Multimodality CT based imaging to determine clot characteristics and recanalization with intravenous tPA in patients with acute ischemic stroke
© The Author(s). 2017
Received: 2 February 2017
Accepted: 9 February 2017
Published: 28 February 2017
Acute ischemic stroke (AIS) is a common neurovascular emergency causing significant burden to society. Currently the main focus of AIS treatment is to restore blood flow to at risk brain tissue. For the last twenty years, intravenous tissue plasminogen activator (tPA) was the only proven therapy for patients with AIS. More recently, five randomized clinical trials established the efficacy of endovascular therapy with or without intravenous tPA in selected patient populations with AIS.
Not all stroke patients benefit from intravenous tPA or endovascular treatment. Nonetheless, the concept of early recanalization of occluded arteries resulting in better clinical outcomes is well established. In this focused review, we will discuss how imaging modalities such as Non-Contrast CT, CT-Angiography, and CT-Perfusion can potentially help physicians determine which patients are likely to recanalize early with intravenous tPA and therefore benefit from this therapy.
KeywordsCT Stroke Clot Imaging Thrombolysis Angiography Perfusion
Stroke is the second leading cause of mortality worldwide [http://www.who.int/mediacentre/factsheets/fs310/en/]. In acute ischemic stroke (AIS), clot lysis and early restoration of blood flow to ischemic brain tissue is the ultimate goal of all reperfusion therapies. Recent data from the ESCAPE trial demonstrated that regardless of treatment modality, early effective restoration of blood supply was associated with smaller infarct volumes and better clinical outcome .
Percentage of patients achieving successful early recanalization “TICI 2b/3” with IV tPA alone in the recent endovascular trials, evaluated during the first angiography run
Percentage of patients received IV tPA in control arm
Percentage of patients received IV tPA in EVT arm
Percentage of TICI 2b/3 in first angiography run
no data available
Theory of clot formation within intracranial arteries
Non-contrast computed tomography
The hyperdense artery sign on NCCT has been shown to predict recanalization. This sign is a marker of clot on NCCT within the cerebral arterial network and normally measures 45–80 Hounsfield units (HU). Post-mortem studies have demonstrated that ischemic stroke can be caused by white, red, or mixed blood cell clots . In in vitro experiments, platelet-enriched plasma and whole blood were mixed to produce samples with varying hematocrit levels ranging from 0 to 0 · 35. These artificial clots were then evaluated by NCCT at various time points from 6 to 144 h. ‘Red clots’, with the highest hematocrit content, showed densities around 70 HU. ‘White clots’, with the highest platelet content, were about 20 HU . Interestingly, clots with lower HU were less likely to recanalize compared to clots with higher HU [14, 15]
Problems with detection of the hyperdense artery sign include false positives and false negatives. The average width of the middle cerebral artery (MCA; the most common site of occlusion in AIS) is 3–4 mm . Scans that exceed this width and are of average signal may potentially miss detecting the hyperdense sign because of the phenomenon of partial volume averaging. Thin slice NCCT (≤2.5 mm) minimizes volume averaging, significantly improving the signal to noise ratio and producing higher object contrast. [17, 18] Thin slice widths (≤2.5 mm) allow for more sensitive and reliable detection of clots occluding the proximal MCA . The clot detectability is slightly reduced in cases with very small clots or if the site of occlusion is superimposed with imaging artifacts . Recent data from the Third International Stroke Trial (IST-3) showed that the sensitivity, but not specificity, of detecting the hyperdense vessel sign improved with thinner NCCT slices. Slice thickness ≤3 mm had a sensitivity 62%, specificity 98%; versus >3 mm slices, sensitivity 41%, specificity 92%, (p = 0.031, p = 0.089, respectively) . A major question to be addressed by future studies involves whether a patient specific threshold, taking the hematocrit level and other patient factors for detecting clot length into consideration, is superior to a priori fixed thresholds.
Clot length on NCCT
The length of the hyperdense sign on NCCT is believed to represent the length of the clot. In a 138-patient study, Reidel et al. showed that clots measuring greater than 8 mm on NCCT had less than 1% chance of recanalization with IVT alone and were associated with worse outcome . Recanalization was assessed on follow up TCD, magnetic resonance angiography (MRA), or CT-angiography (CTA). However, clot length in this study was measured on thin slice NCCT (≤2.5 mm) using a three dimensional semi-automated method, which is very time intensive and currently not used in the clinical world. Nevertheless, a more recent study using CTA and 4D-CTA to calculate the clot length challenges the idea that clot length of 8 mm is the longest clot IV tPA can recanalize, indicating that 11 mm may be a more optimal cut-off value .
Computed tomography angiography (CTA)
Although conventionally NCCT is the only requisite before IVT administration, additional information provided by CTA is useful in decision-making. CTA is obtained from aortic arch to vertex and it provides information on presence of clot, characteristics of thrombus, tissue ischemia and collaterals.
Assessment of Clot
The location and extent of clot on CTA is an important predictor of clinical outcome in AIS. EVT is only performed for those with target clots in CTA [24, 25]. Successful recanalization by IVT is dependent on clot length [22, 26] or clot burden as measured by CT angiography . In analyses of predictors of early reperfusion using baseline imaging, where early reperfusion was defined as TICI 2a/2b/3, and median clot length in the early reperfusers was 19 mm (IQR 12.9 mm) compared with the nonreperfusers (34.9 mm, IQR 30.7 mm, P .001) . Early recanalization is an independent factor for good clinical outcome . In 80 patients treated with IVT for acute M1 occlusion, Rohan et al. determined clot length using CTA and temporal maximum intensity projection. They found that length of less than 12 mm was an independent predictor for recanalization and good outcome . Another approach for measuring the clot length on CTA used the distance from the carotid T (origin of MCA) to the proximal end of the clot; this study found that a long distance from the carotid T to the beginning of the clot measure on coronal maximum intensity projection images (i.e. more distal clot) was significantly correlated with a good clinical outcome, defined as mRS ≤2 at 90 days .
Clot permeability using multiphase CTA/value of CTA in evaluating the clot
With these two markers (visible residual flow and cirHU ≥ 2) related to permeability of clots, the researchers suggested a predictive model for early recanalization of occluded arteries after intravenous thrombolysis, incorporating other characteristics of clots (length, location, and distance from the M1 MCA origin to the proximal clot interface) .
In most cases, distinguishing between permeable and non-permeable clot requires time-resolved images; because of this, mCTA and CTP have a clear advantage over single-phase CTA for detecting anterograde blood flow through the clot. In a post-hoc analysis of MR CLEAN trial, using quantitative methods on baseline single-phase CTA and NCCT (seen in 44%), Santos et al. showed that permeable clots were associated with improved functional outcome, smaller final infarct volume, higher recanalization rate, and may be associated with improved response to EVT . Although one research group observed that discrepancy of clot length according to phases of CTA in dual-phase CT was associated with collateral status, anterograde flow on DSA, and poor clinical outcomes, they could not find the meaning of this discrepancy of clot length with respect to permeability of clots .
Putting it All together: NCCT + CTA
Computed tomography perfusion
Multimodality CT has become an essential tool to evaluate patients with AIS and facilitate treatment decisions. It can provide more details about clot characteristics and can be used to tailor the treatment decision of whether further recanalization with EVT should be attempted. More research effort is needed to help aid the clinical decision about proceeding with EVT or treating with IVT only. Furthermore, neuroimaging of the clot is an important topic in modern stroke management and should be pursued to a greater extent.
Acute ischemic stroke
Computed tomography angiography
Computed tomography perfusion
Intravenous tissue plasminogen activator
No funding to report.
Availability of data and materials
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FSA, BKM review concept and design, drafting the manuscript, critical revision of the manuscript content. EQ, CKK, EPV, LW drafting the manuscript, critical revision of the manuscript content. All authors read and approved the final manuscript.
All authors declare that they have no competing interests.
Consent for publication
Our manuscript does not contain any individual person”s data in any form (including any individual details, images or videos), or in the case of children, their parent or legal guardian. Copyrights for other figures are attached.
Ethics approval and consent to participate
Our current manuscript is a review article that do not report any studies involving human participants, human data or human tissue.
Our current manuscript does not report any studies involving human participants, human data or human tissue.
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