Since anti-VEGF agents linger in the body post-injection and can suppress systemic VEGF levels, and combined with the fact that neuronal health and cognitive function in the CNS have been associated with normal physiological levels of VEGF expression, researchers sought to determine if there is an association between cumulative anti-VEGF exposure and cognitive function. Patients with wet AMD who undergo a large amount of intravitreal (IV) anti-VEGF injections may be at greater risk of worsening cognitive function, the recent study in Retina suggests.

The investigation, called the BHAM study, included 175 wet AMD patients between 65 and 85 years old with vision of at least 20/50 or better in one eye. The participants took a tablet-based brain health assessment that evaluated memory, executive function, speed and visuospatial and language skills. The results were then compared with the total number of anti-VEGF injections per individual. Patients were sorted into groups based on the number of injections they received (zero, one to nine, 10 to 20, 20+). Individuals with 20 or more injections had a higher likelihood of mild cognitive impairment compared with the control group, displayed by statistically significant worse mean Z-scores.

The study was the first to associate worsening cognitive health with more cumulative anti-VEGF injections, yet the researchers stressed that additional investigation is warranted.

It is well-known that healthy neuronal cells are important for cognitive function and that neuronal cell loss and synaptic degradation are closely correlated with the level of a patient’s cognitive decline and dementia, the investigators noted. “This, paired with the knowledge of VEGF’s normal role in neuroprotection, raises the important question of whether anti-VEGF IV injections used for the treatment of retinal disorders pose a risk to higher cognitive function,” they wrote in their paper.

Whether this risk is from direct communication between the vitreous-retina-choroid complex and CNS, via systemic vascular exposure or simply a comorbid association requires further evaluation, the study authors explained. “Systemic VEGF levels can be depressed following IV injections, but additional studies are required to address whether CNS VEGF levels are similarly suppressed. Furthermore, just as IV injection compounds can be found circulating in the systemic circulation, further evaluation will be needed to determine whether repeated injection exposes the CNS to those compounds as well,” they wrote.

Additionally, repeated anti-VEGF injections cause anatomical changes to the optic cup, which is at the interface of the vitreous-retina-choroid complex and CNS barrier. Whether this allows inadvertent exposure of these compounds to the CNS should be evaluated, the researchers noted. This study should not be taken as a guide to alter current treatment protocols, as it clearly needs to be validated with other independent studies, they concluded.

Ray SK, Manz SN. Brain health assessment in macular degeneration patients undergoing intravitreal anti-VEGF injections (the BHAM Study): an interim analysis. Retina. December 20, 2020. [Epub ahead of print].