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

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.

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

“…However, repetitive anti-VEGF-A injections are not without side effects. For example the repetitive treatment increases the risk for hypertension-induced brain hemorrhages 30 and maybe even cognitive decline. 31 …”

“…Increased VEGF-A levels leads to increased eNOS activity, downregulation of occludin, impairment of the blood-brain barrier, activation of local inflammatory markers, recruitment of leukocytes, stalling of capillary flow, and reduced cerebral blood flow. Images taken from Ali et al 19 For example the repetitive treatment increases the risk for hypertension-induced brain hemorrhages 30 and maybe even cognitive decline. 31 A study analyzed 175 patients undergoing anti-VEGF-A treatment for macular degeneration demonstrated those with 20 or more injections had a higher likelihood of mild cognitive impairment as calculated on an iPad-based brain health assessment.…”

Changes of plasma nitric oxide, endothelin-1, and blood coagulation following intravitreal conbercept

“…In effect, how these anti-VEGF agents affect the systemic vascular system and cause possible collateral adverse events may be much more complicated than we are thinking of. The process may be a multifaceted, including patients’ predisposition, specific binding capacity of these agents to host endothelial cells and possible resultant inflammation 36 , as well as acute vascular tonicity change and blood pressure flare-ups via changes of blood vessel vasotonic regulation 37 . Bevacizumab, ranibizumab and aflibercept came into clinical practice earlier and better studied for their systemic adverse events.…”

Normal-Tension Glaucoma and Potential Clinical Links to Alzheimer’s Disease

“…Additional studies support the finding that repeated Anti-VEGF injections can lead to elevated IOP in cohorts of patients diagnosed with DME, neovascular AMD [189,190], and non-diabetic patients [191], thus indicating the complicated interplay between NTG and efficacy of anti-VEGF treatments. Furthermore, the risk for intravitreal anti-VEGF treatments extends outside of the eye and has been implicated in possible Parkinson's-like events, hypertension-induced brain hemorrhage, and dementia [192][193][194]. Further studies examining the implication of VEGF signaling in NTG and AD are necessary to determine targeted anti-VEGF therapeutic efficacy in these diseases.…”