VITREOMACULAR INTERFACE AND OUTER FOVEAL MICROSTRUCTURE IN FELLOW EYES OF PATIENTS WITH UNILATERAL MACULAR HOLES AKINORI UEMURA, MD,* FUTOSHI OTSUJI, MD,* TETSURO NAKANO, MD,* TAIJI SAKAMOTO, MD† Purpose: To investigate the relationship between the vitreomacular interface and the integrity of the photoreceptor microstructures in the normal fellow eyes of patients with unilateral macular holes. Methods: Retrospective observational case series. Fifty-five normal fellow eyes of 55 patients with unilateral macular holes were enrolled in the study. All patients underwent complete ophthalmologic examination including best-corrected visual acuity, slit-lamp biomicroscopy, fundus photography, and spectral domain optical coherence tomography at initial and follow-up visits. The features of the vitreomacular interface were graded based on spectral domain optical coherence tomography findings. Results: At the initial visit, 28 of 55 eyes (51%) had vitreomacular attachments with or without perifoveal posterior vitreous detachment. On their initial visit, a triangular elevation of the cone outer segment tips line was identified in 11 of 18 eyes (61%) with perifoveal posterior vitreous detachment across all quadrants with persistent attachment to the fovea. Conversely, none of the remaining 37 eyes with the other stages of posterior vitreous detachment showed any abnormalities. Over a mean follow-up period of 18 months (range, 12–24 months), the elevation of the cone outer segment tips line resolved after spontaneous vitreomacular separation without macular holes in 3 eyes, remained unchanged in 6 eyes, and showed progression to a full-thickness macular hole in 2 eyes. Conclusion: These findings suggest that an elevation of the cone outer segment tips line in the normal fellow eyes of patients with macular holes is caused by the focal traction of the vitreous at the foveal center. This is considered to be an important primary change observed in the macular tissue in full-thickness macular hole formation. RETINA 34:1229–1234, 2014
G
ass1 described a biomicroscopic classification of the development of a macular hole. He suggested that vitreous traction causes a localized detachment of
the fovea, which is seen as a yellow spot by fundus biomicroscopy. Since the introduction of optical coherent tomography (OCT), the sequence of events leading to a full-thickness macular hole has been well documented.2–4 In addition, the examination of the vitreoretinal interface in the macular area by OCT has expanded our knowledge of the pathogenesis of idiopathic macular holes.5–9 At present, it is widely believed that patients with the earliest stages of macular holes have a localized perifoveal posterior vitreous detachment (PVD) with a persistent vitreous attachment to the fovea. This attachment at the fovea was thought to be a mechanism by which vitreous traction could exert its effects on the fovea leading to the development of a full-thickness macular hole. As a consequence of
From the *Department of Ophthalmology, Kagoshima City Hospital, Kagoshima, Japan; and †Department of Ophthalmology, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan. None of the authors have any financial/conflicting interests to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinajournal.com). Reprint requests: Akinori Uemura, MD, Department of Ophthalmology, Kagoshima City Hospital, 20-17 Kajiya-cho, Kagoshimashi, Kagoshima 892-8580, Japan; e-mail: [email protected]. kagoshima.jp
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the persistent traction on the fovea, several anatomical changes have been reported as the primary findings in the process of macular hole formation, such as intraretinal split, foveal pseudocyst, or foveolar detachment.3,4,10 Studies by spectral domain OCT (SD-OCT) found minor changes in the outer foveolar structure, especially in the cone outer segment tips (COST) line, in either eyes with a foveolar yellow spot or eyes with vitreomacular traction.11,12 They suggested that the change in the outer fovea seemed to be caused by vitreomacular traction and might represent an early phase of macular hole formation. Although the detailed features of vitreomacular traction and the outer foveal change have been clearly identified, the causality of the relationship remains insufficiently demonstrated. Additionally, limited information is available on longerterm follow-up data concerning the minor change of the COST line. The aim of the study is to more clearly demonstrate the relationship by observing vitreomacular attachment and the outer foveal change for those cases which progress over the interval of the study and to improve the understanding of the earliest process of macular hole formation. Methods We retrospectively reviewed patient records to identify patients who underwent vitrectomy for unilateral idiopathic macular holes between June 1, 2010 and March 31, 2012 at a single referral-based hospital with the approval of the Institutional Review Boards of Kagoshima City Hospital. A total of 66 patients had an idiopathic macular hole in 1 eye at the initial visit. Patients were included in this study if they were diagnosed with unilateral idiopathic macular holes in one eye and the fellow eye seemed normal on slit-lamp biomicroscopy. Fellow eyes with myopia .−6 diopters, macular diseases including macular holes, best-corrected visual acuity of #0.7, or history of intraocular surgery including vitrectomy or cataract surgery were excluded. Also excluded from the study were eyes with poor quality OCT images because of cataract or vitreous opacities. The patients underwent comprehensive ophthalmologic examinations including best-corrected visual acuity measurements, slit-lamp biomicroscopy, indirect ophthalmoscopy, fundus photography, and SD-OCT examinations at the initial visit and at follow-up visits. After macular hole surgery, patients were followed every 3 months to 6 months at a minimum. We performed SD-OCT examinations using Cirrus HD OCT (Carl Zeiss Meditec, Inc, Humphrey Division,
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Dublin, CA) after pupil dilatation by fixation on an internal target to define the center of the fovea. The entire macular area was scanned by the Macular Cube mode that consisted of 512 A-scans and 128 B-scans (512 · 128), and high-quality images were obtained with the HD 5-Line Raster mode for horizontal and vertical images 6 mm in length. The distance between each scan line was set to 0.05 mm. We obtained OCT images of the center of the fovea where both photoreceptor inner/outer segment (IS/OS) junction line and external limiting membrane line are located slightly inward. Particular attention was paid to the vitreomacular relationship and the morphology of the photoreceptor layers in the central fovea. The assessment of the outer layer abnormality of the fovea was made by two observers who were masked to any clinical information. Scans were obtained by an experienced OCT examiner at least two times to obtain images with a signal intensity of seven or more. The vitreomacular interface was classified into 5 stages according to a previous report by Uchino et al13 (Figure 1). This classification was carried out independently by two masked observers as follows: no vitreous detachment (Stage 0), partial perifoveal PVD (Stage 1), a perifoveal detachment around the macula but which remained attached to the foveal center (Stage 2), a vitreofoveal detachment over the posterior pole with a vitreopapillar attachment (Stage 3), and a complete PVD with a Weiss ring (Stage 4). Eyes with foveal deformation were defined by the loss of the gradual slope of the foveal contour. To verify Stage 0, we used slit-lamp biomicroscopy, ultrasound, and OCT. In eyes with Stage 2 vitreomacular interface, the horizontal diameter of the vitreous attachment zone in the central macula was measured by software incorporated in the OCT (Figure 2). Visual acuity data were converted to logarithm of the minimal angle of resolution (logMAR) units for statistical analysis. Analysis was performed using a Fisher exact test to compare proportions and a Student’s t-test to compare continuous variables. A 2-sided P , 0.05 was considered statistically significant. Results A total of 55 eyes from 55 patients were included in this study. The mean age of the patients was 65.3 years with a range of 53 years to 83 years. All fellow eyes had a normal macula with a normal foveal contour at the initial examination. The clinical characteristics of the patients are given in Supplemental Digital Content 1 (see Table, http://links.lww.com/IAE/A210). At the initial examination, the posterior hyaloid line was not visible in any OCT image in 22 fellow eyes of
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Fig. 1. Classification of the 5 stages of vitreomacular interface as observed by SD-OCT. A. Stage 0, complete attachment of the posterior hyaloid to the retinal surface. B. Stage 1, focal perifoveal vitreous detachment occurring in 1 to 3 quadrants with persistent attachment to the fovea and optic disk. C. Stage 2, perifoveal vitreous attachment across all quadrants with persistent attachment to the fovea and optic disk. D. Stage 3, detachment of the posterior vitreous face
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the 55 patients. Among these 22 eyes, 3 (5%) were classified as Stage 0 and 19 (35%) were classified as Stage 4. Among the remaining 33 fellow eyes, 7 (13%) were classified as Stage 1, 18 (33%) were classified as Stages 2, and 8 (14%) were classified as Stage 3. Twenty-eight eyes (51%) had vitreomacular attachments at the initial examination with or without perifoveal PVD. In the remaining 27 eyes (49%), the posterior vitreous face had already separated from the macular surface. Of the 55 normal fellow eyes, 11 (20%) had a triangular elevation of the COST line at the center of the fovea on SD-OCT. The COST line seemed to be pulled inward, separating from the retinal pigment epithelium line and merging with the IS/OS junction line, although both IS/OS junction line and external limiting membrane line seemed normal. All eyes with an elevation of the COST line had a Stage 2 vitreomacular interface in which the perifoveal vitreous was detached across all quadrants with persistent attachment to the fovea. None of the eyes with the other stages of PVD had such an abnormality in the photoreceptor layers. We focused on the 18 fellow eyes with vitreomacular interface classified as Stage 2 (see Table, Supplemental Digital Content 2, http://links.lww.com/IAE/A211), and compared the clinical characteristics between eyes with and without an elevation of the COST line (see Table, Supplemental Digital Content 3, http://links.lww.com/IAE/A212). Yellow spots on fundus biomicroscopy were detected in 9 of 11 eyes (82%) with an elevation of the COST line, but none of the 7 eyes without an elevation showed any abnormality. Seven eyes (64%) with an elevation of the COST line showed deformations of the inner foveal contour probably because of the vitreous traction. The mean horizontal diameters of the attachment area of the vitreous to the macular region in eyes with and without an elevation of the COST line were 619 mm (range, 230–1,360 mm) and 1829 mm (range, 784–2,848 mm), respectively (P = 0.004). Over a mean follow-up period of 17.8 months (range, 12–24 months), the elevation of the COST line resolved in 3 of the 11 eyes after spontaneous separation of the hyaloid from the macular surface. In one eye (Patient 3) with a normal COST line at the initial visit, the elevation of the COST line developed and was detected at a follow-up examination. This elevation was associated with localized vitreofoveal attachment,
from the fovea with persistent attachment to the optic disk. E. Stage 4, complete PVD with a Weiss ring. The detached posterior hyaloid is out of the plane of this image.
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Fig. 2. Example of Stage 2 vitreomacular interface. Spectral domain optical coherence tomography image through the fovea showing shallow perifoveal detachment of the posterior hyaloid that remains attached to the foveal center. The inner foveal contour is slightly elevated (arrowhead) at the edge of the area where the vitreous is attached. The horizontal diameter of the vitreous attachment in the central macula was measured (double arrow).
and it resolved after vitreofoveal separation (Figure 3). Two of the 11 eyes developed full-thickness macular holes on follow-up (Figure 4). The remaining 6 eyes still had a persistent elevation of the COST line despite a prolonged follow-up. Discussion This study showed that 11 of the 55 fellow eyes (20%) of patients with unilateral idiopathic macular holes had an elevation of the COST line without any visual symptoms. The COST line seemed elevated in the center of the fovea and it seemed to merge with the IS/OS junction line. In some eyes, a hyperreflective region was observed between the elevated COST line and the IS/OS junction line. Although the finding looked like a tiny detachment of the sensory retina, there was no obvious hyporeflective empty space between the COST line and the retinal pigment epithelium line. No apparent changes were observed in either the IS/OS junction line or the external limiting membrane line, only the COST line seemed to move anteriorly in the center of the fovea. Takahashi et al11 reported a similar finding, which they described as a triangular foveolar detachment of the COST line, in eyes with Stage 1A impending macular hole and that had a yellow spot on biomicroscopy. They concluded that the finding was associated with the appearance of the yellow spot. Similar OCT findings were also reported by Tsunoda et al12 in eyes with vitreomacular traction and epiretinal membranes. They termed the finding as a highly reflective region, which was observed between the photoreceptor IS/OS junction line and the COST line at the center of the fovea on SD-OCT. The findings observed for
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Fig. 3. Spectral domain optical coherence tomography images of a 65-year-old patient (Patient 3) who had a vitreomacular detachment during the follow-up. A. An SD-OCT image at the initial visit demonstrating a shallow perifoveal vitreous detachment (arrowheads) with the attachment of the vitreous to the central macula. No abnormalities were noted in the inner and outer foveal morphology. The diameter of the vitreomacular adhesion zone is 2434 mm horizontally. B. Nine months later, an SD-OCT image showing the progression of the perifoveal vitreous detachment with the remaining attachment to the central fovea (arrowhead). The inner foveal contour is slightly elevated by the vitreous traction and a triangular elevation of the COST line is noted (arrow). The diameter of the adhesion zone is 495 mm horizontally. C. Fifteen months after the initial visit, the vitreous is completely detached from the retinal surface and the elevation of the COST line has resolved.
the cases of vitreomacular traction are considered to be the same as those found in this study. In this study, we showed that an elevation of the COST line is observed only in eyes with a Stage 2 vitreomacular interface, a perifoveal PVD with persistent vitreofoveal attachment, and in 60% of the eyes with Stage 2 vitreomacular interface. None of the other stages of PVD showed such an abnormality, even in eyes with vitreomacular attachment (Stages 0 and 1). The previous reports also showed that the finding is associated with vitreomacular attachment with perifoveal PVD.11,12 Additionally, among eyes with a Stage 2 vitreomacular interface, eyes with a smaller width of the vitreomacular attachment were likely to have an elevation of the COST line. The small diameter of the vitreous attachment in eyes with perifoveal PVD correlates with induced changes in foveal anatomy.14 Kumagai et al15 reported that a higher incidence of foveal deformation in the fellow eyes of patients with unilateral macular holes, which is associated with strong vitreomacular adhesion. These results indicate that focal vitreomacular attachment with anteroposterior traction on the foveal surface plays an important role in the elevation of the COST line. The natural course of the elevation of the COST line in the fellow eyes of patients with macular holes
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Fig. 4. Spectral domain optical coherence tomography images of a 54-year-old patient (Patient 10) who developed a full-thickness macular hole in the fellow eye. A. An SD-OCT image at the initial visit showing an elevation of the COST line (arrow) associated with Stage 2 vitreomacular attachment. B. Two weeks later, an SD-OCT image showing a foveolar detachment (arrow) and intraretinal cysts with the attachment of the vitreous to the foveal surface. It seems that a columnar structure is about to be pulled out of the outer fovea. C. Six weeks after the initial visit, an SD-OCT image showing a Stage 1B macular hole. The remnant of the columnar structure is seen under the roof (arrow). D. Eight weeks after the initial visit, an SD-OCT image showing a full-thickness macular hole.
remains poorly understood. In this study, the elevation spontaneously resolved after vitreofoveal separation in three eyes. Similarly, the previous reports described the complete resolution of the finding after vitreomacular separation.11,12 These facts also indicate that there is a strong relationship between the elevation of the COST line and vitreomacular traction. Six of the 11 eyes with an elevated COST line remained stable during the follow-up period of 24 months. Two eyes progressed to a full-thickness macular hole, in which the elevation of the COST line progressed to a tiny foveolar detachment with or without intrafoveal cyst formation. This indicates that a minor abnormality in the COST line might occur long before the development of the early changes that characterizes a Stage 1A macular hole or impending macular holes. A longer follow-up is needed to understand the natural course of the findings because age-related PVD is an insidious chronic event.16 The pathomechanism of the minor abnormality of the COST line is unclear. However, the change that occurs might be explained by the particular architecture of the foveola, especially the foveal Muller cells.17 Gaudric et al3 proposed that vitreofoveal traction on the inner foveal contour is transmitted to the outer retina and induces deformation of the IS/OS junction line. In a study of eyes with idiopathic macular holes by three-dimensional OCT, Hangai et al18 observed an inverted cone-shaped structure under the roof of the hole. To explain the foveal microstructural change shown in this study, the presence of a columnar structure
is essential to connect the foveal surface to the outer photoreceptor layer.11,19 We sometimes encountered OCT images showing an elevated COST line in healthy adults without any ocular diseases. Because vitreofoveal adhesions with normal foveal contour are frequently observed in the OCT images of healthy eyes in the process of age-related PVD development, they are not always specific to eyes with macular holes and their fellow eyes.9,13 Although this study included only the normal fellow eyes of patients with unilateral macular holes, we believe that an elevation of the COST line might be a common finding observed in the normal eyes of healthy adults with vitreofoveal traction. Fellow eyes of macular holes are likely to develop a full-thickness macular hole,20–22 or to have a stronger vitreofoveal adhesion when compared with normal eyes.15 Moreover, patients with macular holes are more likely to return for the examination of both eyes. Therefore, the possibility of detecting abnormalities might be higher in the fellow eyes of patients with macular holes than in normal eyes. However, we should pay attention to the outer foveal microstructure in eyes with vitreofoveal attachment, even in normal eyes, until the attachment is released. This study has several limitations because it is not a prospective study. The number of patients was small and follow-up periods were limited, although follow-up visits were completed in all patients for at least 12 months. In addition, evaluations of the SD-OCT findings were subjective. However, these limitations will not preclude
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conclusions regarding the significance of the outer foveal abnormality in macular hole formation. In conclusion, our study showed that an elevation of the COST line observed in the normal fellow eyes of patients with macular holes may be a result of persistent vitreofoveal traction. Although the mechanism as to how vitreofoveal traction exerts influence on the microstructure of the outer fovea is still unclear, the finding is considered to be important as one of the first changes observed in the macular tissue in full-thickness macular hole formation. Further studies with a larger sample size are needed to understand the nature of this slight outer foveal abnormality. Key words: fellow eyes, macular hole, posterior vitreous detachment, spectral domain optical coherence tomography, vitreomacular interface. References 1. Gass JD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol 1995; 119:752–759. 2. Hee MR, Puliafito CA, Wong C, et al. Optical coherence tomography of macular holes. Ophthalmology 1995;102: 748–756. 3. Gaudric A, Haouchine B, Massin P, et al. Macular hole formation: new data provided by optical coherence tomography. Arch Ophthalmol 1999;117:744–751. 4. Kishi S, Takahashi H. Three-dimensional observations of developing macular holes. Am J Ophthalmol 2000;130:65–75. 5. Chauhan DS, Antcliff RJ, Rai PA, et al. Papillofoveal traction in macular hole formation: the role of optical coherence tomography. Arch Ophthalmol 2000;118:32–38. 6. Mori K, Abe T, Yoneya S. Dome-shaped detachment of premacular vitreous cortex in macular hole development. Ophthalmic Surg Lasers 2000;31:203–209. 7. Johnson MW, Van Newkirk MR, Meyer KA. Perifoveal vitreous detachment is the primary pathogenic event in idiopathic macular hole formation. Arch Ophthalmol 2001;119:215–222. 8. Chan A, Duker JS, Schuman JS, Fujimoto JG. Stage 0 macular holes: observations by optical coherence tomography. Ophthalmology 2004;111:2027–2032.
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9. Johnson MW. Perifoveal vitreous detachment and its macular complications. Trans Am Ophthalmol Soc 2005;103:537–567. 10. Haouchine B, Massin P, Gaudric A. Foveal pseudocyst as the first step in macular hole formation: a prospective study by optical coherence tomography. Ophthalmology 2001;108: 15–22. 11. Takahashi A, Nagaoka T, Yoshida A. Stage 1-A macular hole: a prospective spectral-domain optical coherence tomography study. Retina 2011;31:127–147. 12. Tsunoda K, Watanabe K, Akiyama K, et al. Highly reflective foveal region in optical coherence tomography in eyes with vitreomacular traction or epiretinal membrane. Ophthalmology 2012;119:581–587. 13. Uchino E, Uemura A, Ohba N. Initial stages of posterior vitreous detachment in healthy eyes of older persons evaluated by optical coherence tomography. Arch Ophthalmol 2001;119: 1475–1479. 14. Spaide RF, Wong D, Fisher Y, Goldbaum M. Correlation of vitreous attachment and foveal deformation in early macular hole states. Am J Ophthalmol 2002;133:226–229. 15. Kumagai K, Hangai M, Larson E, Ogino N. Vitreoretinal interface and foveal deformation in asymptomatic fellow eyes of patients with unilateral macular holes. Ophthalmology 2011;118: 1638–1644. 16. Johnson MW. Posterior vitreous detachment: evolution and complications of its early stages. Am J Ophthalmol 2010; 149:371–382. 17. Gass JD. Muller 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;117:821–823. 18. Hangai M, Ojima Y, Gotoh N, et al. Three-dimensional imaging of macular holes with high-speed optical coherence tomography. Ophthalmology 2007;114:763–773. 19. Takahashi A, Nagaoka T, Ishiko S, et al. Foveal anatomic changes in a progressing stage 1 macular hole documented by spectral-domain optical coherence tomography. Ophthalmology 2010;117:806–810. 20. Bronstein MA, Trempe CL, Freeman HM. Fellow eyes of eyes with macular holes. Am J Ophthalmol 1981;92:757–761. 21. Chew EY, Sperduto RD, Hiller R, et al. Clinical course of macular holes: the Eye Disease Case-Control Study. Arch Ophthalmol 1999;117:242–246. 22. Lewis ML, Cohen SM, Smiddy WE, Gass JD. Bilaterality of idiopathic macular holes. Graefes Arch Clin Exp Ophthalmol 1996;234:241–245.
G
ass1 described a biomicroscopic classification of the development of a macular hole. He suggested that vitreous traction causes a localized detachment of
the fovea, which is seen as a yellow spot by fundus biomicroscopy. Since the introduction of optical coherent tomography (OCT), the sequence of events leading to a full-thickness macular hole has been well documented.2–4 In addition, the examination of the vitreoretinal interface in the macular area by OCT has expanded our knowledge of the pathogenesis of idiopathic macular holes.5–9 At present, it is widely believed that patients with the earliest stages of macular holes have a localized perifoveal posterior vitreous detachment (PVD) with a persistent vitreous attachment to the fovea. This attachment at the fovea was thought to be a mechanism by which vitreous traction could exert its effects on the fovea leading to the development of a full-thickness macular hole. As a consequence of
From the *Department of Ophthalmology, Kagoshima City Hospital, Kagoshima, Japan; and †Department of Ophthalmology, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan. None of the authors have any financial/conflicting interests to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinajournal.com). Reprint requests: Akinori Uemura, MD, Department of Ophthalmology, Kagoshima City Hospital, 20-17 Kajiya-cho, Kagoshimashi, Kagoshima 892-8580, Japan; e-mail: [email protected]. kagoshima.jp
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the persistent traction on the fovea, several anatomical changes have been reported as the primary findings in the process of macular hole formation, such as intraretinal split, foveal pseudocyst, or foveolar detachment.3,4,10 Studies by spectral domain OCT (SD-OCT) found minor changes in the outer foveolar structure, especially in the cone outer segment tips (COST) line, in either eyes with a foveolar yellow spot or eyes with vitreomacular traction.11,12 They suggested that the change in the outer fovea seemed to be caused by vitreomacular traction and might represent an early phase of macular hole formation. Although the detailed features of vitreomacular traction and the outer foveal change have been clearly identified, the causality of the relationship remains insufficiently demonstrated. Additionally, limited information is available on longerterm follow-up data concerning the minor change of the COST line. The aim of the study is to more clearly demonstrate the relationship by observing vitreomacular attachment and the outer foveal change for those cases which progress over the interval of the study and to improve the understanding of the earliest process of macular hole formation. Methods We retrospectively reviewed patient records to identify patients who underwent vitrectomy for unilateral idiopathic macular holes between June 1, 2010 and March 31, 2012 at a single referral-based hospital with the approval of the Institutional Review Boards of Kagoshima City Hospital. A total of 66 patients had an idiopathic macular hole in 1 eye at the initial visit. Patients were included in this study if they were diagnosed with unilateral idiopathic macular holes in one eye and the fellow eye seemed normal on slit-lamp biomicroscopy. Fellow eyes with myopia .−6 diopters, macular diseases including macular holes, best-corrected visual acuity of #0.7, or history of intraocular surgery including vitrectomy or cataract surgery were excluded. Also excluded from the study were eyes with poor quality OCT images because of cataract or vitreous opacities. The patients underwent comprehensive ophthalmologic examinations including best-corrected visual acuity measurements, slit-lamp biomicroscopy, indirect ophthalmoscopy, fundus photography, and SD-OCT examinations at the initial visit and at follow-up visits. After macular hole surgery, patients were followed every 3 months to 6 months at a minimum. We performed SD-OCT examinations using Cirrus HD OCT (Carl Zeiss Meditec, Inc, Humphrey Division,
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Dublin, CA) after pupil dilatation by fixation on an internal target to define the center of the fovea. The entire macular area was scanned by the Macular Cube mode that consisted of 512 A-scans and 128 B-scans (512 · 128), and high-quality images were obtained with the HD 5-Line Raster mode for horizontal and vertical images 6 mm in length. The distance between each scan line was set to 0.05 mm. We obtained OCT images of the center of the fovea where both photoreceptor inner/outer segment (IS/OS) junction line and external limiting membrane line are located slightly inward. Particular attention was paid to the vitreomacular relationship and the morphology of the photoreceptor layers in the central fovea. The assessment of the outer layer abnormality of the fovea was made by two observers who were masked to any clinical information. Scans were obtained by an experienced OCT examiner at least two times to obtain images with a signal intensity of seven or more. The vitreomacular interface was classified into 5 stages according to a previous report by Uchino et al13 (Figure 1). This classification was carried out independently by two masked observers as follows: no vitreous detachment (Stage 0), partial perifoveal PVD (Stage 1), a perifoveal detachment around the macula but which remained attached to the foveal center (Stage 2), a vitreofoveal detachment over the posterior pole with a vitreopapillar attachment (Stage 3), and a complete PVD with a Weiss ring (Stage 4). Eyes with foveal deformation were defined by the loss of the gradual slope of the foveal contour. To verify Stage 0, we used slit-lamp biomicroscopy, ultrasound, and OCT. In eyes with Stage 2 vitreomacular interface, the horizontal diameter of the vitreous attachment zone in the central macula was measured by software incorporated in the OCT (Figure 2). Visual acuity data were converted to logarithm of the minimal angle of resolution (logMAR) units for statistical analysis. Analysis was performed using a Fisher exact test to compare proportions and a Student’s t-test to compare continuous variables. A 2-sided P , 0.05 was considered statistically significant. Results A total of 55 eyes from 55 patients were included in this study. The mean age of the patients was 65.3 years with a range of 53 years to 83 years. All fellow eyes had a normal macula with a normal foveal contour at the initial examination. The clinical characteristics of the patients are given in Supplemental Digital Content 1 (see Table, http://links.lww.com/IAE/A210). At the initial examination, the posterior hyaloid line was not visible in any OCT image in 22 fellow eyes of
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Fig. 1. Classification of the 5 stages of vitreomacular interface as observed by SD-OCT. A. Stage 0, complete attachment of the posterior hyaloid to the retinal surface. B. Stage 1, focal perifoveal vitreous detachment occurring in 1 to 3 quadrants with persistent attachment to the fovea and optic disk. C. Stage 2, perifoveal vitreous attachment across all quadrants with persistent attachment to the fovea and optic disk. D. Stage 3, detachment of the posterior vitreous face
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the 55 patients. Among these 22 eyes, 3 (5%) were classified as Stage 0 and 19 (35%) were classified as Stage 4. Among the remaining 33 fellow eyes, 7 (13%) were classified as Stage 1, 18 (33%) were classified as Stages 2, and 8 (14%) were classified as Stage 3. Twenty-eight eyes (51%) had vitreomacular attachments at the initial examination with or without perifoveal PVD. In the remaining 27 eyes (49%), the posterior vitreous face had already separated from the macular surface. Of the 55 normal fellow eyes, 11 (20%) had a triangular elevation of the COST line at the center of the fovea on SD-OCT. The COST line seemed to be pulled inward, separating from the retinal pigment epithelium line and merging with the IS/OS junction line, although both IS/OS junction line and external limiting membrane line seemed normal. All eyes with an elevation of the COST line had a Stage 2 vitreomacular interface in which the perifoveal vitreous was detached across all quadrants with persistent attachment to the fovea. None of the eyes with the other stages of PVD had such an abnormality in the photoreceptor layers. We focused on the 18 fellow eyes with vitreomacular interface classified as Stage 2 (see Table, Supplemental Digital Content 2, http://links.lww.com/IAE/A211), and compared the clinical characteristics between eyes with and without an elevation of the COST line (see Table, Supplemental Digital Content 3, http://links.lww.com/IAE/A212). Yellow spots on fundus biomicroscopy were detected in 9 of 11 eyes (82%) with an elevation of the COST line, but none of the 7 eyes without an elevation showed any abnormality. Seven eyes (64%) with an elevation of the COST line showed deformations of the inner foveal contour probably because of the vitreous traction. The mean horizontal diameters of the attachment area of the vitreous to the macular region in eyes with and without an elevation of the COST line were 619 mm (range, 230–1,360 mm) and 1829 mm (range, 784–2,848 mm), respectively (P = 0.004). Over a mean follow-up period of 17.8 months (range, 12–24 months), the elevation of the COST line resolved in 3 of the 11 eyes after spontaneous separation of the hyaloid from the macular surface. In one eye (Patient 3) with a normal COST line at the initial visit, the elevation of the COST line developed and was detected at a follow-up examination. This elevation was associated with localized vitreofoveal attachment,
from the fovea with persistent attachment to the optic disk. E. Stage 4, complete PVD with a Weiss ring. The detached posterior hyaloid is out of the plane of this image.
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Fig. 2. Example of Stage 2 vitreomacular interface. Spectral domain optical coherence tomography image through the fovea showing shallow perifoveal detachment of the posterior hyaloid that remains attached to the foveal center. The inner foveal contour is slightly elevated (arrowhead) at the edge of the area where the vitreous is attached. The horizontal diameter of the vitreous attachment in the central macula was measured (double arrow).
and it resolved after vitreofoveal separation (Figure 3). Two of the 11 eyes developed full-thickness macular holes on follow-up (Figure 4). The remaining 6 eyes still had a persistent elevation of the COST line despite a prolonged follow-up. Discussion This study showed that 11 of the 55 fellow eyes (20%) of patients with unilateral idiopathic macular holes had an elevation of the COST line without any visual symptoms. The COST line seemed elevated in the center of the fovea and it seemed to merge with the IS/OS junction line. In some eyes, a hyperreflective region was observed between the elevated COST line and the IS/OS junction line. Although the finding looked like a tiny detachment of the sensory retina, there was no obvious hyporeflective empty space between the COST line and the retinal pigment epithelium line. No apparent changes were observed in either the IS/OS junction line or the external limiting membrane line, only the COST line seemed to move anteriorly in the center of the fovea. Takahashi et al11 reported a similar finding, which they described as a triangular foveolar detachment of the COST line, in eyes with Stage 1A impending macular hole and that had a yellow spot on biomicroscopy. They concluded that the finding was associated with the appearance of the yellow spot. Similar OCT findings were also reported by Tsunoda et al12 in eyes with vitreomacular traction and epiretinal membranes. They termed the finding as a highly reflective region, which was observed between the photoreceptor IS/OS junction line and the COST line at the center of the fovea on SD-OCT. The findings observed for
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Fig. 3. Spectral domain optical coherence tomography images of a 65-year-old patient (Patient 3) who had a vitreomacular detachment during the follow-up. A. An SD-OCT image at the initial visit demonstrating a shallow perifoveal vitreous detachment (arrowheads) with the attachment of the vitreous to the central macula. No abnormalities were noted in the inner and outer foveal morphology. The diameter of the vitreomacular adhesion zone is 2434 mm horizontally. B. Nine months later, an SD-OCT image showing the progression of the perifoveal vitreous detachment with the remaining attachment to the central fovea (arrowhead). The inner foveal contour is slightly elevated by the vitreous traction and a triangular elevation of the COST line is noted (arrow). The diameter of the adhesion zone is 495 mm horizontally. C. Fifteen months after the initial visit, the vitreous is completely detached from the retinal surface and the elevation of the COST line has resolved.
the cases of vitreomacular traction are considered to be the same as those found in this study. In this study, we showed that an elevation of the COST line is observed only in eyes with a Stage 2 vitreomacular interface, a perifoveal PVD with persistent vitreofoveal attachment, and in 60% of the eyes with Stage 2 vitreomacular interface. None of the other stages of PVD showed such an abnormality, even in eyes with vitreomacular attachment (Stages 0 and 1). The previous reports also showed that the finding is associated with vitreomacular attachment with perifoveal PVD.11,12 Additionally, among eyes with a Stage 2 vitreomacular interface, eyes with a smaller width of the vitreomacular attachment were likely to have an elevation of the COST line. The small diameter of the vitreous attachment in eyes with perifoveal PVD correlates with induced changes in foveal anatomy.14 Kumagai et al15 reported that a higher incidence of foveal deformation in the fellow eyes of patients with unilateral macular holes, which is associated with strong vitreomacular adhesion. These results indicate that focal vitreomacular attachment with anteroposterior traction on the foveal surface plays an important role in the elevation of the COST line. The natural course of the elevation of the COST line in the fellow eyes of patients with macular holes
FOVEAL MICROSTRUCTURE IN FELLOW EYES OF MH UEMURA ET AL
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Fig. 4. Spectral domain optical coherence tomography images of a 54-year-old patient (Patient 10) who developed a full-thickness macular hole in the fellow eye. A. An SD-OCT image at the initial visit showing an elevation of the COST line (arrow) associated with Stage 2 vitreomacular attachment. B. Two weeks later, an SD-OCT image showing a foveolar detachment (arrow) and intraretinal cysts with the attachment of the vitreous to the foveal surface. It seems that a columnar structure is about to be pulled out of the outer fovea. C. Six weeks after the initial visit, an SD-OCT image showing a Stage 1B macular hole. The remnant of the columnar structure is seen under the roof (arrow). D. Eight weeks after the initial visit, an SD-OCT image showing a full-thickness macular hole.
remains poorly understood. In this study, the elevation spontaneously resolved after vitreofoveal separation in three eyes. Similarly, the previous reports described the complete resolution of the finding after vitreomacular separation.11,12 These facts also indicate that there is a strong relationship between the elevation of the COST line and vitreomacular traction. Six of the 11 eyes with an elevated COST line remained stable during the follow-up period of 24 months. Two eyes progressed to a full-thickness macular hole, in which the elevation of the COST line progressed to a tiny foveolar detachment with or without intrafoveal cyst formation. This indicates that a minor abnormality in the COST line might occur long before the development of the early changes that characterizes a Stage 1A macular hole or impending macular holes. A longer follow-up is needed to understand the natural course of the findings because age-related PVD is an insidious chronic event.16 The pathomechanism of the minor abnormality of the COST line is unclear. However, the change that occurs might be explained by the particular architecture of the foveola, especially the foveal Muller cells.17 Gaudric et al3 proposed that vitreofoveal traction on the inner foveal contour is transmitted to the outer retina and induces deformation of the IS/OS junction line. In a study of eyes with idiopathic macular holes by three-dimensional OCT, Hangai et al18 observed an inverted cone-shaped structure under the roof of the hole. To explain the foveal microstructural change shown in this study, the presence of a columnar structure
is essential to connect the foveal surface to the outer photoreceptor layer.11,19 We sometimes encountered OCT images showing an elevated COST line in healthy adults without any ocular diseases. Because vitreofoveal adhesions with normal foveal contour are frequently observed in the OCT images of healthy eyes in the process of age-related PVD development, they are not always specific to eyes with macular holes and their fellow eyes.9,13 Although this study included only the normal fellow eyes of patients with unilateral macular holes, we believe that an elevation of the COST line might be a common finding observed in the normal eyes of healthy adults with vitreofoveal traction. Fellow eyes of macular holes are likely to develop a full-thickness macular hole,20–22 or to have a stronger vitreofoveal adhesion when compared with normal eyes.15 Moreover, patients with macular holes are more likely to return for the examination of both eyes. Therefore, the possibility of detecting abnormalities might be higher in the fellow eyes of patients with macular holes than in normal eyes. However, we should pay attention to the outer foveal microstructure in eyes with vitreofoveal attachment, even in normal eyes, until the attachment is released. This study has several limitations because it is not a prospective study. The number of patients was small and follow-up periods were limited, although follow-up visits were completed in all patients for at least 12 months. In addition, evaluations of the SD-OCT findings were subjective. However, these limitations will not preclude
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conclusions regarding the significance of the outer foveal abnormality in macular hole formation. In conclusion, our study showed that an elevation of the COST line observed in the normal fellow eyes of patients with macular holes may be a result of persistent vitreofoveal traction. Although the mechanism as to how vitreofoveal traction exerts influence on the microstructure of the outer fovea is still unclear, the finding is considered to be important as one of the first changes observed in the macular tissue in full-thickness macular hole formation. Further studies with a larger sample size are needed to understand the nature of this slight outer foveal abnormality. Key words: fellow eyes, macular hole, posterior vitreous detachment, spectral domain optical coherence tomography, vitreomacular interface. References 1. Gass JD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol 1995; 119:752–759. 2. Hee MR, Puliafito CA, Wong C, et al. Optical coherence tomography of macular holes. Ophthalmology 1995;102: 748–756. 3. Gaudric A, Haouchine B, Massin P, et al. Macular hole formation: new data provided by optical coherence tomography. Arch Ophthalmol 1999;117:744–751. 4. Kishi S, Takahashi H. Three-dimensional observations of developing macular holes. Am J Ophthalmol 2000;130:65–75. 5. Chauhan DS, Antcliff RJ, Rai PA, et al. Papillofoveal traction in macular hole formation: the role of optical coherence tomography. Arch Ophthalmol 2000;118:32–38. 6. Mori K, Abe T, Yoneya S. Dome-shaped detachment of premacular vitreous cortex in macular hole development. Ophthalmic Surg Lasers 2000;31:203–209. 7. Johnson MW, Van Newkirk MR, Meyer KA. Perifoveal vitreous detachment is the primary pathogenic event in idiopathic macular hole formation. Arch Ophthalmol 2001;119:215–222. 8. Chan A, Duker JS, Schuman JS, Fujimoto JG. Stage 0 macular holes: observations by optical coherence tomography. Ophthalmology 2004;111:2027–2032.
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9. Johnson MW. Perifoveal vitreous detachment and its macular complications. Trans Am Ophthalmol Soc 2005;103:537–567. 10. Haouchine B, Massin P, Gaudric A. Foveal pseudocyst as the first step in macular hole formation: a prospective study by optical coherence tomography. Ophthalmology 2001;108: 15–22. 11. Takahashi A, Nagaoka T, Yoshida A. Stage 1-A macular hole: a prospective spectral-domain optical coherence tomography study. Retina 2011;31:127–147. 12. Tsunoda K, Watanabe K, Akiyama K, et al. Highly reflective foveal region in optical coherence tomography in eyes with vitreomacular traction or epiretinal membrane. Ophthalmology 2012;119:581–587. 13. Uchino E, Uemura A, Ohba N. Initial stages of posterior vitreous detachment in healthy eyes of older persons evaluated by optical coherence tomography. Arch Ophthalmol 2001;119: 1475–1479. 14. Spaide RF, Wong D, Fisher Y, Goldbaum M. Correlation of vitreous attachment and foveal deformation in early macular hole states. Am J Ophthalmol 2002;133:226–229. 15. Kumagai K, Hangai M, Larson E, Ogino N. Vitreoretinal interface and foveal deformation in asymptomatic fellow eyes of patients with unilateral macular holes. Ophthalmology 2011;118: 1638–1644. 16. Johnson MW. Posterior vitreous detachment: evolution and complications of its early stages. Am J Ophthalmol 2010; 149:371–382. 17. Gass JD. Muller 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;117:821–823. 18. Hangai M, Ojima Y, Gotoh N, et al. Three-dimensional imaging of macular holes with high-speed optical coherence tomography. Ophthalmology 2007;114:763–773. 19. Takahashi A, Nagaoka T, Ishiko S, et al. Foveal anatomic changes in a progressing stage 1 macular hole documented by spectral-domain optical coherence tomography. Ophthalmology 2010;117:806–810. 20. Bronstein MA, Trempe CL, Freeman HM. Fellow eyes of eyes with macular holes. Am J Ophthalmol 1981;92:757–761. 21. Chew EY, Sperduto RD, Hiller R, et al. Clinical course of macular holes: the Eye Disease Case-Control Study. Arch Ophthalmol 1999;117:242–246. 22. Lewis ML, Cohen SM, Smiddy WE, Gass JD. Bilaterality of idiopathic macular holes. Graefes Arch Clin Exp Ophthalmol 1996;234:241–245.
