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Multi-layer internal limiting membrane plug technique for management of large full-thickness macular holes

Background To evaluate the efficacy of the multi-layer internal limiting membrane plug (MIP) technique in promoting the closure of large full-thickness macular holes (FTMH) and improvement of visual function. Methods A prospective interventional non-comparative consecutive case series including patients with surgically naïve large FTMH whether primary or secondary. All macular holes were > 400 µm. All patients had 23-gauge pars plana vitrectomy (PPV), MIP technique, and sulfur hexafluoride (SF6) 20% gas tamponade. The main outcome measures were the closure of the hole, improvement of best-corrected visual acuity (BCVA), and detection of complications that might develop due to surgery. Results The study included 15 eyes of 15 patients. The mean age was 44 years (range 10–68; SD 21.5). Primary FTMH constituted 53% of cases. The mean pre-operative minimum linear diameter (MLD) was 702 µm (range 401–1068 µm; SD 154). The mean duration of the macular hole was 6 months (range 1–24; SD 6). The mean pre-operative BCVA was 0.06 decimal units (range 0.01–0.1; SD 0.03). Post-operatively, the macular hole was closed in all patients. U- and V- type closure developed in 93% and 7% of patients, respectively. None of the patients developed W-type closure. Post-operatively, the mean post-operative BCVA was 0.2 decimal units (range 0.05–0.5; SD 0.1). The mean improvement was 5 lines of vision. The mean postoperative follow-up period was 4 months (range 1–10; SD 2.5). None of the patients developed complications attributed to the surgical technique described. Conclusion MIP technique is effective in promoting macular hole closure and improvement of visual function in large FTMH. Supplementary Information The online version contains supplementary material available at 10.1186/s40942-022-00428-7.


Background
Large full-thickness macular holes (FTMH) are prone to become refractory to pars plana vitrectomy (PPV), and conventional internal limiting membrane (ILM) peel described by Kelly and Wendel in 1991, and by Eckardt in 1997, respectively [1][2][3][4][5][6]. The term large hole has been reserved classically to FTMH > 400 µm in diameter per biomicroscopic classification by Gass [7,8], and per the classification of the international vitreomacular traction study group [9]. Recently, the cut-off diameter of large FTMH associated with lower hole closure rates after conventional surgery has been raised to ≥ 500 µm [10,11]. Large FTMH could be primary, persistent, or recurrent after surgery, or secondary to an underlying pathology such as trauma, high myopia, solar injury, traction due to proliferative diabetic retinopathy (PDR), or de-roofing of cystoid macular edema (CME) caused by retinal vascular diseases [12]. Macular holes in the latter category share

Open Access
International Journal of Retina and Vitreous  Retina and Vitreous (2022) 8:80 in common the existence of pathogenetic factors that are significant riders to large size and to the classic pathogenesis of primary FTMH based on transvitreal anteroposterior and tangential traction forces as described by Gass [7,8,13]. Factors like tissue loss in traumatic FTMH [14][15][16][17], outward traction exerted on the macular area by posterior staphyloma in myopic traction maculopathy (MTM) [18][19][20][21], and atrophic and ischemic changes in the macular area secondary to retinal vascular diseases [22,23] perpetuate gaping of the hole and render it either resistant to closure or liable to open-flat closure despite relief of anteroposterior and tangential traction by PPV and conventional ILM peel. In the present series we propose a novel surgical approach, in which we gave the term multi-layer internal limiting membrane plug (MIP) technique for management of large FTMH. The technique consists of peeling a whole area of ILM that is at least double the hole size without avulsing it from the edges of the hole. The ILM is then stacked in multiple layers forming an ILM plug to close the hole and is resilient to displacement. The rationale of the technique is that residual attachment of the ILM to the hole edges and the remnants of the footplates of Müller cells on the retinal side of the ILM would incite glial cell proliferation to close the hole [24]. The aim of the present work is to evaluate the efficacy of this technique in promoting the closure of FTMH, and the improvement of visual function.

Methods
This is a prospective interventional non-comparative consecutive case series conducted in 2 retina tertiary centers in Egypt and Greece during 2021-2022. Inclusion criteria were surgically naïve FTMH > 400 µm in diameter whether primary or secondary. Exclusion criteria were FTMH < 400 µm in diameter, previous conventional ILM peel, media opacity hindering pre-operative evaluation of the macular hole, co-existing retinal detachment due to peripheral hole, or co-existing retinal pathology that would hinder the improvement of vision as agerelated macular degeneration, choroidal rupture bisecting the fovea or extensive atrophy of the retinal pigment epithelium (RPE). The main outcome measures were the closure of the hole, improvement of best-corrected visual acuity (BCVA), and detection of complications that might develop due to surgery. All recruited patients received full ophthalmological examination including history taking, measurement of BCVA using decimal notation, assessment of the intra-ocular pressure (IOP) using applanation tonometry, slit-lamp anterior segment examination, fundus biomicroscopy using the Volk area centralis contact lens for evaluation of the macular hole, retinal examination using indirect ophthalmoscopy including scleral indentation, and optical coherence tomography (OCT) imaging. On biomicroscopy, FTMH was defined as a rounded full-thickness defect in the fovea with a surrounding sub-retinal cuff of fluid and yellowish pigments in the base of the hole. On OCT examination, FTMH was defined as a full-thickness defect of the neurosensory retina in the fovea from the ILM to the RPE with elevated edematous edges and sub-retinal fluid. Mean linear diameter (MLD) refers to the shortest horizontal distance between the hole edges. OCT examination was performed using the spectral domain enhanced-depth imaging (EDI-OCT) Spectralis tracking laser tomography, Heidelberg Engineering GmbH, Heidelberg, Germany.

Surgical technique
All recruited patients had 23-gauge PPV and MIP technique. Three vitreoretinal surgeons from 2 centers (EE, ML, and PS) performed case selection, surgical intervention, and macular hole imaging. The surgical technique consisted of core vitrectomy followed by triamcinolone acetonide-assisted induction of the posterior hyaloid. The surgeon then proceeded to stain the ILM using brilliant blue G 0.025% stain; Dutch Ophthalmic Research Center (DORC), The Netherlands. After aspirating the supernatant stain, the MIP technique was initiated at a point that was distal to the hole by at least double its size using the Grieshaber FINESSE Flex Loop, Alcon, Geneva, Switzerland, or the Tano diamond dusted scraper. First, multiple breaks were created in the ILM in a rosette fashion at 360° degrees around the hole. Afterward, the flap was reflected centripetally towards the hole under perfluorocarbon liquid (PFCL) without avulsing it off the edges and stacked gently over one another using the Flex Loop, Tano scraper, or vitreoretinal forceps to form a multilayer plug. Additional file 1: Video S1, supplemental digital content 1. The surgeon did not perform any attempt to tuck the flap inside the hole. Finally, air/PFCL exchange was performed followed by air/sulfur hexafluoride (SF6) 20% exchange. All patients were asked to initially adopt a face-down position for at least 2 days and then a reading position for 3 more days.
The post-operative follow-up schedule included visits at 1 day, 1 week, and 1 month then 3-monthly visits whenever applicable. The examination included BCVA and OCT imaging to determine the pattern of hole closure whether U, V, or W. U-pattern closure was defined as complete re-approximation of the hole edges with no intervening bare RPE area. V-pattern closure was defined as re-approximation of the hole edges but with a steep foveal contour reminiscent of a notch and no intervening bare RPE area. W-pattern closure was defined as flattened hole edges against the RPE with no sub-retinal fluid, and the presence of an intervening bare RPE area. All patients who completed ≥ 3 months follow-up-had a microperimetry examination to detect macular sensitivity and fixation [Micropeimeter (MP-3)], Nidek, Japan.

Results
The study included 15

Case no. 3
A 62-year-old female presented with a history of defective vision in the right eye of approximately 1-year duration. Her BCVA was 0.1 decimal units. Anterior segment examination revealed pseudophakia with a posterior chamber intra-ocular lens (PCIOL) implanted in the

Case no. 4
A 65-year-old female presented with complaints of defective vision in the right eye and the presence of a round black spot obscuring the center of her visual field for one month. Her BCVA was 0.1 decimal units. Her anterior segment examination revealed pseudophakia with PCIOL located inside the capsular bag. Fundus examination revealed FTMH. MLD by OCT was 650 µm. Postoperatively, OCT examination revealed U-type closure of the hole. Her BCVA at 7 months of follow-up was 0.3 decimal units. Microperimetry examination of the right macula at 7 months of follow-up revealed significant improvement in macular sensitivity and fixation stability Fig. 4.

Discussion
PPV and ILM peel remains the standard surgical approach for the management of macular holes. However, this technique did not yield favorable results in terms of closure rates for large macular holes. Although relieving the anteroposterior and tangential traction forces by the fore-mentioned surgical approach is pivotal in promoting hole closure, this cannot fully counteract the multifactorial pathogenesis of large-size primary and secondary macular holes that perpetuate gaping of the hole edges [1][2][3][14][15][16][17][18][19][20][21][22][23]. Hence, a complementary surgical rider is required to trigger the proliferation of glial cells to close the hole. Michalewska et al. [25] described the inverted ILM flap technique that entailed using the ILM as a scaffold for the proliferating glial cells and to further enhance the healing process by residual foot plates of Müller cells on its retinal surface. In the present study, we deployed the MIP technique. The fundamental difference between our technique and that of Michalewska was that we did not attempt to tuck the ILM flap inside the hole or manipulate the edges of the hole. The rationale was to avoid inflicting damage on the RPE in the base of the hole and to the edges of the hole. Instead, we created multiple layers of ILM and stacked them to cover the hole one layer after another. We found that the resultant multi-layered flap got sucked inside the hole by the negative pressure created once the hole was sealed, eventually acting as a plug. This plug would provide the desired scaffold effect in addition to replenishing the hole with Müller cells residues. We had a macular hole closure rate of 100%, of which 93% was a U-type closure using single surgery. The final mean BCVA improved by 5 lines, nevertheless, the overall visual acuity improvement was marginal as 87% of operated eyes had final BCVA ≤ 0.2. Only 1 patient (7%) achieved a BCVA of 0.5. It is worthy of note that almost 50% of operated eyes in this series had FTMH secondary to a primary pathology that might have compromised the functional outcome. In comparison, Michalewska et al. [25] reported an initial closure rate of 98% using the inverted ILM flap technique and significant improvement of BCVA. The authors recruited exclusively patients with idiopathic macular holes (IMH   The large surface area of the resultant flap compared to the size of the hole facilitates maneuverability and allows stacking the flap in a multi-layer configuration. We found that the layers of ILM tend to stick to each other forming a multi-layered plug that sealed the hole effectively and was resilient to displacement intra-operatively during air/PFC exchange or dislodgement post-operatively as had happened in other techniques used by the forementioned authors [25,26,28]. Moreover, the centripetal force exerted while reflecting the flap towards the hole promotes atraumatic approximation of the edges of the hole. Accordingly, we had not had a single case of flap migration post-operatively and we were able to achieve a 100% closure rate. An important point of strength in the present series is that approximately 50% of our patients had FTMH secondary to other pathologies that could hinder hole closure. Nevertheless, we had not had a single case of W-type closure and only 1 case of V-type closure, which emphasizes the efficiency of the MIP technique in promoting hole closure. In addition, in our study, the mean MLD was 702 µm compared to a mean MLD of 400.8 µm, and a median MLD of 558 µm in the BEAVRS macular hole outcome group study [10], and the Manchester large macular hole study [11], respectively. These studies concluded that conventional ILM peel is associated with lower success rates for macular hole diameters exceeding 500 µm, and 630 µm, respectively, which further corroborates the rationale for using the MIP technique for large-size FTMH. The limitations of the present study include its limited sample size and inhomogeneity of the sample in terms of pathogenesis. Therefore, we can only recommend the MIP technique as promising surgical management for large FTMH awaiting prospective studies with a larger sample size comparing MIP to other surgical techniques.

Conclusion
MIP technique is effective in promoting macular hole closure and improvement of visual function in large FTMH.