Coverage Policy Manual
Policy #: 2012016
Category: Radiology
Initiated: April 2012
Last Review: April 2018
  Computed Tomography (CT) Perfusion Imaging

Description:
Perfusion imaging using computed tomography (CT) provides an assessment of cerebral blood flow that may assist in the identification of ischemic regions of the brain. This technology is proposed as a method to aid treatment decisions in patients being evaluated for acute ischemic stroke, subarachnoid hemorrhage, cerebral vasospasm, brain tumors, and head trauma.
 
Stroke
The goal of acute stroke thrombolytic treatment is to rescue the ischemic penumbra, an area of brain that surrounds the infarct core and is hypoperfused but does not die quickly. Multimodal CT and magnetic resonance imaging (MRI) can be used to assess the cerebral parenchyma, vasculature, and tissue viability in the acute ischemic stroke setting and are used to detect ischemic tissue and exclude hemorrhage and other conditions that mimic acute cerebral ischemia.
 
  • Noncontrast CT is used to rule out intracranial hemorrhage, tumor, or infection. MR diffusion-weighted imaging (DWI) demonstrates acute infarction, and a gradient-recalled echo (GRE) sequence excludes intracerebral hemorrhage.
  • CT angiography (CTA) and MR angiography (MRA) are used to evaluate intra- and extra-cranial vasculature to detect the vascular occlusion and potentially guide therapy (e.g., intravenous thrombolytics, or intra-arterial or mechanical thrombolysis).
 
The approved therapy, intravenous tissue plasminogen activator (tPA), requires only a non-contrast CT scan to exclude the presence of hemorrhage (a contraindication to the use of the drug). Current guidelines are to administer tPA within the first 3 hours after an ischemic event, preceded by a CT scan. Many patients, however, do not present within the 3-hour window, and thrombolysis carries a risk of intracranial hemorrhage. Thus, more sophisticated imaging may be needed to select the proper use of intra-arterial thrombolysis or mechanical thrombectomy in patients who present more than 3 hours after an ischemic stroke. Perfusion imaging is also being evaluated in the management of other neurologic conditions, such as subarachnoid hemorrhage and head trauma.
 
The potential utility of perfusion imaging of acute stroke is described as the following
 
  • identification of brain regions with extremely low cerebral blood flow, which represents the core
  • identification of patients with at-risk brain regions (acutely ischemic but viable penumbra) that may be salvageable with successful intra-arterial thrombolysis beyond the standard 3-hour window
  • triage of patients with at-risk brain regions to other available therapies, such as induced hypertension or mechanical clot retrieval
  • decisions regarding intensive monitoring of patients with large abnormally perfused brain regions
  • biologically-based management of patients who awaken with a stroke for which the precise time of onset is unknown
 
Similar information can be provided by CT and MRI in terms of infarct core and penumbra. However, multimodal CT has a short protocol time (5-6 min), and because it can be performed with any modern CT equipment, is more widely available in the emergency setting. CT perfusion is performed by capturing images as an iodinated contrast agent bolus passes through the cerebral circulation and accumulates in the cerebral tissues. (Older perfusion methodologies such as single-photon emission CT [SPECT] and xenon-enhanced CT [XeCT] scanning use a diffusible tracer.) The quantitative perfusion parameters are calculated from density changes for each pixel over time with commercially available deconvolution-based software, in which cerebral blood flow (CBF) is equal to regional cerebral blood volume (CBV) divided by mean transit time (MTT). CT angiography/CT perfusion requires ionizing radiation and iodinated contrast. It is estimated that a typical perfusion CT deposits a slightly greater radiation dose than a routine unenhanced head CT (approximately 3.3 mSv). CT perfusion covers limited areas of the brain. Commonly used 16- to 64-slice CT scanners can detect an area of 2- to 4-cm of brain tissue.
 
On October 8, 2009, the U.S. Food and Drug Administration (FDA) issued an Initial Communication about excess radiation during perfusion CT imaging to aid in the diagnosis and treatment of stroke from one facility. Together with state and local health authorities, the FDA has identified at least 250 patients who were exposed to excess radiation during CT perfusion scans. The FDA has received reports of possible excess exposures at facilities in other states, involving more than one manufacturer of CT scanners. In response, the FDA has provided recommendations for facilities and practitioners and is continuing to work with manufacturers, professional organizations, and state and local public health authorities to investigate the scope and causes of these excess exposures and their potential public health impact. A December 8, 2009 update of this issue is available online at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm185898.htm.
 
Subarachnoid Hemorrhage and Cerebral Vasospasm
Cerebral vasospasm is one of the major causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (ASAH) in patients who survive the initial hemorrhage and can be seen in about two thirds of patients with ASAH. The typical onset of cerebral vasospasm occurs at 3 to 5 days after hemorrhage, with maximal narrowing on digital subtraction angiography at 5-14 days. Currently, the diagnosis of vasospasm and management decisions rely on clinical examination, transcranial Doppler sonography, and digital subtraction angiography. Although symptomatic vasospasm affects 20% to 30% of patients with ASAH, not all patients with angiographic vasospasm manifest clinical symptoms, and the symptoms can be nonspecific. In addition, patients do not always have both clinical and imaging findings of vasospasm. Due to these limitations, more accurate and reliable methods to detect cerebral vasospasm are being investigated. Two methods being evaluated are CTA and CT perfusion.
 
Brain Tumors
The current standard for tumor grading is histopathologic assessment of tissue. Limitations of histologic assessment include sampling error due to regional heterogeneity and interobserver variation. These limitations can result in inaccurate classification and grading of gliomas. Since malignant brain tumors are characterized by neovascularity and increased angiogenic activity, perfusion imaging has been proposed as a method to assess tumor grade and prognosis. In addition, perfusion imaging can be repeated and may help to assess the evolution of tumors and the treatment response. Traditionally, perfusion imaging of brain tumors has been performed with MRI, which can estimate tumor blood volume, blood flow, and permeability. More recently, CT perfusion has been investigated for glioma grading. Potential advantages, compared with MR perfusion, include the wider availability, faster scanning times, and lower cost. CT perfusion may also be useful in distinguishing recurrent tumor from radiation necrosis.
 
Regulatory Status
Several post-processing software packages (e.g., Siemens’ syngo Perfusion-CT, GE Healthcare’s CT Perfusion 4, Philips Medical System’s Brain Perfusion Option) have received 510(k) marketing clearance from the FDA for use with a CT system to perform perfusion imaging. The software is being distributed with new CT scanners.
 
There is a CPT category III code specific to this test:
 
0042T: Cerebral perfusion analysis using computed tomography with contrast administration, including post-processing of parametric maps with determination of cerebral blood flow, cerebral blood volume, and mean transit time.
  

Policy/
Coverage:
CT-based perfusion imaging for all indications including the diagnosis and management of acute cerebral ischemia (stroke) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, CT-based perfusion imaging for all indications including the diagnosis and management of acute cerebral ischemia (stroke) is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
Acute Cerebral Ischemia
At the time this policy was created, the literature focused on technical capabilities and feasibility. A number of retrospective studies indicated that blood flow values obtained using a diffusible gas indicator are accurate and that the flow rates correlate with physiologic changes such as the onset of neurologic deficits (Kilpatrick, 2001). The limited availability of medical-grade Xe gas was another issue with this approach to computed tomography (CT) perfusion imaging. Because of more widespread availability, studies were also being done using non-diffusible tracers, i.e., contrast agents (Wintermark, 2002) (Wintermark, 2005). As of 2008, studies were identified that reported on the use of CT perfusion imaging to identify infarcted tissue versus viable tissue (penumbra) (Wintermark, 2006) (Tan, 2007) (Dittrich, 2008) (Murphy, 2008). However, many studies evaluating use of thrombolytic therapy in acute stroke beyond 3 hours of symptom onset were based on magnetic resonance (MR) imaging with perfusion-diffusion mismatching (Davis, 2005). As Lev commented in an editorial, although many investigators have advocated CT perfusion imaging as a reliable method for detecting both infarct core and penumbra, almost all the major clinical trials aimed at extending the time window for thrombolysis used advanced MR rather than CT imaging for triage (Lev, 2007). Prospective controlled studies had not been reported that demonstrated that use of perfusion imaging (CT or MR) improved outcomes in patients with acute stroke.
 
In 2009, the American Heart Association (AHA) Council on Cardiovascular Radiology and Intervention, Stroke Council, and the Interdisciplinary Council on Peripheral Vascular Disease published a scientific statement that included a review of the evidence on CT perfusion (Latchaw, 2009). The scientific review determined that:
 
  • Creation of accurate, quantitative CT perfusion has been validated in comparison with xenon-CT, PET [positron emission tomography], and MR perfusion. CT perfusion appears to have greater spatial resolution than MR perfusion, and MR perfusion may be more sensitive to contamination by large vascular structure, leading to the possibility that visual assessment of core/penumbra mismatch is more reliable with CT perfusion than with MR perfusion.
  • Studies are evaluating various thresholds to predict the upper and lower limits of final infarct size, and outcome prediction studies suggest that CT perfusion has the potential to serve as a surrogate marker of stroke severity (final size of infarction), possibly exceeding current predictors of outcome such as the National Institutes of Health Stroke Score (NIHSS). Because of the superior quantitative capability compared to MR perfusion imaging, application of specific CT perfusion thresholds to predict tissue survival or infarction appears promising; however, it is essential that these thresholds be validated in larger patient cohorts for which reperfusion status is known.
  • There is increasing but as yet indirect evidence that even relatively imprecise measures of core/penumbra mismatch may be used to select patients for treatment beyond a strict 3-hour time window for intravenous thrombolysis. Multimodal CT may also determine suitability for other therapies, such as mechanical clot retrieval and intra-arterial thrombolysis, and increase patient access to new treatments.
 
A 2011 report compared outcomes of 106 patients with acute stroke who were assessed with multimodal CT (CT/CT angiography[CTA]/CT perfusion) versus a cohort of 262 patients with acute stroke who were assisted without full multimodal brain imaging during a 5-year period (Obach, 2011). Clinical and imaging data were collected prospectively, and all imaging studies were assessed by investigators blinded to prognostic data. The two groups were comparable at baseline, with the exception of a greater percentage of patients with a time-to-treatment of greater than 3 hours (28% vs. 16%) and a greater percentage treated with endovascular therapy (26% vs. 11%, both respectively) in the multimodal CT group. Good outcome (modified Rankin scale score < 2) at 3 months was increased in the multimodal group compared with controls (adjusted odds ratio [OR] of 2.88) in models adjusted for age, gender, NIHSS, glucose, and treatment delay or modality. Fifty-six percent of patients assessed by multimodal CT had a Rankin score equal to or less than 2 in comparison with 41% of controls (p=0.008). In a sensitivity analysis, multimodal-assisted thrombolysis yielded superior benefits in those patients treated after 3 hours (adjusted OR, 4.48) than for patients treated within 3 hours (adjusted OR, 1.31). For patients treated after 3 hours, 63% of patients assessed by multimodal CT had a Rankin score equal to or less than 2 in comparison with 24% of controls. Mortality (14% and 15%) and symptomatic hemorrhage (5% and 7%m both respectively) were similar in the 2 groups. Randomized trials are needed to establish the value of multimodal CT to assist thrombolytic therapy in acute stroke.
 
Cerebral Vasospasm
A meta-analysis on the diagnostic accuracy of CTA and CT perfusion for cerebral vasospasm was published in 2010 (Greenberg, 2010). Three studies with a total of 64 patients met the inclusion criteria and contained the appropriate data for statistical analysis. In these studies, “vasospasm” was defined on CT perfusion as a perfusion deficit demonstrating prolonged mean transit time and decreased cerebral blood flow. However, there were no standardized thresholds of mean transit time and cerebral blood flow to determine vasospasm, contributing to the heterogeneity among these studies. For this meta-analysis, “angiographic vasospasm” was defined as evidence of arterial narrowing compared with the parent vessel or with a baseline examination, with both symptomatic and asymptomatic patients included. In comparison with digital subtraction angiography, CT perfusion pooled estimates had 74% sensitivity and 93% specificity. Given the small sample size and the heterogeneity in the CT perfusion data, these results are considered preliminary.
 
Brain Tumors
A review by Jain indicates that most of the literature on the utility of perfusion imaging for glioma grading is based on various MR perfusion techniques (Jain, 2010).  One study compared CT perfusion with conventional MRI in 19 patients (Elika, 2007).  With a cutoff point of greater than 1.92 normalized cerebral blood volume (nCBV), there was sensitivity of 85.7% and specificity of 100% to differentiate high-grade gliomas. There were no significant differences in nCBV between grade III or IV tumors. A subsequent study by Jain and colleagues correlated CT perfusion findings with histopathologic grade in 32 patients with astroglial tumors (Jain, 2008). Eight additional patients with oligodendrogliomas were excluded from analysis because of the known higher blood volume compared with astroglial tumors. Of the 32 patients included in the study, 8 had low-grade gliomas and 24 had high-grade gliomas. In this selected set of patients, CT perfusion showed significant differences in the grade III and grade IV tumors. Prospective studies in an appropriate population of patients are needed to evaluate the sensitivity and specificity of CT perfusion glioma grading, with histopathologic assessment of tumors as the independent reference standard.
 
Ongoing Clinical Trials
A search of ClinicalTrials.gov found one ongoing large observational trial, the "Dutch acute stroke trial (DUST): Prediction of outcome with computed tomography (CT) – perfusion and CT-angiography” to assess whether combined CT perfusion and CT angiography parameters can predict patient outcome in acute ischemic stroke (NCT00880113). The study will include patients with acute stroke symptoms who present in the hospital within 9 hours of onset of symptoms. Patients who awaken with stroke symptoms can only be included if they went to sleep without any stroke symptoms, and the time from going to sleep until imaging is less than 9 hours. Estimated enrollment is 1,500 patients with completion in December 2011.
 
Practice Guidelines and Position Statements
In 2009, the American Heart Association (AHA) issued a scientific statement on imaging of acute ischemic stroke (Latchaw, 2009). The statement included the following recommendations regarding perfusion imaging:
 
Perfusion-Derived Values
Quantitative thresholds of tissue that is dead or destined to die versus tissue that is still living and may be salvageable are the goal of all perfusion techniques. Although the performance of such studies may be considered to identify and differentiate the ischemic penumbra and infarct core, their accuracy and usefulness have not been well established (Class IIb, Level of Evidence B).
 
Clinical Role of Perfusion Imaging
 
  • The admission volumes of infarct core and ischemic penumbra may be significant predictors of clinical outcome, possibly exceeding the prognostic value of admission NIHSS score [National Institutes of Health Stroke Score] (Class IIb, Level of Evidence B).
  • There is increasing but as yet indirect evidence that even relatively imprecise measures of core/penumbra mismatch may be used to select patients for treatment beyond a strict 3-hour time window for intravenous thrombolysis. Together with vascular imaging, these approaches may determine suitability for other therapies such as mechanical clot retrieval and intra-arterial thrombolysis, as well as provide a surrogate marker for treatment efficacy (Class IIb, Level of Evidence B).
 
The Agency for Healthcare Research and Quality (AHRQ) published a report on acute stroke in 2005. This report addressed multiple issues regarding CT perfusion and also angiography in terms of how these modalities affect the use of thrombolytic therapy for acute ischemic stroke. This report indicated that studies with prospective use of CT perfusion and angiography techniques in patient selection for thrombolysis were not identified.
 
Summary
While CT perfusion appears to hold promise for improving care of patients with various neurologic conditions, including the potential individualization of therapy for acute stroke, randomized clinical trials are needed. In addition, data on CT perfusion for cerebral vasospasm and brain tumors is limited. The impact of CT perfusion imaging on clinical outcomes is not currently known.
 
2013 Update
A literature search was conducted using the MEDLINE database through March 2013.  There was no new literature identified that would prompt a change in the coverage statement. The following is a summary of the relevant identified literature.
 
Acute Cerebral Ischemia
Four relevant cohort studies have been identified. One of these studies attempted to define the technical CT parameters that best detect perfusion mismatches. In 2011, Bivard et al. reported a prospective clinical validation study of perfusion CT for acute (<6 hr) ischemic stroke in 314 consecutive patients (Bivard, 2011). If eligible, patients were treated with intravenous thrombolysis. All patients underwent baseline multimodal CT examination and follow-up MRI at 24 hours, with MRI used as the gold standard for tissue perfusion. The most accurate CT perfusion threshold at defining infarct core was determined to be cerebral blood flow less than 40% of contralateral with a relative delay time less than 2 sec (area under the curve [AUC] of 0.86). Using this threshold, the correlation between extent of CT perfusion mismatch tissue (the volume of “at-risk” tissue) salvaged from infarction and clinical improvement was R2=0.59 at 24 h (NIHSS) and R2=0.42 at 90 days (Rankin scale).
 
Obach et al. compared outcomes of 106 patients with acute stroke who were assessed with multimodal CT (CT/CT angiography[CTA]/CT perfusion) versus a cohort of 262 patients with acute stroke who were assessed without full multimodal brain imaging during a 5-year period (Obach, 2011). Clinical and imaging data were collected prospectively, and all imaging studies were assessed by investigators blinded to prognostic data. The two groups were comparable at baseline, with the exception of a greater percentage of patients with a time-to-treatment of greater than 3 hours (28% vs. 16%) and a greater percentage treated with endovascular therapy (26% vs. 11%, both respectively) in the multimodal CT group. Good outcome (modified Rankin scale score <2) at 3 months was increased in the multimodal group compared with controls (adjusted odds ratio [OR] of 2.88) in models adjusted for age, gender, NIHSS, glucose, and treatment delay or modality. Fifty-six percent of patients assessed by multimodal CT had a Rankin score equal to or less than 2 in comparison with 41% of controls (p=0.008). In a sensitivity analysis, multimodal-assisted thrombolysis yielded superior benefits in those patients treated after 3 hours (adjusted OR, 4.48) than for patients treated within 3 hours (adjusted OR, 1.31). For patients treated after 3 hours, 63% of patients assessed by multimodal CT had a Rankin score equal to or less than 2 in comparison with 24% of controls. Mortality (14% and 15%) and symptomatic hemorrhage (5% and 7%, both respectively) were similar in the 2 groups.
 
Sztriha et al. evaluated whether CT perfusion imaging mismatch could help to select ischemic stroke patients for thrombolysis between 3 and 6 hours (Sztriha, 2011).  A cohort of 254 thrombolysed patients were studied; 174 (69%) were thrombolysed at 0-3 hours using non-contrast CT, and 80 (31%) were thrombolysed at 3-6 hours by using CT perfusion mismatch criteria, defined as a cerebral blood volume ASPECTS [Alberta Stroke Program Early CT Score] of at least 7 and an ASPECTS mismatch of at least 2. Baseline characteristics were comparable in the 2 groups. Efficacy endpoints included disability at 3 months, as assessed by the Rankin score. Safety endpoints included overall mortality, any intracerebral hemorrhage, and symptomatic intracerebral hemorrhage. At 3 months, there were no differences between patients thrombolysed at 0-3 hours or at 3-6 hours in symptomatic intracerebral hemorrhage (3% vs. 4%), or in any intracerebral hemorrhage (7% vs. 9%). There were also no differences at 3 months in mortality (16% vs. 9%) or the modified Rankin scale score 0-2 (55% vs. 54%, respectively for all). The NIHSS score was the only independent determinant of a favorable functional outcome at 3 months (Rankin score of 0-2; odds ratio [OR]: of 0.89) in patients treated using CT perfusion mismatch criteria beyond 3 hours. This study is limited by the lack of a control group of patients without CT perfusion. The authors also note that results of this study cannot be generalized to patients with symptoms in the posterior circulation, an area where CT perfusion is known to underperform.
 
Rai et al. evaluated rates of recanalization and functional outcomes in a cohort of 99 patients selected by CT perfusion for treatment with endovascular stroke therapy and compared results with historical controls from the MERCI [Mechanical Embolus Removal in Cerebral Ischemia], Multi-MERCI, and Penumbra device trials that treated all comers (Rai, 2012). Patients were included if they had anterior circulation symptoms at presentation with a baseline NIHSS score of 8 or greater and intracerebral vascular occlusion on admission CT angiography correlating with the neurologic deficit. There was no cut-off time for treatment. The type of endovascular therapy involved intra-arterial thrombolytics in 33.3% of patients, mechanical device in 24.2%, and both thrombolytics and mechanical thrombectomy in 42.4%. Successful recanalization was achieved in 55.6%, with a good outcome in 41.4% of patients. The recanalization rate in this study was not significantly different from the 46% for MERCI and 68% for Multi-MERCI but was significantly lower than the 82% recanalization rate in the Penumbra trial. In patients who were successfully recanalized, good outcomes were obtained in 67% of patients in this study in comparison with 46% in MERCI, 49% in Multi-MERCI, and 29% in Penumbra. The rate of futile recanalization (defined as a poor outcome despite successful recanalization) was 33% compared with 54% in MERCI, 51% in Multi-MERCI, and 71% for Penumbra. A small cerebral blood volume abnormality and large mean transit time-cerebral blood volume mismatch were strong predictors of a good outcome. This study is limited by the comparison of a retrospective cohort with results from prospective device trials and by the reliance on recanalization rates as the primary outcome rather than clinical measures.
 
A large number of case series have been published that have retrospectively assessed how CT perfusion at admission might facilitate clinical decision making and predict outcomes in patients with suspected acute ischemic stroke. Prospective trials are needed to evaluate the impact of this technology on health outcomes.
 
Conclusions: Four recent cohort studies describe how CT perfusion can be used in clinical care to select patients for endovascular therapy. However, these trials lack concurrent control groups and, therefore do not provide relevant evidence on the comparative efficacy of this approach compared to alternative strategies. Randomized trials are needed to establish with greater certainty the value of CT perfusion to assist decision making for thrombolytic or mechanical therapy in acute stroke.
 
Subarachnoid Hemorrhage and Cerebral Vasospasm
A 2010 meta-analysis on the diagnostic accuracy of CTA and CT perfusion for cerebral vasospasm identified 3 studies (64 patients) that met the inclusion criteria and contained the appropriate data for statistical analysis (Greenberg, 2010). In these studies, “vasospasm” was defined on CT perfusion as a perfusion deficit demonstrating prolonged mean transit time and decreased cerebral blood flow. However, there were no standardized thresholds of mean transit time and cerebral blood flow to determine vasospasm, contributing to the heterogeneity among these studies. For this meta-analysis, “angiographic vasospasm” was defined as evidence of arterial narrowing compared with the parent vessel or with a baseline examination, with both symptomatic and asymptomatic patients included. In comparison with digital subtraction angiography, CT perfusion pooled estimates had 74% sensitivity and 93% specificity. Given the small sample size and the heterogeneity in the CT perfusion data, these results are considered preliminary.
 
In 2011, Sanelli et al. reported a prospective study with 97 patients that evaluated the accuracy of CT perfusion to diagnose delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage (Sanelli, 2011). CT perfusion was performed between days 6 and 8 in asymptomatic patients and on the day of clinical deterioration in symptomatic patients. Perfusion maps were qualitatively evaluated by 2 neuroradiologists who were blinded to clinical and imaging data and compared to the reference standard. Based on a multistage hierarchical reference standard that incorporated both imaging and clinical criteria, 40 patients (41%) were diagnosed with delayed cerebral ischemia. Overall diagnostic accuracy for CT perfusion, determined from receiver operating characteristic (ROC) curves, was 93% for cerebral blood flow, 88% for mean transit time, and 72% for cerebral blood volume. The study also sought to determine a quantitative threshold for delayed cerebral ischemia with CT perfusion, although it was noted that absolute thresholds may not be generalizable due to differences in scanner equipment and post-processing methods. Clinical outcomes of the delayed cerebral ischemia group included 19 patients (48%) with no permanent neurologic deficit, 16 (40%) with permanent neurologic deficit, and 5 (13%) who died during hospitalization.
 
Sanelli et al. also reported a retrospective study of the development of vasospasm in 75 patients with aneurysmal subarachnoid hemorrhage who had an earlier CT perfusion assessment (likely overlap in subjects with the study described above) (Sanelli, 2011). Based on a multistage reference standard, 28 patients (37%) were classified as vasospasm. CT perfusion values (cerebral blood flow and mean transit time) on days 0-3 were found to be significantly lower in the vasospasm group. Optimal thresholds were then determined for cerebral blood flow (50% sensitivity and 91% specificity), mean transit time (61% sensitivity and 70% specificity) and cerebral blood volume (36% sensitivity and 89% specificity). Clinical outcomes of the vasospasm group included 15 patients (54%) with no permanent neurologic deficit, 11 (39%) with permanent neurologic deficit, and 2 (7%) who died during hospitalization.
 
Conclusions: CT perfusion is being evaluated for the diagnosis of vasospasm and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. A prospective trial showed a qualitative measure of cerebral blood flow to have 93% accuracy for the detection of delayed cerebral ischemia with lower accuracy for cerebral blood volume. Prospective trials are needed to evaluate whether CT perfusion in patients with aneurysmal subarachnoid hemorrhage leads to the early identification of patients at high risk for vasospasm/delayed cerebral ischemia, alters treatment decisions, and improves health outcomes.
 
Brain Tumors
A 2011 review by Jain indicates that most of the literature on the utility of perfusion imaging for glioma grading is based on various MR perfusion techniques (Jain, 2011). One study compared CT perfusion with conventional MRI in 19 patients (Ellika, 2007). With a cut-off point of greater than 1.92 normalized cerebral blood volume (nCBV), there was sensitivity of 85.7% and specificity of 100% to differentiate high-grade gliomas. There were no significant differences in nCBV between grade III or IV tumors. A subsequent study by Jain and colleagues correlated CT perfusion findings with histopathologic grade in 32 patients with astroglial tumors. (21) Eight additional patients with oligodendrogliomas were excluded from analysis because of the known higher blood volume compared with astroglial tumors. Of the 32 patients included in the study, 8 had low-grade gliomas and 24 had high-grade gliomas. In this selected set of patients, CT perfusion showed significant differences in the grade III and grade IV tumors. Prospective studies in an appropriate population of patients are needed to evaluate the sensitivity and specificity of CT perfusion glioma grading, with histopathologic assessment of tumors as the independent reference standard.
 
In 2011, Xyda et al. reported a prospective study of the feasibility and efficacy of volume perfusion CT (VPCT) for the preoperative assessment of cerebral gliomas in 46 consecutive patients with suspected cerebral gliomas (Xyda, 2011). (Whereas typical perfusion CT covers a relatively narrow range of brain tissue, the VPCT system with multispiral acquisition covers the entire tumor.) Two blinded readers independently evaluated VPCT by drawing volumes of interest (VOIs) around the tumor according to maximum intensity projection volumes. The VOIs were mapped onto the cerebral blood volume, flow, and permeability perfusion datasets, which correspond to histopathologic microvascular density. VPCT was followed by stereotactic biopsy or surgery to evaluate the histopathology of the tumor and classified into low-grade (I and II) and high-grade (III and IV). The diagnostic power of the perfusion parameters were analyzed by receiver operating characteristic (ROC) curve analysis. Permeability demonstrated the highest diagnostic accuracy (97% sensitivity, 100% specificity), positive predictive value (100%), and negative predictive value (94%) to identify or exclude high-grade tumors. Potential uses of VPCT are to guide biopsy and to monitor low-grade gliomas. This is the first report using VPCT to differentiate gliomas; therefore, replication of these findings in an independent sample of patients is needed.
 
The American Heart Association (AHA) and American Stroke Association (ASA) 2012 guidelines for the management of aneurysmal subarachnoid hemorrhage recommend that perfusion imaging with CT or MR can be useful to identify regions of potential brain ischemia (Class IIa; Level of Evidence B) (Connolly, 2012). The guidelines state that there are emerging data that perfusion imaging, demonstrating regions of hypoperfusion, may be more accurate for identification of delayed cerebral ischemia than anatomic imaging of arterial narrowing or changes in blood flow velocity by transcranial Doppler. The guidelines concluded that CT perfusion is a promising technology, although repeat measurements are limited by the risks of dye load and radiation exposure.
 
Ongoing Clinical Trials
 
A search of online site ClinicalTrials.gov in August 2012found the following trials:
 
    • Dutch acute stroke trial (DUST): Prediction of outcome with computed tomography (CT) – perfusion and CT-angiography” to assess whether combined CT perfusion and CT angiography parameters can predict patient outcome in acute ischemic stroke (NCT00880113). The study will include patients with acute stroke symptoms who present in the hospital within 9 hours of onset of symptoms. Patients who awaken with stroke symptoms can only be included if they went to sleep without any stroke symptoms, and the time from going to sleep until imaging is less than 9 hours. Estimated enrollment is 1,500 patients with completion in December 2013.
    • The Perfusion Use in Stroke Evaluation Study (PERFUSE)- Open-label, single-center, phase II trial, evaluating the utility of CT perfusion in acute ischemic stroke. To determine  which aspects of CT perfusion imaging can aid in expanding the time window for thrombolysis.  The estimated study completion date is March 2013 with an estimated 100 enrolled. The study is currently recruiting patients.
  
2014 Update
A literature search conducted through February 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2013, Sheth et al. reported a retrospective study of the effect of multi-modal CT on outcomes from endovascular therapy in 556 patients from 10 stroke centers (Sheth, 2013). Patients were included if they presented within 8 hours of symptom onset and were then divided into groups based on the imaging modality employed prior to treatment. Non-contrast CT was used in 51% of patients, CT perfusion in 34%, and MRI in 14% of patients. Patients were selected for endovascular therapy based on specific imaging criteria. Non-contrast CT patients had significantly lower median times to groin puncture (61 min.) compared with CT perfusion (114 min.) or MRI (124 min.). There were no differences in clinical outcomes, hemorrhage rates, or final infarct volumes among the groups. This study is limited by the retrospective analysis and differences between groups at baseline. Patients selected for endovascular treatment by non-contrast CT alone had a higher baseline NIHSS score and were more likely to have been transferred from an outside facility. In addition, there was limited information regarding the patients who did not proceed to endovascular therapy.
 
2015 Update
This policy was reviewed and a literature search conducted using the MEDLINE database and clinicaltrials.org website. No new published clinical trials were identified. The following is a summary of the key identified literature.
A 2014 meta-analysis by Cremers et al included 11 studies (570 patients) on the use of CT perfusion to identify delayed cerebral ischemia.18 CT perfusion measures at admission did not differ between patients who did and did not develop delayed cerebral ischemia. Some measures of CT perfusion (cerebral blood flow and mean transit time, but not cerebral blood volume) were found to differ between the 2 groups during the period of 4 to 14 days after subarachnoid hemorrhage, suggesting a possible role in diagnoses of delayed cerebral ischemia.
 
AHA/ASA 2013 guidelines for the early management of adults with ischemic stroke recommend that CT perfusion and MRI perfusion and diffusion imaging, including measures of infarct core and penumbra, may be considered for selecting patient for acute reperfusion therapy beyond IV fibrinolytic time windows (Jauch, 2013). The guidelines state that these techniques provide additional information that may improve diagnosis, mechanism, and severity of ischemic stroke and allow more informed clinical decision making. (class llb, level of evidence B)
 
In 2013, the American Society of Neuroradiology, the American College of Radiology (ACR), and the Society of NeuroInterventional Surgery issued a joint statement on imaging recommendations for acute stroke and transient ischemic attack patients (Wintermark, 2013). The following statements were made regarding perfusion imaging:
 
    • In acute stroke patients who are candidates for endovascular therapy, vascular imaging (CTA, MRA, DSA) is strongly recommended during the initial imaging evaluation. Perfusion imaging may be considered to assess the target tissue “at risk” for reperfusion therapy. However, the accuracy and usefulness of perfusion imaging to identify and differentiate viable tissue have not been well-established.
 
    • Determination of tissue viability based on imaging has the potential to individualize thrombolytic therapy and extend the therapeutic time window for some acute stroke patients. Although perfusion imaging has been incorporated into acute stroke imaging algorithms at some institutions, its clinical utility has not been proved.
 
    • It is important to note that perfusion imaging has many applications beyond characterization of the penumbra and triage of patients to acute revascularization therapy…. These applications include, but are not limited to, the following: 1) improving the sensitivity and accuracy of stroke diagnosis (in some cases, a lesion on PCT [perfusion CT] leads to more careful scrutiny and identification of a vascular occlusion that was not evident prospectively, particularly in the M2 and more distal MCA branches); 2) excluding stroke mimics; 3) better assessment of the ischemic core and collateral flow; and 4) prediction of hemorrhagic transformation and malignant edema.
 
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov in April 2015 found the following trials:
 
    • Dutch acute stroke trial (DUST): Prediction of outcome with computed tomography (CT) – perfusion and CT-angiography” to assess whether combined CT perfusion and CT angiography parameters can predict patient outcome and guide treatment decisions in acute ischemic stroke (NCT00880113) (van Seeters, 2014). This multicenter cohort study will include patients with acute stroke symptoms who present in the hospital within 9 hours of onset of symptoms. Patients who awaken with stroke symptoms can only be included if they went to sleep without any stroke symptoms, and the time from going to sleep until imaging is less than 9 hours. Estimated enrollment is 1500 patients with completion in December 2013. The recruitment status of this study is unknown; the posting was last verified June 2012.
 
    • Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND, NCT00887328 and NCT01580839) are multicenter randomized, double-blinded, placebo-controlled trials that will test the hypothesis that ischemic stroke patients selected with significant penumbral mismatch at 4.5 (or 3 hours depending on local guidelines) - 9 hours postonset of stroke or after 'wake up stroke' will have improved clinical outcomes when given intravenous tPA compared with placebo. NCT00887328 has an estimated enrollment of 400 patients with completion expected December 2015. NCT01580839 has an estimated enrollment of 200 patients with completion expected December 2015.
 
2016 Update
A literature search conducted using the MEDLINE database through March 2016 did not reveal any new information that would prompt a change in the coverage statement.  
 
2017 Update
A literature search conducted through March 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
One area of active research is defining the technical CT parameters that best detect perfusion mismatches. For example, Bivard and colleagues reported a prospective clinical validation study of CTP imaging for acute (<6 hours) ischemic stroke in 314 consecutive patients (Bivard, 2011).  Using a threshold of cerebral blood flow less than 40% of contralateral with a relative delay time less than 2 seconds, the correlation between the extent of CTP mismatch tissue (volume of “at-risk” tissue) salvaged from infarction and clinical improvement was a coefficient of determination (R2) of 0.59 (p=0.04) at 24 hours (National Institutes of Health Stroke Scale [NIHSS] score) and an R2 of 0.42 (p=0.02) at 90 days (Rankin Scale score). In 2016, this group of investigators reported a validation study on the threshold settings for whole-brain 320-detector CTP imaging and compared its performance to limited-coverage CTP imaging (Bivard, 2016).
 
Evaluation for Thrombolysis
A 2015 study by Bivard and colleagues examined the effectiveness of CTP imaging by assessing health outcomes in patients who qualified for tPA based on standard clinical/non‒contrast CT criteria, who were treated or not treated based on qualitative CTP results, and later had quantitative analysis of CTP imaging data (Bivard, 2015). Patients selected for a tissue plasminogen activator (tPA) based on qualitative analysis of CTP imaging (n=366) had higher odds of an excellent outcome (modified Rankin Scale [mRS] score, 0-1; odds ratio [OR], 1.59, p=0.009) and lower mortality (OR=0.56, p=0.021) than historical controls (n=396) selected for tPA based on clinical/non‒contrast CT information. In addition, of patients treated with tPA, those who had target mismatch by CTP imaging had significantly better outcomes than patients treated with tPA who did not (OR=13.8 for 3-month mRS score, ≤2). However, 83 (31%) of 269 untreated patients had target mismatch and 56 (15%) of 366 treated patients had a large ischemic core. This observational study suggested that CTP imaging has the potential to identify those patients with acute stroke who are likely and unlikely to respond to thrombolysis. However, questions remain about whether CTP imaging is sufficiently reliable to select individual stroke patients for treatment (Schaefer, 2015; Liebeskind, 2015).
 
The value of CTP imaging-based patient selection for intra-arterial acute ischemic stroke treatment was assessed by Borst and colleagues using data from the MR CLEAN trial (Borst, 2015). In this trial, inclusion was not limited to CTP imaging, but investigators could perform it if it was a standard procedure at their institution. Of 500 patients in MR CLEAN, 333 (67%) underwent CTP imaging and 175 (52.6%) had adequate images. Of the 175, 102 fulfilled the CTP mismatch criteria. The primary outcome was mRS score at 90 days, which was compared between patients with and without CTP mismatch. There was no significant interaction for mismatch and treatment (mechanical embolectomy or usual care) for the mRS score at 90 days, suggesting that CTP imaging cannot reliably identify patients who will not benefit from mechanical embolectomy. In both treatment groups, there was a shift towards better outcomes in patients who had CTP mismatch compared to those who did not, suggesting a benefit for prognosis.
 
In 2015, Borst and colleagues (discussed above) reported on the relationship between CTP imaging-derived parameters and functional outcomes from the MR CLEAN trial (Borst, 2015). Functional outcome as measured by mRS score at 90 days was associated with the CTP imaging-derived ischemic core volume (OR=0.79 per 10 mL; 95% CI, 0.73 to 0.87 per 10 mL; p<0.001) and percentage ischemic core (OR=0.82 per 10%; 95% CI, 0.66 to 0.99 per 10%; p=0.002), but not the penumbra. This trial population had been selected for treatment using mechanical embolectomy.
 
A prognostic model, developed with data from the Dutch Acute Stroke Study (DUST), was reported by van Seeters and colleagues (van Seeters, 2015). They analyzed an unselected population of 1374 patients with suspected anterior circulation stroke who underwent multimodal CT. Images were evaluated by an observer blinded to all clinical information except for side of stroke symptoms. The analysis used 60% of patients for a prediction model and 40% for a validation cohort. Poor outcome (90 day mRS score 3-6) occurred in 501 (36.5%) patients. Included in the basic prediction model were patient characteristics (age, stroke severity, time from onset to imaging, dependency prior to stroke symptoms, glucose level, whether treatment had been given) and non‒contrast CT measures. CTA and CTP imaging also were predictive of clinical
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Mechanical Embolectomy
Results of the CRISP (CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project) study were published by Lansberg et al (Lansberg, 2017). CRISP was a multicenter cohort study of 190 acute stroke patients who were assessed by CTP prior to endovascular therapy, although the decision to proceed with endovascular therapy (stent retrievers, manual aspiration, intra-arterial thrombolytic agents, and/or angioplasty with or without stenting, depending on the operator’s preference) was not dependent on the CTP results (automated analysis with RAPID software). Patients up to 18 hours after symptom onset were included. Patients with target mismatch (n=131) had higher odds of a favorable clinical response based on the NIHSS (83% vs 44%, p=0.002; adjusted OR=6.6; 95% CI, 2.1 to 20.9).
 
Evaluation for Prognosis
In 2017, DUST investigators evaluated prediction models with NCCT, CTA, or CTP at baseline and day 3 to predict the outcome at 90 days (Dankbaar, 2017). A total of 224 patients from the DUST trial were selected who had anterior circulation occlusion on CTA with an ischemic deficit on CTP at admission and also had follow-up imaging on day 3. An unfavorable outcome (mRS score of 3-6) at 90 days was identified in 44% of the patients. For models that included baseline variables plus one of the 3 imaging modalities at day 3, the area under the receiver operating characteristics curve was 0.85 for NCCT, 0.86 for CTA, and 0.86 for CTP. All 3 models improved prediction compared with no imaging at day 3, but there was no difference between the models. CTP at day 3 was no better than NCCT in predicting the clinical outcome.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
In 2015, AHA and ASA provided a focused update of their 2013 guidelines, which included a review of endovascular treatment of acute ischemic stroke (Powers, 2015). The 2015 guidelines reviewed the trials on stent retrievers. Regarding CTP, the guidelines concluded that “the benefits of additional imaging beyond CT and CTA [computed tomography angiography] or MRI [magnetic resonance imaging] and MRA [magnetic resonance angiography] such as CT perfusion or diffusion- and perfusion-weighted imaging for selecting patients for endovascular therapy are unknown (Class IIb; Level of Evidence C).

CPT/HCPCS:
0042TCerebral perfusion analysis using computed tomography with contrast administration, including post-processing of parametric maps with determination of cerebral blood flow, cerebral blood volume, and mean transit time

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