Data Presented at Retina 2019 Suggest that the Number of Anti–Vascular Endothelial Growth Factor Injections does not Affect the Rate of Macular Hole Development

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population in the developed world and its prevalence increases with age, ranging from 3.5% in those aged 55–59 years to 17.6% in those aged 85 years or over.¹ Anti–vascular endothelial growth factor (anti-VEGF) agents administered by regular intravitreal injection have become the standard of care for the treatment of AMD and are typically administered every 50–55 days, although this can vary according to country.² Despite slowing disease progression and improving visual outcomes, intravitreal injection of anti-VEGF agents may be associated with systemic adverse events and devastating ocular complications.³ One potential complication is macular hole, a small break in the macular that can cause blurred and distorted central vision. Idiopathic macular hole formation has been reported in 0.02 to 0.8% of the population⁴ and is due to contraction of the prefoveal vitreous cortex, causing focal tangential traction on the fovea.⁵

Individual case reports and small case studies of macular hole formation following anti-VEGF formation have been reported in the literature,^6-10 but it is not clear whether these were coincidental findings or the macular holes were a direct consequence of the injections. It has been speculated that posterior vitreous detachment following intravitreal injections is involved in the formation of these holes. A small prospective observational study of 61 patients found that posterior vitreous detachment occurred in 25% of cases; this increased with increasing age and numbers of injections.¹¹ Other possible mechanisms that have been suggested include an increase in intravitreal traction due to globe deformation during needle insertion,¹⁰ and contraction of the vascular membrane caused by the anti-VEGF agents.⁹

A study presented at the Retina 2019 Meeting, which was held in Waikoloa, Hawaii, investigated whether surgical intervention in cases of macular hole in wet and dry AMD would make a difference in visual acuity and hole closure outcomes. The retrospective, single-center chart review involved 12,716 patients with neovascular AMD and 15,196 patients with non-neovascular AMD. Macular hole developed in 199 eyes (0.7%), a similar incidence to that reported in idiopathic cases in patients without AMD. Of the cases of macular hole, 39 (0.3%) were seen in eyes with wet AMD and 160 (1%) in eyes with dry AMD. The mean number of injections before diagnosis of macular hole in eyes with wet AMD was 2.4.

Among the eyes that developed macular hole, 104 (81.8%) underwent surgery and internal limiting membrane peel. This resulted in closure in 89.8% of cases, but outcomes were worse in wet AMD (closure rate 81%) than in for dry AMD (closure rate 91.5%). There was no difference in visual acuity in eyes with wet AMD that underwent surgery, but there was a statistical difference in eyes with dry AMD (p< 0.001). Even though closure rates were similar in both groups, visual outcomes were better in patients with non-neovascular AMD with macular hole who underwent surgery than they were in those with neovascular AMD. The number of anti-VEGF agents used did not appear to increase the rate of macular hole formation. It seems likely that macular hole may represent only a coexisting pathology in older patients with AMD rather than an adverse effect to anti-VEGF treatment.

Given the large number of patients treated with anti-VEGF injections, this is reassuring news for ophthalmologists. Principal investigator Lisa J Faia, MD, commented: “I am a very aggressive injector. I didn’t want to be causing other problems.” Ophthalmologists should pay attention to the potential for vitreomacular changes following anti-VEGF formations. However, this study adds evidence that the benefits of anti-VEGF therapy greatly outweigh the risks.

Published: 30 January 2019

References

1. Colijn JM, Buitendijk GHS, Prokofyeva E, et al. Prevalence of age-related macular degeneration in Europe: The past and the future. Ophthalmology. 2017;124:1753–63.
2. Ferreira A, Sagkriotis A, Olson M, et al. Treatment frequency and dosing interval of ranibizumab and aflibercept for neovascular age-related macular degeneration in routine clinical practice in the USA. PLoS One. 2015;10:e0133968.
3. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of literature. Eye (Lond). 2013;27:787–94.
4. McCannel CA, Ensminger JL, Diehl NN, et al. Population-based incidence of macular holes. Ophthalmology. 2009;116:1366–9.
5. Gass JD. Idiopathic senile macular hole: Its early stages and pathogenesis. 1988. Retina. 2003;23:629–39.
6. Kabanarou SA, Xirou T, Mangouritsas G, et al. Full-thickness macular hole formation following anti-VEGF injections for neovascular age-related macular degeneration. Clin Interv Aging. 2017;12:911–5.
7. Oshima Y, Apte RS, Nakao S, et al. Full thickness macular hole case after intravitreal aflibercept treatment. BMC Ophthalmol. 2015;15:30.
8. Shif OA, Katz MSJ. Surgical management of full-thickness macular hole superimposed on exudative age-related macular degeneration. Retin Cases Brief Rep. 2018; doi: 10.1097/ICB.0000000000000786.
9. Mukherjee C, Mitra A, Kumar NA, et al. Macular hole formation after intravitreal ranibizumab injection in wet age-related macular degeneration. Open Ophthalmol J. 2015;9:177–80.
10. Grigoropoulos V, Emfietzoglou J, Nikolaidis P, et al. Full-thickness macular hole after intravitreal injection of ranibizumab in a patient with retinal pigment epithelium detachment and tear. Eur J Ophthalmol. 2010;20:469–72.
11. Geck U, Pustolla N, Baraki H, et al. Posterior vitreous detachment following intravitreal drug injection. Graefes Arch Clin Exp Ophthalmol. 2013;251:1691–5.