Retinal Nerve Fiber Layer Thickness in Patients Receiving Chronic Anti–Vascular Endothelial Growth Factor Therapy

doi:10.1016/j.ajo.2010.04.029

American Journal of Ophthalmology

Volume 150, Issue 4, October 2010, Pages 558-561.e1

https://doi.org/10.1016/j.ajo.2010.04.029 Get rights and content

Purpose

To evaluate the effects of multiple intravitreal injections of anti–vascular endothelial growth factor (VEGF) agents on the thickness of the retinal nerve fiber layer (RNFL) in patients with wet age-related macular degeneration (ARMD).

Design

Retrospective, observational, consecutive case series of patients diagnosed with wet ARMD.

Methods

Forty-one eyes of 37 consecutive patients (25 female and 12 male; mean age 79.2 ± 8.7 years) who underwent treatment with pegaptanib, bevacizumab, and/or ranibizumab for ARMD followed by sequential RNFL thickness measurement by optical coherence tomography (OCT) were studied. Patients were included in the analyses if they had greater than 10 total anti-VEGF injections, RNFL measurements prior to the first injection, and at least 12 months of follow-up. Patients were divided into 3 groups depending on which anti-VEGF agent(s) they received. The OCT RNFL measurements at the initial and final follow-up were used for analyses.

Results

Average follow-up for all patients was 27.0 ± 9.7 months and they received an average of 16.0 ± 5.5 intravitreal injections. The average RNFL thickness at presentation was 92.4 ± 15.2 μm and at last follow-up was 93.8 ± 15.2 μm (P = .68). There were no statistically significant differences in RNFL measurements when comparing between individual anti-VEGF treatment groups.

Conclusion

Long-term treatment with anti-VEGF agents did not lead to significant changes in RNFL thickness in a patient population with wet ARMD. Despite the possibility of repeated intraocular pressure (IOP) fluctuations after intravitreal injections and known neurotrophic properties of VEGF in the eye, chronic therapy with intravitreal anti-VEGF agents does not appear to adversely affect RNFL thickness. Further prospective studies with longer follow-up are needed to corroborate the findings of this study.

Section snippets

Methods

This is a retrospective, observational, consecutive case series of patients who had received more than 10 intravitreal injections of pegaptanib sodium, bevacizumab, ranibizumab, or a combination of these anti-VEGF agents at the Rocky Mountain Lions Eye Institute, University of Colorado Department of Ophthalmology. All patients who had a diagnosis of ARMD receiving anti-VEGF therapy between June 2005 and January 2008 were identified and those with documented RNFL thickness measurement by optical

Results

Records were available for 184 patients who had received intravitreal anti-VEGF agents between 2005 and 2008 at the University of Colorado. Of these, 119 received injections for the diagnosis of wet ARMD. Fifty-five patients had received more than 10 intravitreal injections of anti-VEGF agents. There were 37 patients who had more than 1 year of follow-up and an RNFL measurement by OCT before their first injection and at last follow-up visit. A total of 41 eyes of these 37 consecutive patients

Discussion

As the use of intravitreal anti-VEGF agents for the treatment of choroidal neovascular membranes in patients with wet ARMD becomes the standard of care, our understanding of potential postinjection side effects continues to evolve. Multiple studies have shown that there is an IOP elevation associated with intraocular injections of anti-VEGF agents.5, 6, 7, 8, 9, 10 This IOP elevation has been shown to fall below 30 mm Hg by 30 minutes and back to baseline by 30 to 60 minutes for most patients.7

Michael B. Horsley, MD, is currently an ophthalmology resident at the University of Colorado at Denver, Colorado. He received his BA in Spanish from Brigham Young University and then earned his medical degree at The University of Illinois at Chicago. He then completed his transitional internship training at Tucson Hospitals Medical Education Program. After finishing residency at the University of Colorado in 2010, he will begin a glaucoma fellowship at Massachusetts Eye and Ear Infirmary.

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Cited by (83)

Short-term effect of macular edema on the peripapillary retinal nerve fiber layer in patients with wet age-related macular degeneration and diabetic macular edema: A comparative study
2023, Photodiagnosis and Photodynamic Therapy
The combined presence of glaucoma and age-related macular degeneration (ARMD), or glaucoma and diabetes mellitus (DM), occur fairly frequently, especially in elderly patients. This study was intended to compare the effect of resolving macular edema due to DM and wet ARMD on peripapillary retinal nerve fiber layer (RNFL) thickness.
This cross-sectional study included 76 patients with macular edema secondary to DM (n = 40, 52.6%) or wet ARMD (n = 36, 47.4%). The control group was comprised of 34 age and sex-matched healthy subjects. All study participants underwent evaluation of central macular thickness (CMT) and the peripapillary RNFL using spectral domain-optical coherence tomography (SD-OCT). Data from eyes that received an anti-VEGF injection were obtained one month after the procedure and were compared with pre-injection data.
The average initial thickness of the global peripapillary RNFL was 98.9 ± 16.7 (61–163) µm in the macular edema group and 92.0 ± 16.0 (84–115) µm in the control group (p = 0.045). The post-injection global peripapillary RNFL thickness was 97.3 ± 19.0 (61–163) µm in the macular edema group and 92.2 ± 18.0 (81–126) µm in the control group (p = 0.187). In the DM group, the changes in global RNFL thickness, as well as central and temporal quadrant thicknesses, were found to correlate significantly with the change in CMT (r = 0.356, p = 0.024; r = 0.545, p < 0.001, respectively).
Macular edema in wet ARMD appeared not to affect RNFL thickness. Differences in the etiology of macular edema can have varied effects on peripapillary RNFL. It is recommended that peripapillary RNFL thickness be evaluated cautiously in DM patients receiving intravitreal anti-VEGF therapy.
Prophylactic intraocular pressure lowering measures in anti-vascular endothelial growth factor therapy: A systematic review and meta-analysis
2023, Survey of Ophthalmology
Acute intraocular pressure (IOP) elevation following repeat intravitreal anti-vascular endothelial growth factor (VEGF) injections (IVI) may pose a risk to the integrity of the retinal nerve fiber (RNFL). This meta-analysis investigates the role of IOP-lowering interventions such as an anterior chamber paracentesis (ACP) and IOP-lowering medications on the IOP in patients undergoing IVIs.
MEDLINE, EMBASE, and the Cochrane Library were searched up to February, 2021. Studies investigating IOP-lowering interventions in patients undergoing IVI versus controls were included. The primary outcome was the IOP in the short- and long-term post-IVI. Secondary outcomes were changes in the RNFL thickness and best corrected visual acuity (BCVA).
ACP at time of anti-VEGF injection significantly lowered IOP immediately post anti-VEGF (WMD: -27.98 mm Hg, P < 0.001). Patients in the ACP group also had significantly thicker RNFL compared to control (WMD: 2.07 um, P < 0.00001) at median follow-up of 16.5 months. IOP-lowering medications (on the day of injection or in the long-term) significantly reduced IOP up to 30 minutes after injection (WMD: -3.31 mm Hg, P = 0.003). This effect was statistically significant between the 2 arms up to 1 month follow-up. There was no difference in BCVA in intervention versus controls. ACP reduces immediate IOP spikes post-IVI and preserves the RNFL in the short- and longterms IOP-lowering medications also reduce IOP spike, with limited data on RNFL thickness.
Risk, Prevalence, and Progression of Glaucoma in Eyes With Age-Related Macular Degeneration Treated With Intravitreal Anti–Vascular Endothelial Growth Factor Injections
2022, American Journal of Ophthalmology
Citation Excerpt :
There is a lack of consensus on whether intravitreal anti-VEGF treatment impacts structural glaucomatous changes. Previous studies have assessed whether anti-VEGF injections accelerate RNFL thinning in patients receiving intravitreal injections and have found mixed results,11,24,27,28,40,41 with only a few assessing long-term impact.25,26,42,43 Saleh and associates and Du and associates found no significant average RNFL thickness decrease in patients with concurrent glaucoma and long-term anti-VEGF treatment.25,26
To examine the risk, prevalence, and progression of glaucoma development in age-related macular degeneration (AMD) eyes receiving intravitreal anti–vascular endothelial growth factor (anti-VEGF) injections compared to controls.
Retrospective clinical cohort study.
Retrospective review of eyes receiving intravitreal anti-VEGF injections from January 1, 2004, to December 31, 2013, for exudative AMD. Age- and sex-matched control groups of eyes included eyes with nonexudative AMD (NEAMD) and no AMD. Eyes with a diagnosis of glaucoma or glaucoma suspect were reviewed for injection details, type and date of glaucoma diagnosis, glaucoma treatments, standard automated perimetry (SAP), and spectral domain optical coherence tomography (SD-OCT). Qualitative progression was determined by indication of glaucoma progression in provider notes. Quantitative progression was assessed based on change in mean deviation (MD) on SAP, retinal nerve fiber layer thickness on SD-OCT, and intraocular pressure (IOP).
There were 707 eyes of 504 patients treated with anti-VEGF injections and 1008 eyes in the NEAMD and no-AMD cohorts. There was no difference in glaucoma or suspect prevalence at initial presentation between eyes treated with injections and NEAMD (6.9% vs 9.7%, P = .22) or no-AMD controls (vs 8.5%, P = .55). There was no difference in cumulative 5-year probability of new glaucoma diagnosis after anti-VEGF injections compared to NEAMD (1.9% vs 1.0%, P = .69) or no-AMD controls (vs 1.6%, P = .88). There was no difference in qualitative progression of glaucoma in the injection cohort vs NEAMD (P = .19) or no-AMD controls (P = .61). The rate of MD change in injection eyes was similar to NEAMD eyes (P = .74) but greater than no-AMD eyes (P = .02). Eyes receiving injections required more topical glaucoma medications compared with NEAMD (P = .03) and more glaucoma laser treatments compared with no-AMD controls (P = .009). Eyes receiving injections did not require more frequent incisional glaucoma surgery compared with NEAMD (21.0% vs 15.0%, P = .95) or no-AMD controls (vs 10.0%, P = .10).
Eyes treated with intravitreal anti-VEGF injections for exudative AMD did not have increased risk of developing glaucoma compared with controls. Of those with a glaucoma diagnosis, exudative AMD eyes receiving injections required a greater number of topical glaucoma medications compared with NEAMD eyes and had a greater rate of MD loss than no-AMD controls.
Macular ganglion cell complex changes in eyes treated with aflibercept for neovascular age-related macular degeneration
2021, Photodiagnosis and Photodynamic Therapy
Citation Excerpt :
Entezari et al. found that RNFL thickness was significantly decreased at 12 weeks after treatment with 2 intravitreal bevacizumab injections in patients with nAMD, while there was no significant difference at 24 weeks when compared with the baseline [14]. Conversely, in another study, it was found that long-term treatment with anti-VEGF agents caused no significant change in RNFL thickness in patients with AMD [15]. Beck et al. reported that retinal GCL thickness was significantly decreased, without any significant change in RNFL thickness after an average of 31.5 anti-VEGF injections [16].
To evaluate the effect of intravitreal aflibercept injection on macular ganglion cell complex (GCC) in patients with neovascular age-related macular degeneration (nAMD).
In total, 36 eyes of 36 treatment-naïve patients with nAMD (18 female and 18 male) and 36 eyes of 36 healthy subjects (20 female and 16 male) as controls were included in this retrospective study. Spectral-domain optical coherence tomography images were evaluated after each injection for 3 months and at 12 months. Mean GCC thickness of the center, inner ring, and outer ring of the ETDRS grid was automatically quantified.
Mean foveal thickness was statistically significantly decreased at 3 months and at 12 months compared with baseline in the patient group. Ganglion cell layer thickness in the center was statistically significantly decreased in eyes with nAMD at baseline. There was a statistically significant decrease for mean retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thickness at 12 months compared with baseline.
Macular GCC thickness was decreased after intravitreal aflibercept injection in patients with nAMD, in particular at 12 months.
Dose-Response Relationship between Intravitreal Injections and Retinal Nerve Fiber Layer Thinning in Age-Related Macular Degeneration
2021, Ophthalmology Retina
To determine if multiple intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors for unilateral exudative age-related macular degeneration (eAMD) are associated with thinning of the retinal nerve fiber layer (RNFL), we compared RNFL thickness measurements from the injected eye with that of the fellow eye with nonexudative age-related macular degeneration (neAMD).
Retrospective, cross-sectional study.
Patients undergoing anti-VEGF therapy for unilateral eAMD.
Patients receiving anti-VEGF therapy secondary to eAMD in 1 eye with neAMD in their fellow eye were identified. Patients with a known diagnosis of glaucoma were excluded. Spectral domain OCT measurements of the peripapillary RNFL thickness from both eyes were performed and compared. The differences in the RNFL thickness measurements between eyes were correlated with the number of injections and the duration of therapy.
Correlation between the number of anti-VEGF injections and peripapillary RNFL thinning.
A total of 108 eyes of 54 patients were evaluated in this study. The average peripapillary RNFL thickness measurements of the injected eye and fellow eye were 87.3 ± 9.6 μm and 89.0 ± 7.5 μm, respectively (P = 0.055). The RNFL thickness difference (fellow eye minus injected eye) was significantly correlated with the number of injections (r = 0.40, P = 0.002) and months of injections (r = 0.38, P = 0.005). The relationship between the difference in the RNFL thickness and the number of injections had a nonlinear dose-response relationship that became apparent after approximately 30 injections and 50 months of injections.
The difference in RNFL thickness measurements between injected eyes and uninjected fellow eyes was largely within the reported normal limits for interocular differences between healthy eyes. Nevertheless, there was a dose-response relationship between RNFL thinning and number of injections among patients receiving a greater number of injections, suggesting that anti-VEGF injections may have a modest effect on the RNFL thickness after several years of therapy in eyes requiring more anti-VEGF injections; however, we cannot exclude that the RNFL thinning may be secondary to active age-related macular degeneration (AMD) disease progression in both eyes.
Rates of RNFL Thinning in Patients with Suspected or Confirmed Glaucoma Receiving Unilateral Intravitreal Injections for Exudative AMD
2021, American Journal of Ophthalmology
Citation Excerpt :
Most publications regarding the adverse effects of intravitreal injections have focused on IOP elevations and RNFL changes in normal eyes. Although a few studies have identified significant RNFL thinning in injected eyes,31–33 most have found no differences among nonglaucomatous eyes.11,13,34–38 Study design varied greatly among those publications and have been discussed further in review publications on this topic.7,8
This study evaluated whether the rate of retinal nerve fiber layer (RNFL) thinning is faster in eyes receiving intravitreal injections than in fellow uninjected eyes among patients suspected of having or confirmed to have glaucoma and exudative age-related macular degeneration (AMD).
Retrospective comparative cohort study.
Patients with a diagnosis of unilateral exudative AMD and confirmed to have or suspected of having glaucoma in both eyes receiving unilateral intravitreal injections were identified. Those with ≥3 RNFL optical coherence tomography scans and ≥6 injections were included in the study. Rates of RNFL thinning in the injected eye versus the uninjected eye were estimated using linear mixed models. The main outcome measurement was the differences in rates of RNFL thinning in the injected versus the fellow uninjected eye. The effects of postinjection elevation of intraocular pressure (IOP), injection frequency, and number of injections were also evaluated.
A total of 53 patients met the inclusion criteria, receiving 26.4 ± 15.9 intravitreal injections. The average rate of RNFL thinning in uninjected eyes was −0.620 μm/year (P = .029). Injected eyes had an additional incremental loss of −0.385 μm/year, but this value was not statistically significant (95% confidence interval [CI]: −1.147 to 0.379 μm/year; P = .324). Subgroup analysis with only glaucoma patients (n = 33) also demonstrated a nonsignificant effect of injections (−0.568 μm/year; 95% CI: −1.454 to 0.319 μm/year; P = .212). Postinjection IOP elevation, injection frequency, and total number of injections were not associated with faster RNFL loss.
Among exudative AMD patients with glaucoma or suspected of having glaucoma, the rate of RNFL thinning in eyes receiving intravitreal injections did not significantly differ from that of fellow uninjected eyes.

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Original articleRetinal Nerve Fiber Layer Thickness in Patients Receiving Chronic Anti–Vascular Endothelial Growth Factor Therapy

Purpose

Design

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Ophthalmology

ProgBrain Res

Am J Ophthalmol

Am J Ophthalmol

Can J Ophthalmol

Ophthalmology

Am J Pathol

Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and schwann cell proliferation in the peripheral nervous system

J Neurosci

Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections

Ophthalmic Surg Lasers Imaging

Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab

Eye

Original article
Retinal Nerve Fiber Layer Thickness in Patients Receiving Chronic Anti–Vascular Endothelial Growth Factor Therapy