In this study, we demonstrated that CSF flow from the cranial compartment to the spinal subarachnoid space is faster after stroke. We observed that oedema-independent ICP rise is present 18 hours after cortical photothrombotic stroke in rats and that this ICP rise correlates to faster movement of CSF tracer to the spinal subarachnoid space.
Resistance to CSF outflow is increased at 18 and 24 hours post-stroke in cortical and striatal ischaemia models, respectively [10, 11]. We expected stroke animals to have decreased and delayed movement of CSF tracer to the spinal subarachnoid space, indicative of impaired and slowed CSF movement which would possibly explain ICP rise at 24 hours post-stroke . Our data show that animals experiencing an ICP rise post-stroke had faster transit of CSF tracer to the spinal subarachnoid space, while animals that did not experience ICP rise post-stroke were similar to sham animals. This observation was further confirmed when we identified a correlation between ICP rise at 18 hours post-stroke and Evans blue transit time to the C7-T1 spinal subarachnoid space. These findings show that changes to CSF flow post-stroke are linked to ICP rise; however, it remains unclear if ICP rise is the direct result of these changes or vice versa. Previous studies have observed increased transport of CSF tracer into the extracranial lymphatics system and through arachnoid projections with increased ICP [17, 18]. It is possible that increased CSF transit to the spinal subarachnoid space occurs in response to ICP rise following impaired CSF drainage via another cranial drainage pathway post-stroke. This is a possible compensatory mechanism given that CSF drains along spinal nerve routes extending from intervertebral spaces and into the peripheral lymphatics located in the sacral spine .
Despite faster transit to the C7-T1 subarachnoid space, the maximum amount of tracer present at this region between 0 to 90 minutes post-infusion was not significantly different. The lack of significant difference between the groups suggests that increased CSF secretion may not be involved in the ICP rise we observe. If CSF secretion was increased in animals experiencing ICP rise, then we would expect maximum observed contrast to be lower as the tracer becomes more dilute.
We investigated whether oedema could be the underlying cause of ICP elevation at 18 hours post-stroke, perhaps contributing to faster Evans blue transport to the spinal subarachnoid space. We found that oedema volume did not correlate with either ΔICP rise or T50%max. This finding is in line with our previous report that oedema does not correlate with ICP rise at 24 hours after transient MCAo  and with work showing similar observations after permanent MCAo . Oedema volumes were assessed early and would likely be greater at later time points. However, we still observe ICP rise from 18 to 21 hours, which suggests that mechanisms other than oedema contribute to ICP rise and increased tracer movement after photothrombotic stroke.
In this study, 6 out of 12 stroke animals had ICP rise 18 hours post-stroke. This ICP rise was smaller than we previously reported with MCAo at 24 hours and photothrombotic stroke at 22 to 24 hours post-stroke [8, 9, 19]. Here, we used a photothrombotic technique to produce a cortical ischaemia instead of a striatal ischaemia. This was the preferred model for our study of CSF flow as we aimed to maintain choroid plexus integrity throughout our experiments. MCAo, a striatal stroke model, reduces blood flow to the choroid plexus by around 62% and causes choroidal oedema leading to reduced blood-CSF barrier integrity and increased CSF secretion . Further, the earlier time point of our investigation may explain the smaller ICP rise, as we would expect ICP to continue to rise and peak at 22 hours post-stroke as previously observed . We chose this time point to observe any changes that may contribute to ICP rise as we expect changes to reduce later as the system returns to normal.
Experiments to elucidate physiological CSF dynamics are challenging and often involve some sort of intervention. In this study, we infused the CSF tracer, Evans blue, directly into the lateral ventricles of the animals [18, 21, 22]. This type of intervention has the potential to disturb normal CSF dynamics; however, this technique is widely used and we took care to limit the infusion rate to lower than that of CSF production (2.66–2.84 µl/min) to maintain the integrity of the system as much as possible .
Several CSF drainage hypotheses have been presented in recent years and we are yet to meet a consensus on the topic [24–26]. In recent years, lymphatic drainage of CSF from both the cranium and the spinal space have gained merit in the field, with several groups demonstrating the presence of CSF tracers in the peripheral lymphatic system, primarily the cervical lymphatics [21, 27–30]. This may be an interesting direction of investigation to understand how CSF drainage is altered post-stroke.