Visual Acuity Progression
The mean ± SE VA at baseline was 69.9 ± 0.5 letters (Snellen equivalent of 20/40). A mean ± SE of 1.07 ± 0.05 letters were lost per year. The rate of change did not differ by age at study enrollment or sex. There was a difference in the rate when stratified by history of diabetes. The average letters lost per year for participants with a history of diabetes was 1.36 ± 0.10 compared with an average letter lost per year of 0.95 ± 0.12 for participants with no history of diabetes. This loss is not accounted for by progression of diabetic retinopathy. A total of 188 of 1,014 eyes (18%) lost 15 or more letters and 323 of 1,014 (32%) eyes lost 10 or more letters. At 5 years, the probability of a 15 or more letter loss was 15% in eyes with MacTel Type 2, whereas the 5-year probability of a 10 or more letter loss was 27% (Figure 1).
Progression of Ellipsoid Zone Loss
At baseline, there were 974 eyes with OCT data available: 372 of 974 (38%) did not have an ellipsoid (EZ) loss at baseline, 230 (24%) had a loss that did not affect the center of fovea, and 372 (38%) had an EZ loss that affected the center of fovea. The probabilities of progression from no EZ loss to any loss (noncentral and/or central) or progression to a loss affecting the center of fovea by 5 years were 76% and 45%, respectively, Figure 1. There were no differences in the progression rates by various baseline characteristics of interest, such as age, sex, or diabetes.
The location of loss of EZ reflectivity correlated with loss of VA. The mean (SE) change in VA letters was −0.93 ± 0.08 letters per year for participants with no EZ loss at baseline compared with −1.09 ± 0.12 letters per year if the EZ loss was present but did not affect the center (P = 0.18 compared with no EZ loss present at baseline) and −1.40 ± 0.14 letters per year if the EZ loss affected the center (P < 0.001 compared with no EZ loss present at baseline).
Hyperfluorescence on Fluorescein Angiography
A total of 879 eyes had at least one year of FFA follow-up. The mean (±SE) number of subfields with hyperfluorescence at baseline was 2.2 ± 0.05. From a mixed linear model, participants on average progressed with 0.28 ± 0.01 additional fields of hyperfluorescence per year. There was a difference in average change per year by age category. Younger participants had a higher rate of increase hyperfluorescence on FFA compared with older participants (age < 50 years: 0.39 ± 0.04; age < 60 years: 0.34 ± 0.03; age < 70 years: 0.24 ± 0.03; and age ≥ 70 years: 0.16 ± 0.03; compared with older age group P=<0.001, <0.001; and 0.006, respectively). The average change per year also differed by sex (males: 0.26 ± 0.02 vs. females: 0.30 ± 0.01; P = 0.03). There was no difference by history of diabetes or presence of EZ loss at baseline.
A total of 304 (31%) of 992 eyes had crystalline deposits present at baseline. By 5 years, the probability of progression from no deposits to any crystalline deposits was 20%. Younger participants had a higher risk of progression to crystalline deposits compared with older participants (aged younger than 50 years, aged 51–60 years, and aged 61–70 years compared with ≥70 years of age Relative Risk (RR): 3.20; 95% confidence interval: 1.69–6.05; P < 0.001; 2.14; 95% confidence interval: 1.19–3.86; P = 0.01; and 1.86; 95% confidence interval: 1.03–3.36; P = 0.04, respectively). Crystals have been reported to disappear. This effect, however, might be caused by only slight tilt changes in the imaging pane (Sallo et al), wherefore we did not specifically analyze the probability of crystal regression.
A total of 350 (35%) of 995 eyes had hyperpigmentation present in at least one subfield at baseline. By 5 years, the probability of progression to presence of pigment was 33%. There were no differences in the progression rates by age, sex, or presence of diabetes at baseline.
A total of 91 (9%) of 994 eyes had subretinal neovascularization at baseline. By 5 years, the probability of development of subretinal neovascularization was 7%. There were no differences in the progression rates by various baseline characteristics of interest.
Longitudinal data of disease progression accrued in this study could potentially segregate patients into subgroups with respect to rate of progression and long-term prognosis. The data show slow but variable VA loss in participants with MacTel Type 2. The variation does not relate to any baseline phenotypic characteristics other than presence and particularly the central location of an EZ loss. In analysis by categorical variables, the calculated probability of a loss of 15 letters or more and of 10 letters or more of distance VA at 5 years of 17% and 32%, respectively, suggests that some degree of meaningful distance VA loss does occur eventually in a substantial proportion of patients. It is apparent that progression of parafoveal changes has no influence on VA until central involvement occurs.15 This accounts for the rapid loss of VA in a proportion of cases and little change in others, and the association of VA loss with progression of EZ loss to the center of the macula.3 Although statistically significant, the additional loss in mean VA in the presence of EZ loss is modest. However, the relative risk of a meaningful loss in distance VA (≥15 letters) is significant (RR = 1.70) in the presence of a central EZ loss. A reasonable conclusion would be that the presence of an EZ loss heralds the phase of structural degradation that finally leads to photoreceptor atrophy. Once the EZ loss progresses to the foveal center, clinically relevant distance visual loss is likely to occur. This is in accordance with findings of Heeren et al15 who show that VA remains stable while functional loss occurs as progression of a paracentral scotoma and that the proximity of these scotomas to the fovea correlates with the level of VA.
Retinal pigment plaques and crystalline deposits are recognized as characteristic changes in MacTel,1 although their relationship to loss of vision is highly variable. Hyperpigmentation seems to be preceded by demise of photoreceptors thus explaining the universal finding of absolute scotomata corresponding to pigment plaques.15 It is likely that pigment hyperplasia is a consequence of, rather than a cause of photoreceptor loss, in a way similar to that of retinitis pigmentosa.2 Increasing hyperpigmentation may not independently signal progression of visual loss, rather reflecting the underlying progression of photoreceptor loss that is integral to the disease process. Increasing hyperpigmentation at 5 years occurred in a third in our series irrespective of other clinical or demographic baseline parameters. The significance of crystals to visual loss is less clear. The nature of the crystals is unknown, and they may be seen in early disease.19 The probability of progression of crystals at 5 years was 40% in our series with a higher risk encountered in younger patients.
The development of a subretinal neovascularization originating from the retinal vasculature constitutes vision-threatening complication in MacTel Type 2 and can occur at any disease stage, although is more frequently associated with hyperpigmentation.2 In this report, the baseline incidence of such lesions was low (3%), as was the yearly risk of progression and the cumulative risk at 5 years (6.3%), rendering them an unlikely cause for the significant proportion of cases with loss of VA. Male patients had a slightly lower risk of development of subretinal neovascularization than female ones.
By contrast, visual function seems to be related to the integrity of the EZ,3,20,21 and, as shown in this study, to visual prognosis. Our analysis revealed a progression relationship between loss of VA and the appearance of an EZ loss and to its extension toward the center over a 5-year period. No baseline phenotypic findings, namely age, sex, or presence of diabetes, were shown to predispose for a higher rate of progression of structural changes in MacTel Type 2. Studies using adaptive optics have shown intact cone structures in areas of EZ loss and recurring EZ in longitudinal analysis.22 Our results did not show such improvements, which does not mean that this did not occur, as our rather categorical grading might not fully reflect small EZ loss changes.
Fluorescein angiography has been considered the gold standard for confirming the diagnosis of MacTel Type 2, although its importance has been superseded by other imaging modalities such as OCT and fundus autofluorescence that are more directly reflecting the structural changes consistent with our revised understanding of disease pathogenesis.2,23 In this study, the mean number of subfields exhibiting diffuse hyperfluorescence at baseline was 2.1 ± 1.6. In the study by Gass and Oyakawa,1 62% of cases presented paracentral hyperfluorescence involving 90° to 180° circumference around the fovea and virtually always encompassing the temporal sector. Progression of FFA findings as measured by the number of hyperfluorescent subfields was shown to be slow, with a tendency for faster progression in younger participants, female participants and those without a history of diabetes. The lowest progression of hyperfluorescence (0.16 fields/year in patients more than 70 years) may be statistically lower than the highest progression (0.39 fields/year in patients younger than 50 years); however, the clinical significance of this finding is questionable.
The presence of EZ loss was only qualitatively evaluated and was not quantified. We have previously reported on the correlation of the “en face” measurement of the EZ loss with microperimetry.21 To date, other structural alterations that correlate with vision loss, such as loss of outer nuclear layer,15,20,24 have not been analyzed systematically. Therefore, EZ loss might be the best currently available parameter for MacTel disease progression. Other structural alterations that correlate with functional loss such as loss of outer nuclear layer have not yet been analyzed systematically, as there assessment is more difficult than that of EZ loss. As reported, results herein contribute significant new insight into the natural history of MacTel Type 2. Our findings seem to corroborate the slowly progressive course of VA loss in this disease previously implied in smaller case series, although indicating that distance VA loss over time is variable and incomplete as an index of progression. Other measures of visual function, such as microperimetry, reading speed, and near vision, have not been tested in all MacTel study centers and have therefore not been investigated in detail within this article. Except for the presence of an EZ loss, no other phenotypic or demographic findings analyzed had any significant relationship with distance VA or the rate of VA loss. As expected, the presence of a central EZ loss was associated with a higher rate of clinically relevant visual loss, rendering this finding a prognostic marker for higher functional impairment in MacTel Type 2, as we have described in our previous study of en face OCT and microperimetry.21 Ultimately, segregation of patients into groups of varying rates of progression to meaningful visual loss on the basis of baseline fundoscopic or demographic characteristics, such as age, sex, presence of diabetes, crystalline deposits, or hyperpigmentation did not appear possible. Progression patterns of clinical findings and structural changes emerging from this study, however, offer a better understanding of the rate of structural degradation in MacTel Type 2, suggesting photoreceptor loss heralding secondary clinical changes, such as hyperpigmentation. It is of high clinical importance to establish valid surrogate parameters for visual function, both for clinical and scientific purposes. EZ loss is the most promising surrogate parameter for visual function in MacTel to date. Further studies should aim at comparing the progression of EZ loss with functional loss seen for example in microperimetry.
1. Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 1982;100:769–780.
2. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2
. Prog Retin Eye Res 2013;34:49–77.
3. 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.
4. Charbel Issa P, Heeren TF, Kupitz EH, et al. Very early disease manifestations of macular telangiectasia type 2
. Retina 2016;36:524–534.
5. Powner MB, Gillies MC, Tretiach M, et al. Perifoveal muller cell depletion in a case of macular telangiectasia type 2
. Ophthalmology 2010;117:2407–2416.
6. Powner MB, Gillies MC, Zhu M, et al. Loss of Muller's cells and photoreceptors in macular telangiectasia type 2
. Ophthalmology 2013;120:2344–2352.
7. Gillies MC, Mehta H, Bird AC. Macular telangiectasia type 2
without clinically detectable vasculopathy. JAMA Ophthalmol 2015;133:951–954.
8. Shen W, Fruttiger M, Zhu L, et al. Conditional Mullercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J Neurosci 2012;32:15715–15727.
9. Barthelmes D, Gillies MC, Fleischhauer JC, Sutter FK. A case of idiopathic perifoveal Telangiectasia preceded by features of cone dystrophy. Eye (Lond) 2007;21:1534–1535.
10. 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.
11. Charbel Issa P, Finger RP, Kruse K, et al. Monthly ranibizumab for nonproliferative macular telangiectasia type 2
: a 12-month prospective study. Am J Ophthalmol 2011;151:876–886.e1.
12. Kupitz EH, Heeren TF, Holz FG, Charbel Issa P. Poor long-term outcome of anti-vascular endothelial growth factor therapy in nonproliferative macular telangiectasia type 2
. Retina 2015;35:2619–2626.
13. Toy BC, Koo E, Cukras C, et al. Treatment of nonneovascular idiopathic macular telangiectasia type 2
with intravitreal ranibizumab: results of a phase II clinical trial. Retina 2012;32:996–1006.
14. Do DV, Bressler SB, Cassard SD, et al. Ranibizumab for macular telangiectasia type 2
in the absence of subretinal neovascularization
. Retina 2014;34:2063–2071.
15. Heeren TF, Clemons T, Scholl HP, et al. Progression of vision loss in macular telangiectasia type 2
. Invest Ophthalmol Vis Sci 2015;56:3905–3912.
16. Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98:786–806.
17. Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Early treatment diabetic retinopathy study research group. Arch Ophthalmol 1985;103:1796–1806.
18. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early treatment diabetic retinopathy study report number 2. Early treatment diabetic retinopathy study research group. Ophthalmology 1987;94:761–774.
19. Sallo FB, Leung I, Chung M, et al. Retinal crystals in type 2 idiopathic macular telangiectasia. Ophthalmology 2011;118:2461–2467.
20. Charbel Issa P, Helb HM, Rohrschneider K, et al. Microperimetric assessment of patients with type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci 2007;48:3788–3795.
21. 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.
22. Wang Q, Tuten WS, Lujan BJ, et al. Adaptive optics microperimetry and OCT images show preserved function and recovery of cone visibility in macular telangiectasia type 2
retinal lesions. Invest Ophthalmol Vis Sci 2015;56:778–786.
23. Wong WT, Forooghian F, Majumdar Z, et al. Fundus autofluorescence in type 2 idiopathic macular telangiectasia: correlation with optical coherence tomography and microperimetry. Am J Ophthalmol 2009;148:573–583.
24. Charbel Issa P, Troeger E, Finger R, et al. Structure-function correlation of the human central retina. PLoS One 2010;5:e12864.
Keywords:© 2018 by Ophthalmic Communications Society, Inc.
retinal pigment epithelial (RPE) plaque; ellipsoid zone loss; international multicenter prospective cohort study; MacTel type 2; macular telangiectasia Type 2; natural history observation study; neovascularization; structural and clinical disease progression; visual acuity