August 2006
Volume 47, Issue 8
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Retina  |   August 2006
Selective Amplitude Reduction of the PhNR after Macular Hole Surgery: Ganglion Cell Damage Related to ICG-Assisted ILM Peeling and Gas Tamponade
Author Affiliations
  • Shinji Ueno
    From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan; and
  • Mineo Kondo
    From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan; and
  • Chang-Hua Piao
    From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan; and
  • Kazuteru Ikenoya
    From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan; and
  • Yozo Miyake
    From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan; and
    National Institute of Sensory Organs, Tokyo, Japan.
  • Hiroko Terasaki
    From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan; and
Investigative Ophthalmology & Visual Science August 2006, Vol.47, 3545-3549. doi:10.1167/iovs.05-1481
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      Shinji Ueno, Mineo Kondo, Chang-Hua Piao, Kazuteru Ikenoya, Yozo Miyake, Hiroko Terasaki; Selective Amplitude Reduction of the PhNR after Macular Hole Surgery: Ganglion Cell Damage Related to ICG-Assisted ILM Peeling and Gas Tamponade. Invest. Ophthalmol. Vis. Sci. 2006;47(8):3545-3549. doi: 10.1167/iovs.05-1481.

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      © 2016 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. The photopic negative response (PhNR) is a negative component of the photopic electroretinogram (ERG) that is observed after the b-wave and is thought to originate mainly from the activity of ganglion cells and their axons. The purpose of this study was to determine whether there are subclinical functional changes in the inner retina after macular hole surgery, by recording the PhNR before and after surgery.

methods. In addition to the routine ophthalmic examinations, photopic ERGs were recorded in 16 eyes with an idiopathic macular hole, before and 3 months after surgery. Photopic ERGs were elicited by white Ganzfeld flashes on a rod-suppressing blue background. The amplitude of the PhNR and the a- and b-waves of the photopic ERGs before and after surgery were compared. PhNRs were also recorded in 14 eyes with epiretinal membrane, before and after surgery.

results. Macular holes were closed and visual acuities were improved without any serious complications in all eyes with a macular hole. The amplitude of the PhNR was significantly reduced after surgery (P < 0.05), whereas the amplitude of the photopic a- and b-waves were not significantly altered. For eyes with an epiretinal membrane, the mean amplitude of the PhNR was slightly decreased after the surgery, but the degree of reduction was only one half of that after macular hole surgery.

conclusions. These results suggest that there are some functional impairments in the inner retina after macular hole surgery, even though the patients did not show any reduction on subjective visual tests. The PhNR can be a useful clinical test to assess the inner retinal function objectively, before and after vitreoretinal surgery.

Vitrectomy has been successfully used to treat idiopathic macular holes. Although macular hole surgery has been generally regarded as a safe procedure, various complications have been reported. One of the most serious is visual field defects in the peripheral retina. 1 2 3 4 5 6 The exact mechanism causing the visual field defects after the surgery is still not completely known, but it has been proposed that the defects are caused by inner retinal damage due to air-infusion stress, 7 8 prolonged gas tamponade, 2 4 or the removal of the posterior hyaloid. 2 3 5  
More recently, another cause of inner retinal damage has been suggested to arise from indocyanine green (ICG), which is used when the internal limiting membrane is removed. 9 10 11 12 13 These reports motivated us to hypothesize that the function of the inner retina may be extensively impaired after macular hole surgery, even though the patients may not report any subjective visual disturbances. 
The photopic negative response (PhNR) is a negative component of the photopic electroretinogram (ERG) that occurs after the b-wave and has recently been found to originate mainly from the activity of ganglion cells and their axons. 14 15 The amplitude of the PhNR is reduced after the action potentials of ganglion cells are blocked by an intravitreal injection of tetradotoxin (TTX) and in monkeys with experimental glaucoma. 14 In clinical studies, the PhNR is selectively reduced in patients with glaucoma and optic nerve diseases. 16 17 18  
We assessed the inner retinal function objectively by recording the PhNR before and after macular hole surgery. The results show that the amplitude of the PhNR was selectively reduced after the macular hole surgery, even though none of the patients showed any reduction on subjective visual tests. 
Material and Methods
Patients
Photopic ERGs were recorded from 22 eyes of 21 consecutive patients who had undergone surgery for an idiopathic macular hole at the Hospital of Nagoya University School of Medicine. After a full explanation of the purpose of the study and procedures to be used, informed consent was obtained from all patients before the surgery and examinations. This research was conducted in accordance with the tenets of the World Medical Association Declaration of Helsinki. 
Because the amplitude of the PhNR is reduced in patients with ocular hypertension and glaucoma, 15 16 one eye that exhibited ocular hypertension (>22 mm Hg) for longer than 4 weeks after surgery; two eyes with temporary hypertension, with intraocular pressure exceeding 30 mm Hg after the surgery; and three eyes with preoperative glaucoma were excluded. Thus, a total of 16 eyes of 15 patients (age, 61.4 ± 6.9 years, mean ± SD) were studied. Patients’ data including the age, gender, stage of macular hole, and visual acuity before and 3 months after surgery are shown in Table 1
To study whether vitrectomy can cause a reduction in the amplitude of the PhNR, the photopic ERGs were also recorded before and 3 months after surgery in 14 eyes of 14 patients who had successful epiretinal membrane removal (mean age, 67.6 ± 6.4 years). 
Surgical Procedures
All surgeries were performed by one surgeon (TH). The surgical procedures for macular hole included a standard three-port vitrectomy with physiologic saline solution (BSS; Alcon Japan Corp., Tokyo, Japan). After a posterior vitreous detachment was created, the internal limiting membrane (ILM) was peeled. To remove the ILMs, 0.25% ICG solution was flushed onto the surface of the retina to make the ILM more visible. The ICG solution was immediately aspirated with the vitreous cutter. After most of the vitreous gel was removed, a fluid-gas exchange was performed, and perfluoropropane (12%) gas was used as a tamponade. 
Phacoemulsification and IOL implantation were performed in 15 eyes to avoid later cataract surgery. Cataract surgery was not performed in one eye (patient 1) because the crystalline lens was clear. 
Surgery for an epiretinal membrane included a standard three-port vitrectomy and membrane peeling with a forceps. Phacoemulsification and IOL implantation were performed in all patients. ICG was not used when the membrane was removed, and gas tamponade was not performed in all 14 eyes. 
Recording of PhNR
The methods of recording photopic ERGs have been described in detail. 19 Briefly, after the patients’ pupils were fully dilated with 0.5% tropicamide and 0.5% phenylephrine hydrochloride, photopic ERGs were recorded in accordance with the guidelines of the International Society of Clinical Electrophysiology of Vision. 20 The ERGs were elicited by full-field (Ganzfeld) stimuli, and recorded with a Burian-Allen bipolar contact lens electrode (Hansen Ophthalmic Development Laboratories, Iowa City, IA). After 10 minutes of light adaptation, ERGs were elicited by white flashes of 1.9 cd-s/m2 (2.0 log phot td-s) on a rod-suppressing blue background of 18 cd/m2 (3.3 log scot td). Four responses were averaged. 
A representative photopic ERG recorded from a normal subject and the methods of measuring each ERG component are shown in Figure 1 . The amplitude of the a-wave was measured from the baseline to the first negative trough. The amplitude of the b-wave was measured from the trough of the a-wave to the maximum positive peak. The amplitude of the PhNR was measured from the baseline to the first negative trough after the b-wave. In several patients, eye movements cause large shifts in the baseline (patients 1 and 6). In such cases, we were not able to measure the amplitude accurately. To minimize the error in such cases, we measured the amplitude from the trough of the wave to the extrapolated baseline. These measurements were made by a coworker who was masked to the purpose of the study. 
Visual Acuity and Visual Field
The visual acuity was measured before and 3 months after surgery, by using a Japanese standard visual acuity charts and converted to the logarithm of the minimum angle of resolution (logMAR) for later statistical analysis. To examine peripheral visual function, we also performed Goldmann perimetry before and 3 months after surgery (stimulus sizes: I2, I3, I4, and V4). 
Statistics Analysis
The data were analyzed with commercial software (Stat View ver. 5; SAS Institute, Cary, NC). The amplitudes before and after surgery were compared with the nonparametric Wilcoxon signed-ranks test. P < 0.05 was considered to be statistically significant. 
Results
All 16 eyes had the macular hole closed after a single surgery. The best-corrected visual acuity increased 3 month after surgery in all eyes (Table 1) . The mean improvement in visual acuity was 0.46 ± 0.16 logMAR units. All eyes were observed for more than 12 months, and none of them showed any fundus changes or any visual field defects, when examined by Goldmann perimetry. In addition, none of the patients reported any visual complaints after the surgery. 
Photopic ERGs
The photopic ERGs, recorded in 16 eyes before and 3 months after surgery, are shown in Figure 2 . Overall, it is clear that the amplitude of the a- and b-waves did not change before and after surgery. Thus, the amplitude of both the photopic a-wave (before surgery, 30.1 ± 5.7 μV; after surgery, 32.4 ± 5.5 μV) and b-wave (before surgery, 89.3 ± 23.1 μV; after surgery, 99.3 ± 21.0 μV) increased after the surgery. However, these increases were not statistically significant (Fig. 3)
In contrast, the amplitudes of the PhNR were reduced after surgery in 13 of 16 eyes and were increased in the other three eyes (Table 1) . The reduction in the PhNR was most clearly visible in eyes 1 to 5 (Fig. 2 , arrowheads). The mean amplitude of the PhNR was reduced by approximately 31% after the surgery (before surgery, 29.3 ± 10.5 μV; after surgery, 20.1 ± 12.5 μV), and the reduction was statistically significant (P = 0.04). 
To investigate whether simple vitrectomy alone can cause a reduction in PhNR, we also recorded photopic ERGs in 14 eyes of 14 patients who underwent vitrectomy with epiretinal membrane removal before and 3 months after surgery. As in patients with macular hole, the mean amplitude of the a- wave (before surgery, 27.1 ± 8.9 μV; after surgery, 27.6 ± 11.1 μV) and the b-wave (before surgery, 67.4 ± 25.5 μV; after surgery, 73.0 ± 26.4 μV) tended to increase slightly after surgery, but these increases were not statistically significant. 
The mean amplitude of the PhNR was reduced by approximately 15% after the surgery (before surgery, 26.6 ± 11.2 μV; after surgery, 22.8 ± 13.8 μV), but this reduction was not statistically significant (P = 0.33). 
Discussion
Our results demonstrated clearly that the amplitude of the PhNR was selectively reduced after macular hole surgery. After the surgery, 13 of 16 patients had a reduction in the amplitude of the PhNR, and three had an increase. The mean PhNR amplitude was reduced by approximately 31% after the surgery, whereas the amplitudes of photopic a- and b-waves were not significantly changed (Figs. 2 3)
It is widely accepted that the photopic ERG a- and b-waves originate mainly from cone photoreceptors and cone on- and off-bipolar cells, whereas the PhNR originates predominantly from the activities of ganglion cells and their axons. Thus, our results suggest that there were some functional changes in the inner retinal layer after macular hole surgery. 
It was interesting that despite a significant reduction in the amplitude of the PhNR after macular hole surgery, none of the patients reported any subjective visual disturbances after surgery. In fact, visual acuities were improved in all patients (Table 1) , and Goldmann perimetry showed no defects or loss of sensitivity of the peripheral visual field after surgery. All patients have now been observed for more than 1 year, and none of the results of these subjective clinical tests have decreased as yet. From these results, we speculated that the functional changes caused by macular hole surgery must be subtle and probably at a subclinical level. This discrepancy was also noted by Viswanathan et al., 15 who reported that the amplitude of the PhNR was reduced in patients with ocular hypertension who had no abnormalities in the results of subjective clinical tests, including visual acuity and visual fields. Taken together, these findings suggest that the PhNR can be a useful objective clinical test to detect early functional changes in patients with damage to the ganglion cells and optic nerve fibers. 
Which procedure during macular hole surgery causes the amplitude reduction of the PhNR? To determine whether vitrectomy alone caused the amplitude reduction of PhNR, we also recorded the PhNR before and after epiretinal membrane surgery, which included only the vitrectomy and epiretinal membrane peeling. Our results showed that the PhNR amplitude was slightly reduced after surgery in these patients, but the degree of reduction was approximately one half that in patients with macular hole. These results indicated that the procedure of simple vitrectomy can affect the function of the inner retina to some degree. The irrigating solution used during the surgery on the inner retinal function may also have contributed to this slight reduction in the PhNR. 
The amplitude reduction of the PhNR was two times larger after macular hole surgery than after epiretinal membrane surgery, suggesting that the functional impairment was more severe in the former than in the latter. However, we cannot specifically state which procedure in the macular hole surgery was the most responsible for such a further reduction of the PhNR, although the fact that the duration of surgery was approximately 25 minutes longer than ERM surgery may have contributed to the reduction of PhNR. Based on recent clinical studies, 7 8 9 10 11 12 13 we suggest that the stress caused by the air tamponade and/or the use of ICG during ILM removal may be the major cause of the further reduction of the PhNR. Hasumura et al. 8 reported that the air-infusion stress results in significant morphologic alternations at the inner retina in rabbits. In contrast, Gandorfer et al. 10 showed that exposure of the ICG-stained ILM to long-wavelength light results in severe damage to the inner retina. Therefore, a comparison of the changes in the PhNR between the surgery with and without ICG may clarify which procedure is more responsible for the reduction in the PhNR. 
In conclusion, this is the first study to demonstrate that there is some functional impairment in the inner retina after macular hole surgery, even though patients did not report any visual disturbances. Thus, we conclude that the PhNR can be a useful clinical test to assess the inner retinal function before and after the vitreoretinal surgery. Further studies are needed to determine which part of the procedure used for macular hole surgery is most responsible for the functional changes in the inner retina. 
 
Table 1.
 
Clinical Characteristics in our Patients with Idiopathic Macular Hole
Table 1.
 
Clinical Characteristics in our Patients with Idiopathic Macular Hole
Case Age Sex Stage of Macular Hole Pre-op. 3 mo Post-op.
Visual Acuity (log MAR) PhNR Amplitude (μV) Visual Acuity (logMAR) PhNR Amplitude (μV)
1 50 F III 1.00 29.6 0.60 1.5
2* 65 M IV 0.52 28.1 0.22 1.5
3 76 F IV 0.52 37.0 0.30 11.8
4* 65 M III 0.30 39.9 0.00 20.7
5 62 M IV 0.70 56.2 0.22 40.0
6 59 M II 1.00 20.7 0.52 5.9
7 59 F II 0.82 25.1 0.22 14.8
8 60 F II 0.89 39.9 0.52 29.6
9 66 F III 1.00 25.1 0.30 16.2
10 52 M II 1.10 29.6 0.52 22.2
11 53 M II 0.70 29.6 0.22 23.6
12 69 F III 0.89 8.8 0.30 7.4
13 61 M III 0.82 28.1 0.40 26.6
14 54 M III 0.40 22.2 0.10 25.2
15 66 F IV 1.00 28.1 0.22 40.0
16 65 F III 0.82 20.7 0.52 34.0
Figure 1.
 
Representative photopic ERG recorded in a normal subject. The measurements of the amplitude of a-wave, b-wave, and PhNR are shown.
Figure 1.
 
Representative photopic ERG recorded in a normal subject. The measurements of the amplitude of a-wave, b-wave, and PhNR are shown.
Figure 2.
 
Photopic ERGs before and 3 months after surgery in 16 eyes with idiopathic macular hole. Dotted line: baseline of the ERG response. Amplitude reductions in the PhNR were especially prominent in patients 1 to 5 (arrowheads).
Figure 2.
 
Photopic ERGs before and 3 months after surgery in 16 eyes with idiopathic macular hole. Dotted line: baseline of the ERG response. Amplitude reductions in the PhNR were especially prominent in patients 1 to 5 (arrowheads).
Figure 3.
 
The mean ± SD of the amplitudes of the a-wave, b-wave, and PhNR of the photopic ERG before and 3 months after surgery for a macular hole (top trace) and epiretinal membrane (bottom trace).
Figure 3.
 
The mean ± SD of the amplitudes of the a-wave, b-wave, and PhNR of the photopic ERG before and 3 months after surgery for a macular hole (top trace) and epiretinal membrane (bottom trace).
MelbergNS, ThomasMA. Visual field loss after pars plana vitrectomy with air/fluid exchange. Am J Ophthalmol. 1995;120:386–388. [CrossRef] [PubMed]
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EzraE, ArdenGB, Riordan-EvaP, AylwardGW, GregorZJ. Visual field loss following vitrectomy for stage 2 and 3 macular holes. Br J Ophthalmol. 1996;80:519–525. [CrossRef] [PubMed]
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HirataA, YonemuraN, HasumuraT, MurataY, NegiA. Effect of infusion air pressure on visual field defects after macular hole surgery. Am J Ophthalmol. 2000;130:611–616. [CrossRef] [PubMed]
HasumuraT, YonemuraN, HirataA, MurataY, NegiA. Retinal damage by air infusion during vitrectomy in rabbit eyes. Invest Ophthalmol Vis Sci. 2000;41:4300–4304. [PubMed]
GandorferA, HaritoglouC, GassCA, UlbigMW, KampikA. Indocyanine green-assisted peeling of the internal limiting membrane may cause retinal damage. Am J Ophthalmol. 2001;132:431–433. [CrossRef] [PubMed]
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AndoF, YasuiO, HiroseH, OhbaN. Optic nerve atrophy after vitrectomy with indocyanine green-assisted internal limiting membrane peeling in diffuse diabetic macular edema: adverse effect of ICG-assisted ILM peeling. Graefes Arch Clin Exp Ophthalmol. 2004;242:995–999. [CrossRef] [PubMed]
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Figure 1.
 
Representative photopic ERG recorded in a normal subject. The measurements of the amplitude of a-wave, b-wave, and PhNR are shown.
Figure 1.
 
Representative photopic ERG recorded in a normal subject. The measurements of the amplitude of a-wave, b-wave, and PhNR are shown.
Figure 2.
 
Photopic ERGs before and 3 months after surgery in 16 eyes with idiopathic macular hole. Dotted line: baseline of the ERG response. Amplitude reductions in the PhNR were especially prominent in patients 1 to 5 (arrowheads).
Figure 2.
 
Photopic ERGs before and 3 months after surgery in 16 eyes with idiopathic macular hole. Dotted line: baseline of the ERG response. Amplitude reductions in the PhNR were especially prominent in patients 1 to 5 (arrowheads).
Figure 3.
 
The mean ± SD of the amplitudes of the a-wave, b-wave, and PhNR of the photopic ERG before and 3 months after surgery for a macular hole (top trace) and epiretinal membrane (bottom trace).
Figure 3.
 
The mean ± SD of the amplitudes of the a-wave, b-wave, and PhNR of the photopic ERG before and 3 months after surgery for a macular hole (top trace) and epiretinal membrane (bottom trace).
Table 1.
 
Clinical Characteristics in our Patients with Idiopathic Macular Hole
Table 1.
 
Clinical Characteristics in our Patients with Idiopathic Macular Hole
Case Age Sex Stage of Macular Hole Pre-op. 3 mo Post-op.
Visual Acuity (log MAR) PhNR Amplitude (μV) Visual Acuity (logMAR) PhNR Amplitude (μV)
1 50 F III 1.00 29.6 0.60 1.5
2* 65 M IV 0.52 28.1 0.22 1.5
3 76 F IV 0.52 37.0 0.30 11.8
4* 65 M III 0.30 39.9 0.00 20.7
5 62 M IV 0.70 56.2 0.22 40.0
6 59 M II 1.00 20.7 0.52 5.9
7 59 F II 0.82 25.1 0.22 14.8
8 60 F II 0.89 39.9 0.52 29.6
9 66 F III 1.00 25.1 0.30 16.2
10 52 M II 1.10 29.6 0.52 22.2
11 53 M II 0.70 29.6 0.22 23.6
12 69 F III 0.89 8.8 0.30 7.4
13 61 M III 0.82 28.1 0.40 26.6
14 54 M III 0.40 22.2 0.10 25.2
15 66 F IV 1.00 28.1 0.22 40.0
16 65 F III 0.82 20.7 0.52 34.0
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