Metamorphopsia Associated with Branch Retinal Vein Occlusion

Purpose To apply M-CHARTS for quantitative measurements of metamorphopsia in eyes with acute branch retinal vein occlusion (BRVO) and to elucidate the pathomorphology that causes metamorphopsia. Methods This prospective study consisted of 42 consecutive patients (42 eyes) with acute BRVO. Both at baseline and one month after treatment with ranibizumab, metamorphopsia was measured with M-CHARTS, and the retinal morphological changes were examined with optical coherence tomography. Results At baseline, metamorphopsia was detected in the vertical and/or horizontal directions in 29 (69.0%) eyes; the mean vertical and horizontal scores were 0.59 ± 0.57 and 0.52 ± 0.67, respectively. The maximum inner retinal thickness showed no association with the M-CHARTS score, but the M-CHARTS score was correlated with the total foveal thickness (r = 0.43, p = 0.004), the height of serous retinal detachment (r = 0.31, p = 0.047), and the maximum outer retinal thickness (r = 0.36, p = 0.020). One month after treatment, both the inner and outer retinal thickness substantially decreased. However, metamorphopsia persisted in 26 (89.7%) of 29 eyes. The posttreatment M-CHARTS score was not correlated with any posttreatment morphological parameters. However, the posttreatment M-CHARTS score was weakly correlated with the baseline total foveal thickness (r = 0.35. p = 0.024) and closely correlated with the baseline M-CHARTS score (r = 0.78, p < 0.001). Conclusions Metamorphopsia associated with acute BRVO was quantified using M-CHARTS. Initial microstructural changes in the outer retina from acute BRVO may primarily account for the metamorphopsia.


Introduction
Macular edema (ME) is one of the main causes of the decrease in visual acuity (VA) associated with acute branch retinal vein occlusion (BRVO) [1]. The visual prognosis of BRVO has been substantially improved since the introduction of anti-vascular endothelial growth factor agents [2,3]. However, some patients suffer from a decreased quality of vision due to symptomatic metamorphopsia, even after the complete reduction of ME. Recent advancements in ophthalmic instruments have improved our understanding of the pathophysiology of retinal complications associated with BRVO and their correlations with subjective symptoms [4]. However, our understanding of metamorphopsia caused by BRVO remains limited due to the lack of methodologies to quantify the degree of metamorphopsia [5][6][7][8][9][10]. In addition, BRVO, which is caused by a circulatory disturbance within the inner retina, shows various features, such as retinal swelling, retinal cystoid spaces, retinal hemorrhage, non-perfusion area, and serous retinal detachment, and these morphological changes extend from the inner retina to the subretinal spaces [1]. Such complexity in the pathologic features makes it difficult to elucidate the pathogenesis of metamorphopsia associated with acute BRVO.
M-CHARTS, developed by Matsumoto et al. [11], allows us to quantitatively evaluate the degree of metamorphopsia. M-CHARTS consists of a series of 19 dotted line tests in which the intervals of each dot range from 0.2°to 2.0°. In patients with metamorphopsia, a dotted line with a small interval is often recognized as distorted. As the dot interval increases, the distortion of the line decreases. With M-CHARTS, metamorphopsia is quantified as the minimum interval at which no visual distortion is present. To date, quantitative evaluations with M-CHARTS have been applied in epiretinal membrane [11][12][13][14][15][16][17][18][19][20][21], rhegmatogenous retinal detachment [22], age-related macular degeneration [23,24], diabetic macular edema [25], macular hole [26,27], and central serous chorioretinopathy [28,29]. Based on the use of M-CHARTS for epiretinal membrane, it has been reported that the severity of metamorphopsia is related to the thickness of the inner nuclear layer measured with optical coherence tomography (OCT) [15,21,30] or foveal microfolds visualized using adaptive optics-scanning laser ophthalmoscopy [13].
However, few investigators have quantitatively evaluated metamorphopsia associated with BRVO; using M-CHARTS, Nakagawa et al. [6], studied metamorphopsia in 12 eyes with BRVO, and Achiron et al. [5] detected metamorphopsia in 4 eyes with retinal vein occlusion. To the best of our knowledge, no previous reports have described the retinal pathomorphology that is involved in the metamorphopsia associated with BRVO. Therefore, the purposes of the current study were (1) to perform quantitative measurements of metamorphopsia with M-CHARTS in eyes with acute BRVO in order to determine the prevalence and severity of metamorphopsia and (2) to compare the M-CHARTS score with the retinal morphology measured using OCT in order to elucidate the pathomorphology that causes metamorphopsia.

Patients and Methods
This study was approved by the Ethics Committee at Kagawa University Faculty of Medicine and conducted in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from each subject before any study procedures or examinations were performed.
The inclusion criteria of this study were (1) symptomatic BRVO, in which retinal hemorrhage and retinal edema involved the macula, (2) foveal thickness of greater than 250 μm at the initial visit as measured by OCT, and (3) a duration of symptoms prior to the initial examination of less than 3 months. The diagnosis of BRVO was based on fundus examinations and fluorescein angiography findings determined by two retina specialists (KM, AT). Eyes with central retinal vein occlusion or hemi-central retinal vein occlusion were not included in the current study. Eyes with co-existing ocular disease (i.e., age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, retinal macroaneurysm, or senile cataract that resulted in poor image quality), and eyes that had any history of interventions for ME before inclusion in the study were excluded.

Schedule of evaluation
At the initial visit, the medical history was obtained from each patient. Each patient underwent a comprehensive ophthalmologic examination, including measurement of the best-corrected VA using the Landolt chart and the degree of metamorphopsia by M-CHARTS (Inami, Tokyo, Japan), determination of intraocular pressure, indirect ophthalmoscopy, slit-lamp biomicroscopy with a noncontact lens, OCT examinations (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany), and fluorescein angiography (Optos 200Tx imaging system, Optos PLC, Dunfermline, United Kingdom).
Each patient was treated with an intravitreal injection of ranibizumab (Lucentis; Novartis Pharma, Tokyo, Japan) for ME. In order to evaluate the retinal morphology and visual function during the recovery from ME, each patient was scheduled for reevaluation of the retinal morphology and visual function one month after the initial injection. One month after the treatment, all eyes showed a marked reduction of ME and frequently achieved an improvement of visual symptoms and VA. Each patient underwent a complete ophthalmologic examination, including measurement of the VA and M-CHARTS score, slit-lamp biomicroscopy, indirect fundus ophthalmoscopy, and OCT examination. Fluorescein angiography was performed as necessary.
Each patient was examined at our clinic every month. Thereafter, most eyes showed the indeterminate recurrence of ME. Additional injections were performed when ME and/or serous retinal detachment was evident at the fovea on OCT examination.

Metamorphopsia evaluation
M-CHARTS is commercially available to quantify the degree of metamorphopsia. The principal of M-CHARTS has been described in detail previously (Fig 1) [11]. In brief, M-CHARTS is composed of a series of 19 dotted line tests. In each chart, the intervals of each dot range from 0.2°to 2.0°. A fixation point is printed in the center of each line, measuring 0.3°of the visual angle. First, an examiner presents a chart with a solid line at a distance of 30 cm under the correction of the refraction, followed by charts with dotted lines of incrementally increasing spacing. For each chart, the patient is asked to state whether the presented line is distorted or not. As the visual angle increases, the degree of metamorphopsia decreases. When the patient recognizes the presented line as being straight, the visual angle of that line is taken as the degree of metamorphopsia. M-CHARTS were presented to the patient in a vertical direction and then in a horizontal direction. The vertical and horizontal scores were measured, and the higher score was used as the M-CHARTS score for the eye.

Measurement of retinal structural changes with optical coherence tomography
Morphologic evaluations and quantitative measurements of ME associated with BRVO were performed by OCT. The entire macular area was examined with sequential OCT sectioning to detect any serous retinal detachment or cystoid spaces. Quantitative measurements were performed using a vertical section acquired through the foveal center because the BRVO-affected retina was mainly located on either the upper hemisphere or the lower hemisphere of the retina. In the current study, the thickness of the inner retina was defined as the vertical distance between the vitreoretinal interface and the outer surface of the inner nuclear layer. The thickness of the outer retina was defined as the vertical distance between the outer surface of the inner nuclear layer and the inner surface of the retinal pigment epithelium. The total retinal thickness was defined as the distance between the vitreoretinal interface and the inner surface of the retinal pigment epithelium.
On the vertical section through the foveal center, the inner, outer, and total retinal thickness were measured at 1 mm, 2 mm, and 3 mm from the foveal center on the affected retinal side, respectively (Fig 2). The maximum thickness of the inner, outer, or total retina was defined as the maximum value among the three measurements (Fig 2). The thickness of the serous retinal detachment was measured manually at the largest point, which was frequently at the fovea [31]. These measurements were performed at baseline and one month after the initial treatment by one grader (KM) in a masked fashion.

Statistical analysis
Statistical analysis was performed using SPSS, version 21.0.0 (IBM Japan, Tokyo, Japan). All values are presented as the means ± standard deviation. The best-corrected VA was converted to a logarithm of the minimum angle of resolution (logMAR) equivalent for statistical analysis. The M-CHARTS score was considered to be changed when the change in score was greater than 0.1 [11]. Comparisons between baseline and posttreatment values were performed using the paired t-test. Bivariate relationships were analyzed using the Pearson's correlation coefficient to evaluate the correlation between each measurement value and the M-CHARTS score. A value of p < 0.05 was considered statistically significant. Table 1 shows the baseline measurements of all patients eligible in this study. At baseline, all eyes showed visual disturbance associated with acute BRVO; the mean VA was 0.33 ± 0.31, and the mean total foveal thickness was 467.2 ± 191.5 μm. The maximum inner, outer, and total retinal thickness was 312.6 ± 90.4 μm, 294.5 ± 114.3 μm, and 588.3 ± 163.9 μm, respectively. Of 42 eyes, 21 (50.0%) showed serous retinal detachment at the fovea.

Results
Metamorphopsia was quantified using M-CHARTS. Of 42 eyes, no metamorphopsia was detected in 13 (31.0%) eyes. Metamorphopsia was detected in the vertical and/or horizontal directions in 29 (69.0%) eyes. The mean vertical and horizontal scores were 0.59 ± 0.57 and 0.52 ± 0.67, respectively ( Table 2). The vertical score was slightly greater than the horizontal score, although the difference was not significant (p = 0.070).
The higher score of the vertical and horizontal scores was used as the M-CHARTS score. Table 3 shows the association of the baseline M-CHARTS score and the baseline morphological parameters with OCT. While the VA showed no association with the M-CHARTS score, On the vertical section through the foveal center, the inner (yellow arrows), outer (blue arrows), and total (red arrows) retinal thickness was measured at 1 mm, 2 mm, and 3 mm from the center of the fovea toward the affected side of the retina, respectively. The maximum thickness of the inner, outer, or total retina was determined as the largest among the three measurements.  Fig 3). Metamorphopsia seemed to be mainly associated with the morphological changes of the outer aspect of the retina.
One month after the initial treatment, most eyes showed a marked reduction of ME (Table 4). Both the inner and outer retinal thickness were significantly decreased, not only at the fovea, but also at the parafoveal area (p < 0.001). The mean VA was improved from 0.33 ± 0.31 to 0.23 ± 0.29 (p < 0.001). However, metamorphopsia persisted in most eyes, although there was some improvement (Fig 4). Of 29 eyes that had metamorphopsia at baseline, metamorphopsia was completely eliminated in only three (10.3%) eyes, and it persisted in 26 (89.7%) eyes (Fig 5). In addition, two eyes developed metamorphopsia after treatment. Of 42 eyes, the M-CHARTS score was decreased in 13 (31.0%) eyes and increased in 8 (19.0%) eyes after the treatment. The change in the M-CHARTS score after the treatment was significantly correlated with the baseline score (r = -0.48, p = 0.001). The mean M-CHARTS score was decreased with treatment, but the improvement was not significant (p = 0.050). Table 5   score. Table 6 shows the association between the posttreatment M-CHARTS score and the baseline measurement values. The posttreatment M-CHARTS score was weakly correlated with the total foveal thickness (r = 0.35, p < 0.024) and closely correlated with the M-CHARTS at baseline (r = 0.78, p < 0.001). , and M-CHARTS score (D) in eyes with acute branch retinal vein occlusion that were treated with an intravitreal injection of ranibizumab. One month after the initial treatment, the maximum outer retinal thickness and total foveal thickness and was significantly decreased (both p < 0.001). The visual acuity in logMAR was also significantly improved (p < 0.001). The improvement in the mean M-CHARTS score was not significant (p = 0.050), and 28 eyes still had metamorphopsia. doi:10.1371/journal.pone.0153817.g004

Discussion
In the current study, metamorphopsia associated with acute BRVO was quantified by M-CHARTS. Of 42 eyes, metamorphopsia was detected in 29 (69.0%) eyes. The mean vertical and horizontal scores were 0.59 ± 0.57 and 0.52 ± 0.67, respectively. Kinoshita et al. [20] reported that an M-CHARTS score of 0.3 to 0.5 may be the threshold for detecting patients with symptomatic metamorphopsia in their daily life. Twenty-five (59.5%) eyes in the current study had M-CHARTS scores equal to or lager than 0.5 at baseline (data not shown). We can estimate that approximately 60% of patients with acute BRVO have symptomatic metamorphopsia. Previous reports showed that the severity of metamorphopsia due to epiretinal membrane is primarily related to the thickness of the inner nuclear layer [15,21,30]. With the use of an Amsler grid, Watanabe et al. [30] reported that metamorphopsia was detected in the area of edematous inner nuclear layer in eyes with epiretinal membrane. In our patients with BRVO, however, the M-CHARTS score had no correlation with the inner retinal thickness. Rather, the M-CHARTS score was correlated with the height of serous retinal detachment and the maximum outer retinal thickness. We can speculate that metamorphopsia from acute BRVO is mainly involved in the morphological changes of the outer retina. One month after treatment with ranibizumab, the mean M-CHARTS score was slightly decreased. However, most eyes had persistent metamorphopsia in spite of the reduction of ME. Of 29 eyes that had metamorphopsia at baseline, only three eyes achieved complete resolution. In an analysis of 5 eyes with BRVO, Achiron et al. [5] reported that there was no improvement in the M-CHARTS score after the treatments. Similarly, Nakagawa et al. [6] reported that the M-CHARTS score was unchanged of 6 months in 12 eyes with acute BRVO. Metamorphopsia due to various diseases has been reported to be decreased as a result of treatment [5,20,24,29]. However, metamorphopsia from BRVO tends to persist even after complete resolution of the ME.
Of 42 of our patients, 28 had metamorphopsia one month after the treatment. The posttreatment M-CHARTS score was not associated with any posttreatment factors. However, the posttreatment M-CHARTS score showed a close correlation with the baseline M-CHARTS score (r = 0.78, p < 0.001). Once metamorphopsia is induced by morphological changes of the retina caused by acute BRVO, this symptom often persists, even after the resolution of ME. In addition, two eyes developed metamorphopsia after the treatment. At baseline, metamorphopsia may not have been recognized in these patients due to the severe impairment of visual function [6].
To date, various pathophysiological mechanisms have been proposed for metamorphopsia [32][33][34]. Deformation of the foveal pit or uneven focal retinal thickening or the presence of cystoid spaces due to BRVO may cause metamorphopsia [32]. However, based on the limited improvement of metamorphopsia after the complete resolution of ME, these mechanisms could not explain metamorphopsia from acute BRVO. In eyes with epiretinal membrane [15,21,30], Okamoto et al. [15] speculated that the structural changes of horizontal cells, bipolar cells, amacrine cells, and Müller cells would inhibit the normal function of synaptic junctions and lower photoreceptor sensitivity, causing metamorphopsia.
In eyes with BRVO, Yamaike et al. [35] reported a correlation between VA and the integrity of the outer aspect of the foveal photoreceptor layer. Similarly, metamorphopsia from acute BRVO may be caused by the morphological changes of the outer aspect of the retina. In addition, the height of serous retinal detachment was correlated with the M-CHARTS score, and anteroposterior disorganization of the photoreceptor might be involved in metamorphopsia form acute BRVO [31]. Recently, adaptive optics-scanning laser ophthalmoscopy showed the decreased cone density and the disrupted cone mosaic arrangement in the parafoveal area in eyes with resolved BRVO [36]. Such disarray of the photoreceptors after the absorbance of ME may account for the persistent metamorphopsia in eyes with BRVO.
One of the major limitations of the current study is the small sample size. In addition, dense retinal hemorrhage from acute BRVO sometimes made it difficult to analyze the structural condition of the retina. In the current study, we evaluated the morphological changes of the retina using OCT, but it would be difficult to evaluate the disarray of each photoreceptor cell using this technique due to its relatively lower resolution in the retinal plane [37]. In addition, we aimed to elucidate the pathomorphology that caused the metamorphopsia in eyes with acute BRVO. We reevaluated the metamorphopsia one month after the treatment because most eyes showed complete reduction of ME at this time point [38]. We did not identify any factors that were predictive of the final prognosis of the visual symptoms.
Despite these shortcomings, we were able to quantitatively evaluate the metamorphopsia associated with acute BRVO using M-CHARTS. Even after the reduction of ME with anti-vascular endothelial growth factor agents, some patients still suffer from decreased quality of vision due to symptomatic metamorphopsia. Further prospective studies with longer follow-up periods are necessary to elucidate the long-term changes of metamorphopsia associated with BRVO.