During
STAIR XII (12th Stroke Treatment Academy Industry Roundtable),
international experts from academia, industry, and the US government
gathered to share their knowledge and seek consensus on strategies
intended to surmount impediments in stroke research. This article
focuses on 10 priorities identified for advancing neuroimaging in the
diagnostic workup of acute ischemic stroke (Tables 1 and 2).
Table 1. Research Priorities in Imaging and Systems of Care
| Current status | Recommendation |
|---|
| Imaging capabilities at primary and comprehensive stroke centers | There is no consensus of the optimal imaging protocol for primary and comprehensive stroke centers. | Multimodal imaging is desirable for primary stroke centers and should be a requirement for comprehensive stroke centers. |
| Clot analysis and characterization | There is no platform to determine clot characteristics with noninvasive imaging. | The
development of novel postacquisition processing of noninvasive imaging
could potentially determine clot characteristics and improve the
effectiveness of EVT. |
| Imaging criteria that predict response to reperfusion | Recent
trials have shown the benefit of reperfusion in patients with large
core defined as ASPECTS ≤5 or volume between 50 and 100 mL. | Further
studies are needed to determine the optimal combination of factors to
consider in treatment decision-making for patients with large ischemic
core. |
| TICI score in the determination of effective reperfusion | TICI scores are subjective and do not always translate into tissue reperfused. | Volumetric maps of reperfusion should be generated and validated as potential biomarkers of reperfused brain. |
| FPE prediction | There is growing evidence that FPE is a good metric to determine the efficacy of endovascular recanalization. | AI-derived
algorithms that encompass patient-derived data, clot characteristics,
and angio-architecture of the target vessel could potentially improve
the FPE by recommending specific devices and techniques. |
| Imaging post-reperfusion | The
determination of BBB disruption has a low accuracy and is based on the
extravasation of contrast into the parenchyma. Similarly, there is no
reliable way to quantify cerebral edema. | Newer
imaging techniques could potentially identify BBB disruption and
characterize cerebral edema. This could guide post-EVT management and be
used as a biomarker of neuroprotective therapies. |
Table 2. Optimization of Imaging Technologies
| Current status | Recommendation |
|---|
| Detection of early ischemia on NCCT | NCCT is not accurate in detecting acute ischemic changes. Moreover, its reproducibility is not optimal. | More
accurate volumetric and objective measurements of acute ischemia
detection should be developed. Continued education of neuroscience
trainees to learn how to interpret acute ischemic change is important. |
| Utility of CBCT | CBCT does not accurately determine ASPECTS. | New CBCTs should achieve better gray/white matter differentiation for early detection of acute ischemic changes. |
| Imaging in MSU | MSUs have shortened time to thrombolytic with a good safety profile. | CT miniaturization would allow its use in smaller ambulances without compromising image resolution. |
| VWI to understand pathology | It
has been recognized as a useful adjuvant in stroke diagnosis and for
treatment decisions. However, VWI is not routinely used in clinical
practice. | Artificial
intelligence–guided VWI protocols can shorten acquisition times and
improve workflows to improve its generalized adoption. |
RESEARCH PRIORITIES IN IMAGING AND SYSTEMS OF CARE
Imaging Capabilities at Primary and Comprehensive Stroke Centers
In
routine acute stroke practice, critical information for decision-making
is obtained from imaging. Hemorrhage is differentiated from ischemia
using simple anatomic imaging with noncontrast brain computed tomography
(NCCT) or fast protocol magnetic resonance imaging (MRI). Treatment
with intravenous thrombolysis may be initiated based on this imaging
only. Endovascular therapy (EVT) requires a target arterial occlusive
lesion, and this is demonstrated using noninvasive computed tomography
angiography (CTA), magnetic resonance angiography, or, in selected
cases, flat-panel dynamic angiography before proceeding to arterial
access. Choices of how stroke imaging is implemented in clinical routine
vary across the world. The ability to easily acquire CTA and computed
tomography perfusion (CTP) imaging, also known as multimodal stroke
imaging, on contemporary scanners has made it feasible for most
hospitals to perform the initial triage of patients with stroke in the
hyperacute stroke setting. Postprocessing advancements have facilitated
the rapid interpretation of multimodal imaging of the brain. Several
academic and commercial software solutions enable automated large vessel
occlusion (LVO) detection and generation within minutes of CTP maps
that outline the estimated ischemic core and critically hypoperfused
tissue.1
While the use of perfusion imaging is not required by guidelines for
thrombolytic treatment decisions within 4.5 hours and thrombectomy
decisions within 6 hours, the additional diagnostic and prognostic
information can be helpful to support clinical decision-making.2
For instance, when there is uncertainty regarding the diagnosis of
stroke, the presence (or absence) of a perfusion deficit that correlates
with the clinical symptoms can offer informative evidence to confirm
(or exclude) the diagnosis. Routine use of perfusion imaging also
creates greater familiarity with the imaging protocol, which expedites
stroke workup, reduces technical errors in image acquisition, and
improves image interpretation. However, not all the imaging protocols
use the same scan parameters or postacquisition processing metrics. The
estimation of core and penumbra among different academic and
commercially available software may vary. However, when specific
thresholds and postprocessing methods are used to compare different
postacquisition software, a high agreement could be reached. After
controlling for these confounding factors, Pisani et al3
showed substantial agreement between perfusion parametric maps of 3
commonly used commercial software packages in a cohort of 242 patients.
However, to decide whether a patient who presents with stroke symptoms
within 4.5 hours of last known well is eligible for intravenous
thrombolysis, an NCCT to rule out intracerebral hemorrhage and assess
the severity of early ischemic injury suffices.4
Routine neurovascular imaging with CTA or magnetic resonance
angiography is advised to determine eligibility for EVT in the early
(<6 hours) and late (6–24 hours) time windows and provide information
on potential causes of stroke.2,5–7
Current guidelines recommend the acquisition of imaging to determine
the presence of penumbra in patients who present in the late time window
and who may benefit from EVT. However, these recommendations may change
based on the results of recently completed and ongoing large core
studies.8–10
The
routine use of multimodal imaging offers additional advantages in
stroke research based on a survey of the workshop participants. For
example, at comprehensive stroke centers, the routine use of multimodal
imaging is recommended to facilitate endovascular stroke research aimed
at refining EVT eligibility criteria (eg, patients with medium vessel
occlusions or low National Institutes of Health Stroke Scale scores).
Similarly, the recently completed TIMELESS study (Tenecteplase in Stroke
Patients Between 4.5 and 24 Hours) used multimodal imaging to select
patients for intravenous tenecteplase at both primary and comprehensive
stroke centers in the late time window.11
The low proportion of patients enrolled in TIMELESS at primary stroke
centers (5% of the study population) highlights the need to increase the
number of primary stroke centers that are familiar with multimodal
imaging and that have the infrastructure to conduct clinical stroke
trials. Multimodal imaging at primary stroke centers may also benefit
trials of brain cytoprotective therapy. Patients transferred from
primary to comprehensive stroke centers for EVT are likely ideal
candidates for cytoprotective trials. Multimodal imaging may help
identify those transfer patients who are the most at risk of rapid
expansion of their ischemic core and are, therefore, the most likely to
benefit from cytoprotection.12
Clot Analysis and Characterization
Thrombus
characterization on pre-EVT imaging has been suggested as a prognostic
marker of case complexity, first-pass effect (FPE), and clinical
outcome.13
Thrombi vary in composition and morphology, resulting in a wide range
of thrombus sizes, shapes, cohesion, permeability, and textures. Such
thrombus characteristics might be used to guide EVT decisions and device
selection and enable further improvement of procedural and functional
outcomes.
Radiomics is a method that aims to quantify the
phenotypic characteristics of medical imaging using automated
algorithms. Image data are processed by many automatically extracted
data-characterization algorithms, referred to as radiomic features
(RFs). Radiomics was pioneered in oncology for tumor phenotyping and,
more recently, has been applied to stroke imaging.14
Standard-of-care images such as NCCTs and CTAs can be transformed with
radiomics into quantitative image-based data to enable bioinformatics
and artificial intelligence (AI) analyses. This requires segmentation of
the NCCT and CTA to determine the thrombi boundaries before data
extraction.15 Thrombus radiomics have been used to predict successful reperfusion, the number of EVT passes, and functional outcomes.16
A recent analysis of the MR CLEAN registry performed manual
segmentations and measurements of thrombi using a 3-dimensional imaging
software.17
Larger volume thrombi were associated with a lower probability of
functional independence defined as a modified Rankin Scale score ≤2
(odds ratio [OR], 0.78 [95% CI, 0.64–0.96]) and a higher number of
retrieval attempts (OR, 0.16 [95% CI, 0.04–0.28]).18 A recent study by Santo et al19
identified RFs correlated with micro-computed tomography (CT) imaging
and histopathologic samples. RFs computed from NCCT and CTA demonstrated
significant association with red blood cells and fibrin-platelet
components. Phenotyping clot composition by RFs could potentially guide
treatment decisions such as the choice of EVT device or choice of
thrombolytic agent and could determine stroke etiology. The STAIR work
group encourages further research into the use of RFs and other imaging
modalities for detailed clot characterization.
Imaging Criteria That Predict Response to Reperfusion
Early
trials of thrombectomy failed to demonstrate a clinical benefit. An
important contributing factor was the absence of imaging selection
criteria to enrich the trial population with patients who were the most
likely to benefit from treatment. For example, post hoc analysis of the
IMS-3 trial (Interventional Management of Stroke Trial 3) showed that a
positive result favoring thrombectomy would likely have been observed if
the trial had been limited to patients with evidence of an LVO on
baseline imaging.20 Subsequent trials that took this approach and limited inclusion to patients with an LVO showed a substantial benefit from EVT.21–25
As had previously been observed in trials of intravenous thrombolytics,
the treatment effect of EVT diminishes with longer onset-to-treatment
times. More recently, trials with penumbral selection criteria have
demonstrated that patients with evidence of salvageable tissue on CT or
MRI benefit from EVT and intravenous thrombolytics even in the late time
window.26,27
Taken together, these trials have demonstrated the power of vascular
and perfusion imaging to identify patients who are likely to benefit
from reperfusion therapy. Specifically, patients whose baseline imaging
indicates the presence of an LVO involving the internal carotid artery
or middle cerebral artery M1 segment, a small ischemic core, and a
substantial territory of salvageable brain tissue. Patients with these
characteristics are more likely to benefit from reperfusion therapy.
These criteria have been endorsed in international guidelines.7
What remains unanswered is which patients who do not meet the penumbral
selection criteria of these trials are nevertheless likely to benefit
from reperfusion. Recently published trials of EVT in patients with
large cores have tried to address this issue.28–30
These trials suggest that patients with low Alberta Stroke Program
Early Computed Tomography Score (ASPECTS; ranging from 3 to 5) or large
cores on CTP or MRI (≥50 mL) may benefit from reperfusion. The number
needed to treat for benefit, however, is larger when stricter penumbral
selection criteria are applied. In the SELECT2 trial (Randomized
Controlled Trial to Optimize Patient’s Selection for Endovascular
Treatment in Acute Ischemic Stroke) there was no clear upper limit to
the core volume associated with thrombectomy benefit in ordinal analysis
of modified Rankin Scale.10
However, the proportion of patients achieving modified Rankin Scale
score of 0 to 2 or 0 to 3 was low in individuals with large core
volumes. The core volume remained strongly prognostic but likely needs
to be considered alongside other factors including core location,
patient comorbidities and frailty, and patient preferences around
acceptable levels of disability. The core and penumbral threshold
volumes that determine whether a patient is likely to benefit from EVT
remain unknown and most likely would have to be tailored for each
patient.
Workshop participants recognized the importance of
understanding the potential combinations of factors that may cause EVT
to be futile or even detrimental. A recent subanalysis of RESCUE-Japan
LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute
Embolism-Japan Large Ischemic Core Trial) compared outcomes of patients
with ASPECTS ≤3 versus 4 and 5. EVT was not associated with improved
functional outcome at 90 days in patient with ASPECTS ≤3. Moreover, this
group had a higher incidence of symptomatic ICH.31 The median ischemic core in the ASPECTS ≤3 group was 126 cm3, versus 89 cm3 in the ASPECTS 4 to 5 group (P<0.001).
It should be noted that RESCUE-Japan LIMIT was primarily an MRI
selection study in which ASPECTS was assessed on diffusion-weighted
imaging in 86.1% of the cohort. This approach yields, on average,
ASPECTS that are 1 point lower than ASPECTS measured by NCCT.32
Individual
patient data meta-analysis may further provide data on the potential
benefit of EVT in patients with large cores and without the presence of a
salvageable penumbra on baseline imaging.
Thrombolysis in Cerebral Infarction Score in the Determination of Effective Reperfusion
The
Thrombolysis in Cerebral Infarction (TICI) scale is a widely used
scoring system to evaluate the degree of reperfusion achieved after
mechanical thrombectomy. The TICI scale was originally proposed in a
position statement that attempted to standardize clinical trial design
and reporting for intra-arterial therapy.33
The TICI grading system is divided in 3 grades, 0 corresponds to no
perfusion and 3 to complete perfusion, with antegrade flow into the bed
distal to the obstruction.33
Grade 2 can be divided into partial filling with less than two-thirds
of the entire vascular territory (2a) or complete filling of all the
expected vascular territory, but the filling is slower than normal (2b).34
Studies have demonstrated that a detailed 6-step grading scale is more
accurate in determining clinical outcomes than the standard TICI grading
system.35
The inclusion of a TICI score 2c to label patients with near-complete
reperfusion, except for slow flow in 1 or 2 distal cortical vessels or
the presence of minor distal emboli, provides a more granular assessment
of reperfusion than the standard TICI scoring system.36
The HERMES (Highly Effective Reperfusion evaluated in Multiple
Endovascular Stroke Trials) group core laboratory introduced an expanded
TICI (eTICI), encompassing all the various thresholds used to define
reperfusion after EVT.37
The eTICI system further refines grade 2 into distinct percentages of
perfusion. Specifically, eTICI score 2a denotes reperfusion in less than
half or 1% to 49% of the affected territory; eTICI score 2b, 50
indicated 50% to 66% reperfusion; eTICI score 2b, 67 represents 67% to
89% reperfusion, eTICI score 2c is equivalent to TICI score 2C or 90% to
99% reperfusion; and eTICI score 3 denotes complete or 100%
reperfusion, akin to TICI score 3. Despite these improvements in
defining reperfusion, TICI-based systems of determining effective
reperfusion are highly subjective and may not reflect restoration of
blood flow in microcirculatory vessels. Moreover, TICI assessments by
visual inspection are prone to error, as they may be affected by the
experience level of the rater, operator bias, and field of view. TICI
scores are generally overestimated by operators during EVT compared with
core laboratory raters.38
The inclusion of finer scales and AI-based automated protocols can
potentially provide a better assessment of reperfusion and may be a
better prognostic tool than coarser scales. A study by Prasetya et al39
used a semiautomated platform for the segmentation of the downstream
vascular territory of the occluded vessel. Quantified TICI was defined
as the percentage of reperfused area in the target downstream territory.
The determination of reperfusion with quantified TICI was comparable
with eTICI and performed similarly in predicting favorable outcome. A
study by Su et al40
used convolutional neural networks to generate a fully automatic and
quantitative perfusion-based TICI score. This auto TICI performed on par
with human experts. On the MR CLEAN (The Multicenter Randomized
Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in
the Netherlands) registry, there was a statistically significant
association between auto TICI and eTICI, and both accurately predicted
functional outcome.40
The
STAIR work group recommends the development and implementation of
automated perfusion scores in assessing flow to the downstream target
territory. Automating these scores will eliminate subjectivity, improve
standardization, and facilitate comparison among studies. Granular
automated data would ultimately be used for the estimation of
reperfusion of eloquent territories.
FPE Prediction
The
FPE concept entails achieving near-complete or complete
revascularization of the occluded large vessel and its downstream
territory (modified TICI score 2c/3) through a single revascularization
attempt without the need for rescue therapy.41 FPE is associated with better clinical outcomes, lower mortality, and fewer procedural adverse events.41
As a result, FPE has been proposed as a potential benchmark to assess
the technical efficacy of EVT techniques and devices and as a potential
surrogate measure for their clinical efficacy. The analysis of a cohort
of 930 patients demonstrated that FPE could be achieved in 40.5% of
patients.42
This study reported 2 variables as independent predictors of FPE:
non-internal carotid artery occlusion and the use of a balloon guide
catheter for EVT. Achievement of FPE may be a function of 3 interrelated
factors: patient-related variables, occlusion characteristics, and
procedural factors. Patient-related predictors include age and stroke
etiology.43
Occlusion-related predictors are associated with the occlusion’s
location, the clot’s characteristics, and the angio-architecture of the
target occlusion. Device- and technique-related variables include using
balloon guide catheters,43,44 the device length in case of stent retrievers,45 and bore size of the aspiration catheter in case of contact aspiration devices.46
The analysis of the MR CLEAN Registry showed that history of
hyperlipidemia (OR, 1.05 [95% CI, 1.01–1.10]), middle cerebral artery
occlusion versus intracranial internal carotid artery occlusion (OR,
1.11 [95% CI, 1.06–1.16]), and aspiration versus stent thrombectomy (OR,
1.07 [95% CI, 1.03–1.11]) were associated with FPE.47
Neurointerventionalist experience increased the likelihood of FPR (OR,
1.03 per 50 patients previously treated [95% CI, 1.01–1.06]). Therefore,
the technical acumen of the neurointerventionalist is also an important
factor in FPE.
Whether FPE can be used as a valid surrogate end
point in EVT trials remains to be determined. Although, the latest
advancements in AI have opened opportunities for the integration of
machine learning in determining FPE,16
considerable validation effort remains to be done. Notably, the
assessment of clot characteristics through NCCT and CTA has been
leveraged to predict the ease of clot extraction with variable success.48,49
Other AI-based models that account for patient-specific
characteristics, clot information derived from noninvasive imaging, and
the angio-architecture of the target artery have the potential to assist
in technique and device selection, which may improve FPE. The workshop
participants support the study and validation of FPE as a benchmark to
assess the effectiveness of EVT in stroke studies.
Imaging Post-Reperfusion Therapy
Brain
imaging after EVT may help determine prognosis and adjuvant treatment.
Perfusion imaging obtained after reperfusion therapy (medical therapy or
EVT) can quantify the quality of macrovascular and microvascular
reperfusion, blood-brain barrier (BBB) disruption, infarct evolution,
and edema status. A study of CTP post-EVT determined the presence of
hypoperfused brain tissue (time-to-maximum, >6 s) within 30 minutes
of mechanical thrombectomy in most patients who achieved complete or
angiographic reperfusion (modified TICI score, 2a–3).50
Even among patients who were deemed to have achieved complete
angiographic reperfusion (modified TICI score, 3), 42.5% demonstrated
areas of cerebral hypoperfusion on post-thrombectomy perfusion imaging.
Achieving recanalization after the first pass was associated with
smaller volumes of hypoperfused tissue on post-EVT CTP, supporting the
clinical benefit of first-pass recanalization. A hypoperfusion volume
<3.5 mL was independently associated with dramatic clinical recovery
(OR, 4.1 [95% CI, 2.0–8.3]; P<0.01). Despite the profound
effect of effective EVT on long-term functional outcome, a reduced
infarct volume only accounts for ≈12% of the treatment effect of EVT.51,52
Thus, novel post-EVT imaging metrics may provide a better prediction of
long-term outcome and identify opportunities for adjuvant therapy.
The
status of the BBB can be assessed with brain MRI or NCCT. Disruption of
the BBB due to ischemia can be seen as delayed gadolinium enhancement
of cerebrospinal fluid spaces (sulci) on fluid-attenuated inversion
recovery imaging.53 This phenomenon has been named hyperintense acute reperfusion marker.54
Hyperintense acute reperfusion marker has been associated with
hemorrhagic transformation and worse clinical outcomes. On a
postprocedural NCCT, disruption of the BBB can be seen as parenchymal
hyperdensity.55
The hyperdensity on NCCT likely represents extravasation of contrast
medium into the extracellular spaces because of increased permeability
of the BBB. This hyperdensity may be differentiated from the
hyperdensity caused by hemorrhage, based on its selective localization
in the gray matter (cortex or basal ganglia) and the absence or
near-absence of mass effect on adjacent structures. Dual energy CT can
be used to confirm this through iodine subtraction. A recent study
identified BBB disruption in 58.2% (95% CI, 51.4%–64.9%) of patients who
underwent EVT.56 Patients with BBB disruption had lower rates of early major neurological improvement (8.6% versus 31.5%; P<0.001), favorable outcome (39.8% versus 61.8%; P=0.002), and higher rates of 90-day mortality (34.4% versus 14.6%; P=0.001), and hemorrhagic complications (42.2% versus 8.7%; P<0.001)
than those without BBB disruption. Ng et al assessed BBB disruption on a
24-hour postprocedure MRI. The study analyzed the associations between
microvascular dysfunction in BBB disruption with ICH occurrence and
edema formation in 238 patients.57
Interestingly, BBB permeability was associated with worse outcomes and
increased cerebral edema. The quantification of the degree and extent of
BBB disruption and cerebral edema may be used to set blood pressure
parameters, consider the intravenous infusion of hypertonic saline, or
perform hemicraniectomy.
Another phenomenon that commonly can be
observed on postthrombectomy perfusion imaging is an increase in
relative cerebral blood flow in tissue that was ischemic. Postischemic
reactive hyperemia causes an ≈57% increase in relative cerebral blood
flow of the recanalized vascular territory that can last for a week
after EVT.58
This phenomenon may be related to the loss of cerebral autoregulation
or hypermetabolism. An accurate quantification of hyperemia may be used
in quantifying the response to cytoprotective agents. Disruption of the
BBB coupled with hyperemia can lead to brain parenchyma edema, another
phenomenon that can be observed on post-EVT imaging.59
The
workshop participants emphasized the need to quantify BBB disruption
and characterize cerebral edema to optimize post-EVT management and to
measure the potential benefit of new cytoprotective treatments.
Furthermore, there is a need for post-EVT imaging biomarkers of
functional outcome.
OPTIMIZATION OF IMAGING TECHNOLOGY
Detection of Early Ischemia on NCCT
Detection
of early ischemia on NCCT is notoriously difficult. Highly trained
readers have achieved a sensitivity of 43% to 71% in detecting early
stroke (3–6 hours) with NCCT, compared with 97% with diffusion-weighted
imaging.60
The ASPECTS was developed to simplify and standardize the rating of
early ischemia on NCCT. The ASPECTS rating is based on a binary
interpretation of 10 regions within the middle cerebral artery
territory. For each region, the rater determines the presence or absence
of hypoattenuation. At the extremes, patients with no hypoattenuation
score a 10 on the ASPECTS, whereas patients with extensive early
ischemia, involving all 10 regions, score a zero. ASPECTS has been used
extensively in clinical practice to triage patients with acute ischemic
stroke for acute treatment, and several trials have used ASPECTS in the
selection of patients for EVT. For example, almost all endovascular
trials that first demonstrated the efficacy of EVT excluded patients
with low (≤5) ASPECTS. In contrast, some recent trials that aimed to
assess the effect of EVT in patients with large ischemic cores have
recruited patients with low ASPECTS (3–5).28,61
While ASPECTS has helped standardize the rating of early ischemic
changes on NCCT, the interpretation of ASPECTS is variable, even between
experts.62,63
Key factors that contribute to the interrater variability in ASPECTS
are the subtle nature of early ischemic changes on the NCCT, the lack of
clearly defined boundaries of the 10 ASPECTS regions, and variation in
the proportion of a region that is required to be abnormal to deduct a
point.64
Another limitation of ASPECTS is that the degree of hypoattenuation—a
feature that might correlate with the reversibility of ischemic
changes—is not captured in the score. Further, the ASPECTS regions
differ in volume, and, therefore, the ischemic core volume for a given
ASPECTS can vary markedly.
The workshop participants identified
the need for a reproducible volumetric method to describe the extent of
early ischemic changes on NCCT. Commercially available software programs
already exist for the automated qualitative evaluation of ASPECTS.65,66 Bouslama et al67
reported that automated NCCT performs similarly to CTP in assessing
postreperfusion final infarct volume. Recent data suggest that
machine-learning NCCT estimated ischemic core is more accurate when
obtained beyond 1 hour from stroke onset.68
Furthermore, automated NCCT software can select patients with low
likelihood of achieving a good outcome (eg, ≥70 mL core at baseline) and
who may not benefit from a transfer to a comprehensive stroke center
for EVT.69
While these programs reduce interrater variability, they do not address
the need for a quantitative volumetric measure of early ischemia. New
approaches can overcome this limitation. One method is the generation of
relative NCCT maps using the hemisphere contralateral to the lesion as a
reference. Hypodense brain tissue can be segmented based on its
appearance, which can be measured in relative (eg, >5% attenuation of
the CT signal) or absolute (eg, attenuation of >5 Hounsfield units
of the CT signal) values. In addition to determining the location and
volume of the early ischemic changes, the relative NCCT map can
visualize the degree of hypoattenuation.70 Another approach to quantify the degree of hypoattenuation on NCCT is the determination of net water uptake.71,72
Broocks et al showed in a cohort of 254 patients that patients with low
ASPECTS had elevated net water uptake and that the degree of net water
uptake increased over time while ASPECTS did not change.73
AI
may help to overcome the limited accuracy of early stroke detection on
NCCT. Early ischemic changes can be automatically detected using deep
learning models.74
AI-assisted stroke detection could also be advantageous in telemedicine
approaches supporting nonprimary stroke centers and could even be
performed on mobile stroke units (MSUs), thus potentially increasing
access to reperfusion treatments and reducing time to treatment. AI is
currently being extensively tested regarding its performance in early
stroke detection. An AI model outperformed expert readers in detecting
early ischemic changes on NCCT in a recent study,75
and a systematic review including 11 studies and 1976 cases revealed
that AI-based ASPECTS performed similar or better than radiologists in
identifying early stroke changes on NCCT.76 Moreover, AI-based NCCT-ASPECTS was reported as good or better as human rating for posterior circulation stroke.77
However, the accuracy and reliability of AI- and human-based
NCCT-ASPECTS depends on time from stroke onset to imaging and is lower
in hyperacute stroke and fast stroke progressors.78
Although AI-driven diagnostic processing is usually faster, it is not
always superior to human rating, with AI showing less sensitivity in
detecting LVO in CT angiography.79
Implications of NCCT-ASPECTS using AI are unclear, AI may be used best
under study protocols or under the supervision of human expert raters
until proven clearly superior in a clinical setting. AI-assisted stroke
diagnosis is feasible for all stroke imaging modalities, and the
continuous evolvement of AI-based approaches is expected to result in
significant performance improvements and wider applicability in stroke
diagnosis.
Utility of Cone Beam Computed Tomography
Cone
beam CT (CBCT) imaging assessment of acute ischemic stroke patients
with LVO in the angiography suite may improve stroke workflow and
decrease time to recanalization. There are several advantages in
obtaining a CBCT before EVT. Protocols that include the direct transfer
to the angio suite for EVT rely on CBCT to exclude hemorrhage and
estimate the degree of early ischemic injury. The direct-to-angio
approach may reduce time to treatment and functional outcomes.80
In the ANGIOCAT trial (Direct to Angiography Suite Without Stopping for
Computed Tomography Imaging for Patients With Acute Stroke), CBCT was
performed to exclude ICH or large established ischemic lesions that
would contraindicate EVT.81
The study suggested better clinical outcomes in patients who were
transferred directly to the angio suite and who were imaged with CBCT
compared with patients who underwent a conventional NCCT before going to
the angiography suite. Improvements in clinical outcomes may have
resulted from increased rates of successful EVT and shorter
door-to-puncture times in the CBCT group. The higher rate of EVT in the
CBCT group is likely the result of less stringent selection because CBCT
imaging provides a less thorough parenchymal assessment than
conventional NCCT imaging.
Compared with NCCT, CBCT imaging
suffers from poorer delineation of the brain parenchyma and worse signal
to noise, which limits ischemia delineation.82
However, the new generation of CBCT exhibits better gray-white
differentiation due to the high dynamic range flat detector, enabling 4
times more gray value differentiation, approaching the contrast
resolution of conventional NCCT. Furthermore, the latest generation of x
ray tubes enables better penetration during the acquisition, especially
in larger sized patients. In addition, it provides sharper images in
all viewing directions. A study by Leyhe et al reported detection of
ischemic lesions was feasible on CBCT scans with 71% sensitivity and 94%
specificity (P<0.001; area under the curve, 0.83 [95% CI,
0.74–0.89]) compared with NCCT scans. Additionally, ASPECTS ratings on
CBCT showed a mean difference of only 0.5 points (95% CI, 0.12–0.88) in
the Bland-Altman plot compared with ratings of NCCT images.83
Another study that compared the latest CBCT technology with NCCT showed
that early ischemic lesions were detected with a sensitivity of 73.3%
and specificity of 94.7%, when compared with NCCT.84 Further refinements in the x ray tube trajectory to include caudal and cranial angulations have decreased artifacts.85
Novel motion correction algorithms to improve imaging quality and
diagnostic assessment of the brain parenchyma have been implemented.86
Despite these advances, delineating gray-white matter differentiation
and the visualization of infratentorial structures remains a limiting
factor of CBCT. The workshop emphasized the need for collaboration
between academia and industry to accelerate the development of
high-definition CBCT. This advanced imaging technology holds significant
promise and was recognized as a key area for focused efforts.
Imaging in MSUs
An MSU was first implemented in 2008 in Germany, with the goal of prehospital care optimization.87
MSUs are equipped with a CT scanner that can obtain an NCCT and a CTA.
An MSU can triage patients and initiate thrombolytics. The first MSU
trial conducted in Germany demonstrated shorter treatment times to
intravenous thrombolysis (72 versus 153 minutes; P=0.001).
Approximately 57% of patients were treated with thrombolysis within 1
hour as compared with 4% of patients treated with standard management.88 The benefits of MSU in screening, triaging, and treating patients with thrombolysis have been confirmed by several studies.89,90
The BEST-MSU study (Benefits of Stroke Treatment Delivered by a Mobile
Stroke Unit Compared With Standard Management by Emergency Medical
Services) confirmed the shorter administration of thrombolysis in
patients screened and treated at an MSU versus conventional emergency
medical services (72 versus 108 minutes, respectively; P<0.001).91
MSU management also resulted in significantly less disability at 90
days compared with conventional treatment (mean utility-weighted
modified Rankin Scale score, 0.72 versus 0.66; P=0.002).
The
workshop participants noted that MSUs are a positive addition to
treating patients with AIS. However, technological and reimbursement
challenges must be overcome to make this technology operational. In
addition to the current uses of the MSU, the participants believed that
in the field, imaging of patients with acute stroke could facilitate
cytoprotective studies. However, some technical developments are
desired. Most MSUs utilize a portable 8-slice CT scanner that can
complete an NCCT of the brain and a CTA.92
Perfusion is limited to 1-cm slab, which is unlikely to be clinically
useful. CT scanners that allow for imaging of aortic arch and neck
vessels are larger and, therefore, cannot be housed in a standard
12-foot ambulance. Workshop participants agree that further improvements
in CT scanner miniaturization, while not compromising image resolution,
are needed. Similarly, optimizing the quality and capability of mobile
MRI scanners is encouraged. Portable low-field MRI scanners are already
in use at some hospitals, but the inability to acquire good-quality and
rapid diffusion-weighted imaging scans is a limiting factor in the
evaluation of stroke.93
Finally, developing other technology for ischemic stroke
identification, hemorrhagic stroke exclusion, and large vessel occlusion
detection in the field is similarly encouraged.
Vessel Wall Imaging to Understand Pathology
Vascular
pathology, such as cervical or intracranial atherosclerosis, is one of
the most common causes of ischemic stroke worldwide. Historically, the
imaging evaluation of atherosclerosis has focused on the assessment of
the degree of luminal narrowing because more severe narrowing is
associated with an increased risk of ischemic stroke.94,95 However, 30% to 40% of patients who experience an ischemic stroke do not have a clearly identifiable etiology for their stroke,96 and nonflow limiting atherosclerosis or other arterial vascular abnormalities may be the culprit in many of these patients.97–100 The use of vessel wall imaging on 3T high-resolution MRI is increasingly used to characterize stroke etiology.101
In 1 study, vessel wall imaging identified the probable cause of a
patient’s stroke in 55% of cases, primarily by enhancing the detection
of intracranial atherosclerotic disease.102
Similar studies have used high-resolution vessel wall imaging to
identify the presence of underlying atherosclerosis and culprit plaques
in patients previously deemed to have a cryptogenic stroke.98
These data suggest that high-resolution MRI and vessel wall imaging may
add diagnostic value in patients with ischemic stroke, but the adoption
of these techniques has been relatively modest.
During the
workshop, participants highlighted that lengthy acquisition times for
vessel wall imaging have hindered its widespread adoption. They
emphasized the importance of advancements in technology to shorten
acquisition times. Additionally, the workshop underscored the necessity
for high-quality prospective studies aimed at gaining a deeper
understanding of the effectiveness of vessel wall imaging in
characterizing intracranial atherosclerotic disease and other
vasculopathies. By conducting such studies, we can enhance our knowledge
and improve the utility of vessel wall imaging in clinical practice.
Finally, clinical studies need to establish whether these imaging
approaches have a utility in assessing patient response to statins and
antiplatelet medications.
CONCLUSIONS
The
participants in the neuroimaging workshop of STAIR XII have identified
10 key areas of imaging that hold great promise in enhancing stroke
outcomes. The development of novel imaging techniques and AI-based
protocols aimed at early stroke detection through noninvasive imaging,
identification of BBB damage following a stroke, characterization of
clots before reperfusion, and vessel wall imaging for determining stroke
etiology has garnered significant interest. Moreover, the
implementation of newer CBCTs and MSUs could greatly enhance the
workflow of LVO treatment. The workshop participants agreed on the
importance of a collaborative effort involving investigators, industry,
and regulators to advance imaging research and ultimately improve
patient outcomes.
