Think Medically About Macular Holes

Stages of macular hole development - Stage 4
Stages of macular hole development – Stage 4
Karen Wai, MD, and Nimesh Patel, MD, review the literature on alternatives to surgery for patients with macular holes.

Full-thickness macular holes (FTMHs) are full thickness defects of the neurosensory retina involving the internal limiting membrane (ILM) to the retinal pigment epithelium (RPE). Managing them properly requires swift intervention, as they can lead to permanent visual impairment if untreated. Most patients will be managed using surgical intervention. Diagnostic techniques have improved significantly in the last couple of decades and, as a result, macular holes are better identified and characterized. That gives physicians the option to, in some cases, treat with a medical approach. 

Not every macular hole requires prompt surgery, but every case should be carefully evaluated. Knowing what medical therapies are available and understanding its limitations are elemental in nonsurgical management. Patients treated medically will require long-term follow up and clinicians should be keenly aware of which patients will require an operation for hole closure. 

Macular Hole Statistics 

The estimated incidence of macular holes is 8.69 eyes per 100,000 population per year.1 FTMHs can lead to visual symptoms such as distorted central vision, scotoma, and metamorphopsia. They typically present in patients older than 60 years and are more common in women than men. Researchers believe macular holes likely develop from anteroposterior or tangential vitreoretinal traction of the posterior hyaloid on the parafovea.2,3 

Surgeons have had options for macular hole repair for more than 30 years (with the first successful report of FTMH closure with surgical intervention demonstrated in 1991).4 With improvements in surgical techniques, the successful closure rate for macular hole surgery today is high, exceeding 80 to 90 percent.5,6 Typically, surgical approach includes a pars plana vitrectomy with possible internal limiting membrane peeling, and a possible gas tamponade. However, vitrectomy is associated with risks that can include cataract formation, infection, bleeding, or retinal detachment. Further, if intraocular gas is used, patients typically need to position face-down for 3 to 7 days pending surgeon preference, which can be inconvenient and difficult for patients. 

A small percentage of macular holes can spontaneously close without any intervention. The incidence of spontaneous closure of idiopathic FTMH without any treatment varies from 4 to 11.5 percent, typically occurring about 3 to 4 months after initial examination.7 A 2019 study shows that FTMHs with spontaneous closure tend to have a smaller diameter (<250 µm) with optical coherence tomography (OCT) characteristics of release of vitreomacular traction or cystic structures.7

Medical Therapies

Previous research has explored intravitreal ocriplasmin, an FDA-approved medication for treatment of symptomatic vitreomacular adhesion. Ocriplasmin is a proteolytic enzyme with activity against fibronectin and laminin, which are components of the vitreoretinal interface.8 It can perform enzymatic vitreolysis, thus separating the hyaloid from underlying retina and relieving the traction on the FTMH. Studies show ocriplasmin tends to work best for smaller and medium sized FTMH, and for patients without an epiretinal membrane at baseline.9 However, ocriplasmin treatment is associated with a relatively poor rate of hole closure.10 A recent meta-analysis demonstrates a 34% rate of closure with ocriplasmin.10 Further, some research indicates a risk of serious adverse side effects including electroretinography (ERG) changes, lens subluxation, and dyschromatopsia.11 Given the relatively low success rate and suboptimal side effect profile, ocriplasmin has not been widely adapted and distribution of the drug was discontinued by its manufacturers in 2020. 

Pneumatic vitreolysis has also been proposed as a possible mechanism to close macular holes, especially in the setting of vitreomacular traction. Pneumatic vitreolysis consists of an intravitreal injection of an expansile gas bubble, commonly 100% perfluoropropane (C3F8). However, the closure rates with pneumatic vitreolysis are relatively poor, with reviews demonstrating rates of approximately 45%.8 A recent study of 14 eyes with vitreomacular traction and macular hole reported successful closure of 4 eyes with a pneumatic vitreolysis; however, of the 10 that did not close, their FTMH enlarged in diameter.12 

Multiple small studies have utilized various eye drops for FTMH closure. A recent case series demonstrated 14 patients who had successful hole closure with topical medical treatment in 2 to 8 weeks.13 The topical medical regimen consisted of a topical steroid eye drop (such as prednisone or difluprednate, dosed every 6 to 12 hours), anti-inflammatory drops (ketorolac or bromfenac, dosed every 6 to 24 hours), and carbonic anhydrase inhibitor (brinzolamide or dorzolamide, dosed every 6 to 12 hours). Of note, the FTMHs in this study were also of smaller diameter, with an average diameter of 166 µm. The mechanism of closure of FTMH by medical therapy is not fully understood, but researchers hypothesize that medications may facilitate macular hole closure by decreasing inflammation, reducing swelling, and dehydrating the retina. The retinal pigment epithelium pump is able to shrink the cystoid fluid pockets, and this process allows for the edges of the macular hole to reappose back together.13 

The majority of FTMHs do require surgical intervention for closure; however, there are some holes that may be more amenable to closure by medical management.14 Holes that are most amenable to closure by medical management are typically smaller in minimum linear diameter (<250 µm). In a 2022 case series, for example, investigators reviewed 7 eyes of 7 patients with FTMH treated with medical therapy. Of the 6 patients who were kept on medical therapy, 1 developed recurrence (the seventh patient was taken off of maintenance therapy and later developed a recurrent macular hole that did require surgery). That research team concluded that medical therapy could decrease macular edema and may facilitate macular hole closure, making it a viable option, especially in the case of small macular holes with significant edema.15 

Eyes without pre-existing vitreomacular traction may respond better to topical management rather than vitrectomy. Eyes that have previously been vitrectomized or show cystoid hydration may also better respond to topical treatment.13 Even though topical medications are less invasive when compared to surgical treatment, it is important to remember that there are potential side effects from topical therapy including elevations in intraocular pressure, corneal melting, and surface irritation. 

Know When Surgery is Necessary 

Conversely, some FTMH require surgical intervention for closure, especially larger holes.13 Holes with residual traction from vitreoretinal and epiretinal layers are also less likely to close with medical treatment and may require surgical intervention to relieve the traction on the hole. Holes that have developed in the setting of high myopia or those that do not have surrounding edema are also more likely to require surgical treatment.13,14

Larger studies with randomization are needed to assess the true efficacy of medical management compared with surgical treatment of macular holes. 

Some situations may warrant a trial of topical therapy relative to surgical treatment, such as patients who are poor surgical candidates, patients who cannot tolerate face down position, or patients who may have a lengthy preoperative waiting period.13

Ophthalmologists should be aware of characteristics that may allow a FTMH to be more amenable to a trial of topical therapy first, taking into consideration patient specific factors and patient choice. 

Karen M. Wai, MD, is a surgical vitreoretinal fellow at Byers Eye Institute, Stanford Ophthalmology. Nimesh Patel, MD, is an Instructor of ophthalmology at Massachusetts Eye and Ear and Harvard Medical School and Director of Pediatric Retina at Boston Children’s Hospital, Boston.

References

1. McCannel CA, Ensminger JL, Diehl NN, Hodge DN. Population based incidence of macular holes. Ophthalmol. 2009;116(7):1366-1369. doi:10.1016/j.ophtha.2009.01.052.Population

2. Gentile RC, Landa G, Pons ME, Eliott D, Rosen RB. Macular hole formation, progression, and surgical repair: Case series of serial optical coherence tomography and time lapse morphing video study. BMC Ophthalmol. 2010;10(1):2-7. doi:10.1186/1471-2415-10-24

3. Takezawa M, Toyoda F, Kambara C, Yamagami H, Kakehashi A. Clarifying the mechanism of idiopathic macular hole development in fellow eyes using spectral-domain optical coherence tomography. Clin Ophthalmol. 2011;5(1):101-108. doi:10.2147/OPTH.S16549

4. Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular holesresults of a pilot study. Arch Ophthalmol. 1991;109(5):654-659. doi:10.1001/archopht.1991.01080050068031

5. Sheidow TG, Blinder KJ, Holekamp N, et al. Outcome results in macular hole surgery: An evaluation of internal limiting membrane peeling with and without indocyanine green. Ophthalmol. 2003;110(9):1697-1701. doi:10.1016/S0161-6420(03)00562-1

6. Kumagai K, Furukawa M, Ogino N, Uemura A, Demizu S, Larson E. Vitreous surgery with and without internal limiting membrane peeling for macular hole repair. Retina. 2004;24(5):721-727. doi:10.1097/00006982-200410000-00006

7. Liang X, Liu W, Ohira A. Characteristics and risk factors for spontaneous closure of idiopathic full-thickness macular hole. J Ophthalmol. Published online March 13, 2019. doi:10.1155/2019/4793764

8. Madi HA, Masri I, Steel DH. Optimal management of idiopathic macular holes. Clin Ophthalmol. 2016;10:97-116. doi:10.2147/OPTH.S96090

9. Dugel PU, Regillo C, Eliott D. Characterization of anatomic and visual function outcomes in patients with full-thickness macular hole in ocriplasmin phase 3 trials. Am J Ophthalmol. 2015;160(1):94-99.e1. doi:10.1016/j.ajo.2015.03.017

10. Yu BE, Sheidow T, Sambhi RDS, Hooper P, Malvankar-Mehta MS. The effectiveness of ocriplasmin versus surgery for the treatment of macular holes: A systematic review and meta-analysis. Eur J Ophthalmol. 2021;31(4):2003-2012. doi:10.1177/1120672120946925

11. Shaikh M, Miller JB, Papakostas TD, Husain D. The efficacy and safety profile of ocriplasmin in vitreomacular interface disorders. Semin Ophthalmol. 2017;32(1):52-55. doi:10.1080/08820538.2016.1228416

12. Baumann C, Sabatino F, Zheng Y, et al. Anatomical and functional outcomes of pneumatic vitreolysis for treatment of vitreomacular traction with and without macular holes. Graefe’s Arch Clin Exp Ophthalmol. Published online February 5, 2022. doi:10.1007/s00417-022-05568-y

13. Sokol JT, Schechet SA, Komati R, et al. Macular hole closure with medical treatment. Ophthalmol Retin. 2021;5(7):711-713. doi:10.1016/j.oret.2020.11.018

14. Ittarat M , Somkijrungroj T, Chansangpetch S , Pongsachareonnont P. Literature review of surgical treatment in idiopathic full-thickness macular hole. Clin Ophthalmol. Published online July 13, 2020. doi:10.2147/OPTH.S262877

15. Kokame G, Johnson M, Lim J, et al. Closure of full-thickness macular holes associated with macular edema with medical therapy. Ophthalmologica. 2022;245(2):179–186. doi:10.1159/000516018.