Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-016-3382-2

RETINAL DISORDERS

Relationship between metamorphopsia and foveal microstructure in patients with branch retinal vein occlusion and cystoid macular edema Tomoya Murakami 1 & Fumiki Okamoto 1 & Masaharu Iida 1 & Yoshimi Sugiura 1 & Yoshifumi Okamoto 1 & Takahiro Hiraoka 1 & Tetsuro Oshika 1

Received: 25 February 2016 / Revised: 29 April 2016 / Accepted: 3 May 2016 # Springer-Verlag Berlin Heidelberg 2016

Abstract Purpose We aimed to investigate the relationship between the severity of metamorphopsia and the foveal microstructure measured with spectral-domain optical coherence tomography (SD-OCT) in patients with cystoid macular edema caused by branch retinal vein occlusion (BRVO-CME). Methods The study included 30 eyes of 30 patients with BRVO-CME. We examined visual acuity and the severity of metamorphopsia using M-CHARTS. Central foveal thickness, central retinal thickness at the fovea (CRT-1 mm), and macular volume were measured with SD-OCT software. The status of ellipsoid zone (EZ), external limiting membrane (ELM), outer retinal cyst, and inner retinal cyst was also evaluated. Results The mean metamorphopsia score was 0.77 ± 0.50, with 28 of 30 patients (93 %) having metamorphopsia (metamorphopsia score ≥ 0.2). The vertical metamorphopsia score (0.89 ± 0.54) was significantly higher than the horizontal metamorphopsia score (0.64 ± 0.53) (p < 0.005). The status of EZ and ELM was significantly associated with visual acuity, but not with the mean metamorphopsia score. The mean metamorphopsia score was significantly related to CRT-1 mm (p < 0.05) and the presence of inner retinal cyst (p < 0.05). Conclusions The severity of metamorphopsia was significantly associated with central retinal thickness and the presence of inner retinal cyst. Keywords Branch retinal vein occlusion . Cystoid macular edema . Metamorphopsia . Optical coherence tomography * Fumiki Okamoto [email protected]

1

Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan

Introduction Retinal vein occlusions are the second most common sightthreatening vascular disorder after diabetic retinopathy [1]. The prevalence of branch retinal vein occlusion (BRVO) was reported to be 0.6 to 2.0 % [2–6], and 9-year cumulative incidence of BRVO was 3.0 % in adults aged 40 years or older [7]. Cystoid macular edema (CME) may occur in eyes with BRVO, and it has been reported that 5 to 15 % of eyes developed cystoid macular edema (CME) over a 1-year period [8]. CME in retinal disorders leads to not only reduction in visual acuity, but also metamorphopsia or aniseikonia [9]. Metamorphopsia is common symptom in eyes with macular disease. Several studies have quantified metamorphopsia and evaluated vision-related quality of life in patients with various vitreoretinal disorders by using the 25-item National Eye Institute Visual Function Questionnaire [10–12]. Okamoto et al. reported that severity of metamorphosia strongly influences vision-related quality of life in eyes with epiretinal membrane (ERM) and macular hole (MH) [11, 12]. To date, however, little information is available on quantification of metamorphopsia in patients with CME accompanying BRVO (BRVO-CME) [13, 14]. Several studies have investigated the relationship between metamorphopsia and retinal microstructure using spectraldomain optical coherence tomography (SD-OCT) in patients with retinal disorders [15–23]. Inner retinal thickness [15, 16], central foveal thickness [17, 18], and the integrity of photoreceptor line [18] were associated with the severity of metamorphopsia in patients with ERM. In MH, fluid cuff size [19] and asymmetric elongation of foveal tissue [20] were related to metamorphopsia. The incidence of focal retinal pigment epithelial detachment was related to metamorphopsia in central serous chorioretinopathy (CSC) [21]. In patients with BRVOCME, several studies showed that the integrity of the foveal photoreceptor layer and central foveal thickness were associated

Graefes Arch Clin Exp Ophthalmol

with visual acuity [22, 23]. However, no studies have addressed the relationship between metamorphopsia and OCT findings. The purpose of this study is to quantify metamorphopsia using M-CHARTS and to investigate the relationship between the severity of metamorphopsia and the foveal microstructure in patients with BRVO-CME.

Methods We analyzed 30 eyes of 30 patients with BRVO-CME, who were referred to the Tsukuba University Hospital between October 2013 and February 2016. There were 20 males and ten females, averaging 64.0 ± 11.3 years of age (mean ± SD). This study was approved by the Institutional Review Board at the Tsukuba University Hospital and was in adherence to the tenets of the Declaration of Helsinki. Signed informed consent was obtained from all study subjects. The diagnoses of BRVOCME were made by fundus examination and SD-OCT examination, and confirmed by fluorescein angiography. Exclusion criteria included patients with a previous history of vitreoretinal surgery and ophthalmic disorders except mild refractive errors and mild cataract. Patients with logarithm of minimal angle of resolution best-corrected visual acuity (logMAR BCVA) of > 1.0 were also excluded because of possible incorrect measurement of the severity of metamorphopsia. At the first visit, all patients underwent comprehensive ophthalmologic examinations, including slit-lamp biomicroscopy, indirect fundus ophthalmoscopy, and SD-OCT examination, while BCVA and the severity of metamorphopsia were also measured. BCVAwas measured with the Landolt Chart, and the severity of metamorphopsia was quantified using M-CHARTS (Inami Co., Tokyo, Japan). The M-CHARTS comprises 19 dotted lines with dot intervals ranging from 0.2 to 2.0° of visual angle. When the straight line is substituted with a dotted line and the dot interval is changed from fine to coarse, the line distortion reduces with the enhanced dot interval until the line seems straight. [24, 25] First, we showed vertical straight lines (0°) to the patient. If the patient recognized a straight line as straight, the metamorphopsia score was determined to be 0. If the patient recognized a straight line as irregular or curved, then we showed subsequent pages of M-CHARTS, where the dot intervals of the dotted line change from fine to coarse, one after another. When the patient recognized a dotted line as straight, the visual angle separating the dots was determined to represent his/her metamorphopsia score for vertical lines. Then the M-CHARTS was rotated 90° and the same test was performed with horizontal lines. The examinations were repeated three times, and their mean values were used for data analyses. The examiners administrating the M-CHARTS tests were experienced orthoptists and were masked to the fundus findings of the patients. The images of foveal microstructure were obtained with an SD-OCT (Cirrus high-definition OCT; Carl Zeiss, Dublin, CA)

after pupil dilation. Macular cube 512 × 128 scans and five-line Raster scans were performed for each eye using Cirrus analysis software version 3.0. The horizontal scans nearest to the fovea center were selected for analysis. Scans with signal strength of more than 8/10 were considered to be appropriate, and a representative image was selected. Using these OCT images, the central foveal thickness (CFT), central retinal thickness at the fovea (CRT-1 mm: within a circle of diameter of 1 mm), and macular volume (MV: volume of the 5 mm × 5 mm retinal area centered on the fovea) were evaluated. The OCT device automatically calculates CFT, CRT-1 mm, and MV. The continuity of ellipsoid zone (EZ), external limiting membrane (ELM) line, and the presence of inner retinal cyst, outer retinal cyst and serous retinal detachment (SRD) were evaluated on SD-OCT images at the 1.0 mm × 1.0 mm area centered on the fovea. A disruption of each line was diagnosed when there was a loss in each hyper-reflective line. Two graders (YS, TH) assessed the status of the EZ and ELM line. Both graders were masked to the clinical findings of the patients, including their visual acuity and metamorphopsia scores. When graders’ evaluations disagreed, the opinion of one of the authors (FO) who was also unaware of the clinical findings was invited and the results were discussed until consensus was reached. All values are presented as mean ± standard deviation. The associations between visual functions (metamorphopsia score and logMAR BCVA) and OCT parameters (CFT, CRT-1 mm, and MV) were examined by the Spearman rank correlation test. Paired t-test was performed to compare between the vertical metamorphopsia score and the horizontal metamorphopsia score. Unpaired t-test was run to compare the visual functions between the two groups based on the status of EZ, ELM, and the presence of outer retinal cyst, inner retinal cyst and SRD. The level of statistical significance was set at p < 0.05. The analyses were carried out using a commercial software package (StatView software, version 5.0; SAS, Inc., Cary, NC).

Results Table 1 shows the visual function and foveal microstructure of eyes with BRVO-CME. The mean metamorphopsia score was 0.77 ± 0.50, with 28 of 30 patients having metamorphopsia (metamorphopsia score ≥ 0.2). The vertical metamorphopsia score was significantly higher than the horizontal metamorphopsia score in patients with BRVO-CME (p < 0.05). Eighteen of 30 eyes (60 %) had inner retinal cyst, while all of eyes had outer retinal cyst. There were nine eyes (30 %) having SRD. The mean metamorphopsia score exhibited a significant correlation with CRT-1 mm (r = 0.443, p < 0.05), but not with CFT (r = 0.048, p = 0.797) or MV (r = −0.009, p = 0.968). LogMAR BCVA exhibited a significant correlation with CFT (r = 0.397, p < 0.05), but not with CRT1mm (r = 0.414, p = 0.058) and MV (r = 0.181, p = 0.417).

Graefes Arch Clin Exp Ophthalmol Table 1 Visual function and foveal microstructure of eyes with branch retinal vein occlusion with cystoid macular edema Number of eyes

30

Age (years) Gender (men / women)

64.0 ± 11.3 [33–83] 20 / 10

BCVA (logMAR)

0.35 ± 0.25 [−0.08–1.00]

Metamorphopsia score vertical

0.89 ± 0.54 [0.0–2.0]

horizontal mean

0.64 ± 0.53 [0.0–2.0] 0.77 ± 0.50 [0.0–2.0]

CFT (μm)

450 ± 175 [196–963]

CRT-1 mm (μm) MV (mm2)

438 ± 111 [281–685] 12.2 ± 1.7 [9.9–17.2]

EZ disruption (+ / -)

6 / 24

ELM disruption (+ / -) Inner retinal cyst (+ / -)

10 / 20 18 / 12

Outer retinal cyst (+ / -) SRD (+ / -)

30 / 0 9 / 21

Values are presented as mean ± standard deviation; BCVA best-corrected visual acuity, logMAR logarithm of the minimum angle of resolution, CFT central foveal thickness, CRT-1 mm central retinal thickness at the fovea, MV macular volume, EZ ellipsoid zone, ELM external limiting membrane, SRD serous retinal detachment

Table 2 lists a correlation between OCT parameters and visual function of eyes with BRVO-CME. The mean metamorphopsia score was significantly related to the presence of inner retinal cyst (p < 0.05), whereas EZ and ELM disruption and the presence of SRD were not related. LogMAR BCVA was significantly related to EZ (p < 0.01) and ELM disruption (p < 0.005), whereas the presence of inner retinal cyst and SRD were not related. Representative cases We present three representative cases: Case 1 (Fig. 1a and b), Case 2 (Fig. 1c and d), and Case 3 (Fig. 1e and f). While LogMAR BCVA was about equal in Case 1 (0.50), Case 2 (0.50) and Case 3 (0.52), the mean metamorphopsia score was 0.6 in Case 1, 2.0 in Case 2, and 2.0 in Case 3. Case 1 had outer retinal cyst only (Fig. 1b), but Case 2 and Case 3 exhibited both inner and outer retinal cyst (Fig. 1d and f).

Discussion As shown in the results, most BRVO-CME patients (93 %) exhibited metamorphopsia. Previous studies evaluating metamorphopsia using M-CHARTS have reported on various retinal disorders such as ERM [16, 17, 23], MH [19, 20], diabetic macular edema (DME) [9], conditions following retinal detachment (RD) surgery

[26], CSC [21], and age-related macular degeneration (AMD) [27]. The mean metamorphopsia score was 0.77 ± 0.50 in patients with BRVO-CME in this study. This score was similar to that of patients with ERM or MH, but higher than that of patients with DME or RD. In BRVO patients, vision-related quality of life (QoL), evaluated using the 25-item National Eye Institute Visual Function Questionnaire, was relatively low compared with patients with MH or ERM. [23] In addition, metamorphopsia, not visual acuity, was significantly associated with vision-related quality of life, ERM, and MH [10–12]. Judging from the findings of previous reports and our present study, it is considered that not only visual acuity, but also metamorphopsia in BRVO-CME may disturb QoL. In our results, the vertical metamorphopsia score was significantly higher than the horizontal metamorphopsia score in patients with BRVO-CME. In most BRVO patients, the lesion is localized either above or below the fovea. It is therefore considered that the detection power tends to be stronger in vertical lines than in horizontal lines on M-CHARTS. Metamorphopsia scores in BRVO-CME were associated with the presence of inner layer cyst in this study. Several studies have investigated the association between metamorphopsia and retinal microstructures in ERM and found that thickness of the inner nuclear layer was considered to be a factor that influenced metamorphopsia [15, 16, 28]. It is unclear why damaged inner retina deteriorates metamorphopsia. Our speculation is that when inner layer cysts exist, the horizontal, bipolar, amacrine, and Muller cell body structures that comprise INL may change. Inhibiting normal function of synaptic junctions and reducing photoreceptor sensitivity would cause metamorphopsia. In addition, previous studies using electroretinography have discussed the relationship between inner retinal functions and CME [29–31]. Terasaki et al. [29] examined full-field ERG in eyes with aphakic or pseudophakic CME and demonstrated that the mean summed amplitude of the oscillatory potentials (OPs) was significantly reduced and the mean implicit time of the first OPs was significantly delayed. As OPs were generated by amacrine cells or interplexiform cells [32–34], their observation that the OPs were significantly reduced in eyes with phakic or pseudophakic CME would indicate physiologic changes in the inner retinal layers. Noma et al. [30, 31], investigating ERG findings in patients with RVO, reported that 30-Hz flicker and cone b-wave implicit times were significantly longer in the eyes with BRVOCME than in the unaffected contralateral eyes. Both the cone b-wave and the 30 Hz flicker have been reported to reflect inner retinal function [35–37]. Thus, an inner retinal cyst in BRVO-CME caused not only morphologic, but also functional damage, resulting in metamorphopsia.

Graefes Arch Clin Exp Ophthalmol Table 2 Correlation between optical coherence tomography parameters and visual function of eyes with branch retinal vein occlusion with cystoid macular edema Metamorphopsia score

p value

BCVA (logMAR)

p value

EZ disruption

(+) (−)

0.83 ± 0.51 0.49 ± 0.39

0.139

0.41 ± 0.24 0.11 ± 0.14

0.006 *

ELM disruption

(+) (−)

0.88 ± 0.54 0.54 ± 0.37

0.075

0.45 ± 0.25 0.17 ± 0.13

0.003 *

Inner retinal cyst

(+) (−)

0.92 ± 0.57 0.53 ± 0.27

0.037 *

0.42 ± 0.27 0.25 ± 0.20

0.065

SRD

(+) (−)

0.74 ± 0.45 0.77 ± 0.53

0.886

0.26 ± 0.21 0.39 ± 0.26

0.175

Values are presented as mean ± standard deviation; EZ ellipsoid zone, ELM external limiting membrane, SRD serous retinal detachment, BCVA bestcorrected visual acuity, logMAR logarithm of the minimum angle of resolution * Significant at P < 0.05

The mean metamorphopsia score in BRVO-CME was significantly related to CRT-1 mm, while metamorphopsia was not related to CFT. Metamorphopsia exhibited a significant correlation with CFT [16–18] and CRT [16] in ERM. In

patients with AMD and MH, no relationship was found between metamorphopsia and CFT or CRT. [27, 38] This discrepancy between the results of previous studies and the present study could not be clarified. The length of the dotted lines

Fig. 1 a and b: Image of the right eye of a 74-year-old woman with branch retinal vein occlusion accompanying cystoid macular edema (BRVO-CME). Her horizontal optical coherence tomography (OCT) image revealed only an outer retinal cyst. She exhibited logarithm of minimum angle of resolution best-corrected visual acuity (logMAR BCVA) of 0.50 and her mean metamorphopsia score was 0.6. c and d: Image of the left eye of a 64-year-

old man with BRVO-CME. His horizontal OCT image showed both inner and outer retinal cysts. His logMAR BCVA was 0.50 and mean metamorphopsia score was 2.0. e and f: Image of Image of the left eye of a 60-year-old man with BRVO-CME. His horizontal OCT image showed both inner and outer retinal cysts. His logMAR BCVA was 0.52 and mean metamorphopsia score was 2.0

Graefes Arch Clin Exp Ophthalmol

of the M-CHARTS is 20°visual angle, thus metamorphopsia score is considered to be associated with abnormality of wide area of macular lesion. In addition, the lesion of BRVO-CME is localized either above or below the fovea, so CFT was normal in some cases, but CRT was of high values. Therefore, it is considered that CRT, rather than CFT, is a good indicator of the severity of metamorphopsia in patients with BRVO-CME. Visual acuity in BRVO-CME was significantly related to CFT, and these results were consistent with the findings of previous reports. Ingrid et al. reported that CFT had a correlation with visual acuity in patients with BRVO-CME [39]. Browning et al. reported that CFT had a correlation with visual acuity in patients with DME [40]. Thus, it is considered that CFT correlates with visual acuity in patients with macular edema. The status of EZ and ELM was associated with visual acuity in patients with BRVO-CME, and these results were consistent with the findings of previous reports [22, 23]. Ota et al. [22] reported that integrity of EZ was associated with visual acuity in eyes with BRVO-CME. Yamane et al. [23] suggested that integrity of the ELM in the foveal region had a direct correlation with visual acuity. Thus integrity of the photoreceptor layer is apparently necessary for good visual acuity. The limitations of this study include a small sample size and analysis based on only horizontal B-scan crosssection. It would be more appropriate to examine vertical B-scan cross-sectional images since the lesion of BRVOCME causes a larger retinal structural change in the vertical direction. Future studies with a larger sample size and more accurate OCT analysis will be needed. In conclusion, a majority of BRVO-CME patients exhibited metamorphopsia, which was more severe in the vertical than in the horizontal direction. The presence of a inner retinal cyst and central retinal thickness were significantly associated with the severity of metamorphopsia.

References

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Funding No funding was received for this research. Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent Informed consent was obtained from all individual participants included in the study.

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Financial support None.

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