Imaging Variables that Predict Recanalization in Acute Ischemic Stroke Patients

Imaging Variables that Predict Recanalization in Acute Ischemic Stroke Patients receiving Intravenous Tissue-Type Plasminogen Activator

Table of Contents

1. Introduction

2. Method

3. Discussion

3.1 Current Understanding and Approaches

3.2 Brain and Vascular Imaging

3.3 Current Management

3.4 Outcome Scales

3.5 Mechanisms of Therapeutic Thrombolysis

3.6 Imaging Variables that Predict Recanalization

4. Conclusion

5. References

Introduction

Stroke continues to be a major contributor to the global burden of disease. In 2010, it was the second leading cause of death, and the third leading cause of disability worldwide.  Fortunately, the incidence of stroke is decreasing.(1) This can be attributed to improvements in the prevention and management of stroke. In ischemic stroke, the key to improving patient outcomes is the rapid restoration of blood flow to the brain to rescue salvageable cerebral tissue.(2) Intravenous tissue-type plasminogen activator (tPA) and endovascular thrombectomy are the two proven methods to achieve reperfusion and improve outcomes. In particular, endovascular thrombectomy has markedly improved clinical outcomes of patients with acute ischemic stroke caused by occlusion of the proximal anterior circulation.(3)

With the proliferation and continued advances in imaging such as multimodal computed tomography and diffusion-weighted magnetic resonance imaging (DWI), clinicians have access to an unprecedented amount of information. Some important information includes thrombus location, size and density, the degree of reversibility of injury (ischemic core volume, diffusion-perfusion mismatch), and hemodynamic status (collateral flow, cerebral blood flow, mean tissue transit time). These factors have been used to predict increased risk of intracranial hemorrhage, the likelihood of success of intervention, and therefore may influence guidelines regarding both indications and contraindications to therapy.

Recanalization, the reopening of occluded vessels, is a strong predictor of improved clinical outcome and has been linked to many of the aforementioned variables.(2) Recent findings on computed tomography perfusion (CTP) imaging have demonstrated an association of recanalization with thrombus permeability, residual flow, and retrograde collateral flow. In recent years, there has been increased research focus on dynamic computed tomography angiography (CTA) and CTP, which points to a trend towards a future emphasis on imaging-based patient selection. Some important considerations include increasing the time window for patient eligibility for intervention, identifying patients who may not benefit from treatment, and identifying those who are unlikely to achieve early recanalization with tPA and should proceed to more interventional treatment. A combination of clinical and radiological assessment may also provide more accurate prognostication in acute ischemic stroke. This review aims to provide a comprehensive update on the current approach to acute ischemic stroke, with a focus on imaging variables that predict recanalization with tPA in acute ischemic stroke. As tPA is used to treat thromboembolic stroke, this review will focus on thromboembolic stroke and exclude rare causes such as vasculitis and hemodynamic stroke.

Methods

The literature used in this review has been sourced using the MEDLINE (Ovid) database in April 2017. The search relating to imaging variables predicting recanalization used the MeSH terms: stroke, tissue plasminogen activator, thrombolytic therapy and the following keywords: recanalization, revascularization, and imaging. To be eligible, studies needed to examine imaging variables that predicted recanalization in the context of acute ischemic stroke treated with intravenous thrombolysis only. Reference lists of all selected articles were examined, and relevant articles were screened manually to identify any additional pertinent studies. The search was not limited by publication date or publication status. Studies that were not in the English language were excluded. This review also excluded studies that performed an assessment of recanalization following intra-arterial thrombolysis and endovascular thrombectomy.

Discussion

Current Understanding and Approaches

According to an updated definition, an ischemic stroke is an episode of neurological dysfunction caused by focal cerebral, spinal or retinal infarction.(4) Infarction, refers to cell death attributable to ischemia, based on pathological, imaging, or clinical evidence(symptoms persisting ≥24 hours or until death) of focal ischemic injury in a defined vascular distribution. Typical focal features include hemiparesis, hemisensory loss, hemispatial neglect, hemianopia, monocular blindness, diplopia, dysphasia, ataxia and vertigo.(5)

Given that ‘time is brain’, it is essential to minimize the time delay between stroke symptom onset and initiation of intravenous thrombolysis (“door to needle time”). This comprises public education on recognizing features of stroke, the need to call emergency services, avoiding transport delays,  performing pre-hospital assessment where possible and optimizing hospital pathways.(6) A recent intervention comprising a mobile stroke unit, an ambulance equipped with a CT scanner, has significantly reduced time to thrombolysis.(7) Once in the emergency department, physicians should make a quick and accurate clinical assessment, and perform tests to exclude stroke mimics, intracranial haemorrhage and assess for serious co-morbid disease. Laboratory tests to consider include full blood examination, blood glucose, serum electrolytes with renal function studies, and coagulation studies however, none of this should delay thrombolysis and generally occurs afterward, unless there is a clinical suspicion of a problem. Electrocardiogram and cardiac biomarkers may be performed to identify cardiac arrhythmias or concurrent myocardial ischemia.(6)

Brain and Vascular Imaging

Imaging is key to guiding management of patients with acute ischemic stroke, with each modality contributing to information regarding the parenchyma, clot characteristics and cerebral hemodynamic status. Non-contrast computed tomography (NCCT) has been widely documented to be highly sensitive for excluding intracranial hemorrhage, hence it is the key rate-limiting step to intravenous thrombolysis. In addition, the “hyperdense MCA sign” and “MCA dot sign” have been found to be highly specific for identifying thrombus occluding the middle cerebral artery (MCA).(8) However, NCCT is poor at detecting acute and small infarctions, especially in the posterior fossa.

Computed tomography angiography (CTA), magnetic resonance angiogram (MRA) and digital subtraction angiography (DSA) use an injection of contrast material to evaluate the site of vessel occlusion. CTA has a high sensitivity and specificity for the detection of intracranial occlusions.(9) In addition, it can detect circle of Willis variants and carotid stenosis.(10) However, as it provides a static image of the vasculature, it is inadequate for assessing flow rate and direction. MRA may also be used to identify acute large-vessel occlusions and stenoses, however when compared to CTA, has a lower sensitivity and specificity, and is unreliable for detecting distal or branch occlusions.(9) Although DSA is the traditional “gold standard” for assessing arterial occlusion, it is invasive and therefore carries a risk of serious complications. Therefore, if there is confidence in the predictive value of non-invasive imaging, conventional angiography (DSA) may not be required.(11) DSA is now almost exclusively a therapeutic modality rather than a diagnostic test.
Computed tomography perfusion (CTP) imaging utilizes cerebral blood flow to measure penumbra (salvageable tissue at risk) and ischemic core. CTP has played a key role in recent positive trials that selected individuals likely to benefit from therapy, with favorable collateral profiles, perfusion lesion >20% greater than infarct core, and small ischemic cores (<70ml).(12-14) However, a fundamental weakness is the poor signal-to-noise ratio of post-processed CTP images compared to diffusion-weighted magnetic resonance imaging (DWI). In addition, cerebral blood flow core measurements can vary significantly, and may therefore lead to exclusion of patients who may benefit from treatment.(15, 16) Despite these drawbacks, multimodal CT imaging is widely available, easily integrated into one scan and can swiftly assess cerebral perfusion, hemorrhage, arterial occlusion, collateral status and risk of hemorrhagic transformation due to reperfusion, guiding therapeutic decision making. Ongoing studies aim to further validate CTP as an important selection tool, with the Stroke Imaging Research (STIR) group leading discussion to develop and standardize the optimal imaging protocol.(17, 18)

There are other imaging modalities that may be considered for acute ischemic stroke. DWI is sensitive to early parenchyma changes of infarction and deemed the gold standard method for measuring volume of ischemic core.(19) Its higher spatial resolution enables clinicians to distinguish small acute cortical, deep and posterior fossa infarcts, which can be difficult to visualise on NCCT and CTP. Furthermore, patients avoid exposure to ionizing radiation. However compared with multimodal CT, it is less widely available and more time-consuming compared to CT. Transcranial doppler (TCD) ultrasonography can be used to evaluate occlusions and predict tPA outcomes. It provides real-time imaging and can therefore assess timing of recanalization.(20) However, it is dependent on operator experience and a multi-institutional study deemed its accuracy to be inferior compared to CTA.(21)

Current Management

In 1995 a landmark trial sparked hope for impactful treatment in acute ischemic stroke. The NINDS tPA study (22) set the stage for further studies showing that IV tPA conferred clinical significant benefits in patients presenting within 4.5 hours of symptom onset (ECASS, ECASSII, ATLANTIS A/B, ECASSIII, IST3, EPITHET). Trials evaluating advanced imaging selection in patients presenting in the extended time window (EXTEND, WAKE-UP, ECASS4), and patients with ‘mild’ and ‘rapidly improving’ symptoms (PRISMS) are currently ongoing. In 2012 a Phase II trial applying selection with CTP showed that tenecteplase provided better outcomes clinically when compared to alteplase.(13) A large Phase III “Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation” (TASTE) trial, aims to confirm this finding and apply to a broad group of eligible stroke patients.

Prior to tPA administration, the patient should be assessed for a tendency to bleed, as symptomatic ICH and major systemic haemorrhage are rare but potentially fatal risks.(23). NCCT should be performed to exclude haemorrhage, intracranial mass, intradural cerebral aneurysm, and arteriovenous malformations. Infarction that measures greater than one-third of (MCA) territory of 70-100ml is also a relative contraindication to reperfusion therapy given the increased risk of ICH. If there are no contraindications, all adults presenting within 4.5 hours of stroke symptom onset with a measurable neurological deficit should receive tPA.

Initial results of endovascular treatment studies published in 2013 were neutral. However, with targeted selection criteria, second-generation devices and reduced treatment delay, randomised trials have shown endovascular thrombectomy to confer major benefit to patients with AIS caused by occlusion of arteries in the proximal anterior circulation (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, REVASCAT, THRACE).(14, 24-28) Mocco et al. have also demonstrated aspiration thrombectomy to be a safe and efficacious alternative method of treatment for large vessel occlusions.(29)

Outcome Scales

Outcome scales are important for standardising how we evaluate treatment impact, thereby enabling reliable comparison of clinical trials and data collection from multiple centres. In regards to acute ischemic stroke, these include assessment of stroke severity, extent of reperfusion, recanalization and disability.

The National Institutes of Health Stroke Scale (NIHSS) is used to objectively assess the severity of stroke. Abilities such as motor function, sensation, coordination, language, visual fields and eye movements are scored from 0 to 4. The maximum total score is 42, with a higher score indicating a greater level of impairment. It is an excellent predictor of patient outcomes, moreover, minimum and maximum NIHSS scores have been used to assess tPA eligibility.(30)

The modified Treatment in Cerebral Ischemia Scale (mTICI) has been adopted as the standard reperfusion grading scale.(31) This score is a simplified version of the original Thrombolysis in Cerebral Infarction Scale (TICI) developed by Higashida et al., which was a modified version of the Thrombolysis in Myocardial Ischemia Scale (TIMI).(32) The mTICI that provides subclassification of grade 2, into grades 2a and 2b. The mTICI uses contrast filling in previously occluded target artery ischemic territory to stratify the wide range of partial reperfusion. mTICI grade 2b and 3 on initial angiogram is regarded as a successful angiographic outcome. However, there is much variation in the application of the TICI scale in the literature, which may affect our understanding of results of recanalization studies.(33) Other revascularization grading methods include the Arterial Occlusive Lesion (AOL) scoring system, Mori reperfusion scale, and Qureshi scale.

The Modified Rankin Scale (mRS) is a reliable tool that measures degree of disability or dependence in the daily activities of people who have suffered from stroke. (34) It is adapted from the original scale introduced in 1957 by Dr. John Rankin.  Scores range from 0 (no symptoms) to 6 (death). Studies often use mRS scores at 90 days to assess functional outcome, with a score of 0-2 being regarded as a favourable outcome.

Mechanisms of Therapeutic Thrombolysis

Many mechanisms and models of thrombolysis have been proposed. Understanding the factors that influence clot formation and breakdown are an integral part of developing ways to predict treatment outcome. Mathematical models and in vitro experiments predict that the most important determinant of fibrinolytic rate is the delivery of tPA into thrombi and resultant dissolution of fibrin.(35) Logically, the delivery of tPA will be influenced by location and length (total surface area of contact), permeability (contact within the thrombus), and the average flow rate (pressure gradients). Animal experiments suggest the rate of clot breakdown is also dependent on pressure gradients.(35)

A model using multicomponent convection-diffusion equations shows that thrombolysis depends on the ability of tPA to permeate thrombus.(36) This is elucidated by an in vivo model that demonstrates changes in intrathrombi solute transport rates relate to platelet packing density.(37) Lastly, thrombus composition may have a part to play. In an animal model, IV tPA is significantly more efficient at lysing erythrocyte-rich thrombi, compared to platelet-rich clots.(38)

Imaging Variables that Predict Recanalization

Location

A recent systematic review and meta-analysis have identified several key factors that contribute to non-recanalization, the most significant being proximal artery occlusion (OR 2.09).(39)The incidence of early recanalization (defined as recanalization occurring ≤3 hours after initiation of intravenous thrombolysis) in occlusions of ICA and M1 were 4% (1,8) and 21% (15,29), compared to 38% (22,54) in M2 and M3 occlusions. Seners et al. included studies with patients solely treated by intravenous thrombolysis, which increases the homogeneity of the sample, strengthening the link between recanalization rates and IV tPA only. However, different revascularization scales and post-thrombolysis imaging were applied between studies.

Other studies confirmed the consensus that proximal vessel occlusions (ICA and/or M1) are associated with low rates of early recanalization with IV tPA.(40, 41) Bhatia et al. found that distal ICA (4.4%) and basilar artery occlusions (4%) were less likely to recanalize when compared to M1-MCA (32.3%) and M2 (30.8%) occlusions.(40) It should be noted that these figures relate to patients who were assessed with either TCD monitoring following tPA administration or angiography prior to endovascular thrombectomy. As not all patients underwent an angiogram, this may introduce potential bias. TCD has lower sensitivity and specificity for partial and complete occlusions, however it is comparable to angiography for assessing complete MCA recanalization (42) Lee and colleagues also demonstrated an increased recanalization rate in distal MCAs (27.3%) compared to ICA or proximal MCAs (12.5%), however the numbers were too small to draw definite conclusions.(41)

Mishra et al. demonstrated thatcarotid T/L occlusions rarely reperfused (1.7%) In addition there was an association of distance <10mm from M1 MCA origin with no early reperfusion (OR 3.06).(43) These studies utilised CTA, an accurate tool to measure arterial occlusions. However, they only include patients who underwent intra-arterial therapy, which may have introduced a selection bias for patients with larger clots which are less likely to recanalize.

There are a few possible reasons for the strong association between location and early recanalization with tPA. Mishra et al. have postulated that the proximal end of distal M1 clots may be exposed to more shear stress due to patent flow in the lenticulostriate arteries. Distal clots are likely smaller, and therefore more susceptible to thrombolysis with a given shear stress.(44, 45) Moreover patent flow may increase the pressure gradient at the proximal clot interface, compared to a more proximal M1 occlusion with no patent lenticulostriate artery flow. Lastly, a larger clot at a proximal location may have a lower ‘exposed surface area’ to volume ratio compared to a smaller distal clot, and therefore require more time to lyse.

Thrombus Length

As thrombus length increases along a vessel, thrombus volume increases, but with little increase in surface area exposed to blood. Therefore it is not surprising that in acute middle cerebral artery stroke, the rate of recanalization decreases as thrombus length increases.

Two studies have used NCCT to demonstrate an association of clot length with recanalization.(46, 47) Riedal et al. showed that intravenous thrombolysis has nearly no potential to recanalize occluded vessels if thrombus length exceeds 8mm.(46) In addition, Shobha et al. stratified their subjects into three groups <10mm, 10-20mm, and >20mm) based on length of the hyperdense middle cerebral artery sign (HMCAS), and found that the HMCAS was less likely to disappear when HMCAS length was over 10mm. Although this is a significant finding, we should take note that thick slice NCCT was used to assess the thrombus, which is a less accurate tool compared to thin slice NCCT (1mm thickness). In addition, the study conducted by Shobha et al. used the disappearance of HMCAS as a primary endpoint, rather than endovascular assessment such as CTA, MRA or DSA. This may lead to overestimation of ‘recanalization’ in these patients.

In subsequent studies assessing patients on bridging intravenous thrombolysis using CTA or MRA, long thrombi were also significantly associated with decreased rate of recanalization.(43, 48-50) Optimum cut-off for recanalization in these studies varied between 11-16mm. Mishra et al. found patients with residual flow and a shorter clot length (<15mm) were most likely to reperfuse (70.6%).(43) However this value (<15mm) should be heeded. The majority of patients in this study had an M1 segment occlusion, were destined for mechanical thrombectomy and therefore had a larger clot burden compared to ‘average’ patients receiving tPA only. In addition, the mean time from thrombolysis to angiographic series was 1h 38 mins, and would therefore yield relatively low short-term recanalization rates.(48) Despite this, there is a clear shared trend demonstrating increased recanalization rates with shorter clot length.

Lastly, it has been postulated single phase CTA overestimates thrombus length, and that 4D-CT angiography or multiphase CTA are able to improve this measurement, due to visualisation of the distal end of thrombus via contrast enhanced backflow. A major strength of the study conducted by Rohan et al. is the use of 4D CTA and therefore more accurate measurements of thrombus length.(49)

Collaterals

The positive association between good baseline collateral status and improved outcomes in acute ischemic stroke patients receiving endovascular therapy has been successfully assessed in multiple studies and a meta-analysis.(12, 51, 52) There is evidence to suggest that leptomeningeal collaterals may influence the rate of recanalization after intervention.(53) However the association between collateral status and recanalization in AIS patients treated with IV tPA only, has not been readily assessed. As collateral circulation provides essential blood flow to maintain the viability of ischemic penumbra, it is feasible that this circulation could reach the distal interface of an occlusive thrombus, thereby increasing contact surface area and likelihood of early recanalization.

Ahn et al. demonstrates that greater retrograde filling is due to good collaterals, defined as low difference in T0 value (<2 seconds) between distal and proximal thrombus interface. This has a higher probability of early recanalization with tPA, compared to those with higher difference in T0 value.(54) Although the T0 value difference (<2 seconds) has not been validated in other studies, it is likely to be comparable to a good ASPECT-Collateral score of 4 in which there is a delay of one phase in filling of peripheral vessels compared to the contralateral hemisphere. A weakness of the study is that the retrograde flow was not validated with another imaging tool such as DSA.

In comparison, Nicoli et al. took a different approach, utilising MR perfusion-weighted imaging (MR-PWI) to quantify normalised collateral circulation deficit (nCCD) derived from Tmax maps, and then correlating nCCD to M1 recanalization assessed by CTA at 24 hours.(55) This parameter is associated with increased recanalization for patients who were treated within a 3-hour time window. However, a key limitation of this study is that the nCCD index value could not be correlated with a standard angiographic collateral grading technique (ASPECT-Collateral). The use of MRA in assessing recanalization may also overestimate the degree of MCA occlusion at presentation, and therefore overestimate the effect of IV thrombolysis.

Zhang et al. recently studied the relationship of collateral velocity (defined as arrival time delay (ATD) of contrast between hemispheres detected on MRP) with recanalization and found a significant positive correlation. Patients with rapid collaterals (ATD < 2.3 seconds) may apply higher shear stress to the thrombus, and are more likely to obtain a higher AOL score. This finding suggests that high flow at the proximal thrombus interface, and around the clot may also facilitate early recanalization.(56) A strength of this method was negating factors such as contrast injection and cardiac output, which would have influenced retrograde filling times in a dynamic CTA study such as that conducted be Menon et al.(53)

Permeability/Perviousness

Permeability refers to increased blood infiltrating thrombus, assessed by an increased attenuation (HU) on CTA compared to NCCT, due to contrast entering the clot. Two studies led by Santos have assessed perviousness represented by thrombus attenuation increase on CTA compared to NCCT (data from the DUST and MR CLEAN trials).(57, 58) However the MR CLEAN data is from patients who received IAT, so focus shall be on the former, which analysed tPA only patients. Complete recanalization was much higher in tPA only patients with a pervious thrombus (OR 6.3), whereas the impervious group had no significant effect due to tPA (OR 1.4, P=0.47). A weakness of the study was that recanalization status was assessed was follow-up CTA after 3±1.5 days, meaning that patients may have had late reperfusion with little cerebral tissue salvaged.(57) Furthermore, mean attenuation values were used with may not reflect the heterogeneity of a thrombus, and may also overestimate attenuation. This association between permeability and recanalization is encouraging and should be further explored with a study that involves patients with follow-up imaging occurring within 24 hours.

Residual flow/Anterograde flow

Blood flow around and traveling past a clot is a known predictor of complete recanalization, and has been largely assessed by transcranial doppler. Patients with residual flow detectable on TCD at presentation, are more likely to have early complete recanalization.(59, 60) Furthermore, no detectable residual flow (TIBI 0) results in a decreased likelihood of recanalization (OR 0.4, p=0.0008) and longer time to recanalization (+35 min, p=0.048).(60) While these tools are able to provide non-invasive assessment and monitoring of arterial status, they have fallen out of favour. With the advent of endovascular treatment, CTA offers higher sensitivity and specificity and is now the preferred modality for pre-treatment assessment of both extra and intracranial vasculature.

4D CTA supports these findings, with the presence of anterograde flow associating with a greater likelihood of early recanalization (37.5% vs. 0%).(61) However, this result should be taken with caution, as early recanalization (ER) was defined as complete recanalization following bridging thrombolysis immediately prior to endovascular intervention. This considerably shortens the timeframe for the thrombus to lyse, and also resulted in a small (n=3) sample of patients with ER. Christoforidis et al. showed a similar relationship between anterograde flow and recanalization (mTIMI 3: outline sign (68.4%) vs. no outline sign (29.4%)). The study used arteriograms to identify the ‘outline sign’, i.e. delayed anterograde contrast opacification distal to occlusion site, in patients who received thrombolytic agents.(62) Although arteriograms are the reference standard for assessing vasculature, they are now seldom used pre-thrombolysis. Moreover, this study had a heterogeneous population with patients receiving 1 or 3 intraarterial thombolytic agents, therefore it may be more difficult to apply these findings in current practice.

Residual flow may be subjectively visualised in a single phase CTA, however Mishra et al. developed an objective marker of residual flow by comparing the Hounsfield units at the proximal and distal end of the thrombus.(43) They coined this comparison the clot interface ratio (cirHU), and found that early reperfusion was more likely to be seen in patients with a cirHU < 2 (36.6%) compared to cirHU ≥ 2 (14.1%). The disadvantage of such a technique is that images needed to be selected for the appropriate phase (mid to late arterial). Furthermore this marker does not distinguish between retrograde collateral flow, and anterograde residual flow, however this limitation can be rectified by investigated the cirHU with multimodal or 4D CTA.

Ahn et al. build on this body of work by demonstrating that occult anterograde flow (OAF) i.e. incomplete occlusion of the thrombus with some residual blood flow passing through to the distal circulation, allows greater access of alteplase to the clot. This phenomenon has been termed “occult” as CTA does not detect this low level of delayed flow past the clot. In comparison to patients with retrograde flow, those with OAF were found to be more likely to recanalize early (66.7% vs. 29.7%).(54) This paves the way for further assessment of thin slice CTP capabilities as a robust predictor of recanalization. However, limitations include deconvolution algorithm noise amplification causing nonlinear oscillatory patterns and lack of comparator, such as DSA, to validate the novel measure.

These studies encompass a range of imaging modalities, and indicate that even when assessed with different parameters, incomplete occlusions respond favourably to tPA, thereby improving reperfusion and clinical outcomes.

Issues

When reviewing and comparing study results there are common issues to consider. The majority of included papers investigating imaging variables are observational studies, which utilised data from a prospective stroke registry. This may be due to practical and ethical reasons, as patient welfare and best practice are prioritised over optimal study design. Nevertheless, this introduces potential sources of bias such as treatment selection, and variable follow-up imaging. Multivariate statistical analysis may partially compensate for this, but the study may not match the reliability of a randomised equivalent.

All of the included studies vary in regards to imaging variable ‘definitions’, imaging modalities, methods and scoring systems, therefore introducing substantial heterogeneity and making it difficult to generalise findings to specific hospitals . For example, there is much uncertainty about the optimal time to assess vessel status as a marker of therapeutic efficacy. Early recanalization was defined in many different ways: some studies used the angiogram prior to endovascular thrombectomy, while others utilised the 24hr follow-up assessment with CTA, MRA or TCD. Earlier studies even used continuous 2 hour monitoring with TCD to track flow rates and recanalization. Furthermore, detecting permeable thrombi on TCD, single phase CTA, and dynamic CTA is subjective and requires expertise.(43, 53, 63) None of these techniques are quantitative and are difficult to apply to thrombi in distal middle cerebral arteries. This can introduce significant inter-observer variability, and increase the standard deviation of results. Variable recanalization scales also introduce significant heterogeneity. Older studies used TIMI and TICI, while TCD studies assess recanalization with TIBI, as opposed to the currently adopted mTICI scale.

Lastly, studies assessing patient groups who received IV tPA only were often unable to perform invasive imaging and therefore unable to validate their novel methods. Conversely, more recent studies have focused on endovascular intervention, which therefore increases the proportion of subjects with proximal artery occlusions, long thrombi, and poor recanalization rates with bridging tPA. The heterogeneity of these studies must be taken into account.

Conclusion

With the evolution of advanced imaging modalities and software, there is a need to frequently assess and revise protocols to best facilitate a quick and accurate diagnosis, and predict the likelihood of reperfusion and good functional outcome. Imaging-based selection for acute ischemic stroke therapy is becoming an increasingly common entity. Current evaluation of salvageable penumbra, ischemic core volume, and thrombus location are key to guiding decision-making, however clot characteristics and hemodynamic assessment will become increasingly important. It is widely accepted that clot location, length, residual flow and collateral flow have a significant impact on recanalization rates and therefore patient outcomes.

Of note, the effectiveness of intravenous alteplase in achieving reperfusion reduces as time from symptom onset increases, however the mechanism is uncertain. Residual flow and occult anterograde flow may have a role to play. Moreover, their association with time from symptom onset has not previously been explored. With the increasing availability of dynamic CTA, further study to clarify the associations between residual flow, thrombus permeability and early recanalization may extend tPA treatment time windows, identify patients with greater likelihood of successful treatment with clot-dissolving therapies and those who may not require endovascular thrombectomy.

Acknowledgements

No financial support was received for this review.

Conflicts of Interest

The author declares no conflicts of interest associated with this review.

References

1. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383(9913):245-54.

2. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967-73.

3. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-31.

4. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064-89.

5. Hankey GJ, Blacker DJ. Is it a stroke? BMJ (Clinical research ed). 2015;350:h56.

6. Jauch EC, Saver JL, Adams HP, Jr., Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.

7. Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: A randomized clinical trial. JAMA. 2014;311(16):1622-31.

8. Leary MC, Kidwell CS, Villablanca JP, Starkman S, Jahan R, Duckwiler GR, et al. Validation of computed tomographic middle cerebral artery “dot”sign: an angiographic correlation study. Stroke. 2003;34(11):2636-40.

9. Bash S, Villablanca JP, Jahan R, Duckwiler G, Tillis M, Kidwell C, et al. Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. AJNR American journal of neuroradiology. 2005;26(5):1012-21.

10. Nguyen-Huynh MN, Wintermark M, English J, Lam J, Vittinghoff E, Smith WS, et al. How accurate is CT angiography in evaluating intracranial atherosclerotic disease? Stroke. 2008;39(4):1184-8.

11. Barr JD. Cerebral angiography in the assessment of acute cerebral ischemia: guidelines and recommendations. J Vasc Interv Radiol. 2004;15(1 Pt 2):S57-66.

12. Liebeskind DS. Collateral lessons from recent acute ischemic stroke trials. Neurological research. 2014;36(5):397-402.

13. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-107.

14. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-18.

15. Schaefer PW, Souza L, Kamalian S, Hirsch JA, Yoo AJ, Kamalian S, et al. Limited Reliability of Computed Tomographic Perfusion Acute Infarct Volume Measurements Compared With Diffusion-Weighted Imaging in Anterior Circulation Stroke. Stroke. 2015;46(2):419-24.

16. Bivard A, Levi C, Krishnamurthy V, McElduff P, Miteff F, Spratt NJ, et al. Perfusion computed tomography to assist decision making for stroke thrombolysis. Brain. 2015;138(Pt 7):1919-31.

17. Heit JJ, Wintermark M. Perfusion Computed Tomography for the Evaluation of Acute Ischemic Stroke: Strengths and Pitfalls. Stroke. 2016;47(4):1153-8.

18. Warach SJ, Luby M, Albers GW, Bammer R, Bivard A, Campbell BC, et al. Acute Stroke Imaging Research Roadmap III Imaging Selection and Outcomes in Acute Stroke Reperfusion Clinical Trials: Consensus Recommendations and Further Research Priorities. Stroke. 2016;47(5):1389-98.

19. Fiebach JB, Schellinger PD, Jansen O, Meyer M, Wilde P, Bender J, et al. CT and diffusion-weighted MR imaging in randomized order: diffusion-weighted imaging results in higher accuracy and lower interrater variability in the diagnosis of hyperacute ischemic stroke. Stroke. 2002;33(9):2206-10.

20. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38(3):948-54.

21. Suwanwela NC, Phanthumchinda K, Suwanwela N. Transcranial doppler sonography and CT angiography in patients with atherothrombotic middle cerebral artery stroke. AJNR American journal of neuroradiology. 2002;23(8):1352-5.

22. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-7.

23. Miller DJ, Simpson JR, Silver B. Safety of thrombolysis in acute ischemic stroke: a review of complications, risk factors, and newer technologies. Neurohospitalist. 2011;1(3):138-47.

24. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20.

25. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-30.

26. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-95.

27. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296-306.

28. Bracard S DX, et al. THRACE: Trial and cost effectiveness evaluation of intra-arterial thrombectomy in acute ischemic stroke. european stroke organisation (ESO) conference. 2015.

29. Mocco J, Zaidat OO, von Kummer R, Yoo AJ, Gupta R, Lopes D, et al. Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone. Stroke. 2016;47(9):2331-8.

30. Adams HP, Jr., Davis PH, Leira EC, Chang KC, Bendixen BH, Clarke WR, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;53(1):126-31.

31. Zaidat OO, Yoo AJ, Khatri P, Tomsick TA, von Kummer R, Saver JL, et al. Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement. Stroke. 2013;44(9):2650-63.

32. Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, et al. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003;34(8):e109-37.

33. Fugate JE, Klunder AM, Kallmes DF. What is meant by “TICI”? AJNR American journal of neuroradiology. 2013;34(9):1792-7.

34. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-7.

35. Blinc A, Francis CW. Transport processes in fibrinolysis and fibrinolytic therapy. Thromb Haemost. 1996;76(4):481-91.

36. Diamond SL, Anand S. Inner clot diffusion and permeation during fibrinolysis. Biophys J. 1993;65(6):2622-43.

37. Welsh JD, Stalker TJ, Voronov R, Muthard RW, Tomaiuolo M, Diamond SL, et al. A systems approach to hemostasis: 1. The interdependence of thrombus architecture and agonist movements in the gaps between platelets. Blood. 2014;124(11):1808-15.

38. Jang IK, Gold HK, Ziskind AA, Fallon JT, Holt RE, Leinbach RC, et al. Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. A possible explanation for resistance to coronary thrombolysis. Circulation. 1989;79(4):920-8.

39. Seners P, Turc G, Maier B, Mas JL, Oppenheim C, Baron JC. Incidence and Predictors of Early Recanalization After Intravenous Thrombolysis: A Systematic Review and Meta-Analysis. Stroke. 2016;47(9):2409-12.

40. Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke. 2010;41(10):2254-8.

41. Lee KY, Han SW, Kim SH, Nam HS, Ahn SW, Kim DJ, et al. Early recanalization after intravenous administration of recombinant tissue plasminogen activator as assessed by pre- and post-thrombolytic angiography in acute ischemic stroke patients. Stroke. 2007;38(1):192-3.

42. Burgin WS, Malkoff M, Felberg RA, Demchuk AM, Christou I, Grotta JC, et al. Transcranial doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke. 2000;31(5):1128-32.

43. Mishra SM, Dykeman J, Sajobi TT, Trivedi A, Almekhlafi M, Sohn SI, et al. Early reperfusion rates with IV tPA are determined by CTA clot characteristics. AJNR American journal of neuroradiology. 2014;35(12):2265-72.

44. Hirano T, Sasaki M, Mori E, Minematsu K, Nakagawara J, Yamaguchi T. Residual vessel length on magnetic resonance angiography identifies poor responders to alteplase in acute middle cerebral artery occlusion patients: exploratory analysis of the Japan Alteplase Clinical Trial II. Stroke. 2010;41(12):2828-33.

45. Anand M, Rajagopal K, Rajagopal KR. A model for the formation and lysis of blood clots. Pathophysiology of haemostasis and thrombosis. 2005;34(2-3):109-20.

46. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke. 2011;42(6):1775-7.

47. Shobha N, Bal S, Boyko M, Kroshus E, Menon BK, Bhatia R, et al. Measurement of length of hyperdense MCA sign in acute ischemic stroke predicts disappearance after IV tPA. J Neuroimaging. 2014;24(1):7-10.

48. Behrens L, Mohlenbruch M, Stampfl S, Ringleb PA, Hametner C, Kellert L, et al. Effect of thrombus size on recanalization by bridging intravenous thrombolysis. European journal of neurology. 2014;21(11):1406-10.

49. Rohan V, Baxa J, Tupy R, Cerna L, Sevcik P, Friesl M, et al. Length of occlusion predicts recanalization and outcome after intravenous thrombolysis in middle cerebral artery stroke. Stroke. 2014;45(7):2010-7.

50. Strbian D, Sairanen T, Silvennoinen H, Salonen O, Lindsberg PJ. Intravenous thrombolysis of basilar artery occlusion: thrombus length versus recanalization success. Stroke. 2014;45(6):1733-8.

51. Leng X, Fang H, Leung TW, Mao C, Miao Z, Liu L, et al. Impact of collaterals on the efficacy and safety of endovascular treatment in acute ischaemic stroke: a systematic review and meta-analysis. Journal of neurology, neurosurgery, and psychiatry. 2016;87(5):537-44.

52. Nambiar V, Sohn SI, Almekhlafi MA, Chang HW, Mishra S, Qazi E, et al. CTA collateral status and response to recanalization in patients with acute ischemic stroke. AJNR American journal of neuroradiology. 2014;35(5):884-90.

53. Menon BK, O’Brien B, Bivard A, Spratt NJ, Demchuk AM, Miteff F, et al. Assessment of leptomeningeal collaterals using dynamic CT angiography in patients with acute ischemic stroke. J Cereb Blood Flow Metab. 2013;33(3):365-71.

54. Ahn SH, d’Esterre CD, Qazi EM, Najm M, Rubiera M, Fainardi E, et al. Occult anterograde flow is an under-recognized but crucial predictor of early recanalization with intravenous tissue-type plasminogen activator. Stroke. 2015;46(4):968-75.

55. Nicoli F, Lafaye de Micheaux P, Girard N. Perfusion-weighted imaging-derived collateral flow index is a predictor of MCA M1 recanalization after i.v. thrombolysis. AJNR American journal of neuroradiology. 2013;34(1):107-14.

56. Zhang S, Zhang X, Yan S, Lai Y, Han Q, Sun J, et al. The velocity of collateral filling predicts recanalization in acute ischemic stroke after intravenous thrombolysis. Scientific reports. 2016;6:27880.

57. Santos EM, Dankbaar JW, Treurniet KM, Horsch AD, Roos YB, Kappelle LJ, et al. Permeable Thrombi Are Associated With Higher Intravenous Recombinant Tissue-Type Plasminogen Activator Treatment Success in Patients With Acute Ischemic Stroke. Stroke. 2016;47(8):2058-65.

58. Santos EM, Marquering HA, den Blanken MD, Berkhemer OA, Boers AM, Yoo AJ, et al. Thrombus Permeability Is Associated With Improved Functional Outcome and Recanalization in Patients With Ischemic Stroke. Stroke. 2016;47(3):732-41.

59. Labiche LA, Malkoff M, Alexandrov AV. Residual flow signals predict complete recanalization in stroke patients treated with TPA. J Neuroimaging. 2003;13(1):28-33.

60. Saqqur M, Tsivgoulis G, Molina CA, Demchuk AM, Shuaib A, Alexandrov AV. Residual flow at the site of intracranial occlusion on transcranial Doppler predicts response to intravenous thrombolysis: a multi-center study. Cerebrovascular diseases (Basel, Switzerland). 2009;27(1):5-12.

61. Frolich AM, Psychogios MN, Klotz E, Schramm R, Knauth M, Schramm P. Antegrade flow across incomplete vessel occlusions can be distinguished from retrograde collateral flow using 4-dimensional computed tomographic angiography. Stroke. 2012;43(11):2974-9.

62. Christoforidis GA, Mohammad Y, Avutu B, Tejada A, Slivka AP. Arteriographic demonstration of slow antegrade opacification distal to a cerebrovascular thromboembolic occlusion site as a favorable indicator for intra-arterial thrombolysis. AJNR American journal of neuroradiology. 2006;27(7):1528-31.

63. Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, et al. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke. 2001;32(1):89-93.