INTRODUCTION

Idiopathic epiretinal membrane (iERM) is found in 4% of the adults aged over 40 years^1–3; its incidence is rising in the current ageing society.¹ Due to the advances in optical coherence tomography (OCT) and surgical instruments, pars plana vitrectomy (PPV) is widely applied for the treatment of iERM to improve quality of vision (QOV). Both central visual acuity, determined by foveal function, and the paracentral visual field, determined by retinal neural sensitivity surrounding the fovea, are implicated in achieving good QOV and treatment outcomes.

Better central visual acuity after PPV for iERM can be obtained in patients with better preoperative best-corrected visual acuity (BCVA)^{4 5} and/or less severe photoreceptor misalignment determined by the absence or lesser extent of a disrupted external limiting membrane and ellipsoid zone^6–8 recorded by OCT. Additionally, population-based cohort analyses have shown that ERM is associated with a biomarker of glaucoma, that is, the defect of the retinal nerve fibre layer (RNFL), composed of retinal ganglion cell (RGC) axons, while it is not associated with another biomarker of glaucoma, that is, optic disc cupping.^9–11 This suggests that iERM affects both the health condition of photoreceptor cells^{4 6–8} and RGCs and/or their axons. Thus, measuring the visual field would also be of value when evaluating the quality of the treatment outcome.

Several previous reports have shown large postoperative visual field defects (VFDs) after PPV for iERM.^12–16 There are reports of large VFDs recorded by Goldmann perimetry being only observed in groups having undergone intravitreal injection of indocyanine green (ICG) during PPV for visualising the internal limiting membrane (ILM) for easier peeling, and not in groups where the ILM has been peeled without using ICG^12–14; thus, the toxicity of ICG, but not ILM peeling itself, was assumed to be the cause of large postoperative VFDs. Because ILM removal was found to reduce the recurrence of ERM after PPV from over 20% to 2%,¹⁷ many surgeons perform ILM peeling, although ICG may not be used. Recurrence of ERM and repeated surgery may be harmful to the retinal neurons, consuming time and resources, and increasing the mental burden. However, we still experience VFDs after PPV without using ICG.^{15 18} Considering that the ILM is the basement membrane of the Müller glial cells, which contribute to the homoeostasis of the microenvironment,^{16 19} its removal may affect Müller glial-cell function and/or surrounding neural tissue.

Under the recent trend of early glaucoma treatment, standard automated perimetry is basically used to sensitively detect VFDs. Thus, standard automated perimetry should also be used to evaluate VFDs as a surgical adverse event. Furthermore, currently, pre-perimetric glaucoma is diagnosed based on the inner retinal thickness measured using OCT.^{20 21} Analyses of both total central retinal thickness (CRT) and postoperative neural thickness in each layer will help in sensitively evaluating neural loss.

Here, we analysed the data of patients who did not have VFDs before surgery to determine the incidence of postoperative VFDs recorded by standard automated perimetry and the change in retinal neural thickness in each layer to explore the pathogenesis of the VFDs. The impact of ILM peeling on the VFDs and neural thickness was also evaluated. The study results will help determine whether the surgical procedure should include processes such as ILM peeling by considering the risk–benefit balance in daily clinical practice.

RESULTS

Baseline characteristics and surgical outcome of iERM

Of 30 eyes of 30 patients (mean age, 66.1±1.9 (range, 43–84) years), 15 belonged to males (50%) (online supplemental table 1). Mean BCVA was 0.202±0.034 (range, −0.079 to 0.523) in LogMAR, mean CRT was 376±25 (range, 72–630) μm and mean CCT was 180±9 (range, 110–294) μm at baseline. Nineteen eyes (63.3%) underwent combined cataract surgery, and 17 eyes (56.7%) underwent ILM peeling during PPV. Twenty-eight eyes (93.3%) received Brilliant Blue G staining during surgery.

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Table 1

Differences between eyes with or without postoperative visual field defect

Overall, mean BCVA improved to 0.041±0.026 (p=0.0007) (online supplemental figure 1A) and CRT decreased to 283±19 μm (p=0.0002) (online supplemental figure 1B) while CCT did not change (188±9 μm; p=0.512) at 1 month postoperatively (data not shown).

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Figure 1

Preoperative and postoperative optical coherence tomography (OCT) images and visual field tests of a patient with postoperative visual field defect (VFD). Preoperative (A) and postoperative (B) OCT images of a patient with idiopathic epiretinal membrane who underwent pars plana vitrectomy with internal limiting membrane peeling. The respective preoperative and postoperative best-corrected visual acuities were 0.398 and −0.079 in LogMAR, and respective thicknesses of the ganglion cell layer at 2000 μm temporal to the foveal centre were 72 μm (C, arrow) and 18 μm (D, arrow). The greyscale (E, F) and pattern deviation map (G, H) analysed by the Humphrey visual field analyser showed nasal VFD after surgery (F, H), which was not present preoperatively (E, G).

Supplemental material

[bjophthalmol-2020-317478supp001.pdf]

DISCUSSION

VFD, defined by the Anderson and Patella’s criteria, appeared in 22 eyes (73.3%) after PPV for iERM, although ICG was not used and the most recent PPV systems were used. ILM peeling was a significant risk factor for VFD development after adjusting for age. Several eyes had VFDs in multiple quadrants, and most frequently nasally, and GCL thinning was also frequently noted temporal to the fovea. Thinning of the superior and inferior RFNL and temporal GCL were significantly observed in the eyes that underwent ILM peeling during PPV.

VFD was found in 73% of the eyes in the current study using the central 30-2 (HFA 30-2) program of the standard automated perimetry, Humphrey visual field analyser. Previous reports have shown that large VFDs measured by Goldmann perimetry tests were found in 35%,¹² 57%¹³ and 63%¹⁴ of postoperative eyes with iERM, but only in eyes where ICG was used during ILM peeling. Conversely, VFDs determined by standard automated perimetry were found at a high frequency in postoperative eyes with iERM in this study, although ICG was not used, possibly because standard automated perimetry can detect slight defects and is more sensitive than the Goldmann perimetry tests. Another report using the Humphrey visual field analyser showed that postoperative mean visual field sensitivity in the eyes with iERM or macular hole treated with PPV decreased in the 10° eccentricity (centre), but was preserved in eyes without glaucoma; moreover, the values of the remaining peripheral test points within 24º improved postoperatively even in eyes that originally had glaucoma.¹⁵ The differences in the results could be because the previous study used the 24-2 program and evaluated the mean values of sensitivity, and this study used the 30-2 program; thus, wider analyses were performed, and VFDs were evaluated using the Anderson and Patella’ criteria, according to which VFD was defined when a local abnormality was detected. Considering these points, this study may have more sensitively detected local neural damage than all previous reports listed earlier.

ILM peeling was found to be a risk factor for postoperative VFD in this study. ILM is a basement membrane and a part of the Müller glial cells. Moreover, in the surgically peeled ILM, cellular components of Müller glial cells themselves were reported to be contaminated by electron microscopy.¹² Considering that Müller glial cells have a critical role in the homoeostasis of the retinal neural microenvironment,²⁴ abnormality or loss of Müller glial cells may easily cause retinal degeneration. This mechanism may also be involved in addition to the direct mechanical stress to the neurons at the time of peeling; one report showed that neural components were found in the pathological analysis of resected ERM,¹⁶ suggesting that retinal neurons could be incidentally removed during surgery, and the possibility could be theoretically increased with ILM peeling.

Although we did not use ICG to visualise the ILM, we used Brilliant Blue G, which could have affected the retinal neurons. However, most (93%) eyes were injected with brilliant Blue G even when the ILM was not peeled; in these eyes, the injection was performed to confirm that the ILM was not peeled. Brilliant blue G was reported to be safer than ICG in a neural cell line,²⁵ and its intravitreal injection did not cause RGC reduction²⁶ or visual function impairment as measured by electroretinography.^{26 27} The safety was also analysed by comparing it with ICG and trypan blue, by injecting Brilliant Blue G into the subretinal space to find no apoptotic cells in the outer and inner layers of the retina and the RPE in animals.²⁸ Therefore, Brilliant Blue G may have minimally influenced the appearance of VFDs in this study. Taken together with the fact that we did not use ICG, which was proven to be toxic for the retina,^12–14 the VFDs observed in the current study were most likely due to the ILM peeling itself.

VFD was frequently found in the nasal part. Consistently, GCL thinning temporal to the fovea was greater in eyes with postoperative VFD than in those without. Additionally, VFDs spread to both the superior and inferior quadrants, which is not observed in typical glaucoma. ILM peeling decreased the thickness of the RNFL, both superior and inferior to the fovea, and the GCL temporal to the fovea, suggesting that ILM peeling may have damaged the RGCs at the temporal area of the fovea including the superior and inferior quadrants. However, whether cell bodies had been damaged first and axons were then affected or vice versa should be further analysed. Postoperative dissociated optic nerve fibre layer (DONFL), whose relationship with VFD remains controversial,^{29 30} was only observed in one eye, which had a postoperative VFD. However, this could be because DONFL was found to have clearly developed approximately 6 months postoperatively, and its relative absence 1 month postoperatively is reasonable.³⁰

The ILM was directly grasped with forceps and slowly peeled, and the grasping point was determined in each eye; thus, it varied among the eyes. However, the RGCs of the temporal area to the fovea were the most affected. Thus, the damage was most likely unrelated to the mechanical damage at the time of ILM grasping. RGCs at the temporal area of the fovea involve more RGCs positive for calcium-binding proteins: parvalbumin, calbindin and calretinin,³¹ and these cells show distinct photopic responses when they are stressed by increased intraocular pressure in animal models,³¹ suggesting the possibility that RGCs temporal to the fovea may have different and vulnerable characteristics than the RGCs in other parts of the retina.

Alternatively, thinning of the GCL temporal to the fovea could be related to the displacement of the retina after ILM peeling towards the optic disc, as reported for macular hole³² and diabetic macular oedema,³³ possibly because of the contraction and/or linearisation of the retinal tissue after removing the tension of the ILM to retain the retinal neurons arcuate, and the contractile force may have damaged the RGCs including their synapses and axons.

Not performing ILM peeling could increase ERM recurrences,^{17 34 35} which would be disadvantageous. However, one should carefully consider whether to include ILM peeling to the procedure, considering that it may increase the risk of VFD. Particularly, if the eye shows signs of glaucoma, ILM peeling in the first operation for iERM may be avoided. Moreover, apart from the iERM clinic, at the time of screening glaucoma, we could ask patients who meet the Anderson and Patella’s criteria in perimetry tests whether they have histories of PPV for iERM.

The limitations of this study were a relatively small sample, a retrospective design and the inclusion of patients whose eyes were injected with Brilliant Blue G and patients whose eyes were not, although the last point may not have had a marked impact, as discussed earlier. ILM peeling was performed at the surgeon’s discretion at the time of surgery, and this could have introduced bias. Further prospective studies would be required. Combined cataract surgery was performed in some of the patients; however, it may not cause VFDs.

In summary, ILM peeling was found to be a risk factor for developing VFDs after PPV for iERM. Postoperative GCL thinning was significant at the temporal part of the fovea, and VFDs frequently appeared at the nasal part. ILM peeling reduced the thickness of the GCL temporal to the fovea and of the RNFL both superior and inferior to the fovea. Although ILM peeling during iERM might have merit in preventing recurrences,^{17 34 35} further study is warranted to reconsider the impact of ILM peeling for iERM on QOV.