Computed tomography (CT)-based imaging remains the most common imaging modality to evaluate patients presenting with acute stroke symptoms. It is easily available, safe, and fast which is critical in acute stroke management. CT has high sensitivity for the detection of intracerebral hemorrhage. However, apart from hyperdense arteries that may indicate acute thrombus, the brain parenchyma is often normal on CT in the early few hours after AIS [16]. Early ischemic changes (loss of the grey-white matter differentiation or effacement of the cortical sulci) can be seen in approximately 30% of patients with anterior circulation large vessel occlusion (LVO) within the first 3 hours [16], and 60% within the first 6 hours after symptom onset (Figure 1) [17]. The Alberta Stroke Program Early CT Score (ASPECTS) is a semi-quantitative score used to summate the extent of early ischemic changes in the middle cerebral artery (MCA) territory on non-contrast CT (NCCT) scan (Figure 2) [18]. Most EVT RCTs published in 2015 (except MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands]) required an ASPECTS of 6 or greater to be eligible for inclusion in the trial [19]. A meta-analysis of the pooled data from the five landmark studies published in 2015 showed a benefit of thrombectomy in patients with ASPECTS ≥6 and therefore an ASPECTS 6–10 is considered a surrogate marker of small infarct volume and a strong predictor of favorable clinical outcome after EVT for LVO [20]. The AHA/ASA guidelines recommend mechanical thrombectomy for patients with LVO and ASPECTS ≥6 who present within 6 hours of last known well time based on pre-specified inclusion criteria from randomized trials, without additional advanced imaging [6].

Moreover, the benefit of EVT over medical management was observed in patients with ASPECTS scores ranging from 3 to 5 after central adjudication of imaging from the early window EVT trials [21]. The RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan Large IscheMIc core Trial) was the first published randomized clinical trial that evaluated the efficacy and safety of EVT in patients with LVO and an established large infarct (ASPECTS of 3 to 5). Patients selected within 6 hours of arrival were eligible with a CT ASPECTS of 3–5, while patients in the 6 to 24 hour window were eligible if their diffusion-weighted imaging (DWI)-ASPECTS was 3–5 and they had no fluid-attenuated inversion recovery (FLAIR) correlate. In this population, better outcomes were observed at 90 days in patients who underwent EVT versus medical management (rate of modified Rankin Scale [mRS] 0–3, 31.0% vs. 12.7%, P=0.002) [22].

Despite its widespread use, the limitations of ASPECTS include its relatively low sensitivity and inter-rater reliability for the detection of early ischemic changes [23]. CT angiogram (CTA) source image and DWI-ASPECTS are more sensitive than NCCT ASPECTS in the detection of early ischemic changes and prediction of final infarct volume (Figure 1) [24].

A posterior circulation version of the ASPECTS has been developed (the pc-ASPECTS), and has been shown to predict functional outcome in posterior circulation stroke (Figure 3) [25]. While the pc-ASPECTS can be calculated from an NCCT brain, beam hardening artifact in the posterior fossa and poor spatial resolution of brainstem structures are major limiting factors, but accuracy is improved when calculated based on CTA source images [25,26].

Recently, two RCTs (ATTENTION [Endovascular Treatment For Acute Basilar Artery Occlusion] and BAOCHE [Basilar Artery Occlusion Chinese Endovascular]) evaluating EVT versus best medical therapy in patients presenting with acute basilar artery occlusion (BAO) showed high rates of successful recanalization, improved outcome, and decreased mortality up to 24 hours after estimated symptom onset [27,28]. These two trials were the first to use an imaging scoring system in the selection of patients into the trial [29]. In ATTENTION, BAO was confirmed on CTA, magnetic resonance angiography, or digital subtraction angiography (DSA) within 12 hours after the estimated time of stroke onset and patients were included if they had a pc-ASPECTS of ≥6 points among patients younger than 80 years of age and a score of ≥8 points among those 80 years of age or older. In BAOCHE, patients were included if they had a pc-ASPECTS of ≥6 on NCCT, CTA-source images or DWI, or Pons-Midbrain Index of ≤2 points. In both the ATTENTION and BAOCHE trials, the extent of early ischemic changes was limited. In ATTENTION, the median pc-ASPECTS was 9 in the EVT group and 10 in the control group. In BAOCHE, the median pc-ASPECTS was 8 in both EVT and control groups [27,28].

In addition to the evaluation of the brain parenchyma, the NCCT brain is also helpful to determine the thrombus location, density, composition, and length. The “hyperdense artery sign” represents the red blood cell (RBC) rich intra-luminal thrombus and is considered a surrogate of arterial obstruction (Figure 4). The hyperdense artery sign is highly specific (95%) for MCA occlusion according to some reports [30] but can only be visualized in 30%–52% of MCA occlusions on routine 3–5 mm source images [30,31]. Thin slice reformats (1 mm) increase this sensitivity to approximately 90% [32]. In clinical practice, a hyperdense vessel can appear similar to calcified intracranial atherosclerosis and sometimes be misinterpreted as hemoconcentration, therefore it must be interpreted in the appropriate clinical context. The hyperdense vessel sign can also be identified in M2 occlusions (known as the “dot sign”), BAO, or any newly occluded blood vessel (Figure 4) [33-36]. For patients who are unable to undergo non-invasive vascular imaging, the “hyperdense vessel sign” can guide decisions for EVT [7]. Knowledge of these clot factors can provide insights into stroke etiology and can impact the choice of revascularization techniques. The RBC rich thrombi are easier to retrieve by stent retriever technique and have higher chance of recanalization with fibrinolytic therapies due to their decreased stiffness, greater permeability, and less friction with the vessel wall. This contrasts with fibrin-rich thrombi which are more adherent and have higher friction with the vessel wall [37]. RBC rich thrombi are also more prone to fragmentation, highlighting the potential need for proximal flow arrest with balloon guide catheters [38,39].

CTA plays a critical role in the detection of LVO for AIS and the historical success of RCTs published after 2014. The 2013 LVO RCTs did not demonstrate a benefit of EVT for LVO, in part, due to inclusion of patients who did not harbor an intracranial occlusion despite elevated National Institutes of Health Stroke Scale (NIHSS) on presentation [40-42]. The subsequent AIS clinical trials required inclusion of patients with LVO that was confirmed by non-invasive vascular imaging (usually CTA), thus enriching the population to those who might benefit from EVT [19]. CTA informs the presence, site, permeability, and length of vessel occlusion, as well as the collateral circulation (Figure 5) [43-45]. Collateral vessel status is a valuable and sometimes underappreciated surrogate for infarct growth, and can be useful for the early identification of “rapid progressors” or patients with a high probability of rapid growth of irreversible tissue injury [43,46]. However, single phase CTA is often timed at peak arterial phase when the contrast may not have yet opacified collateral vessels and may therefore underestimate the extent of collateral blood flow. CTA can aid in understanding the underlying pathophysiology of the stroke, including arterial dissection, carotid or intracranial atherosclerosis, carotid web, and intracranial vasculopathy (Figure 6) [35,36,47-49]. The ability to discern carotid pseudo-occlusion from a carotid terminus occlusion versus tandem proximal internal carotid artery (ICA) atherosclerotic occlusion remains a limitation of CTA, even when adjudicated by experienced radiologists [50]. CTA evaluating the head and neck vessels informs neurointerventionalists who are planning an endovascular procedure on the access of an intracranial target, including bovine or hostile aortic arch and whether radial or femoral arterial access is more appropriate [51,52]. CTA source images are also better to adjudicate ASPECTS in the anterior and posterior circulations [24]. However, radiation exposure, cost, and ionized contrast media are to be considered, especially when CT perfusion (CTP) is added to the protocol [53,54].

CTA (also using thin-section CT) is also useful in clot imaging. Thrombus perviousness (also known as permeability), the degree to which contrast agents penetrate the thrombus on CTA, has been associated with cardioembolic source of clot [55] and with improved functional and angiographic outcomes after EVT and increased reperfusion after tissue plasminogen activator administration [56,57].

Multiphase CTA can be used to evaluate the collateral circulation with greater accuracy than single phase CTA as it is less dependent on contrast timing [58,59]. The cerebral collateral circulation is a network of vascular channels that sustains blood flow to the ischemic regions in case of failure of the principal conduits (Figure 5) [1,60]. Collateral blood vessels comprise extracranial (external carotid artery branches), and intracranial routes (communicating arteries of the circle of Willis and leptomeningeal collaterals). Leptomeningeal collaterals consist of pre-existing collateral routes between the cortical vessels that may be recruited in the event of a proximal occlusion). Collateral circulation has an important role in the AIS evolution, management, and prognosis [61,62]. Good collateral circulation maintains the blood supply to the penumbral area in the acute stage and is associated with higher recanalization rate, smaller infarct volume, lower rate of hemorrhagic transformation, and better neurological outcome after medical treatment or EVT [63,64].

Although DSA is considered the gold standard for dynamic evaluation of the collateral circulation, CTA is a commonly used modality to evaluate the collateral status before EVT. Several collateral scores on single or multiphase CTA have been described in AIS [65,66]. The collaterals on the affected side are usually compared to the contralateral side and they are generally categorized as absent, less, equal, or greater collaterals compared to the other side. These scores have been shown to be predictors of clinical outcomes after EVT. Several societal guidelines recommend assessing collateral status when selecting patients for EVT [9,67]. The use of collateral-based imaging using multiphase CTA compared well with CTP-based blood flow measurements in predicting final tissue fate [68] and in selecting patients for EVT in the late window [69]. The “Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE)” trial showed that a collateral-based imaging paradigm was capable of selecting patients with LVO who would benefit from EVT up to 12 hours from onset/last known well. However, it is important to note patients with no or minimal collaterals on multiphase CTA were excluded from the ESCAPE trial [70].

Multiphase CTA is readily available at many centers which utilize CTA and requires no additional contrast material or post-processing software. It may improve the sensitivity to detect vessel occlusion, the length of clot and potentially the extent of ischemic core [71]. The typical 3-timepoint multiphase CTA requires rescanning of the patient’s head twice after the initial CTA acquisition, increasing the radiation dose. However, the mean effective dose of multi-phase CTA was estimated approximately 20% above that of single phase CTA, compared with 70% added dose for CTP [59,72]. Additional limitations of multiphase CTA include the suboptimal assessment of collateral status in case of poor hemodynamics (e.g., heart failure) and in case of flow-limiting stenosis in the neck vessels that can potentially delay opacification of pial vessels in both ischemic and non-ischemic tissue [71].

The main goal of perfusion imaging in patients with AIS is to identify patients with small regions of critical hypoperfusion (often termed “ischemic core”), which is commonly estimated using a relative cerebral blood flow (rCBF) threshold of <30% of that in normally perfused brain tissue. Differentiating the ischemic core from the surrounding penumbra is crucial for tailoring treatment strategy for patients with AIS. The estimation of irreversible injury based on reduced blood flow relies on assumptions about the duration of reduced flow. In clinical practice, the reduced flow has generally been present sufficiently long to induce irreversible injury. However, in patients with fluctuating blood flow or very fast reperfusion, the rCBF <30% threshold may overestimate the extent of irreversible injury [73]. This is more common in regions of white matter [74], which may remain viable for longer periods when compared to grey matter although it is designated as “ischemic core” on perfusion maps. In addition to identifying regions of critical hypoperfusion, perfusion imaging may also estimate regions of tissue at risk of infarction in the absence of reperfusion (termed the ischemic penumbra). Penumbra is the hypoperfused area surrounding the ischemic core (critically hypoperfused region with irreversible damage). The penumbra can be salvaged if perfusion is improved, or it can progress to tissue infarction if blood flow is not restored. Penumbra is identified using a threshold of >6 seconds in time-to-maximum residue function (Tmax) [75]. This improves estimates compared to visual assessments as the perfusion abnormality includes benign oligemia that is not at risk of infarction. However, this too is a probabilistic threshold. Generally, such a delay in contrast transit is insufficient to cause irreversible ischemia, but it may be sufficient to cause focal cerebral dysfunction until perfusion may be restored. The more severe the delay, the greater the risk of infarction without reperfusion. Of note, perfusion imaging is increasingly automated, with volumetric outputs generated minutes following image acquisition. Several automated CTP software applications have been developed to provide support in the definition of ischemic core and penumbra in AIS. However, the available software packages can vary substantially in their output [76]. In addition to estimating tissue viability, perfusion imaging increases the diagnostic accuracy for acute stroke and provides prognostic information regarding functional outcome [75].

The presence of a favorable perfusion profile (mismatch between small rCBF <30% volume and large Tmax >6 seconds lesion or severe clinical presentation) indicates that rapid reperfusion is likely to salvage substantial brain tissue and was the basis of selection in the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo), DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke), and EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits) trials that extended EVT and intravenous thrombolytic beyond standard time windows. An alternative approach for patients with unknown onset time is to use a mismatch between abnormal diffusion but normal FLAIR magnetic resonance imaging (MRI) to infer that a patient is likely to be in the first 4.5 hours after stroke onset. DWI-FLAIR mismatch was used in the WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) trial to extend thrombolytic eligibility in patients with stroke on awakening [77,78].

Perfusion imaging was used in two of the early window LVO trials [79,80] but became more widespread after the release of the DAWN and DEFUSE-3 trial results which used perfusion for selection of patients for thrombectomy versus medical management [12].

When added to unenhanced imaging, perfusion imaging can facilitate the diagnosis and triage of AIS in several ways. Perfusion imaging can enable the detection of distal and posterior circulation vessel steno-occlusive disease using the Tmax maps [36,48,81,82]. Perfusion imaging may further help identify a subset of patients with a large region of established infarct who may benefit from EVT when there remains considerable tissue at risk [83]. In the event of multiple intracranial occlusions or stenosis, perfusion imaging may identify the symptomatic site (Figure 7), provided the reference artery selected for the arterial input function is physiologically appropriate [84]. Importantly, partial or complete reperfusion of infarcted tissue may elevate CBF above the threshold for ischemic core and this can be recognized if there is NCCT hypodensity [85].

CTP radiation exposure is a consideration in younger patients but is reducing with hardware advances (e.g., use of lower CT tube voltage, 70 kV). If using CTP, it is important to make treatment decisions in parallel to avoid treatment delay. Thrombolytic decisions within 4.5 hours can be made on clinical and NCCT grounds in many cases, but the additional diagnostic and prognostic information from CTP can assist in cases of uncertainty. Likewise, EVT decisions can often be initiated based on a severe clinical syndrome with a hyperdense proximal artery, but the additional information from CTA and CTP can assist in procedural planning and more finely balanced risk and benefit scenarios, such as in patients with moderate or large core infarct, distal vessel occlusion, or co-morbidities. Cost related to post-processing software is a consideration in some environments and availability varies widely. In some regions (e.g., Australia), CTP is routine at primary stroke centers but in the United States, as well as low- and middle-income countries, it is less used outside comprehensive stroke centers [8,9,12]. The value of the additional diagnostic information gained by perfusion imaging should be weighed against potential treatment delays, cost of CTP, and added radiation exposure [43].