Macular telangiectasia Type 2 (MacTel) is a bilateral disease of neurodegenerative origin. The MacTel Natural History Observation Study has been running in 27 centers since 2005, currently having 1,008 patients enrolled. Such a rich resource allowed for increased research activity and is leading to better understanding and new insights into the disease process. Characteristic phenotypic findings have been identified using noninvasive imaging techniques allowing for an improved clinical differentiation of this entity from other retinal diseases and have been described in detail in a recent review.1
Functional impairment typically starts with reading problems or, less frequently, metamorphopsias in the fifth or sixth decade of life2–6 and is mainly because of paracentral field loss rather than loss of visual acuity at least in early disease.2,4 The presence of paracentral scotomas gives rise to prefixational blindness when occurring bilaterally and affects the central visual field at 4°, which is required to sufficiently process words and perform adequate eye movements for efficient reading.7 Therefore, loss of parafoveal sensitivity affects reading performance more and reflects functional loss in MacTel better than best-corrected visual acuity, which might be relatively preserved until late disease stages.3,4 Parafoveal sensitivity can be measured by fundus controlled perimetry (microperimetry, MP),2,4,8 which has been performed systematically in five of the MacTel Study centers. Microperimetry moreover allows for point-to-point comparisons with spectral-domain optical coherence tomography. Loss of retinal sensitivity in MP correlates with loss of structural integrity in spectral-domain optical coherence tomography, in particular areas of outer retinal alterations.6,9,10 Relative scotomas correlate with ellipsoid zone disruption, whereas absolute scotomas correlate with loss of outer nuclear layer (and associated pigment plaques).2,4,6,9,10 Only limited correlation was found between retinal sensitivity and total retinal thickness or changes in the inner retina.2,6,9–14
In a smaller sample, some characteristic features of the scotoma in MacTel have been identified: there is usually only one scotoma per eye that always seems to affect the temporal parafoveal area, supporting the idea of predilection of this particular zone.4 Once an absolute scotoma emerges, it is very likely to grow.
Although there is reason to believe that the scotoma may not exceed the so-called “MacTel area,” an oval-shaped area of 2 disc diameters centered on the foveola, no systematic analysis was undertaken to look for a possible endpoint of scotoma growth.1,2,4,9,15 Charbel Issa et al9 indicated that scotomas might be defined by rather sharp borders, a crucial feature when scotoma growth might be considered as outcome measure in investigational trials. However, these observations have not yet been analyzed systematically. The aim of this study was therefore to characterize location, size, and growth of the scotoma and by doing so providing further insights into the pathophysiology of this disease.
Materials and Methods
Patients were selected from the five centers (Jules Stein Eye Institute [Los Angeles, CA], Moorfields Eye Hospital [London, United Kingdom], St. Franziskus Hospital [Münster, Germany], Save Sight Institute [Sydney, Australia], and University Eye Hospital [Bonn, Germany]) of the MacTel Natural History Observation Study, which systematically performed mesopic MP under standard conditions. Other examinations were performed as part of the MacTel Study and are described elsewhere.16 Inclusion criterion for this analysis was that the participant had at least one gradable MP1 examination completed as part of the MacTel Natural History Observation Study.
Microperimetry was performed after pupillary dilatation using the MP1 Microperimeter (Nidek, Gamagori, Japan). This technique was described in detail previously.2,17 As fixation targets, a 2° red cross was used or in case of poor fixation a 5° red cross. We used standard examinations settings (white background at 4 asb, Goldman III stimulus with 100-ms projection time, 4-2 staircase strategy). Patient underwent 5 minutes of mesopic light adaptation before the test was started. Seven different grids were used (Table 1; see Figure 1, Supplemental Digital Content 1, http://links.lww.com/IAE/A650). Two different examination strategies were used to test functional loss: 1) fixed grids (all grids except Grid 5) and 2) function-adapted grids (Grid 5). The latter means that stimuli were added manually at the end of each examination if a scotoma crossed the border of the dense grid to outline the scotoma area. The duration of the test was graded in 5-minute intervals (i.e., 0 minute to 5 minutes, 5 minutes to 10 minutes, etc.).
All printouts of MP images were sent to Moorfields Eye Hospital Reading Centre where three retinal specialists with large experience in image grading (S.V., T.F.C.H., and T.P.) independently graded all images in a masked fashion. Each grader evaluated the reliability of the examination by evaluating the presence of false-positive results and duration of examination, mean sensitivity, and stability and site of fixation.
The size of relative and absolute scotomas was evaluated according to a simple strategy named thresholding, suggested by Sallo and Pauleikhoff (personal communication, submitted). Thresholding is a straightforward strategy to analyze large numbers and has been shown to deliver comparable results to analysis of scotoma volume (aggregate sensitivity loss).18Thresholding means the stimuli under a predefined threshold are counted. For example, thresholding 12 dB means counting all stimuli with 12 dB and less (example in Figure 1). This was performed with retinal sensitivity thresholds of 12, 10, and 8 dB (defining relative scotomas) and <0 dB (defining absolute scotomas, i.e., when the brightest stimulus [0 dB] could not be seen). As it has been shown previously that retinal function is unimpaired in MP1 MP outside the central 12°,4 we assumed that relative or absolute scotomas in this outer area were not related to MacTel and therefore did not take them into account.
Focality of Scotoma
One scotoma focus was defined as contiguous scotoma test points without interposed “healthy” retina (retinal sensitivity of 14 dB and higher). Unifocal was consequentially defined as one focus per eye.
Microperimetry was performed in 632 eyes of 294 patients, of whom 174 (59%) were females. Altogether, 565 of these eyes (97%) had gradable results. Mean age of all patients was 61.1 ± 9.1 years. Seven different test patterns were used (characteristics of the grids see Table 1, illustration of grids see Figure 1, Supplemental Digital Content 1, http://links.lww.com/IAE/A650).
Absolute scotomas were present in 47% (n = 247) of eyes. The temporal quadrant was affected in 98% of eyes and 99.5% were unifocal. Because of the unifocality of the scotoma, confirmed in our data,4 we were confident to assume that significantly reduced retinal sensitivity affect only one area. When this is the case, thresholding (see Materials and Methods) would give a good estimate of the size of the relative or absolute scotoma. Figure 2 shows the distribution of scotoma sizes in a subgroup analysis of 192 eyes with the densest grids (Grids 2 and 5) that allowed calculation of affected retinal area. The graphs show the size at baseline and after a follow-up of mean 5 years. There is a shift toward higher number of test points, reflecting scotoma growth. However, most of the scotomas do not exceed a size of around 25 deg2 and only 2 eyes exceed 30 deg2. No eye exceeds 40 deg2. This suggests a limitation of scotoma growth to an extent of 40 deg2 (equivalent to the central 5° × 8° of the “MacTel” area).
For relative scotomas, we chose thresholding values of 12, 10, and 8 dB, meaning relative scotomas of increasing depth. Because of the nature of the scotoma, the ratios of stimulus numbers of different thresholds show the steepness of the scotoma (Figure 3). When the scotoma is steeply sloped, the number of threshold points would be very similar and the ratio low (“1” being the same). Our results show that absolute scotomas with <10 stimuli are shallower than larger scotomas of >10 stimuli, where the ratio approaches 1 as a sign of steep slope (Figure 3).
We conclude that MacTel scotomas might not exceed a certain size and become more and more steeply sloped, implicating that scotoma progression means not only growth but also deepening of scotoma.
We herein present not only the by far largest study of MP in MacTel patients but also one of the largest MP studies in general.19 This underlines the importance and impact of the MacTel Natural History Observation Study. Although our data are based on different grids, we were able to examine qualitative characteristics and relative sizes in this large and representative sample of MacTel patients.
It has not yet been demonstrated whether every patient will develop a scotoma. It is conceivable that this might not be the case given that MacTel may not be a single monogenic disorder but rather several monogenic disorders or even a complex disorder.1,20 As with other studies, we found that 50% of all examined eyes had absolute scotomas.4 In addition, it may be that the disorder progresses more rapidly in some cases than others, as has been demonstrated,4 because of different genetic risk factors.
Our results using the complete MacTel cohort confirmed findings made in a smaller sample showing that only one scotoma is found per eye, which always at least partially affects the temporal quadrant.4 No eye shows two separate absolute scotomas with completely healthy retina in between. However, rarely, an area of relative scotoma can show two dips into absolute scotoma, usually one dip being temporal and the other nasal of the fovea. The significance of this predominance of the temporal parafoveal area as shared by other characteristic features of MacTel is not understood. It might be related to vascular asymmetry or to developmental differences, for example, in differences of anatomical or metabolic characteristics of this region.21–23
Scotomas in MacTel appear to be steep and confined in size. To test this concept, we used the thresholding method as conceived by Pauleikhoff and Sallo because it allows for rather straightforward analysis of large samples. This allowed calculation of the relative size of different thresholds instead of a structure-based approach, such as that developed by Hariri et al,24 who measured scotoma steepness in geographic atrophy in age-related macular degeneration. Scotoma steepness in MacTel is related to its size. Large scotomas are steeper edged than smaller scotomas. In addition, the largest absolute scotoma in our cohort extends over a retinal area of no greater than 40 deg2 however advanced the disease. We conclude from this that 1) the extent of absolute scotoma is limited and 2) it starts as area of relative scotoma, which then deepens into absolute scotoma during progression. It seems possible that scotoma growth might be limited to the area of macular pigment depletion, which can be visualized with dual wavelength fundus autofluorescence and might be one of the earliest signs of the disease.25–27 Loss of photoreceptors, seen as loss of outer nuclear layer in spectral-domain optical coherence tomography, is likely to be the structural correlate to absolute scotomas and might not exceed the MacTel area either. This might help to define photoreceptor atrophy as natural endpoint of the disease. Detailed structure function comparisons are warranted to elucidate this further.
We herein present characteristics of scotomas in MacTel in one of the largest published MP studies. We confirmed previous findings that scotomas, found in about half of all eyes, always affect the temporal quadrant and are always unifocal. Furthermore, we provided evidence that areas of relative scotomas seem to deepen during scotoma progression and eventually lead to steep absolute scotomas in later stages. Growth of scotoma and therefore functional deterioration seems to be confined to an estimated area of 40 deg2. Phenotypic characteristics need to be determined that would allow for a better prediction of progression and final size of the scotoma.
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