Third nerve palsy following intravitreal anti-VEGF therapy for bilateral neovascular age-related macular degeneration

Editor, Despite the dramatic therapeutic effect of anti-Vascular Endothelial Growth Factor (VEGF) therapy for neovascular age-related macular degeneration (NV-AMD), concerns still linger regarding the potential for adverse events. Among its important physiological roles, VEGF maintains the microcirculation (Baffert et al. 2006; Papadopoulou et al. 2009) and protects neurons in the adaptive response to ischemic injury (Nishijima et al. 2007), which may be compromised by repeated intravitreal injection of anti-VEGF agents. Previous reports have documented suspected adverse systemic events including a sixth nerve palsy (Park & Guy 2007) and early loss of pregnancy following intravitreal injection of bevacizumab (Petrou et al. 2009). Here, we describe a patient who developed a microvascular third nerve palsy after multiple injections of bevacizumab and ranibizumab for NV-AMD. A 64 -year-old man with bilateral NV-AMD presented to the emergency room late at night with a marked reduction in adduction and elevation as well as ptosis of the right eye that were not initially documented earlier in the day by a general ophthalmologist or a family physician with whom the patient visited after waking up feeling dizzy and confused. In the ER, his pupils were reactive to light, there were no visual field cuts on confrontation test, optic disc margins were distinct, and there was no note of proptosis. CT angiogram revealed no evidence of any abnormalities of the major cerebral vessels, and a subsequent MRI scan showed no evidence of infarction and no abnormalities on the T2-weighted series. The patient’s past medical history includes 13 intravitreal bevacizumab injections in the right eye (last injection 16 days prior to incident) and seven injections of intravitreal bevacizumab followed by six ranibizumab injections in the left eye (last injection 14 days prior to incident). The patient’s medications also include candesartan for hypertension with which he takes faithfully (his blood pressure was measured to be 127/88 and 129/84 on two monthly visits for injection) and rabeprazole for gastroesophageal reflux. No other systemic conditions were reported. Follow-up evaluation 53 days later revealed a resolution of his double vision and ptosis with no abnormality of his eye movements. The clinical evidence points to an infarction of the third cranial nerve in the periphery because of a gradually developing occlusion of one of the small penetrating arteries on the surface of the nerve itself. As a vasodilator and endothelial survival factor, VEGF functions to maintain the tone and health of the microcirculation; intravitreal inhibition with ranibizumab has been reported to lead to significant arteriolar vasoconstriction from baseline 7 and 30 days after injection (Papadopoulou et al. 2009), and systemic VEGF inhibition in animal models leads to capillary regression and the disappearance of fenestrations over time (Baffert et al. 2006). VEGF also has a critical role as a neuroprotectant in the adaptive response to ischemic injury by directly promoting anti-apoptotic gene expression in neurons and upregulating blood flow via nitric oxide (Nishijima et al. 2007). However, both ranibizumab and bevacizumab can enter the systemic circulation; the latter may utilize endogenous immunoglobulin receptors to more effectively avoid degradation and circulate with a half life of approximately 10 days in humans (Cousins & Csaky 2009) while sustaining serum levels as high as 1 ug/ml 29 days post-injection in rabbits (Bakri et al. 2007). Since mean adult serum VEGF-A levels have been reported to be in the order of 100 pg/ml (Kimura et al. 2007), there could still be enough free bevacizumab in the human circulation after intravitreal injection to neutralize some VEGF actions. Consequently, physicians should remain cognizant of the potential relationship between microvascular disturbances and anti-VEGF therapy in an elderly AMD population. Funding/support: none; financial disclosures: none; other acknowledgements: none.

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