Extensive internal limiting membrane peeling for proliferative vitreoretinopathy

The aim of this study was to describe the anatomical outcomes of Brilliant Blue G (BBG)–assisted extensive internal limiting membrane peeling for proliferative vitreoretinopathy (PVR) under three-dimensional (3D) visualization. This study constitutes a retrospective case series conducted in a private retina practice, of 14 consecutive patients (14 eyes) with rhegmatogenous retinal detachment complicated by PVR who underwent pars plana vitrectomy between January 2019 and January 2020. The internal limiting membrane (ILM) was selectively stained with BBG, and perspectives were enhanced with a 3D visualization system. We peeled off the ILM beyond the vascular arcades up to the periphery. The main outcome was anatomical success, defined as persistent retinal reattachment after removal of the silicone oil tamponade. Anatomic success was achieved with a single surgery in 11 of 14 (78.6%) eyes, and eventual success was achieved in all eyes. The mean patient follow-up time was 12.3 months (range, 7–16 months). The mean preoperative best-corrected visual acuity (BCVA) was 2.93 ± 0.79 logMAR which improved to 1.75 + 0.91 at the last follow-up. Extensive ILM peeling allowed the creation of a cleavage plane underlying the PVR membranes that facilitated its complete removal, thereby achieving anatomically reattached retina and reducing the risk of recurrence of retinal detachment. The long-term effects of this technique need further research.


Introduction
Proliferative vitreoretinopathy (PVR) occurs in 5-10% of rhegmatogenous retinal detachment (RRD) cases and is a significant prognostic factor for surgical failure [1]. The process is characterized by repeated cellular proliferation, which creates very adherent and contractile periretinal membranes; there is no clear consensus on how to approach this condition [2]. Once cells become established in the epiretinal membrane (ERM), they become an important source of chemotactic and mitogenic stimuli that contribute to proliferation and redetachment [3]. Surgical eradication of ERMs can decrease the stimulation of cytokines, which that may catalyze recurrent PVR. Histopathological studies have found that the ILM creates a scaffold for ERM cell proliferation [4].
Foveau et al. [5] showed a reduction in ERM development in eyes that underwent ILM peeling for complicated RRD, and Abdullatif et al. [6] recently reported the feasibility of extended ILM peeling in pediatric retinal detachment.
Brilliant Blue G (BBG) ophthalmic solution selectively stains the ILM and facilitates the management of ERM [7]. Furthermore, the view of the ILM and ERM can be improved with the use of color filters and manipulation of light levels, which boost dye staining using a three-dimensional (3D) visualization system [8].
In accordance with these findings, we hypothesized that extensive ILM peeling (eILMp) might improve PVR eradication and can increase the rate of long-term retinal reattachment. The aim of this study was to report the outcomes of pars plana vitrectomy (PPV) in retinal detachment (RD) accompanied by PVR after extensive BBG-assisted ILM peeling using a 3D visualization system.

Methods
This is a retrospective, observational and consecutive chart review of patients with PVR-RD who underwent PPV combined with eILMp at a single private ophthalmic center in Buenos Aires, Argentina, between January 1, 2019, and January 1, 2020. Written informed consent was obtained from all subjects. The inclusion criterion was the presence of RRD complicated by PVR grade B or C [9] and treated with BBG assisted eILMP during PPV surgery. Exclusion criteria were age < 18 years, evidence of PVR grade D-1 or worse, severe ocular hypotony, choroidal detachment, corneal opacification, open globe injury, and postoperative follow-up time < 6 months after removal of silicone oil. A single experienced vitreoretinal surgeon (M.C.) performed all surgeries. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the center's institutional review board. Study investigators assessed post-treatment responses during follow-up visits at 24 h, 1 week, 1 month, and every month after surgery through August 30, 2020. Patient demographic and medical information was retrieved from their medical records, along with preand postoperative data.
Supplemental digital content (Video) demonstrates the key steps of the surgical procedure. All patients underwent PPV using the Constellation 25-gauge vitrectomy system under a noncontact wide-angle viewing operating system (BIOM 5, Oculus Optikgeräte GmbH, Wetzlar, Germany) with using a lens with a 120° field of view and the Ngenuity 3D Visualization System (Alcon, Geneva, Switzerland). A 25-gauge chandelier light source was used in all cases. After the PVR membranes were removed, the ILM was stained using 0.3 to 0.5 ml of 0.05% w/v BBG solution (Ocublue Plus, Aurolab, Madurai, India), and excess dye was removed.
The eILMp surgical technique was defined as the peeling off the ILM using ILM forceps for the macular area and using serrated forceps (Alcon, Geneva, Switzerland) for any remaining ILM beyond the vascular arcades up to the periphery. The peeling was extended up to 4-disc diameter beyond the vascular arcades. In case of performing a retinectomy, peeling was attempted up to the edge of it. This process ensured total removal of the overlying vitreous and preretinal PVR membrane remnants responsible for recurrent detachment. To reveal new ILM edges, frequent restaining with BBG was used, especially over areas of severe contraction and retinal infolding.
Once the retina-ILM-PVR complex was sufficiently relaxed, perfluorocarbon liquid (PFCL) was introduced with a dual-bore cannula to stabilize the posterior retina. In cases of bullous RD, ILM peeling was performed under PFCL. The surgeon adjusted the zoom on the foot pedal of the microscope to locate the ILM; when moving to the periphery, a slight tilting of the eye was necessary, and the x-y axis of the microscope followed the instruments. The view of the ILM was enhanced with the use of red-free filters on the Ngenuity system.
For phakic patients, phacoemulsification and placement of the posterior chamber intraocular lens were performed. For persistent peripheral retinal contraction, peripheral relaxing retinectomy followed by endolaser photocoagulation was used. Silicone oil tamponade was used in all cases and was removed after 3 months if laser retinopexy scars occurred around the retinal breaks or retinectomy was performed, along with a clinically stable and completely attached retina.
Descriptive statistical analysis included sex, age at presentation, intraocular pressure, macular and retina status (attached or nonattached), presence of PVR (preretinal, subretinal, and intraretinal), prior vitreoretinal surgeries, final lens status, duration of follow-up, time to extraction of silicone oil, anatomical success, difference between preoperative and final visual acuity, and complications. The primary outcome was the anatomical success defined as persistent retinal reattachment at the last follow-up visit after removal of the silicone oil tamponade. The secondary outcome was the change in best-corrected visual acuity (BCVA) from baseline to last followup. BCVA was measured using Snellen charts and converted into the logarithm of the minimal angle of resolution (logMAR) values for statistical analysis. We equated counting ringers, hand motion, and light perception, to 1/200, 0.5/200, 0.025/200, respectively [10]. Improvements in BCVA were reported in letters of improvement (ETDRS chart). The procedure for determining the optimal sample size in this retrospective chart review study with descriptive objectives was the level of precision in the estimation of the primary outcome (nominal dichotomous/binary data: attached or detached) [11]. For numeric variables, it was checked if it was adjusted to a normal distribution or not (Shapiro-Wilk test), to apply a parametric test (T-test) or not (Mann-Whitney or Wilcoxon). Comparisons between categorical variables were made using Fisher's test or correspondence analysis. An alpha of 0.05 was taken as significance level. Statistical computations were performed using Statistica 13 PL (Tibco, Palo Alto, CA, USA).

Results
We successfully performed eILMp in 14 eyes of 14 patients diagnosed with PVR-RD. Table 1 lists the demographic data of the patients. The mean age at presentation was 55.1 years (range, 23-77 years), and 8 of the patients were men (8/14, 57.1%). All eyes had total or subtotal RD with severe PVR (subretinal and preretinal membranes). Nine patients (64.3%) underwent two vitreoretinal procedures before presentation, whereas the remaining five patients required three or more surgeries to fix the RD. Six eyes were phakic (42.9%), and eight (57.1%) had posterior chamber intraocular lens implants (PCIOLs). Phacoemulsification surgery and PCIOL implantation were performed during the RD surgery in the phakic eyes.
Retinas were reattached with one procedure in 11 of the 14 cases (78.6%) and with two procedures in three cases (21.4%). The recurrence of PVR-and subsequent RD-was diagnosed in 21.4% of cases (3 eyes). In these cases, spectral domain optical coherence tomography (SD-OCT) scan did not detect PVR over the area where ILM was previously peeled accordingly with patient's surgical operation notes, while ERM associated with full-thickness neurosensory retina retraction was observed in the areas where the ILM had not been removed (Fig. 1). In all cases, silicone oil was removed after 3 months, with a mean duration of 3.2 months (range, 3.1-4 months). All patients had a completely attached retina at the last postoperative follow-up visit, with a mean follow-up duration of 12.3 months (range, 7-16 months). Of the 14 cases, 1 (7.1%) presented with severe hypotony.

Discussion
This case series reinforces the hypothesis that massive ILM peeling might remove the support of the Fig. 1 Ultra-wide-field fundus photography and spectraldomain optical coherence tomography findings in a retinectomy under silicone oil for rhegmatogenous retinal detachment complicated by proliferative vitreoretinopathy. a Ultra-wide-field color fundus photograph showing the retina and its change after relaxing retinectomy (black arrowheads: denote the approximate location of the retinectomy edge). Colored lines indicate the exact location through which spectral domain optical coherence tomography (SD-OCT) scans (B and C) were taken. b Scan shows the area of the retina that had (white arrowhead), or had not (yellow arrowhead), received internal limiting membrane peeling; proliferative vitreoretinopathy membrane reproliferation (short white arrow), full-thickness neurosensory retina retraction with cystic space (white star) -similar to a idiopathic macular hole-and unsuccessful laser scar (white asterisk). c Scan shows the attached retina after complete internal limiting membrane peeling (white short arrows), laser scarring along the retinectomy -completely healed-(white asterisk), hyperreflective spherical bodies representing silicone oil emulsion (short white arrow) and the retina-silicone oil interface (long white arrow) epithelial cells, thereby preventing the recurrence of proliferative membranes. We detected that in the eyes that needed reoperation due to recurrent proliferation, preretinal PVR stopped clinically at the edge of the previously peeled retina, as shown in Fig. 1. Furthermore, research on the peeling of the internal limiting membrane (ILM) in conjunction with repair of proliferative vitreoretinopathy-retinal detachment (PVR-RD) has demonstrated that removal of the ILM can create a PVR dissection plane and reduce the likelihood of the recurrence of epiretinal membrane (ERM) [5].
In this new technique, eILMp-extended up to 4-disc diameter beyond the vascular arcades-may create a cleavage plane between the ERM-PVR complex and the retina, facilitating the total removal of the overlying vitreous and preretinal PVR remnants that are responsible for recurrent detachment. The edges of the ERM are often undefined, and access can be limited by severe infolding of the retina; consequently, total removal is often difficult. Stripping the ILM allows the contracted retina to be completely released from the ERM, resulting in its relaxation.
However, grasping and striping the ILM over an extensively detached and mobile retina is challenging. To overcome this difficulty, the use of PFCL after BBG staining flattens the detached retina, while the ILM-PVR complex membranes are dissected under heavy liquid counter traction. Restaining is often necessary and may reveal new ILM edges that in turn expose further dissection planes. Intraoperative visualization can dramatically influence the surgical outcome. A wide field lens assisted by a 3D system can achieve high magnification and enhanced depth perception while maintaining a wide field of view, which greatly increases the ability to detect peripheral ILM [3]. Determining the presence or absence of a ILM intraoperatively is generally possible with the combination of excellent staining, clear media, optimal light source and modern optical system. Despite all this, Fig. 1 shows that if ILM remnants are not seen and removed at the time of surgery, these can provide a scaffold for PVR recurrence. Visualization agents may assist in the identification of remaining ILM. Absence of staining, however, does not guarantee absence of ILM; staining can be variable-intense in some eyes and faint in other. In future, intraoperative Although peeling of the ILM is now a widely used technique, among the well-known complications are paracentral retinal holes, the appearance of a dissociated optic nerve fiber layer, microscotoma, loss of light sensitivity, hemorrhage, and postoperative microcystoid macular edema [12,13]. The enormous number of attempts at ILM elevation and subsequent regrasping were associated with a higher risk of iatrogenic retinal breaks. Intraoperative tears were detected and treated, none of these cases developed postoperative retinal detachment, anatomical recovery seems not to be conditioned by iatrogenic retinal holes. In our technique, the effects on the integrity and function of a retina already subjected to RD stress are unknown, as is the toxicity of subretinal BBG migration [7,14]. These aspects require further study.
For the secondary outcome, overall visual acuity improved in the majority of eyes following eILMp. This improvement in visual acuity could be due to the fact that 12 out of 14 eyes had the macula detached prior to the procedure and the 14 eyes kept the macula attached following removal of the silicone oil. As noted in other series, BCVA may be also independently associated with the slow functional recovery of the naturally reattached retina, cessation of silicone oil-induced toxicity, altered optics during silicone oil tamponade, cataract extraction, corneal decompensation and/or hypotony [15][16][17]. Additionally, we realize one major drawback of this study which includes patients with CF, HM and LP vision, because these are detection tasks and do not estimate vision on a comparable scale [18]. There are indeed still controversies how to analyze visual fractions < 20/800; based on preview researches, we arbitrarily took the logMAR of these visual fractions for statistical analysis [10]. Thus, allocating a LogMAR value to PL may artificially reduce the mean preoperative visual acuity however; even so, the difference between CF, HM, LP, and no LP is quite relevant for the patient and for the ophthalmologist. We also explored Holladay's work [19] in which he estimates a visual acuity of 0.01 for CF and 0.001 for HM. In fact, his estimates suggest a difference of 1-log-unit step between CF and HM, performing a back-conversion. Holladay included an equivalence table in his work in which LogMAR takes negative values for visual acuity worse than 20/20, while the reviewed literature uses negative values for visual acuity better than 20/20. In order to avoid confusion, we opted to use the most widely used values. We await that future studies in patients with low vision will develop the ability to estimate visual acuity reliably in the very low visual acuity range [20].
The current study was retrospective in design with all of the inherent limitations of such studies and the follow-up period was limited. In addition, we analyzed a small sample size without a control group. Furthermore, this was a single-surgeon series, which may limit the generalizability of the results. Although we included RRD complicated by PVR grade B or C; owing to the limitations of the study, this technique could be useful for different degrees of PVR, if it uses with caution in detached retinas, because dye may migrate under the neurosensory tissue, resulting in toxicity.
To summarize, we describe a new surgical approach of creating a cleavage plane to split the PVR-retina complex that seems to remove epithelial cells, thereby improving the anatomic success rate. Further investigations, with larger prospective studies are required to confirm the long-term results and to assess potential complications.