Intracranial pressure elevation alters CSF clearance pathways

Abstract

Background: Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models. Methods: We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters. Results: At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/ (mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route. Conclusions: The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.

Realistic boundary conditions for perivascular pumping in the mouse brain reconcile theory, simulation, and experiment

“…expect that more accurate measurements of the rest of the because our brain-wide measurements are likely affected by shunt paths that allow CSF to exit the skull without passing through the brain parenchyma, as proposed recently (50,51).…”

Acute systemic LPS-exposure impairs perivascular CSF distribution in mice

“…While Erickson studied more parameters with very interesting results, including decreased amyloid beta efflux after LPS exposure [ 4 ], our study used a less invasive method of CSF tracing [ 9 ]. Since intracerebroventricular injections may cause inflammation, they could influence CSF flow readouts [ 28 ]. Observations even suggest that inserting a cannula through the cortex decreases glymphatic flow [ 29 ].…”

Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection

“…One such mechanism is the injection of tracers into the CM, which might cause a pressure gradient that drives a flow in the PVSs of pial arteries (Smith et al, 2017;Smith and Verkman, 2018;Croci et al, 2019;Sharp et al, 2019;van Veluw et al, 2020;Vinje et al, 2020;Kedarasetti et al, 2020a;Faghih and Sharp, 2021). Injection of CSF tracers is known to raise the intracranial pressure (ICP) by 1 -3 mmHg (Iliff et al, 2013;Mestre et al, 2020), consistent with the fact that a volume of fluid is being added to the rigid skull (Hladky and Barrand, 2018;Bakker et al, 2019).…”