CTP (using automated post-processing software algorithmic analysis) is
medically reasonable and necessary in patients with small acute ischemic
stroke (AIS) caused by unilateral large vessel occlusion (LVO) in the proximal
anterior circulation evaluated at stroke centers; CTP can be used to aid in
selection for endovascular mechanical thrombectomy (EVT) if 1 of the following
other conditions is fulfilled:

  1. Treatment (femoral puncture) can be started within **6-24 hours** of the time last known to be at neurologic baseline and who meet the pre-CTP inclusion/exclusion criteria as defined by the DAWN trial,1 or
  2. Treatment (femoral puncture) can be started within **6-16 hours** of the time last known to be at neurologic baseline and who meet the pre-CTP inclusion/exclusion criteria as defined by the DEFUSE 3 trial.2

*excluding criteria purely related to study mechanics (e.g., able to return for protocol required follow-up visits, etc.) 

****

**Table 1: Key Inclusion Criteria for DAWN and DEFUSE 3**

mRS= modified Rankin scale, NIHSS= National Institutes of Health Stroke Scale,
ICA= internal carotid artery, MCA= middle cerebral artery

****

**Parameter**

|

**DAWN**

|

**DEFUSE 3**  
  
---|---|---  
  
Prestroke baseline mRS (0-6)

|

mRS 1 (no significant disability)

|

mRS 2 (slight disability)  
  
Last known well to treatment time

|

6-24 h

|

6-16 h  
  
Minimum NIHSS score (0-42)

|

10 (moderate stroke)

|

6 (moderate stroke)  
  
LVO by MR or CT angiography

|

ICA (intracranial) and/or M1 segment of MCA

|

ICA (cervical or intracranial) and/or M1 segment of MCA  
  
  |   |  
  


**Background**

Stroke is the leading cause of adult disability in the United States (U.S.)
with limited treatment options.3 The U.S. Food and Drug Administration (FDA)
approved treatment for stroke is intravenous tissue plasminogen activator
(tPA)within 3 hours after onset of symptoms. Often treatment is not initiated
since most patients do not present within this narrow time window, resulting
in only 4% of patients receiving tPA treatment. Even with treatment, only
12-25% benefit as irreversible injury may have already occurred, or the
treatment fails to recanalize the occluded artery with reported recanalization
rate of 10-50%.2,4 Endovascular stroke therapy involves mechanical removal of
blood clots or intra-arterial administration of thrombolytics. This offers an
alternative to patients who fail tPA or are not eligible. Recanalization rates
are as high as 82% for thrombectomy.5 Initial studies on EVT failed to
demonstrate clinical benefits.2 Further investigation suggested the lack of
benefit was related to patient selection. Subsequent studies identified
imaging criteria to determine patients with potentially salvageable tissues
and improved outcomes from EVT.6-8 In stroke victims, there is the ischemic
penumbra, potentially salvageable tissue, and ischemic core, which is
irreversibly injured. Patients with >50% reperfusion have been shown to have
an improved outcome compared to those with <50% reperfusion. Treatment of
patients with a higher likelihood of improved outcomes demonstrates the
benefit of EVT in select patients. Expansion of the treatment window up to
16-24 hours has promising results in appropriately selected patients expanding
the possibility for acute stroke treatment.2,9 CTP plays a role, as it can be
used to calculate the ischemic penumbra and help to identify which patients
may benefit from EVT. Reperfusion treatment was found to be more common in
patients who had imaging with CT angiography (CTA) (13%) or CTP (17.6%).10
Noncontrast CT (NCCT) is the mainstay for initial AIS imaging due to
widespread availability, rapid scan times, and detection of intracranial
hemorrhage (which leads to very different management from infarction).
Multimodal CT includes NCCT, CTA (to assess the site of vascular occlusion),
and CT Perfusion Imaging (CTP). CTP is typically performed after NCCT and
consists of a temporal sequence of head CT scans obtained during the wash-in
and wash-out of an IV bolus of iodinated contrast agent. Post-acquisition data
analysis by dedicated software allows the creation of multiple hemodynamic
parametric maps (based on contrast time-density curves) for clinical
interpretation. Hemodynamic parameters include time to maximum contrast
intensity (Tmax), mean transit time (MTT), cerebral blood flow (CBF), and
cerebral blood volume (CBV), mathematically related by the equation CBF =
CBV/MTT.11 The CBV is calculated as the millimeters of blood per 100g of brain
tissue. These maps can estimate brain regions with a high probability of
irreversible infarction (ischemic core) versus areas of potentially reversible
ischemia (penumbra). Both core and penumbra are estimates of probabilistic
tissue fate. Penumbra imaging has been proposed as a useful predictor of
hemorrhagic transformation (HT) in AIS.12 HT occurs in up to 40% of stroke
patients and is related to rapid deterioration and poor outcomes. CTP has been
studied in AIS for decades,13 only recently was it found likely to influence
treatment decision.14 Subsequently, 2 level I randomized controlled trials
(RCTs) (DAWN and DEFUSE 3) found CTP helped determine eligibility for EVT in
the late time period (6-24 hr) of an acute (<24 hr) ischemic stroke (AIS),2,9
a paradigm shift away from confinement to the early window (< 6 hr) CTP has
the advantage of being able to be performed by most multi-slice scanners and
add minimal time, usually less than 10 minutes, to the evaluation. There are
limitations to CTP technology, emphasizing that CTP must be performed in
properly selected patients. There are potential technical issues, such as
patient movement and poor contrast bolus that can impact results. While
experienced providers can typically recognize abnormalities caused by
artifacts, calculations provided by the software may include artifacts,
risking overestimating the penumbral volume. This requires manual correction
to avoid miscalculations. Another challenge is there are multiple CTP vendor
software and postprocessing techniques, which may lead to variations in
calculated core and mismatch.11,15 Ideally, the software programs would be
standardized, but given the variability, providers must be familiar with the
software package being used and potential variations in calculated values.
Automation has the potential to reduce human variability; however, even with
fully automated software, a significant clinician interpretation learning
curve remains.16 Limitations of arterial flow, which can be caused by low
cardiac output, arrhythmias, chronic carotid stenosis, may result in
overestimations. Chronic infarction, vascular stenosis, chronic white matter
changes, seizures, and vasospasm can demonstrate abnormal CTP patterns and
potentially mimic acute ischemia, so the provider must consider the full
medical picture when interpreting results.11,17 CTP requires contrast, so
those with renal failure or known serious allergy to iodine and previously
refractory to pretreatment medications may not be candidates. Protocols should
include care to avoid excess radiation exposure and avoid treatment delays.

**CTP for AIS**

_CTP in acute stroke management_ :

A 2020 systematic review aimed to evaluate the diagnostic accuracy of CTP in
the prediction of HT and patient outcome in AIS reported CTP sensitivity as
85.9%, a specificity of 73.9%, positive predictive value 60.3% and negative
predictive value of 92.9%.12 A 2017 systematic review identified 27 studies
with a total of 2168 patients. The pooled sensitivity of CTP for AIS was 82%
(95% CI 75-88%), and the specificity was 96% (95% CI 89-99%). They determined
CTP was more sensitive than NCCT and had a similar accuracy with CTA, but also
that the evidence was not strong, and there is a need for high-quality
evidence to confirm results.18 Older systematic reviews report mixed results
with a wide range in sensitivity and specificity of CTP for the detection of
AIS.18 A 2019 systematic review and meta-analysis comparing imaging modalities
for evaluation of AIS concludes that while CTP was more accurate than NCCT for
detection of AIS, it was less accurate than diffusion-weighted imaging (DWI)
magnetic resonance imaging (MRI) (sensitivity 82%, specificity 96% vs.
sensitivity 15-86%, specificity 100%, respectively).19

A 2020 systematic review reported prediction of the HT could guide decision
making in regards to consideration at thrombolysis decision point and
concludes CTP is a useful prognostic tool for clinicians at the point of
intervention decision making for AIS.12 This review, however, consisting of 3
prospective and 9 retrospective studies, is subject to inaccuracy given the
risk of bias and a high degree of heterogenicity in the selected studies. On
the contrary, a large prospective trial with 545 patients treated with IV tPA
or thrombectomy had CTP at admission, and day 3 follow-up looked at the
ability of the technology to predict HT (by measurement of the blood-brain
barrier permeability (BBBP)). While univariate analysis associated BBBP
measured by CTP as an independent predictor of HT, the multivariant analysis
did not reproduce those findings, and the addition of BBBP as a variable did
not change the AUC (0.77, 95% CI 0.71-0.83) of the model. The authors
concluded BBBP measured by CTP did not improve prediction of HT, and
improvements are needed before being considered "a useful addition to decision
making."20

Most studies evaluating the role of CTP in AIS are retrospective with
variability in inclusion and exclusion criteria, outcomes reported, and
sampling procedures, which introduces a high risk for bias, heterogenicity,
and overall reduced quality of evidence. The evidence for routine use of CTP
for evaluation for AIS is low quality, and there is a need for high-quality
evidence to determine the role it may play in AIS evaluation. The exception is
the role of CTP for evaluation for patient selection for EVT.

There are 2 level I randomized controlled trials (RCTs), which both conclude
CTP is useful in determining eligibility for EVT in the late time period (6-24
hr) of an acute (<24 hr) ischemic stroke (AIS). The DAWN trial (DWI or CTP
Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting
Strokes Undergoing Neurointervention with Trevo) studied whether patients with
a clinical deficit that is disproportionately severe relative to the infarct
volume may benefit from late EVT.9 See the table for key inclusion criteria.
All patients had evidence of occlusion in ICA with CT or MRI imaging with CTP
or DWI to determine infarct volume, and the cut-off values for clinical-core
mismatch varied based on age, and NIHSS score ranging from 20-50mL. Patients
were randomly assigned to EVT plus standard medical management (MM) (N=107,
mean age 69.4 yr) or to MM alone (N=99, mean age 70.7 yr). Median NIHSS score
was 17 (moderate to severe stroke) for both groups. The trial was stopped for
efficacy at the first interim analysis. At 90 days, the rate of functional
independence, as defined by a score of 0-2 on the mRS of 0-6, was greater for
EVT than MM (49% versus 13%; adjusted difference, 33%; 95% CI, 21-44;
posterior probability of superiority >0.999). The rate of symptomatic
intracranial hemorrhage did not differ significantly between the 2 groups (6%
in the EVT group and 3% in the MM group, P=0.50), nor did 90-day mortality
(19% and 18%, respectively; P=1.00). The DEFUSE 3 trial (Diffusion and
Perfusion Imaging Evaluation for Understanding Stroke Evolution) was a
multicenter, randomized, open-label trial randomizing patient with occlusion
in the ICA or magnetic resonance angiography (MCA) based on CTA or MRA (Table
1). Perfusion study with CTP or MRI diffusion was used to determine perfusion-
core mismatch (70 mL and NIHSS 6) and maximum core size (penumbra volume 15
mL (Tmax >6 s volume minus core volume) and a penumbra to core ratio of 1.8)
as imaging criteria to select patients for late EVT.21 See the table for key
inclusion criteria. Patients were randomly assigned to EVT plus standard MM or
standard MM alone. The trial was conducted at 38 US centers and terminated
early for efficacy after 182 patients had undergone randomization (EVT N=92,
median age 70; MM N=90, median age 71). The median NIHSS score was 16
(moderate to severe stroke) for both groups. The EVT group showed a benefit in
functional outcome at 90 days (mRS score 0-2, 44.6% versus 16.7%; RR, 2.67;
95% CI, 1.60-4.48; P<0.0001). The 90-day mortality rate trended in favor of
EVT (14% vs. 26% (P=0.05)), and there was no significant difference between
groups in the rate of symptomatic intracranial hemorrhage (7% and 4%) or
serious adverse events (43% and 53%). In a subgroup analysis, both the
favorable outcome rate and treatment effect did not decline in transfer
patients compared to direct-admission patients.22 The DAWN and DEFUSE 3 trials
differed in their approach in identifying salvageable brain (table). The DAWN
trial selected patients based on a clinical-core mismatch, whereas the DEFUSE
3 trial focused on a penumbra-core mismatch. Both target the same conceptual
goal, identifying patients with enough salvageable, at risk, tissue to warrant
EVT. In both cases, brain tissue was designated as having irreversible injury
if CBF was less than 30% of that seen in contralateral perfused tissue by CTP
(or less commonly, magnetic resonance MR (MR) perfusion-weighted imaging (MR-
PWI)) as detected by RAPID automated perfusion post-processing software. Both
trials demonstrated a large clinical benefit, with numbers needed to treat
(NNT) of 3-4 to prevent functional dependence. There were differences in the
protocols as well. DAWN excluded patients with an infarct involving more than
one-third of the territory of the MCA at baseline. DEFUSE 3 enrolled patients
with lower NIHSS score (less clinical severity), larger core infarct, and
slightly higher baseline mRS disability score. One-third of DAWN eligible
patients are DEFUSE 3 ineligible. Epidemiologic data suggest that about one-
third of AIS patients present between 6-24 hours, and only 9.2% of these (or
2.7% overall) meet DAWN or DIFFUSE 3 inclusion criteria.23,24 Of all patients
with AIS presenting to a single comprehensive stroke center, 1.7% of patients
qualified for DAWN clinical trial enrollment with an additional 0.6-1%
qualifying for the DEFUSE 3 trial.23 Both studies employed CTP or MR-PWI to
select patients for EVT, with CTP predominating. DEFUSE 3 subgroup analysis
showed no statistical difference in treatment effect between "patients
selected on the basis of diffusion/perfusion MRI and those selected on the
basis of CT perfusion imaging;" however, the authors admit statistical power
was limited by the lower number of patients enrolled as a result of early
termination. DAWN subgroup analysis did not include comparison by qualifying
image method. One criticism of both studies was the large number of "wake-up
strokes" (50%) vs. 14-28% in the general population, perhaps contributing to
overestimation of stroke age, and therefore, better outcomes.25,26 The authors
note that a higher proportion of unwitnessed strokes are expected in trials
enrolling patients late after onset, as witnessed strokes are typically
treated early, and that the benefit persisted even after stratification into
witnessed and unwitnessed stroke groups.27,28 They also explain that outcomes
were "paradoxically" superior to early window (< 6 hr) treatment trials,
probably due to selection for a large volume of penumbral (i.e., salvageable)
tissue. A subsequent prospective review29 and retrospective registry30
analysis also support the value of CTP in late period EVT eligibility
assessment, while also emphasizing the need to correlate perfusion
abnormalities with other imaging (NCCT, CTA) and clinical information; they
may be more sensitive than CTP for detecting irreversibly damaged tissue as
time progresses. While DWI is considered the gold standard, CTP has the
advantage of more availability, faster acquisition, and a similar estimate of
mismatch, therefore becoming the dominant advanced imaging tool for
identifying the core and penumbra.31 Results, however, must still be
interpreted with caution. A 2020 retrospective study that evaluated patients
undergoing CTP for EVT triage included 176 consecutive patients undergoing CTP
and CTA. Automated calculations were performed with proprietary software, and
failures were reprocessed manually. The primary outcome was postprocessing
failure, defined as the presence of perfusion abnormalities caused by artifact
and verified on follow-up images, and was reported in 11% of cases (20/176).
Causes included severe motion, streak artifact, and poor arrival of contrast.
Half of the failures (n=6) led to erroneous ischemic core volumes that may
have resulted in different treatment decisions if the CTP results had not been
corrected. The authors conclude that results from automated CTP should be
interpreted with caution, and failures should be recognized and corrected to
ensure appropriate management decisions are made.32 In most cases, the key to
improved diagnostic certainty is to interpret the CTP, not in isolation, but
in conjunction with the NCCT, CTA, NIHSS, and clinical history.31

**Non-AIS indications**

__

_CTP for cerebral ischemia due to_ _subarachnoid hemorrhage (SAH)_ _:_

One non-ischemic stroke CTP potential use is in determining delayed cerebral
ischemia (DCI), occurring in approximately 30% of patients within 2 weeks
after aneurysmal SAH.33 The most common etiology of DCI is thought to be
vasospasm produced by spasmogenic substances generated during lysis of
subarachnoid blood. Monitoring for DCI can be done with CTA to confirm
vasospasm in patients with elevated velocities on transcranial Doppler (TCD)
ultrasound.33 However, brain perfusion asymmetry on CTP has been studied for
this purpose as well. A 2014 systematic review and meta-analysis,33 included 4
small observational studies of 188 patients.35-38 The weighted averages and
ranges of the pooled sensitivity and specificity of CTP in the determination
of DCI were 0.84 (0.7-0.95) and 0.77 (0.66-0.82), respectively. The pooled
odds ratio was 23.14 (95% CI, 5.87-91.19). The authors conclude that
"perfusion deficits on CTP" may be helpful in identifying patients with
delayed DCI before the development of infarction and neurologic deficits."
However, they also cite many definitional and methodology limitations of the
underlying studies (nonuniform DCI definition as an outcome measure, CTP
protocol and postprocessing software differences, lack of consistency of what
constitutes an abnormal CTP test result, the optimal time to perform CTP, and
nonstandard hemodynamic parameter thresholds). In addition, accurate
quantification is dependent on an intact blood-brain barrier, which may not be
functioning in DCI.

_CTP for Traumatic Brain Injury:_

Small cohort studies have explored the potential role of CTP for patients with
traumatic brain injury (TBI). A small study of 48 patients reported NCCT had a
sensitivity of 39.6% compared to improved sensitivity of CTP of 87.5% for
cerebral contusions diagnosed on delayed follow-up imaging.39 Additional
studies suggest reductions in blood flow and volumes determined by CTP are
associated with worse outcomes.40 A subset analysis of 30 patients from an
observational study reported the information obtained from CTP is useful in
decision making.41

_CTP for neoplasia:_

CTP has been proposed as a possible modality for non-invasive assessment of
brain tumors. Several small (<20 patients) retrospective reports evaluated CTP
to disguise malignant verses normal tissue, evaluation for metastatic disease,
and differentiating tissue type in brain tumors report promising early
results.42,43 A small prospective trial of 49 consecutive patients with brain
tumors or tumor-like lesions were evaluated with CT and CTP. The results
suggest CTP can aid in distinguishing glioma and lymphomas based on
quantitative measurements of cerebral blood volume (CBV) and permeability.4
The reports indicate the need for further investigation of cut-off values,
accuracy, and patient selection criteria to determine if clinically useful. A
meta-analysis of 13 prospective studies totaling 389 patients with head and
neck tumors demonstrated feasibility for routine clinical use of CTP, but
reported small size of the patient population, heterogeneity of the patient
population, considering different end points of outcome and enrolling HNC in
various stages limited the results and results would need to be validated.45

The 2019 update to the 2018 American Heart Association (AHA)/American Stroke
Association (ASA) guidelines46 for the early management of patients with AIS
state, "In selected patients with AIS within 6 to 24 hours of last known
normal who have LVO in the anterior circulation, obtaining CTP, DW-MRI, with
or without MRI perfusion is recommended to aid in patient selection for
mechanical thrombectomy, but only when imaging and other eligibility criteria
from RCTs showing benefit are being strictly applied in selecting patients for
mechanical thrombectomy". (Class of recommendation I-strong; level (quality)
of evidence A).47 Since only the DAWN and DEFUSE 3 RCTs show a benefit of
late-period EVT, they further warn: "DAWN or DEFUSE 3 eligibility should be
strictly adhered to in clinical practice." These guidelines do not recommend
CTP to determine eligibility for either thrombolytic therapy or EVT in the
early (<6 hours) period (Class of recommendation I-strong; level (quality) of
evidence B-Nonrandomized), or for any other indication (e.g., prediction of
hemorrhagic transformation in acute ischemic injury). Other guidelines have
similar recommendations.48-50 National Institute for Health and Care
Excellence recommends: "If thrombectomy might be indicated, perform imaging
with CT contrast angiography following initial non-enhanced CT. Add CT
perfusion imaging (or MR equivalent) if thrombectomy might be indicated beyond
6 hours of symptom onset."51 This recommendation uniquely also includes
posterior circulation stroke. However, there is minimal evidence regarding the
appropriate threshold and utility of CTP in the posterior circulation, and MRI
is a better alternative.11

The 2017 American College of Radiology (ACR)-American Society of
Neuroradiology (ASNR)-Society of Pediatric Radiology (SPR) guidelines lists
primary and secondary indications for CTP in neuroradiology, including
evaluation of AIS, neoplasia, trauma, cerebral hemorrhage, and vasospasm
following subarachnoid hemorrhage.52 The 2017 ACR Appropriateness Criteria
Cerebrovascular Disease grades CTP at the level of "may be appropriate" and
report that "CTP can be used to evaluate cerebrovascular reserve; however, its
role in the evaluation of acute stroke remains unproven." They also state,
"CTP may play a role to evaluate for ischemia when MRI is contraindicated or
cannot be performed." Additionally, CTP has shown some promise in identifying
patients who may benefit from therapy outside the accepted treatment
window."53

The 2012 AHA/ASA guidelines for the management of aneurysmal SAH state that
"perfusion imaging with CT or magnetic resonance can be useful to identify
regions of potential brain ischemia" (Class Ia; Level of Evidence B).54
However, current UpToDate guidance concludes that CTP "clinical
utility...remains to be established" and that "the use of this technique as a
monitoring tool may be limited by risks of recurrent dye loads and radiation
exposure,"55 as well as by lack of standardized methodology.34 The 2015
AHA/ASA guidelines for the management of spontaneous intracerebral hemorrhage
has no mention of CTP,56 nor does UpToDate.57 Regarding trauma and oncologic
indications, there appears to be insufficient evidence to support the routine
use of CTP.

In summary, we consider the concordant level I evidence of a large clinical
benefit after CTP imaging (using automated post-processing software
algorithmic analysis) in AIS secondary to LVO, to assist in late EVT
eligibility determination per AHA/ASA guidelines, medically reasonable and
necessary. Other stroke or non-stroke indications lack level I evidence and
are not considered medically reasonable and necessary at this time.