- Title
- Intracranial pressure elevation and cerebrospinal fluid change after ischaemic stroke
- Creator
- Bothwell, Steven William
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Neurological deterioration in the first days after minor stroke occurs in around 10-20% of patients. Failure of the leptomeningeal collateral blood vessels that supply the ischaemic penumbra, resulting in infarct expansion, is the most likely underlying mechanism of this deterioration. A transient rise in intracranial pressure (ICP) occurs around 20-24 hours after minor stroke. The timing of this rise suggests that it may be involved in the failure of collateral blood vessels and subsequent infarct expansion. Experimental evidence demonstrates that this ICP rise occurs independent of oedema, raising the imperative question: what is the underlying cause of this rise? Further work has shown that cerebral blood volume does not contribute; therefore, we propose that an increase in cerebrospinal fluid (CSF) volume is likely an underlying mechanism. We and others found that there is an increase in resistance to CSF clearance 18 and 24 hours after experimental ischemia, which indicates reduced CSF clearance after stroke, with changes appearing as early as 18 hours post-stroke. Reduced CSF clearance post-stroke has not been tested. CSF clearance is complex and multifaceted. The traditional understanding of CSF clearance explains direct movement of CSF from the subarachnoid space into the cranial venous sinuses via small structures called arachnoid villi. However, recent discoveries have pivoted our understanding, with experimental evidence indicating that CSF clears into the peripheral lymphatics system (primarily the deep cervical and spinal lymph nodes) via perineural transport or uptake into the dural lymphatics. The impact of stroke on this clearance pathway remains to be determined, as do the implications for ICP after stroke. Aims: The aims of this PhD were to: 1) Determine whether CSF tracer clearance from the cranium into the deep cervical lymph nodes is reduced in stroke rats with elevated ICP 18 hours post-stroke; 2) Determine whether movement of CSF tracer into the spinal subarachnoid space is altered in stroke rats with elevated ICP 18 hours post-stroke and whether this correlates with ICP rise; 3) Assess the therapeutic potential of antagonism of the choroid plexus proteins, NKCC1 and TRPV4, to reduce CSF secretion in rats; 4) Determine whether movement of intraventricularly infused CSF tracer into peripheral blood is disrupted in rats 18 hours post-stroke. Methods: CSF tracer movement was assessed in outbred Wistar rats 18 hours after photothrombotic stroke or sham surgical procedures. ICP, infarct volume, and oedema volume were all measured in the same animals. Tracer was infused into the lateral ventricles and concentration of tracer in the deep cervical lymph nodes was assessed ex vivo to determine differences in lymphatic CSF clearance in stroke and sham animals. A spinal window was made to assess entry of CSF into the spinal compartment in vivo. Transport of a fluorescent CSF tracer into the peripheral blood from the CNS was measured by imaging the saphenous vein. For CSF secretion experiments, a direct approach to measuring CSF secretion rate from the lateral ventricles was implemented. Secretion rate was measured at baseline and after systemic administration of bumetanide (10 mg/kg) or RN1734 (10 mg/kg), antagonists of NKCC1 and TRPV4, respectively. Acetazolamide (10 mg/kg) was used as a positive control. Results: Stroke animals had significantly higher ICP 18 hours post-stroke compared to sham animals, which was independent of oedema. There was a significant reduction in cranial clearance of CSF tracer to the deep cervical lymph nodes of stroke rats compared to sham rats. This was independent of ICP. There was a significant increase in CSF tracer transport to the spinal compartment of stroke rats, which correlated with ICP. Tracer clearance to the peripheral blood was significantly impaired by surgical intervention and anaesthetic exposure and was not significantly different between stroke and sham animals. Neither NKCC1 nor TRPV4 antagonism reduced CSF secretion in rats. Acetazolamide consistently reduced CSF secretion by ~50%. Conclusions: Oedema independent ICP rise occurs as early as 18 hours post-stroke, offering a beneficial timepoint for studying changes to CSF circulation that precede peak ICP rise. There is significant impairment of cranial CSF clearance to the deep cervical lymphatics 18 hours after stroke, which is independent of ICP rise. Increased CSF clearance to the spinal compartment suggests there is compensatory uptake at spinal exit sites when cranial clearance is impaired. Surgical intervention and anaesthetic exposure severely impair CSF clearance to peripheral blood and limits the potential to draw conclusions regarding the influence of stroke on this clearance pathway. However, the lack of difference between stroke and sham animals suggests potential utilisation of compensatory clearance mechanisms to peripheral blood. Ultimately, I have shown that CSF flow and clearance are impaired after stroke; however, the influence of these changes on ICP requires further exploration. Additionally, the absence of changes to CSF secretion in response to NKCC1 and TRPV4 antagonism suggests that these proteins are not suitable targets for managing CSF secretion and possibly ICP.
- Subject
- stroke; cerebrospinal fluid; intracranial pressure; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1470168
- Identifier
- uon:48391
- Rights
- Copyright 2022 Steven William Bothwell
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 5 MB | Adobe Acrobat PDF | View Details Download | ||
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