Abstract
Purpose.:
To document the progression of a break in the photoreceptor inner segment/outer segment (IS/OS) junction layer and its functional correlates over time in the natural history of type 2 idiopathic macular telangiectasia (type 2 MacTel).
Methods.:
Patients with at least 1 year of follow-up were selected from the MacTel Study. En face images were created by manual segmentation of the IS/OS junctional line in volume scans acquired using a spatial-domain optical coherence tomography retinal imaging unit. Retinal sensitivity thresholds were determined using a retinal microperimeter unit. Aggregate retinal sensitivity loss within IS/OS lesions was calculated. Changes over time in an area of IS/OS defects and retinal sensitivity were analyzed.
Results.:
Thirty-nine eyes of 23 patients (mean age: 62.3 ± 9.2 years) were analyzed. Mean follow-up time was 1.9 years (range: 1–3 years). Mean IS/OS break area at baseline was 0.575 mm2 (SE = 0.092, 95% confidence interval [CI]: 0.394–0.756 mm2). The cluster-adjusted mean annual progression rate in IS/OS break area was 0.140 mm2 (SE = 0.040, 95% CI: 0.062–0.218 mm2, P < 0.001). Mean aggregate retinal sensitivity loss was at baseline 28.56 dB (SE = 5.43, 95% CI: 17.32–39.80 dB, n = 28), a positive correlation with IS/OS lesion area was present (P < 0.001). The mean annual rate of change in aggregate sensitivity loss was 5.14 dB (SE = 1.51, 95% CI: 2.19–8.10 dB, P < 0.001, n = 37), a significant correlation with lesion area increase was found (P = 0.006).
Conclusions.:
Both IS/OS break area and rate of enlargement correlate with aggregate retinal sensitivity loss in type 2 MacTel. En face OCT imaging of the IS/OS layer provides a functionally relevant method for documenting disease progression in type 2 MacTel.
The mean BCVA at baseline was 71 letters (Snellen equivalent 20/36, SE = 2.02 letters, 95% CI: 67–75 letters, n = 39). Mean yearly loss was 0.267 letters (SE = 0.591 letters, 95% CI: −1.43 to 0.89 letters, P = 0.65). From a generalized linear model (GLM) accounting for clustering, the relationship with the annual rate of change in the area of disruption did not meet statistical significance (regression model = 0.115 + 0.032 × [annual rate of change in BCVA]; P value for slope = 0.19). The slope, interpreted as an increase for each unit annual rate of change in BCVA, is associated with an estimated increase of 0.032 mm2 in the mean annual rate of change in area of disruption.
Mean aggregate MP1 retinal sensitivity loss at baseline was 28.56 dB (SE = 5.43, 95% CI: 17.32–39.80 dB, n = 28). From a GLM the model was computed as 0.183 + 0.013 × [MP1 retinal sensitivity], with a P value for the slope of <0.001. The slope, interpreted as an increase of 1 dB in baseline MP1 retinal sensitivity loss, is associated with an estimated increase of 0.013 mm2 in the mean baseline IS/OS break measurement. The mean annual rate of change in aggregate sensitivity loss was 5.14 dB (SE = 1.51, 95% CI: 2.19–8.10 dB, P < 0.001, n = 37). From a GLM accounting for clustering, the relationship with the annual rate of change in the area of disruption met statistical significance (regression model = 0.079 + 0.006 × [MP1 aggregate retinal sensitivity loss annual rate of change]; P value for slope = 0.006). The slope, interpreted as an increase for each unit annual rate of change in MP1 aggregate retinal sensitivity loss annual rate of change, is associated with an estimated increase of 0.006 mm2 in the mean annual rate of change in the area of disruption.
We undertook this study to identify a sensitive, functionally relevant outcome to monitor progression of type 2 MacTel. Visual acuity is a poor measure since the disease may become advanced in the perifoveal region without affecting visual acuity. Microperimetry is a functional measure, but it is subjective. We have demonstrated in this study that en face imaging of the area of IS/OS disruption correlates strongly with loss of macular sensitivity measured by microperimetry, and that expansion of the area of photoreceptor dysfunction correlates with progressive loss of macular sensitivity. En face imaging of the area of the IS/OS break may therefore be considered as an outcome measure for clinical trials of interventions for type 2 MacTel.
The main change over time in the morphology of a manifest break in the IS/OS junction layer is an increase in its area. This was observed both by progression of distinct edges as well as a gradual diffuse fading over a larger area (
Fig. 1). The mean annual increase in area of 0.140 mm
2 in our cohort was easily detectable at the currently available resolution of the en face images. An outright recovery of a clear IS/OS break was not seen, although a variation between scans in break shape was noted, possibly due to the optical properties of the layer or the OCT system used. We previously found variation in break area size between fellow eyes to be smaller than that between patients.
26 However, a similar significant symmetry between left and right eyes of the increase in IS/OS area over time could not be demonstrated in this cohort. This may be attributable to the relatively short follow-up time in this study.
We found a significant and close correlation between area size of an IS/OS break and aggregate mesopic retinal sensitivity loss. Furthermore, an enlargement of the break area over time was associated with an increase in aggregate sensitivity loss, although the correlation of break area change with BCVA was not significant.
Within the area of the break, cross-sections of outer retinal cavities, islands of preserved IS/OS, or cross-sections of an abnormal retinal tissue with a vertical orientation may be present (“collapsed layers”; see
Fig. 2). These features are smaller and some are scattered and indistinct, such that their changes over time are not amenable to accurate quantification. However, as a trend it was noted that an increase in break area was often accompanied by a progression of retinal restructuring (“collapsed layers”), with a simultaneous overall decrease of the adjacent outer atrophic spaces.
Based on our own and previous observations by other authors
3,6,25 a hypothetical sequence of neurodegenerative signs in MacTel may be outlined: Inner hyporeflective spaces near the foveal center appear, initially convex both anteriorly and posteriorly, distending the retina, the IS/OS junction layer deviates toward the retinal pigment epithelium (RPE) (
Fig. 3A). Subsequently, the convexity disappears, leaving the impression of an inner atrophic cavity (
Figs. 2G,
5A). Minor vertically oriented oblong spaces along the border of the outer nuclear and outer plexiform layers (OPL and ONL) may also be present. Temporal to the foveal center, the IS/OS signal attenuates and breaks and outer retinal spaces appear, with a shape suggesting atrophy (lateral boundaries in B-scans near the RPE appear vertical, in line with photoreceptor morphology). Focally, the ONL thickness decreases, layers internal to the ONL deviate toward the RPE/choroid, become disorganized, and “collapse” onto the RPE. As the collapse widens, outer empty spaces shrink. Some authors characterize the “collapse” as a “contraction” of retinal layers.
5 Indeed, a contraction in the plane of the retina centered on these foci is frequently seen in fundus images (see
Fig. 4), along with apparent anastomoses between branches of the supero- and inferotemporal venous systems. A vertical component is also conceivable. We noted in en face images that the cross-section of the collapsed tissue often colocalized with the tips of blunted veins in the fundus image (
Fig. 5). We were unable to clearly demonstrate blood vessels within the collapsing layers, possibly due to the relatively low resolution of the en face images. However, aberrant blood vessels within the outer retina, near the foveal center, have been reported previously,
25,36 and vascular involvement in the “collapse” is possible. Although the pigment plaques characteristic of type 2 MacTel are in the mid layers of the retina, smaller foci were observed in the deeper layers of the retina also in this cohort. Vessels with a vertical disposition combined with the propensity of pigment for propagating along vessels
37 may offer an explanation for pigment plaque genesis. Progression of the phenotype, however, may not necessarily always pass through the same sequence of events in all cases.
We acknowledge some limitations of this study. Sample size and follow-up time were limited. For an accurate calibration of measurements within OCT images, the axial length and the refractive power of the eye must be taken into consideration. In our study these data were not collected; “typical” values were used as provided by the manufacturer. However, we compared each individual eye over time in terms of structure and function. Unless there is a significant change in the main parameters (due to, e.g., cataract or refractive surgery, a change in the refractive index of the lens due to maturing cataract, or an increase in axial length in progressive myopia), differences in area measured are expected to emanate from the progression of the lesion alone. The low test point density of the MP1 grid used did not permit a detailed analysis of whether function loss is associated with the IS/OS break itself or lesions within. It was noted, however, that high loss was consistently present over “collapsed layers.” A progression of the collapsing layers may have a functional relevance that would not be fully reflected in increasing lesion area size alone. Furthermore, we used volume scans from a commercially available SD-OCT machine without a real-time eye-tracking system. Fixation stability in type 2 MacTel patients is affected early and motion artifacts may be a source of error in 3D analysis. In en face images, near the foveal center, in the absence of vascular landmarks, it may not always be possible to detect these. OCT devices with active eye tracking have a significant advantage.
SD-OCT and other recent imaging techniques offer possibilities for characterizing the neurodegenerative aspects of the disease
3,5,6,25,38,39 and may provide new morphologic landmarks for refining the staging system, especially in early disease.
40 Break area in en face images of the IS/OS layer is a quantifiable morphologic sign that correlates with function also in its progression over time, even at stages of the disease where vascular signs may be less sensitive indicators. The IS/OS break and “collapsing tissue” may potentially be new landmarks for following disease progression in the natural history as well as in interventional studies of MacTel.
Jose-Alain Sahel, MD, PhD, Centre Hopitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France;
Robyn Guymer, MD, Centre for Eye Research, East Melbourne, Australia;
Gisele Soubrane, MD, PhD, FEBO, Clinique Ophtalmologie de Creteil, Creteil, France;
Alain Gaudric, MD, Hopital Lariboisiere, Paris, France;
Steven Schwartz, MD, Jules Stein Eye Institute, UCLA, Los Angeles, CA (USA);
Ian Constable, MD, Lions Eye Institute, Nedlands, Australia;
Michael Cooney, MD, MBA, Manhattan Eye, Ear, and Throat Hospital, New York, NY (USA);
Catherine Egan, MD, Moorfields Eye Hospital, London, England (UK);
Lawrence Singerman, MD, Retina Associates of Cleveland, Cleveland, OH (USA);
Mark C. Gillies, MD, PhD, Save Sight Institute, Sydney, Australia;
Martin Friedlander, MD, PhD, Scripps Research Institute, La Jolla, CA (USA);
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 (USA);
Robert Murphy, MD, The Retina Group of Washington, Fairfax, VA (USA);
Frank Holz, MD, University of Bonn, Bonn, Germany;
Grant Comer, MD, University of Michigan, Kellogg Eye Center, Ann Arbor, MI (USA);
Barbara Blodi, MD, University of Wisconsin, Madison, WI (USA);
Diana Do, MD, The Wilmer Eye Institute, Baltimore, MD (USA);
Alexander Brucker, MD, Scheie Eye Institute, Philadelphia, PA (USA);
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 (USA);
Paul S. Bernstein, MD, PhD, Moran Eye Center, University of Utah, UT (USA);
Joan W. Miller, MD, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA (USA)