Non-invasive Assessment of Neurovascular Coupling After Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Trial Using Retinal Vessel Analysis

Abstract

Objective: Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) and can lead to infarction and poor clinical outcome. The underlying mechanisms are still incompletely understood, but animal models indicate that vasoactive metabolites and inflammatory cytokines produced within the subarachnoid space may progressively impair and partially invert neurovascular coupling (NVC) in the brain. Because cerebral and retinal microvasculature are governed by comparable regulatory mechanisms and may be connected by perivascular pathways, retinal vascular changes are increasingly recognized as a potential surrogate for altered NVC in the brain. Here, we used non-invasive retinal vessel analysis (RVA) to assess microvascular function in aSAH patients at different times after the ictus.Methods: Static and dynamic RVA were performed using a Retinal Vessel Analyzer (IMEDOS Systems GmbH, Jena) in 70 aSAH patients during the early (d0−4), critical (d5−15), late (d16−23) phase, and at follow-up (f/u > 6 weeks) after the ictus. For comparison, an age-matched cohort of 42 healthy subjects was also included in the study. Vessel diameters were quantified in terms of the central retinal arterial and venous equivalent (CRAE, CRVE) and the retinal arterio-venous-ratio (AVR). Vessel responses to flicker light excitation (FLE) were quantified by recording the maximum arterial and venous dilation (MAD, MVD), the time to 30% and 100% of maximum dilation (tMAD30, tMVD30; tMAD, tMVD, resp.), and the arterial and venous area under the curve (AUCart, AUCven) during the FLE. For subgroup analyses, patients were stratified according to the development of DCI and clinical outcomes after 12 months.Results: Vessel diameter (CRAE, CRVE) was significantly smaller in aSAH patients and showed little change throughout the whole observation period (p < 0.0001 vs. control for all time periods examined). In addition, aSAH patients exhibited impaired arterial but not venous responses to FLE, as reflected in a significantly lower MAD [2.2 (1.0–3.2)% vs. 3.6 (2.6–5.6)% in control subjects, p = 0.0016] and AUCart [21.5 (9.4–35.8)%*s vs. 51.4 (32.5–69.7)%*s in control subjects, p = 0.0001] on d0−4. However, gradual recovery was observed during the first 3 weeks, with close to normal levels at follow-up, when MAD and AUCart amounted to 3.0 [2.0–5.0]% (p = 0.141 vs. control, p = 0.0321 vs. d5−15) and 44.5 [23.2–61.1]%*s (p = 0.138 vs. control, p < 0.01 vs. d0−4 & d5−15). Finally, patients with clinical deterioration (DCI) showed opposite changes in the kinetics of arterial responses during early and late phase, as reflected in a significantly lower tMAD30 on d0−4 [4.0 (3.0–6.8) s vs. 7.0 (5.0–8.0) s in patients without DCI, p = 0.022) and a significantly higher tMAD on d16−23 (24.0 (21.0–29.3) s vs. 18.0 (14.0–21.0) s in patients without DCI, p = 0.017].Conclusion: Our findings confirm and extend previous observations that aSAH results in sustained impairments of NVC in the retina. DCI may be associated with characteristic changes in the kinetics of retinal arterial responses. However, further studies will be required to determine their clinical implications and to assess if they can be used to identify patients at risk of developing DCI.Trial Registration:ClinicalTrials.gov Identifier: NCT04094155.

Activation of HIF-1α/VEGF-A pathway by deferoxamine ameliorates retinal hypoxia in a rat subarachnoid hemorrhage model

“…Now people further realized that retinal vascular changes are increasingly recognized as a potential surrogate for altered neurovascular coupling in the brain because of the perivascular pathways connection between cerebral and retinal microvasculature. Also, SAH is associated with sustained vasoconstriction and impairments of vessels in retinal vessels by pointing to a sustained reduction in the diameter of retinal microvessels after SAH compared to control subjects [16]. In correspondence with these views, in our study, we also noticed a marked retinal new vessels after SAH and these abnormal vessels might be caused by the brain vasospasm after SAH.…”

Vascular Reactivity to Hypercapnia Is Impaired in the Cerebral and Retinal Vasculature in the Acute Phase After Experimental Subarachnoid Hemorrhage

“…Our findings underscore the latest clinical research, where altered RVD and impairment of neurovascular coupling days after SAH were observed in patients. Importantly, changes were in parts reversible at the time of follow up implying an acute but transient effect of SAH on the retinal vasculature (20)(21)(22). However, information about the degree of parallel CBF impairment in these patients is lacking precluded by the invasive and extensive character of the necessary diagnostic procedures.…”

“…Days after SAH, retinal arteries were constricted, and neurovascular coupling was impaired compared to healthy controls. These changes were reversible in parts 3 mo after SAH indicating a time-dependent process of the observed alterations (20)(21)(22).…”

Automated Retinal Vessel Analysis Based on Fundus Photographs as a Predictor for Non-Ophthalmic Diseases—Evolution and Perspectives

“…Since retinal photography is usually performed with the patient in a sitting position, but RVA would also be useful for prognostic purposes in patients who are confined to bed, a maneuverable RVA has been devised for examining supine patients (for instance, patients with acute subarachnoidal hemorrhage). However, because of the limited maneuverability of the fundoscope when a patient is in a supine position, there is also work in progress to develop a miniaturized, wearable device for RVA comparable to "smart glasses" [13].…”