Jpn J Ophthalmol DOI 10.1007/s10384-014-0323-7
CLINICAL INVESTIGATION
Vision-related quality of life and visual function following intravitreal bevacizumab injection for persistent diabetic macular edema after vitrectomy Yoshifumi Okamoto • Fumiki Okamoto Takahiro Hiraoka • Tetsuro Oshika
•
Received: 9 December 2013 / Accepted: 24 March 2014 Ó Japanese Ophthalmological Society 2014
Abstract Purpose To investigate the vision-related quality of life (VR-QOL) and visual function in patients undergoing intravitreal injection of bevacizumab (IVB) for persistent diabetic macular edema (DME) after vitrectomy. Methods This institutional study enrolled 20 consecutive patients (20 eyes) who had received 1.25 mg IVB for persistent macular edema after vitrectomy for DME at least 3 months previously. Visual function and VR-QOL were measured before, and 1 and 3 months after IVB. Measurements included the logarithm of the minimum angle of resolution (logMAR), best corrected visual acuity (BCVA), letter contrast sensitivity, severity of metamorphopsia using M-CHARTS, central retinal thickness using optical coherence tomography, and VR-QOL with the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Results One month after IVB, statistically significant improvements were observed in central retinal thickness, letter contrast sensitivity, and the VFQ-25 ‘‘mental health’’ subscale score (P \ 0.05, Dunnett test). LogMAR BCVA, metamorphopsia, and the VFQ-25 composite score did not improve significantly. Three months after IVB, there were no significant improvements in any parameters examined. Conclusions Intravitreal bevacizumab injection for persistent DME after vitrectomy temporarily improved central retinal thickness, contrast sensitivity, and the psychometric aspect of the VR-QOL, but these effects did not last for over 3 months.
Y. Okamoto (&) F. Okamoto T. Hiraoka T. Oshika Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan e-mail: [email protected]
Keywords Diabetic macular edema Bevacizumab Vitrectomized
Introduction Diabetic macular edema (DME) is a common disease that can cause severe deterioration in vision. There are several therapeutic modalities for DME, such as focal laser photocoagulation [1], intravitreal or sub-Tenon’s injection of triamcinolone acetonide [2, 3], and pars plana vitrectomy [4, 5]. The decision concerning the therapeutic modality for DME is based on the patient’s ocular status and/or ophthalmologist’s preference as there is no clear-cut treatment protocol. Pars plana vitrectomy with internal limited membrane peeling is effective for DME in terms of both the morphological and of histopathological aspects [6, 7]. We previously reported that vitrectomy for DME significantly improved visual function and vision-related quality of life (VRQOL) [8]. Nonetheless, many eyes show no improvement or even worsening visual function and central retinal thickness despite multiple medical or surgical therapies. Recently, intravitreal injection of bevacizumab (IVB), an anti-vascular endothelial growth factor (VEGF) agent, was shown to improve both visual acuity and central retinal thickness for a few months in patients with DME [9, 10]. In practice, many eyes suffer from persistent macular edema after vitrectomy for DME, but the influences of IVB on visual function and VR-QOL in those patients have not been evaluated. The purpose of the current study was to investigate the efficacy of IVB for persistent DME in vitrectomized eyes with regard to visual function and VR-QOL.
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Subjects and methods This institutional study population consisted of 20 eyes of 20 consecutive patients (15 males and 5 females; 56–75 years old) with DME. Their age averaged 64.2 ± 5.8 years (mean ± SD). All patients had undergone vitrectomy for DME at least 3 months previously and were scheduled to receive IVB for persistent DME. The crystalline lens was removed by phacoemulsification, and intraocular lens implantation was performed when required; prior pars plana vitrectomy was performed with internal limited membrane peeling using indocyanine green stain. Because only limited improvement of DME was attained during the 3-month period following vitrectomy, further therapy was warranted, and patients received one IVB (1.25 mg/0.05 ml) injection. DME was defined as retinal thickening of two or more disc areas involving the foveal avascular zone with or without cystoid changes attributable to diffuse leakage from dilated retinal capillaries, the retinal pigment epithelium, and ischemic retina by fluorescein angiography. The increase in central retinal thickness (CRT) greater than 250 lm measured by optical coherence tomography (OCT) was also defined as DME. In all patients, the best corrected visual acuity (BCVA), CRT with OCT (Stratus 3000, Carl Zeiss Ophthalmic Systems Humphrey Division, Dublin, CA, USA), degree of metamorphopsia with M-CHARTS (Inami Co., Tokyo, Japan), letter contrast sensitivity with CSV-1000LV (Vector Vision, Columbus, OH, USA), and vision-related quality of life with the National Eye Institute 25-item visual function questionnaire (VFQ-25) were recorded before, 1 and 3 months following IVB. The exclusion criteria included patients with ophthalmic disorders and previous history of ocular surgery except for prior vitrectomy for DME. The attending physicians explained the nature of research and ethical considerations to the participants, who then indicated their understanding by signing an informed consent form. This study was approved by the Institutional Review Board at the Tsukuba University Hospital and was in adherence with the tenets of the Declaration of Helsinki. M-CHARTS M-CHARTS was used for quantitative assessment of the severity of metamorphopsia. In patients with symptoms of metamorphopsia, a straight line projected onto the retina is recognized as a curved or irregular line. If the straight line is replaced with a dotted line and the dot interval is changed from fine to coarse, the distortion of the line decreases with increasing dot interval until finally the dotted line appears straight. When the patient has recognized a dotted line as being straight, the visual angle that
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separates the dots is considered to represent patients’ metamorphopsia score. The metamorphopsia chart consists of 19 dotted lines with dot intervals ranging from 0.2° to 2.0° of the visual angle [11, 12]. CSV-1000LV This test was performed monocularly in eyes with undilated pupils at the testing distance of 2.5 m under best spectacle correction. Background illumination of the translucent chart was provided by a fluorescent luminance source of the instrument and was automatically calibrated to 85 cd/m2. The CSV-1000LV chart uses letter optotypes, each of which is the same size and is of low spatial frequency (2.4 cyc/deg) [13]. There are eight contrast levels (standard 35.5, 17.8, 8.9, 6.3, 4.5, 2.2 and 1.1 %), and each contrast level has three letters. Test results were recorded not as the contrast sensitivity or contrast threshold, but as the number of correctly identified letters [14, 15]. Visual function questionnaire (VFQ-25) The patients were requested to answer the VFQ-25 before injection, 1 and 3 months after injection to assess VRQOL. The VFQ-25 comprises 25 items wherein patients are expected to assess the level of difficulty of particular visual symptoms and day-to-day activities. Each item is assigned to 1 of the 12 subscales, namely, ‘‘general health,’’ ‘‘general vision,’’ ‘‘ocular pain,’’ ‘‘near activities,’’ ‘‘distance activities,’’ ‘‘social functioning,’’ ‘‘mental health,’’ ‘‘role difficulties,’’ ‘‘dependency,’’ ‘‘driving,’’ ‘‘color vision,’’ and ‘‘peripheral vision.’’ The subscales are scored on a 0 to 100-point scale, where 100 indicates the highest possible function or minimal subjective impairment. The VFQ-25 composite score is calculated as the unweighted average response to all items, excluding the questions regarding ‘‘general health’’ [16]. The Japanese version of VFQ-25 was used in this study; it has modifications to adjust for Japanese culture and lifestyle. This modified VFQ-25 instrument has been assessed for its reliability and validity and has been proven to appropriately measure VR-QOL in Japanese individuals [17]. Statistical analysis For each clinical parameter, the obtained data at baseline, 1 and 3 months after IVB were analyzed using repeatedmeasures analysis of variance (ANOVA) to assess the time course of changes. If significant differences were observed, a Dunnett test was performed. Differences were considered statistically significant at P \ 0.05. All statistical analyses were performed using SPSS version 20.0.0 software.
VR-QOL following IVB for persistent DME Table 1 Baseline characteristics of the recruited patients with vitrectomized diabetic macular edema (20 patients) Age (years)
64.2 ± 5.8 (range 56–75)
Gender (male/female)
15/5
Duration of diabetes (years)
7.6 ± 7.4
Time since diagnosis of diabetic macular edema (months)
17.9 ± 12.4
Glycosylated hemoglobin (%)
6.9 ± 1.3
Pretreatment
20 (100 %)
Intravitreal bevacizumab injection
0 (0 %)
Intravitreal injection of triamcinolone acetonide
0 (0 %)
Sub-Tenon’s injection of triamcinolone acetonide
16 (80 %)
Panretinal photocoagulation Baseline logMAR BCVA
20 (100 %) 0.66 ± 0.25 (range 0.15–1.00)
Fellow eye logMAR BCVA (n = 19)a
0.34 ± 0.32 (range 0.08–1.00)
Discussion
Classification of diabetic macular edema Cystoid macular edema
18
Sponge-like diffuse retinal thickening
2
Serous retinal detachment
0
Baseline central macular thickness (lm)
480 ± 127 (312–751)
All data are presented as mean ± SD a
improved from 10.3 ± 5.83 at baseline to 11.3 ± 5.79 at 1 month (P \ 0.05), and CRT improved from 480 ± 127 lm at baseline to 440 ± 110 lm at 1 month (P \ 0.05). However, the logMAR BCVA, severity of metamorphopsia and VFQ-25 composite score did not significantly improve during the study period (P [ 0.05). Table 3 shows the changes in the VFQ-25 composite score and subscale scores following IVB. The VFQ-25 composite score and all subscale scores except the ‘‘ocular pain’’ subscale score tended to improve from baseline to 1 month. However, the changes were modest, and all subscale scores except ‘‘mental health’’ (P \ 0.05, ANOVA) did not improve significantly during the study period. A Dunnett test showed that the ‘‘mental health’’ subscale score significantly improved from 54.2 ± 27.5 at baseline to 62.5 ± 30.2 at 1 month (P \ 0.05), but not thereafter.
Fellow eye excluded one eye with no light perception
Results The patients’ demographic characteristics are shown in Table 1. The mean duration of DME was 17.9 ± 12.4 months. The patients had received therapies for DME prior to pars plana vitrectomy, including subTenon’s injection of triamcinolone acetonide (STTA) in 16 of 20 eyes and laser photocoagulation in all eyes. As demonstrated by the CRT values in Table 1, there was substantial DME, which persisted even after pars plana vitrectomy. DME had been classified according to the OCT patterns: cystoid macular edema (n = 18) and sponge-like diffuse retinal thickening (n = 2). Serous retinal detachment was not observed in any of the current patients. After IVB, several patients showed a mild elevation of intraocular pressure that did not require additional therapy. There were no serious complications in any patients during the study period. Table 2 summarizes the changes in clinical parameters following IVB for persistent DME. There was a significant difference in letter contrast sensitivity and CRT during the study period (P \ 0.05, ANOVA). Furthermore, the Dunnett test, performed to assess changes from the baseline, showed that letter contrast sensitivity significantly
In patients with DME, there are several therapeutic modalities using focal laser photocoagulation, IVTA, STTA, IVB and pars plana vitrectomy [1–5, 8–10]. Yanyali et al. reported that pars plana vitrectomy with internal limiting membrane removal was effective in reducing macular edema and improving visual acuity in eyes with DME, likely because vitrectomy reduces the intraocular VEGF level and raises the partial pressure of oxygen in the vitreous cavity [18, 19]. However, the disadvantage of vitrectomized eyes is that the half-life of drugs becomes shorter compared with nonvitrectomized eyes. Kakinoki et al. [20] reported that the differences in the half-lives of 1.25 mg IVB between vitrectomized and nonvitrectomized monkey models were 1.5 ± 0.6 and 2.8 ± 0.6 days, respectively. The result suggests that IVB treatment is less effective for persistent DME in eyes following vitrectomy. Therefore, the indication of vitrectomy treatment for DME should be deliberately judged. Although our study showed that letter contrast sensitivity significantly improved from baseline to 1 month, previous studies reported that IVB did not improve visual function in patients with DME after vitrectomy. The recent ‘‘metabolic memory’’ theory attracts attention as a key to solve the mechanism of diabetic microangiopathy [21, 22]. ‘‘Metabolic memory’’ is a concept that previous hyperglycemia and diabetic exposure affect the progression of diabetic complications. In patients with proliferative diabetic retinopathy, preoperative diabetic statuses were strongly associated with postoperative visual function [23]. The diabetic control status in our participants was relatively good compared with previous studies, on the basis of lower glycosylated hemoglobin levels and shorter diabetes
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Y. Okamoto et al. Table 2 The changes in clinical parameters after bevacizumab intravitreal injection for vitrectomized diabetic macular edema Baseline (pre-injection)
1 month
3 months
ANOVA P value
LogMAR BCVA
0.65 ± 0.25
0.69 ± 0.26
0.72 ± 0.29
0.25
Letter contrast sensitivity
10.3 ± 5.83
11.3 ± 5.79
11.3 ± 6.35
0.04*
Severity of metamorphopsia (M-CHARTS)
0.64 ± 0.58
0.67 ± 0.57
0.69 ± 0.53
0.46
CRT (lm)
480 ± 127
440 ± 110
467 ± 127
0.03*
VFQ-25 composite score
62.0 ± 17.0
67.1 ± 25.1
65.3 ± 17.8
0.26
Dunnett test P \ 0.05
All data are presented as mean ± SD logMAR BCVA logarithm of the minimum angle of resolution best-corrected visual acuity, CRT central macular thickness, VFQ-25 National Eye Institute 25-item visual function questionnaire, ANOVA analysis of variance * Statistically significant difference among three groups
Statistically significant difference between baseline and 1 month
Table 3 The changes of National Eye Institute 25-item visual function questionnaire (VFQ-25) composite score and covariates after bevacizumab intravitreal injection for vitrectomized diabetic macular edema Baseline (pre-injection)
1 month
3 months
ANOVA P value
General health
46.4 ± 21.3
48.3 ± 11.4
42.9 ± 16.1
0.20
General vision
56.2 ± 16.3
60.0 ± 16.9
54.5 ± 16.4
0.14
Ocular pain Near activities
78.6 ± 17.3 57.1 ± 21.5
71.7 ± 26.9 64.4 ± 25.5
78.0 ± 117.6 60.7 ± 24.5
0.41 0.27
Distance activities
61.5 ± 22.0
64.4 ± 27.2
63.1 ± 18.9
0.32
Social functioning
68.5 ± 19.6
72.5 ± 26.4
73.8 ± 21.3
0.49
Mental health
54.2 ± 27.5
62.5 ± 30.2
60.4 ± 27.3
0.05*
Role difficulties
63.1 ± 22.2
64.2 ± 29.1
68.5 ± 22.6
0.46
Dependency
68.7 ± 27.5
71.7 ± 33.5
71.0 ± 22.5
0.45
Driving
52.0 ± 29.2
56.3 ± 33.9
51.4 ± 30.0
0.43
Color vision
82.1 ± 16.1
83.3 ± 20.4
78.6 ± 119.8
0.32
Peripheral vision
51.2 ± 21.6
63.3 ± 28.1
59.5 ± 16.7
0.07
Composite score
63.1 ± 15.8
66.8 ± 23.9
65.7 ± 16.7
0.26
Dunnett test P \ 0.05
All data are presented as mean ± SD VFQ-25 National Eye Institute 25-item visual function questionnaire, ANOVA analysis of variance * Statistically significant difference among three groups
Statistically significant difference between baseline and 1 month
duration [24, 25]. As DME is one of the representative features of diabetic microangiopathy, good diabetic control status in our patients might have led to greater recovery of visual function compared with previous studies. To evaluate metamorphopsia, the Amsler charts have been widely used in patients with macular diseases [26]. With the Amsler charts, however, it is difficult to quantify the severity of metamorphopsia because the patients have to self-describe the degree of image distortion. In contrast, M-CHARTS is an instrument that can easily and quantitatively evaluate the degree of metamorphopsia associated with macular diseases, and the patients only need to answer whether the line is
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distorted or not distorted [11, 12]. We previously reported that the severity of metamorphopsia strongly influenced VR-QOL in patients with MH and ERM [8]. The current study is the first to quantitatively evaluate metamorphopsia in patients with DME, and there were no significant improvements in metamorphopsia during the study period. Almost all cases (18 of 20 eyes) in the current study presented cystoid macular edema type DME. These cystoid changes occur in the inter nuclear layer and/or outer plexiform layer [27], and disorder and thickening of inner nuclear layer cause exacerbation of metamorphopsia [28]. Although the fine foveal microstructure could not be evaluated by using time-domain
VR-QOL following IVB for persistent DME
OCT, changes in the inner nuclear layer may also be associated with metamorphopsia and VR-QOL. We found that IVB improved contrast sensitivity for at least 1 month, but did not improve logMAR BCVA. It is known that BCVA is not necessarily a good predictor of many aspects of visual functions during daily life [29, 30], whereas contrast sensitivity has been shown to correlate well with visual functions required for various activities, such as orientation, mobility, reading and driving [31, 32]. Additionally, contrast sensitivity was significantly correlated with VFQ-25 composite scores in patients with DME [8]. In patients who had undergone retinal detachment surgery, the VFQ-25 composite score showed significant correlation with contrast sensitivity, but not with BCVA [33]. Thus, the improvement of contract sensitivity by IVB, despite the lack of recovery of BCVA, observed in the current study can be meaningful in the context of patients’ vision in daily life. CRT significantly improved at 1 month following injection, but returned to the pre-injection level by 3 months. This may be attributable to the rapid clearance of intravitreal bevacizumab from the vitreous cavity and insufficient therapeutic levels of the drug in vitrectomized eyes [20]. In terms of the durability of response in vitrectomized eyes, STTA may be a better choice than IVB or IVTA. There are a few reports about the effectiveness of IVB for DME in eyes after vitrectomy. Nagasawa et al. [34] reported that IVB for DME in vitrectomized eyes improved CRT but not visual acuity, and Yanyali et al. [25] reported that IVB for DME in eyes after vitrectomy did not improved CRT or visual acuity. Thus, previous studies reported that IVB has little benefit in patients with DME after vitrectomy. On the other hand, our study revealed that IVB improved not only CRT, but also visual function at least temporarily as shown by letter contrast sensitivity, suggesting that IVB can be a worthwhile treatment even in vitrectomized eyes with DME. These improvements led to recuperation of patients’ quality of vision as well. We previously reported that VR-QOL significantly improved following pars plana vitrectomy in patients with DME [8]. To the best of our knowledge, no previous study has assessed VR-QOL using VFQ-25 in patients with persistent DME after vitrectomy. We found that the subscale score ‘‘mental health’’ was significantly improved at 1 month. The ‘‘mental health’’ subscale score at 1 month tended to be correlated with letter contrast sensitivity at 1 month (r = 0.42, P = 0.09, Spearman’s rank coefficient). Increasing the number of the patients may help evaluate the significant correlation between these two parameters. VFQ-25 is a useful tool that measures the vision-related difficulties of physical, psychological and social aspects. In this study, psychological and social aspects of four subscale scores, such as ‘‘social
functioning,’’ ‘‘mental health,’’ ‘‘role difficulties’’ and ‘‘dependency,’’ were improved throughout the study period. This result suggests that IVB for vitrectomized DME is an effective treatment to improve psychological and social aspects of the VR-QOL, but is not enough to improve the comprehensive composite VR-QOL including the physical aspect. Repetitive IVB treatment may be able to maintain the improvement of these aspects of the VRQOL throughout the patient’s life. Further studies with larger series of patients are required for more precise reports. Our previous report showed that the postoperative VFQ25 composite score in the patients with DME was significantly correlated with the better-seeing BCVA, not with the worse-seeing BCVA [8]. In this study, many eyes receiving IVB treatment were the worse-seeing eye (15 of 20 eyes). Therefore, the effectiveness of IVB treatment might be limited to only the ‘‘mental health’’ subscale. In addition, 11 of 20 patients had clinically significant DME in both eyes. If we deliberately selected the worse-seeing eye when performing IVB treatment for these patients, better VRQOL results might be obtained than in this study’s results. One of the limitations of our present study is that CRT was measured using time-domain OCT. Although timedomain OCT is a valuable tool, it cannot provide detailed information as well as spectral-domain OCT. Spectraldomain OCT has higher resolution and can obtain an abundance of data. We recently reported associations between metamorphopsia and foveal microstructure in patients with epiretinal membrane using spectral-domain OCT [28]. Spectral-domain OCT may also aid in understanding associations between the macular microstructure and VR-QOL in patients with DME. In conclusion, the current study indicates that IVB temporarily improved CRT and contrast sensitivity in patients with persistent DME after vitrectomy. There was a modest improvement of VR-QOL as well. However, these effects did not last longer than 3 months. Acknowledgments Publication of this article was supported by the Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. Conflicts of interest Y. Okamoto, None; F. Okamoto, None; T. Hiraoka, None; T. Oshika; None.
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CLINICAL INVESTIGATION
Vision-related quality of life and visual function following intravitreal bevacizumab injection for persistent diabetic macular edema after vitrectomy Yoshifumi Okamoto • Fumiki Okamoto Takahiro Hiraoka • Tetsuro Oshika
•
Received: 9 December 2013 / Accepted: 24 March 2014 Ó Japanese Ophthalmological Society 2014
Abstract Purpose To investigate the vision-related quality of life (VR-QOL) and visual function in patients undergoing intravitreal injection of bevacizumab (IVB) for persistent diabetic macular edema (DME) after vitrectomy. Methods This institutional study enrolled 20 consecutive patients (20 eyes) who had received 1.25 mg IVB for persistent macular edema after vitrectomy for DME at least 3 months previously. Visual function and VR-QOL were measured before, and 1 and 3 months after IVB. Measurements included the logarithm of the minimum angle of resolution (logMAR), best corrected visual acuity (BCVA), letter contrast sensitivity, severity of metamorphopsia using M-CHARTS, central retinal thickness using optical coherence tomography, and VR-QOL with the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Results One month after IVB, statistically significant improvements were observed in central retinal thickness, letter contrast sensitivity, and the VFQ-25 ‘‘mental health’’ subscale score (P \ 0.05, Dunnett test). LogMAR BCVA, metamorphopsia, and the VFQ-25 composite score did not improve significantly. Three months after IVB, there were no significant improvements in any parameters examined. Conclusions Intravitreal bevacizumab injection for persistent DME after vitrectomy temporarily improved central retinal thickness, contrast sensitivity, and the psychometric aspect of the VR-QOL, but these effects did not last for over 3 months.
Y. Okamoto (&) F. Okamoto T. Hiraoka T. Oshika Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan e-mail: [email protected]
Keywords Diabetic macular edema Bevacizumab Vitrectomized
Introduction Diabetic macular edema (DME) is a common disease that can cause severe deterioration in vision. There are several therapeutic modalities for DME, such as focal laser photocoagulation [1], intravitreal or sub-Tenon’s injection of triamcinolone acetonide [2, 3], and pars plana vitrectomy [4, 5]. The decision concerning the therapeutic modality for DME is based on the patient’s ocular status and/or ophthalmologist’s preference as there is no clear-cut treatment protocol. Pars plana vitrectomy with internal limited membrane peeling is effective for DME in terms of both the morphological and of histopathological aspects [6, 7]. We previously reported that vitrectomy for DME significantly improved visual function and vision-related quality of life (VRQOL) [8]. Nonetheless, many eyes show no improvement or even worsening visual function and central retinal thickness despite multiple medical or surgical therapies. Recently, intravitreal injection of bevacizumab (IVB), an anti-vascular endothelial growth factor (VEGF) agent, was shown to improve both visual acuity and central retinal thickness for a few months in patients with DME [9, 10]. In practice, many eyes suffer from persistent macular edema after vitrectomy for DME, but the influences of IVB on visual function and VR-QOL in those patients have not been evaluated. The purpose of the current study was to investigate the efficacy of IVB for persistent DME in vitrectomized eyes with regard to visual function and VR-QOL.
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Subjects and methods This institutional study population consisted of 20 eyes of 20 consecutive patients (15 males and 5 females; 56–75 years old) with DME. Their age averaged 64.2 ± 5.8 years (mean ± SD). All patients had undergone vitrectomy for DME at least 3 months previously and were scheduled to receive IVB for persistent DME. The crystalline lens was removed by phacoemulsification, and intraocular lens implantation was performed when required; prior pars plana vitrectomy was performed with internal limited membrane peeling using indocyanine green stain. Because only limited improvement of DME was attained during the 3-month period following vitrectomy, further therapy was warranted, and patients received one IVB (1.25 mg/0.05 ml) injection. DME was defined as retinal thickening of two or more disc areas involving the foveal avascular zone with or without cystoid changes attributable to diffuse leakage from dilated retinal capillaries, the retinal pigment epithelium, and ischemic retina by fluorescein angiography. The increase in central retinal thickness (CRT) greater than 250 lm measured by optical coherence tomography (OCT) was also defined as DME. In all patients, the best corrected visual acuity (BCVA), CRT with OCT (Stratus 3000, Carl Zeiss Ophthalmic Systems Humphrey Division, Dublin, CA, USA), degree of metamorphopsia with M-CHARTS (Inami Co., Tokyo, Japan), letter contrast sensitivity with CSV-1000LV (Vector Vision, Columbus, OH, USA), and vision-related quality of life with the National Eye Institute 25-item visual function questionnaire (VFQ-25) were recorded before, 1 and 3 months following IVB. The exclusion criteria included patients with ophthalmic disorders and previous history of ocular surgery except for prior vitrectomy for DME. The attending physicians explained the nature of research and ethical considerations to the participants, who then indicated their understanding by signing an informed consent form. This study was approved by the Institutional Review Board at the Tsukuba University Hospital and was in adherence with the tenets of the Declaration of Helsinki. M-CHARTS M-CHARTS was used for quantitative assessment of the severity of metamorphopsia. In patients with symptoms of metamorphopsia, a straight line projected onto the retina is recognized as a curved or irregular line. If the straight line is replaced with a dotted line and the dot interval is changed from fine to coarse, the distortion of the line decreases with increasing dot interval until finally the dotted line appears straight. When the patient has recognized a dotted line as being straight, the visual angle that
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separates the dots is considered to represent patients’ metamorphopsia score. The metamorphopsia chart consists of 19 dotted lines with dot intervals ranging from 0.2° to 2.0° of the visual angle [11, 12]. CSV-1000LV This test was performed monocularly in eyes with undilated pupils at the testing distance of 2.5 m under best spectacle correction. Background illumination of the translucent chart was provided by a fluorescent luminance source of the instrument and was automatically calibrated to 85 cd/m2. The CSV-1000LV chart uses letter optotypes, each of which is the same size and is of low spatial frequency (2.4 cyc/deg) [13]. There are eight contrast levels (standard 35.5, 17.8, 8.9, 6.3, 4.5, 2.2 and 1.1 %), and each contrast level has three letters. Test results were recorded not as the contrast sensitivity or contrast threshold, but as the number of correctly identified letters [14, 15]. Visual function questionnaire (VFQ-25) The patients were requested to answer the VFQ-25 before injection, 1 and 3 months after injection to assess VRQOL. The VFQ-25 comprises 25 items wherein patients are expected to assess the level of difficulty of particular visual symptoms and day-to-day activities. Each item is assigned to 1 of the 12 subscales, namely, ‘‘general health,’’ ‘‘general vision,’’ ‘‘ocular pain,’’ ‘‘near activities,’’ ‘‘distance activities,’’ ‘‘social functioning,’’ ‘‘mental health,’’ ‘‘role difficulties,’’ ‘‘dependency,’’ ‘‘driving,’’ ‘‘color vision,’’ and ‘‘peripheral vision.’’ The subscales are scored on a 0 to 100-point scale, where 100 indicates the highest possible function or minimal subjective impairment. The VFQ-25 composite score is calculated as the unweighted average response to all items, excluding the questions regarding ‘‘general health’’ [16]. The Japanese version of VFQ-25 was used in this study; it has modifications to adjust for Japanese culture and lifestyle. This modified VFQ-25 instrument has been assessed for its reliability and validity and has been proven to appropriately measure VR-QOL in Japanese individuals [17]. Statistical analysis For each clinical parameter, the obtained data at baseline, 1 and 3 months after IVB were analyzed using repeatedmeasures analysis of variance (ANOVA) to assess the time course of changes. If significant differences were observed, a Dunnett test was performed. Differences were considered statistically significant at P \ 0.05. All statistical analyses were performed using SPSS version 20.0.0 software.
VR-QOL following IVB for persistent DME Table 1 Baseline characteristics of the recruited patients with vitrectomized diabetic macular edema (20 patients) Age (years)
64.2 ± 5.8 (range 56–75)
Gender (male/female)
15/5
Duration of diabetes (years)
7.6 ± 7.4
Time since diagnosis of diabetic macular edema (months)
17.9 ± 12.4
Glycosylated hemoglobin (%)
6.9 ± 1.3
Pretreatment
20 (100 %)
Intravitreal bevacizumab injection
0 (0 %)
Intravitreal injection of triamcinolone acetonide
0 (0 %)
Sub-Tenon’s injection of triamcinolone acetonide
16 (80 %)
Panretinal photocoagulation Baseline logMAR BCVA
20 (100 %) 0.66 ± 0.25 (range 0.15–1.00)
Fellow eye logMAR BCVA (n = 19)a
0.34 ± 0.32 (range 0.08–1.00)
Discussion
Classification of diabetic macular edema Cystoid macular edema
18
Sponge-like diffuse retinal thickening
2
Serous retinal detachment
0
Baseline central macular thickness (lm)
480 ± 127 (312–751)
All data are presented as mean ± SD a
improved from 10.3 ± 5.83 at baseline to 11.3 ± 5.79 at 1 month (P \ 0.05), and CRT improved from 480 ± 127 lm at baseline to 440 ± 110 lm at 1 month (P \ 0.05). However, the logMAR BCVA, severity of metamorphopsia and VFQ-25 composite score did not significantly improve during the study period (P [ 0.05). Table 3 shows the changes in the VFQ-25 composite score and subscale scores following IVB. The VFQ-25 composite score and all subscale scores except the ‘‘ocular pain’’ subscale score tended to improve from baseline to 1 month. However, the changes were modest, and all subscale scores except ‘‘mental health’’ (P \ 0.05, ANOVA) did not improve significantly during the study period. A Dunnett test showed that the ‘‘mental health’’ subscale score significantly improved from 54.2 ± 27.5 at baseline to 62.5 ± 30.2 at 1 month (P \ 0.05), but not thereafter.
Fellow eye excluded one eye with no light perception
Results The patients’ demographic characteristics are shown in Table 1. The mean duration of DME was 17.9 ± 12.4 months. The patients had received therapies for DME prior to pars plana vitrectomy, including subTenon’s injection of triamcinolone acetonide (STTA) in 16 of 20 eyes and laser photocoagulation in all eyes. As demonstrated by the CRT values in Table 1, there was substantial DME, which persisted even after pars plana vitrectomy. DME had been classified according to the OCT patterns: cystoid macular edema (n = 18) and sponge-like diffuse retinal thickening (n = 2). Serous retinal detachment was not observed in any of the current patients. After IVB, several patients showed a mild elevation of intraocular pressure that did not require additional therapy. There were no serious complications in any patients during the study period. Table 2 summarizes the changes in clinical parameters following IVB for persistent DME. There was a significant difference in letter contrast sensitivity and CRT during the study period (P \ 0.05, ANOVA). Furthermore, the Dunnett test, performed to assess changes from the baseline, showed that letter contrast sensitivity significantly
In patients with DME, there are several therapeutic modalities using focal laser photocoagulation, IVTA, STTA, IVB and pars plana vitrectomy [1–5, 8–10]. Yanyali et al. reported that pars plana vitrectomy with internal limiting membrane removal was effective in reducing macular edema and improving visual acuity in eyes with DME, likely because vitrectomy reduces the intraocular VEGF level and raises the partial pressure of oxygen in the vitreous cavity [18, 19]. However, the disadvantage of vitrectomized eyes is that the half-life of drugs becomes shorter compared with nonvitrectomized eyes. Kakinoki et al. [20] reported that the differences in the half-lives of 1.25 mg IVB between vitrectomized and nonvitrectomized monkey models were 1.5 ± 0.6 and 2.8 ± 0.6 days, respectively. The result suggests that IVB treatment is less effective for persistent DME in eyes following vitrectomy. Therefore, the indication of vitrectomy treatment for DME should be deliberately judged. Although our study showed that letter contrast sensitivity significantly improved from baseline to 1 month, previous studies reported that IVB did not improve visual function in patients with DME after vitrectomy. The recent ‘‘metabolic memory’’ theory attracts attention as a key to solve the mechanism of diabetic microangiopathy [21, 22]. ‘‘Metabolic memory’’ is a concept that previous hyperglycemia and diabetic exposure affect the progression of diabetic complications. In patients with proliferative diabetic retinopathy, preoperative diabetic statuses were strongly associated with postoperative visual function [23]. The diabetic control status in our participants was relatively good compared with previous studies, on the basis of lower glycosylated hemoglobin levels and shorter diabetes
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Y. Okamoto et al. Table 2 The changes in clinical parameters after bevacizumab intravitreal injection for vitrectomized diabetic macular edema Baseline (pre-injection)
1 month
3 months
ANOVA P value
LogMAR BCVA
0.65 ± 0.25
0.69 ± 0.26
0.72 ± 0.29
0.25
Letter contrast sensitivity
10.3 ± 5.83
11.3 ± 5.79
11.3 ± 6.35
0.04*
Severity of metamorphopsia (M-CHARTS)
0.64 ± 0.58
0.67 ± 0.57
0.69 ± 0.53
0.46
CRT (lm)
480 ± 127
440 ± 110
467 ± 127
0.03*
VFQ-25 composite score
62.0 ± 17.0
67.1 ± 25.1
65.3 ± 17.8
0.26
Dunnett test P \ 0.05
All data are presented as mean ± SD logMAR BCVA logarithm of the minimum angle of resolution best-corrected visual acuity, CRT central macular thickness, VFQ-25 National Eye Institute 25-item visual function questionnaire, ANOVA analysis of variance * Statistically significant difference among three groups
Statistically significant difference between baseline and 1 month
Table 3 The changes of National Eye Institute 25-item visual function questionnaire (VFQ-25) composite score and covariates after bevacizumab intravitreal injection for vitrectomized diabetic macular edema Baseline (pre-injection)
1 month
3 months
ANOVA P value
General health
46.4 ± 21.3
48.3 ± 11.4
42.9 ± 16.1
0.20
General vision
56.2 ± 16.3
60.0 ± 16.9
54.5 ± 16.4
0.14
Ocular pain Near activities
78.6 ± 17.3 57.1 ± 21.5
71.7 ± 26.9 64.4 ± 25.5
78.0 ± 117.6 60.7 ± 24.5
0.41 0.27
Distance activities
61.5 ± 22.0
64.4 ± 27.2
63.1 ± 18.9
0.32
Social functioning
68.5 ± 19.6
72.5 ± 26.4
73.8 ± 21.3
0.49
Mental health
54.2 ± 27.5
62.5 ± 30.2
60.4 ± 27.3
0.05*
Role difficulties
63.1 ± 22.2
64.2 ± 29.1
68.5 ± 22.6
0.46
Dependency
68.7 ± 27.5
71.7 ± 33.5
71.0 ± 22.5
0.45
Driving
52.0 ± 29.2
56.3 ± 33.9
51.4 ± 30.0
0.43
Color vision
82.1 ± 16.1
83.3 ± 20.4
78.6 ± 119.8
0.32
Peripheral vision
51.2 ± 21.6
63.3 ± 28.1
59.5 ± 16.7
0.07
Composite score
63.1 ± 15.8
66.8 ± 23.9
65.7 ± 16.7
0.26
Dunnett test P \ 0.05
All data are presented as mean ± SD VFQ-25 National Eye Institute 25-item visual function questionnaire, ANOVA analysis of variance * Statistically significant difference among three groups
Statistically significant difference between baseline and 1 month
duration [24, 25]. As DME is one of the representative features of diabetic microangiopathy, good diabetic control status in our patients might have led to greater recovery of visual function compared with previous studies. To evaluate metamorphopsia, the Amsler charts have been widely used in patients with macular diseases [26]. With the Amsler charts, however, it is difficult to quantify the severity of metamorphopsia because the patients have to self-describe the degree of image distortion. In contrast, M-CHARTS is an instrument that can easily and quantitatively evaluate the degree of metamorphopsia associated with macular diseases, and the patients only need to answer whether the line is
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distorted or not distorted [11, 12]. We previously reported that the severity of metamorphopsia strongly influenced VR-QOL in patients with MH and ERM [8]. The current study is the first to quantitatively evaluate metamorphopsia in patients with DME, and there were no significant improvements in metamorphopsia during the study period. Almost all cases (18 of 20 eyes) in the current study presented cystoid macular edema type DME. These cystoid changes occur in the inter nuclear layer and/or outer plexiform layer [27], and disorder and thickening of inner nuclear layer cause exacerbation of metamorphopsia [28]. Although the fine foveal microstructure could not be evaluated by using time-domain
VR-QOL following IVB for persistent DME
OCT, changes in the inner nuclear layer may also be associated with metamorphopsia and VR-QOL. We found that IVB improved contrast sensitivity for at least 1 month, but did not improve logMAR BCVA. It is known that BCVA is not necessarily a good predictor of many aspects of visual functions during daily life [29, 30], whereas contrast sensitivity has been shown to correlate well with visual functions required for various activities, such as orientation, mobility, reading and driving [31, 32]. Additionally, contrast sensitivity was significantly correlated with VFQ-25 composite scores in patients with DME [8]. In patients who had undergone retinal detachment surgery, the VFQ-25 composite score showed significant correlation with contrast sensitivity, but not with BCVA [33]. Thus, the improvement of contract sensitivity by IVB, despite the lack of recovery of BCVA, observed in the current study can be meaningful in the context of patients’ vision in daily life. CRT significantly improved at 1 month following injection, but returned to the pre-injection level by 3 months. This may be attributable to the rapid clearance of intravitreal bevacizumab from the vitreous cavity and insufficient therapeutic levels of the drug in vitrectomized eyes [20]. In terms of the durability of response in vitrectomized eyes, STTA may be a better choice than IVB or IVTA. There are a few reports about the effectiveness of IVB for DME in eyes after vitrectomy. Nagasawa et al. [34] reported that IVB for DME in vitrectomized eyes improved CRT but not visual acuity, and Yanyali et al. [25] reported that IVB for DME in eyes after vitrectomy did not improved CRT or visual acuity. Thus, previous studies reported that IVB has little benefit in patients with DME after vitrectomy. On the other hand, our study revealed that IVB improved not only CRT, but also visual function at least temporarily as shown by letter contrast sensitivity, suggesting that IVB can be a worthwhile treatment even in vitrectomized eyes with DME. These improvements led to recuperation of patients’ quality of vision as well. We previously reported that VR-QOL significantly improved following pars plana vitrectomy in patients with DME [8]. To the best of our knowledge, no previous study has assessed VR-QOL using VFQ-25 in patients with persistent DME after vitrectomy. We found that the subscale score ‘‘mental health’’ was significantly improved at 1 month. The ‘‘mental health’’ subscale score at 1 month tended to be correlated with letter contrast sensitivity at 1 month (r = 0.42, P = 0.09, Spearman’s rank coefficient). Increasing the number of the patients may help evaluate the significant correlation between these two parameters. VFQ-25 is a useful tool that measures the vision-related difficulties of physical, psychological and social aspects. In this study, psychological and social aspects of four subscale scores, such as ‘‘social
functioning,’’ ‘‘mental health,’’ ‘‘role difficulties’’ and ‘‘dependency,’’ were improved throughout the study period. This result suggests that IVB for vitrectomized DME is an effective treatment to improve psychological and social aspects of the VR-QOL, but is not enough to improve the comprehensive composite VR-QOL including the physical aspect. Repetitive IVB treatment may be able to maintain the improvement of these aspects of the VRQOL throughout the patient’s life. Further studies with larger series of patients are required for more precise reports. Our previous report showed that the postoperative VFQ25 composite score in the patients with DME was significantly correlated with the better-seeing BCVA, not with the worse-seeing BCVA [8]. In this study, many eyes receiving IVB treatment were the worse-seeing eye (15 of 20 eyes). Therefore, the effectiveness of IVB treatment might be limited to only the ‘‘mental health’’ subscale. In addition, 11 of 20 patients had clinically significant DME in both eyes. If we deliberately selected the worse-seeing eye when performing IVB treatment for these patients, better VRQOL results might be obtained than in this study’s results. One of the limitations of our present study is that CRT was measured using time-domain OCT. Although timedomain OCT is a valuable tool, it cannot provide detailed information as well as spectral-domain OCT. Spectraldomain OCT has higher resolution and can obtain an abundance of data. We recently reported associations between metamorphopsia and foveal microstructure in patients with epiretinal membrane using spectral-domain OCT [28]. Spectral-domain OCT may also aid in understanding associations between the macular microstructure and VR-QOL in patients with DME. In conclusion, the current study indicates that IVB temporarily improved CRT and contrast sensitivity in patients with persistent DME after vitrectomy. There was a modest improvement of VR-QOL as well. However, these effects did not last longer than 3 months. Acknowledgments Publication of this article was supported by the Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. Conflicts of interest Y. Okamoto, None; F. Okamoto, None; T. Hiraoka, None; T. Oshika; None.
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