Medical Policy



Subject: Cerebral Perfusion Imaging Using Computed Tomography
Document #: RAD.00045 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses the use of perfusion-computed tomography for cerebral perfusion imaging. 

Perfusion-computed tomography (CT) was developed to assist in the evaluation of cerebral blood flow.  It provides a detailed study of cerebral blood perfusion, which is intended to identify ischemic brain regions, especially within the first few hours after stroke onset.  In clinical practice, perfusion CT requires the use of a non-diffusible indicator, such as an iodine contrast agent. 

For information regarding cerebral perfusion studies using magnetic resonance imaging (MRI), please refer to

Position Statement

Investigational and Not Medically Necessary:

Cerebral perfusion-computed tomography is considered investigational and not medically necessary for all indications including, but not limited to, the evaluation of cerebral ischemia.

Rationale

Perfusion CT (PCT, CT perfusion) can be performed with a diffusible gas indicator such as xenon (Xe), however in clinical practice an iodinated contrast agent is typically used, given the limited availability of medical grade Xe.  Images are obtained in the cine mode depicting the cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT).  These parameters can be combined to identify the core and penumbra.  One of the appeals of PCT is that the standard imaging of individuals with stroke symptoms is an unenhanced (plain) CT scan in the emergency room to both diagnose acute infarction and exclude intracranial hemorrhage.  Therefore, a PCT can be added to a plain CT scan both to increase the detection of early strokes and to distinguish between the infarcted core and the ischemic penumbra.  When plain CT, PCT and CT angiography are used together, the combined imaging test may be referred to as multimodal CT.  Multimodal CT is designed to demonstrate the infarcted tissue (plain CT or PCT), the site of arterial occlusion (CT angiography) and its hemodynamic consequences (PCT).  Following an occlusion of a major intracerebral artery (i.e. stroke), a gradient of hypoperfusion emerges, characterized as the infarcted core of irreversible damage, surrounded by a region of relative hypoperfusion, known as the "penumbra."  Tissue within the penumbra is functionally impaired, but may be salvagable by effective reperfusion, such as with thrombolytic treatment.  Currently candidates for thrombolytic therapy are primarily identified by the time since symptom onset, with a target window of opportunity of 3 hours, based on randomized trials of tissue plasminogen activator (tPA).  However, it is hypothesized that the subset of individuals with a penumbra persisting beyond 3 hours could still be potentially salvaged with thrombolytic therapy.  Therefore, one potential role of cerebral perfusion CT is its use to distinguish between the infarcted core and the ischemic penumbra and to identify candidates for thrombolytic therapy. 

In 2008, Provenzale and colleagues published a systematic review of both CT and MRI perfusion imaging in the assessment of acute cerebrovascular disease.  The authors identified 8 different roles for this imaging:

  1. Perfusion to guide treatment
  2. Predict clinical outcomes
  3. Predict final infarct size
  4. Determine effects of a therapy on perfusion abnormalities
  5. Characterize infarct types or to better understand infarct-like processes
  6. As a comparison with diffusion weighted imaging, but no outcome measure
  7. Compare perfusion with an imaging technique other than MRI
  8. Solely as an entry criteria (for clinical trials)

For the purposes of this document, studies of clinical utility are the basis of medical necessity, specifically data demonstrating that the results of the test can be used to direct and improve clinical decision making and treatment.  Of the categories listed above, only the first category, perfusion to guide treatment, clearly relates to clinical decision making.  For individuals with symptoms of acute stroke, the key management decisions are related to whether or not the person is a candidate for thrombolytic therapy, based on infarct size, size of penumbra or time from symptom onset.  Studies in category 2 and 3 essentially validate perfusion imaging as a test and provide information that could be used in decision making.  Category 4 included articles that documented the effect of treatment on the perfusion imaging deficits, but this information was not used to guide the clinical management of individuals.  Categories 5 to 7 explore the underlying pathophysiology of acute ischemia.  Category 8 described research studies where results of perfusion imaging defined trial eligibility. 

The authors did not identify any article of CT perfusion that fell into category 1.  In categories 2 and 3, the authors identified 46 articles that used a variety of trial designs and outcomes to explore the predictive value of perfusion imaging.  While the authors concluded that in general the studies showed the perfusion defects are related to clinical outcomes, i.e. the clinical validity, the authors point out that there is still insufficient data to determine how this information can be used in making decisions regarding treatment, i.e. the clinical utility.  

In 2010, researchers initiated a clinical trial assessing "The effect of implementing hyper-acute stroke guidelines on decision-making for or against thrombolytic therapy for stroke in the emergency department" (NCT01050049).  According to the information available on the clinicaltrials.gov website, the objective of this completed study was to determine if use of multimodal CT alters the time to decision making for or against the use of tissue plasminogen activator (tPA), the time to therapy, and time to transfer from the emergency department.  A secondary objective was to determine whether using CT perfusion/CT angiography acute stroke guidelines improves safety by decreasing mortality and symptomatic intracerebral hemorrhage in individuals who receive tPA.  This study was completed as of April 2011, but at the time of this review no additional information regarding the outcomes of this study was identified.

Obach and colleagues (2011) compared the outcomes of 106 individuals with acute stroke who were evaluated with multimodal CT (CT/CT angiography/CT perfusion) to 262 individuals with acute stroke who were assessed without full multimodal brain imaging during a 5-year period.  Clinical and imaging data were prospectively collected and all imaging studies were evaluated by investigators who were blinded to the prognostic data.  The two cohorts were similar at baseline with the exception of a greater percentage of subjects with a time-to-treatment of greater than 3 hours (28% vs. 16%) and a greater percentage treated with endovascular therapy (26% vs. 11%, respectively) in the multimodal CT group.  At 3 months, 56% of subjects assessed by multimodal CT demonstrated good outcomes (defined as a modified Rankin scale score less than or equal to 2 at 90 days) in comparison with 41% of controls (p=0.008).  In a sensitivity analysis, multimodal CT-assisted thrombolysis yielded superior benefits in those participants treated after 3 hours (adjusted odds ratio [OR], 4.48) than for subjects treated within 3 hours (adjusted OR, 1.31).  For individuals treated after 3 hours, 63% of those assessed by multimodal CT exhibited good outcomes in comparison with 24% of the control group.  Symptomatic hemorrhage (5% and 7%) and mortality (14% and 15%, both respectively) were comparable in both groups.  While the authors concluded that the use of multimodal CT in routine clinical practice may improve the overall efficacy of thrombolytic therapy in acute ischemic stroke, they also acknowledged that additional randomized clinical trials are needed to confirm these results. 

Van Seeters and colleagues (2015) investigated the prognostic value of CT angiography and CT perfusion for clinical outcome whether they had additional prognostic value over individual characteristics and non-contrast CT.  The study included a total of 1374 subjects with suspected acute ischemic stroke in the prospective multicenter Dutch acute stroke study.  A portion of the cohort (60%) was used for deriving the predictors and the remaining 40% for validating them.  The authors calculated the predictive values of CT angiography and CT perfusion predictors for poor clinical outcome (modified Rankin Scale score 3-6).  Associations between CT angiography and CT perfusion predictors and poor clinical outcome were assessed with odds ratios (OR). Multivariable logistic regression models were developed based on participant characteristics and non-contrast CT predictors, and subsequently CT angiography and CT perfusion predictors were included.  The increase in area under the curve (AUC) value was used to determine the additional prognostic value of CT angiography and CT perfusion.  Model validation was performed by calculating discrimination and calibration.  Poor outcomes occurred in 501 participants (36.5%).  Every one of the evaluated CT angiography measures strongly predicted outcome in univariable analyses: the positive predictive value (PPV) was 59% for Alberta Stroke Program Early CT Score (ASPECTS) ≤ 7 on CT angiography source images (OR 3.3; 95% confidence interval [CI], 2.3-4.8), 63% for existence of a proximal intracranial occlusion (OR 5.1; 95% CI, 3.7-7.1), 66% for poor leptomeningeal collaterals (OR 4.3; 95% CI, 2.8-6.6), and 58% for a > 70% carotid or vertebrobasilar stenosis/occlusion (OR 3.2; 95% CI, 2.2-4.6).  Similar results were seen with CT perfusion measures, as the PPVs were 65% for ASPECTS ≤ 7 on cerebral blood volume maps (OR 5.1; 95% CI, 3.7-7.2) and 53% for ASPECTS ≤ 7 on mean transit time maps (OR 3.9; 95% CI, 2.9-5.3).  The prognostic model based on subject characteristics and non-contrast CT measures was highly predictive for poor clinical outcome (AUC 0.84; 95% CI, 0.81-0.86).  Including CT angiography and CT perfusion predictors to this model did not increase the predictive value (AUC 0.85; 95% CI, 0.83-0.88).  In the validation group, the AUC values were 0.78 (95% CI, 0.73-0.82) and 0.79 (95% CI, 0.75-0.83), respectively.  Calibration of the models was acceptable.  The authors concluded that in subjects with suspected acute ischemic stroke, admission CT angiography and CT perfusion parameters are solid predictors of poor outcome and may be used to predict long-term clinical outcome.  However, in multivariable prediction models, their additional prognostic value over individual characteristics and non-contrast CT is limited in an unselected stroke population.

Bivard and colleagues (2015) evaluated the effectiveness of CT perfusion imaging by assessing health outcomes in individuals who qualified for tPA based on standard clinical/non‒contrast CT criteria, who were either treated or not treated based on qualitative CT perfusion results, and later had quantitative analysis of CT perfusion data.  Participants selected for tPA based on qualitative analysis of CT perfusion (n=366) had higher odds of an excellent outcome (modified Rankin Scale [mRS] score, 0-1; OR, 1.59; p=0.009) and lower mortality (OR=0.56, p=0.021) than historical controls (n=396) who had been chosen to receive tPA based on clinical/non‒contrast CT information.  In addition, of the participants treated with tPA, those who had target mismatch by CT perfusion had significantly better outcomes than the participants treated with tPA who did not have target mismatch (OR=13.8 for 3-month mRS of ≤ 2).  However, 83 of 269 (31%) of the untreated participants had target mismatch and 56 of 366 (15%) treated participants had a large ischemic core.  The results of this study suggest that CT perfusion has the potential to identify those individuals with acute stroke who are likely and unlikely to respond to thrombolysis.  However, questions remain about whether CT perfusion is reliable enough to select individuals with stroke for treatment.

Schaefer and colleagues (2015) investigated whether threshold computed tomographic cerebral blood flow (CT-CBF) and CT-cerebral blood volume (CT-CBV) maps are sufficiently accurate to substitute for diffusion-weighted imaging (DWI) for estimating the critically ischemic tissue volume.  Ischemic volumes of 55 participants with acute anterior circulation stroke were assessed on DWI by visual segmentation and on CT-CBF and CT-CBV with segmentation using 15% and 30% thresholds, respectively.  The contrast:noise ratios of ischemic regions on the DWI and CT perfusion images were assessed.  Correlation and Bland-Altman analyses were used to determine the reliability of CT perfusion.  The authors found that the poor contrast:noise ratios of CT-CBV and CT-CBF compared with those of DWI result in large measurement error, making it difficult to substitute CT perfusion for DWI when selecting individual acute stroke subjects for treatment.  The authors concluded that CT perfusion could be used for treatment studies of patient groups, but the number of individuals needed to identify a significant effect is much higher than the number needed if DWI is used.

Van Seeter and colleagues (2016) explored whether baseline CT angiography and CT perfusion in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging.  The researchers analyzed 906 participants with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST).  All study participants underwent baseline non-contrast CT, CT angiography, CT perfusions and follow-up non-contrast CT/MRI after 3 days.  Multivariable regression models were developed including individual characteristics, non-contrast CT, CT angiography and CT perfusion measures.  The increase in AUC and R2 was assessed to determine the additional value of CTA and CT perfusion.  At follow-up, 612 participants (67.5 %) demonstrated a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8-69.6).  Regarding infarct existence, the AUC of 0.82 (95 % CI, 0.79-0.85) for individual characteristics and non-contrast CT was improved with addition of CT angiography measures (AUC 0.85 [95 % CI, 0.82-0.87]; p<0.001) and was even higher after addition of CT perfusion measures (AUC 0.89 [95 % CI, 0.87-0.91]; p<0.001) and combined CTA/CT perfusion measures (AUC 0.89 [95 % CI, 0.87-0.91]; p<0.001).  For infarct volume, including combined CT angiography/CT perfusion measures (R (2)=0.58) was superior to participant characteristics and non-contrast CT alone (R (2)=0.44) and to addition of CT angiography alone (R (2)=0.55) or CT perfusion alone (R (2)=0.54; all p<0.001).  The authors concluded that during the acute stage, CT angiography and CT perfusion have additional value over participant characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging.

The Agency for Healthcare Research and Quality (AHRQ) published an Evidence Report/Technology Assessment on Acute Stroke: Evaluation and Treatment in 2005 which addressed multiple issues regarding CT perfusion and angiography, in terms of how these modalities affect the safety and efficacy of thrombolytic therapy for acute ischemic stroke.  The AHRQ Report stated that, "Prospective use of CT perfusion and angiography techniques in patient selection for thrombolysis was not identified" (AHRQ, 2005).

In 2013, the American Heart Association published clinical guidelines for the early management of adults with ischemic stroke (Jauch, 2013).  These guidelines downgraded the evidence rating for perfusion CT from Class IA to a Class IIb recommendation and state the following:

CT perfusion and MRI perfusion and diffusion imaging, including measures of infarct core and penumbra, may be considered for the selection of patients for acute reperfusion therapy beyond the time windows for intravenous fibrinolysis.  These techniques provide additional information that may improve diagnosis, mechanism, and severity of ischemic stroke and allow more informed clinical decision making.  

However despite this recommendation the text of the guidelines notes, "A current technical challenge is that methods for processing of perfusion data to derive perfusion parameters vary, and the most biologically salient perfusion parameters and thresholds for acute decision making have not been fully defined."  Published studies have used various hemodynamic parameters (cerebral blood flow, cerebral blood volume and mean transit time), different thresholds for determining hemodynamic abnormality (absolute versus relative threshold and degree of reduction in cerebral blood volume), and different thresholds for the amount of penumbral tissue that warrants treatment.

Background/Overview

Both perfusion CT and perfusion/diffusion MRI (discussed in RAD.00046) are imaging techniques that have been investigated to provide more detailed diagnostic and prognostic information related to acute and chronic cerebral ischemia, primarily related to stroke.  For example, plain computed tomography (i.e. without contrast) is highly sensitive in the detection of acute intracranial hemorrhage, but is much less sensitive in the identification of ischemic brain lesions within the first few hours of stroke onset.  Chronic, progressive, occlusive disease and ischemia from vasospasm are also conditions that have been difficult to diagnose with current imaging techniques.

Definitions

Cerebral (Ischemic) Infarction: An area of coagulation necrosis in brain tissue, (i.e., tissue death), due to local anemia resulting from obstruction of the circulation to the area.

Modified Rankin Scale: A scale used to measure the degree of dependence or disability in the daily activities of individuals who have suffered a stroke. The scale ranges from 0 (no symptoms, perfect health) to 6 (death).

Perfusion-computed tomography: This newer imaging technique uses either a diffusible inert gas indicator, (i.e., xenon/Xe) or a non-diffusible indicator, (such as iodine) to measure cerebral blood flow (CBF), as well as other measures, such as mean transit time (of cerebral blood through the cerebral arteries and vascular bed) and cerebral blood volume; the ability to measure these perfusion parameters has been made possible with the development of high-speed helical/spiral CT scanners.

Stroke: A generic term used to represent any one or all of a group of disorders, including cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage; stroke is characterized by a non-convulsive, focal, neurologic deficit that lasts greater than 24 hours in duration.

Subarachnoid Hemorrhage: Bleeding into the subarachnoid space, characterized by the sudden onset of severe headache that is typically dramatic; there may also be rapid alteration of consciousness, or vomiting, or both; other symptoms include minimal headache, nuchal rigidity (stiff neck), fixed neurologic deficits, cranial nerve palsy, drowsiness, confusion, stupor, or coma.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary:

CPT  
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
   
ICD-10 Diagnosis  
  All diagnoses
   
References

Peer Reviewed Publications:

  1. Bivard A, Levi C, Krishnamurthy V, et al. Perfusion computed tomography to assist decision making for stroke thrombolysis. Brain. 2015; 138(Pt 7):1919-1931.
  2. Goyal M, Demchuk AM, Menon BK et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015; 372(11):1019-1030.
  3. Hoeffner EG, Case I, Jain R, et al. Cerebral perfusion CT: technique and clinical applications. Radiology. 2004; 231(3):632-644.
  4. Kloska SP, Nabavi DG, Gaus C, et al. Acute stroke assessment with CT: Do we need multimodal evaluation.  Radiol. 2004; 233(1):79-86.
  5. Koenig M, Kraus M, Theek C, et al. Quantitative assessment of the ischemic brain by means of perfusion-related parameters derived from perfusion CT. Stroke. 2001; 32(2):431-437.
  6. Lev MH. Perfusion imaging of acute stroke: its role in current and future clinical practice. Radiology. 2013; 266(1):22-27.
  7. Moustafa RR, Baron JC. Clinical review: imaging in ischaemic stroke – implications for acute management.  Crit Care. 2007; 11(5):227-236.
  8. Obach V, Oleaga L, Urra X et al. Multimodal CT-assisted thrombolysis in patients with acute stroke: a cohort study. Stroke. 2011; 42(4):1129-1131.
  9. Provenzale JM, Shah K, Patel U, McCrory DC. Systematic review of CT and MR perfusion imaging for assessment of acute cerebrovascular disease. AJNR Am J Neuroradiol. 2008; 29(8):1476-1482.
  10. Schaefer PW, Souza L, Kamalian S, et al. Limited reliability of computed tomographic perfusion acute infarct volume measurements compared with diffusion-weighted imaging in anterior circulation stroke. Stroke. 2015; 46(2):419-424.
  11. Schellinger PD, Fiebach JB, Hacke W. Imaging-based decision making in thrombolytic therapy for ischemic stroke: present status. Stroke. 2003; 34(2):575-583.
  12. Schramm P, Schelllinger PD, Klotz E, et al. Comparison of perfusion computed tomography and computed tomography angiography source images with perfusion-weighted imaging and diffusion-weighted imaging in patients with acute stroke of less than 6 hours' duration. Stroke. 2004; 35(7):1652-1658.
  13. Touho H, Karasawa J. Evaluation of time-dependent thresholds of cerebral blood flow and transit time during the acute stage of cerebral embolism: a retrospective study. Surg Neurol. 1996; 46(2):135-145.
  14. van Seeters T, Biessels GJ, Kappelle LJ, et al. CT angiography and CT perfusion improve prediction of infarct volume in patients with anterior circulation stroke. Neuroradiology. 2016; 58(4):327-337.  
  15. van Seeters T Biessels GJ, Kappelle LJ, et al. The prognostic value of CT angiography and CT perfusion in acute ischemic stroke. Cerebrovasc Dis. 2015; 40(5-6):258-269.
  16. Wintermark M, Flanders AE, Velthuis B, et al. Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric stroke. Stroke. 2006; 37(4):979-985.
  17. Wintermark M, Reichhart M, Thiran JP, et al. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol. 2002; 51(4):417-432.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke. 2007; 38(5):1655-1711.
  2. Agency for Healthcare Research and Quality. Acute stroke: evaluation and treatment. Health Technology Evidence Reports (Summary). 2005; (127):1-7. 
  3. American College of Radiology. (2014). ACR-ASNR-SPR Practice parameter for the performance of computed tomography (CT) perfusion in neuroradiologic imaging. Available at: http://www.acr.org/~/media/ACR/Documents/PGTS/guidelines/CT_Perfusion.pdf. Accessed on June 27, 2017.
  4. American College of Radiology. (2015). ACR-ASNR-SPR Practice parameter for the performance of computed tomography (CT) of the brain. Available at: http://www.acr.org/~/media/1C1F7C7A570D469A9C411D95067BDF94.pdf. Accessed on June 27, 2017.
  5. Centers for Medicare and Medicaid Services. National Coverage Determination: Computerized Tomography. NCD #220.1. Effective November 22, 1985. Available at: http://www.cms.hhs.gov. Accessed on June 27, 2017.
  6. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013; 44(3):870-947.
Index

Cerebral Perfusion Computed Tomography

Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale, References and History sections.
Reviewed 08/04/2016 MPTAC review. Updated review date, Rationale, References and History sections. Removed ICD-9 codes from Coding section.
Reviewed 08/06/2015 MPTAC review. Updated review date, References and History sections.
Reviewed 08/14/2014 MPTAC review. Updated review date, Description/Scope, References and History sections.
Reviewed 08/08/2013 MPTAC review. Updated review date, Rationale, References and History sections.
Reviewed 08/09/2012 MPTAC review. Updated review date, Definitions, References and History sections.
Reviewed 08/18/2011 MPTAC review. Updated review date, References and History sections.
Reviewed 08/19/2010 MPTAC review. Updated review date, references and history sections.
Reviewed 08/27/2009 MPTAC review. Updated review date, rationale, background/overview, references and history sections.
Reviewed 08/28/2008 MPTAC review. Updated review date, references and history sections.
  02/21/2008 The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 08/23/2007 MPTAC review. Updated review date, description, references and history sections of document.
Reviewed 09/14/2006 MPTAC review. No change to position statement.  References were updated including the 2005 AHRQ Evidence Report on Acute Stroke.
  11/17/2005 Added reference for Centers for Medicare and Medicaid Services (CMS) – National Coverage Determination (NCD).
Revised 09/22/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization. 
     
Pre-Merger Organizations

Last Review Date

Document Number

Title

Anthem, Inc.

 

  No prior document
WellPoint Health Networks, Inc.

06/24/2004

4.03.05 Cerebral Perfusion Imaging Using Computed Tomography