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 . 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 ≥15 ml, (2) penumbra to core ratio ≥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 minus core volume, and the core volume is measured by CTP or MRI diffusion). 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 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 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 outcomes25,26. 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 review 29 and retrospective registry 30 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 CPT 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 history 31.
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) ultrasound 33. However, brain perfusion asymmetry on CTP has been studied for this purpose as well. A 2014 systematic review and meta-analysis 34, 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 distinguish 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 44. 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.