the center involved compared with eyes without a large area of decreased AF (68.7 ± 0.9). Eyes with the presence of localized decreased AF at the end of a retinal vessel had significantly lower mean visual acuity (62.2 ± 1.4 letters) compared with eyes without this feature (70.9 ± 1.2 letters; P , 0.001). Table 3 also summarizes the associations between specific patterns on AF and change in

Discussion The “MacTel Project” (http://www.mactelresearch. org) unites clinical and basic science laboratories with the view to establishing the pathogenetic model and potential treatment options in MacTel type 2.11,12,15–18 In the present report, the associations between features identified on AF imaging and BCVA in a subgroup of patients with at least 2-years of follow-up are presented. Using a 488 nm excitation stimulus, lipofuscin, a byproduct of the metabolism of the photoreceptor outer segments by the retinal pigment epithelium8 is considered the primary source of AF. Masking of AF by absorbing pigments can affect AF patterns.19 Macular pigments, such as lutein and zeaxanthin, in particular, strongly absorb short wavelengths, resulting in the typical appearance of the normal retina on blue light AF images that shows foveal masking because of the central accumulation of macular pigment.8 A typical pattern of AF in MacTel type 2 consists of loss of the normal central attenuation and consequent increase in central AF primarily because of loss of masking from macular pigment.9,10 The loss of luteal

Table 2. Visual Acuity for MacTel Type 2 Eyes (N = 413) VA at Baseline Mean (SE)* VA at baseline (all) Newly diagnosed ,2 years ,5 years $5 years

71.7 73.1 69.3 63.8 63.8

(0.9)‡ (1.0) (1.7) (3.0) (1.8)

95% CI 70.0–73.5 71.3–75.0 66.0–72.5 57.8–69.7 60.2–67.4

VA at 2 years Mean (SE)* 69.5 71.4 66.5 62.4 63.5

(0.9)‡ (1.0) (1.7) (3.2) (1.8)

95% CI 67.7–71.3 69.5–73.5 63.2–69.8 56.1–68.7 60.0–67.0

Change in VA Mean (SE)* −2.2 −1.7 −2.8 −1.4 −0.2

(0.6) (0.7) (1.2) (0.9) (1.3)

P† ,0.001 0.02 0.02 0.11 0.84

*Mean visual acuity or change in visual acuity in study eyes using generalized linear models and the generalized estimation equation method to account for correlation between eyes. †P from test of whether mean differs from zero. ‡Means adjusted for time (years) between diagnosis and enrollment. VA, visual acuity; SE, standard error; CI, confidence interval.

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2014  VOLUME 34  NUMBER 8

Table 3. Association Between Visual Acuity at Baseline and Change in Visual Acuity at 2 Years and MacTel Type 2 Features Measured by AF at Baseline (N = 413) Baseline VA

AF Increased AF within 1 DD (center-involving) Absent Present Increased AF within 1 DD (non-center-involving) Absent Present Large area of decreased AF Absent Present, center point not involved Present, center point involved Localized decreased AF at vessel Absent Present

P†

0.004

−1.1 (1.0) −1.6 (0.6)‡

0.69

70.1 (1.9) 66.7 (1.0)

0.07

−0.9 (1.0) −1.7 (0.6)‡

0.44

390 (94) 7 (2) 16 (4)

68.7 (0.9) 54.2 (5.5) 51.4 (4.4)

0.01 ,0.001

−1.84 (0.5)‡ 1.5 (2.1) 2.8 (2.6)

0.11 0.08

276 (67) 137 (33)

70.9 (1.2) 62.2 (1.4)

,0.001

−1.1 (0.7) −2.1 (0.8)‡

0.31

Mean (SE)*

93 (23) 320 (77)

71.4 (1.6) 66.5 (1.1)

95 (23) 318 (77)

P†

Change in VA at 2 Years Mean (SE) Change in VA

Eyes (%)

*Mean visual acuity in study eyes using generalized linear models and the generalized estimation equation method to account for correlation between eyes and adjusted for time between diagnosis and enrollment. †P-value from generalized linear model compared with the reference (“absent”) group. ‡Change in visual acuity significantly different from zero for the characteristic of interest (P , 0.001). VA, visual acuity; SE, standard error; DD, disk diameter.

pigment starts temporal of the foveal center, progresses to a loss of the central peak to finally encompass an oval area of loss around the foveal center, with a margin of increased pigment content in the parafovea.20 Although an increased macular AF secondary to loss of luteal pigment can accompany any case of photoreceptor drop-out, the characteristic oval-shaped configuration with predilection for the temporal macula and gradual progression to encompass an area of approximately 1 disk diameter in size centered on the fovea is strongly suggestive of the condition. On AF in MacTel type 2, dense pigment at the end of retinal vessels is visible, corresponding to decreased AF at the end of the vessel.21 Presence of a large area of decreased AF, although exceedingly rare in MacTel type 2, was included in the analysis as a separate AF pattern in view of its seemingly significant detrimental effect on visual acuity. In relevant cases, decreased AF was most commonly caused by masking of the underlying AF by a pigment plaque present in the foveal area or corresponded to neuroretinal and retinal pigment epithelium atrophy. It should be underlined that while half of included patients enrolled at the time of diagnosis of MacTel type 2, 16% of cases enrolled more than 5 years after the initial diagnosis. Patients with a longer disease history presented with lower mean visual acuity at baseline, although their vision did not seem to become significantly worse at the end of follow-up. However, patients with recent diagnosis, although exhibiting better initial visual acuity, had a subtle although

significant drop over a 2-year period. This discrepancy in disease progression in relation to the time elapsed between disease diagnosis and enrollment to the study may allow some speculation as regards the natural history of the disease. It is likely that patients with MacTel type 2 go through a period of undefined duration when visual symptoms are minimal and the disease remains elusive, followed by a period of aggravation that prompts ophthalmologic assessment leading to disease diagnosis. Slowly progressive loss of central vision occurs for a period of several years, reaching a plateau beyond which further deterioration does not occur but for the development of subretinal neovascularization or foveal extension of photoreceptor loss. Increased AF was significantly associated with worse visual acuity at baseline. A reasonable assumption would be that the presence of the MacTel type 2 AF pattern at baseline may signify a more advanced stage of the disease already at diagnosis and may be suggestive of a higher rate of photoreceptor loss. In a recent study, increased AF in MacTel type 2 was associated with areas of photoreceptor drop-out or retinal cysts,20 signifying that increased AF is a reflection of the structural degradation of retinal tissue in the disease process, thus justifying the association with functional compromise. Müller cell dysfunction has been suggested as a central feature in the pathogenesis of MacTel type 2. Through their intimate connections with cone photoreceptors, Müller cells provide nutritional and regulatory support both to retinal neurons

AUTOFLUORESCENCE AND VISUAL ACUITY IN MACTEL 2  BALASKAS ET AL

and vascular cells. Loss of macular pigment in MacTel type 2 could conceivably be triggered by impairment in Müller cells. A subtle, yet statistically significant, drop in visual acuity was observed at 2 years when the typical AF pattern of MacTel type 2 was present. This small worsening of visual acuity in patients presenting the typical AF pattern over a 2-year period may originate from extension of macular pigment depletion and photoreceptor drop-out encroaching toward the fovea. However, patients without the typical AF pattern also presented with a comparable subtle loss in BCVA after 2 years, although this was not found to be statistically significant. When comparing changes in BCVA at 2 years between eyes presenting increased AF versus those that did not, the difference was not found to be statistically significant. This may be due to the relatively short follow-up period of our study; it may, however, also suggest, in essence, that the presence of increased AF predisposes to a significant change in visual acuity at 2 years, although the change is very subtle and does not stand out from the overall very slowly progressive natural history of the disease. Its role, therefore, as a prognosticator of functional progression is of limited clinical usefulness, at least regarding distance visual acuity. In MacTel type 2, dense pigment at the end of retinal vessels appears as decreased AF.21 Even when larger, decreased AF was caused by masking of underlying AF by a pigment plaque present in the foveal area rather than retinal pigment epithelium atrophy. The presence of decreased AF, irrespective of its extent, correlated significantly with worse initial visual acuity. Patients with large area of decreased AF at baseline, corresponding to pigment plaques, were more severely affected and did not show signs of further deterioration over a 2-year period, presumably because of already present advanced disease changes with minimal scope for further deterioration. A particular consideration in any attempt to correlate structural changes as evidenced by AF and function in MacTel type 2 relates to the fact that in this condition, distance visual acuity may be preserved until late into the disease.22,23 Decline in paracentral sensitivity temporally to the fovea, however, is of particular importance23 because these paracentral scotomata have a detrimental effect on reading ability.22 Although distance visual acuity does not seem to be a sensitive marker of progression in MacTel type 2, it remains the most widely accepted clinical endpoint in ophthalmology and was deemed an appropriate outcome measure for this preliminary attempt to ascribe functional relevance to observed AF patterns. Structural changes detected on AF imaging can be more

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functionally meaningful than suggested by the sole analysis of distance visual acuity, however, and other measures of visual performance, such as reading speed, may be disproportionately affected. Moreover, the follow-up interval of 2 years may be inadequate for the prognostic value of AF patterns to be fully appreciated against the backdrop of a very slowly progressive natural history. In conclusion, our findings indicate that AF imaging may offer useful clues about disease severity in MacTel type 2. Further study may serve to accrue information on the associations between AF patterns and other meaningful measures of visual function, such as reading performance. Key words: idiopathic macular telangiectasia type 2, autofluorescence, visual acuity, imaging. Acknowledgments The authors wish to thank the Lowy Medical Research Institute and the National Institute for Health Research for providing support for funding this study. The Lowy Medical Research Institute also participated in the design of the study and in the review and approval of the manuscript. References 1. Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and follow-up study. Ophthalmology 1993;100:1536–1546. 2. Cherepanoff S, Killingsworth MC, Zhu M, et al. Ultrastructural and clinical evidence of subretinal debris accumulation in type 2 macular telangiectasia. Br J Ophthalmol 2012;96:1404–1409. 3. Esposti SD, Egan C, Bunce C, et al. Macular pigment parameters in patients with macular telangiectasia (MacTel) and normal subjects: implications of a novel analysis. Invest Ophthalmol Vis Sci 2012;53:6568–6575. 4. Powner MB, Gillies MC, Tretiach M, et al. Perifoveal Müller cell depletion in a case of macular telangiectasia type 2. Ophthalmology 2012;117:2407–2416. 5. Sallo FB, Peto T, Egan C, et al. En face OCT imaging of the IS/OS junction line in type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci 2012;53:6145–6152. 6. Sallo FB, Peto T, Egan C, et al. The IS/OS junction layer in the natural history of type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci 2012;53:7889–7895. 7. Issa PC, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Prog Retin Eye Res 2013;34:49–77. 8. Delori FC, Dorey CK, Staurenghi G, et al. In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci 1995;36: 718–729. 9. Theelen T, Berendschot TT, Boon CJ, et al. Analysis of visual pigment by fundus autofluorescence. Exp Eye Res 2008;86: 296–304. 10. Wong WT, Forooghian F, Majumdar Z, et al. Fundus autofluorescence in type 2 idiopathic macular telangiectasia:

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correlation with optical coherence tomography and microperimetry. Am J Ophthalmol 2009;148:573–583. Schmitz-Valckenberg S, Ong EE, Rubin GS, et al. Structural and functional changes over time in MacTel patients. Retina 2009;29:1314–1320. Clemons TE, Gillies MC, Chew EY. Baseline characteristics of participants in the natural history study of macular telangiectasia (MacTel) MacTel Project Report No. 2. Ophthalmic Epidemiol 2010;17:66–73. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796–1806. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995;39:367–374. Charbel Issa P, Berendschot TT, Staurenghi G, et al. Confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci 2008;49:1172–1177. Clemons TE, Gillies MC, Chew EY, et al. The National Eye Institute visual function questionnaire in the macular telangiectasia (MacTel) project. Invest Ophthalmol Vis Sci 2008;49: 4340–4346. Parmalee NL, Schubert C, Merriam JE, et al. Analysis of candidate genes for macular telangiectasia type 2. Mol Vis 2010; 16:2718–2726. Sallo FB, Leung I, Chung M, et al. Retinal crystals in type 2 idiopathic macular telangiectasia. Ophthalmology 2011;118: 2461–2467. Imamura Y, Fujiwara T, Spaide RF. Fundus autofluorescence and visual acuity in central serous chorioretinopathy. Ophthalmology 2011;118:700–705. Degli Esposti S, Egan C, Bunce C, et al. Macular pigment parameters in patients with macular telangiectasia (MacTel) and normal subjects: implications of a novel analysis. Invest Ophthalmol Vis Sci 2012;53:6568–6575. Bottoni F, Eandi CM, Pedenovi S, et al. Integrated clinical evaluation of type 2a idiopathic juxtafoveolar retinal telangiectasis. Retina 2010;30:317–326. Finger RP, Charbel Issa P, Fimmers R, et al. Reading performance is reduced due to parafoveal scotomas in patients with macular telangiectasia type 2. Invest Ophthalmol Vis Sci 2009; 50:1366–1370. Charbel Issa P, Helb HM, Rohrschneider K, et al. Microperimetric assessment of patients with type II macular telangiectasia. Invest Ophthalmol Vis Sci 2007;48:3788–3795.

Appendix. Participating Centers and Principal Investigators in the MacTel Study Jose-Alain Sahel, MD, PhD, Centre Hopitalier National D’Optalmologie des Quinze-Vingts, Paris, France. Robyn Guymer, MD, Centre for Eye Research, East Melbourne, Australia.



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Gisele Soubrane, MD, PhD, FEBO, Clinique Ophtalmolgie de Creteil, Creteil, France. Alain Gaudric, MD, Hopital Lariboisiere, Paris, France. Steven Schwartz, MD, Jules Stein Eye Institute, UCLA, Los Angeles, CA. Ian Constable, MD, Lions Eye Institute, Nedlands, Australia. Michael Cooney, MD, MBA, Manhattan Eye, Ear, & Throat Hospital, New York, NY. Catherine Egan, MD, Moorfields Eye Hospital, London, United Kingdom. Lawrence Singerman, MD, Retina Associates of Cleveland, Cleveland, OH. Mark C. Gillies, MD, PhD, Save Sight Institute, Sydney, Australia. Martin Friedlander, MD, PhD, Scripps Research Institute, La Jolla, CA. Daniel Pauleikhoff, Prof. Dr., St. Franziskus Hospital, Muenster, Germany. Joseph Moisseiev, MD, The Goldschleger Eye Institute, Tel Hashomer, Israel. Richard Rosen, MD, The New York Eye and Ear Infirmary, New York, NY. Robert Murphy, MD, The Retina Group of Washington, Fairfax, VA. Frank Holz, MD, University of Bonn, Bonn, Germany. Grant Comer, MD, University of Michigan, Kellogg Eye Center, Ann Arbor, MI. Barbara Blodi, MD, University of Wisconsin, Madison, WI. Diana Do, MD, The Wilmer Eye Institute, Baltimore, MD. Alexander Brucker, MD, Scheie Eye Institute, Philadelphia, PA. Raja Narayanan, MD, LV Prasad Eye Institute, Hyderabad, India. Sebastian Wolf, MD, PhD, University of Bern, Bern, Switzerland. Philip Rosenfeld, MD, PhD, Bascom Palmer, Miami, FL. Paul S. Bernstein, MD, PhD, Moran Eye Center, University of Utah, Salt Lake City, UT. Joan W. Miller, MD, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.