Abstract
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.
Macular telangiectasia type 2 (MacTel) is a degenerative disease of the central retina with typical vascular alterations.1 The first symptoms usually are reading problems, distorted central vision, or both in the fifth, sixth, or seventh decade of life, but age of onset may vary considerably.2 A characteristic feature of vision loss is a progressive focal paracentral scotoma resulting from photoreceptor loss that first occurs temporal to the foveal center and that may be mapped using microperimetry testing.3,4
Best-corrected visual acuity (BCVA) may remain well preserved over prolonged periods. Several larger case series indicate that a significant drop in BCVA may occur when the scotoma (or a structural surrogate marker) progresses also to involve the foveal center4 or when the disease course is complicated by the development of a neovascular membrane or macular hole.1 Overall, however, loss in BCVA is slow, with a documented mean decrease of approximately 1 letter per year, based on longitudinal data from the MacTel Project with a mean follow-up of 4.2 years (range, 1–6 years).5
The frequency distribution of BCVA levels in people with MacTel has not been investigated yet in detail. Moreover, little is known about the retinal phenotype of those with the worst visual function, representing the natural end point of the disease. A limitation of functional loss to the central macular area was suggested previously,4,6 and characteristic findings on advanced imaging such as confocal blue light reflectance or dual-wavelength autofluorescence indicate that structural damage is also limited to a specific oval-shaped area, which is referred to as the MacTel area.7–9 A better characterization of the topographic dimensions of disease-related alterations in eyes with late-stage disease could strengthen the concept of such a MacTel area to which degeneration would remain limited, even in late disease stages.
The aim of this study was to report the range of visual acuity measures from the MacTel Natural History Observation Registration Study and to investigate and describe phenotypic findings in eyes with substantial vision loss resulting from MacTel. The findings prepare the ground for a better understanding of the natural history of MacTel and its anatomic and functional end points and may guide patient counselling.
Methods
The MacTel Natural History Observation Study recruited patients with MacTel from 2005 through 2011, as well as age-matched, unrelated control participants without retinal disease. Participants in the Natural History Observation Study were followed up for at least 5 years. After 2011, new participants were enrolled in the MacTel Natural History Observation Registration Study for a single clinic visit only and an annual telephone review. Patients were identified and recruited at participating study centers, and family members also were invited to be screened for presence of MacTel. The diagnosis of MacTel was confirmed by the Moorfields Eye Hospital Reading Center (MEHRC), based on diagnostic features on multimodal imaging. Initially, this mainly included color fundus and fluorescein angiography images in accordance with the classification by Gass and Blodi.10 Later, characteristic findings on OCT scans and fundus autofluorescence images were used increasingly for confirming the diagnosis.1 At database access, 60 centers worldwide were actively recruiting patients. Institutional review board or ethics committee approval was obtained at each center. The study was conducted in accordance with the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. The presence of common phenotypic characteristics of MacTel, such as retinal crystals, retinal greying, blunted retinal vessels, and pigment plaques, was graded in all eyes by certified graders of the MEHRC. Other details of the study protocol were published previously.11
Best-Corrected Visual Acuity Analysis
Best-corrected visual acuity (BCVA) was obtained using the standard Early Treatment Diabetic Retinopathy Study (ETDRS) protocol.12 The clinical databases of both the Natural History Observation Study and the Natural History Observation Registration Study were accessed on May 30, 2019, to extract data of all patients with a confirmed diagnosis of MacTel. Best-corrected visual acuity of the last study visit was extracted. Severe vision loss was defined as BCVA of 38 letters or fewer, which is approximately equivalent to a Snellen visual acuity of 20/200, the threshold for legal blindness in the United States. Other BCVA cutoffs were 68 letters or fewer (Snellen equivalent, approximately 20/50) and 23 letters or fewer (Snellen equivalent, approximately ≤20/400), the thresholds for driving and for legal blindness in many European countries, respectively.
Eyes with other causes for severe vision loss were excluded from analysis (Fig S1 and Table S1, both available at www.aaojournal.org). All eyes with severe vision loss were reviewed for plausibility of the BCVA test result based on the previous ocular and medical history as well as retinal imaging data—stored on MEHRC servers—including color fundus photography (CFP), fluorescein angiography (FA), and OCT scans. This included grading of presence of outer retinal atrophy, subretinal fibrosis, or full-thickness macular hole (FTMH) within the foveal area (corresponding to ETDRS field 1). The center of the foveal area was defined as the center of the foveal avascular zone as seen on FA. In advanced cases or when imaging did not allow for visualization of foveal capillaries, the location of the foveal center was estimated based on the location of the second- and third-degree retinal vasculature. Whenever the foveal structure or other ocular findings did not explain low BCVA sufficiently in the experience of 2 retinal specialists (P.C.I. and T.F.C.H.), the sites were contacted and asked for data confirmation. A suspected data entry error was confirmed in 106 cases, and the information obtained from database access was updated. Thirty-six queries were not resolved, and those eyes were excluded from analysis (Fig S1).
Eyes with Neovascularization and Full-Thickness Macular Holes
Eyes were graded for presence of neovascular changes and FTMHs. Neovascular changes included large hemorrhages or fibrotic scars on CFP; neovascular membranes on FA; subretinal fibrosis, fibrovascular (hyperreflective) pigment epithelium detachment, or both with or without intraretinal or subretinal fluid on OCT.
Asymmetry of Earliest Cases
Because the BCVA data suggested an asymmetry between right and left eyes (see Results section), we analyzed phenotypic asymmetry in patients with very early stages of disease, because subtle differences between eyes in later disease stages may not be as obvious. For this, all eyes that had been labelled as early MacTel by the MEHRC were readjudicated by one of the authors (T.F.C.H.) to group those eyes into 2 categories: (1) eyes with no retinal abnormality on any imaging method used, but in which the fellow eye showed typical signs of the condition (apparently unilateral MacTel), and (2) eyes with no changes on CFP, no or only very little leakage on FA, and very mild changes on OCT images, such as foveal asymmetry or mild inner retinal hyperreflectivity (asymmetric MacTel).13
Quantification of the Macular Telangiectasia Area
The area of any visible changes (staining and leakage) on late-phase FA images of eyes with BCVA of 20/200 or worse was measured using Fiji imaging softwar14 (version 2.0.0) by a single grader (T.F.C.H.). The maximum horizontal and vertical dimensions of the retinal changes were set in relation to the distance between the temporal optic margin and the foveal center as a reference (Fig S2, available at www.aaojournal.org). The foveal center was defined as described above.
Measurement of Retinal Thickness Based on OCT
Retinal thickness was measured using OCT imaging data obtained with Heidelberg Spectralis devices (Heidelberg Engineering, Heidelberg, Germany). The ETDRS grid was centered on the foveal center, and the average total retinal thickness as provided by the manufacturer’s proprietary software (HEYEX) was noted for each ETDRS subfield. Eyes with neovascularization were excluded. The values were compared with published data from a device- and age-matched normative sample.15 Right and left eyes were analyzed separately.
Statistical Analysis
Analysis was performed with the R software (R Foundation for Statistical Computing, Vienna, Austria). A Wilcoxon signed-rank test was used for comparison of visual acuity in right versus left eyes. For analysis of occurrence of early stages (asymmetry) in eyes, the Fisher exact test was used. The average retinal thickness of ETDRS fields was compared with unpaired t tests, for right and left eyes separately, with Bonferroni correction for multiple testing. Data were checked visually for normality using histograms. Simple linear regression was used to model mean BCVA as predicted by age. Linear logistic regression was used to model the proportion of eyes with severe visual impairment, with age as the predictor variable, and to model the proportion of eyes with severe vision loss, with typical MacTel characteristics as predictor variables. The significance level for all tests was 5%. Data was visualized in figures and tables with the ggplot2, patchwork, and sjPlot packages.16
Results
At database access, 4517 eyes of 2259 patients (mean age, 62.7 years; standard deviation [SD], 9.5 years; range, 21–93 years) were available for analysis (Fig S1). Neovascular changes were present in 439 eyes of 329 patients (9.7%; bilateral in 110 patients [33%]), and an FTMH was found in 63 eyes of 54 patients (1.4%; bilateral in 9 patients [17%]). Right eyes more frequently demonstrated more advanced morphologic changes (Table S2, available at www.aaojournal.org): neovascularization or an FTMH were more common in right than in left eyes. In contrast, no obvious or a very mild disease manifestation was more common in left eyes of patients with very asymmetric disease in which only 1 eye clearly allowed the diagnosis of MacTel (apparently unilateral disease, n = 78; 3.4% of the entire cohort).
Visual Acuity
A total of 4449 eyes of 2248 patients were included in the BCVA analysis (Fig S1). Median BCVA was 73 letters (Snellen equivalent, 20/40). Best-corrected visual acuity was 20/50 or worse, 20/200 or worse, and 20/400 or worse in 37.3%, 3.8%, and 0.9% of all eyes, respectively (Fig 3). Bilateral BCVA of 20/50 or worse was found in 414 patients (18.4%), bilateral BCVA of 20/200 or worse was found in 15 patients (0.7%), and bilateral BCVA of 20/400 or worse was found in 2 patients (0.09%).
Figure 3.
Frequency distribution of best-corrected visual acuity values for all eyes, and for right and left eyes separately. The vertical dashed lines show Snellen visual acuity cutoffs at 20/50 (68 letters) as the threshold for the ability to drive, as well as 20/200 (38 letters) and 20/400 (23 letters) as the limits for legal blindness in the United States and many European countries, respectively. Box plots show median (thick line), interquartile range (IQR; box), and data extremes (end of whiskers) at 1.5 times the IQR away from the lower or upper quartile (or upper maximum). ETDRS = Early Treatment Diabetic Retinopathy Study.
An asymmetry of visual impairment was found between right and left eyes, with a median BCVA of 71 letters in right eyes and 74 letters in left eyes (P < 0.0001). Best-corrected visual acuity was 20/50 or worse, 20/200 or worse, and 20/400 or worse in 42.3%, 4.4%, and 1.1% of right eyes, respectively, as opposed to 32.4%, 3.2%, and 0.7% of left eyes, respectively (Fig 3). In control participants and family members enrolled in the study who were not diagnosed with MacTel, BCVA distribution was not different between right and left eyes (Fig S4, available at www.aaojournal.org).
A mild effect of age was found on the relative frequency of severe vision loss (Fig 5, upper and middle graph). From an overall risk of 3.8% for severe visual impairment (BCVA, ≤20/200) in at least 1 eye, the likelihood is predicted to increase to 5.7% over 10 years, equivalent to an increase of the odds ratio of approximately 4% for each year increase in age (Table S3, available at www.aaojournal.org). Age was a significant predictor for BCVA, although the effect was only small (Fig 5, lower graph). For each decade increase in age, mean BCVA decreased 2.2 letters (95% confidence interval, 2.9–1.6 letters).
Figure 5.
Graphs showing effect of age on best-corrected visual acuity (BCVA) in macular telangiectasia type 2 (MacTel). A, B, Frequency and relative frequency (in percent) of severe vision loss (≤20/200) and BCVA between better than 20/100 to 20/50. The eye with lower visual acuity was selected for this analysis (n = 2247 eyes, because age was not available for 1 patient of the BCVA analysis group). The graph in (A) shows the distribution of BCVA ranges as a function of age. (B) The fraction of patients with severe vision loss (≤20/200, black dots) does not seem to he higher in older patients. C, Median BCVA (dots) as a function of age. The gap represents the interquartile distance, and the whiskers extend to the data extremes. The dashed line shows the regression line (with error) from a simple linear regression model.
Structural Changes in Eyes with Low Vision
Eyes with BCVA of 20/200 or worse (168 eyes of 153 patients) were analyzed for structural alterations of the macula on OCT images to identify causes for MacTel-related severe vision loss (clinical examples in Fig 6). Most of these eyes showed photoreceptor or outer retinal atrophy involving the fovea, either without (72 eyes [43%]) or with (22 eyes [13%]) a paracentral or fovea-involving (61 eyes [36%]) subretinal fibrosis or active neovascularization. Thirteen eyes (8%) demonstrated an FTMH. However, neovascularization and FTMH were not necessarily associated with severe visual impairment: BCVA was better than 20/200 in most eyes with neovascularization (n = 345 [79%]) and FTMH (n = 49 [78%]) and was 20/50 or better in 26% (n = 111) and 13% (n = 8), respectively (Figs 7 and 8). We did not perform a similar analysis in eyes with BCVA of better than 20/200 for presence of photoreceptor atrophy in the absence of an FTMH or neovascularization because this parameter was not part of the original reading center (MEHRC) grading, and therefore the relevant structured information was not available for all eyes.
Figure 6.
Images showing exemplary cases for structural correlates to low visual function (best-corrected visual acuity [BCVA], ≤20/200): color fundus photographs (CFPs; first column), fundus autofluorescence images (second column), fluorescein angiography images (third column), and spectral-domain (SD) OCT images (fourth column). Dashed lines in the CFPs show the position of the SD OCT scans. The OCT images show regular retinal layers outside the macular telangiectasia area in all cases.
Figure 7.
Bar graphs showing best-corrected visual acuity (BCVA) distribution of eyes with (A) neovascular changes and (B) full-thickness macular holes. Most eyes demonstrated best-corrected visual acuity of better than 20/200 (38 Early Treatment Diabetic Retinopathy Study letters).
Figure 8.
Images showing examples for eyes with fibrosed neovascularization or full-thickness macular hole (FTMH) with good and poor best-corrected visual acuity (BCVA), respectively. A, Small subretinal fibrosis temporal to the foveal center with well-preserved BCVA (20125 Snellen). B, Large subretinal fibrosis with poor BCVA. The diagnosis of macular telangiectasia was made based on historic images. C, Small, slightly paracentral FTMH with well-preserved BCVA (20/25 Snellen). D, Large FTMH with complete outer retinal atrophy, especially in the temporal parafovea, with poor BCVA (20/320, Snellen).
Grading of CFP images was available for 3921 eyes of 1990 patients. Eyes with severe visual impairment (BCVA, ≤20/200) consistently showed hyperpigmentation, but rarely greying. After adjusting for the presence of the other features, BCVA on average was 11 letters lower in eyes with pigment and 3.5 letters higher in eyes with greying. The odds ratio for severe vision loss was increased significantly with the presence of pigment plaques and was decreased significantly with the presence of greying, but did not change with the presence of crystals or blunted, right-angled vessels (Fig 9; Table S4, available at www.aaojournal.org).
Figure 9.
Bar graphs showing frequency of funduscopic findings characteristic for macular telangiectasia type 2, grouped according to different ranges of best-corrected visual acuity (BCVA): (A) greying, (B) pigment, (C) crystals, and (D) blunted vessels. Missing information was because of unavailable or ungradable fundus images.
The maximum size of the retinal area affected by MacTel (i.e., the MacTel area) was investigated in eyes with severe visual impairment (BCVA, ≤20/200), which likely represent the phenotypic spectrum of end-stage disease. Measurements were based on FA images, which were available for 134 of 168 eyes with BCVA of 20/200 or worse. The oval retinal area with MacTel-related changes was larger in the horizontal than in the vertical direction. In eyes without neovascular changes, the horizontal width did not exceed the distance between the temporal optic disc margin and foveal center (distance, d), and the vertical height did not exceed approximately 0.8 times d (Fig 10). Mean width was 0.73 d (SD, 0.15 d), and mean height was 0.53 d (SD, 0.12 d). Eyes with neovascular changes showed a larger affected area exceeding these limits (mean width, 0.91 d [SD, 0.35 d]; mean height, 0.78 d [SD, 0.41 d]).
Figure 10.
Diagrams showing the extension of macular telangiectasia-relared fluorescein-angiographic changes in eyes with severe vision loss (best-corrected visual acuity, ≤20/200) (A) without and (B) with neovascular change. Right and Left eyes were considered equally. Gray level represents the cumulative frequency of angiographically visible changes at a given location, plotted for each eye based on horizontal and vertical measures. Darker gray level indicates higher frequency. d = distance between temporal optic disc margin and foveal center.
After exclusion of eyes with neovascularization, OCT measurements suitable for ETDRS sector analysis were available for 2923 eyes of 1545 patients of the entire cohort and for 60 eyes of 55 patients from the low-vision sample. In the total cohort, retinal thickness was significantly thinner in all 4 sectors of the inner ring and in the foveal center. It was thinner than normal in the nasal outer field of right eyes (difference of the means, 10 µm) and thicker than normal in the temporal outer field in left eyes (difference of the means, 5 µm), but was similar to normal in all other outer ETDRS fields (Table S5, available at www.aaojournal.org). In eyes with severe visual impairment, retinal thickness was significantly thinner in all inner ETDRS fields (inner ring and central subfield), but was similar to normal in all outer fields (Table S6, available at www.aaojournal.org).
Discussion
Macular telangiectasia only rarely results in legal blindness. Most eyes (approximately 60%) in this large cohort retained a visual acuity of 20/50 or higher, and only few patients (0.7%) demonstrated bilateral severe visual acuity loss (BCVA, ≤20/200). Approximately 20% of all people showed bilateral BCVA of less than the legal threshold for driving in most countries (Snellen equivalent, 20/50 in the better eye). Severe vision loss was associated with outer retinal atrophy in most cases. The disease seems to be constrained naturally to a macular area with specific dimensions, that is, the MacTel area.
An unexpected finding was the mild interocular asymmetry with significantly worse BCVA and a higher frequency of FTMH or neovascularizations in right eyes and more frequent early disease stages in left eyes. Hence, MacTel may be an asymmetric disease. Another explanation may be a systematic error resulting from a learning effect if right eyes were tested consistently first, as per study protocol. However, control participants without MacTel who underwent BCVA testing following the same protocol did not show a similar difference between eyes. A third explanation is that reading the BCVA test chart may be more difficult with right eyes, in which the paracentral scotoma is projected to the left of fixation. A fourth possibility is that the study cohort may have been biased by ocular dominance, which is more frequently right sided.17 Patients may be more likely to seek help for vision problems in their dominant eye, which may explain the more frequently affected right eyes in patients with apparently unilateral disease. The cause and significance of disease asymmetry needs to be explored further.
Another unexpected finding was the small effect of age on vision loss. Age was almost normally distributed, with an only mild left skew and a mode of approximately 70 years. Although age was a significant predictor for mean BCVA and the frequency of severe vision loss, the effect size was small and clinically negligible. The proportion of people with at least 1 eye with severe vision loss remains overall on a stable low level across all age groups of this sample. If MacTel is a progressive disorder ultimately leading to vision loss, one would expect the proportion of patients with severe vision loss to increase more with higher age. Possible explanations for this discrepancy include a selection bias resulting from mistaking late MacTel disease stages for other diseases such as age-related macular degeneration or macular dystrophies. Without a diagnosis of MacTel, patients would not be referred to a MacTel center and thus would not appear in our statistics. Another explanation also may be an increased mortality of patients with more severe types of MacTel, preventing an accumulation of patients with severe vision loss over time. Previous studies that have shown associations of MacTel with systemic morbidities such as obesity and diabetes or neurologic disorders11,18–20 may be supportive of this alternative explanation.
The predominant structural alteration in eyes with severe vision loss was atrophy of the foveal photoreceptor layer, detected on OCT images. Such neurodegeneration most frequently occurred without evidence for a subretinal neovascularization (46%), or the neovascularization was located slightly eccentric to the foveal atrophic changes (13%), indicating possible independence from the neovascular process. In eyes with subfoveal neovascularization (36%), photoreceptor degeneration may have developed independently or secondary to the neovascular process. Severe vision loss in eyes with FTMH may occur either subsequent to the FTMH itself or as a result of adjacent photoreceptor atrophy involving the foveal center. Photoreceptor atrophy as the most common cause of severe vision loss is in keeping with previous studies on functional loss in patients with MacTel: the structural correlate of the characteristic deep paracentral scotomas is atrophy of the photoreceptor layer, and proximity of such scotomas to the foveal center has been found to be associated with loss of visual acuity.4,21
Severe vision loss was associated with the presence of pigment proliferation within the MacTel area. This would be in keeping with the assumption that such pigmentation develops subsequently to outer retinal atrophy, thus representing a surrogate marker for photoreceptor degeneration.1 The pathophysiologic features of MacTel-related pigment proliferation may reflect observations in a mouse model in which photoreceptor atrophy and approximation of retinal vessels to the retinal pigment epithelium results in intraretinal pigment migration.22 As a reliable feature,3 pigmentation thus may serve as one useful criterion in future disease classifications. In contrast, loss of retinal transparency (retinal greying) was a rather rare observation in eyes with severe vision loss. Because the exact cause of this characteristic funduscopic feature is not well understood yet, reasons for its absence remain speculative. Retinal greying also is often absent in very early disease, and hence, it may represent a particularly dynamic, active phase of the disease. Its loss in late disease stages with severe functional loss might be explained if its presence depended on intact Müller cells, photoreceptors, or both.
In the entire study cohort, eyes with neovascularization often had relatively preserved vision, possibly because of a noncentral localization of the neovascular lesion or because of lack of extensive photoreceptor atrophy of the overlying retina. Whether anti–vascular endothelial growth factor therapy has played a role for preservation of visual acuity in eyes with neovascularization cannot be concluded from this dataset. Similarly, a substantial proportion of eyes with a FTMH showed a BCVA of better than 20/200. Possible explanations include a small and nonprogressive size of MacTel-related FTMHs or a slightly paracentral location. To explore this further, a systematic structure–function analysis and longitudinal data capture are required. Some MacTel patients may have predisposing factors for neovascularizations or FTMHs developing. Calculated based on our sample prevalence, one would expect bilateral occurrence of neovascularization or FTMH by chance in approximately 4% and 1% of patients with neovascularization or FTMH, respectively. In our cohort, however, bilateral lesions were observed in 33% and 17%, respectively.
One of the most striking features of MacTel is the restriction of the disease to an oval area in the macula, which we call the MacTel area. Its horizontal dimension does not exceed the distance between the temporal optic disc margin and the foveal center, and its vertical dimension does not exceed approximately 80% of this distance. Even in eyes with the most advanced disease manifestation, angiographic changes and retinal thinning remained limited to this area. Retinal changes beyond this area either were not related to MacTel or resulted from neovascular complications, including retinal edema, subretinal hemorrhages, fibrosis, or a combination thereof. Such limitation of retinal changes to the MacTel area is in agreement with investigations of visual function showing that the central scotoma in nonneovascular disease does not extend beyond a macular area of approximately 8 × 5 fundal degrees.4,6
Only when retinal thickness was analyzed in the entire nonneovascular cohort, was a very mild retinal thinning within the nasal outer sector of the ETDRS grid (i.e., outside the MacTel area) found, which was significant in right eyes. A possible explanation is a retrograde neurodegeneration of inner retinal neurons secondary to chronic macular photoreceptor degeneration or dysfunction. In contrast, the temporal outer field in left eyes revealed a very mild but significant thickening. The left temporal thickening may be driven by only a small area just outside the inner rings, by those cases where the MacTel area extends just beyond the inner ring. This may correspond to a mild temporal thickening that sometimes can be observed before atrophy develops.1 Overall, these observations are in keeping with the generally observed asymmetry where more severe disease is found in right eyes.
Limitations of our study are the cross-sectional nature of the data, which would not allow conclusions on individual disease progression. Also, ascertainment bias may have resulted in a disproportionate frequency of certain disease stages or even phenotypes, for example, when the diagnosis of MacTel is not considered in patients with large neovascularizations, macular holes, or apparently unilateral disease. Moreover, the prevalence estimates for neovascularization mainly were based on color fundus and angiography images and thus may underestimate the true prevalence of neovascularization in our sample, because those imaging methods may not always detect a MacTel-related neovascular process.
Our study is relevant for patient counselling. Most MacTel patients will retain a level of vision to perform most daily tasks, although the legal ability to drive may be lost in approximately 20% of patients in countries with a legal BCVA limit of 20/50. Previous studies indicate that reading function is increasingly impaired by progression of MacTe1,23,24 but a certain degree of reading function is likely to be maintained even in late disease stages, although special reading aids may be necessary. Our findings corroborate previous evidence for a natural end point of MacTel that needs to be taken into account when modelling disease progression. Finally, our study indicates an asymmetry between right and left eyes, the significance of which needs to be determined.
Supplementary Material
Acknowledgments
The authors thank Professor Alan Bird for his continuous inspiration for this project.
Supported by the Lowy Medical Research Institute, La Jolla, California (T.F.C.H., C.A.E); the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford, United Kingdom (P.C.I.); and the National Institute of Health Research Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom (C.A.E., M.F.). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. The sponsor or funding organizations had no role in the design or conduct of this research.
Abbreviations and Acronyms:
- BCVA
best-corrected visual acuity
- d
distance between temporal optic disc margin and foveal center
- ETDRS
Early Treatment Diabetic Retinopathy Study
- FA
fluorescein angiography
- FTMH
full-thickness macular hole
- MacTel
macular telangiectasia
- MEHRC
Moorfields Eye Hospital Reading Center
- SD
standard deviation
Footnotes
Presented in part at: Association for Research in Vision and Ophthalmology Annual Meeting, May 2018, Honululu, Hawaii.
Supplemental material available at www.aaojourna1.org.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): C.A.E.: Financial support – Heidelberg Engineering, Novartis Pharmaceuticals. P.C.1.: Research support – Heidelberg Engineering.
HUMAN SUBJECTS: Human subjects were included in this study. Institutional Review Board (IRB)/Ethics Committee approval was obtained at each center. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent.
No animal subjects were included in this study.
References
- 1.Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Prog Retin Eye Res 2013;34:49–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Heeren TF, Holz FG, Charbel Issa P. First symptoms and their age of onset in macular telangiectasia type 2. Retina 2014;34(5):916–919. [DOI] [PubMed] [Google Scholar]
- 3.Charbel Issa P, Helb HM, Rohrschneider K, et al. Microperimetric assessment of patients with type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci 2007;48(8): 3788–3795. [DOI] [PubMed] [Google Scholar]
- 4.Heeren TF, Clemons T, Scholl HP, et al. Progression of vision loss in macular telangiectasia type 2. Invest Ophthalmol Vis Sci 2015;56(6):3905–3912. [DOI] [PubMed] [Google Scholar]
- 5.Peto T, Heeren TFC, Clemons TE, et at Correlation of clinical and structural progression with visual acuity loss in macular telangiectasia type 2: MacTel Project report no. 6–the MacTel Research Group. Retina 2018;38(Suppl 1):S8–S13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Vujosevic S, Heeren TFC, Florea D, et al. Scotoma characteristics in macular telangiectasia type 2: MacTel Project report no. 7—the MacTel Research Group. Retina 2018;38(Suppl 1):S14–519. [DOI] [PubMed] [Google Scholar]
- 7.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(3): 1172–1177. [DOI] [PubMed] [Google Scholar]
- 8.Sallo FB, Leung I, Zeimer M, et al. Abnormal retinal reflectivity to short-wavelength light in type 2 idiopathic macular telangiectasia. Retina 2018;38 (Suppl 1):S79–S88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Charbel Issa P, van der Veen RL, Stijfs A, et al. Quantification of reduced macular pigment optical density in the central retina in macular telangiectasia type 2. Exp Eye Res 2009;89(1): 25–31. [DOI] [PubMed] [Google Scholar]
- 10.Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and follow-up study. Ophthalmology 1993;100(10):1536–1546. [PubMed] [Google Scholar]
- 11.Clemons TE, Gillies MC, Chew EY, et al. Baseline characteristics of participants in the natural history study of macular telangiectasia (MacTel) MacTel Project report no. 2. Ophthalmic Epidemiol 2010;17(1): 66–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103(12):1796–1806. [PubMed] [Google Scholar]
- 13.Charbel Issa P, Heeren TF, Kupitz EH, et al. Very early disease manifestations of macular telangiectasia type 2. Retina 2016;36(3):524–534. [DOI] [PubMed] [Google Scholar]
- 14.Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012;9(7):676–682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Nieves-Moreno M, Martínez-de-la-Casa JM, Cifuentes-Canorea P, et al. Normative database for separate inner retinal layers thickness using spectral domain optical coherence tomography in Caucasian population. PloS One 2017;12(7). e0180450–e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Wickham H ggplot2: Elegant Graphics for Data Analysis New York: Springer-Verlag; 2016. [Google Scholar]
- 17.Hillcmanns M Die funktionelle Asymmetric der Augen, die Vorherrschaft eines derselben and die binokulare Richtung-slokalisation. Klin Monbl Augenheilkd 1927;78:737–761. [Google Scholar]
- 18.Clemons TE, Gillies MC, Chew EY, et al. Medical characteristics of patients with macular telangiectasia type 2 (MacTel type 2): MacTel Project report no. 3. Ophthalmic Epidemiol 2013;20(2):109–113. [DOI] [PubMed] [Google Scholar]
- 19.Chew EY, Murphy RP, Newsome DA, Fine SL. Parafoveal telangiectasis and diabetic retinopathy. Arch Ophthalmol 1986;104(1):71–75. [DOI] [PubMed] [Google Scholar]
- 20.Gantner ML, Eade K, Wallace M, et al. Serine and lipid metabolism in macular disease and peripheral neuropathy. N Engl J Med 2019;381(15):1422–1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Charbel Issa P, Trocger E, Finger R, et al. Structure-function correlation of the human central retina. PLoS One 2010;5(9):e12864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Jaissle GB, May CA, van de Pavert SA, et al. Bone spicule pigment formation in retinitis pigmentosa: insights from a mouse model. Graefes Arch Clin Exp Ophthalmol 2010;248(8):1063–1070. [DOI] [PubMed] [Google Scholar]
- 23.Tzaridis S, Herrmann P, Charbel Issa P, et al. Binocular inhibition of reading in macular telangiectasia type 2. Invest Ophthalmol Vis Sci 2019;60(12):3835–3841. [DOI] [PubMed] [Google Scholar]
- 24.Finger RP, Charbel Issa P, Fimmers R, et al. Reading performance is reduced by parafoveal scotomas in patients with macular telangiectasia type 2. Invest Ophthalmol Vis Sci 2009;50(3):1366–1370. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.