'Quantitative OCT Analysis of Idiopathic Perifoveal Telangiectasia'

Barthelmes, D; Gillies, M C; Sutter, F K P (2008). Quantitative OCT analysis of idiopathic perifoveal telangiectasia. Investigative Ophthalmology and Visual Science (IOVS), 49(5):2156-2162. Postprint available at: http://www.zora.uzh.ch University of Zurich Posted at the Zurich Open Repository and Archive, University of Zurich. Zurich Open Repository and Archive http://www.zora.uzh.ch Originally published at: Investigative Ophthalmology and Visual Science (IOVS) 2008, 49(5):2156-2162.

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Year: 2008

Quantitative OCT analysis of idiopathic perifoveal telangiectasia

Barthelmes, D; Gillies, M C; Sutter, F K P

Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch

Originally published at: Investigative Ophthalmology and Visual Science (IOVS) 2008, 49(5):2156-2162. Quantitative OCT analysis of idiopathic perifoveal telangiectasia

Abstract

PURPOSE: To identify and quantitate specific changes in optical coherence tomography (OCT) images of patients with type 2 idiopathic perifoveal telangiectasia (IPT). METHODS: In a prospectively designed, observational, case-control study, 28 eyes of 14 consecutive patients with IPT were examined with OCT and compared with eyes of 14 unaffected control subjects. Light reflectivity profiles of raw scan data of OCT images were quantitatively analyzed for differences in distance between different retinal reflectivity layers and their respective reflectivities. Maculae were examined in four separate regions: (1) central fovea, (2) nasal perifovea, (3) temporal perifovea, and (4) outside the fovea. RESULTS: Retinal thinning, shortening of the photoreceptor outer segments and loss of reflectivity of the photoreceptor ellipsoid region were found in the central foveal region as well as the nasal and temporal perifoveal regions in eyes with IPT. In addition, increased reflectivity of the outer nuclear layer was found in a sharply demarcated area of the inferotemporal perifoveal region in all affected eyes. Retinal tissue located more than 2000 mum away from the foveola was indistinguishable from that in normal eyes. CONCLUSIONS: Quantitative OCT analysis shows unique and specific changes in the photoreceptors of the central macula in IPT which can be detected from first clinical presentation. These changes may be of use as an additional diagnostic tool. Correlation of the findings in the outer nuclear layer with histologic studies may help identify the nature of the reflectivity increase and define more clearly the type of damage sustained by the photoreceptors in this condition. Quantitative OCT Analysis of Idiopathic Perifoveal Telangiectasia

Daniel Barthelmes,1 Mark C. Gillies,2 and Florian K. P. Sutter3

PURPOSE. To identify and quantitate specific changes in optical angiography but without retinal thickening or exudation. Loss coherence tomography (OCT) images of patients with type 2 of central macular transparency is a common early feature, idiopathic perifoveal telangiectasia (IPT). discrete superficial white crystals may also be found. The ETHODS clinical onset of the disease is usually in the fifth decade, with M . In a prospectively designed, observational, case– 1,2 control study, 28 eyes of 14 consecutive patients with IPT no preference for sex or race. were examined with OCT and compared with eyes of 14 Optical coherence tomography (OCT) is a noncontact, non- unaffected control subjects. Light reflectivity profiles of raw invasive imaging technology, that is already established as a frequently used tool for the diagnosis and follow-up of various scan data of OCT images were quantitatively analyzed for 4,5 differences in distance between different retinal reflectivity retinal diseases. OCT scans through a normal macula, cen- layers and their respective reflectivities. Maculae were exam- tered on the foveola, show clearly distinguishable reflective ined in four separate regions: (1) central fovea, (2) nasal peri- layers. An analysis of the reflectivity of these layers as a func- fovea, (3) temporal perifovea, and (4) outside the fovea. tion of scan-depth (Fig. 1) results in a curve with several peaks, from now on referred to as P1 to P6.6,7 Corresponding to RESULTS. Retinal thinning, shortening of the photoreceptor retinal anatomy,8 these peaks represent the retinal pigment outer segments and loss of reflectivity of the photoreceptor epithelium (P1), a highly reflective layer between the inner and ellipsoid region were found in the central foveal region as well outer segments of the photoreceptors (P2), the external limit- as the nasal and temporal perifoveal regions in eyes with IPT. ing membrane (P3), the outer plexiform layer (P4), the inner In addition, increased reflectivity of the outer nuclear layer was plexiform layer (P5), and the nerve fiber layer–vitreoretinal found in a sharply demarcated area of the inferotemporal interface (P6). It has been suggested that P2 arises from tightly perifoveal region in all affected eyes. Retinal tissue located ␮ packed mitochondria in the ellipsoid region of the photore- more than 2000 m away from the foveola was indistinguish- ceptors.6 Because of its unique anatomy, the foveola lacks P4 able from that in normal eyes. and P5. CONCLUSIONS. Quantitative OCT analysis shows unique and spe- A quantitative analysis of these light-reflection profiles cific changes in the photoreceptors of the central macula in (LRPs) has been used to examine changes in animal models9 IPT which can be detected from first clinical presentation. and in rare human retinal diseases.6 In this study, quantitative These changes may be of use as an additional diagnostic tool. (q)OCT was used to detect and quantify changes in eyes with Correlation of the findings in the outer nuclear layer with IPT. histologic studies may help identify the nature of the reflectivity increase and define more clearly the type of damage sustained by the photoreceptors in this condition. (Invest Oph- METHODS thalmol Vis Sci. 2008;49:2156–2162) DOI:10.1167/iovs.07- 0478 Twenty-eight eyes of 14 consecutive patients participating in a natural history study of IPT (see www.mactelresearch.org) and 28 eyes of 14 diopathic macular telangiectasia is an uncommon, slowly healthy control subjects were studied. Patients had no other macular Iprogressive disease of the macula. A recent revised classifi- diseases, such as diabetic retinopathy or age-related changes. The cation stresses two distinct disease processes: type 1, or aneu- diagnosis was made by a retinal specialist (MG) based on the unique rysmal telangiectasia with exudation and type 2, idiopathic clinical features of the disease and confirmed by the Reading Center of perifoveal telangiectasia (IPT).1–3 IPT, the most common form, Moorfields Eye Hospital (London, UK). All patients underwent slit lamp usually occurs bilaterally and is characterized by small telangi- examination, fluorescein angiography, fundus photography, and OCT ectatic vessels characteristically found inferotemporally within scanning (Stratus OCT software ver. 4.01; Carl Zeiss Meditec AG, 1 disc diameter of the foveola, with staining by fluorescein on Oberkochen, Germany). Best corrected logMAR visual acuity was mea- sured by certified refractionists using ETDRS (Early Treatment of Dia- betic Retinopathy Study) charts. OCT studies were performed twice

1 over a period of 9 months. A custom-designed scan program was used From the Klinik und Poliklinik fu¨r Augenheilkunde, Inselspital to create a dense raster of data points across the macula. A scan of 12 Bern, Bern, Switzerland; the 2Save Sight Institute, University of Sydney, radial scan-lines of 6-mm length at 15° intervals centered on the fovea Sydney, Australia; and the 3Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland. (similar to the built-in Macular Thickness Map program) was per- Supported by the Paul Schiller Foundation Zurich Switzerland and formed (Fig. 2). Raw scan data were exported from the OCT device for the Lowy Medical Research Foundation. MCG is Executive Scientific further analysis. For the analysis the raw data from the Stratus OCT Manager of the MacTel Research Project. were opened as a 32-bit gray-scale image resulting in gray-scale values Submitted for publication April 22, 2007; revised September 5 and ranging from 0 to 4095. Since levels of gray were used when analyzing October 17, 2007; accepted March 27, 2008. the reflectivity and not decibels, as provided by the Stratus OCT, Disclosure: D. Barthelmes, None; M.C. Gillies, None; F.K.P. arbitrary units (AU) were used instead of decibels. Calculation of the Sutter, None LRP was performed with a scientific graphing, data analysis, and visu- The publication costs of this article were defrayed in part by page alization software package (IGOR 5.04a; Wavemetrics Inc., Lake Os- charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. wego, OR). LRP reflectivity, which ranged from 0 to 4095 AU, was Corresponding author: Mark C. Gillies, Save Sight Institute, Sydney calculated every 50 ␮m along each scan. Based on the results from Eye Hospital Campus, 8 Macquarie Street, Sydney 2000 GPO Box 4337, healthy control subjects, ranges for detecting peaks in the LRPs were 2001 Sydney, Australia; [email protected]. defined. The P2 wave in affected eyes was defined as the major positive

Investigative Ophthalmology & Visual Science, May 2008, Vol. 49, No. 5 2156 Copyright © Association for Research in Vision and Ophthalmology IOVS, May 2008, Vol. 49, No. 5 Quantitative Analysis in MacTel 2157

mm centrifugally from the foveola. Zone 4 was located more than 2 mm from the foveal center inferotemporally. Neuroretinal morphology is comparable in both eyes of healthy control subjects whereas in IPT, despite an often bilateral occurrence, severity may vary between both eyes of an affected patient. Therefore, analysis of LRPs was performed separately in each specified area of the left and right eyes in patients with IPT. Photoreceptor outer segment (POS) length was defined as distance P1 to P2. Outer nuclear layer width was defined as the distance between P3 and P4. If a peak was not detected, dependent analyses could not be performed (if no P2 could be detected, no calculation of POS length was performed). Statistical analyses were performed with commercial software (Sta- tistica 6; StatSoft Inc., Tulsa, OK). One-way ANOVA, bivariate correlation analysis, and unpaired t-test were used when appropriate. Statis- tical significance was defined as P Ͻ 0.05. Statistical differences between the groups were calculated by one-way ANOVA. Post hoc testing revealed no statistical differences between right and left eyes with IPT in equal regions examined.

RESULTS Patient Characteristics Of the 14 patients participating, 5 were males. As is character- istic of the disease, all patients with IPT had clinically evident disease in both eyes. The average age of the males was 58 Ϯ 8 years, and that of the females was 56 Ϯ 6.7 years (P ϭ 0.65). Control subjects were matched for sex and age. Mean visual FIGURE 1. (A) A 6-mm OCT scan through the foveola calculated from acuities of affected eyes was significantly less than that of the raw data. (B) An enlarged area from the scan from (A) illustrating control eyes (71.8 Ϯ 12 vs. 92 Ϯ 6 letters; P Ͻ 0.05). All eyes the different retinal reflective layers from the normal perifovea. (C) were staged for the status of IPT according to Gass’s classifi- The corresponding LRP calculated from the region illustrated in (B). cation1: 7 eyes were stage 2, 9 eyes were stage 3, 11 eyes were Each peak (P1–P6) represents a highly reflective layer. (D)AnOCT stage 4, and 1 eye was stage 5. scan of a patient with IPT, the LRPs calculated within the white rectangular regions are displayed on the right.(E) An OCT scan of a healthy control patient, with LRPs from the white rectangular regions Conventional OCT displayed on the right. As previously reported,3,10–14 eyes affected by IPT often have hyporeflective spaces in both the inner and outer neurosensory retina. These regions are characterized by cavities without deflection of the LRP curve in the region between P1 and the mean swelling of the surrounding retinal tissue, such as is observed Ϯ position 2 SD of the P2 wave in normal eyes. If there was no positive in diabetic macular edema or aneurysmal macular telangiecta- deflection in this region, the value for P2 was recorded as 0. For P3, P4, sia. In our study group 17 (61%) of 28 eyes had hyporeflective and P5 in affected eyes, the position was set as the mean position of spaces that were detectable in 228 of 672 scans. Areas with a Ϯ these waves in normal eyes 2 SD in relation to the detection of P6 disrupted ellipsoid region were seen in 385 of 672 scans (57%). (the first peak from the vitreous side). A built-in routine in the software As an interesting finding, three (11%) of the eyes examined for multi-peak detection was used. No manual corrections were made. showed changes similar to those found in exudative age-related OCT images showing heavily distorted retinal architecture were ex- macular degeneration (Fig. 4), including disruption of the cluded from further analysis, since no reliable results could be ob- highly reflective RPE in association with intraretinal masses of tained. increased reflectivity, probably reflecting gliosis, and pro- Cystoid spaces were identified by their very low reflectivity (about the reflectivity of the vitreous). LRPs crossing a region of a cystoid space showed an abrupt loss of reflectivity in the region of the cystoid lesion, although the remaining ONL showed preserved reflectivity (Fig. 3). Because of this abrupt loss, no additional peaks were detected by the algorithm: The first-order derivation of the LRP was not conclusive for a maximum at the edges. Using these criteria just described, we ensured that cystoid spaces did not affect peak detection. All OCT recordings were performed after signed, informed consent had been obtained from the patient. Approval for this study was obtained from the Ethics Committee from the University of Sydney. The study was performed in accordance with the tenets of the Decla- ration of Helsinki 1975 (1983 revision). Observations were made and compared in four areas of interest in affected and control eyes: (1) central fovea, (2) nasal perifovea, (3) temporal perifovea, (4) outside the fovea (Fig. 2). Zone 1 (central fovea) was defined as a small circular area of 0.3-mm diameter. Zone 2 FIGURE 2. This illustration shows the regions examined (zone 1–4) as (nasal perifovea) extended from 0.3 to 1.5 mm centrifugally from the well as the scan pattern used in the custom scan protocol for left and foveola, and zone 3 (temporal perifovea) also extended from 0.3 to 1.5 right eyes. 2158 Barthelmes et al. IOVS, May 2008, Vol. 49, No. 5

FIGURE 3. (A) OCT scan across a centrally located cystoid space (arrow). The LRP calculated from the region of the dashed line is illustrated in (B). (B) LRP across a cystoid space. P1–P6 still can be detected, as well preserved parts of the ONL (#). The cystoid space corresponds to an abrupt loss of reflectivity (*). No additional peaks are detected at the border of the cystoid space. nounced cystic retinal thickening. These patients had ad- for the analysis of zones 1, 2, and 3. The remaining 24 OCT vanced disease with intraretinal pigment migration. During the recordings in several patients were excluded because of bad observation period of 9 months, no changes in the size of the scan quality or intraretinal pigment deposits that made an cavities and the disruption of the RPE/Bruch’s membrane le- analysis within zones 1 to 3 impossible. For analysis of zone 4 sions were detected. all OCT images could be used. Two eyes in two patients could not be quantitatively analyzed because of heavily distorted retinal reflectivity curves. Of qOCT Characteristics 672 OCT images, 72 were excluded (including the 48 scans There were three specific changes that were found in all three from the two eyes with heavily distorted retinal morphology) zones of every affected eye examined: (1) decreased reflectiv-

FIGURE 4. (A, C) Two left eyes with IPT. Solid white line: region of reduction of the P2 wave (presumably photoreceptor damage). Dashed white line: area of increased reflectivity of the ONL. Black line: the scan direction of the OCT scan shown in (E). (B, D) Corresponding fluorescein angiography images of two eyes with IPT. There is some correlation between the grayish areas seen on the color photographs (A, C) and the P2 change areas that represent photoreceptor damage. There is also some degree of correlation between the leak in FFA and P2 but not as good as between P2 changes and the grayish areas. Areas with increased ONL reflectivity do not correlate well with FFA or with the grayish areas. (E) Representative OCT image (horizontal scan, orienta- tion shown in C) illustrating the changes in the central region (arrow- head, reduction of retinal thickness, loss of photoreceptors) and in the temporal–inferior region (arrows, area of loss of P2; ✽, area of increased reflectivity of the ONL). The progres- sive reduction in thickness of the ONL is evident, moving from the symbol toward the center of the fovea. These features are not found in the nasal perifoveal region, where photoreceptors still seem to be normal. (F) An example of a subretinal neovascularization, in such cases quantitative analysis could not be performed. IOVS, May 2008, Vol. 49, No. 5 Quantitative Analysis in MacTel 2159

ity of the photoreceptor ellipsoid region (P2 wave amplitude), (2) shortening of the POS, and (3) thinning of the neurosensory retina. These changes were less pronounced in the nasal peri- 95% CI fovea (zone 2) than they were in the central and temporal 95% and ؉ perifoveal regions, but they were signiﬁcantly less than in the ؊ control eyes in all three regions (Table 1, Fig. 5). Post hoc testing revealed no signiﬁcant differences between left and SD 80.1 1153.6–1163.9 165.8 1151.8–1162.5 136.7 1134.3–1189.7 81.9 1148.9–1209.6 115.9 1176.0–1261.9 115.6 1162.9–1248.6 81.5 1138.6–1224.1 150.1 1261.3–1372.5 169.5 1230.9–1324.9

؎ right eyes with IPT in the regions examined. The area of Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ photoreceptor change extended 891 Ϯ 332 ␮m from the Ϯ center of the fovea in the temporal parafoveal region and 607 Ϯ 445 ␮m in the nasal region (Figs. 5A, 5B). POS length in zone 1 was 45.1 Ϯ 10.6 ␮m (mean Ϯ SD) in normal eyes; 23.5.8 Ϯ 13.3 ␮m in right eyes with IPT and 26.0 Ϯ 14.9 ␮m in left eyes with IPT. The measurements taken

in normal eyes by OCT imaging were similar to measurements 95% CI Mean 95% and ؉ performed on histologic cross-sections of the human fovea ؊ centralis which showed lengths of POS centrally of 41 to 63 ␮m in adults and are comparable with reports on measure- 8,15,16 SD 207.9 1472.9–1588.1 1158.8 162.1 1501.4–1572.4 1162.6 172.7 1495.8–1571.52 1166.7 74.6 1600.3–1641.6 1179.2 113.0 1530.3–1583.2 1218.9 159.4 1481.4–1551.3 1205.8 68.5 1591.6–1629.6 1181.4 115.4 1530.8–1581.3 1316.9 ments of PROS in OCT images. In zone 2 control eyes had 172.0 1508.8–1586.1 1278.0 Reﬂectivity (AU) ؎ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ a POS length of 37.1 Ϯ 7.3 ␮m, whereas right and left eyes in Ϯ participants with IPT had lengths of 21.6 Ϯ 10.8 and 24.1 Ϯ 11.2 ␮m, respectively. Zone 3 showed a POS length of 38.9 Ϯ 8.9 ␮m in control eyes; 23.1 Ϯ 10.3 ␮m in right eyes with IPT; and 21.6 Ϯ 9.7 ␮m in left eyes with IPT (Table 1). No differences in POS length or reﬂectivity of P2 were observed outside the regions shown in Figure 5. 95% CI Mean 95% and ؉

A unique finding that was observed only in the inferotem- ؊ poral region of affected eyes was a significant increase in reflectivity of the outer nuclear layer (Figs. 5C, 5D, 6B, 6D).

This region was 628 Ϯ 282 ␮m in diameter starting at a mean SD 173.7 1864.2–1965.1 1530.5 224.7 1636.1–1737.4 1536.9 239.0 1556.3–1661.3 1533.7 236.1 1848.0–1985.2 1620.9 202.2 1739.8–1834.8 1556.8 238.1 1668.5–1775.9 1516.3 306.7 1865.1–2124.1 1610.6 209.6 1631.8–1730.3 1556.1 223.6 1588.5–1689.3 1547.4

؎ Ϯ ␮ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ distance of 184 109 m from the center of the fovea. This Ϯ 0.00001 0.980 0.462 0.00001 0.0008 0.3377 increased reflectivity of the outer nuclear layer was found in 0.00001 0.14957 0.00069 Ͻ Ͻ every eye examined, irrespective of the clinical stage (Table 1, Ͻ Figs. 5C, 5D). There was a significant linear correlation between the degree of increased reflectivity in the ONL and of the amount of shortening of the POS in the temporal perifoveal ϭ ϭ region (Fig. 6C; r 0.52, P 0.003). 95% CI Mean 95% and ؉ Cystoid spaces, which were found in 17 (61%) of 28 eyes, ؊ did not confound the analysis of thickness of retinal layers or

peak amplitudes. They did not interfere with peak detection on SD 11.8 118.0–124.9 1914.6 28.5 106.1–118.7 1608.8 33.8 85.6–100.8 1686.7 14.7 112.5–121.0 1916.6 14.3 106.4–112.8 1722.2 18.4 85.4–94.0 1787.3 7.2 100.2–106.3 1994.6 25.9 50.0–62.2 1681.0 29.2 54.4–67.6 1638.9 ؎ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ LRP curves, because their reflectivity was very low (less than Ϯ Layer Thickness P2 P6 ONL 0.01 0.0001 0.00001 Ͻ the reflectivity of the vitreous, Fig. 3B). The cystoid spaces P3–P4 Outer Nuclear Ͻ were characteristically small and located centrally just below Ͻ the vitreoretinal interface without extension into the ONL, particularly in the inferotemporal perifoveal zone where increased reflectivity of this layer was detected (Fig. 4). 95% CI Mean 95% and m)

There was some correspondence between the extent of ؉ ␮ changes in the ellipsoid region and the outer nuclear layer on ؊ the one hand and areas of reduced macular transparency as SD 9.7 191.4–196.7 121.5 42.8 99.9–118.7 93.2 58.3 114.1–139.6 112.4 28.2 230.1–245.7 116.8 27.1 206.4–219.1 89.7 32.2 212.9–227.0 109.6 33.9 236.8–255.6 103.3 31.3 148.5–162.2 56.1 32.9 157.8–172.6 70.0 Width (

؎ well as the regions of early and late hyperfluorescence on Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ fluorescein angiography on the other (Fig. 4). In 12 (43%) of 28 Ϯ 0.00001 0.00001 Ͻ eyes, there was a rough topographic correspondence between Ͻ the regions of increased ONL reflectivity and areas of capillary telangiectasis, seen as early hyperfluorescence on fluorescein angiography (Fig. 4) in the inferotemporal perifoveal region. 95% CI Mean

Otherwise, the zones of increased ONL reﬂectivities were 95% and ؉ smaller than the areas of early hyperﬂuorescence, which often ؊ extended into nasal zone 2. In 10 (35%) of 28 eyes, there was SD 10.6 42.0–48.2 194.1 13.3 20.5–26.53 109.3 14.9 22.7–29.3 126.9 7.3 34.9–39.2 237.9 10.8 19.1–24.2 212.8 11.2 21.6–26.5 219.9 10.3 20.7–25.5 155.4 8.9 35.2–42.7 246.2 a good correspondence between the extent of the defects in 9.7 19.4–23.8 165.2 ؎ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ the photoreceptor ellipsoid region (P2 wave) and the periph- Ϯ 0.0001 0.0001 0.00004 0.0001 Ͻ Ͻ Ͻ

eral margins of the areas of late hyperﬂuorescence, in other P1–P2 Outer Segments P1–P6 Total Retina eyes there was poor correspondence of these two phenomena. Mean Regions 2000 ␮m beyond the center of the fovea in affected eyes were indistinguishable from those in normal control eyes

by qOCT analysis (not shown). Summary of Quantitative OCT Data Concerning the Thickness and Reﬂectivity of Retinal Layers

There was a strong positive, linear correlation between 1. periovea) visual acuity and the degree of shortening of the outer seg- Periovea) Control 45.1 RE 23.5 LE 26.0 P Control 37.1 RE 21.6 LE 24.1 P Control 38.9 RE 23.11 LE 21.6 P ABLE Zone 1 (Foveola) T Zone 2 (Nasal ments (P1–P2), in the central foveolar region (zone 1) of Zone 3 (Temporal 2160 Barthelmes et al. IOVS, May 2008, Vol. 49, No. 5

affected eyes (r ϭ 0.59, P ϭ 0.0085). There also appeared to be a correlation between the degree of loss of reflectivity of the photoreceptor ellipsoid region (P2) and visual acuity in affected eyes; however, it was not statistically significant (r ϭ 0.41, P ϭ 0.08). There was no correlation between the degree of shortening of the outer segments, the reflectivity of the ellipsoid region, or the reflectivity changes in the outer nuclear layer with the presence or absence of retinal cavities (not shown).

DISCUSSION Patients with IPT show unique features on qOCT analysis that have not been described previously. All three zones (central, nasal perifoveal, and temporal perifoveal) showed shortening of the POS and reduced reflectivity of the photoreceptor ellipsoid region. The inferotemporal zone was most markedly affected, with, additionally, an increase of reflectivity of the outer nuclear layer. These changes were found in all the patients we examined, irrespective of clinical stage, and were significantly different from unaffected eyes. We propose that the qOCT changes in the outer nuclear layer and the photoreceptor ellipsoid region, particularly in the inferotemporal perifoveal zone, may be used as an additional marker for the clinical diagnosis of the disease. It appears that the reduction of reflectivity of the photoreceptor ellipsoid region (P2) and shortening of the outer segments, which were the most consistent findings throughout the foveal and perifoveal regions of affected eyes, may be early events in the course of IPT, since they were found as consis- FIGURE 5. (A, B) Regions affected by decreased P2 reflectivity. The tently in eyes with stage 2 disease as they were in eyes with central macula is affected both nasally and temporally with a slight more advanced changes. The regression curve of the correla- preponderance toward the temporal region. (C, D) Frequency of tion of the extent of the ONL reflectivity increase and the increase in reflectivity of the ONL of affected eyes. The ONL reflectivity increase is found only in the temporal region and is centered just degree of outer segment shortening intercepted the vertical below the horizontal midline. Difference from normal eyes was de- axis (corresponding to outer segment shortening) at 0.7 mm fined as a deviation of more than 2 SD from the mean values of (Fig. 6C) suggesting that outer segment damage occurs first to controls. a certain extent and is followed by the development of increased reflectivity of the ONL. Because of the slow nature of

FIGURE 6. (A) Control LRP across the temporal perifovea. The peaks representing the RPE (P1), the ellipsoid region (P2), the ELM (P3), and the ONL can clearly be seen. (B) LRP across the temporal perifoveal retina in an eye affected by IPT. Note the significantly lower P2 reflectivity, the decreased distance from P1 to P2, and the decrease in reflectivity of P3 compared to that in control eyes. The ONL is reduced in thickness and shows an increased reflectivity compared to (A). (C) Scatterplot of the maximum linear dimension of the zone of increased ONL reflectivity versus the degree of outer segment shortening (r ϭ 0.52, P ϭ 0.003). (D) Boxplot showing the reflectivities of controls (controls) and left (IPT OS) and right (IPT OD) eyes with IPT. The differences are clearly visible, the increase in reflectivity in IPT is highly significant. IOVS, May 2008, Vol. 49, No. 5 Quantitative Analysis in MacTel 2161 disease progression; however, we were unable to demonstrate all eyes examined had definite IPT. Moreover, histologic reports this in any individual patient examined over a period of 9 on IPT do not show a telangiectatic change or an increase of months, nor did we observe the presence of P2 changes in the the number of vessels but a thickening of capillary vessel walls, absence of ONL changes in any affected eye. whereas the vessel diameter is within normal ranges.19,20 Also This finding concerning P2 is consistent with previous ob- the discrepancy between areas of leakage and areas of ONL servations,10,13 where a disruption of the inner–outer photo- (57% poor correlation) changes that we found does not suggest receptor junction (i.e., the ellipsoid region) line was observed a vascular origin of these changes (Fig. 4). in the temporal perifovea, as well as throughout the whole There are several environmental and genetic defects that fovea.13 Disruption of the IS/OS PR junction line accompanied could underlie the pathogenesis of IPT. Hypoxic and nutri- by reduction of ONL thickness in IPT has been proposed as a tional diseases have been proposed.12,14,21 A genetic basis is marker for photoreceptor degeneration previously.12 These suggested by the fact that the disease almost always affects changes on OCT are also found in patients with retinal degen- both eyes, and that it has been described in identical twins.22,23 erative diseases such as retinitis pigmentosa, where a loss of An environmental contribution is also possible; one such factor the P2 signal is accompanied by thinning of the ONL (Fischer that could result in such symmetrical bilateral damage to the MD, et al. IOVS 2006;47:ARVO E-Abstract 5799). photoreceptors is phototoxicity. Light damage would also be The areas of change detected by quantitative OCT analysis, expected predominantly to damage the photoreceptors rather particularly the reduced P2 wave reflecting photoreceptor the second- or third-order neurons, which is consistent with damage and the increased reflectivity of the OCT, did not the qOCT appearance described. Such damage may lead to correlate consistently with changes that were discernible on reactive gliosis, which could result in the increased reflectivity clinical examination, including loss of macular transparency; of the ONL that we observed. early hyperfluorescence on angiography, which was confined Cystoid spaces, which were observed in 61% of our study to the area of telangiectatic change in the normal capillary bed; sample, did not decrease ONL reflectivity due to their size and and late hyperfluorescence, the origin of which is poorly un- spatial distribution. Most frequently, they were located in the derstood (Fig. 4). Loss of retinal transparency may be mani- innermost retinal layers, and therefore they did not affect the fested as a blunted reflexes with grayish discoloration17,18 in detection of peaks on the LRP curve or the measurement of other conditions characterized by photoreceptor decay such as ONL reflectivity. Previous studies were unable to relate these cone dystrophies or retinitis pigmentosa. In a minority (43%) of cavities to hyperfluorescence or leak on fluorescein. The area eyes there was a rough correlation between the zones of affected by hyperfluorescence was usually much larger than increased ONL reflectivity and the zones of early hyperfluores- the area occupied by the cavities.10,12,14 cence, as there was also in a smaller proportion of eyes (35%) It would be very helpful in further understanding IPT to between the zones of reduced P2 amplitude and late hyper- establish the temporal relationship of the neuronal changes fluorescence. The fact that good correlation between the zones described with the more easily recognized vascular features of of these respective abnormalities were found only in a minority the disease. Since IPT progresses slowly, a certain degree of of cases suggests that each may be associated with the same damage has already presumably occurred by the time the pathologic process; however, one does not seem to follow the patient presents to an ophthalmologist. Examination of pa- other directly in either comparison. tients in the preclinical phase, which may be possible if a large The decrease in overall retinal thickness in the regions number of unaffected first-degree relatives of affected individ- affected by IPT was mainly related to outer segment shortening uals were targeted, might identify the earliest changes and shed and the thinning of the outer nuclear layer and therefore light on the initiating events in the disease. represents principally photoreceptor damage. This finding is Some limitations of this study should be considered when consistent with previous ones that emphasize the degenerative assessing the data. The resolution of the Stratus OCT may be 12,14 nature of the disease in the neurosensory retina. In our insufficient to detect the P2 wave in some patients with advanced study the outer retinal damage was consistent across all af- disease, leading to miscalculation of the width of the photorecep- fected areas. Particularly in the central fovea, changes in the tor layer. This problem did not appear to occur with any of the photoreceptor layer detected by OCT imaging correlated sig- eyes we examined. The automated algorithm to measure P2 used nificantly with reduced visual acuity, which is in accordance in this study worked reliably in most OCT images, though images with previous findings describing a correlation between a showing heavily distorted morphology could not be analyzed (Fig. disruption of the photoreceptor layer and reduced visual acu- 10 4). This problem should be addressed in the further development ity. These correlations confirm that the morphologic changes of the software. Another factor that could influence the qOCT described have functional significance. The thinning is proba- analysis of IPT is photoreceptor density. Reliable OCT analysis bly of major importance for the understanding of IPT. Other may not be possible in IPT if photoreceptor density were reduced reports on OCT in IPT show reduction of foveal thickness to below a critical level. various degrees. Although previous reports qualitatively de- The results presented herein shed light on IPT, since they scribed a disruption of the inner–outer photoreceptor junction demonstrate that previously undetected changes in the neural (P2 signal), this study now adds quantitative data on the extent 10,12–14 retina, particularly in the photoreceptor region, occur consis- of damage. tently and in the early phases of the disease. Further research A unique finding of the present study is the increased is warranted to correlate the changes observed in qOCT with reflectivity in the outer nuclear layer in the perifoveal temporal functional (multifocal ERG, microperimetry) and histologic region. Changes in the ONL located temporally with areas of studies. Follow-up of the patients over time and examination of increased reflectivity were previously interpreted as deep ret- 10 family members of affected individuals may provide insights on inal vascularizations. Our observations showed ONL reflec- the temporal course of the changes, which in turn may suggest tivity increase in all patients with IPT, which contrasts with hypotheses concerning the pathogenesis of the disease. 21% of the sample in a previous report.10 The interpretation of this reflectivity increase is difficult. On the one hand, this change could be the OCT equivalent to deeper retinal vascu- Acknowledgments larization. On the other, in previous studies with high-resolution OCT, only 21% of the eyes examined showed changes at The authors thank Emily Chew and Alan Bird for helpful discussion and this level that were supposed to be vascular in origin, whereas critical comments on the manuscript. 2162 Barthelmes et al. IOVS, May 2008, Vol. 49, No. 5

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