Abstract
purpose. To test the hypothesis that hyporeflective spaces in the neuroretina found on optical coherence tomography (OCT) examination have different optical reflectivities according to whether they are associated with exudation or degeneration.
methods. Retrospective analysis of eyes with idiopathic perifoveal telangiectasia (IPT), diabetic macular edema (DME), idiopathic central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), or cone dystrophy (CD) and eyes of healthy control subjects. OCT scans were performed. Raw scan data were exported and used to calculate light reflectivity profiles. Reflectivity data were acquired by projecting three rectangular boxes, each 50 pixels long and 5 pixels wide, into the intraretinal cystoid spaces, centrally onto unaffected peripheral RPE, and onto the prefoveolar vitreous. Light reflectivity in the retinal pigment epithelium (RPE), vitreous, and intraretinal spaces for the different retinal conditions and control subjects were compared.
results. Reflectivities of the vitreous and the RPE were similar among the groups. Hyporeflective spaces in eyes with exudation (DME, RP, and CSC) had higher reflectivity compared with the mean reflectivity of the vitreous, whereas the cystoid spaces in the maculae of the eyes without exudation (CD and IPT) had a lower reflectivity than did the normal vitreous.
conclusions. Analysis of the light reflectivity profiles may be a tool to determine whether the density of hyporeflective spaces in the macula is greater or less than that of the vitreous, and may be a way to differentiate degenerative from exudative macular disease.
Several retinal diseases, such as diabetic retinopathy, exudative age-related macular degeneration, or retinitis pigmentosa, exhibit intraretinal cystoid spaces that are related to exudation (seen in fluorescein angiography), whereas in other conditions, such as macular telangiectasia or cone dystrophy (CD), such spaces occur without retinal thickening and thus are presumably due to degenerative processes. These intraretinal spaces can be documented by optical coherence tomography (OCT).
1 2 3 4 To date, the true nature and composition of the content of these spaces is unknown. However, clinicians and scientists may be interested in whether these spaces exhibit different optical properties in the noninvasive OCT, and having this information may help them to evaluate retinal diseases more thoroughly. For example, the presence of retinal cysts may be an indication for retreatment with ranibizumab for age-related exudative macular degeneration; however, if these cysts are degenerative rather than exudative, retreatment may best be withheld.
Macular telangiectasia is an uncommon condition characterized by dilatation and incompetence of the perifoveal retinal capillaries.
5 6 7 In contrast to type 1, or aneurysmal, telangiectasis, which is characterized by exudation and is usually unilateral, type 2, or idiopathic perifoveal telangiectasis (IPT), is generally found in both eyes and is characterized by progressive thinning of the neurosensory macula without exudation.
5 6 7
Cone dystrophies (CDs) are rare hereditary retinal diseases that primarily affect the cones.
8 9 Slow decay of the cone photoreceptors leads to photophobia and decreased visual acuity; some patients eventually become legally blind. The retina may appear normal in clinical examination in the early stages of CD, whereas in later stages subtle atrophic changes with pigmentary reaction may be found. The Ganzfeld electroretinogram (ERG) shows decreased signal amplitudes for cone-driven signals, whereas the rod-driven signals remain within normal ranges.
Inner and outer retinal cystoid spaces are commonly found in IPT.
10 The nature of the inner cystoid spaces, which do not appear to be the result of exudation, since they are not associated with macular thickening, is entirely obscure. Until now, it was believed that these spaces were mainly found in IPT; however, we have found an identical appearance in an eye that subsequently developed typical features of CD.
11 We have also observed outer retinal, also apparently nonexudative, cystoid spaces in eyes with CD (Barthelmes D, Gillies MC, unpublished data, 2006).
It has been shown that there is little variation in the reflectivity of the retinal pigment epithelium and the vitreous between patients with inherited retinal diseases and those with normal eyes, while differences in the reflectivity of intraretinal layers can be used to distinguish different diseases when analyzed quantitatively.
12
We used OCT to evaluate intraretinal spaces in eyes with IPT and CD and to compare them with those found in DME, CSC, and RP to test the hypothesis that hyporeflective spaces have different optical reflectivities according to whether they are associated with exudation or degeneration.
In this retrospective study, we examined eyes of patients with cone dystrophy (CD), idiopathic perifoveal telangiectasia (IPT), diabetic macular edema (DME), idiopathic central serous chorioretinopathy (CSC), or retinitis pigmentosa (RP). Three patients with CD were included; for the other diseases, six patients were included in each group, and one eye was examined in each patient. Eyes with type II IPT were chosen from 14 patients participating in a natural history study of that condition (see www.mactelresearch.org/ The Macular Telangiectasia Project conducted by a consortium of scientists at centers in the United Kingdom and the United States). Diagnostic criteria for IPT were the presence of small telangiectatic vessels characteristically found inferotemporally within 1 disc diameter of the foveola; staining by fluorescein on angiography but without retinal thickening or exudation; loss of central macular transparency; and the potential presence of discrete superficial white crystals.
The diagnosis was confirmed in all cases by the Reading Centre at Moorfields Eye Hospital (London, UK). Eyes with CD and RP were chosen from patients referred to the Electrophysiology Laboratory at the Department of Ophthalmology of the University Hospital (Zurich, Switzerland). CD and RP were diagnosed based on best corrected visual acuity, slit lamp examination, Ganzfeld electroretinography (ERG), and funduscopy.
13 14 Patients with cystoid DME, secondary to diabetic retinopathy, and idiopathic CSC were chosen by sequential retrospective review of patient records, fluorescein angiography, and OCT findings from the retina clinics of the Sydney Eye Hospital. In addition, 20 eyes of 10 healthy control subjects were examined with OCT.
We identified six eyes with intraretinal spaces for each of four diagnoses—IPT, macular edema secondary to RP, DME, and idiopathic CSC—and three eyes with intraretinal space in the CD group. Based on the appearance of exudation in fluorescein angiography and its correlation with intraretinal spaces, these groups were chosen to represent exudative and degenerative, nonexudative maculopathies. Eyes for analysis were identified before performance of quantitative OCT analysis. Ethics committee supervision for this noninterventional retrospective analysis was not required. The study was performed in accordance with the tenets of the Declaration of Helsinki 1975 (1983 revision).
OCT scanning was performed (Stratus OCT, software ver. 4.01; Carl Zeiss Meditec AG, Oberkochen, Germany) with the built-in macular thickness scanning program, consisting of six radially arranged scan lines, each 6 mm long, 30° apart, and centered in the foveola. All OCT recordings were performed under the same conditions.
Only scans with excellent quality (quality factor, 9 or 10) were used. For quantitative analysis, unprocessed raw scan data were exported from the OCT machine. Interpreting the raw scan data as 32-bit gray-scale images resulted in 4096 levels of gray, ranging from 0 to 4095. Light reflection profiles (LRP) for each image were calculated for each OCT image (IGOR 5.05a; Wavemetrics, Inc., Lake Oswego, OR).
12 Reflectivity data were acquired by placing three rectangular boxes, each 50 pixels long and 5 pixels wide, into the cystoid spaces, centrally onto unaffected peripheral RPE, and in the prefoveolar vitreous, by using the built-in image line profile procedure
(Fig. 1) . Instead of analyzing single data points, which can have rather high or low reflectivity values, we calculated the mean reflectivity of 250 data points from every area measured (RPE, vitreous, and cystoid space) in every eye. Details are given in
Table 1 . Because raw data were used, reflectivity was expressed in arbitrary units (AU) according to the reflectivity values instead of decibels.
A 21-year-old male presented with progressive loss of visual acuity (20/60 in both eyes). Some pigment epithelial changes were visible in the central macula in both eyes. Fluorescein angiography showed a window defect but no leakage, consistent with attenuation of the RPE.
OCT revealed outer retinal cystoid spaces in the central macula of both eyes. Ganzfeld ERG revealed normal rod-driven responses and significantly reduced cone-driven amplitudes in both single flash and 30-Hz flicker stimulation. Implicit times were abnormally increased under both conditions.
By quantitatively analyzing light reflectivity profiles from OCT studies, we have demonstrated that retinal hyporeflective spaces in IPT and CD—conditions in which cysts occur without exudation—consistently have lower optical reflectivity than do spaces occurring in conditions associated with exudation. That exudative retinal cysts, for example in AMD, eventually subside in most eyes on treatment with anti-VEGF agents, whereas cysts associated with a nonexudative disease (IPT) are unaffected by such treatment, is further evidence of a difference between hyporeflective spaces and is consistent with the hypothesis that spaces without exudation have a degenerative etiology.
16 17
The demonstration that intraretinal spaces of low reflectivity can have variations in appearance on OCT that are related to the underlying disease has the potential to improve clinical decision-making. For example, persistent intraretinal fluid, as evidenced by cystoid hyporeflective intraretinal spaces, may be used as an indication to continue treatment with vascular endothelial growth factor inhibitors.
1 However, if these spaces result from nonexudative, or dry, degeneration, then the degeneration might be exacerbated by further treatment, and this treatment should be withheld.
The location of the cystoid spaces in these degenerative maculopathies may provide clues to their nature. Cystoid spaces in the outer retina are not unexpected in CD. Inner retinal spaces may also be anticipated in IPT, since the vascular changes that characterize the condition point to involvement of the inner retina as well. It is the presence of inner retinal cystoid spaces in eyes with CD that is surprising, since CD is understood to affect primarily the photoreceptors. The presence of inner retinal hyporeflective spaces in eyes with CD suggests an influence of the outer retina on the inner retina, the nature of which is obscure. One possibility is that the death of photoreceptors results in retrograde degeneration of the inner retina, which eventually leads to formation of a cystoid space.
It has been proposed that the degeneration of the neural retina that characterizes IPT is primarily due to Müller cell damage.
18 19 Gass
20 drew attention to the “Müller cell cone,” a layer of Müller cells above the layer of Henle immediately beneath the inner limiting membrane (ILM) in the base of the foveal depression. Disease of the Müller cells may thus explain the “ILM drape” across cavities in the inner retina at the base of the foveal depression that are commonly found in eyes with IPT on OCT.
10
Although the OCT reveals neither the origin nor the composition of the intraretinal spaces, the lower reflectivity of the spaces found in IPT and CD, compared with RP, CSC, and DME, may be due to the presence of albumin and acute-phase serum reactants in the latter, causing more backscattering. Macular edema secondary to diabetes and RP is recognized to be caused by a breakdown of the blood–retinal barrier, as is the subretinal fluid in CSC.
21 22 23 24 The lower reflectivity of spaces found in the putative degenerative maculopathies suggests that they have lower protein content, in which case they are probably not the result of breakdown of the blood–retinal barrier. It is more likely that the cysts represent areas of cell loss by apoptosis, which is not associated with inflammation or exudation.
18 Therefore, we propose that cysts with an optical index greater than the vitreous have an exudative etiology, whereas those with reflectivity less than the vitreous are degenerative.
This study is limited by the relatively small number of participants. In particular, only two eyes of one participant with CD had inner retinal spaces identical with those seen in IPT. We have reported another case in which the development of inner retinal cystoid spaces typical of IPT was preceded by clinical and electrophysiological features of CD.
11 In the unlikely event that the association of inner cystoid spaces with CD was a coincidence, then conclusions drawn about the influence of the outer retina on the inner retina would be unfounded. However, the clear, quantifiable differentiation of intraretinal spaces on the basis of their optical reflectivity still stands.
Analyzing the light refection profiles from OCT to determine whether the density of hyporeflective spaces in the macula is greater or less than that of the vitreous may be a way to differentiate processes in the central macula. Further research is warranted to determine how this approach may be used to improve diagnosis and treatment of macular diseases.
Supported by a grant from the Lowy Medical Research Foundation.
Submitted for publication October 12, 2007; revised December 2, 2007, and January 28, 2008; accepted June 9, 2008.
Disclosure:
D. Barthelmes, None;
F.K.P. Sutter, None;
M.C. Gillies, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “
advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Daniel Barthelmes, Department of Ophthalmology, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland;
[email protected].
Table 1. Reflectivity in Each Eye in Each Region
Table 1. Reflectivity in Each Eye in Each Region
Group | Region Tested | Eye Tested | | | | | |
| | 1 | 2 | 3 | 4 | 5 | 6 |
Normal | RPE | 2215.7 ± 195.7 | 2211.6 ± 189.6 | 2153.24 ± 199.02 | 2194.83 ± 183.15 | 2281.87 ± 225.4 | 2166.44 ± 206.82 |
| Vitreous | 966.86 ± 59.32 | 969.46 ± 66.08 | 964.46 ± 60.8 | 970.87 ± 62.25 | 969.85 ± 85.71 | 964.89 ± 64.44 |
| Cystoid space | NA | NA | NA | NA | NA | NA |
CSC | RPE | 2226.3 ± 213.7 | 2219.58 ± 177.83 | 2215.78 ± 208.4 | 2236.07 ± 212.05 | 2076.91 ± 235.05 | 2110.17 ± 219.88 |
| Vitreous | 968.4 ± 66.98 | 962.3 ± 83.32 | 960.5 ± 41.64 | 965.06 ± 41.16 | 971.42 ± 46.27 | 974.22 ± 62.83 |
| Cystoid space | 1009.79 ± 69.84 | 1016.38 ± 80.56 | 996.27 ± 52.33 | 997.8 ± 51.86 | 993.49 ± 48.04 | 1030.46 ± 89.15 |
DME | RPE | 2097.32 ± 236.29 | 2047.41 ± 216.15 | 2131.45 ± 206.9 | 2221.72 ± 205.31 | 2239.83 ± 276.41 | 2356.29 ± 297.03 |
| Vitreous | 965.95 ± 55.64 | 967.36 ± 50.95 | 964.94 ± 56.71 | 970.05 ± 64.63 | 968.91 ± 56.16 | 962.37 ± 57.69 |
| Cystoid space | 968.18 ± 62.88 | 969.06 ± 58.66 | 970.6 ± 58.31 | 982.13 ± 59.98 | 989.75 ± 56.93 | 964.89 ± 56.64 |
IPT | RPE | 2217.15 ± 163.55 | 2205.68 ± 167.96 | 2216.87 ± 215.69 | 2231.14 ± 238.78 | 2176.53 ± 244.95 | 2052.77 ± 199.01 |
| Vitreous | 963.23 ± 49.3 | 952.69 ± 53.68 | 968.17 ± 78.01 | 987.82 ± 72.95 | 996.11 ± 75.15 | 979.28 ± 90.22 |
| Cystoid space | 940.04 ± 60.97 | 952.49 ± 62.35 | 969.28 ± 57.67 | 936.05 ± 57.78 | 938.68 ± 48.73 | 961.99 ± 59.01 |
RP | RPE | 2149.32 ± 245.88 | 2254.83 ± 219.34 | 2153.15 ± 231.33 | 2192.37 ± 210.23 | 2114.88 ± 226.17 | 2220.47 ± 212.48 |
| Vitreous | 968.65 ± 49.76 | 965.36 ± 56.32 | 962.26 ± 55.72 | 962.39 ± 57.91 | 970.5 ± 52.63 | 971.65 ± 61.66 |
| Cystoid space | 971.69 ± 54.78 | 967.18 ± 54.31 | 975.58 ± 57.47 | 981.27 ± 54.08 | 973.89 ± 54.5 | 979.84 ± 59.19 |
CD | RPE | 2179.57 ± 162.57 | 2206.38 ± 235.82 | 2183.48 ± 287.08 | | | |
| Vitreous | 967.38 ± 70.09 | 967.17 ± 81.42 | 969.05 ± 57.96 | | | |
| Cystoid space | 940.43 ± 50.55 | 958.09 ± 79.95 | 961.43 ± 87.99 | | | |
The authors thank Jeannie Wurz for careful editing of the manuscript.
FungAE, LalwaniGA, RosenfeldPJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143(4)566–583.
[CrossRef] [PubMed]MassinP, DuguidG, ErginayA, HaouchineB, GaudricA. Optical coherence tomography for evaluating diabetic macular edema before and after vitrectomy. Am J Ophthalmol. 2003;135(2)169–177.
[CrossRef] [PubMed]MeloGB, FarahME, AggioFB. Intravitreal injection of bevacizumab for cystoid macular edema in retinitis pigmentosa. Acta Ophthalmol Scand. 2007;85(4)461–463.
[CrossRef] [PubMed]GaudricA, Ducos de LahitteG, CohenSY, MassinP, HaouchineB. Optical coherence tomography in group 2A idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol. 2006;124(10)1410–1419.
[CrossRef] [PubMed]GassJD, BlodiBA. Idiopathic juxtafoveolar retinal telangiectasis: update of classification and follow-up study. Ophthalmology. 1993;100(10)1536–1546.
[CrossRef] [PubMed]GassJD, OyakawaRT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol. 1982;100(5)769–780.
[CrossRef] [PubMed]YannuzziLA, BardalAM, FreundKB, ChenKJ, EandiCM, BlodiB. Idiopathic macular telangiectasia. Arch Ophthalmol. 2006;124(4)450–460.
[CrossRef] [PubMed]MichaelidesM, HuntDM, MooreAT. The cone dysfunction syndromes. Br J Ophthalmol. 2004;88(2)291–297.
[CrossRef] [PubMed]PaunescuLA, KoTH, DukerJS, et al. Idiopathic juxtafoveal retinal telangiectasis: new findings by ultrahigh-resolution optical coherence tomography. Ophthalmology. 2006;113(1)48–57.
[CrossRef] [PubMed]BarthelmesD, GilliesMC, FleischhauerJC, SutterFK. A case of idiopathic perifoveal telangiectasia preceded by features of cone dystrophy. Eye. 2007;21(12)1534–1535.
[CrossRef] [PubMed]BarthelmesD, SutterFK, Kurz-LevinMM, et al. Quantitative analysis of OCT characteristics in patients with achromatopsia and blue-cone monochromatism. Invest Ophthalmol Vis Sci. 2006;47(3)1161–1166.
[CrossRef] [PubMed]GerberDM, MunierFL, NiemeyerG. Cross-sectional study of visual acuity and electroretinogram in two types of dominant drusen. Invest Ophthalmol Vis Sci. 2003;44(2)493–496.
[CrossRef] [PubMed]MarmorMF, ZrennerE. Standard for clinical electroretinography (1999 update). International Society for Clinical Electrophysiology of Vision. Doc Ophthalmol. 1998;97(2)143–156.
[CrossRef] [PubMed]SurguchV, GamulescuMA, GabelVP. Optical coherence tomography findings in idiopathic juxtafoveal retinal telangiectasis. Graefes Arch Clin Exp Ophthalmol. 2007;245(6)783–788.
[CrossRef] [PubMed]Charbel IssaP, HolzFG, SchollHP. Findings in fluorescein angiography and optical coherence tomography after intravitreal bevacizumab in type 2 idiopathic macular telangiectasia. Ophthalmology. 2007;114(9)1736–1742.
[CrossRef] [PubMed]SchulzeS, MennelS. Treatment of idiopathic juxtafoveolar retinal telangiectasis with bevacizumab (avastin) (in German). Klin Monatsbl Augenheilkd. 2007;224(10)787–790.
[CrossRef] [PubMed]CohenSM, CohenML, El-JabaliF, PautlerSE. Optical coherence tomography findings in nonproliferative group 2a idiopathic juxtafoveal retinal telangiectasis. Retina. 2007;27(1)59–66.
[CrossRef] [PubMed]KoizumiH, IidaT, MarukoI. Morphologic features of group 2A idiopathic juxtafoveolar retinal telangiectasis in three-dimensional optical coherence tomography. Am J Ophthalmol. 2006;142(2)340–343.
[CrossRef] [PubMed]GassJD. Müller cell cone, an overlooked part of the anatomy of the fovea centralis: hypotheses concerning its role in the pathogenesis of macular hole and foveomacular retinoschisis. Arch Ophthalmol. 1999;117(6)821–823.
[CrossRef] [PubMed]VinoresSA, KuchleM, DerevjanikNL, et al. Blood-retinal barrier breakdown in retinitis pigmentosa: light and electron microscopic immunolocalization. Histol Histopathol. 1995;10(4)913–923.
[PubMed]PrunteC, FlammerJ. Choroidal capillary and venous congestion in central serous chorioretinopathy. Am J Ophthalmol. 1996;121(1)26–34.
[CrossRef] [PubMed]PrunteC, FlammerJ. Circulatory disorders of the choroid in patients with central serious chorioretinopathy (in German). Klin Monatsbl Augenheilkd. 1996;208(5)337–339.
[CrossRef] [PubMed]QaumT, XuQ, JoussenAM, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001;42(10)2408–2413.
[PubMed]