Central retinal vein occlusion (CRVO) is a common retinal vascular disorder that often leads to severe reduction in vision for which intravitreal anti-vascular endothelial growth factor (VEGF) injections are useful.1,2 Intravitreal injection of triamcinolone acetonide has also been shown to be effective in reducing macular edema and improving vision in eyes with CRVO, but this treatment is often limited by well-documented untoward effects such as cataract and steroid-induced glaucoma.3,4 In contrast to ranibizumab and triamcinolone, little has been published about possible adverse events associated with bevacizumab, a monoclonal IgG1 antibody specific to human VEGF, when used intravitreally for CRVO.5 Moreover, given concerns of a potential increased risk of myocardial infarction and stroke in patients receiving ranibizumab for neovascular age-related macular degeneration,6,7 it is possible that VEGF blockade may increase the risk of vascular occlusion through an unknown mechanism. The purpose of the current study is to report the clinical features and outcomes of macular infarction following intravitreal administration of bevacizumab for CRVO.
The Vitreoretinal Division of the Department of Ophthalmology, Stanford Hospital and Clinics (Stanford, CA) has undertaken active surveillance of patients undergoing intravitreal bevacizumab injections as part of an ongoing quality assurance program to study and report any resultant adverse events.8 Each patient has undergone a full evaluation by a retinal specialist. The period under review spanned January 1, 2005, until April 15, 2009, and was compliant with the Health Insurance Portability and Accountability Act. A systematic review of 110 patients with the diagnosis of CRVO who had received intravitreal bevacizumab revealed two cases of apparent macular infarction occurring shortly after injection. Similarly, the Vitreoretinal Service at the Bascom Palmer Eye Institute (Miami, FL) also identified one patient from 88 injections given between January 1, 2005, and April 15, 2009, for the same indication with similar macular findings. All patients’ medical records were examined with attention to pretreatment and posttreatment visual acuity, clinical examination, fundus photography, fluorescein angiography, and optical coherence tomography (OCT) findings.
Case 1 (Fig. 1)
A 71-year-old woman presented with decreased vision in the right eye for 3 days. Ocular history included ocular hypertension for which she was using brinzolamide (1%) three times per day. Her medical history included hypertension and asthma. Visual acuity measured 20/70 and intraocular pressure was 15 mm Hg in the right eye. The posterior segment examination demonstrated moderate intraretinal hemorrhages and venous tortuosity and dilation consistent with non-ischemic CRVO. Fluorescein angiography (FA) showed blockage due to intraretinal hemorrhages and late staining of the retinal veins. The superior nasal portion of the foveal avascular zone was slightly enlarged, with mild loss of the perifoveal capillary network but no widespread non-perfusion. OCT revealed macular edema with a central macular thickness (CMT) of 398 μm.
Intravitreal bevacizumab (1.25 mg/0.05 mL) was administered in an attempt to reduce edema and improve visual acuity. On follow-up 3 weeks later, the patient reported progressive vision loss since the injection, with a best-corrected visual acuity (BCVA) of counting fingers at 5 feet. The posterior segment examination at that time showed macular whitening. Repeat FA demonstrated marked closure of the macular capillary vessels. Over the subsequent 12 months, she developed progressive retinal ischemia and recalcitrant macular edema. Twenty-three months after initial presentation, the eye developed iris rubeosis with associated glaucoma, which was treated with a repeat bevacizumab injection and panretinal photocoagulation. The patient ultimately required glaucoma tube shunt surgery at 25 months. The retina was profoundly ischemic and the visual acuity remained counting fingers at 3 feet on most recent follow-up at 60 months after initial presentation (Table 1).
Table 1: Title AQ2
Case 2 (Fig. 2)
A 65-year-old woman presented with a CRVO of the left eye of approximately 5 months’ duration. Her medical history included hypertension and hypercholesterolemia. Visual acuity measured 20/70 and intraocular pressure was 18 mm Hg in the left eye. The posterior segment examination of the left eye showed a hemorrhagic ischemic CRVO. FA showed predominantly blockage of fluorescence due to intraretinal hemorrhage in addition to diffuse leakage from the retinal veins in the mid and late frames. Marked cystoid macular edema was noted on OCT (734 μm).
Intravitreal bevacizumab (1.25 mg/0.05 mL) was administered. After a subjective initial improvement for 5 days, the patient reported a rapid severe reduction in her vision. Six weeks later, the visual acuity in the left eye was reduced to 20/400. The posterior segment examination showed a diffuse whitening of the perimacular retina. Repeat FA demonstrated marked capillary non-perfusion of the macula. Repeat OCT showed a near-complete resolution of macular edema, but also a thickening and dramatically increased reflectance of the inner retinal layers with a hyporeflective band between the inner retina and the retinal pigment epithelium, in a pattern characteristically seen after an acute ischemic event. The patient subsequently developed progressive, severe retinal ischemia, and visual acuity dropped to counting fingers over 3 months. Recurrent macular edema was treated with intravitreal triamcinolone. An increase in intraocular pressure was believed to be a response to the intraocular steroid injection because no rubeosis was noted on any examination. However, panretinal photocoagulation was performed to reduce the risk of neovascular glaucoma. After resolution of the macular edema, significant macular thinning and atrophy was noted on OCT, and visual acuity at most recent follow-up (29 months after initial presentation) was counting fingers at 1 foot.
Case 3 (Fig. 3)
A 64-year-old man was referred with a CRVO of the left eye of 12 days’ duration. Ocular history was significant for neovascular glaucoma in the right eye from a CRVO occurring 12 years prior while the patient was receiving chemotherapy for chronic lymphocytic leukemia. Medical history was significant for hypertension, anemia, renal insufficiency, and chronic lymphocytic leukemia (in remission for 11 years). Visual acuity was light perception in the right eye and hand motions in the left eye. Intraocular pressure was 10 and 8 mm Hg in the right and left eyes, respectively. The posterior segment examination of the left eye demonstrated intraretinal hemorrhages in all quadrants, venous dilation and tortuosity, and macular edema and cotton wool spots. Macular edema was confirmed by OCT, with a CMT of 529 μm.
Intravitreal bevacizumab (1.25 mg/0.05 mL) was administered to the left eye to improve vision in the patient’s only functional eye. Although visual acuity improved to 20/400 by 1 month later, a large area of macular whitening and moderate pallor of the optic nerve was noted. Repeat OCT demonstrated decreased macular edema (CMT was 326 μm) but increased reflectivity of the inner retina and resultant shadowing of the outer retina and choroid consistent with infarction of the inner retina. Because of the improved visual acuity and reduced OCT macular thickness, intravitreal bevacizumab (1.25 mg/0.05 mL) was again administered to the left eye. Follow-up examination 1.5 months later revealed unchanged visual acuity in the left eye with resolving intraretinal hemorrhages and decreasing macular whitening. OCT demonstrated worsened macular edema with CMT of 631 μm, prompting a third administration of intravitreal bevacizumab (1.25 mg/0.05 mL). Over the following 12 months, the patient suffered from fluctuating macular edema and was treated with another injection of intravitreal bevacizumab and a single injection of intravitreal triamcinolone acetonide (4 mg/0.1 mL) in his left eye.
Examination approximately 14 months after initial presentation demonstrated visual acuity of 20/200 in the left eye and resolving macular whitening and hemorrhages. OCT revealed loss of foveal contour and retinal thinning with a CMT of 177 μm. Over the subsequent 48 months, the patient’s course was complicated by epiretinal membrane formation and recurrent vitreous hemorrhages for which the patient underwent pars plana vitrectomy, endolaser panretinal photocoagulation, air–fluid exchange, and membrane peeling. His visual acuity was 5/200 at last follow-up, approximately 48 months after initial presentation, with macular thinning and optic nerve pallor noted at this visit.
All patients described had systemic hypertension, whereas additional dyscrasias favoring endothelial damage and increased blood viscosity were noted in patients 2 and 3. Although the Central Vein Occlusion Study observed 34% of perfused eyes converted from non-ischemic to ischemic status within 3 years,9 our patients are distinguished by dramatic opacification of the inner retina within the macula—thus far unreported in untreated eyes with CRVO. Ischemic events following intravitreal anti-VEGF therapy have been reported. Initial phase II and III clinical trials of systemic bevacizumab for its foremost intended anti-neoplastic use demonstrated worsened hypertension in 22% to 32% of patients10 and arterial or venous thrombosis in 13% to 26% of patients (versus 9% of controls)11 putatively from endothelial apoptosis, thrombomodulin, and nitric oxide reduction, and overexpression of (prothrombotic) tissue factor.12
Intravitreal administration of bevacizumab has similarly been associated with systemic vascular-related consequences such as worsened systemic hypertension, myocardial infarction, cerebrovascular accident, and even internal carotid artery occlusion.5,13 Similar to the patients described here, most patients suffering these events had a prior history of similar events or risk factors. In contrast, larger retrospective studies have tempered these findings, deeming such vascular events as unexceptional in patient populations for whom intravitreal bevacizumab is indicated (largely patients with age-related macular degeneration) while suggesting that no correlation exists between the number of bevacizumab injections and event incidence.14
Vascular alterations limited to the retina have also been reported after intraocular bevacizumab use, although exclusively in the context of case reports. Kim et al. reported angiographic severe widespread capillary non-perfusion 3 weeks after administration of intravitreal bevacizumab for macular edema associated with CRVO.15 However, these authors do not report a fundus appearance consistent with inner retinal macula infarction. Additionally, Von Hanno et al. described a patient with an ischemic CRVO who suffered a perifoveal branch retinal artery occlusion 2 days after treatment with intravitreal bevacizumab.16 Interestingly, these authors also reported a separate but similar case of central retinal artery occlusion within 1 month of administration of ranibizumab in the treatment of ischemic CRVO, implicating retinal ischemia as a possible repercussion of anti-VEGF therapy in general, rather than a specific association with bevacizumab administration.
The clinical appearance of the patients described in this series closely resembles macular infarction described in the setting of intravitreal aminoglycoside toxicity. Such toxicity is described as acute macular opacity and edema accompanying intraretinal hemorrhages, cotton wool spots, venous beading, and arteriolar attenuation, usually occurring within 2 weeks of aminoglycoside administration.17 Electroretinography denotes variable amplitude attenuation of oscillatory potentials, a-waves, b-waves, and c-waves.18 There are several described mechanisms accounting for the severe visual loss: direct toxicity to retinal ganglion cells (their high macular density predisposing this region to insult19), granulocytic plugging of macular capillaries,19 and impaired retinal pigment epithelium homeostasis with consequent impairment of the choroid and photoreceptor outer segments.20 The mechanism by which anti-VEGF therapy might produce a similar appearing macular infarction remains to be elucidated.
Two mechanistic factors may lead to macular infarction in these patients: (1) the role of basal constitutive secretion of VEGF in the normal retina and (2) the role of VEGF in maintaining perfusion in the ischemic retina. Basal levels of VEGF in healthy retina mediate retinal vascular autoregulation, through both modulation of nitric oxide-mediated vasodilation and maintenance of retinal vascular architecture.21–23 In the ischemic retina, VEGF has a presumed endothelial-protective role, preventing intravascular thrombocyte aggregation and maintaining vascular patency.23 In the current study, all cases of anti-VEGF–induced ischemia occurred in patients with both a predisposition to endothelial damage and evidence of similar prior ischemic events. In addition, prior immunohistochemical studies have shown localization of bevacizumab to the posterior pole, and specifically the fovea,24 explaining a disproportionate effect on the macula and the fundus appearances described in this study.
As yet, the true mechanism by which bevacizumab might lead to this clinical picture is unknown and although evidence from animal studies may suggest causality, at this point we can only report that it is an interesting and clinically important, if idiosyncratic and rare, occurrence in our experience.
It is noteworthy that despite the widespread use of other anti-VEGF agents such as ranibizumab or pegaptanib for age-related macular degeneration, macular infarction has not previously been reported in that clinical setting. Additionally, preliminary data have demonstrated visual and anatomic improvement, as well as a favorable safety profile following ranibizumab injection for CRVO,1 and the incidence of serious adverse events associated with bevacizumab injection appears to be fairly low. There is significant therapeutic benefit of using anti-VEGF agents for the treatment of macular edema secondary to CRVO; in many cases the benefits outweigh the risks associated with the medication. However, given the severity of the adverse event reported here, clinicians using other anti-VEGF agents should be aware of this possible association. In particular, careful observation to differentiate between ischemic and non-ischemic CRVO is suggested, given the generally poor visual prognosis of non-perfused vein occlusions. Additionally, an accurate assessment of baseline visual acuity is warranted because eyes with relatively good acuity on presentation have been shown to have a good chance of maintaining good vision without intervention.
- Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1124–1133. doi:10.1016/j.ophtha.2010.02.022 [CrossRef]
- Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127:1115–1128. doi:10.1001/archophthalmol.2009.233 [CrossRef]
- Patel PJ, Zaheer I, Karia N. Intravitreal triamcinolone acetonide for macular oedema owing to retinal vein occlusion. Eye (Lond). 2008;22:60–64. doi:10.1038/sj.eye.6702518 [CrossRef]
- Ip MS, Gottlieb JL, Kahana A, et al. Intravitreal triamcinolone for the treatment of macular edema associated with central retinal vein occlusion. Arch Ophthalmol. 2004;122:1131–1136. doi:10.1001/archopht.122.8.1131 [CrossRef]
- Roth DB, King A, Weiss M, Klein D. Systemic adverse events after bevacizumab. Ophthalmology. 2009;116:1226. doi:10.1016/j.ophtha.2009.02.011 [CrossRef]
- Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am. 2006;19:361–372.
- Ueta T, Yanagi Y, Tamaki Y, Yamaguchi T. Cerebrovascular accidents in ranibizumab. Ophthalmology. 2009;116:362. doi:10.1016/j.ophtha.2008.09.046 [CrossRef]
- Wong LJ, Desai RU, Jain A, et al. Surveillance for potential adverse events associated with the use of intravitreal bevacizumab for retinal and choroidal vascular disease. Retina. 2008;28:1151–1158. doi:10.1097/IAE.0b013e31817e100f [CrossRef]
- The Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol. 1997;115:486–491.
- Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology. 2005;69(suppl 3):25–33. doi:10.1159/000088481 [CrossRef]
- Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–65. doi:10.1200/JCO.2003.10.066 [CrossRef]
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- Huang ZL, Lin KH, Lee YC, et al. Acute vision loss after intravitreal injection of bevacizumab (Avastin) associated with ocular ischemic syndrome. Ophthalmologica. 2009;224:86–89. doi:10.1159/000235726 [CrossRef]
- Sheybani A, Kymes S, Schlief S, Apte R. Vascular events in patients with age-related macular degeneration treated with intraocular bevacizumab. Retina. 2009;29:1404–1408. doi:10.1097/IAE.0b013e3181b32d13 [CrossRef]
- Kim KS, Chang HR, Song S. Ischaemic change after intravitreal bevacizumab (Avastin) injection for macular oedema secondary to non-ischaemic central retinal vein occlusion. Acta Ophthalmol. 2008;86:925–927. doi:10.1111/j.1755-3768.2008.01175.x [CrossRef]
- von Hanno T, Kinge B, Fossen K. Retinal artery occlusion following intravitreal anti-VEGF therapy. Acta Ophthalmol. 2010;88:263–266. doi:10.1111/j.1755-3768.2008.01406.x [CrossRef]
- McDonald HR, Schatz H, Allen AW, et al. Retinal toxicity secondary to intraocular gentamicin injection. Ophthalmology. 1986;93:871–877.
- Hancock HA, Guidry C, Read RW, et al. Acute aminoglycoside retinal toxicity in vivo and in vitro. Invest Ophthalmol Vis Sci. 2005;46:4804–4808. doi:10.1167/iovs.05-0604 [CrossRef]
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- Julien S, Heiduschka P, Hofmeister S, Schraermeyer U. Immunohistochemical localisation of intravitreally injected bevacizumab at the posterior pole of the primate eye: implication for the treatment of retinal vein occlusion. Br J Ophthalmol. 2008;92:1424–1428. doi:10.1136/bjo.2008.141317 [CrossRef]
|Age (y)||Gender||Pre-treatment BCVA||Initial BCVA After Intravitreal Bevacizumab||CMT (μm)||Final BCVA||Length of Follow-up (mo)|