Less than a decade ago most stroke centers only performed a non-contrast CT (NCCT) in the emergency setting of patients with suspected ischemic stroke. Since then, the imaging modalities have improved substantially and also major advances have been made in the identification of imaging parameters that predict patient outcome.(1) One of the great challenges in ischemic stroke research is the large heterogeneity of this disease. Prediction of clinical outcome in acute ischemic stroke is important, but quite challenging when based on patients’ characteristics, clinical findings and NCCT alone.(2) Advanced imaging techniques could improve the prediction of patient outcome since traditional anatomic imaging has progressed to dynamic and functional imaging in recent years.(3)
At the start of this project in 2013, intravenous thrombolysis (within 4.5 h after symptom onset) was the only proven reperfusion therapy for acute ischemic stroke patients.(4) After publication of the neutral results of 3 randomized-controlled trials (RCTs) of intra-arterial treatment (IAT) in 2013(5-7), concerns and questions were raised in the medical community regarding the future of IAT for acute ischemic stroke.(8;9) In 2015 (the “annus mirabilis” for IAT), the treatment of patients with acute ischemic stroke changed after publication of multiple RCTs evaluating IAT.(10-14) A pooled analysis of these five trials showed an absolute risk difference of almost 20% in favor of the intervention population with regards to good clinical outcome at follow-up (modified Rankin Scale score 0-2 at 90 days of 46.0% in the intervention population vs 26.5% in the control population).(15) Improved identification of prognostic imaging features, faster workflows and technical improvements in IAT are important contributors to this success.(16;17) These RCTs have shown efficacy of imaging-based patient selection in predicting benefit from IAT after acute proximal occlusion in the anterior circulation. The underlying concept of imaging-based criteria rests on the assumption that a small irreversible infarct (core lesion) in relation to a large area of potentially treatable hypoperfused critical ischemia identifies a patient with the optimal constellation for reperfusion therapy.(18)
The research presented in this thesis has been performed just before and at the time of this shift in acute stroke treatment. For a majority of studies presented in this thesis, we selected patients from the Dutch Acute Stroke (DUST) study, a prospective multicentre cohort study(19) and the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN).(10) Although multimodal CT imaging was done for all of our DUST and MR CLEAN patients before their inclusion, the results of imaging data were not used to select patients into the studies (for the MR CLEAN trial no imaging-based criteria were used beyond the requirement for anterior circulation large-vessel occlusion). More specifically, patients were not selected on the basis of infarct size at presentation, collateral status or cerebral perfusion results. This wide patient selection, sharply contrasts with the other endovascular therapy trials published in 2015(11-14), and thus provided us with a unique dataset. Other important and innovative features of the research presented in this thesis, are 1) CT perfusion (CTP) with whole brain coverage and 2) dynamic CT angiography (4D CTA) which provided us with time-resolved images of the arterial, parenchymal and venous phases in acute ischemic stroke patients.
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Because of the heterogeneous and relatively unselected stroke populations we used for our dynamic CTA studies (Chapters 2 and 3), the focus in our work has been on prediction of outcome. As a substantial amount of patients were not randomized for treatment in a subset of our studies(19), our research was not suited to appraise the relation between treatment and clinical outcome. Only in Chapter 8, we have made cautious remarks about the treatment modifying effect of cortical venous filling. The main limitation of our dynamic CTA studies is the performance of post-hoc analyses with patients from two different studies. This inevitably created complexity in interpreting outcomes of patients receiving different therapies. However, all IAT patients from the DUST study in our cohort fulfilled the additional inclusion criteria from the MR CLEAN trial and all clinical data were collected prospectively in both studies. Moreover, our broad inclusion criteria lead to a wider generalizability of our results. Despite the recent focus on imaging selection for endovascular stroke treatment, we should keep in mind that, more than two-thirds of patients with acute ischemic stroke do not have a large vessel occlusion.(20) The other parts of this thesis explore the value of our multimodal CT imaging protocol for predicting outcome: in transient ischemic attack (TIA) and minor ischemic stroke patients (Chapter 4), in a relatively unselected cohort of ischemic stroke patients presenting within 9 hours after symptom onset with CT perfusion (Chapter 5) and in pediatric stroke (Chapter 6). Treatment and imaging of stroke patients due to intracranial atherosclerotic stenosis is described in Chapter 7.
Outcome prediction in anterior circulation ischemic stroke due to a large vessel occlusion
Detailed information from vascular imaging can help to estimate prognosis and make treatment decisions in stroke patients.(1;12;21) CTA is a fast and widely available imaging tool. CTA provides information on the presence, location and extent of the arterial occlusion. Moreover, collateral status can be assessed with CTA and the anatomy of the aortic arch and necks vessels help in planning IAT. (1) Of important note, the term “collaterals” has gained tremendous importance in the stroke field,(12) but a more accurate term for what we evaluate on CTA would be “retrograde leptomeningeal vessel filling”.
Conventional CTA techniques provide only a snap-shot in time and lack information about changes in blood flow over time which makes this technique prone to error due to its static nature.(22). Because of the importance of the hemodynamic changes of the intracerebral circulation during acute ischemic stroke, we were interested in developing a noninvasive dynamic method that would allow evaluation of these changes.
Collateral status evaluated by dynamic CTA
We showed in Chapters 2 and 3 that our whole-brain time-resolved CTA was able to visualize changes in pial arterial filling over time. This additional hemodynamic information increased accuracy for prediction of infarct volume and clinical outcome at follow-up as compared with single-phase CTA.(23;24) In our study, a higher percentage of poor collateral status (filling of <50% of the affected middle cerebral artery territory) was seen with single-phase CTA when compared with dynamic CTA. This observation was in line with the earlier reported underestimation of collateral circulation assessment with single-phase
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CTA.(25) We demonstrated good reproducibility of our collateral scoring system. With our dynamic CTA studies we showed that, on average, the affected hemisphere reaches a lower extent of leptomeningeal vessel filling at a later time point in comparison with the unaffected hemisphere. With dynamic CTA we evaluated the velocity of leptomeningeal vessel filling and defined fast filling as an optimal filling within 4.5 seconds after optimal filling in the unaffected hemisphere. The extent of collateral vessel filling was more strongly associated with clinical outcome than the speed of filling. We showed that the timing of dynamic CTA acquisition in relation to intravenous contrast administration is critical for the optimal assessment of the extent of collaterals. Most importantly, we have shown that collateral assessment with dynamic CTA better predicts clinical outcome than single-phase conventional CTA.
From a clinical point of view, imaging modalities need to be quick to obtain, to be widely available and easy to read.
Time requirement for image acquisition and reconstruction of dynamic CTA
The dynamic CTA images can be acquired noninvasively and rapidly, in which acquisition of 19 CTA volumes is completed within 1 minute. Each volume has 320 slices (0.5mm thickness), resulting in a total of 6080 (19x320) images that are constructed for each patient. The reconstruction is performed with a speed of 20 images per second, which results in a total reconstruction time of roughly 5 minutes. This timeframe seems acceptable for clinical practice, however with the alternative technique of multiphase CTA, images are even faster (within 2-3min) available for review.
Accessibility of dynamic CTA
At this moment introduction of dynamic CTA in clinical practice will probably not be an easy task, since many hospitals do not have access to the newest generation CT scanners.
Time-resolved images of dynamic CTA are usually constructed from whole-brain CTP data sets. Therefore, a 64-row detector CT cannot provide data for the same detailed analysis as used in our study, since spatial coverage is limited. Spatial coverage of a 128-row detector CT scanner (6cm) already includes Alberta Stroke Program Early CT score (ASPECTS) level 1 (basal-ganglionic level) and level 2 (supra-ganglionic level), enabling dynamic CTA evaluation at different levels in the brain.(25) A 256-row detector CT scanner (0.5 mm detector width) results in Z-axis coverage of 12.8 cm, providing dynamic CTA for evaluation of the entire anterior circulation. Furthermore, methods are available to extend the anatomic area for acquisition of dynamic CT/CTP with 64-row or 128-row CT scanners. A possible method for this increased spatial coverage is the use of toggling-table technique (which increases coverage by continuously switching between adjacent regions with fast table movements). (26;27)Although use of this technique will limit temporal resolution of dynamic CTA/CTP acquisition to some extent, accurate analysis of CTP results has been shown to be possible. (26;27) A fast and reliable method that will more likely be implemented in clinical practice is the use of multiphase CTA in which the peak arterial phase, midvenous phase and late venous phase are acquired separately.(12)
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Magnetic resonance imaging
MRI diffusion weighted imaging (DWI) is the most accurate method to identify hyperacute infarction. The sensitivity and specificity of DWI for detecting infarction in the first 6 hours is above 90%(28,39). However, its primary drawback is limited availability for emergent stroke imaging. Although DWI can be acquired in 2 minutes using ultrafast echo planar imaging, screening to ensure MRI safety can be time consuming if in-hospital stroke workflow has not been optimized. Only a minority of hospitals have 24/7 MRI availability at this moment.
Magnetic resonance angiography (MRA) is an alternative tool in which angiographic information can be obtained non-invasively but without the use of ionization radiation. Compared with MRA, CTA is less susceptible to artifactual vessel narrowing caused by turbulent flow and susceptibility artifacts. However, non-contrast MRA techniques can be helpful in special circumstances like contrast allergy, pregnancy or renal failure.(1;21) Moreover, in clinical practice MRI could also be very useful in certain subgroups such as patients with unknown time of stroke onset(29), posterior circulation symptoms such as acute vertigo(30) or stroke mimics.(31) Also, MRI-based methods for the evaluation of the cerebral metabolic rate of oxygen provide a promising field for future stroke research. (32;33) In our center we use multimodal CT imaging in the emergency setting of acute ischemic stroke. MRI/MRA in the emergency setting of stroke was not investigated in this thesis. Considering the time dependency of treatment success in acute ischemic stroke, we think it is important to keep the (pre-randomization) time for imaging in future clinical trials as short as possible.
Use in clinical practice of time-resolved CTA and future perspectives
Based on our research on dynamic CTA(23;24) and work by others on multiphase CTA(34), we expect that time-resolved CTA will replace single-phase CTA in clinical practice. Compared with single phase CTA, time-resolved CTA is a more reliable imaging tool for collateral assessment but also a beneficial imaging tool in clot detection especially for less experienced physicians.(35) Considering the importance of time to reperfusion in clinical practice (each minute 2 million neurons are lost on average in acute large vessel stroke(36)), we think that the evaluation of 19 separate volumes on dynamic CTA is not feasible in the emergency setting. Respecting the proposed intervals of image acquisition(24), we found indirect support for the earlier results from others(34) that multiphase CTA (acquisition at 3 strategic intervals) can also deliver accurate information about the collateral circulation. Multiphase CTA has advantages, including the speed of acquisition and interpretation, minimal additional radiation, less sensitivity to motion artifacts and a good applicability on most CT scanners.(34) Another option to speed up the process with dynamic CTA, is the use of postprocessed angiography-like movies of the 19 volumes.(37) We plan to explore collateral assessment with this postprocessed angiography-like movies in a future study. An advantage of dynamic CTA over multiphase CTA is the fact that information from CTP is also available.(11) Since we only had a small group of endovascular treated patients in our cohort we were not able to investigate whether dynamic CTA collateral status modified the
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treatment effect. However, for single phase CTA the MR CLEAN investigators have recently demonstrated that the benefit of IAT was greatest in patients with good collaterals, while treatment benefit appeared less and may be absent in patients with poor or absent collaterals. (38) The treatment modifying effect of the collateral circulation must also be more robustly validated in prospective acute ischemic stroke trials. Future studies comparing single-phase and multiphase CT angiography for this purpose are warranted.(39) Collateral assessment with time-resolved CTA is a new modality and we believe that standardization of scoring systems is important. To speed up the process of collateral assessment and to reduce human error we expect validated automatic methods with advanced software to be developed. Efforts to refine and standardize imaging selection must also inform the concept of futility in stroke reperfusion therapy. A futile profile should identify groups of patients in whom a therapy offers little to no clinical benefit particularly if an increased risk of harm is greater than any predicted benefit.(39) This would improve efficacy and cost-effectiveness of acute
stroke treatment.
In the future, imaging and treatment will likely be performed in new angiography suites with improved imaging capabilities.(17) To avoid potential in-hospital transportation delays, a future IAT candidate could be triaged directly from pre-hospital transportation to an imaging equipped angiography suite.(40-42) Especially the latest developments to minimize door- to-groin times with flat-detector CT (FD-CT) and multiphase FD-CTA which can provide images in the angiography suite, look promising (Psychogios MN, personal communication). However, current FD-CT imaging seems not yet ready for wide adoption, which makes the alternative of a hybrid angiosuite with a mobile CT scanner a more attractive option at this moment.
CT perfusion
Some studies have suggested that imaging of the ischemic penumbra can help in therapeutic decision-making in patients with acute ischemic stroke.(43) However, CTP is not part of the standard of care in treatment decisions because penumbral imaging guided treatment has not been validated yet in a large phase-3 clinical trial. One of the reasons for this delay in validation is the lack of standardization in CTP imaging.(39)
In Chapter 5 we evaluated the role of quantitative CT perfusion analysis for identification of patients likely to respond to acute stroke treatment. Because CTP analysis largely depends on the specific software used, we chose to use CTP analysis methods (with different perfusion parameters and cut-off values for penumbra and core), which have been previously validated for our specific postprocessing software.(44;45)
As stated recently in the “acute stroke imaging research roadmap”, perfusion-derived entities, such as the core and penumbra, are the imaging biomarkers that will require the largest effort in terms of standardization considering the number of existing definitions and the differences between imaging modalities.(39)
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Our scanner with whole brain CTP coverage enabled us to simulate and compare different coverage sizes. As previously demonstrated by others, we found that CTP findings are predictors of radiological outcome and, to a lesser extent of, clinical outcome at follow-up.(46) We could not find support for our hypothesis that CTP would improve identification of acute stroke patients likely to respond to acute stroke treatment, although an important limitation of our study was the small sample-size. We conclude that in relatively unselected stroke populations, CTP penumbra-core mismatch classification should not be used for exclusion of patients from IVT. Our data on stroke patients with a proximal large vessel occlusion in the anterior circulation also confirm the recent findings from the MR CLEAN investigators who could not find support for the use of CTP-based selection of patients for IAT.(47)
As discussed above, dynamic angiography generated from raw CTP data can be used to grade collaterals with excellent temporal resolution. In current clinical practise, NCCT and CTA are the minimum standard in acute ischemic stroke(21). At this point in time we think that evidence is lacking to support the use of CTP for patient selection. In our opinion, perfusion imaging has the potential to become useful for analysis of certain subgroups. For example, identification of CTP parameters in patients with large vessel stroke which can predict hemorrhage after IVT(48), since these patients could have potential benefit of not receiving IVT before endovascular stroke treatment in future trials.
Next to the evaluation at admission, CTP may perhaps be used to monitor the treatment effect by non-invasive assessment of the reperfusion status.(49;50). However, finding a single threshold for CT/MRI perfusion studies is complicated by dependency of perfusion imaging on its precise protocol that often lacks standardization.(51) Direct evaluation of reperfusion during IAT with CTP in the angiosuite could become a next step in clinical practice but this modality requires first technical improvement and then validation in new trials(52).
Outcome prediction after transient ischemic attack (TIA) and stroke with minor symptoms at presentation
In Chapter 4 we studied the role of whole brain CTP in the emergency diagnosis of TIA and minor stroke in predicting clinical outcome. We found that almost 20% of TIA/stroke patients with minor neurological symptoms at presentation (National Institutes of Health Stroke Scale score of < 4) had poor clinical outcome at 3 months follow-up. Similar outcomes were found in the Cerebrovascular Events to Identify High Risk Patients (CATCH) study.(53) The