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Effect of intravitreal injections due to neovascular age-related macular degeneration on retinal nerve fiber layer thickness and minimum rim width: a cross sectional study
BMC Ophthalmology volume 24, Article number: 185 (2024)
Abstract
Purpose
The present study tested the hypothesis that repeated anti-VEGF injections are associated with reduced retinal nerve fiber layer (RNFL) and minimum rim width (MRW) of the optic nerve head.
Patients and methods
Sixty-six patients with a history of intravitreal injections due to neovascular age-related macular degeneration were included. RNFL and MRW were measured using optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany).
Results
Mean global RNFL was 90.62 μm and both RNFL as well as MRW significantly decreased with advanced age (p = 0.005 and p = 0.019, respectively). Correlating for the number of injections, no significant impact on RNFL was found globally (p = 0.642) or in any of the sectors. In contrast, however, global MRW was significantly reduced with increasing numbers of intravitreal injections (p = 0.012). The same holds true when adjusted for the confounding factor age (RNFL p = 0.566 and MRW p = 0.023).
Conclusion
Our study shows that repeated intravitreal injections due to choroidal neovascularization seem to have a deleterious effect on MRW but not on RNFL. This suggests that MRW is a more sensitive marker than RNFL for evaluating the effect of frequent intravitreal injections on the optic nerve head since it seems to be the first structure affected.
Background
Around 15 years ago, the introduction and utilization of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) antibodies has tremendously enhanced the treatment options and visual outcome for several eye diseases associated with macular edema, such as neovascular age-related macular degeneration (n-AMD), retinal vein occlusion, and diabetic retinopathy [1,2,3,4,5,6,7,8,9]. In general, anti-VEGF injections are considered safe and the benefits outweigh by far the possible ocular complications [10]. However, unlike laser therapy, patients usually have to undergo frequent reinjections each year to remain visually and morphologically stable. Subsequently, the risk of adverse events may be increased by the continuous long-term. As one would assume, the loading of additional fluid into the eyeball can raise intraocular pressure (IOP). Therefore, several studies were conducted investigating IOP following anti-VEGF injections [11,12,13]. A meta-analysis of 46 studies on this topic showed that IOP was significantly increased for all measured time-intervals of the day of injection, but slightly decreased on the day after injection and returned to normal thereafter [14]. These IOP fluctuations along with possible fluctuations in blood perfusion of the optic nerve head may lead to glaucoma over time.
The introduction of Optical Coherence Tomography (OCT) made it possible to detect early structural changes and at the same time deliver objective parameters in contrast to perimetry. In addition to a thinning of peripapillary retinal nerve fiber layer thickness (RNFL), another OCT parameter, i.e. Bruch’s membrane opening minimum rim width (MRW) has been established more recently for the assessment of optic discs. Hence, the present study tested the hypothesis that repeated anti-VEGF injections are associated with reduced RNFL and MRW of the optic nerve head.
Materials and methods
This cross sectional study was conducted after approval from the Ethics Committee of the City of Vienna had been obtained (EK 20-352-VK) and adhered to the tenets of the Declaration of Helsinki. Due to the retrospective character of the study, informed consent was waived in agreement with the positive vote of the above-mentioned Ethics Committee. Patients with a history of intravitreal injections due to neovascular AMD were included. Intravitreal injections with anti-VEGF were applied without paracentesis and according to the pro-re-nata regimen. RNFL and MRW were measured using optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) and analyzed using the build in software (Heyex 2, Figs. 1 and 2) with included age-matched reference values. If necessary, manual corrections of retinal nerve fiber layer segmentation and Bruch’s membrane opening were undertaken by a trained physician. Exclusion criteria were presence of uncontrolled elevated IOP over 21mmHg prior to injections, a history of ischemic opticus atrophy, diagnosis of glaucoma prior to anti-VEGF treatment as well as presence of a clinically significant epiretinal membrane and high myopia. Statistical analysis and linear regression models were carried out in R (version 4.0.3, R Foundation for Statistical Computing, Vienna, Austria).
Results
Sixty-six eyes of patients with CNV and a mean age of 83.4 years and an average of 12.58 prior injections were included (Fig. 3).
Mean global RNFL was 90.62 μm and significantly decreased with advanced age (p = 0.005, Fig. 4).
Similarly, RNFL of the nasal-superior (p = 0.025), temporal-superior (p < 0.001), temporal-inferior (p = 0.004) sectors highly significantly correlated with age as well, whereas this did not hold true for the nasal (p = 0.237), the temporal (p = 0.216), and the nasal-inferior (p = 0.862) sector. Advanced age was also significantly associated with lower global MRW (p = 0.019, Fig. 5), nasal-superior (p = 0.020), temporal-superior (p = 0.014), temporal (p = 0.004), and temporal-inferior (p = 0.019) MRW, but not with nasal (p = 0.272) and nasal-inferior (p = 0.103) MRW.
Correlating for the number of injections, no significant impact on RNFL was found globally (p = 0.642, Fig. 6) or in any of the sectors.
In contrast, however, global MRW was significantly reduced with increasing number of intravitreal injections (p = 0.012, Fig. 7).
Adjusting for the confounding factor age, the level of significance neither changed for RNFL (p = 0.566, Fig. 8) nor for MRW (p = 0.023, Fig. 9).
Looking at the MRW sectors individually, the temporal (p = 0.011), and the temporal-inferior (p = 0.044) sector also significantly correlated with number of injections, whereas the other sectors did not (nasal p = 0.079; nasal-superior p = 0.099; temporal-superior p = 0.065; nasal-inferior p = 0.141).
Discussion
Our study shows that repeated intravitreal injections due to choroidal neovascularization seem to have a deleterious effect on MRW but not on RNFL. The latter is in accordance with the majority of previous studies conducted on this topic [14,15,16,17,18,19,20,21,22]. However, two studies by Parlak et al. and Martinez-de-la-Casa et al. found a significant thinning of RNFL after administration of ranibizumab in patients with CNV [23, 24]. The former study found a significant reduction in RNFL in both, the treatment arm as well as the untreated control arm with dry AMD at follow up, but no significant difference between both groups which questions the hypothesis that anti-VEGF injections caused this effect. The latter study only included treatment naïve patients, and as such they showed increased macular thickness, especially in the nasal quadrant, which was significantly reduced after treatment. One can speculate that the reduction of fluid in the nasal macula may also have an impact on RNFL measurements especially given that most reduction happened in the temporal sector of the optic nerve head as well as at first follow-up at 3 months and did not significantly change thereafter over the course of 12 months [24]. This effect may also explain the findings of another study that associated a thickening on the temporal RNFL quadrant to repeated anti-VEGF injections [25].
Limitations of our own study are the lack of axial eye length measurements which may have an effect on MRW analysis. We tried to minimize this by excluding patients with high myopia.
The lack of effect on RNFL in our study may be attributed to the average number of injections of 12.58 prior to inclusion, and RNFL thinning possibly presents itself just after a longer period of treatment which may also explain the results of the afore mentioned studies mainly in treatment naïve patients. Whether this can only be seen after a higher number of injections (> 30 and more) as suggested by a cross-sectional paper [26] remains to be seen in further studies.
To the best of our knowledge, only one other study investigated the effect of repeated intravitreal injections on other biomarkers of the optic nerve head, such as Bruch’s membrane opening (BMO) [27]. In the study conducted in 29 patients with CNV, diabetic edema, and retinal vein occlusion, a significant increase in BMO was found immediately, i.e. 5 min after each of the first 3 anti-VEGF injections, but this effect did not seem to persist after 12 months. In accordance with our paper, they found no negative effect on RNFL.
The mechanisms underlying the different response of MRW and RNFL to anti-VEGF injections are not clearly understood. However, recent papers have suggested that the rate of change in MRW is significantly greater than RNFL in patients with glaucoma over the course of disease and thus per se a more sensitive biomarker [28, 29].
Since IOP fluctuations after intravitreal injections are only temporary, one also needs to take other potential pathways of optic nerve head damage into account. As such, blood perfusion has been shown to play a critical role in the pathogenesis of glaucoma [30]. VEGF can induce the release of nitric oxide [31] and thereby improve blood flow. Another mechanism may be that VEGF seems to have a neuroprotective effect [32, 33]. Therefore, VEGF inhibition potentially leads to both lower perfusion of the optic nerve had and to limited neuroprotection.
Conclusion
In conclusion, our study suggests that MRW is a more sensitive marker than RNFL for evaluating the effect of frequent intravitreal injections on the optic nerve head since it seems to be the first structure affected. However, further longitudinal studies are warranted to widen our understanding of the potential role of anti-VEGF injections in the pathogenesis of glaucoma.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–31.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus Verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432–44.
CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and Bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.
Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration [published correction appears in Ophthalmology. 2013;120(1):209– 10]. Ophthalmology. 2012;119(12):2537–2548.
Kornhauser T, Schwartz R, Goldstein M, Neudorfer M, Loewenstein A, Barak A. Bevacizumab treatment of macular edema in CRVO and BRVO: long-term follow-up. (BERVOLT study: Bevacizumab for RVO long-term follow-up). Graefes Arch Clin Exp Ophthalmol. 2016;254(5):835–44.
Tadayoni R, Waldstein SM, Boscia F, et al. Individualized stabilization criteria-driven ranibizumab versus laser in Branch Retinal vein occlusion: six-Month results of BRIGHTER. Ophthalmology. 2016;123(6):1332–44.
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789–801.
Clark WL, Boyer DS, Heier JS, et al. Intravitreal Aflibercept for Macular Edema following branch retinal vein occlusion: 52-Week results of the VIBRANT study. Ophthalmology. 2016;123(2):330–6.
Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2017;237(4):185–222.
Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013;27(7):787–94.
Hollands H, Wong J, Bruen R, Campbell RJ, Sharma S, Gale J. Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol. 2007;42(6):807–11.
Lemos V, Cabugueira A, Noronha M, et al. Intraocular pressure in eyes receiving Intravitreal Antivascular endothelial growth factor injections. Ophthalmologica. 2015;233(3–4):162–8.
Lee JW, Park H, Choi JH, et al. Short-term changes of intraocular pressure and ocular perfusion pressure after intravitreal injection of bevacizumab or ranibizumab. BMC Ophthalmol. 2016;16:69. Published 2016 May 31.
de Vries VA, Bassil FL, Ramdas WD. The effects of intravitreal injections on intraocular pressure and retinal nerve fiber layer: a systematic review and meta-analysis. Sci Rep. 2020;10(1):13248. Published 2020 Aug 6.
Demirel S, Batioğlu F, Özmert E, Erenler F. The effect of multiple injections of ranibizumab on retinal nerve fiber layer thickness in patients with age-related macular degeneration. Curr Eye Res. 2015;40(1):87–92.
Valverde-Megías A, Ruiz-Calvo A, Murciano-Cespedosa A, Hernández-Ruiz S, Martínez-de-la-Casa JM, García-Feijoo J. Long-term effect of intravitreal ranibizumab therapy on retinal nerve fiber layer in eyes with exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2019;257(7):1459–66.
Sobacı G, Güngör R, Ozge G. Effects of multiple intravitreal anti-VEGF injections on retinal nerve fiber layer and intraocular pressure: a comparative clinical study. Int J Ophthalmol. 2013;6(2):211–5. Published 2013 Apr 18.
Shin HJ, Shin KC, Chung H, Kim HC. Change of retinal nerve fiber layer thickness in various retinal diseases treated with multiple intravitreal antivascular endothelial growth factor. Invest Ophthalmol Vis Sci. 2014;55(4):2403–11. Published 2014 Apr 15.
Ahn J, Jang K, Sohn J, Park JI, Hwang DD. Effect of intravitreal ranibizumab and aflibercept injections on retinal nerve fiber layer thickness. Sci Rep. 2021;11(1):5010. Published 2021 Mar 3.
Zivkovic M, Radosavljevic A, Zlatanovic M, et al. Influence of multiple Anti-VEGF injections on retinal nerve Fiber layer and Ganglion Cell-Inner Plexiform Layer Thickness in patients with exudative age-related Macular Degeneration. Med (Kaunas). 2023;59(1):138. Published 2023 Jan 10.
Jun SY, Hwang DD. Short-term effect of intravitreal brolucizumab injections in patients with neovascular age-related macular degeneration on retinal nerve fiber layer thickness. Sci Rep. 2023;13(1):6685. Published 2023 Apr 24. https://0-doi-org.brum.beds.ac.uk/10.1038/s41598-023-32024-6.
Wichrowska M, Goździewska E, Kocięcki J. The safety of Anti-VEGF treatment, in the context of the retinal nerve Fibre Layer, in patients with wet age-related Macular Degeneration: a review. Front Biosci (Landmark Ed). 2023;28(9):222.
Parlak M, Oner FH, Saatci AO. The long-term effect of intravitreal ranibizumab on retinal nerve fiber layer thickness in exudative age-related macular degeneration. Int Ophthalmol. 2015;35(4):473–80.
Martinez-de-la-Casa JM, Ruiz-Calvo A, Saenz-Frances F, et al. Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab. Invest Ophthalmol Vis Sci. 2012;53(10):6214–8. Published 2012 Sep 14.
Yau GL, Campbell RJ, Li C, Sharma S. Peripapillary RNFL thickness in nonexudative versus chronically treated exudative age-related macular degeneration. Can J Ophthalmol. 2015;50(5):345–9.
Wang L, Swaminathan SS, Yang J, et al. Dose-response relationship between Intravitreal injections and retinal nerve Fiber layer thinning in Age-Related Macular Degeneration. Ophthalmol Retina. 2021;5(7):648–54.
Gómez-Mariscal M, Puerto B, Muñoz-Negrete FJ, de Juan V, Rebolleda G. Acute and chronic optic nerve head biomechanics and intraocular pressure changes in patients receiving multiple intravitreal injections of anti-VEGF. Graefes Arch Clin Exp Ophthalmol. 2019;257(10):2221–31.
Cho HK, Kee C. Rate of change in Bruch’s membrane opening-minimum Rim Width and Peripapillary RNFL in early normal tension Glaucoma. J Clin Med. 2020;9(8):2321.
Choi HS, Joo CW, Park SP, Na KI. A decrease in Bruch’s membrane opening-minimum Rim Area precedes decreased retinal nerve Fiber layer thickness and visual field loss in Glaucoma. J Glaucoma. 2021;30(12):1033–8.
Flammer J, Orgül S, Costa VP, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21(4):359–93.
Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol. 1998;274(3):H1054–8.
Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol. 2007;171(1):53–67.
Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals. 2005;14(5):207–21.
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A.B. was primary responsible for the study design, protocol and manuscript.T.S. was responsible for protocol and manuscript.W.H. was responsible for statistical analysis and figures.B.W. and V.V. provided general supervision and feedback and reviewed the manuscript.All authors reviewed and approved the final manuscript.
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This cross sectional study was conducted after approval from the Ethics Committee of the City of Vienna had been obtained (EK 20-352-VK) and adhered to the tenets of the Declaration of Helsinki. Due to the retrospective character of the study, informed consent was waived in agreement with the positive vote of the above-mentioned Ethics Committee.
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Boltz, A., Spöttl, T., Huf, W. et al. Effect of intravitreal injections due to neovascular age-related macular degeneration on retinal nerve fiber layer thickness and minimum rim width: a cross sectional study. BMC Ophthalmol 24, 185 (2024). https://0-doi-org.brum.beds.ac.uk/10.1186/s12886-024-03453-2
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DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s12886-024-03453-2