CTP (using automated post-processing software algorithmic analysis) is
medically reasonable and necessary in patients with 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 one 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 DIFUSE 3**



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

**Background**

Stroke is the leading cause of adult disability in the United States with
limited treatment options.3 The FDA approved treatment for stroke is
intravenous tissue plasminogen activator (tPA) within three 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 occulted 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
EVT6-8. 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 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, CT angiography (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 millimeters11. The
CBV is calculated as the milliliters 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 AIS12. HT occurs in up to 40% of stroke patients and is
related to rapid deterioration and poor outcomes. CTP has been studied in
acute ischemic stroke for decades13, only recently was it found likely to
influence treatment decision14. Subsequently, two 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 results11,17. 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 hemorrhagic transformation 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 acute ischemic stroke 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) 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
three prospective and nine 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 three 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 two 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 EVT9. 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 National
Institutes of Health Stroke Scale (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 modified Rankin scale (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 two 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 MCA based on CTA or MRA
(Table 1). In patients with NIHSS 6, (1) penumbra volume 15ml, (2) penumbra
to core ratio of 1.8, and (3) core volume  70 ml were used as imaging
eligibility criteria to select patients for late EVT (where penumbra volume is
the perfusion-core mismatch which is defined as the Tmax>6s volume, and the
core volume is measured by CTP or MRI diffusion)." 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 U.S. 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 patientspatients22.

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 acute
ischemic stroke 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 penumbra31.
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 made32. 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 history31.

**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 two weeks after
aneurysmal SAH33. 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) ultrasound33.
However, brain perfusion asymmetry on CTP has been studied for this purpose as
well. A 2014 systematic review and meta-analysis34, included four small
observational studies of 188 patients35-38. 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 outcomes40 . 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 results42,43. 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 permeability44. 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 validated45.



The 2019 update to the 2018 American Heart Association (AHA)/American Stroke
Association (ASA) guidelines 46 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 alternative11 .

ECRI Clinical Evidence Assessment on Perfusion CTP reviewed the literature on
CTP as an alternative imaging evaluation in addition to NCCT. It determined
the evidence was "inconclusive" due to mixed results. They report "CTP's
clinical utility compared with that of NCCT and magnetic resonance imaging
(MRI) for assessing AIS has not been established because of too few data. No
studies compared CTP clinical utility with other imaging methods. The RCT
focused on treatment and did not randomly assign imaging methods, which
created a risk of selection bias when comparing CTP to perfusion MRI. Most
studies assessed in the SRs, as well as the diagnostic accuracy studies
published after the SRs, were at high risk of bias due to retrospective design
and single-center focus 52.

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 53. 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"54.

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) 55.
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" 56,  as well as by lack of standardized mehotdology34. The 2015
AHA/ASA guidelines for the management of spontaneous intracerebral hemorrhage
has no mention of CTP 57, nor does UpToDate 58. Regarding trauma and oncologic
indications, there appears to be insufficient evidence to support the routine
use of CTP 57, nor does UpToDate 58. 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.