INJECTION SITE ISCHEMIA AND INFLAMMATION AFTER INTRAVITREAL BEVACIZUMAB Nikolaos D. Georgakarakos, MB, BS (Lond), MRCOphth,* Paul Sullivan, FRCOphth,† Jonathan Dowler, FRCOphth†

Background: Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) used in the treatment of a variety of ocular conditions. It is known to exert an inhibitory effect on new vessels but has not previously been documented to affect mature vascular beds. Methods: The authors present an uncommon side effect of intravitreal bevacizumab, consisting of inflammation and transient nonperfusion of conjunctival, episcleral, and scleral vessels surrounding the injection site. Results: Possible mechanisms of this complication, including ischemia and inflammation, are considered. Conclusion: The possibility of this complication should be recognized by clinicians treating patients with intravitreal bevacizumab, and measures should be taken to limit drug reflux at the injection site. RETINAL CASES & BRIEF REPORTS 4:294–296, 2010

centered at the injection site. Anterior segment fluorescein angiography showed nonperfusion of conjunctival, episcleral, and scleral vasculature around the injection site (Figure 2). The patient was treated with topical steroid therapy; over a period of 3 weeks, symptoms and signs resolved, and the area around the injection site became reperfused.

From the *Institute of Ophthalmology, University College London, London, United Kingdom; and †Moorfields Eye Hospital, London, United Kingdom.

A

60-year-old woman awaiting pars plana vitrectomy with delamination for proliferative diabetic retinopathy underwent intravitreal injection of 1.25 mg of bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) a week before surgery. The drug was administered in 0.05 mL via a 30-gauge needle 4 mm posterior to the inferotemporal limbus under aseptic conditions using a drape and a lid speculum under topical anesthesia. The procedure was uncomplicated. The patient was given G chloramphenicol 4 times daily for 4 days after injection. Five days after injection, the patient had a sore, red eye (Figure 1). Visual acuity was unaffected, and there was no anterior chamber inflammatory activity. There was vascular congestion surrounding a white area

Discussion Vascular endothelial growth factor (VEGF) participates in developmental vasculogenesis1 and is known to play a key role in ischemia-induced ocular angiogenesis. It binds and activates tyrosine kinase receptors on vascular endothelial cells and promotes their mobilization and differentiation.2 It also increases vascular permeability by fenestrae induction.1 VEGF is a powerful mediator of ischemia-induced ocular angiogenesis in the iris, cornea, retina, and choroid.3 Therefore, VEGF itself contributes to the pathogenesis of vascular disease in diabetic retinopathy, and VEGF levels are known to be elevated in diabetic patients with ocular neovascularization.4 In diabetes mellitus, the prolonged hyperglycemic state

The authors have no conflicts of interest to disclose. Reprint requests: Nikolaos Georgakarakos, MB, BS (Lond), MRCOphth, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom; e-mail: ndg@ hotmail.co.uk

294

ISCHEMIA AFTER INTRAVITREAL BEVACIZUMAB

295

Fig. 1. A white avascular region of the conjunctiva with no vascular congestion centered at the injection site.

activates protein kinase C, which in turn upregulates VEGF production. This results in neovascularization (proliferative diabetic retinopathy) and macular edema.5 Bevacizumab, a monoclonal antibody that binds to isoforms of VEGF-A, has a potent antiangiogenic effect. Bevacizumab is considered as adjunctive therapy for the treatment of selected cases of diabetic macular edema or proliferative diabetic retinopathy. Intravitreal injection of bevacizumab may be carried out before pars plana vitrectomy to reduce intraoperative bleeding.4 We present a case in which a patient treated in this way developed inflammation and transient nonperfusion of conjunctival, episcleral, and scleral vessels. Although the effect of bevacizumab on ocular neovascularization is recognized, an effect on mature vascular beds has not previously been reported. Many functions of VEGF are still unknown, including the levels required for the maintenance of normal vascular endothelial cell population.3 It is therefore possible that bevacizumab may have an inhibitory effect on mature vascular beds in the absence of any other

Fig. 2. Anterior segment flu-orescein angiography showing the absence of conjunctival, episcleral, and scleral vasculature around the injection site.

predisposition. However, in a recent study of 10 patients with corneal neovascularization in which bevacizumab at a dose twice that of typical intravitreal therapy (2.5 mg/0.1 mL) was administered at the limbus, injection site ischemia was not encountered.5 The patient whose case we present, however, was a long-standing type 1 diabetes patient with severe retinal disease. Conjunctival microvascular abnormalities secondary to diabetes have been described and correlate significantly with retinal disease severity and diabetes duration.6 In this patient, the presence of severe diabetic retinopathy may thus represent a risk factor for this complication. It is also possible that this complication arose as a result of an inflammation. The Fc component of bevacizumab is murine in origin, and it has been suggested that this might lead to increased cellmediated immune response and may be responsible for bevacizumab-induced uveitis.7 It is also possible that diabetes-related abnormalities of immunity rendered this patient more susceptible to such inflammation. It is hypothesized that the effect observed arose from a direct action of bevacizumab on the vascular beds

296

RETINAL CASES & BRIEF REPORTS´  2010  VOLUME 4  NUMBER 4

involved. Such an effect presumes a significant local dose of the drug, arising from reflux from the injection site. It may be prudent, therefore, in treating patients with intravitreal bevacizumab to take measures to limit drug reflux at the injection site. Key words: bevacizumab, side effects, ischemia, injection site, diabetic retinopathy. References 1. Maharaj AS, D’Amore PA. Roles for VEGF in the adult. Microvasc Res 2007;74:100–113. 2. Andreoli CM, Miller W. Antivascular endothelial growth factor for ocular neovascular disease. Curr Opin Ophthalmol 2007;18:502–508.

3. Lu M, Adamis A. Molecular biology of choroidal neovascularisation. Ophthalmol Clin North Am 2006;19:323–334. 4. Avery RL, Pearlman J, Pieramici DJ. Intravitreal bevacizumab in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695.el–1695.el5. 5. Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularisation. Cornea 2008;27:142–147. 6. Cheung AT, Ramanujam S, Greer DA, Kumagai LF, Aoki TT. Microvascular abnormalities in the bulbar conjunctiva of patients with type 2 diabetes mellitus. Endocr Pract 2001;7: 358–363. 7. Hasler S, Schmid MK, Becht CN. Acute anterior nongranulomatous uveitis after intravitreal injection of bevacizumab. Klin Monatsbl Augenheilkd 2008;225:446–447.

Injection site ischemia and inflammation after intravitreal bevacizumab.

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) used in the treatment of a variety of ocular conditions. It is known...
182KB Sizes 4 Downloads 8 Views