Int Ophthalmol (2015) 35:19–26 DOI 10.1007/s10792-014-0012-z
ORIGINAL PAPER
Photopic negative response in branch retinal vein occlusion with macular edema Hidetaka Noma • Tatsuya Mimura Manami Kuse • Kanako Yasuda • Masahiko Shimura
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Received: 23 January 2014 / Accepted: 30 October 2014 / Published online: 11 November 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract In patients with branch retinal vein occlusion (BRVO) and macular edema, the relations among full-field electroretinogram (ffERG) parameters and parameters of retinal function or morphology remain uncertain. The objective of this study was to investigate the correlations between parameters of the ffERG, including the photopic negative response (PhNR), and retinal functional or morphological parameters in these patients. In 62 consecutive BRVO patients (mean age: 68.5 ± 10.6 years; 32 women and 30 men), the amplitude and implicit time of the a-wave cone, b-wave cone, 30 Hz flicker, and PhNR were
H. Noma (&) Department of Ophthalmology, Yachiyo Medical Center, Tokyo Women’s Medical University, 477-96, Owadashinden, Yachiyo, Chiba 276-8524, Japan e-mail: [email protected] H. Noma K. Yasuda M. Shimura Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan T. Mimura Department of Ophthalmology, Medical Center East, Tokyo Women’s Medical University, Tokyo, Japan M. Kuse Department of Ophthalmology, National Hospital Organization Mie Central Medical Center, Tsu, Japan M. Kuse Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan
calculated from the ffERG. Microperimetry was employed to measure the macular sensitivity within the central 4°, 10°, and 20° fields, while macular thickness and volume within these fields were measured by optical coherence tomography. Best-corrected visual acuity (BCVA) was determined on the logarithm of the minimum angle of resolution scale. The cone b-wave, 30 Hz flicker, and PhNR amplitudes showed a significant correlation with BCVA. In addition, the cone a-wave, cone b-wave, 30 Hz flicker, and PhNR amplitudes all showed a significant correlation with macular sensitivity within the central 4°, 10°, and 20° fields. Only the 30 Hz flicker amplitude showed a significant correlation with the macular thickness and volume within the 4°, 10°, and 20° fields, while the other ERG parameters did not. These findings suggest that PhNR may be a useful ERG parameter for evaluating inner retinal function in BRVO patients. Keywords Photopic negative response Macular sensitivity Macular thickness Macular volume Branch retinal vein occlusion Macular edema
Introduction Branch retinal vein occlusion (BRVO) is a common retinal vascular disease that usually affects people older than 50 years of age [1]. The most common cause of visual disturbance in BRVO patients is
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macular edema, which has been reported in 60 % of these patients [2]. The full-field electroretinogram (ffERG) investigates the response of the entire retina and is used widely for functional assessment in various ocular diseases. Previous studies performed in monkeys and cats have shown that the slow negative potential known as the photopic negative response (PhNR), which follows the b-wave, may be a sensitive index of retinal dysfunction associated with diseases of the inner retina [3]. Recently, Machida et al. [4] reported that the PhNR was severely affected by central retinal artery occlusion despite relative preservation of the cone b-wave. In addition, Chen et al. [5] reported that the amplitude of the PhNR is strongly influenced by BRVO, suggesting that PhNR may be useful for assessing inner retinal damage and evaluating the response to treatment. Thus, the PhNR could be a useful parameter for objective assessment of macular function in patients with BRVO. More recently, Ogino et al. [6] reported that the relative amplitudes of the PhNR and cone b-wave on the focal macular ERG (fmERG) were significantly correlated with retinal sensitivity at the central point and in the 4° and 8° fields. We previously reported that the retinal thickness and volume of the temporal subfields were significant ‘‘determinants’’ of the implicit time of the cone b-wave and 30-Hz flicker, as well as the amplitude of the 30-Hz flicker [7]. However, little information is available about the relations among ffERG parameters and parameters of retinal function or morphology obtained by microperimetry and optical coherence tomography (OCT). Accordingly, we performed ffERG, microperimetry, and OCT in BRVO patients with macular edema, and then investigated the correlations between ERG parameters (including PhNR) and functional or morphological parameters.
Methods Patients Sixty-two consecutive patients (62 eyes) were included in this prospective uncontrolled study, which was conducted at the Department of Ophthalmology of Tokyo Women’s Medical University from March 2008 to May 2012. The 62 unaffected eyes were used as controls. Informed consent was obtained from each participant. This study was performed in accordance
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with the Helsinki Declaration of 1975 (1983 revision). The study was approved by the ethics committee at Tokyo Women’s Medical University. Each study patient presented with cystoid macular edema of C250 lm using OCT, involving the foveal center. The main exclusion criteria were (1) intraocular surgery including cataract extraction within the 6 months before enrollment, (2) diabetes mellitus with diabetic retinopathy, (3) previous macular laser photocoagulation, (4) intravitreal triamcinolone or antiVEGF agents, (5) prior ocular inflammation, (6) retinal degeneration, (7) masked retinal hemorrhage (including macular bleeding in the intrafoveal or subfoveal space), and (8) primary open angle glaucoma. Thirty-one patients had superior vein occlusion and the other 31 had inferior occlusion. Each patient underwent baseline screening that included slit-lamp examination and ophthalmoscopy, ERG, and OCT for assessment of retinal thickness and retinal volume parameters. Measurement of BCVA Each patient underwent measurement of best-corrected visual acuity (BCVA) with an SC-2000 System chart (Nidek, Gamagori, Japan). BCVA was measured in decimal units on a Landolt chart by the orthoptists. The chart brightness was set at 80–320 cd/m2, and chart contrast was more than 74 %. The results were converted to the logarithm of the minimum angle of resolution scale (logMAR). Fundus findings A masked grader independently assessed ischemic retinal vascular occlusion by examining fluorescein angiograms. The ischemic region of the retina was measured with the public domain Scion Image program, as reported previously [8–10]. On digital fundus photographs, the disk area was outlined with a cursor and then measured, and the same was done for the nonperfused area. The severity of retinal ischemia was assessed as the nonperfused area divided by the disk area. Measurement of optical coherence tomography OCT was performed with an instrument from ZeissHumphrey Ophthalmic Systems (Zeiss Stratus OCT3,
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Carl Zeiss Meditec, Dublin, CA, USA) to measure the foveal thickness. At each visit, all patients underwent Stratus OCT examination in the vertical cross-section with the instrument centered on the fovea and in the fast macular thickness mode. On these views, retinal thickness was defined as the distance between the inner surface of the neurosensory retina and the retinal pigment epithelium. Foveal thickness was calculated as the average retinal thickness within a circle of 500-lm radius centered on the fovea. A retinal thickness map and retinal volume map were obtained by scanning 6 9 6 mm (20° 9 20°) areas of the macular region, which was divided into the following nine subfields: (1) fovea, (2) superior inner macula, (3) nasal inner macula, (4) inferior inner macula, (5) temporal inner macula, (6) superior outer macula, (7) nasal outer macula, (8) inferior outer macula, and (9) temporal outer macula [11]. The diameters of the central, inner, and outer circles were 1, 3, and 6 mm, respectively. In each region, measurement of retinal thickness and volume was automatically performed by computer software. The mean macular thickness at the one subfield (fovea) covering the central 1 9 1 mm (4° 9 4°), at five subfields (fovea, superior inner, nasal inner, inferior inner, and temporal inner) covering the central 3 9 3 mm (10° 9 10°), and at all nine subfields covering the entire central 6 9 6 mm (20° 9 20°) were thus determined. Retinal volume was calculated as follows. A central macular thickness map measuring 6.00 mm in diameter was generated. The circular map was subdivided into nine quadrants. The middle and inner circle diameters were 3.00 mm and 1.00 mm, respectively. The mean retinal thickness was calculated for each of the nine quadrants from the obtained radial scans. Multiplying the mean retinal thickness by the area of the quadrant generated the volume for each of the nine quadrants. The total macular volume for the one subfield (fovea) covering the central 1 9 1 mm (4° 9 4°), for five subfields (fovea, superior inner, nasal inner, inferior inner, and temporal inner) covering the central 3 9 3 mm (10° 9 10°), and for all nine subfields covering the entire central 6 9 6 mm (20° 9 20°) were thus determined as the sum of the quadrant volumes. Functional mapping by microperimetry Microperimetry was performed with the MP-1 system (Nidek, Gamagori, Japan), using an infrared fundus
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camera controlled by software that allowed automatic tracking of fundus movements (every frame acquired was assessed for shift in the x and y directions relative to an initial reference frame). Goldmann III stimuli were presented randomly according to a 4-2-1 double staircase paradigm. Stimulus intensity was varied from 0 to 20 decibels (dB) (0 dB = the maximal signal intensity of 127 cd/m2) in 1-dB steps, and the stimulus duration was 200 ms. Target size was varied according to the patient’s visual acuity. Retinal sensitivity maps were obtained by using the MP-1 software (macula 20° program), with background illumination set at 1.27 cd/m2, and the mean retinal sensitivity was calculated from the sensitivity in each of the nine subfields on the map. Mean macular sensitivity was measured at five locations in the central 4° field, 29 locations in the central 10° field (fovea, superior inner, nasal inner, inferior inner, and temporal inner subfields), and 57 locations in the central 20° field (all nine subfields) [11]. ERG recording After OCT and microperimetry were performed in each patient, the photopic ERG was recorded in both eyes using a Portable LE2000 ERG system (Tomey Co., Ltd., Nagoya, Japan), which had a contact lens electrode equipped with a light-emitting diode that mimicked a Ganzfeld dome system. First, the patient’s pupils were maximally dilated and then dark adaptation was allowed for 20 min. Next, the contact lens recording electrode was positioned on each eye under dim red light, with the reference electrode being located on the forehead and the ground electrode on one earlobe. After another 10 min, the photopic ERG (a-wave, b-wave, and 30 Hz flicker ERG) was recorded with white light (the stimulus intensity was set at 3, 3, and 10 cd s/m2, respectively, and the background intensity was 25 cd/m2) according to the International Society of Clinical Electrophysiology of Vision recommendations [12]. The PhNR amplitude was measured from baseline to the trough immediately after the b-wave according to the method of Viswanathan et al. [3, 13] (Fig. 1). Implicit time was defined as the interval from the start of stimulation to the peak of each component (Fig. 1). The photopic ERG was measured 10 times and the best waveform was used in this study. Single responses obtained from both eyes were analyzed.
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Fig. 1 Representative fullfield electroretinogram. The waveforms of a 63-year-old man (photopic waveform and 30 Hz flicker waveform) obtained with the LE2000 ERG system are shown (red arrow a-wave cone, black arrow b-wave cone, blue arrowhead PhNR)
Statistical analyses All analyses were performed with SAS System 9.1 software (SAS Institute Inc., Cary, NC, USA). Data are presented as the mean ± SD or frequencies. To examine the relation between macular sensitivity, macular thickness/volume or nonperfused area of the retina and ERG parameters, Pearson correlation coefficients were calculated. Two-tailed P values of less than 0.05 were considered to indicate a statistically significant difference. Results We examined 62 eyes of 62 patients with BRVO (32 women and 30 men), who ranged in age from 29 to 89 years (mean ± SD 68.5 ± 10.6 years) (Table 1). The mean duration of symptoms was 4.1 ± 2.3 months (range 1–12 months). At the first visit, visual acuity (logMAR) was 0.58 ± 0.45. Mean macular sensitivity within the central 4°, 10°, and 20° fields was 6.7 ± 5.8, 8.1 ± 5.2, 8.8 ± 4.8 dB, respectively. In addition, mean macular thickness within the 4°, 10°, and 20° fields was 511 ± 164, 455 ± 112, 406 ± 85 lm, respectively, while mean macular volume was 0.40 ± 0.13, 3.17 ± 0.76, 10.5 ± 1.97 mm3, respectively. In the affected eyes, the amplitudes of the b-wave, 30 Hz flicker, and PhNR were significantly smaller compared with the healthy contralateral eyes (P = 0.022, 0.001, and\0.001) (Table 2). In addition,
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Table 1 Clinical and demographic data of the BRVO patients BRVO patients No (female/male)
62 (32/30)
Age (years)
68.5 ± 10.6*
Hypertension
40 (64.5 %)
Systolic blood pressure (mmHg)
135 ± 15*
Diastolic blood pressure (mmHg)
82 ± 10*
Hyperlipidaemia
27 (43.5 %)
Duration of BRVO (months) BCVA (logMAR)
4.1 ± 2.3* 0.58 ± 0.45*
Macular sensitivity central 4°
6.7 ± 5.8*
10°
8.1 ± 5.2*
20°
8.8 ± 4.8*
Macular thickness central 4°
511 ± 164*
10°
455 ± 112*
20°
406 ± 85*
Macular volume central 4°
0.40 ± 0.13*
10°
3.17 ± 0.76*
20°
10.5 ± 1.97*
BRVO branch retinal vein occlusion, No number of eyes, BCVA best-corrected visual acuity, logMAR logarithm of the minimum angle of resolution scale * Mean ± standard deviation
the implicit times of the b-wave, 30 Hz flicker, and PhNR were significantly longer in the affected eyes compared with the contralateral eyes (P = 0.015, \0.001, and \0.001) (Table 2).
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Table 2 Comparison of ERG parameters between affected eyes and unaffected contralateral eyes Affected eyes
Unaffected fellow eyes
P value
Cone a-wave Amplitude (lm)
42.4 ± 16.3
44.6 ± 15.8
0.429
Implicit time (ms)
14.8 ± 1.8
14.9 ± 1.9
0.795
135.5 ± 47.1
154.4 ± 43.7
0.022
32.3 ± 6.1
30.3 ± 1.6
0.015
Amplitude (lm)
87.9 ± 29.4
103.9 ± 25.0
Implicit time (ms)
37.7 ± 3.1
36.1 ± 2.1
24.7 ± 17.2 44.3 ± 3.2
40.2 ± 18.1 \0.001 41.9 ± 2.2 \0.001
Cone b-wave Amplitude (lm) Implicit time (ms) 30 Hz Flicker 0.001 \0.001
PhNR Amplitude (lm) Implicit time (ms)
The cone a-wave, 30 Hz flicker, and PhNR amplitudes were not significantly correlated with age (r = 0.01, P = 0.914; r = -0.11, P = 0.371; and r = 0.04, P = 0.772; respectively) or with the duration of symptoms (r = -0.13, P = 0.283; r = -0.24, P = 0.060; r = -0.12, P = 0.350; and r = 0.02, P = 0.859; respectively). However, the cone b-wave amplitude was significantly correlated with age (r = -0.35, P = 0.005). In addition, the implicit times of the cone a-wave, cone b-wave, and 30 Hz flicker were not significantly correlated with age (r = 0.18, P = 0.141; r = -0.03, P = 0.823; and r = 0.23, P = 0.068; respectively) or with the duration of symptoms (r = 0.18, P = 0.156; r = -0.02, P = 0.885; r = 0.03, P = 0.793; and r = 0.19, P = 0.138; respectively). However, the implicit time of PhNR was significantly correlated with age (r = 0.40, P = 0.002). When we evaluated correlations between the ERG parameters and functional parameters (BCVA and macular sensitivity within the central 4°, 10°, and 20° fields), the cone b-wave, 30 Hz flicker, and PhNR amplitudes were significantly correlated with BCVA. In addition, the cone a-wave, cone b-wave, 30 Hz flicker, and PhNR amplitudes showed a significant correlation with macular sensitivity within the 4°, 10°, and 20° fields (Table 3). Furthermore, we evaluated the correlations between ERG parameters and macular thickness or volume within the 4°, 10°, and 20° fields (Table 3). The amplitude of the 30 Hz flicker showed a significant correlation with macular thickness and
volume within the three fields, but the other ERG parameters did not show any significant correlations with either macular thickness or volume in any of the fields (Table 3). The implicit time of the PhNR (q = 0.34, P = 0.007) was significantly correlated with the nonperfused area of the retina (Table 4). However, the amplitude of the cone a-wave (q = -0.12, P = 0.339), cone b-wave (q = -0.19, P = 0.148), 30 Hz flicker (q = -0.21, P = 0.109), and PhNR (q = -0.16, P = 0.221), as well as the implicit time of the cone a-wave (q = 0.04, P = 0.733) cone b-wave (q = -0.05, P = 0.723), and 30 Hz flicker (q = 0.12, P = 0.355), showed no significant correlation with the nonperfused area of the retina (Table 4).
Discussion BRVO causes pathological changes (such as bleeding) that not only affect the fovea, but also the entire macular region. Considering the pathological mechanism of BRVO, we divided the macular region into central 4°, 10°, and 20° fields for investigation of correlations among the ERG, functional, and morphological parameters. We found that the cone a-wave, cone b-wave, 30 Hz flicker, and PhNR amplitudes all showed significant correlations with the macular sensitivity within the 4°, 10°, and 20° fields, suggesting that these ERG parameters may reflect macular function. This conclusion is supported by a report that the cone b-wave, 30 Hz flicker, and PhNR originate from the inner retina [3]. On the other hand, the cone b-wave, 30 Hz flicker, and PhNR amplitudes were also significantly correlated with BCVA, suggesting that these ERG parameters may reflect foveal function. However, the amplitude of the cone a-wave was not significantly correlated with BCVA. This may have been because Ganzfeld stimulation was used in this study, which elicited a response from photoreceptors throughout the retina. Furthermore, the cone b-wave, 30 Hz flicker, and PhNR amplitudes were more strongly correlated with macular sensitivity within the 4°, 10°, and 20° fields than with BCVA. The fovea consists entirely of cones and has an important role in detailed vision [14], so BCVA is primarily influenced by foveal function. However, BRVO not only affects the fovea, but also the entire macular region, which
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Table 3 Correlations between ERG parameters and parameters of macular function or morphology Variable
Macular thickness
Macular volume
Macular sensitivity 4° r P value
10° r P value
Visual acuity (logMAR)
4° r P value
10° r P value
20° r P value
4° r P value
10° r P value
20° r P value
20° r P value
-0.13
-0.18
-0.20
-0.13
-0.18
-0.21
0.45
0.43
0.40
0.23
0.317
0.166
0.113
0.301
0.158
0.091
\0.001
\0.001
0.001
0.067
-0.19
-0.21
-0.20
-0.19
-0.21
-0.18
-0.01
-0.08
-0.11
-0.14
0.129
0.099
0.119
0.136
0.097
0.172
0.930
0.516
0.404
0.266
-0.15
-0.16
-0.20
-0.15
-0.15
-0.23
0.42
0.42
0.43
0.232
0.220
0.121
0.234
0.224
0.067
\0.001
\0.001
\0.001
r P value
Cone a-wave Amplitude (lm) Implicit time (ms) Cone b-wave Amplitude (lm) Implicit time (ms)
0.35 0.005
0.17
0.16
0.19
0.17
0.16
0.20
-0.04
-0.10
-0.12
0.02
0.182
0.205
0.146
0.182
0.214
0.117
0.744
0.435
0.342
0.831
-0.35
-0.33
-0.40
-0.33
-0.32
-0.44
0.47
0.48
0.48
0.007
0.008
0.001
0.008
0.010
\0.001
\0.001
\0.001
\0.001
-0.05
-0.04
-0.01
-0.03
-0.04
0.03
-0.01
-0.08
-0.10
0.01
0.725
0.755
0.951
0.774
0.763
0.818
0.947
0.537
0.422
0.941
-0.15
-0.16
-0.18
-0.15
-0.16
-0.19
0.36
0.36
0.36
0.27
0.244
0.213
0.156
0.230
0.225
0.138
0.004
0.004
0.004
0.031
-0.15 0.235
-0.12
-0.08
-0.14
-0.11
-0.03
-0.40
-0.41
-0.48
-0.50
0.354
0.522
0.257
0.402
0.811
0.001
\0.001
\0.001
\0.001
30 Hz flicker Amplitude (lm) Implicit time (ms)
0.27 0.031
PhNR Amplitude (lm) Implicit time (ms)
PhNR photopic negative response, logMAR logarithm of the minimum angle of resolution scale, r correlation coefficient
Table 4 Correlations between ERG parameters and the nonperfused area of the retina r
P value
Cone a-wave Amplitude (lm)
-0.12
0.339
0.04
0.733
Amplitude (lm)
-0.19
0.148
Implicit time (ms)
-0.05
0.723
-0.21
0.109
0.12
0.355
-0.16
0.221
0.34
0.007
Implicit time (ms) Cone b-wave
30 Hz flicker Amplitude (lm) Implicit time (ms) PhNR Amplitude (lm) Implicit time (ms)
PhNR photopic negative response, r correlation coefficient
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may explain why data obtained by Ganzfeld stimulation (the cone b-wave, 30 Hz flicker, and PhNR amplitudes) showed a stronger correlation with macular sensitivity within the 4°, 10°, and 20° fields than with BCVA. Interestingly, not only the PhNR amplitude, but also its implicit time, showed a significant correlation with both BCVA and macular sensitivity within the 4°, 10°, and 20°fields. BRVO chiefly damages the inner retina and PhNR has been reported to reflect inner retinal function [3, 15, 16]. In addition, Ogino et al. [6.] reported that the relative PhNR amplitude showed a significant correlation with retinal sensitivity at the center point and within the 4° and 8° fields. Taken together with our results, it seems that PhNR may provide a better indication of inner retinal function in BRVO patients than the other ERG parameters. It has
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been reported that there are no differences of fmERG parameters between ischemic BRVO and nonischemic BRVO, although some ischemic eyes showed such changes of PhNR [6]. Nonperfusion of the inner retina could well cause functional impairment and would have a substantial effect on the PhNR. Retinal ischemia caused by BRVO often occurs outside the vascular arcades and does not alter fmERG parameters, which only reflect the function of the macular region. However, this study revealed that the implicit time of the PhNR obtained by ffERG was significantly correlated with the nonperfused area of the retina. In fact, the correlation between PhNR implicit time and macular sensitivity became stronger from the 20° field to the 4° field (Table 3). Thus, both the amplitude and the implicit time of PhNR may be useful photopic ERG parameters of inner retinal function in BRVO patients. However, this study was limited by the lack of a control group, and various confounding factors might have influenced the ERG responses (including age, sex, cataract grade, and refractive error). Accordingly, the relations among ERG parameters and retinal (functional and morphological) parameters need to be investigated further in BRVO patients with macular edema. We also found that the functional outcome was more closely correlated with the amplitude of ERG parameters than with the implicit time (Table 3). This result may have been obtained because BRVO affects the retina nearer to the central fovea compared with CRVO. Furthermore, the 30 Hz flicker amplitude showed stronger correlations with macular thickness, volume, and sensitivity than the other ERG parameters. Cone density declines rapidly away from the center of the fovea and is an order of magnitude lower even 1 mm from its center [17], and the 30 Hz flicker amplitude/ implicit time alter in accordance with cone density. Thus, it is reasonable that the 30 Hz flicker corresponds more closely to macular thickness, volume, and sensitivity than the other ERG parameters, particularly because lesions tend to be limited to the posterior pole of the retina in BRVO patients. This study also had some other limitations. For example, OPs are another relatively sensitive parameter of retinal vein occlusion, but we did not measure OPs, so the relation of retinal (functional and morphological) parameters to OPs in BRVO patients
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with macular edema will need to be investigated in the future. In conclusion, the amplitude and implicit time of the PhNR were significantly correlated with both BCVA and macular sensitivity within the central 4°, 10°, and 20° fields. Accordingly, PhNR may be a useful parameter for evaluating inner retinal function in patients with BRVO. Acknowledgment Conflict of interest The authors do not have any Conflict of interest in this manuscript.
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ORIGINAL PAPER
Photopic negative response in branch retinal vein occlusion with macular edema Hidetaka Noma • Tatsuya Mimura Manami Kuse • Kanako Yasuda • Masahiko Shimura
•
Received: 23 January 2014 / Accepted: 30 October 2014 / Published online: 11 November 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract In patients with branch retinal vein occlusion (BRVO) and macular edema, the relations among full-field electroretinogram (ffERG) parameters and parameters of retinal function or morphology remain uncertain. The objective of this study was to investigate the correlations between parameters of the ffERG, including the photopic negative response (PhNR), and retinal functional or morphological parameters in these patients. In 62 consecutive BRVO patients (mean age: 68.5 ± 10.6 years; 32 women and 30 men), the amplitude and implicit time of the a-wave cone, b-wave cone, 30 Hz flicker, and PhNR were
H. Noma (&) Department of Ophthalmology, Yachiyo Medical Center, Tokyo Women’s Medical University, 477-96, Owadashinden, Yachiyo, Chiba 276-8524, Japan e-mail: [email protected] H. Noma K. Yasuda M. Shimura Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan T. Mimura Department of Ophthalmology, Medical Center East, Tokyo Women’s Medical University, Tokyo, Japan M. Kuse Department of Ophthalmology, National Hospital Organization Mie Central Medical Center, Tsu, Japan M. Kuse Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan
calculated from the ffERG. Microperimetry was employed to measure the macular sensitivity within the central 4°, 10°, and 20° fields, while macular thickness and volume within these fields were measured by optical coherence tomography. Best-corrected visual acuity (BCVA) was determined on the logarithm of the minimum angle of resolution scale. The cone b-wave, 30 Hz flicker, and PhNR amplitudes showed a significant correlation with BCVA. In addition, the cone a-wave, cone b-wave, 30 Hz flicker, and PhNR amplitudes all showed a significant correlation with macular sensitivity within the central 4°, 10°, and 20° fields. Only the 30 Hz flicker amplitude showed a significant correlation with the macular thickness and volume within the 4°, 10°, and 20° fields, while the other ERG parameters did not. These findings suggest that PhNR may be a useful ERG parameter for evaluating inner retinal function in BRVO patients. Keywords Photopic negative response Macular sensitivity Macular thickness Macular volume Branch retinal vein occlusion Macular edema
Introduction Branch retinal vein occlusion (BRVO) is a common retinal vascular disease that usually affects people older than 50 years of age [1]. The most common cause of visual disturbance in BRVO patients is
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macular edema, which has been reported in 60 % of these patients [2]. The full-field electroretinogram (ffERG) investigates the response of the entire retina and is used widely for functional assessment in various ocular diseases. Previous studies performed in monkeys and cats have shown that the slow negative potential known as the photopic negative response (PhNR), which follows the b-wave, may be a sensitive index of retinal dysfunction associated with diseases of the inner retina [3]. Recently, Machida et al. [4] reported that the PhNR was severely affected by central retinal artery occlusion despite relative preservation of the cone b-wave. In addition, Chen et al. [5] reported that the amplitude of the PhNR is strongly influenced by BRVO, suggesting that PhNR may be useful for assessing inner retinal damage and evaluating the response to treatment. Thus, the PhNR could be a useful parameter for objective assessment of macular function in patients with BRVO. More recently, Ogino et al. [6] reported that the relative amplitudes of the PhNR and cone b-wave on the focal macular ERG (fmERG) were significantly correlated with retinal sensitivity at the central point and in the 4° and 8° fields. We previously reported that the retinal thickness and volume of the temporal subfields were significant ‘‘determinants’’ of the implicit time of the cone b-wave and 30-Hz flicker, as well as the amplitude of the 30-Hz flicker [7]. However, little information is available about the relations among ffERG parameters and parameters of retinal function or morphology obtained by microperimetry and optical coherence tomography (OCT). Accordingly, we performed ffERG, microperimetry, and OCT in BRVO patients with macular edema, and then investigated the correlations between ERG parameters (including PhNR) and functional or morphological parameters.
Methods Patients Sixty-two consecutive patients (62 eyes) were included in this prospective uncontrolled study, which was conducted at the Department of Ophthalmology of Tokyo Women’s Medical University from March 2008 to May 2012. The 62 unaffected eyes were used as controls. Informed consent was obtained from each participant. This study was performed in accordance
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with the Helsinki Declaration of 1975 (1983 revision). The study was approved by the ethics committee at Tokyo Women’s Medical University. Each study patient presented with cystoid macular edema of C250 lm using OCT, involving the foveal center. The main exclusion criteria were (1) intraocular surgery including cataract extraction within the 6 months before enrollment, (2) diabetes mellitus with diabetic retinopathy, (3) previous macular laser photocoagulation, (4) intravitreal triamcinolone or antiVEGF agents, (5) prior ocular inflammation, (6) retinal degeneration, (7) masked retinal hemorrhage (including macular bleeding in the intrafoveal or subfoveal space), and (8) primary open angle glaucoma. Thirty-one patients had superior vein occlusion and the other 31 had inferior occlusion. Each patient underwent baseline screening that included slit-lamp examination and ophthalmoscopy, ERG, and OCT for assessment of retinal thickness and retinal volume parameters. Measurement of BCVA Each patient underwent measurement of best-corrected visual acuity (BCVA) with an SC-2000 System chart (Nidek, Gamagori, Japan). BCVA was measured in decimal units on a Landolt chart by the orthoptists. The chart brightness was set at 80–320 cd/m2, and chart contrast was more than 74 %. The results were converted to the logarithm of the minimum angle of resolution scale (logMAR). Fundus findings A masked grader independently assessed ischemic retinal vascular occlusion by examining fluorescein angiograms. The ischemic region of the retina was measured with the public domain Scion Image program, as reported previously [8–10]. On digital fundus photographs, the disk area was outlined with a cursor and then measured, and the same was done for the nonperfused area. The severity of retinal ischemia was assessed as the nonperfused area divided by the disk area. Measurement of optical coherence tomography OCT was performed with an instrument from ZeissHumphrey Ophthalmic Systems (Zeiss Stratus OCT3,
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Carl Zeiss Meditec, Dublin, CA, USA) to measure the foveal thickness. At each visit, all patients underwent Stratus OCT examination in the vertical cross-section with the instrument centered on the fovea and in the fast macular thickness mode. On these views, retinal thickness was defined as the distance between the inner surface of the neurosensory retina and the retinal pigment epithelium. Foveal thickness was calculated as the average retinal thickness within a circle of 500-lm radius centered on the fovea. A retinal thickness map and retinal volume map were obtained by scanning 6 9 6 mm (20° 9 20°) areas of the macular region, which was divided into the following nine subfields: (1) fovea, (2) superior inner macula, (3) nasal inner macula, (4) inferior inner macula, (5) temporal inner macula, (6) superior outer macula, (7) nasal outer macula, (8) inferior outer macula, and (9) temporal outer macula [11]. The diameters of the central, inner, and outer circles were 1, 3, and 6 mm, respectively. In each region, measurement of retinal thickness and volume was automatically performed by computer software. The mean macular thickness at the one subfield (fovea) covering the central 1 9 1 mm (4° 9 4°), at five subfields (fovea, superior inner, nasal inner, inferior inner, and temporal inner) covering the central 3 9 3 mm (10° 9 10°), and at all nine subfields covering the entire central 6 9 6 mm (20° 9 20°) were thus determined. Retinal volume was calculated as follows. A central macular thickness map measuring 6.00 mm in diameter was generated. The circular map was subdivided into nine quadrants. The middle and inner circle diameters were 3.00 mm and 1.00 mm, respectively. The mean retinal thickness was calculated for each of the nine quadrants from the obtained radial scans. Multiplying the mean retinal thickness by the area of the quadrant generated the volume for each of the nine quadrants. The total macular volume for the one subfield (fovea) covering the central 1 9 1 mm (4° 9 4°), for five subfields (fovea, superior inner, nasal inner, inferior inner, and temporal inner) covering the central 3 9 3 mm (10° 9 10°), and for all nine subfields covering the entire central 6 9 6 mm (20° 9 20°) were thus determined as the sum of the quadrant volumes. Functional mapping by microperimetry Microperimetry was performed with the MP-1 system (Nidek, Gamagori, Japan), using an infrared fundus
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camera controlled by software that allowed automatic tracking of fundus movements (every frame acquired was assessed for shift in the x and y directions relative to an initial reference frame). Goldmann III stimuli were presented randomly according to a 4-2-1 double staircase paradigm. Stimulus intensity was varied from 0 to 20 decibels (dB) (0 dB = the maximal signal intensity of 127 cd/m2) in 1-dB steps, and the stimulus duration was 200 ms. Target size was varied according to the patient’s visual acuity. Retinal sensitivity maps were obtained by using the MP-1 software (macula 20° program), with background illumination set at 1.27 cd/m2, and the mean retinal sensitivity was calculated from the sensitivity in each of the nine subfields on the map. Mean macular sensitivity was measured at five locations in the central 4° field, 29 locations in the central 10° field (fovea, superior inner, nasal inner, inferior inner, and temporal inner subfields), and 57 locations in the central 20° field (all nine subfields) [11]. ERG recording After OCT and microperimetry were performed in each patient, the photopic ERG was recorded in both eyes using a Portable LE2000 ERG system (Tomey Co., Ltd., Nagoya, Japan), which had a contact lens electrode equipped with a light-emitting diode that mimicked a Ganzfeld dome system. First, the patient’s pupils were maximally dilated and then dark adaptation was allowed for 20 min. Next, the contact lens recording electrode was positioned on each eye under dim red light, with the reference electrode being located on the forehead and the ground electrode on one earlobe. After another 10 min, the photopic ERG (a-wave, b-wave, and 30 Hz flicker ERG) was recorded with white light (the stimulus intensity was set at 3, 3, and 10 cd s/m2, respectively, and the background intensity was 25 cd/m2) according to the International Society of Clinical Electrophysiology of Vision recommendations [12]. The PhNR amplitude was measured from baseline to the trough immediately after the b-wave according to the method of Viswanathan et al. [3, 13] (Fig. 1). Implicit time was defined as the interval from the start of stimulation to the peak of each component (Fig. 1). The photopic ERG was measured 10 times and the best waveform was used in this study. Single responses obtained from both eyes were analyzed.
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Fig. 1 Representative fullfield electroretinogram. The waveforms of a 63-year-old man (photopic waveform and 30 Hz flicker waveform) obtained with the LE2000 ERG system are shown (red arrow a-wave cone, black arrow b-wave cone, blue arrowhead PhNR)
Statistical analyses All analyses were performed with SAS System 9.1 software (SAS Institute Inc., Cary, NC, USA). Data are presented as the mean ± SD or frequencies. To examine the relation between macular sensitivity, macular thickness/volume or nonperfused area of the retina and ERG parameters, Pearson correlation coefficients were calculated. Two-tailed P values of less than 0.05 were considered to indicate a statistically significant difference. Results We examined 62 eyes of 62 patients with BRVO (32 women and 30 men), who ranged in age from 29 to 89 years (mean ± SD 68.5 ± 10.6 years) (Table 1). The mean duration of symptoms was 4.1 ± 2.3 months (range 1–12 months). At the first visit, visual acuity (logMAR) was 0.58 ± 0.45. Mean macular sensitivity within the central 4°, 10°, and 20° fields was 6.7 ± 5.8, 8.1 ± 5.2, 8.8 ± 4.8 dB, respectively. In addition, mean macular thickness within the 4°, 10°, and 20° fields was 511 ± 164, 455 ± 112, 406 ± 85 lm, respectively, while mean macular volume was 0.40 ± 0.13, 3.17 ± 0.76, 10.5 ± 1.97 mm3, respectively. In the affected eyes, the amplitudes of the b-wave, 30 Hz flicker, and PhNR were significantly smaller compared with the healthy contralateral eyes (P = 0.022, 0.001, and\0.001) (Table 2). In addition,
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Table 1 Clinical and demographic data of the BRVO patients BRVO patients No (female/male)
62 (32/30)
Age (years)
68.5 ± 10.6*
Hypertension
40 (64.5 %)
Systolic blood pressure (mmHg)
135 ± 15*
Diastolic blood pressure (mmHg)
82 ± 10*
Hyperlipidaemia
27 (43.5 %)
Duration of BRVO (months) BCVA (logMAR)
4.1 ± 2.3* 0.58 ± 0.45*
Macular sensitivity central 4°
6.7 ± 5.8*
10°
8.1 ± 5.2*
20°
8.8 ± 4.8*
Macular thickness central 4°
511 ± 164*
10°
455 ± 112*
20°
406 ± 85*
Macular volume central 4°
0.40 ± 0.13*
10°
3.17 ± 0.76*
20°
10.5 ± 1.97*
BRVO branch retinal vein occlusion, No number of eyes, BCVA best-corrected visual acuity, logMAR logarithm of the minimum angle of resolution scale * Mean ± standard deviation
the implicit times of the b-wave, 30 Hz flicker, and PhNR were significantly longer in the affected eyes compared with the contralateral eyes (P = 0.015, \0.001, and \0.001) (Table 2).
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Table 2 Comparison of ERG parameters between affected eyes and unaffected contralateral eyes Affected eyes
Unaffected fellow eyes
P value
Cone a-wave Amplitude (lm)
42.4 ± 16.3
44.6 ± 15.8
0.429
Implicit time (ms)
14.8 ± 1.8
14.9 ± 1.9
0.795
135.5 ± 47.1
154.4 ± 43.7
0.022
32.3 ± 6.1
30.3 ± 1.6
0.015
Amplitude (lm)
87.9 ± 29.4
103.9 ± 25.0
Implicit time (ms)
37.7 ± 3.1
36.1 ± 2.1
24.7 ± 17.2 44.3 ± 3.2
40.2 ± 18.1 \0.001 41.9 ± 2.2 \0.001
Cone b-wave Amplitude (lm) Implicit time (ms) 30 Hz Flicker 0.001 \0.001
PhNR Amplitude (lm) Implicit time (ms)
The cone a-wave, 30 Hz flicker, and PhNR amplitudes were not significantly correlated with age (r = 0.01, P = 0.914; r = -0.11, P = 0.371; and r = 0.04, P = 0.772; respectively) or with the duration of symptoms (r = -0.13, P = 0.283; r = -0.24, P = 0.060; r = -0.12, P = 0.350; and r = 0.02, P = 0.859; respectively). However, the cone b-wave amplitude was significantly correlated with age (r = -0.35, P = 0.005). In addition, the implicit times of the cone a-wave, cone b-wave, and 30 Hz flicker were not significantly correlated with age (r = 0.18, P = 0.141; r = -0.03, P = 0.823; and r = 0.23, P = 0.068; respectively) or with the duration of symptoms (r = 0.18, P = 0.156; r = -0.02, P = 0.885; r = 0.03, P = 0.793; and r = 0.19, P = 0.138; respectively). However, the implicit time of PhNR was significantly correlated with age (r = 0.40, P = 0.002). When we evaluated correlations between the ERG parameters and functional parameters (BCVA and macular sensitivity within the central 4°, 10°, and 20° fields), the cone b-wave, 30 Hz flicker, and PhNR amplitudes were significantly correlated with BCVA. In addition, the cone a-wave, cone b-wave, 30 Hz flicker, and PhNR amplitudes showed a significant correlation with macular sensitivity within the 4°, 10°, and 20° fields (Table 3). Furthermore, we evaluated the correlations between ERG parameters and macular thickness or volume within the 4°, 10°, and 20° fields (Table 3). The amplitude of the 30 Hz flicker showed a significant correlation with macular thickness and
volume within the three fields, but the other ERG parameters did not show any significant correlations with either macular thickness or volume in any of the fields (Table 3). The implicit time of the PhNR (q = 0.34, P = 0.007) was significantly correlated with the nonperfused area of the retina (Table 4). However, the amplitude of the cone a-wave (q = -0.12, P = 0.339), cone b-wave (q = -0.19, P = 0.148), 30 Hz flicker (q = -0.21, P = 0.109), and PhNR (q = -0.16, P = 0.221), as well as the implicit time of the cone a-wave (q = 0.04, P = 0.733) cone b-wave (q = -0.05, P = 0.723), and 30 Hz flicker (q = 0.12, P = 0.355), showed no significant correlation with the nonperfused area of the retina (Table 4).
Discussion BRVO causes pathological changes (such as bleeding) that not only affect the fovea, but also the entire macular region. Considering the pathological mechanism of BRVO, we divided the macular region into central 4°, 10°, and 20° fields for investigation of correlations among the ERG, functional, and morphological parameters. We found that the cone a-wave, cone b-wave, 30 Hz flicker, and PhNR amplitudes all showed significant correlations with the macular sensitivity within the 4°, 10°, and 20° fields, suggesting that these ERG parameters may reflect macular function. This conclusion is supported by a report that the cone b-wave, 30 Hz flicker, and PhNR originate from the inner retina [3]. On the other hand, the cone b-wave, 30 Hz flicker, and PhNR amplitudes were also significantly correlated with BCVA, suggesting that these ERG parameters may reflect foveal function. However, the amplitude of the cone a-wave was not significantly correlated with BCVA. This may have been because Ganzfeld stimulation was used in this study, which elicited a response from photoreceptors throughout the retina. Furthermore, the cone b-wave, 30 Hz flicker, and PhNR amplitudes were more strongly correlated with macular sensitivity within the 4°, 10°, and 20° fields than with BCVA. The fovea consists entirely of cones and has an important role in detailed vision [14], so BCVA is primarily influenced by foveal function. However, BRVO not only affects the fovea, but also the entire macular region, which
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Table 3 Correlations between ERG parameters and parameters of macular function or morphology Variable
Macular thickness
Macular volume
Macular sensitivity 4° r P value
10° r P value
Visual acuity (logMAR)
4° r P value
10° r P value
20° r P value
4° r P value
10° r P value
20° r P value
20° r P value
-0.13
-0.18
-0.20
-0.13
-0.18
-0.21
0.45
0.43
0.40
0.23
0.317
0.166
0.113
0.301
0.158
0.091
\0.001
\0.001
0.001
0.067
-0.19
-0.21
-0.20
-0.19
-0.21
-0.18
-0.01
-0.08
-0.11
-0.14
0.129
0.099
0.119
0.136
0.097
0.172
0.930
0.516
0.404
0.266
-0.15
-0.16
-0.20
-0.15
-0.15
-0.23
0.42
0.42
0.43
0.232
0.220
0.121
0.234
0.224
0.067
\0.001
\0.001
\0.001
r P value
Cone a-wave Amplitude (lm) Implicit time (ms) Cone b-wave Amplitude (lm) Implicit time (ms)
0.35 0.005
0.17
0.16
0.19
0.17
0.16
0.20
-0.04
-0.10
-0.12
0.02
0.182
0.205
0.146
0.182
0.214
0.117
0.744
0.435
0.342
0.831
-0.35
-0.33
-0.40
-0.33
-0.32
-0.44
0.47
0.48
0.48
0.007
0.008
0.001
0.008
0.010
\0.001
\0.001
\0.001
\0.001
-0.05
-0.04
-0.01
-0.03
-0.04
0.03
-0.01
-0.08
-0.10
0.01
0.725
0.755
0.951
0.774
0.763
0.818
0.947
0.537
0.422
0.941
-0.15
-0.16
-0.18
-0.15
-0.16
-0.19
0.36
0.36
0.36
0.27
0.244
0.213
0.156
0.230
0.225
0.138
0.004
0.004
0.004
0.031
-0.15 0.235
-0.12
-0.08
-0.14
-0.11
-0.03
-0.40
-0.41
-0.48
-0.50
0.354
0.522
0.257
0.402
0.811
0.001
\0.001
\0.001
\0.001
30 Hz flicker Amplitude (lm) Implicit time (ms)
0.27 0.031
PhNR Amplitude (lm) Implicit time (ms)
PhNR photopic negative response, logMAR logarithm of the minimum angle of resolution scale, r correlation coefficient
Table 4 Correlations between ERG parameters and the nonperfused area of the retina r
P value
Cone a-wave Amplitude (lm)
-0.12
0.339
0.04
0.733
Amplitude (lm)
-0.19
0.148
Implicit time (ms)
-0.05
0.723
-0.21
0.109
0.12
0.355
-0.16
0.221
0.34
0.007
Implicit time (ms) Cone b-wave
30 Hz flicker Amplitude (lm) Implicit time (ms) PhNR Amplitude (lm) Implicit time (ms)
PhNR photopic negative response, r correlation coefficient
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may explain why data obtained by Ganzfeld stimulation (the cone b-wave, 30 Hz flicker, and PhNR amplitudes) showed a stronger correlation with macular sensitivity within the 4°, 10°, and 20° fields than with BCVA. Interestingly, not only the PhNR amplitude, but also its implicit time, showed a significant correlation with both BCVA and macular sensitivity within the 4°, 10°, and 20°fields. BRVO chiefly damages the inner retina and PhNR has been reported to reflect inner retinal function [3, 15, 16]. In addition, Ogino et al. [6.] reported that the relative PhNR amplitude showed a significant correlation with retinal sensitivity at the center point and within the 4° and 8° fields. Taken together with our results, it seems that PhNR may provide a better indication of inner retinal function in BRVO patients than the other ERG parameters. It has
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been reported that there are no differences of fmERG parameters between ischemic BRVO and nonischemic BRVO, although some ischemic eyes showed such changes of PhNR [6]. Nonperfusion of the inner retina could well cause functional impairment and would have a substantial effect on the PhNR. Retinal ischemia caused by BRVO often occurs outside the vascular arcades and does not alter fmERG parameters, which only reflect the function of the macular region. However, this study revealed that the implicit time of the PhNR obtained by ffERG was significantly correlated with the nonperfused area of the retina. In fact, the correlation between PhNR implicit time and macular sensitivity became stronger from the 20° field to the 4° field (Table 3). Thus, both the amplitude and the implicit time of PhNR may be useful photopic ERG parameters of inner retinal function in BRVO patients. However, this study was limited by the lack of a control group, and various confounding factors might have influenced the ERG responses (including age, sex, cataract grade, and refractive error). Accordingly, the relations among ERG parameters and retinal (functional and morphological) parameters need to be investigated further in BRVO patients with macular edema. We also found that the functional outcome was more closely correlated with the amplitude of ERG parameters than with the implicit time (Table 3). This result may have been obtained because BRVO affects the retina nearer to the central fovea compared with CRVO. Furthermore, the 30 Hz flicker amplitude showed stronger correlations with macular thickness, volume, and sensitivity than the other ERG parameters. Cone density declines rapidly away from the center of the fovea and is an order of magnitude lower even 1 mm from its center [17], and the 30 Hz flicker amplitude/ implicit time alter in accordance with cone density. Thus, it is reasonable that the 30 Hz flicker corresponds more closely to macular thickness, volume, and sensitivity than the other ERG parameters, particularly because lesions tend to be limited to the posterior pole of the retina in BRVO patients. This study also had some other limitations. For example, OPs are another relatively sensitive parameter of retinal vein occlusion, but we did not measure OPs, so the relation of retinal (functional and morphological) parameters to OPs in BRVO patients
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with macular edema will need to be investigated in the future. In conclusion, the amplitude and implicit time of the PhNR were significantly correlated with both BCVA and macular sensitivity within the central 4°, 10°, and 20° fields. Accordingly, PhNR may be a useful parameter for evaluating inner retinal function in patients with BRVO. Acknowledgment Conflict of interest The authors do not have any Conflict of interest in this manuscript.
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