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Abstract
Current national guidelines advocate intravenous thrombolysis to treat patients with acute ischaemic stroke presenting within 4.5 hours from symptom onset, and thrombectomy for patients with anterior circulation ischaemic stroke from large vessel occlusion presenting within 6 hours from onset. However, a substantial group of patients presents with acute ischaemic stroke beyond these time windows or has an unknown time of onset. Recent studies are set to revolutionise treatment for these patients. Using MRI diffusion/FLAIR (fluid-attenuated inversion recovery) mismatch, it is possible to identify patients within 4.5 hours from onset and safely deliver thrombolysis. Using CT perfusion imaging, it is possible to identify subjects with a middle cerebral artery syndrome who have an extensive area of ischaemic brain but as yet have only a small area of infarction who may benefit from urgent thrombectomy in up to 24 hours. Here, we highlight the recent advances in late window stroke treatment and their potential contribution to clinical practice.
- wake up stroke
- stroke with unknown time of onset
- thrombolysis
- thrombectomy
- CT perfusion
- DWI-FLAIR mismatch
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- wake up stroke
- stroke with unknown time of onset
- thrombolysis
- thrombectomy
- CT perfusion
- DWI-FLAIR mismatch
Introduction
Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) has been the standard reperfusion therapy for acute ischaemic stroke for almost two decades. It provides modest benefit with a ‘number needed to treat’ to achieve functional independence of 9 by 3 hours and of 14 by 4.5 hours.1 It carries a small but significant risk of intracerebral haemorrhage and has to be given in a time-critical fashion.2 Intravenous thrombolysis alone was often ineffective in patients with a large, proximal vessel occlusion,3 4 which led to the hypothesis that mechanical extraction of the occluding thrombus may be needed to achieve reperfusion and improve clinical outcome. This approach revolutionised stroke care with a series of landmark trials led by MR CLEAN.5 In 2015, five of these studies were combined in the HERMES collaboration, including more than 1000 patients with acute ischaemic stroke with large vessel occlusion. The conclusion was that mechanical thrombectomy performed within 7.3 hours from symptoms onset resulted in significant improved independence at 90 days compared with controls, with a number needed to treat of about five.1
While both thrombolysis and thrombectomy offer significant benefits, only a small proportion of patients with acute stroke with or without large vessel occlusion present within conventional time windows. Up to 27% of patients with ischaemic stroke have an unknown time of onset.6 7 On the other hand, information provided by bystanders regarding the time the patient was last seen well is sometimes unreliable. Moreover, not all patients presenting with ischaemic stroke secondary to large vessel occlusion who currently reach local hospitals within the early time window can be transferred to the thrombectomy hub rapidly.8
All stroke physicians will recognise the feeling of disappointment when admitting a patient who has woken up with a significant stroke syndrome and has a normal looking CT scan, knowing the uncertain time of onset means they cannot offer treatment. However, this is starting to change. Prospective studies suggest that many wake-up strokes probably occur close to waking up.9 Recent late window trials have shown that neuroimaging can successfully estimate the stroke onset time or identify a favourable perfusion pattern in patients with an unclear onset time or wake-up stroke, who may still benefit from intravenous thrombolysis or thrombectomy.
The pathophysiology of acute ischaemic stroke (figure 1)
The pathophysiology of acute ischaemic stroke and corresponding imaging examples. DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery.
Occlusion of an intracranial artery results in ischaemia and reduced cerebral blood flow (. As cerebral blood flow falls, normal cellular processes start to switch off. These may be recoverable until the blood flow reaches a very low level. However, at less than 45% of normal cerebral blood flow, cells may be irreversibly damaged and inevitably progress to infarction. Simplified, very low cerebral blood flow at the cellular level results in deprivation of energy causing membrane pump failure, influx of sodium, water and cell depolarisation. Cells swell due to the redistribution of water. This is cytotoxic oedema. Cells seldom, if ever, recover from this. Plain CT scan of head is not reliable at this stage, identifying only 50%–70% cases10 during the first 3 hours, whereas MR diffusion-weighted imaging (DWI) is very sensitive at detecting cytotoxic oedema11 showing a hyperintense area (with corresponding apparent diffusion coefficient hypointensity (restricted diffusion)) within minutes of onset. This improves hyperacute stroke detection to 95%.12
The next stage is ionic oedema. Here, sodium and water influx depletes them from the extracellular space, creating a sodium gradient that pulls fluid from capillaries into the extracellular space.13 At this stage, there should be some swelling of the infarcted tissue but it may not be very obvious on CT scanning. This marks a transition between cytotoxic oedema and vasogenic oedema. As ionic and early vasogenic oedema develop, ischaemic changes—such as loss of grey and white matter differentiation and hypo-attenuation may become visible on CT. On MRI, the T2 or fluid-attenuated inversion recovery (FLAIR) sequence may start to show hyperintensity, while DWI is clearly positive. The hyperintense DWI signal change correlates to ‘core infarction’. However some conditions causing diffusion abnormalities, such as transient ischaemic attack or migraine, might be reversible.
As the ischaemic cascade continues, the brain–blood barrier breaks down, and macromolecules such as albumin and plasma proteins leak into the extracellular space along with water. This stage is called ‘vasogenic oedema’ and is normally visible on imaging (hypointense on CT or hyperintense on T2 and FLAIR), often with obvious swelling and sometimes with additional evidence of haemorrhage.
It is important to note that while DWI becomes positive almost immediately after stroke onset, the FLAIR does not become positive until oedema has developed. The T2 signal value correlates closely with time from stroke symptom onset.14 Imaging studies12 15–17 tested the utility of DWI/FLAIR mismatch as a ‘tissue clock’ to identify those whose stroke likely occurred within 3–4.5 hours from symptoms onset. A positive DWI lesion and a negative FLAIR sequence showed a 78%–93% specificity and 65% sensitivity to predict that stroke onset was less than 4.5 hours previously.17 This therefore supported the hypothesis that MRI could be used as a tissue clock to identify infarcts less than 4.5 hours old.
Core, perfusion lesion and penumbra
Consider the acute occlusion of a middle cerebral artery. The cerebral blood flow will drop in the affected part of brain, usually with appropriate symptoms in the patient. The volume of brain affected by hypoperfusion is known as the perfusion lesion. The cerebral blood flow will not be uniformly low throughout the whole perfusion lesion. There is likely to be a deeply ischaemic region that has been irreversibly damaged. That volume is known as the core. The rest of the perfusion lesion will contain areas that may or may not go on to infarct, depending on the length of time they are ischaemic or the severity of the ischaemia. These areas may be recoverable if adequate perfusion is re-established rapidly and constitute the penumbra.
The question is, why does part of the perfusion lesion survive longer than the core? The answer is the collateral circulation. Blood may be able to access the ischaemic area through other arterial channels (such as the pial collaterals). If the collateral circulation is very good, blood may even be able to reach the distal end of the occluding thrombus with only a few seconds delay from normal perfusion. Collaterals are critically important for the survival of brain tissue. Better collaterals are associated with better clinical outcome18 and smaller infarcts.19
CT or MR angiography are very sensitive and specific in identifying a large proximal vessel occlusion.20 21 CT angiography can also be used to assess the collateral circulation. However, modern CT angiography is so fast that while it may show the occlusion, insufficient time may have elapsed to demonstrate the collaterals. Therefore, multiphase CT angiography, where the subject moves back and forth a couple of times through the scanner, is a more sensitive and specific method for identifying collaterals.22 23
Identifying the core and perfusion lesion is more difficult. Consider the core first. Most authorities agree that the DWI lesion represents the core and is probably the best method to use. However, CT or MR perfusion scans can also identify the core by setting parameters to identify tissue that has been very ischaemic and therefore, has little probability of recovery.
The ischaemic core or DWI lesion may evolve quickly—within minutes in some patients—whereas in those patients with a good collateral supply or tissue that is inherently more tolerant of ischaemia, evolution may be slower. Therefore, some patients with a clinically significant stroke have a big perfusion lesion but still only a small ischaemic core. There may be quite a large mismatch between the core and the perfusion lesion. National Institute Health Stroke Scale (NIHSS) is a good surrogate for tissue at risk, as is CT perfusion or MR perfusion. The higher the NIHSS, the larger the perfusion lesion. Figure 2 shows an example that illustrated this well. The RAPID software was created as an application to quantify tissue that comprised the ischaemic core and tissue at risk. It was used to identify core and penumbra in DEFUSE-3 and the core in DAWN. The core was defined as having a relative cerebral blood flow of <30% of contralesional blood flow and the penumbra as having a Tmax>6 s with a relative cerebral blood flow of >30% of the contralesional side.
Example of perfusion imaging showing a disproportionately large region of hypoperfusion as compared with the size of early infarction.
Common measurements used in perfusion imaging to define core and penumbra
Cerebral blood flow is a measure of blood flow and is defined as the volume of blood flowing through a given volume of brain per unit time.
Tmax represents the time from the start of the scan until the maximum intensity of contrast material arrives at each voxel. The longer the Tmax, the more hypoperfused of the tissue.24 Other similar parameters used are time to peak and mean transient time.
C erebral blood volume is the total volume of flowing blood in a given volume in the brain; low flow is considered a marker of already infarcted tissue.
Putting theory into practice
The question is, can we use our understanding of pathophysiology of stroke with modern imaging to identify candidates for thrombolysis or thrombectomy? Can we make decisions based on pathophysiology rather than simple strict time criteria? Over the last year, three landmark studies have answered that question with a resounding, ‘Yes’. They are WAKE-UP, DEFUSE-3 and DAWN, summarised in table 1.
The summary of three reperfusion studies for late presentation of ischaemic stroke up to 24 hours
The WAKE-UP study25 used MRI DWI/FLAIR mismatch to identify those who were likely to be within 4.5 hours of stroke onset, among patients with strokes on waking or with unknown time of onset (figure 3). It successfully showed that it is feasible in practice to use DWI/FLAIR mismatch as a ‘tissue clock’ to identify those whose stroke occurred less than 4.5 hours before the examination and that intravenous thrombolysis is safe and effective in these selected patients (number needed to treat was nine).
An example of wake-up stroke MRI :A. DWI showed an area of hyperintensity in the right MCA territory; B. Correspoding restricted diffusion on ADC map; C. FLAIR is still negative.
DEFUSE-3 and DAWN were similar studies in that they each hypothesised that if one could identify patients with large vessel occlusion who had large perfusion lesions but still only a small core volume, they may benefit from thrombectomy performed at up to 16 hours (DEFUSE-3) or 24 hours (DAWN). Both studies were stopped early because of efficacy. There was no significant difference in adverse events between the thrombectomy group and the best medical group. The number needed to treat to yield one extra person independent (modified Rankin Scale 0–2) at 90 days after stroke was 3.6 in DEFUSE-3 and 2.8 in DAWN. Intriguingly, DEFUSE-3 and DAWN had better efficacy up to 24 hours than studies recruiting patients up to 6 hours. The population in each of the two studies was highly selected. The median volume of ischaemic core was around 10 mL for DEFUSE-3 and<10 mL in DAWN. Their strict selection criteria yielded a small core volume with a large penumbra: a group of patients with an excellent imaging profile. This may explain why patients presenting between 12 and 16 hours had similar or even better outcome than those presenting between 6 and 12 hours from symptom onset. However, both studies confirmed benefit of treating patients who presented between 6 and 24 hours, and the American Heart and Stroke Association guidelines both have already endorsed them.26 The studies also emphasised the role of advanced stroke imaging in future clinical practice. MRI and perfusion imaging should be readily available to all patients with late presentation in order to select potential candidates for reperfusion therapy. Other studies that are currently recruiting a similar patient group include ECASS 4, EXTEND and TWIST. It is worth noting that TWIST uses CT scanning only to screen wake-up stroke.
The evidence suggests that modern imaging techniques that increase the precision of patient selection could allow clinicians better to identify subjects who are likely to respond to treatment (figure 4).
The comparison of NNT in thrombolysis and thrombectomy studies with or without imaging selection. Note that studies that recruited using more detailed neuroimaging yielded better results. NNT, number needed to treat; MT, mechanic thrombectomy; rtPA, recombinant tissue plasminogen activator.
Treatment paradigm
Below we suggest a paradigm treating patients with acute stroke with or without large vessel occlusion presenting within 24 hours of symptoms onset. Box 1 summarises the evidence.
Treatment paradigm: rtPA, recombinant tissue plasminogen activator.
Acute stroke with known time of onset 0–4.5 hours
If no thrombectomy target, intravenous rtPA (NINDS Trial, ECASS III Trial).
Thrombectomy target, intravenous rtPA and then thrombectomy (MR CLEAN et al).
Acute stroke with known time of onset 4.5–6 hours
Thrombectomy target, proceed to thrombectomy (MR CLEAN et al.).
Presents with no known time of onset (but <24 hours).
If there is no thrombectomy target, MRI DWI/FLAIR mismatch, intravenous rtPA (WAKE-UP).
Thrombectomy target determine the core and penumbra.
CT (or MR) perfusion and treat up to 16 hours (DEFUSE-3 Trial).
MRI DWI with NIHSS and treat up to 24 hours (DAWN Trial).
Conclusion
A very exciting new era in stroke management has dawned. In patients with no clear time of onset of stroke, many of whom suffered a stroke while asleep, it is possible to use CT scanning and CT angiography first to confirm that there is no established infarct and then to decide whether or not there is a potential target for thrombectomy. If the CT scan looks normal and there is no thrombectomy target, DWI/FLAIR mismatch can serve as a tissue clock to allow thrombolysis administered if there is no contraindication. Where there is a thrombectomy target, perfusion imaging either alone or combined with clinical assessment can identify brain at risk of infarction; provided the core remains small, thrombectomy will have a high chance of success. In the future, these techniques may be used to select patients better for treatment within the traditional 6-hour timeframe.
Key Points
Consider using CT and CT angiography in all patients with suspected stroke who present with unclear onset time up to 24 hours, to exclude haemorrhage and to identify a proximal occlusion and potential thrombectomy target.
Consider using DWI (diffusion-weighted imaging)/FLAIR (fluid-attenuated inversion recovery) mismatch as a ‘tissue clock’ to identify those whose stroke occurred within 4.5 hours when there is no clear time of onset, such as on waking.
Consider using perfusion imaging to complement CT scanning and CT angiography and select patients with a favourable ischaemic core and penumbra pattern for potential thrombectomy up to 24 hours.
Intravenous thrombolysis or thrombectomy can have a high success rate in patients selected by the above means and WAKE-UP or DEFUSE-3 or DAWN inclusion and exclusion criteria.
Time is brain: patients with suspected stroke who present with an unclear onset time up to 24 hours may be potential candidates for thrombolysis and/or thrombectomy and should be investigated and treated as quickly as possible.
Acknowledgments
We are very grateful to Dr Ajay Bhalla (Consultant stroke physician) and Dr Arani Nitkunan (consultant neurologist) for reading and commenting on the manuscript.
References
Footnotes
Contributors XH wrote the first draft and did subsequent revision. VA and NK reviewed the article, provided comments and revisions. ACP oversaw the writing process, the organisation and the direction of the paper and provided revision of the paper.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned. Externally peer reviewed by Tom Hughes, Cardiff, UK.
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