Macular ganglion cell complex thickness after vitrectomy with the inverted flap technique for idiopathic macular holes

Espessura do complexo de células maculares e ganglionares após vitrectomia com técnica de flap invertido para orifício macular idiopático

Diego Valera-Cornejo Marlon García-Roa Paulina Ramírez-Neria Veronica Romero-Morales Renata García-Franco About the authors

ABSTRACT

Purpose:

To analyze the macular ganglion cell-inner plexiform and retinal nerve fiber layer thicknesses after vitrectomy with the inverted flap technique for idiopathic macular holes.

Methods:

A prospective study was conducted on 28 eyes treated with surgery for idiopathic macular holes. The inverted internal limiting membrane flap technique assisted with Brilliant Blue staining (0.05%) was performed. Ophthalmologic examinations and quantitative analysis of the macular ganglion cell complex thickness were performed at baseline,1 and 3 months after surgery.

Results:

The preoperative mean thicknesses of the ganglion cell-inner plexiform layer and ganglion cell-inner plexiform layer + retinal nerve fiber layer were 88.9 and 124.8 µm, respectively. The mean ganglion cell-inner plexiform layer thicknesses at 1 and 3 months after surgery were reduced to 72.8 and 65.2 µm, respectively (p<0.001 and p<0.001, respectively). The mean postoperative ganglion cell-inner plexiform layer + retinal nerve fiber layer thickness was also reduced at 1 and 3 months (108.8 and 99.3 µm, respectively; p<0.001 and p<0.001, respectively). No significant difference was found between the preoperative and postoperative best-corrected visual acuities at 1 and 3 months (p<0.73 and p<0.14, respectively).

Conclusion:

The macular ganglion cell-inner plexiform layer and ganglion cell-inner plexiform layer + retinal nerve fiber layer thicknesses were significantly reduced after vitrectomy with the inverted flap technique assisted with Brilliant Blue staining (0.05%) for idiopathic macular holes.

Keywords:
Retinal ganglion cells; Nerve fiber layer; Retina; Vitrectomy

RESUMO

Objetivo:

Analisar a camada plexiforme interna de células maculares e ganglionares e as espessuras da camada de fibras nervosas da retina após vitrectomia com técnica de flap invertido para orifício macular idiopático.

Métodos:

Estudo prospectivo de 28 olhos submetidos à cirurgia de orifícios ma culares idiopáticos. Foi realizada a técnica de flap invertido da membrana limitante interna usando Azul Brilhante (0,05%). Os exames oftalmológicos e a análise quantitativa da espessura do complexo de células maculares ganglionares foram analisados na linha de base com 1 mês e 3 meses após a cirurgia.

Resultados:

A espessura média pré-operatória da camada plexiforme interna de células ganglionares e da camada plexiforme interna de células ganglionares ± camada de fibra nervosa da retina foi de 88,9 µm e 124,8 µm, respectivamente; a espessura média da camada plexiforme interna de células ganglionares com 1 mês e 3 meses após a cirurgia foi reduzida para 72,8 µm e 65,2 µm (p<0,001 e p<0,001, respectivamente). A espessura média da camada plexiforme interna de células ganglionares pós-operatórias + da camada de fibra nervosa da retina também foi reduzida com 1 e 3 meses (108,8 µm e 99,3 µm; p<0,001 e p<0,001, respectivamente). Nenhuma diferença significativa foi observada entre a acuidade visual melhor corrigida pré e pós-operatória com 1 e 3 meses (p <0, 73 e p<0, 14, respectivamente).

Conclusão:

A camada plexiforme interna de células maculares ganglionares e a camada plexiforme interna de células ganglionares ± as espessuras da camada de fibra nervosa da retina foram significativamente reduzidas após vitrectomia com técnica de flap invertido usando azul brilhante (0,05%) para orifício macular idiopático.

Descritores:
Células ganglionares da retina; Camada de fibras nervosas; Retina; Vitrectomia

INTRODUCTION

Idiopathic macular hole (IMH) is a full-thickness neurosensory retinal defect on the center of the fovea that mostly affects women (67%-91%) between the fifth and seventh decades of life and is bilateral in approximately 3%-27% of cases(11 Brooks HL Jr. Macular hole surgery with and without internal limiting membrane peeling. Ophthalmology. 2000;107(10):1939-48.). Vitrectomy associated with peeling of the internal limiting membrane (ILM) is the most widely used surgical procedure for the management of IMH owing to its higher success rates of 80-90%(11 Brooks HL Jr. Macular hole surgery with and without internal limiting membrane peeling. Ophthalmology. 2000;107(10):1939-48.,22 Ando F, Sasano K, Ohba N, Hirose H, Yasui O. Anatomic and visual outcomes after indocyanine green-assisted peeling of the retinal internal limiting membrane in idiopathic macular hole surgery. Am J Ophthalmol. 2004;137(4):609-14.). Triamcinolone acetonide (TA), indocyanine green (ICG), and Brilliant Blue G (BBG) are the vital dyes used to assist in the ILM peeling(33 Enaida H, Hisatomi T, Hata Y, Ueno A, Goto Y, Yamada T, et al. Brilliant blue G selectively stains the internal limiting membrane/brilliant blue G-assisted membrane peeling. Retina. 2006;26(6):631-6.,44 Shah GK, Rosenblatt BJ, Blinder KJ, Grand MG, Smith M. Triamcinolone-assisted internal limiting membrane peeling. Retina. 2005;25(8):972-5.). However, functional and histological damages have been reported after the procedure when assisted with ICG staining(22 Ando F, Sasano K, Ohba N, Hirose H, Yasui O. Anatomic and visual outcomes after indocyanine green-assisted peeling of the retinal internal limiting membrane in idiopathic macular hole surgery. Am J Ophthalmol. 2004;137(4):609-14.,55 Gandorfer A, Haritoglou C, Gass CA, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane may cause retinal damage. Am J Ophthalmol. 2001;132(3):431-3.,66 Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: A clinicopathologic correlation. Am J Ophthalmol. 2002;134(6):836-41.), and some dyes such as BBG and TA appear to be safer for the retina(77 Ejstrup R, la Cour M, Heegaard S, Kiilgaard JF. Toxicity profiles of subretinal indocyanine green, Brilliant Blue G, and triamcinolone acetonide: A comparative study. Graefes Arch Clin Exp Ophthalmol. 2012;250(5):669-77.). Losses of nerve fibers and ganglion cells after ILM peeling have also been reported as a result of toxicity related to the staining substance, direct mechanical injury, or increased intraocular pressure during vitrectomy(88 Tosi GM, Martone G, Balestrazzi A, Malandrini A, Alegente M, Pichierri P. Visual field loss progression after macular hole surgery. J Ophthalmol. 2009;2009:617891.). The peeling itself induces retinal changes on the inner surface of the retina, with minor changes on the thickness of the retinal nerve fiber layer (RNFL)(99 Capelanes NC, Diniz AV, Magalhães ÉP, Marques KO. Comparisons of retinal nerve fiber layer thickness changes after macular hole surgery. Arq Bras Oftalmol. 2018;81(1):37-41.). Some controversy exists about the effect of ILM peeling and the use of vital dyes on the retinal ganglion cell complex (GCC)(1010 Baba T, Sato E, Oshitari T, Yamamoto S. Regional reduction of ganglion cell complex after vitrectomy with internal limiting membrane peeling for idiopathic macular hole. J Ophthalmol. 2014;2014:372589.

11 Sabater AL, Velázquez-Villoria Á, Zapata MA, Figueroa MS, Suárez-Leoz M, Arrevola L, et al. Evaluation of macular retinal ganglion cell-inner plexiform layer thickness after vitrectomy with internal limiting membrane peeling for idiopathic macular holes. BioMed Res Int. 2014;2014:458631.

12 Sevim MS, Sanisoglu H. Analysis of retinal ganglion cell complex thickness after Brilliant Blue-assisted vitrectomy for idiopathic macular holes. Curr Eye Res. 2013;38(1):180-4.
-1313 Demirel S, Abdullayev A, Yanik Ö, Batioglu F, Özmert E. Evaluation of ganglion cell-inner plexiform layer thickness after vitreoretinal surgery with internal limiting membrane peeling in cases with idiopathic macular hole. Turk J Ophthalmol. 2017;47(3):138-43.). Peeling of the ILM may produce microscotomas and reduce retinal sensitivity(1414 Tadayoni R, Svorenova I, Erginay A, Gaudric A, Massin P. Decreased retinal sensitivity after internal limiting membrane peeling for macular hole surgery. Br J Ophthalmol. 2012;96(12):1513-6.,1515 Haritoglou C, Ehrt O, Gass CA, Kristin N, Kampik A. Paracentral scotomata: a new finding after vitrectomy for idiopathic macular hole. Br J Ophthalmol. 2001;85(2):231-3.).

The innermost layers are the RNFL, ganglion cells (GC), and inner plexiform layer (IPL). These three layers correspond to the cell bodies, axons, and dendrites of GC, which in combination form the well-known ganglion cell complex. This complex serves as an early indicator of retinal damage due to the fact that these cells respond very early to ischemic changes(1616 Sellés-Navarro I, Villegas-Pérez MP, Salvador-Silva M, Ruiz-Gómez JM, Vidal-Sanz M. Retinal ganglion cell death after different transient periods of pressure-induced ischemia and survival intervals. A quantitative in vivo study. Invest Ophthalmol Vis Sci. 1996;37(10):2002-14.). However, not much research has been conducted regarding the effect of these dyes during the peeling of the ILM on the GCC, and different outcomes have been reported(1010 Baba T, Sato E, Oshitari T, Yamamoto S. Regional reduction of ganglion cell complex after vitrectomy with internal limiting membrane peeling for idiopathic macular hole. J Ophthalmol. 2014;2014:372589.,1212 Sevim MS, Sanisoglu H. Analysis of retinal ganglion cell complex thickness after Brilliant Blue-assisted vitrectomy for idiopathic macular holes. Curr Eye Res. 2013;38(1):180-4.). The recently available spectral-domain optical coherence tomography (SD-OCT) technology and algorithms provide better stratification and measurement of the GCC. The purpose of this report was to analyze the changes in the thickness of the macular GCC after macular hole surgery with the inverted flap technique.

METHODS

Study design

This study included a prospective case series of 28 eyes (28 patients) with IMH. All the eyes were treated with pars plana vitrectomy and ILM peeling with the inverted flap technique assisted with BBG staining. The Mexican Institute of Ophthalmology ethics committee approved the study. Patients from November 2018 through August 2019 were enrolled. Written informed consent was obtained from all the patients before enrollment in the study.

Eligibility and exclusion criteria

We included patients (1) older than 18 years of age who had (2) an idiopathic full-thickness macular hole, defined as a full-thickness neurosensory retinal defect on the center of the fovea, detected on spectral-domain optical coherence tomography (SD-OCT; SD-OCT Revo NX, Optopol Technology SA, Zawiercie, Poland) and (3) no macular disease, including macular hole in the contralateral eye. Patients with a lamellar macular hole, an axial length >26 mm, a spherical equivalent exceeding -6 diopters, or a myopic macular hole were excluded. Those with histories of diabetic retinopathy, retinal neovascularization, trauma, inflammatory disease, vascular occlusion, or conditions (cataract or corneal opacities) that could interfere with the OCT measurement (signal strength <6) or visual acuity were also excluded.

Subjects, follow-up, and optical coherence tomography analysis

The baseline examination included an evaluation of the best-corrected visual acuity (BCVA) using a Snellen chart (converted to logarithm of the minimal angle of resolution [logMAR] for analysis), slit-lamp evaluation, intraocular pressure measurement using a rebound tonometer (ICare, Tiolat AB, Helsinki, Finland), fundus examination, and tomographic analysis. The evaluations were performed at baseline, 1 and 3 months after the surgery.

Previous pupil dilation with 0.8% tropicamide/5% phenylephrine (T-P Ofteno, Sophia Laboratories, Guadalajara, Mexico), the tomographic evaluation was performed using a three-dimensional protocol scan from the SD-OCT Revo NX. At baseline, the minimum diameter (minimal extent of the hole), base diameter (measured at the level of the RPE), height, hole form factor (HFF)(1717 Uemoto R, Yamamoto S, Aoki T, Tsukahara I, Yamamoto T, Takeuchi S. Macular configuration determined by optical coherence tomography after idiopathic macular hole surgery with or without internal limiting membrane peeling. Br J Ophthalmol. 2002; 86(11):1240-2.,1818 Hoerauf H. Predictive values in macular hole repair. Br J Ophthalmol. 2007;91(11):1415-6.), macular hole index (MHI)(1919 Kusuhara S, Teraoka Escaño MF, Fujii S, Nakanishi Y, Tamura Y, Nagai A, et al. Prediction of postoperative visual outcome based on hole configuration by optical coherence tomography in eyes with idiopathic macular holes. Am J Ophthalmol. 2004;138(5):709-16.) and tractional hole index (THI)(2020 Ruiz-Moreno JM, Staicu C, Piñero DP, Montero J, Lugo F, Amat P. Optical coherence tomography predictive factors for macular hole surgery outcome. Br J Ophthalmol. 2008;92(5):640-4.) of the IMH were manually measured. The macular holes were classified according to the classification proposed by the International Vitreomacular Traction Study based on the minimum diameter as follows: large (>400 µm), medium (250-400 µm), or small (<250 µm)(2121 Duker JS, Kaiser PK, Binder S, de Smet MD, Gaudric A, Reichel E, et al. The international vitreomacular traction study group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. 2013;120(12):2611-9.). MHI was defined as the ratio of the hole height to the base diameter. THI was defined as the ratio of the maximal height to the minimum diameter, and HFF was calculated as the quotient of the sum of the right and left arm lengths divided by the basal diameter of the hole.

The GCC was measured using the ganglion cell analysis protocol, which is used to determine the boundaries of the RNFL and IPL and automatedly calculates the sum of the ganglion cell-inner plexiform layer (GCIPL) and/or RNFL thicknesses. The segmentation software uses an automated algorithm to evaluate the GCC (GCIPL or RNFL + GCIPL) thickness. The complex is measured with two elliptical circles (the inner oval with horizontal and vertical diameters of 1.2 and 1.0 mm, respectively, and the outer oval with vertical and horizontal diameters of 4.0 and 4.8 mm, respectively) centered on the fovea. The mean and sectoral thicknesses (superotemporal, superonasal, superior inferonasal, inferotemporal, and inferior) were evaluated. The SD-OCT Revo NX ganglion cell analysis software does not allow a complete manual macular segmentation but allows relocation of the area to be analyzed. The SD-OCT ganglion cell analysis was performed at baseline and 1 and 3 months after vitrectomy. The macular closure type at 3 months was classified into two groups, type 1 (the hole closed without defect of the neurosensory retina at the fovea) and type 2 (the foveal defect persists but the rim of the hole is attached to the retinal pigment epithelium, and the cuff is flat)(2222 Kang SW, Ahn K, Ham DI. Types of macular hole closure and their clinical implications. Br J Ophthalmol. 2003;87(8):1015-9.).

Outcome measures

The primary end point was the mean change from the baseline GCC (GCIPL and RNFL + GCIPL) thickness at 3 months. The secondary outcome measures included the mean change in the baseline BCVA logMAR score over time to 3 months, and the proportion and types of anatomical closure. A correlation analysis between the baseline anatomic parameters and visual acuity was performed. Associations between the type of macular hole closure and preoperative tomographic prognostic factors were also evaluated.

Surgical procedure

A standard 25-gage 3-port pars plana vitrectomy was performed with the Constellation Vision System (Alcon, Fort Worth, Texas, US) in all the patients. Surgeries were performed by different vitreoretinal surgeons from the retina department of the institute. In eyes with cataract, the lens was removed by phacoemulsification, followed by intraocular lens implantation before vitreoretinal surgery. Core vitrectomy was performed, and the posterior vitreous was detached. Active suction with the probe was used to separate the posterior hyaloid; detachment of the posterior vitreous was not assisted with TA. With the infusion closed using a soft-tipped cannula attached to an insulin syringe, 0.1-ml BBG (0.05% BBG, Aurolab, Madurai, India) was injected in the vitreous cavity. Infusion was reopened after 30 seconds, and the dye was aspirated. The ILM was grasped at the temporal quadrant and peeled off with the ILM forceps (Alcon Grieshaber-Switzerland/Alcon Labs, Inc., Fort Worth, TX), covering an area of 2 disc diameters around the hole. Once peeled, it was not completely removed but was left attached at the edges of the hole, so small remnants of the ILM remain around it. Then, the ILM was manipulated over the hole from all sides until it became inverted (flap technique). Fluid/air exchange was performed (air pressure at 30 mmHg), and 20% sulfur hexafluoride (SF6) or 18% hexafluoroethane (C2F6) gas was used as a postoperative tamponade. The choice of gas was made according to surgeon preference. Sclerotomies were closed with a single 7-0 Vicryl suture if leakage was observed. Patients were asked to stay with a face-down position for at least 3 days (at least 16 hours a day). OCT examinations were performed after the gas bubble had completely dispersed from the vitreous cavity, which was 4 weeks for C2F6 and 2 weeks for SF6.

Statistical analysis

Descriptive statistics were performed, reporting the variables with summary measures of central tendency and dispersion for quantitative variables and absolute and relative frequencies for qualitative variables. The normality of the quantitative variables was evaluated using the Shapiro-Wilk test, with a significance level of 0.05. Regarding inferential statistics, Student T tests and Pearson correlation were used, with a significance level of 0.05 using the Stata statistical package version 15.1 (StataCorp. 2015, Stata Statistical Software: Release 15. College Station, Texas, US: StataCorp LP).

RESULTS

Twenty-eight eyes of 28 patients who underwent pars plana vitrectomy with BBG-assisted ILM peeling and the inverted flap technique for idiopathic macular holes in the retina service of the Mexican Institute of Ophthalmology were included. Twenty-four patients (85.7%) were female, with a mean age of 67.6 ± 5.2 years (57-79 years) and mean visual loss time of 10.4 ± 7.1 months (0-24 months). Baseline demographic and clinical characteristics are described in Table 1. Phacoemulsification with intraocular lens implantation combined with vitreoretinal surgery was performed in all the eyes. Twenty percent sulfur hexafluoride (SF6) was used as a postoperative tamponade in 93% of the eyes. The GCIPL thickness was significantly reduced from 88.9 ± 10.4 µm to 72.8 ± 8.3 µm after 1 month and to 65.2 ±10.4 µm at 3 months after surgery (p<0.001 and p<0.001, respectively). The GCIPL+ RNFL thickness was also significantly reduced from 124.8 ± 13.4 µm to 108.8 ± 9.9 µm after 1 month and to 99.3 ± 14.2 µm at 3 months after the procedure (p<0.001 and p<0.001, respectively; Figure 1).

Table 1
Baseline demographic and clinical characteristics (n=28)

Figure 1.
Ganglion cell complex thickness change at 1 and 3 months after surgery.

The mean BCVA changed from 1.2 ± 0.27 logMAR units at baseline to 1.2 ± 0.30 at 1 month and 1.1 ± 0.33 logMAR units at 3 months. No statistically significant changes were observed at 1 month (p=0.73) or 3 months (p=0.14) after the surgical procedure (Figure 2). The primary anatomical success rate was 92%, as two eyes required a second surgery due to failure of macular hole closure. The final anatomical success rate was 100%. Of the different indexes and parameters, the HFF presented a statistically significant moderate correlation (p<0.05) with type 1 closure (Table 2).

Table 2
Correlations of the different indexes and parameters with visual acuity and type 1 closure at 3 months (n=28)

Figure 2.
Best-corrected visual acuity change at 1 and 3 months after surgery.

DISCUSSION

The inverted flap technique is considered effective and is used to enhance the anatomical closure rate of complicated cases (large or myopic macular holes), similar to those shown in our report, as almost all cases were large macular holes(2323 Michalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology. 2010;117(10):2018-25.). Whether anatomical and functional changes after ILM peeling for the management of macular holes are associated with the use of vital dyes or due to the micro traumas produced during ILM peeling is not well established.

We found that the reduction of the mean GCC (GCIPL and GCIPL + RNFL) thickness was evident 3 months after surgery, and several authors (described in Table 3) reported the same reduction in GCIPL and RNFL thicknesses in patients who underwent ILM peeling (assisted with Brilliant Blue staining) at 3 and 6 months(1010 Baba T, Sato E, Oshitari T, Yamamoto S. Regional reduction of ganglion cell complex after vitrectomy with internal limiting membrane peeling for idiopathic macular hole. J Ophthalmol. 2014;2014:372589.,1111 Sabater AL, Velázquez-Villoria Á, Zapata MA, Figueroa MS, Suárez-Leoz M, Arrevola L, et al. Evaluation of macular retinal ganglion cell-inner plexiform layer thickness after vitrectomy with internal limiting membrane peeling for idiopathic macular holes. BioMed Res Int. 2014;2014:458631.,1313 Demirel S, Abdullayev A, Yanik Ö, Batioglu F, Özmert E. Evaluation of ganglion cell-inner plexiform layer thickness after vitreoretinal surgery with internal limiting membrane peeling in cases with idiopathic macular hole. Turk J Ophthalmol. 2017;47(3):138-43.,2424 Hashimoto Y, Saito W, Fujiya A, Yoshizawa C, Hirooka K, Mori S, et al. Changes in inner and outer retinal layer thicknesses after vitrectomy for idiopathic macular hole: implications for visual prognosis. PLoS One. 2015;10(8):e0135925.

25 Ambiya V, Goud A, Khodani M, Chhablani J. Inner retinal thinning after Brilliant Blue G-assisted internal limiting membrane peeling for vitreoretinal interface disorders. Int Ophthalmol. 2017;37(2):401-8.

26 Seo KH, Yu SY, Kwak HW. Topographic changes in macular ganglion cell-inner plexiform layer thickness after vitrectomy with indocyanine green-guided internal limiting membrane peeling for idiopathic macular hole. Retina. 2015;35(9):1828-35.
-2727 Baba T, Yamamoto S, Kimoto R, Oshitari T, Sato E. Reduction of thickness of ganglion cell complex after internal limiting membrane peeling during vitrectomy for idiopathic macular hole. Eye (Lond). 2012;26(9):1173-80.). However, Sevim et al. reported no significant reduction in the mean GCIPL thickness after BBG-assisted ILM peeling(1212 Sevim MS, Sanisoglu H. Analysis of retinal ganglion cell complex thickness after Brilliant Blue-assisted vitrectomy for idiopathic macular holes. Curr Eye Res. 2013;38(1):180-4.). Others studies used ICG stain as a vital dye and reported a significant thinning of the RNFL(2828 Yamashita T, Uemura A, Kita H, Sakamoto T. Analysis of the retinal nerve fiber layer after indocyanine green-assisted vitrectomy for idiopathic macular holes. Ophthalmology. 2006;113(2):280-4.). Baba et al. compared the BBG and ICG stains and showed a significant reduction of the GCC at 6 months, but the retinal sensitivity and visual acuity were better in the patients in whom BBG staining was used during the vitrectomy(2929 Baba T, Hagiwara A, Sato E, Arai M, Oshitari T, Yamamoto S. Comparison of vitrectomy with brilliant blue G or indocyanine green on retinal microstructure and function of eyes with macular hole. Ophthalmology. 2012;119(12):2609-15.). Some studies found a significant thinning of the temporal retina only in the eyes with ILM peeling(2929 Baba T, Hagiwara A, Sato E, Arai M, Oshitari T, Yamamoto S. Comparison of vitrectomy with brilliant blue G or indocyanine green on retinal microstructure and function of eyes with macular hole. Ophthalmology. 2012;119(12):2609-15.,3030 Ohta K, Sato A, Senda N, Fukui E. Comparisons of foveal thickness and slope after macular hole surgery with and without internal limiting membrane peeling. Clin Ophthalmol. 2018;12:503-10.). The mechanisms by which the GCC became progressively thinner after IMH surgery with ILM peeling are unclear. Our study did not determine whether the ILM peeling is directly responsible for the reduction of the thickness of the GCC because we did not include a non-ILM-peeling group. However, we believe that the direct mechanical damage to the ILM during the peeling rather than the cytotoxicity of the dye may have played a greater role in the GCC thinning postoperatively. The ILM is the basement membrane of the Müller cells, and the damage that occurs to these cells after ILM peeling has been electroretinographically and histologically demonstrated(3131 Wolf S, Schnurbusch U, Wiedemann P, Grosche J, Reichenbach A, Wolburg H. Peeling of the basal membrane in the human retina: Ultrastructural effects. Ophthalmology. 2004;111(2):238-43.,3232 Nakamura T, Murata T, Hisatomi T, Enaida H, Sassa Y, Ueno A, et al. Ultrastructure of the vitreoretinal interface following the removal of the internal limiting membrane using indocyanine green. Curr Eye Res. 2003;27(6):395-9.). After the ILM peeling, retinal fragments can be observed on the retinal surface, regardless of the use BBG or ICG; this may lead us to believe that the mechanical traction from the pulling of the Müller cells during the peeling can be transmitted to the inner retina, damaging the entire region(3333 Konstantinidis L, Uffer S, Bovey EH. Ultrastructural changes of the internal limiting membrane removed during indocyanine green assisted peeling versus conventional surgery for idiopathic macular epiretinal membrane. Retina. 2009;29(3):380-6.). ILM peeling is also associated with microscotomas and reduced retinal sensitivity(1414 Tadayoni R, Svorenova I, Erginay A, Gaudric A, Massin P. Decreased retinal sensitivity after internal limiting membrane peeling for macular hole surgery. Br J Ophthalmol. 2012;96(12):1513-6.,1515 Haritoglou C, Ehrt O, Gass CA, Kristin N, Kampik A. Paracentral scotomata: a new finding after vitrectomy for idiopathic macular hole. Br J Ophthalmol. 2001;85(2):231-3.,3434 Gelman R, Stevenson W, Prospero Ponce C, Agarwal D, Christoforidis JB. Retinal damage induced by internal limiting membrane removal. J Ophthalmol. 2015; 2015: 939748.). ILM peeling has been associated with dissociated optic nerve fiber layer (DONFL), which is seen in blue filter photography as a hatched retina with striae along the optic nerve fibers; these are dimples in the inner layers that are visible on OCT(1414 Tadayoni R, Svorenova I, Erginay A, Gaudric A, Massin P. Decreased retinal sensitivity after internal limiting membrane peeling for macular hole surgery. Br J Ophthalmol. 2012;96(12):1513-6.,3535 Ito Y, Terasaki H, Takahashi A, Yamakoshi T, Kondo M, Nakamura M. Dissociated optic nerve fiber layer appearance after internal limiting membrane peeling for idiopathic macular holes. Ophthalmology. 2005;112(8):1415-20.,3636 Michalewska Z, Michalewski J, Nawrocki J. Continuous changes in macular morphology after macular hole closure visualized with spectral optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2010;248(9):1249-55.). The idea of minimizing the iatrogenic trauma associated with ILM peeling can be achieved by decreasing the area to be peeled, which is reported by Michalewska et al. as a temporal ILM flap. With this technique, the risk of surgical trauma in the area of the papillomacular bundle is reduced, and unnecessary trauma to the RNFL is minimized; in addition, patients with a temporal ILM flap have a lower incidence of DONFL(3737 Michalewska Z, Michalewski J, Dulczewska-Cichecka K, Adelman RA, Nawrocki J. Temporal inverted internal limiting membrane flap technique versus classic inverted internal limiting membrane flap technique: A comparative study. Retina. 2015;35(9):1844-50.). However, DONFL has not been consistently associated with reduced visual acuity or microperimetric changes, and DONFL may reflect the healing process of the weakened retinal structure after the peeling(3535 Ito Y, Terasaki H, Takahashi A, Yamakoshi T, Kondo M, Nakamura M. Dissociated optic nerve fiber layer appearance after internal limiting membrane peeling for idiopathic macular holes. Ophthalmology. 2005;112(8):1415-20.,3737 Michalewska Z, Michalewski J, Dulczewska-Cichecka K, Adelman RA, Nawrocki J. Temporal inverted internal limiting membrane flap technique versus classic inverted internal limiting membrane flap technique: A comparative study. Retina. 2015;35(9):1844-50.). Multiple dark dots over the RNFL were observed when the appearance of the DONFL was examined using en face SD-OCT and named “concentric macular dark spots” (CMDS)(3838 Alkabes M, Salinas C, Vitale L, Burés-Jelstrup A, Nucci P, Mateo C. En face optical coherence tomography of inner retinal defects after internal limiting membrane peeling for idiopathic macular hole. Invest Ophthalmol Vis Sci. 2011;52(11):8349-55.). Sabry et al. observed that after ILM peeling, two patterns of inner retinal layers changes occurred, CMDS with intact GCIPL and CMDS with localized defects in GCIPL; the latter was associated with a thinning of the GCIPL thickness at 6 months after surgery(3939 Sabry D, El-Kannishy A, Kamel R, Abou Samra W. Correlation between en face optical coherence tomography defects of the inner retinal layers and ganglion cell inner plexiform layer analysis after internal limiting membrane peeling for idiopathic full-thickness macular hole. Invest Ophthalmol Vis Sci. 2016 01;57(9):444-50.). The authors suggested that even with a successful anatomical closure, inner retinal defects may play a role in the reduced postoperative visual acuity gain(3939 Sabry D, El-Kannishy A, Kamel R, Abou Samra W. Correlation between en face optical coherence tomography defects of the inner retinal layers and ganglion cell inner plexiform layer analysis after internal limiting membrane peeling for idiopathic full-thickness macular hole. Invest Ophthalmol Vis Sci. 2016 01;57(9):444-50.).

Table 3
Reports evaluating the topographical changes of GCIPL thickness after macular hole surgery with ILM peeling

Brilliant Blue stain was used in all of our surgeries. Despite that some vital dyes have been reported to be toxic to retinal cells, we believe that the influence of the dye used is minimal. In addition, the BBG stain has been reported to have a protective effect on retinal cells and better anatomical and functional outcomes after macular hole surgery than ICG (2929 Baba T, Hagiwara A, Sato E, Arai M, Oshitari T, Yamamoto S. Comparison of vitrectomy with brilliant blue G or indocyanine green on retinal microstructure and function of eyes with macular hole. Ophthalmology. 2012;119(12):2609-15.,4040 Notomi S, Hisatomi T, Kanemaru T, Takeda A, Ikeda Y, Enaida H, et al. Critical involvement of extracellular ATP acting on P2RX7 purinergic receptors in photoreceptor cell death. Am J Pathol. 2011;179(6):2798-809.). ICG was reported to be toxic to the retinal GC in in vitro studies(4141 Iriyama A, Uchida S, Yanagi Y, Tamaki Y, Inoue Y, Matsuura K, et al. Effects of indocyanine green on retinal ganglion cells. Invest Ophthalmol Vis Sci. 2004;45(3):943-7.) and could also remain in the vitreous cavity for 3 months after the procedure(1414 Tadayoni R, Svorenova I, Erginay A, Gaudric A, Massin P. Decreased retinal sensitivity after internal limiting membrane peeling for macular hole surgery. Br J Ophthalmol. 2012;96(12):1513-6.,4242 Ciardella AP, Schiff W, Barile G, Vidne O, Sparrow J, Langton K, et al. Persistent indocyanine green fluorescence after vitrectomy for macular hole. Am J Ophthalmol. 2003;136(1):174-7.). However, its toxicity during surgery is not clinically significant, and no clinical evidence supports its superiority over other dyes. Moreover, ICG was not used in our study(4343 Wu Y, Zhu W, Xu D, Li YH, Ba J, Zhang XL, et al. Indocyanine green-assisted internal limiting membrane peeling in macular hole surgery: a meta-analysis. PLoS One. 2012;7(11):e48405.).

The mean visual acuities at 1 and 3 months after surgery (logMAR 1.2 ± 0.30 and 1.1 ± 0.33, respectively) were unchanged and did not improve, which may be related to other factors rather than the GCC thinning because most eyes did not have good baseline predictive factors and had large macular holes, with long visual loss time and poor anatomical indexes (Table 1). The automatic segmentation performed by the ganglion analysis software of the SD-OCT Revo NX may be altered in eyes where the morphology is distorted by the macular hole (Figure 3). These measurement problems may be the reason for the higher baseline thickness reported and greater initial differences in the mean GCIPL and GCIPL + RNFL thicknesses in our study. A real manual segmentation may be useful for the measurement needed for these analyses.

Figure 3.
Best-corrected visual acuity change at 1 and 3 months after surgery.

Significant correlations between several OCT indexes (MHI, THI, and HFF) and postoperative BCVA have been reported in other studies(1919 Kusuhara S, Teraoka Escaño MF, Fujii S, Nakanishi Y, Tamura Y, Nagai A, et al. Prediction of postoperative visual outcome based on hole configuration by optical coherence tomography in eyes with idiopathic macular holes. Am J Ophthalmol. 2004;138(5):709-16.,2020 Ruiz-Moreno JM, Staicu C, Piñero DP, Montero J, Lugo F, Amat P. Optical coherence tomography predictive factors for macular hole surgery outcome. Br J Ophthalmol. 2008;92(5):640-4.,4444 Wakely L, Rahman R, Stephenson J. A comparison of several methods of macular hole measurement using optical coherence tomography, and their value in predicting anatomical and visual outcomes. Br J Ophthalmol. 2012;96(7):1003-7.). Our study shows a trend similar to the aforementioned results, but it was not significant (Table 2). Contrary to our outcomes, those in other studies showed a strong correlation between MHI and postoperative BCVA as compared with other indexes(1919 Kusuhara S, Teraoka Escaño MF, Fujii S, Nakanishi Y, Tamura Y, Nagai A, et al. Prediction of postoperative visual outcome based on hole configuration by optical coherence tomography in eyes with idiopathic macular holes. Am J Ophthalmol. 2004;138(5):709-16.,4444 Wakely L, Rahman R, Stephenson J. A comparison of several methods of macular hole measurement using optical coherence tomography, and their value in predicting anatomical and visual outcomes. Br J Ophthalmol. 2012;96(7):1003-7.,4545 Chhablani J, Khodani M, Hussein A, Bondalapati S, Rao HB, Narayanan R, et al. Role of macular hole angle in macular hole closure. Br J Ophthalmol. 2015;99(12):1634-8.). Among several OCT indexes, we found a significant correlation between HFF (p=0.03) and closure type 1. However, other reports found that MHI strongly correlated with type 1 closure(4545 Chhablani J, Khodani M, Hussein A, Bondalapati S, Rao HB, Narayanan R, et al. Role of macular hole angle in macular hole closure. Br J Ophthalmol. 2015;99(12):1634-8.). Determining the associations of several MH indexes with postoperative BCVA and closure type were not the primary objective of our study, and the small sample size could also explain this difference. The observation period was short (3 months), and the entire retinal thickness was reported to continue to diminish up to 24 months(4646 Kumagai K, Hangai M, Larson E, Ogino N. Progressive changes of regional macular thickness after macular hole surgery with internal limiting membrane peeling. Invest Ophthalmol Vis Sci. 2013;54(7):4491-7.). Even so, we report a significant reduction in GCC thickness in this short period, and longer follow-up periods are needed. Finally, the limitations of this study include its small sample size and design, the lack of a control group, and the short follow-up period.

In conclusion, the GCIPL and GCIPL + RNFL thicknesses are progressively decreased when the BBG-assisted ILM inverted flap technique is performed during vitrectomy for IMH treatment. Further research to understand the mechanisms related to the inner retinal damage during this procedure is necessary.

ACKNOWLEDGMENTS

We gratefully thank the patients for participation in this study.

  • Approved by the following research ethics committee: Instituto Mexicano de Oftalmología (CEI/011-2/2019).
  • Funding: This study received no specific financial support.

REFERENCES

  • 1
    Brooks HL Jr. Macular hole surgery with and without internal limiting membrane peeling. Ophthalmology. 2000;107(10):1939-48.
  • 2
    Ando F, Sasano K, Ohba N, Hirose H, Yasui O. Anatomic and visual outcomes after indocyanine green-assisted peeling of the retinal internal limiting membrane in idiopathic macular hole surgery. Am J Ophthalmol. 2004;137(4):609-14.
  • 3
    Enaida H, Hisatomi T, Hata Y, Ueno A, Goto Y, Yamada T, et al. Brilliant blue G selectively stains the internal limiting membrane/brilliant blue G-assisted membrane peeling. Retina. 2006;26(6):631-6.
  • 4
    Shah GK, Rosenblatt BJ, Blinder KJ, Grand MG, Smith M. Triamcinolone-assisted internal limiting membrane peeling. Retina. 2005;25(8):972-5.
  • 5
    Gandorfer A, Haritoglou C, Gass CA, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane may cause retinal damage. Am J Ophthalmol. 2001;132(3):431-3.
  • 6
    Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: A clinicopathologic correlation. Am J Ophthalmol. 2002;134(6):836-41.
  • 7
    Ejstrup R, la Cour M, Heegaard S, Kiilgaard JF. Toxicity profiles of subretinal indocyanine green, Brilliant Blue G, and triamcinolone acetonide: A comparative study. Graefes Arch Clin Exp Ophthalmol. 2012;250(5):669-77.
  • 8
    Tosi GM, Martone G, Balestrazzi A, Malandrini A, Alegente M, Pichierri P. Visual field loss progression after macular hole surgery. J Ophthalmol. 2009;2009:617891.
  • 9
    Capelanes NC, Diniz AV, Magalhães ÉP, Marques KO. Comparisons of retinal nerve fiber layer thickness changes after macular hole surgery. Arq Bras Oftalmol. 2018;81(1):37-41.
  • 10
    Baba T, Sato E, Oshitari T, Yamamoto S. Regional reduction of ganglion cell complex after vitrectomy with internal limiting membrane peeling for idiopathic macular hole. J Ophthalmol. 2014;2014:372589.
  • 11
    Sabater AL, Velázquez-Villoria Á, Zapata MA, Figueroa MS, Suárez-Leoz M, Arrevola L, et al. Evaluation of macular retinal ganglion cell-inner plexiform layer thickness after vitrectomy with internal limiting membrane peeling for idiopathic macular holes. BioMed Res Int. 2014;2014:458631.
  • 12
    Sevim MS, Sanisoglu H. Analysis of retinal ganglion cell complex thickness after Brilliant Blue-assisted vitrectomy for idiopathic macular holes. Curr Eye Res. 2013;38(1):180-4.
  • 13
    Demirel S, Abdullayev A, Yanik Ö, Batioglu F, Özmert E. Evaluation of ganglion cell-inner plexiform layer thickness after vitreoretinal surgery with internal limiting membrane peeling in cases with idiopathic macular hole. Turk J Ophthalmol. 2017;47(3):138-43.
  • 14
    Tadayoni R, Svorenova I, Erginay A, Gaudric A, Massin P. Decreased retinal sensitivity after internal limiting membrane peeling for macular hole surgery. Br J Ophthalmol. 2012;96(12):1513-6.
  • 15
    Haritoglou C, Ehrt O, Gass CA, Kristin N, Kampik A. Paracentral scotomata: a new finding after vitrectomy for idiopathic macular hole. Br J Ophthalmol. 2001;85(2):231-3.
  • 16
    Sellés-Navarro I, Villegas-Pérez MP, Salvador-Silva M, Ruiz-Gómez JM, Vidal-Sanz M. Retinal ganglion cell death after different transient periods of pressure-induced ischemia and survival intervals. A quantitative in vivo study. Invest Ophthalmol Vis Sci. 1996;37(10):2002-14.
  • 17
    Uemoto R, Yamamoto S, Aoki T, Tsukahara I, Yamamoto T, Takeuchi S. Macular configuration determined by optical coherence tomography after idiopathic macular hole surgery with or without internal limiting membrane peeling. Br J Ophthalmol. 2002; 86(11):1240-2.
  • 18
    Hoerauf H. Predictive values in macular hole repair. Br J Ophthalmol. 2007;91(11):1415-6.
  • 19
    Kusuhara S, Teraoka Escaño MF, Fujii S, Nakanishi Y, Tamura Y, Nagai A, et al. Prediction of postoperative visual outcome based on hole configuration by optical coherence tomography in eyes with idiopathic macular holes. Am J Ophthalmol. 2004;138(5):709-16.
  • 20
    Ruiz-Moreno JM, Staicu C, Piñero DP, Montero J, Lugo F, Amat P. Optical coherence tomography predictive factors for macular hole surgery outcome. Br J Ophthalmol. 2008;92(5):640-4.
  • 21
    Duker JS, Kaiser PK, Binder S, de Smet MD, Gaudric A, Reichel E, et al. The international vitreomacular traction study group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. 2013;120(12):2611-9.
  • 22
    Kang SW, Ahn K, Ham DI. Types of macular hole closure and their clinical implications. Br J Ophthalmol. 2003;87(8):1015-9.
  • 23
    Michalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology. 2010;117(10):2018-25.
  • 24
    Hashimoto Y, Saito W, Fujiya A, Yoshizawa C, Hirooka K, Mori S, et al. Changes in inner and outer retinal layer thicknesses after vitrectomy for idiopathic macular hole: implications for visual prognosis. PLoS One. 2015;10(8):e0135925.
  • 25
    Ambiya V, Goud A, Khodani M, Chhablani J. Inner retinal thinning after Brilliant Blue G-assisted internal limiting membrane peeling for vitreoretinal interface disorders. Int Ophthalmol. 2017;37(2):401-8.
  • 26
    Seo KH, Yu SY, Kwak HW. Topographic changes in macular ganglion cell-inner plexiform layer thickness after vitrectomy with indocyanine green-guided internal limiting membrane peeling for idiopathic macular hole. Retina. 2015;35(9):1828-35.
  • 27
    Baba T, Yamamoto S, Kimoto R, Oshitari T, Sato E. Reduction of thickness of ganglion cell complex after internal limiting membrane peeling during vitrectomy for idiopathic macular hole. Eye (Lond). 2012;26(9):1173-80.
  • 28
    Yamashita T, Uemura A, Kita H, Sakamoto T. Analysis of the retinal nerve fiber layer after indocyanine green-assisted vitrectomy for idiopathic macular holes. Ophthalmology. 2006;113(2):280-4.
  • 29
    Baba T, Hagiwara A, Sato E, Arai M, Oshitari T, Yamamoto S. Comparison of vitrectomy with brilliant blue G or indocyanine green on retinal microstructure and function of eyes with macular hole. Ophthalmology. 2012;119(12):2609-15.
  • 30
    Ohta K, Sato A, Senda N, Fukui E. Comparisons of foveal thickness and slope after macular hole surgery with and without internal limiting membrane peeling. Clin Ophthalmol. 2018;12:503-10.
  • 31
    Wolf S, Schnurbusch U, Wiedemann P, Grosche J, Reichenbach A, Wolburg H. Peeling of the basal membrane in the human retina: Ultrastructural effects. Ophthalmology. 2004;111(2):238-43.
  • 32
    Nakamura T, Murata T, Hisatomi T, Enaida H, Sassa Y, Ueno A, et al. Ultrastructure of the vitreoretinal interface following the removal of the internal limiting membrane using indocyanine green. Curr Eye Res. 2003;27(6):395-9.
  • 33
    Konstantinidis L, Uffer S, Bovey EH. Ultrastructural changes of the internal limiting membrane removed during indocyanine green assisted peeling versus conventional surgery for idiopathic macular epiretinal membrane. Retina. 2009;29(3):380-6.
  • 34
    Gelman R, Stevenson W, Prospero Ponce C, Agarwal D, Christoforidis JB. Retinal damage induced by internal limiting membrane removal. J Ophthalmol. 2015; 2015: 939748.
  • 35
    Ito Y, Terasaki H, Takahashi A, Yamakoshi T, Kondo M, Nakamura M. Dissociated optic nerve fiber layer appearance after internal limiting membrane peeling for idiopathic macular holes. Ophthalmology. 2005;112(8):1415-20.
  • 36
    Michalewska Z, Michalewski J, Nawrocki J. Continuous changes in macular morphology after macular hole closure visualized with spectral optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2010;248(9):1249-55.
  • 37
    Michalewska Z, Michalewski J, Dulczewska-Cichecka K, Adelman RA, Nawrocki J. Temporal inverted internal limiting membrane flap technique versus classic inverted internal limiting membrane flap technique: A comparative study. Retina. 2015;35(9):1844-50.
  • 38
    Alkabes M, Salinas C, Vitale L, Burés-Jelstrup A, Nucci P, Mateo C. En face optical coherence tomography of inner retinal defects after internal limiting membrane peeling for idiopathic macular hole. Invest Ophthalmol Vis Sci. 2011;52(11):8349-55.
  • 39
    Sabry D, El-Kannishy A, Kamel R, Abou Samra W. Correlation between en face optical coherence tomography defects of the inner retinal layers and ganglion cell inner plexiform layer analysis after internal limiting membrane peeling for idiopathic full-thickness macular hole. Invest Ophthalmol Vis Sci. 2016 01;57(9):444-50.
  • 40
    Notomi S, Hisatomi T, Kanemaru T, Takeda A, Ikeda Y, Enaida H, et al. Critical involvement of extracellular ATP acting on P2RX7 purinergic receptors in photoreceptor cell death. Am J Pathol. 2011;179(6):2798-809.
  • 41
    Iriyama A, Uchida S, Yanagi Y, Tamaki Y, Inoue Y, Matsuura K, et al. Effects of indocyanine green on retinal ganglion cells. Invest Ophthalmol Vis Sci. 2004;45(3):943-7.
  • 42
    Ciardella AP, Schiff W, Barile G, Vidne O, Sparrow J, Langton K, et al. Persistent indocyanine green fluorescence after vitrectomy for macular hole. Am J Ophthalmol. 2003;136(1):174-7.
  • 43
    Wu Y, Zhu W, Xu D, Li YH, Ba J, Zhang XL, et al. Indocyanine green-assisted internal limiting membrane peeling in macular hole surgery: a meta-analysis. PLoS One. 2012;7(11):e48405.
  • 44
    Wakely L, Rahman R, Stephenson J. A comparison of several methods of macular hole measurement using optical coherence tomography, and their value in predicting anatomical and visual outcomes. Br J Ophthalmol. 2012;96(7):1003-7.
  • 45
    Chhablani J, Khodani M, Hussein A, Bondalapati S, Rao HB, Narayanan R, et al. Role of macular hole angle in macular hole closure. Br J Ophthalmol. 2015;99(12):1634-8.
  • 46
    Kumagai K, Hangai M, Larson E, Ogino N. Progressive changes of regional macular thickness after macular hole surgery with internal limiting membrane peeling. Invest Ophthalmol Vis Sci. 2013;54(7):4491-7.

Publication Dates

  • Publication in this collection
    18 Aug 2021
  • Date of issue
    2022

History

  • Received
    20 July 2020
  • Accepted
    28 Sept 2020
Conselho Brasileiro de Oftalmologia Rua Casa do Ator, 1117 - cj.21, 04546-004 São Paulo SP Brazil, Tel: 55 11 - 3266-4000, Fax: 55 11- 3171-0953 - São Paulo - SP - Brazil
E-mail: abo@cbo.com.br