Altered Cerebrospinal Fluid Clearance and Increased Intracranial Pressure in Rats 18 h After Experimental Cortical Ischaemia.

Steven W Bothwell,Rebecca J Hood,Adjanie Patabendige,Debbie-Gai Pepperall,Neil J Spratt,Daniel Omileke,Sara Azarpeykan

doi:10.3389/fnmol.2021.712779

Abstract

Oedema-independent intracranial pressure (ICP) rise peaks 20–22-h post-stroke in rats and may explain early neurological deterioration. Cerebrospinal fluid (CSF) volume changes may be involved. Cranial CSF clearance primarily occurs via the cervical lymphatics and movement into the spinal portion of the cranio-spinal compartment. We explored whether impaired CSF clearance at these sites could explain ICP rise after stroke. We recorded ICP at baseline and 18-h post-stroke, when we expect changes contributing to peak ICP to be present. CSF clearance was assessed in rats receiving photothrombotic stroke or sham surgery by intraventricular tracer infusion. Tracer concentration was quantified in the deep cervical lymph nodes ex vivo and tracer transit to the spinal subarachnoid space was imaged in vivo. ICP rose significantly from baseline to 18-h post-stroke in stroke vs. sham rats [median = 5 mmHg, interquartile range (IQR) = 0.1–9.43, n = 12, vs. −0.3 mmHg, IQR = −1.9–1.7, n = 10], p = 0.03. There was a bimodal distribution of rats with and without ICP rise. Tracer in the deep cervical lymph nodes was significantly lower in stroke with ICP rise (0 μg/mL, IQR = 0–0.11) and without ICP rise (0 μg/mL, IQR = 0–4.47) compared with sham rats (4.17 μg/mL, IQR = 0.74–8.51), p = 0.02. ICP rise was inversely correlated with faster CSF transit to the spinal subarachnoid space (R = −0.59, p = 0.006, Spearman’s correlation). These data suggest that reduced cranial clearance of CSF via cervical lymphatics may contribute to post-stroke ICP rise, partially compensated via increased spinal CSF outflow.

Highlights

Ischaemic stroke is a leading cause of death and disability worldwide (Mathers and Loncar, 2006)
We previously identified a dramatic rise in intracranial pressure (ICP) present at 24 h after minor ischaemic stroke in rats, which peaked at 20–22 h (Murtha et al, 2014a; Beard et al, 2016)
We showed that clearance of cranial cerebrospinal fluid (CSF) tracer into the deep cervical lymphatics is reduced, and there is faster movement of tracer into the spinal subarachnoid space 18 h after photothrombotic stroke in rats

Summary

Introduction

Ischaemic stroke is a leading cause of death and disability worldwide (Mathers and Loncar, 2006). The most likely cause of infarct expansion is failure of leptomeningeal collateral vessels. Failure of initially good collateral blood flow is associated with infarct growth following ischaemic stroke (Campbell et al, 2013). After stroke, blood flow in these vessels is largely driven by cerebral perfusion pressure, which is sensitive to changes in intracranial pressure (ICP) (Czosnyka and Pickard, 2004). Our previous work showed that elevation of ICP during middle cerebral artery occlusion (MCAo) in rats caused a linear reduction of collateral blood flow (Beard et al, 2015). We previously identified a dramatic rise in ICP present at 24 h after minor ischaemic stroke in rats, which peaked at 20–22 h (Murtha et al, 2014a; Beard et al, 2016). The time point of this ICP rise, taken with our understanding of how ICP influences collateral blood flow, suggests a possible mechanism of collateral failure and infarct expansion

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