Hypertensive cerebral hemorrhage with undetectable plasma vascular endothelial growth factor levels in a patient receiving intravitreal injection of aflibercept for bilateral diabetic macular edema: a case report
Authors: Yoshimoto Miwako , Takeda Nobuhiko , Yoshimoto Takayuki , Matsumoto Shun 
Published: July 2021

Abstract
Background
Intravitreal injections of anti-vascular endothelial growth factor are commonly used to treat macular diseases, including diabetic macular edema. Anti-vascular endothelial growth factor drugs can enter the systemic circulation after intravitreal injections and appear to suppress circulating vascular endothelial growth factor levels. However, whether this can cause any systemic adverse events remains unknown.

Case presentation
A 70-year-old Japanese man diagnosed with diabetic macular edema in both eyes was treated with anti-vascular endothelial growth factor intravitreal injections. One month after receiving two intravitreal injections of aflibercept 1 week apart for diabetic macular edema in both eyes, he complained of a severe acute headache. The patient was diagnosed with hypertensive cerebral hemorrhage of the occipital lobe based on an elevated blood pressure of 195/108 mmHg and the results of computed tomography and magnetic resonance imaging of his brain. The patient was treated with an intravenous injection of nicardipine hydrochloride to lower his systemic blood pressure. Two days after the stroke, the patient began oral treatment with 80 mg/day telmisartan, which was continued for 3 days, and the telmisartan dose was reduced to 40 mg/day thereafter. His blood pressure promptly dropped to 130/80 mmHg, and his severe headache disappeared. One year after the cerebrovascular stroke, the telmisartan was discontinued because his blood pressure stabilized at a normal level. His plasma vascular endothelial growth factor levels were measured via specific enzyme-linked immunosorbent assay before and after the intravitreal injections of aflibercept. Immediately before the injections, the vascular endothelial growth factor level was 28 pg/ml, but it rapidly fell below the detection limit within 1 week, where it remained for over 2 months. Two days before the cerebral hemorrhage, his plasma vascular endothelial growth factor level was below the detection limit, and 2 months later after the stroke, his plasma vascular endothelial growth factor level recovered to 41 pg/ml.

Conclusion
This case suggests that hypertension and resultant cerebral hemorrhage can occur in patients with diabetic macular edema when plasma vascular endothelial growth factor levels are systemically decreased below the detection limit for a prolonged time after local injections of anti-vascular endothelial growth factor agents into the vitreous cavity. Therefore, severely reduced plasma vascular endothelial growth factor levels could be a higher risk factor to develop generally infrequent stroke. Ophthalmologists should be aware of possible severe reduction of plasma vascular endothelial growth factor levels and resultant increase in blood pressure after intravitreal injections of an anti-vascular endothelial growth factor drug. If the plasma vascular endothelial growth factor levels could be monitored more easily and quickly during the treatment, it would help to prevent adverse events.