Intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors are known to result in systemic distribution of medication, which may impact circulating VEGF levels.1,2 Previous reports have observed a treatment effect in the fellow untreated eye of patients after receiving anti-VEGF therapy for retinovascular disease.3,4 Most of this literature surrounds the use of bevacizumab (Avastin; Genentech, South San Francisco, CA) and ranibizumab (Lucentis; Genentech, South San Francisco, CA); however, to date, there are limited data regarding the fellow eye effects after aflibercept (Eylea; Regeneron, Tarrytown, NY) therapy.3–5 Here, we report a case of dramatic improvement of diabetic macular edema (DME) in both the treated and untreated fellow eye after a single in-travitreal aflibercept injection.
A 61-year-old female with bilateral treatment-naïve diffuse DME and associated severe nonproliferative diabetic retinopathy (hemoglobin A1c persistently > 11%) had repeatedly refused therapeutic intervention during 1 year of follow-up (Figure 1). After experiencing a progressive decline in vision to 20/80 in both eyes, she consented to a trial of intravitreal anti-VEGF therapy starting with only her left eye. The pre-injection central retinal thickness (CRT) was 599 µm and 721 µm in the right and left eyes, respectively.
Persistent, bilateral, treatment-naïve diabetic macular edema with central macular thickness readings before and after a single unilateral intravitreal injection of aflibercept (denoted by dashed line) in the left eye, demonstrating a bilateral treatment effect.
Two weeks after the initial aflibercept injection in her left eye, a marked bilateral reduction of DME was measured (CRT right eye: 395 µm; CRT left eye: 341 µm) with associated visual improvement to 20/30 bilaterally (Figure 2). Notably, the patient did not start any new medications or undergo any modification to her diabetes regimen during this period. Additionally, her blood pressure remained relatively unchanged during this 1-year interval (mean systolic pressure: 143.9 mm Hg ± 15.2 mm Hg, diastolic pressure: 77.9 mm Hg ± 15.2 mm Hg over nine recorded visits to her primary care physician).
Spectral-domain optical coherence tomography demonstrating bilateral diffuse diabetic macular edema prior to (A, B) and 2 weeks following a single intravitreal injection of aflibercept (C, D) in only the left eye, with a marked bilateral response.
The mechanism of contralateral response after intravitreal anti-VEGF therapy remains controversial. Hypothetically, such an effect is secondary to escape of medication into the systemic circulation. Conditions where significant breakdown of the blood-retinal barrier is present, such as diabetic retinopathy, may potentiate intravascular penetrance of these compounds and facilitate both escape of the drug from the treated eye as well as entry into the fellow eye.
Because ranibizumab is the smallest molecule (48 kDa) of the three commercially available VEGF inhibitors, it may be expected to pass to the fellow eye more easily than either bevacizumab (149 kDa) or aflibercept (115 kDa). However, previous studies have conversely demonstrated that intravitreal bevacizumab more often generates a fellow-eye response compared to ranibizumab.3,4 Thus, molecular size is unlikely to be the principal factor driving this phenomenon. More likely, the systemic half-lives of these medications influence their degree of fellow-eye impact, as bevacizumab has a serum half-life of nearly 20 days, whereas ranibizumab's is less than 6 hours.2,3 In comparison, aflibercept has a serum half-life of 5 days to 6 days. Molecularly, bevacizumab and aflibercept share a common Fc fragment, which binds the endothelial Fc receptor. In the retina, this interaction enables translocation across the blood-retina barrier and may spare these molecules from rapid clearance.6 Ranibizumab, however, lacks the Fc region, lasting only several hours before being systemically removed.
Our case is unique in that this patient was previously treatment-naïve with more than 1 year of clinical follow-up for severe disease before finally consenting to therapy. That our patient had persistent and progressively worsening DME with relatively stable blood pressure recordings and an unchanged systemic medication regimen is strongly suggestive of a true bilateral response from the single aflibercept injection rather than a chance occurrence. Future reports corroborating these findings may help better elucidate whether certain baseline clinical or demographic factors predispose some patients to accumulating meaningful systemic levels of aflibercept and a commensurate fellow-eye effect.
- Avery RL. What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned?Br J Ophthalmol. 2014;98Suppl 1:i7–10. doi:10.1136/bjophthalmol-2013-303844 [CrossRef]
- Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98(12):1636–1641. doi:10.1136/bjophthalmol-2014-305252 [CrossRef]
- Bakbak B, Ozturk BT, Gonul S, Yilmaz M, Gedik S. Comparison of the effect of unilateral intravitreal bevacizumab and ranibizumab injection on diabetic macular edema of the fellow eye. J Ocul Pharmacol Ther. 2013;29(8):728–732. doi:10.1089/jop.2013.0049 [CrossRef]
- Hanhart J, Tiosano L, Averbukh E, et al. Fellow eye effect of unilateral intravitreal bevacizumab injection in eyes with diabetic macular edema. Eye (Lond). 2014;28(6):646–653. doi:10.1038/eye.2014.94 [CrossRef]
- Calvo CM, Sridhar J, Shahlaee A, Ho AC. Reduction of diabetic macular edema in the untreated fellow eye following intravitreal injection of aflibercept. Ophthalmic Surg Lasers Imaging Retina. 2016;47(5):474–476. doi:10.3928/23258160-20160419-12 [CrossRef]
- Kim H, Robinson SB, Csaky KG. FcRn receptor-mediated pharma-cokinetics of therapeutic IgG in the eye. Mol Vis. 2009;15:2803–2812.