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  • Mechanical cisternal occlusion and subsequent Glymphatic disruption are linked to an acute decrease in cerebral blood volume following subarachnoid hemorrhage.

    Final Number:

    Tristan Michael Stani BA MD; Jeff Iliff PhD; Zoe Teton; Justin Schultz Cetas MD, PhD

    Study Design:
    Laboratory Investigation

    Subject Category:
    Aneurysm/Subarachnoid Hemorrhage

    Meeting: AANS/CNS Cerebrovascular Section 2018 Annual Meeting

    Introduction: Glymphatic dysfunction has recently been described following experimental subarachnoid hemorrhage (SAH) in murine and primate models. The Glymphatic system is a brain-wide waste clearance system akin to the lymphatic system for peripheral organ tissue. Glymphatics may be an important new therapeutic target against delayed cerebral ischemia following SAH, yet so far there has been little research to explain what contribution if any glymphatic disruption contributes to the overall injury pattern following SAH.

    Methods: Treatment groups consisted of aCSF (n=5), autologous blood (n=5) and microbeads (n=7) injected into the prechiasmatic cistern of adult male rats. A cranial window was made over the middle cerebral artery territory and relative cerebral blood volume change (rCBV) was assessed in real time using optical intrinsic signaling. Intracranial pressure (ICP) was assessed using an intraparenchymal pressure transducer. Glymphatic integrity was assessed by injecting 20 µl of Evans Blue dye into the cisterna magna and quantifying brain surface fluorescence.

    Results: Microbead and blood injection both produced comparable acute glymphatic dysfunction. rCBV decreased precipitously in both blood and microbead treatments and remained depressed by 10-40% with variable recovery over 40 minutes of recording. rCBV area under the curve (AUC) over 40 min was microbeads: minus 544, p=0.009, blood: minus 400, p=0.004 vs aCSF: positive 249 (units % change rCBV x min). All treatment groups showed a transient increase in ICP with cisternal injection which returned to near-baseline levels within 10 minutes. AUC of ICP injection profiles was also quantified and compared across groups.

    Conclusions: Both cisternal, microbead, and blood injection produce comparable acute Glympathic dysfunction. Furthermore, in both cases this is accompanied by a significant and comparable deficit in CBV. These results isolate a purely mechanical effect of cisternal microthrombi following SAH and provide initial evidence linking Glymphatic dysfunction to homeostatic mechanisms governing cerebral hemodynamics.

    Patient Care: This research provides initial evidence in support of developing new targeted therapies aimed at restoring Glymphatic function following aneurysmal subarachnoid hemorrhage.

    Learning Objectives: Understand normal Glymphatic function and its possible contribution to cerebral injury following SAH

    References: Iliff, JJ et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012 Aug 15;4(147):147ra111 Gaberel, T et al. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke. 2014 Oct;45(10):3092-6. Goulay, R et al. Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman Primate. Stroke. 2017 Aug;48(8):2301-2305

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