July 2020 · Vol. 51, No. 7 375

Practical RetinaIncorporating current trials and technology into clinical practice

Approaches to Refractory or Large Macular Holesby Ajay E. Kuriyan, MD, MS; and Claire E. Fraser, MD, PhD

There is no uncertainty that advances in vitreoretinal surgical techniques

have allowed for high rates of sur-gical success after macular hole (MH) surgery. Therefore, a less-than-perfect outcome can be particularly dis-heartening for the surgeon. Less-than-perfect outcomes are more frequent-

ly seen in patients who present with larger holes or those who have failed macular surgery in the past.

I have asked Ajay E. Kuriyan, MD, MS, and Claire E. Fraser, MD, PhD, to discuss their thoughts and experi-ence regarding approaches to refrac-tory or large MHs. They will discuss risk factors for unsuccessful surgery and various techniques reported in the literature to address this situa-tion that many of us have faced who perform MH surgery. This clearly is an evolving landscape, and an added challenge is that no one technique has been proven to be superior to another.

I am certain that their insights will be very valuable, as it will provide several options for surgeons dealing with MH patients at high risk for fail-ing traditional methods.

Macular holes (MHs) can cause a sudden change in vision and central scotomas.1 The prevalence of MHs range from 0.02% to 0.8%.1-6 Surgical repair often includes a pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling and gas tamponade. Overall, MH surgery is very successful, with reported closure rates of 90% or greater.7,8 Risk factors for unsuccessful surgery include not peeling ILM, large size, chronicity, trauma, previous unsuccessful MH surgery (refractory MHs), concurrent retinal detachment, and myopic MHs.7,9

Several techniques have been utilized to improve MH surgery success, especially in cases with the previously listed risk fac-tors. This review outlines some of these ap-proaches, including additional conventional surgical methods (broader ILM peeling and repeat fluid-gas exchange), MH scaffolds (inverted ILM, ILM free, posterior capsule

flaps), increasing retinal tissue compliance (retinal incisions, macular detachment), use of growth factors/cytokines to aid healing (macular laser and placement of adjuvant agents into the MH), tissue replacement (autologous neurosensory retinal transplant), and pre- and subretinal amniotic membrane (AM) placement in the MH to act as both a scaffold and release growth factors/cytokines to promote healing.

ADDITIONAL CONVENTIONAL SURGICAL METHODS

For refractory MHs, simply widening the previous ILM peel may help further relieve the tangential traction on the MH and yield subsequent closure in 47% to 69% of cases (Figure 1).10,11 Of note, one study found limited visual improvement even with anatomic improvement.10 Repeat fluid-gas exchange performed in clinic for refractory or reopened MHs yielded a 74% to 89% closure rate and improved vision.12,13

MH SCAFFOLDS

Scaffolds for Müller cell and tissue proliferation within the MH have been proposed as a method to aid the closure of MHs. There are several approaches for this, including the in-verted ILM, ILM free, and lens capsule flap techniques. In ad-

Claire E. Fraser

Ajay E. Kuriyan

doi: 10.3928/23258160-20200702-02

Seenu M. Hariprasad Practical Retina

Co-Editor

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Practical Retina

dition to providing a scaffold, the ILM tissue may contain Müller cell fragments, which has been pos-tulated to induce gliosis, and in turn may enhance MH closure.9,14,15

The inverted ILM flap technique for large MHs, which was first described by Michalewska et al., uti-lizes a wide ILM with care to detach the peripheral

macular ILM while keeping the ILM attached around the MH.14 The detached ILM is then inverted and placed into the MH, followed by fluid-air-exchange.14 This approach yielded a higher rate of closure in patients (98%) compared to traditional MH surgery (88%), along with improved visual outcomes.14 A multicenter series by Narayanan et al. comparing the

Figure 1. Broader internal limiting membrane (ILM) peeling for a refractory macular hole (MH). A 76-year-old man with recent MH and best-corrected visual acuity (BCVA) of 20/200 (A) underwent vit-rectomy, ILM peeling, and gas tamponade with in-complete closure of his MH after 1 month (B) and mild improvement of BCVA to 20/100. A subsequent broader ILM peel was performed and repeat gas tamponade with resulting closure of the MH (C) 1 month after surgery and improvement in BCVA to 20/30.

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Figure 2. Free internal limiting membrane (ILM) flap place-ment for a refractory, traumatic macular hole (MH). A 57-year-old man with a history of ocular trauma resulting in a MH and choroidal rupture (temporal macula) underwent vitrectomy, ILM peeling, and gas tamponade with 1 day of face-down positioning. His hole was refractory (A) and un-derwent a vitrectomy with free ILM flap placement into the hole followed by gas tamponade and 1 week of face-down positioning, with hole closure after 1 month (B), 3 months (C), and 6 months (D) after surgery. His best-corrected vi-sual acuity improved from 20/200 to 20/50.

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Figure 3. Autologous retinal transplant for a large traumatic macular hole (MH). A 59-year-old man with a history of a metal intraocular foreign body in the macula resulting in a large MH with underlying choroidal atrophy (A) and count fingers at 4 feet vision. He underwent vitrectomy, internal limiting membrane peeling, autologous retina transplant into the MH, and silicone oil tamponade for 3 months. The patient had hole closure with gradual integration of the au-tologous retina tissue over 1 week, 3 months, and 6 months after surgery. His best-corrected visual acuity improved to 20/200-1.

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Figure 4. Pre-retinal human amniotic membrane (AM) for a chronic, large macular hole (MH). A 58-year-old man presented with a chronic MH of at least 2 years duration noted initially during prior repair of macula-involving retinal detachment, which did not close after vitrectomy and tam-ponade without internal limiting membrane (ILM) peeling (A). He underwent vitrectomy, ILM peeling, and pre-retinal placement of human AM membrane over the MH, which can be seen plugging the hole with slow partial closure over 1 week (B), 3 months (C), and 8 months of follow-up. Of note, there are still areas where the MH is not fully closed with persistent AM plug. The best-corrected visual acuity improved from count fingers at 3 feet to 20/150.

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outcomes of traditional ILM peeling and the inverted ILM flap technique for MHs 800 µm or larger in di-ameter found nonstatistically significantly improved hole closure (89% vs. 78%) and greater vision recov-ery using the inverted ILM flap technique.16 A larger study by Rizzo et al. found in MHs 400 µm and greater in diameter had significantly higher closure rates us-ing the inverted ILM flap technique (96%) compared to conventional ILM peeling (79%), with better visual outcomes.

Several variations of this technique have been re-ported with positive anatomic and visual outcomes, including peeling only the ILM temporal to the MH, with the edges of the ILM still attached to the MH and then draping the ILM flap over the MH (tempo-ral inverted ILM flap technique),17 and peeling the nasal ILM just beyond the temporal edges of MH and then draping the ILM flap over the MH (Texas taco technique).18

The use of a free ILM flap as a MH scaffold was de-scribed by Morizane et al., which is necessary in cases with a prior complete macular ILM peel (Figure 2).19 Their study found 90% anatomic closure and vision improvement in 10 patients with refractory MHs.19 Similar outcomes were found in another small series

of refractory MHs20 and in a series of large, chronic, and refractory MHs.21 Non-ILM tissue, such as lens capsule, has also been reported to be effective at achieving anatomic closure and improved vision in refractory MHs.22 Additionally the use of viscoelastic agents and perfluorocarbon (PFC) (Perfluoron; Alcon Laboratories, Fort Worth, TX) can help maintain the flap in position and limit the redundancy of the flap in the MH.23,24

INCREASING RETINAL TISSUE COMPLIANCE

Several approaches have been utilized to in-crease the retinal tissue compliance. Charles et al. described a technique, in which an arcuate full-thickness incision 500 µm to 700 µm temporal to the MH was performed followed by gas tamponade for six patients with large, refractory MHs.25 This tech-nique resulted in an 83% MH closure rate and 50% of patients experiences improved vision.25 Reiss et al. described performing five radial incisions cen-tered on the MH, extending one hole diameter away from the MH border, followed by gas tamponade in seven patients with refractory MHs.26 They reported 100% anatomic success rate with a mean gain of 5.6 lines of vision.26

Figure 5. Subretinal human amniotic membrane (AM) graft for a chronic, large macular hole (MH). A 65-year-old woman presented with a 1,310 µm diameter MH of 3 years’ duration that had previously failed repair. A 2-mm human AM graft was placed in a subretinal position. Visual acuity improved from 20/100 to 20/60. (A) Widefield fundus photography of preoperative and (B) postoperative MH. (C) Optical coherence tomography scans show preoperative large MH with (D) closure of the hole at 2 weeks and (E) improving retinal morphology at 10 weeks.

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Another approach to increasing the retinal com-pliance is to induce a macular detachment. Oliver and Wojcik first described successful refractory MH closure after subretinal injection of balanced salt solution within the arcades to create a bleb of subretinal fluid contiguous with the MH in all quadrants, followed by fluid-air exchange to re-move the subretinal fluid, and gas tampoade in a single patient.27 Szigiato et al. reported 10 patients with refractory or recurrent MHs who underwent the same procedure with a 90% closure rate with visual improvement.28 Felfeli and Manderlcorn de-scribed a modification of this technique in which a silicone soft-tip extrusion cannula is initially used to inject subretinal fluid through the MH and then brush the edges of the MH together under passive extrusion, followed by a fluid-air exchange and gas tamponade.29 In a series of 39 refractory, chronic, or 400 µm or larger diameter MHs, they found a 95% closure rate with vision improvement in 95% of patients.29

GROWTH FACTORS/CYTOKINES TO AID HEALING

Growth factors and cytokines drive the wound healing response and their release may aid the clo-sure of MHs.30 Cho et al. found a higher rate of clo-sure of large MHs (≥ 400 µm in diameter) with laser photocoagulation at the center of MH prior to vit-rectomy followed by traditional surgery compared to traditional surgery without presurgical laser photocoagulation.31 The laser group also had sig-nificantly better visual outcomes.31

Another approach to inducing growth factor and cytokine release is the placement of adjuvants into the MH. Smiddy et al. found that utilizing TGFβ2 for refractory MHs led to a 83% closure rate with 3 or more lines of vision in 52% of patients.32 The use of autologous platelet rich plasma (PRP) has been studied in myopic and refractory holes with high closure rates and improved vision.33,34 One study found low rates of closure in refractory MHs with autologous blood,34 but another found high rates when combining the inverted ILM flap tech-nique and autologous blood for large MHs.35

TISSUE REPLACEMENT

Grewal et al. reported 88% closure with sig-nificantly improved vison in refractory MHs after placement of peripheral autologous retina into the MH, followed by gas, oil, or short-term perfluoro-n-octane tamponade (Figure 3).36 This technique has also been successful in myopic MHs.37 It is recom-mended that the retina graft is 0.5 disc diameter larger than the size of the MH.36

AMNIOTIC MEMBRANE

Rizzo et al. first described subretinal human AM (obtained from a tissue bank) placement, followed by gas tamponade in eight patients with refractory MHs, which resulted in 100% closure and improvement of vision.38 Others have used commercially available human amniograft from Biotissue (Tissue Tech, Mi-ami, FL) using sub- and pre-retinal placement (Fig-ures 4 and 5) with improved anatomic and visual outcomes. AM has been shown to be nontoxic to the retina in animal studies, promotes wound healing, and acts as a scaffold.39,40

CONCLUSION

Traditional MH surgery is generally successful, making refractory holes especially vexing for sur-geons. At this point, although no technique has been found to be superior, there are several options sur-geons can utilize for repair of refractory MHs or holes at high risk for failing traditional methods.

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Ajay E. Kuriyan, MD, MS, can be reached at Retina Service/Mid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, 840 Walnut Street, Suite #1020, Philadelphia, PA 19107; email: ajay.kuriyan@gmail.com.

Seenu M. Hariprasad, MD, can be reached at University of Chicago, Department of Ophthalmology and Visual Science, 5841 S. Maryland Ave., Room S-439, Chicago, IL 60637; email: retina@uchicago.edu.

Claire E. Fraser, MD, PhD, can be reached at University of Kentucky, Department of Ophthalmology and Visual Sciences, 110 Conn Terrace, Ste. 550, Lexington, KY 40508; email: claire.fraser@uky.edu.

Disclosures: Dr. Kuriyan receives consulting fees from Genentech/Roche, Regeneron, Alimera Sciences, Allergan, and Bausch Health, as well as grants from Second Sight and Genentech/Roche. Dr. Hariprasad is a consultant or on the speakers bureau for Allergan, Novartis, Biogen, Graybug, EyePoint, Alimera Sciences, Spark, and Regeneron. Dr. Fraser reports no relevant financial disclosures.This work was supported in part by an unrestricted grant to the Flaum Eye Institute from Research to Prevent Blindness and and grant P30EY001319-35 from the National Institutes of Health. The sponsors and funding organizations had no role in the design or conduct of this research.