C H P

CIGNA HEALTHCARE COVERAGE POSITION
Subject Cerebral Perfusion Analysis
Using Computed Tomography
Table of Contents
Coverage Position............................................... 1
General Background ........................................... 1
Coding/Billing Information ................................. 13
References ........................................................ 14
Revised Date ............................. 2/15/2008
Original Effective Date ............. 2/15/2006
Coverage Position Number ............. 0442
Hyperlink to Related Coverage Positions
Computed Tomography Angiography (CTA)
Magnetic Resonance Angiography (MRA)
Nuclear Imaging including Single-Photon
Emission Computed Tomography
(SPECT)
Positron Emission Tomography (PET)
Transcranial Doppler (TCD)
Ultrasonography
INSTRUCTIONS FOR USE
Coverage Positions are intended to supplement certain standard CIGNA HealthCare benefit plans. Please note, the terms of a
participant’s particular benefit plan document [Group Service Agreement (GSA), Evidence of Coverage, Certificate of Coverage,
Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which
these Coverage Positions are based. For example, a participant’s benefit plan document may contain a specific exclusion related to
a topic addressed in a Coverage Position. In the event of a conflict, a participant’s benefit plan document always supercedes the
information in the Coverage Positions. In the absence of a controlling federal or state coverage mandate, benefits are ultimately
determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require
consideration of 1) the terms of the applicable group benefit plan document in effect on the date of service; 2) any applicable
laws/regulations; 3) any relevant collateral source materials including Coverage Positions and; 4) the specific facts of the particular
situation. Coverage Positions relate exclusively to the administration of health benefit plans. Coverage Positions are not
recommendations for treatment and should never be used as treatment guidelines. Proprietary information of CIGNA. Copyright
©2008 CIGNA
Coverage Position
CIGNA HealthCare covers cerebral perfusion analysis using computed tomography (CT) as
medically necessary for the emergent evaluation of suspected acute stroke when thrombolytic
therapy is being considered.
CIGNA HealthCare does not cover cerebral perfusion analysis using CT for any other indications
because they are considered experimental, investigational or unproven.
General Background
Stroke is the third most frequent cause of death in the U.S. after cardiovascular diseases and cancers.
In Western societies, about 80% of strokes are caused by focal cerebral ischemia due to arterial
occlusion, and the remaining 20% are caused by hemorrhages (Feigin, et al., 2003; van der Worp, et al.,
2007). “Cerebral infarction cannot be distinguished with certainty from intracerebral hemorrhage on the
basis of symptoms and signs alone. In all patients with suspected ischemic stroke, computed tomography
(CT) or magnetic resonance imaging (MRI) of the brain is therefore required. Noncontrast CT may suffice;
as compared with MRI, it is more widely available, faster, less susceptible to motion artifacts, and less
expensive” (Chalela, et al., 2007; van der Worp, et al., 2007). The American Heart Association (AHA)/
American Stroke Association (ASA) states that “it is agreed that emergency, non–contrast-enhanced CT
scanning of the brain accurately identifies most cases of intracranial hemorrhage and helps discriminate
Page 1 of 18
Coverage Position Number: 0442
nonvascular causes of neurological symptoms (e.g., brain tumor).” The AHA/ASA also notes that
“information about multimodal CT and MRI of the brain suggests that these diagnostic studies may help in
the diagnosis and treatment of patients with acute stroke (Adams, et al., 2007).
The National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator
(NINDS rt-PA) Stroke Study demonstrated the efficacy of treatment with intravenous rt-PA (alteplase)
started within three hours after the onset of symptoms. A pooled analysis of six randomized trials has
suggested a potential benefit within up to six hours after the onset of stroke (Hacke, et al., 2004; van der
Worp, et al., 2007). The use of thrombolysis for ischemic stroke in the United States from 1999 to 2004
was infrequent (used in 1.12% of ischemic stroke hospitalizations) and showed significant differences,
depending on hospital and patient demographic characteristics (Schumacher, et al., 2007).
Perfusion CT
Perfusion CT (i.e., CT perfusion) is proposed for use in emergency department stroke and head trauma
patients (Wintermark, et al., 2005b). Perfusion CT imaging tracks transient attenuation changes in the
blood vessels and brain parenchyma during the first pass passage of an intravenously injected contrast
medium. Maps of cerebral blood volume (CBV), mean transit time (MTT), and cerebral blood flow (CBF)
can be obtained from a pixel-by-pixel analysis of the density changes over time. The maps generated
depend on the algorithm used in the processing of the perfusion CT data (Grainger, 2001). Even in an
acute ischemic stroke, CBV can be either increased, normal, or decreased, depending on the severity of
hypoperfusion and collateral flow. Thus, the perfusion CT technique was expanded to assess the whole
dynamics of a contrast-agent transit curve (i.e., dynamic perfusion CT).
Analysis software is commercially available, and algorithms have been developed to actually quantify flow
in cerebral tissue. Dynamic perfusion CT is a technique for measuring brain hemodynamics that uses
first-pass tracer methodology after bolus infusion of intravenous iodinated contrast material. Typically,
continuous cine scanning is performed during a total scanning time of 40–45 seconds, with a scan rate of
one image per second. The bolus, typically 40–50 cc of 300–370 mg/dL iodinated contrast material, is
administered via an arm vein (Eastwood, et al., 2003a; Wintermark, et al., 2005b). Low milliamperes (100
to 150 mA) or kilovolt protocols (80–90 kilovolt peaks) are typically used for perfusion CT studies to limit
dose. Iodinated contrast should not be used in patients with renal failure or diabetes mellitus. Ideally,
images of CBF, CBV, and MTT are interpreted together on a workstation permitting the use of visual
assessment combined with quantitative analysis with regions of interest (ROIs) (Wintermark, et al.,
2005b). The linear relationship between CT numbers or Hounsfield units (HU) and the amount of
iodinated contrast material in an image pixel, together with the high spatial and temporal resolution
characteristics of the scanning paradigm, make perfusion CT “a valuable tool for evaluating blood supply
to neoplastic and non-neoplastic tissue (including normal and ischemic tissue). In particular, the
evaluation of cerebral ischemia or the angiogenesis state of a tumor is readily performed with perfusion
CT imaging” (American College of Radiology [ACR], 2007).
There are two major classes of perfusion techniques: those that utilize a diffusible tracer and those that
rely on a nondiffusible agent. The physiological principles underlying these two classes of techniques and
the mathematical models used to attempt quantification of their data are different. A diffusible tracer
technique will pass the blood-brain barrier and pass into the cerebral parenchyma (e.g., xenon-enhanced
CT, single photon emission computed tomography [SPECT]). Xenon-enhanced CT provides a
quantitative measurement of CBF by employing inhaled xenon. The nondiffusible tracer technique uses
an agent that remains within the vasculature (e.g., perfusion CT, perfusion and diffusion MRI). Among the
many perfusion imaging techniques, perfusion-weighted MRI (PWI) and perfusion CT are the two most
frequently used in clinical practice. Perfusion CT can be performed rapidly and has the potential for wide
availability, whereas PWI is a more time-consuming procedure and less readily available (Hoeffner,
2005).
There are three perfusion CT approaches that use different data acquisition and analysis methods:
• Whole brain CT perfused blood volume—Whole brain CT perfused blood volume is assessed by
acquiring a helical scan through the whole brain with and without contrast.
• First pass perfusion CT—A first pass or bolus tracking CT perfusion study is performed by
acquiring repeated images at the same location (a cine scan) through a volume of interest during
bolus injection and passage of contrast through the region of interest.
Page 2 of 18
Coverage Position Number: 0442
•
Dynamic perfusion CT—Acquiring a temporal set of images through an extended volume of
interest during a bolus injection of contrast constitutes a dynamic perfusion CT study. In this
context, the extended volume of interest refers to imaging of tissue beyond the absolute width of
the detector array (ACR, 2007).
Limitations: Numerous concerns have been raised regarding the proposed use of perfusion CT. In a
review article, Hoeffner et al. (2004) states that “although quantitative values may be acquired with
perfusion CT, the accuracy of the flow values obtained has not been fully validated. It has not been
determined if normal and disease thresholds as measured with positron emission tomography (PET) or
xenon CT can be applied in perfusion CT. Further studies comparing perfusion CT with more established
methods of measuring cerebral perfusion are needed to fully validate the quantitative value of this
technique. Uncertainties also exist regarding how the quantitative values should be calculated. The
reproducibility of perfusion CT has also not been fully validated. Another limitation of perfusion CT is its
restricted anatomic coverage. Further investigations are necessary to determine the accuracy, reliability,
and reproducibility of the quantitative results.” In a review article, Gomori and Cohen (2005) state that “CT
perfusion techniques suffer from limited brain coverage of present multislice scanners. MRI offers whole
brain coverage, but suffers from less availability and higher cost than CT. Both suffer from limited
absolute quantitative accuracy. Presently, development is directed towards increasing the quantitative
accuracy of cerebral perfusion imaging and validation of surrogate parameters, such as time to peak
(TTP). In the future, the need for rapid and frequent assessment of cerebral perfusion and its metabolic
correlates, with minimal or no radiation, will probably be met by MRI.” Wintermark et al. (2005b) state that
“perfusion CT has a limited spatial coverage (20–48 mm thickness); however, the issue of spatial
coverage will be addressed in the near future through the development of multislice CT scanners with
greater arrays of elements.”
U.S. Food and Drug Administration (FDA)
Perfusion CT post-processing software packages are FDA approved as Class II devices. They are
“accessory to computed tomography system” devices.
Literature Review: Acute Stroke
Comparison with follow-up non-contrast CT: Murphy et al. (2006) used perfusion CT to differentiate
between penumbra and infarcted gray matter in stroke patients, compared to nonenhanced (i.e., noncontrast) follow-up CT images. A total of 25 patients who presented to the ER within seven hours of acute
stroke with signs and symptoms of middle cerebral artery occlusion, underwent a non-contrast CT, CT
angiography (CTA), and perfusion CT. Also, patients underwent non-contrast CT and CTA at 24 hours,
and non-contrast CT at five to seven days. The patients were subsequently divided into two groups: those
with recanalization at 24 hours (n=16) and those without (n=9). Penumbral regions were characterized by
a mismatch between CBF and CBV, whereas infarcted areas showed a matched decrease in both
parameters. Logistic regression analysis identified the interaction term between CBF and CBV
(CBFXCBV) as best predictor for differentiating between penumbra and infarct data points, significantly
better than CBF or CBV thresholds alone, suggesting that the CBV threshold for infarction varies with
CBF. Lack of recanalization resulted in infarct of entire ischemic area, suggesting that the CBF threshold
for defining tissue that would progress to infarction was appropriate in this study. The authors stated that
“defining the penumbra and infarct using CBF and CBV values from perfusion CT could help in selecting
patients for thrombolytic therapy within and possibly outside the current 3–6 hour treatment window,
where it has been shown that penumbra may persist for > 12 hours.” The authors concluded that this
study “provides preliminary evidence that CBF and CBV derived from an admission perfusion CT can
identify infarct from penumbral tissue with sensitivity (97.0%), and specificity (97.2%). This technique
needs to be tested in a larger, randomized, prospective trial to examine its efficacy and whether it could
be used to guide treatment decisions and possibly improve clinical outcome.”
Maruya et al. (2005) evaluated the effectiveness of simultaneous assessment of perfusion CT and CTA in
patients with acute ischemic stroke. Perfusion CT and CTA were performed simultaneously in a series of
31 consecutive acute ischemic stroke patients. Patients were included if within 48 hours after the onset of
acute stroke symptoms. The final ischemic lesions were assessed with follow-up conventional CT or MRI,
and the final cerebral vascular status was assessed with MR angiography or digital subtraction
angiography (DSA). Simultaneous assessment of perfusion CT and CT angiography has an excellent
Page 3 of 18
Coverage Position Number: 0442
sensitivity and specificity in the diagnosis of large territorial ischemic stroke; whereas sensitivity of
nonterritorial lacunar infarcts or small subcortical infarcts was 47.4%. The authors concluded that
“perfusion CT and CT angiography could clearly demonstrate the extent and the location of ischemia in
almost all of the territorial infarct, and some of the lacunar infarcts. The information was very helpful for
treatment planning, and follow-up perfusion CT and CT angiography could evaluate the therapeutic
response. Perfusion CT and CT angiography are safe imaging techniques to evaluate cerebral ischemia,
and can easily be performed in an emergency department equipped with a multi-detector CT scanner.”
The authors noted that perfusion CT has three limitations which require careful consideration in clinical
use. First, the anatomical coverage of data acquisition is limited. Second, methodologies of data
acquisition and kinetic analyses in perfusion CT differ from established perfusion studies like PET or
Xenon CT. Third, the choice of reference artery might strongly influence the final perfusion parameter
maps, and various pitfalls, such as the error introduced by inadvertent inclusion of vascular structures.
In 2005a, Wintermark and colleagues studied the accuracy of perfusion CT in detecting acute
hemispheric stroke in 46 patients with symptoms of 12 hours' duration or less. Compared with noncontrast CT, perfusion CT was significantly more accurate in detecting stroke, MTT maps were
significantly more sensitive, and relative CBF and CBV maps were significantly more specific. Regarding
stroke extent, perfusion CT maps were significantly more sensitive than non-contrast CT. For the
computerized map, sensitivity, specificity, and accuracy, respectively, were 68.2%, 92.3%, and 88.1% in
detecting ischemia, and 72.2%, 91.8%, and 87.9% in showing the extent. The authors concluded that
dynamic perfusion CT maps are more accurate than non-contrast CT in detecting hemispheric strokes.
They stated that perfusion CT is highly reliable to assess the stroke extent, despite limited spatial
coverage. The authors noted that they did not directly compare the performances of perfusion CT and
diffusion-weighted MRI (DWI) in the early detection of brain ischemia.
Koenig et al. (2001) conducted a trial to determine whether measurements of the relative cerebral blow
flow (rCBF), relative cerebral blood volume (rCBV), and relative time to peak (rTTP) can be used to
differentiate areas undergoing infarction from reversible ischemic tissue in 34 patients with acute
hemispheric ischemic stroke < six hours after onset. The authors compared the perfusion impairment
shown on the rCBF, rCBV, and rTTP maps with the findings on follow-up CT or MRI studies. The authors
stated that, within a certain time window, patients suffering from symptoms of acute stroke may be
candidates for thrombolytic therapy if further criteria of an adequate selection are fulfilled. The authors
concluded that “the ischemic brain by means of perfusion CT may play an increasing role for the selection
of a subset of patients who may be successfully treated with potentially harmful therapeutic regimens
such as thrombolysis.” The authors noted that “for different states of hypoperfusion, the results of CBV
measurements may strongly depend on the algorithm used, making a comparison of the data obtained
with different techniques a challenge.”
MRI/Comparison with MRI: Wintermark et al. (2007) reviewed the records of 42 patients with suspected
acute stroke who were admitted within three to nine hours following symptom onset. CT studies
(noncontrast CT [NCT], perfusion CT, CTA and contrast-enhanced cerebral CT) were obtained 4.4 ± 1.3
hours (range: 2.5 to 8.0 hours) after symptom onset; MRI studies (fluid-attenuated inversion recovery,
DWI, PWI, and time-of-flight MRA) were obtained 0.8 ± 0.4 hour (range: 0.5 to 1.5 hours) after the CT
study. Imaging criteria assessed included infarct core < 1/3 middle cerebral artery (MCA) territory,
penumbra exceeding infarct core by ≥ 20%, cortical involvement by ischemia and absence of internal
carotid occlusion on side of ischemia. Two reviewers’ evaluation of the criteria, as well as the final
hypothetic treatment decision based on the criteria, were compared using χ2 and κ statistics to
characterize CT and MRI agreement (α=0.00 to 0.20: poor; 0.21 to 0.40: fair; 0.41 to 0.60: moderate; 0.61
to 0.80: substantial; 0.81 to 1.00: excellent). Compared to MRI, there were two cases where perfusion CT
visual evaluation overestimated the infarct core size, two cases where perfusion CT visual evaluation
overestimated the penumbra/infarct core ratio, and two cases where perfusion CT underestimated the
penumbra/infarct core ratio. There was one case of disagreement between MRI and CT. Perfusion CT
visual evaluation indicated the penumbra/infarct ratio to be less than 20%, whereas MRI found it to be
more than 20%. Quantitative perfusion CT demonstrated the penumbra/infarct core ratio in this case to be
23%. Kappa values were as follows: infarct core < 1/3 MCA territory, κ = 0.89; penumbra exceeding
infarct core by ≥ 20%, κ = 0.79; cortical involvement by ischemia, κ = 0.95; absence of internal carotid
occlusion on side of ischemia, κ = 1.00; and treatment decision, κ = 0.95. The authors stated that the
correlation between perfusion CT/CTA and MRI was excellent for the infarct size, cortical involvement,
Page 4 of 18
Coverage Position Number: 0442
and arterial occlusion site and substantial for the penumbra/infarct ratio. The authors also stated that
correlation between CT and MRI for a final hypothetical treatment decision was excellent. The authors
noted study limitations with respect to the number of patients studied and that there was no quantitative
analysis performed for MRI, citing no commercially available software.
Parsons et al. (2007) prospectively evaluated 40 patients within six hours of symptom onset to: 1)
correlate regional early ischemic change with regional quantitative CT perfusion values, and 2) compare
the rates of progression to infarction for these regions, based on presence and type of early ischemic
change (EIC) and quantitative perfusion CT values. Patients underwent non-contrast CT/perfusion
CT/CTA at baseline and follow-up (day three) MRI unless there were contraindications to MRI, in which
case NCCT/CTA was performed. Reperfusion and presence of infarction were determined from follow-up
MRI. Nineteen patients received open-label thrombolytic therapy with standard dose IV rt-PA. Of the 202
regions acutely hypoperfused on perfusion CT, 123 were normal on NCCT, 58 had parenchymal
hypoattenuation (PH), and 21 had isolated focal swelling (IFS). Acute CBV was low in PH regions, and
elevated in IFS regions. Acute CBF was reduced in IFS regions, but more so in PH regions. Progression
to infarction occurred in virtually all PH regions, but IFS regions had much lower rates of infarction with
major reperfusion. The authors stated that they “have demonstrated that the pathophysiology of IFS is
markedly different from PH. Regions with PH have substantially reduced CBV and CBF, and are
irreversibly injured. Regions with IFS have reduced CBF but elevated CBV, and are potentially
salvageable from infarction with major reperfusion, indicating penumbral tissue. However, the majority of
acutely hypoperfused regions appear normal on NCCT. Normal appearing regions on NCCT when
assessed with perfusion CT may be irreversibly ischemic (reduced CBV), or be hypoperfused and at risk
of progression to infarction (normal or increased CBV), or not hypoperfused at all. For this reason,
perfusion CT provides improved predictive accuracy over NCCT alone.” The authors noted that the
quantitative perfusion CT assessment “allowed stratification of the risk of infarction from almost certain
(hypoperfused with reduced CBV) to zero (no hypoperfusion). In between these extremes, there is tissue
at risk of progression to infarction, and the level of risk depends both on CBV level and whether
subsequent major reperfusion occurs.”
The primary hypothesis of the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke
Evolution (DEFUSE) study was that patients with a diffusion/perfusion mismatch per MRI would have a
more favorable clinical response after early reperfusion compared with nonmismatch patients (Albers, et
al., 2006). An MRI perfusion/diffusion mismatch has been proposed as a surrogate for the ischemic
penumbra, and patients with a mismatch are hypothesized to be more likely to benefit from early
reperfusion than patients with other MRI patterns. In this prospective multicenter study, Albers et al.
(2006) administered intravenous tPA to 74 patients with National Institutes of Health Stroke Scale
(NIHSS) score greater than five, and who could be treated with tPA within three to six hours after
symptoms onset. The patients underwent MRI of the brain after their baseline CT scan. Regardless of the
MRI results, patients were treated with intravenous tPA as quickly as possible after their initial MRI scan
and no later than six hours from the onset of their stroke symptoms. Baseline MRI profiles were used to
categorize patients into subgroups, and clinical responses were compared based on whether early
reperfusion was achieved. The baseline MRI and first follow-up MRI scans included the following
sequences: diffusion-weighted imaging (DWI), dynamic susceptibility PWI after a bolus of intravenous
gadolinium, three-dimensional time-of-flight magnetic resonance angiography (MRA) of the intracranial
circulation, conventional T1, and gradient-recalled echo imaging, all with a 1.5T scanner. Study results
demonstrated that for the entire patient population, the association between early reperfusion and
desirable clinical outcomes was modest and not statistically significant. However, for patients with the
Mismatch profile (odds ratio, 5.4; p=0.039), especially the Target Mismatch profile (odds ratio, 8.7;
p=0.011), there was a strong and highly significant association between early reperfusion and favorable
clinical outcomes. The authors concluded that MRI findings appear to differentiate patient subgroups that
will benefit from therapies that lead to early reperfusion from those who are unlikely to benefit or may be
harmed.
Tan et al. (2007) reviewed the records of 113 patients with suspected acute stroke who underwent
noncontrast CT (NCT), perfusion CT, CTA and contrast-enhanced cerebral CT on admission. The
patient’s symptoms were of 48 hours in duration or less since first observed. Follow-up MRI/MRA (67
patients) or CT/CTA (46 patients) were used as the gold standard. Follow-up imaging was obtained a
median of four days after initial imaging, with a range of three days to six months. Results demonstrated
Page 5 of 18
Coverage Position Number: 0442
include sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and
accuracy as follows: non-contrast CT sensitivity 52.9%, specificity 95.3%, PPV 85.7%, NPV 79.2%, and
accuracy 80.6%; perfusion CT sensitivity 88.2%, specificity 95.3%, PPV 90.9%, NPV 93.9%, and
accuracy 92.9%; CTA maximum intensity projections (MIPs) sensitivity 91.4%, specificity 98.4%, PPV
97.0%, NPV 95.4% and accuracy 95.9%; and CTA source images sensitivity 94.6%, specificity 100.0%,
PPV 100.0%, NPV 96.8%, and accuracy 98.0%. The authors conclude that “the most accurate
assessment of the site of occlusion, infarct core, salvageable brain tissue, and collateral circulation
in patients suspected of having acute stroke is a combination of different CT modalities, involving
perfusion CT, CTA source images, and CTA MIPs. Perfusion CT and CTA MIPs offer complementary
information. Perfusion CT-derived salvageable brain tissue is the best predictor of the final infarct
volume in stroke patients with persistent occlusion, whereas CTA MIPs are a predictor of the final
infarct volume both in patients with persistent arterial occlusion and in patients with recanalization;
patients with poor collateral circulation at baseline are prone to further growth of their infarcts before
recanalization, because irreversible changes occur early; and patients with rich collateral circulation will
have smaller infarcts, even in a setting of persistent occlusion. Further studies are necessary to validate
these findings prospectively.”
Wintermark et al. (2006a) evaluated 130 patients with suspected acute stroke to identify which one of the
commonly used simple perfusion CT models most accurately predicts infarct and penumbra. Patients with
symptoms lasting 12 hours or less underwent a non-contrast CT of the brain, followed by perfusion CT,
cervical and intracranial CT angiography (CTA), a post-contrast CT of the brain and optional admission
diffusion-weighted MRI (DWI), and a mandatory follow-up DWI. Based on the admission CTA and followup MRA findings, and on the optional admission MRI, patients were distributed into four groups. Perfusion
CT maps were assessed for absolute and relative reduced CBV, reduced cerebral blood flow, increased
MTT, and increased time-to-peak. Receiver-operating characteristic curve analysis was performed to
determine the most accurate perfusion CT parameter, and the optimal threshold for each parameter,
using DWI as the gold standard. The authors stated their results demonstrated “the optimal approach to
define the infarct core and the penumbra is a combined approach using two distinct perfusion CT
-1
parameters. The absolute CBV, with a threshold at 2.0 ml X100 g , is the parameter allowing the most
accurate delineation of the acute infarct core. The mismatch between the absolute CBV, with a threshold
at 2.0 ml X100 g-1, and the relative MTT, with a threshold at 145%, affords the most accurate delineation
of the tissue at risk of infarction in the absence of recanalization.” The authors noted that a general
comparison of admission perfusion CT and follow-up DWI studies on all patients was not performed
because of the large variation in time interval between the two examinations. Also, the patients differed
with respect to recanalization and type of infarction. The authors also noted their approach used one
single absolute CBV threshold to define the infarct core.
Wintermark et al. (2002b) studied the prognostic accuracy of perfusion CT performed at the time of
emergency room admission in 22 acute stroke patients. Accuracy was determined by comparison of
perfusion CT with delayed MR and by monitoring the evolution of each patient's clinical condition.
Thrombolysis was begun at a median of three hours after stroke onset. The authors concluded that
“perfusion CT allowed the accurate prediction of the final infarct size and the evaluation of clinical
prognosis for acute stroke patients at the time of emergency evaluation.” They stated that perfusion CT
“may also provide information about the extent of the penumbra and therefore may be a valuable tool in
the early management of acute stroke patients.” The authors noted that examined cerebral slices were
not the same in the perfusion CT and MRI.
Wintermark et al. (2002a) compared quantitative perfusion CT and qualitative diffusion- and perfusionweighted MRI (DWI and PWI) DWI and PWI in 13 acute stroke patients at the time of their emergency
evaluation. Imaging was performed ≤ 3 hours after symptom onset. The authors stated that an imaging
technique may be helpful in the identification of cerebral penumbra in acute stroke patients and thus in
the selection of patients for thrombolytic therapy. They concluded that perfusion CT and DWI/PWI are
equivalent in this task.
A comparative study measured the degree of correlation between abnormalities seen on perfusion CT
scans and the volumes of abnormality seen on whole brain DWI and PWI in 14 patients with acute
hemispheric stroke symptoms less than 12 hours in duration (Eastwood, et al., 2003b). The authors
Page 6 of 18
Coverage Position Number: 0442
concluded that there was good correlation seen between CT and MR for CBF and MTT abnormalities.
The authors noted this study was limited to a population of patients with proximal large-vessel (ICA and
MCA) occlusion. It remains uncertain whether a study of a heterogeneous group of patients with smallvessel strokes or distal emboli would show similar correlation between CT and MR.
Multimodal CT Evaluation (i.e., Combined CT Imaging): Lev et al. (2001) states that whole brain
perfusion CT helps to predict final infarct volume and clinical outcome in patients presenting with
angiographically proven acute MCA embolic stroke. Lev et al. retrospectively reviewed 22 consecutive
patients who presented within six hours of onset of signs and symptoms suggesting proximal MCA
occlusion. The patients underwent noncontrast head CT scanning (NCCT), followed immediately by CTA
of the circle of Willis and skull base vessels with concurrent perfusion CT imaging. All eligible patients
underwent intra-arterial thrombolytic treatment per clinical protocol. Only patients with angiographically
proven MCA occlusions were included in this analysis. Follow-up NCCT imaging was available for 21
patients. The arteriographic images and clinical records were retrospectively reviewed by a
neuroradiologist and neurologist, who classified the success of recanalization as complete recanalization
(M1 and M2 branches widely patent post-thrombolysis, n=10), partial recanalization (M1 and ≥1 but not all
M2 branches patent, n=8), or no recanalization (persistent proximal MCA occlusion, n=4). “Overall initial
perfusion CT hypodensity volume correlated significantly with follow-up infarct volume by linear
regression (p<0.002). The correlation between initial perfusion CT hypodensity and final infarct volume
was strongest for the patient subgroups with complete recanalization (p<0.0001) and partial
recanalization (p=0.003) and was less robust for the combined partial or no recanalization groups
(p=0.01). Clinical outcome (Rankin score) also correlated significantly by linear regression with initial
perfusion CT lesion volume (p=0.01) but not with initial NIHSS score (p=0.13). All patients with either
initial perfusion CT lesion volumes > 100 mL or no recanalization had poor outcomes. Mean admission
NIHSS scores and mean lesion volumes in the poor outcome group were significantly different compared
with the good or fair outcome group (p=0.01). Patients with initial volumes < 100 mL and partial or
complete recanalization all had good or fair outcomes. Thus, an initial perfusion CT lesion volume > 100
mL had 100% predictive value for a poor clinical outcome, and a value < 100 mL (with complete or partial
recanalization) had 77% positive predictive value for a good clinical outcome.” The authors state that
“lesion volumes on admission perfusion CT images approximate final infarct volume for patients with early
complete recanalization of MCA stem occlusion.” The authors also conclude that “in this homogeneous,
highly selected patient group, initial perfusion CT lesion volume is a stronger overall predictor of clinical
outcome than is admission NIHSS score, especially for those with successful recanalization. In
comparison, patients with partial recanalization demonstrate enlargement of their initial perfusion CT
lesion volume on follow-up imaging, and clinical outcome is more likely to be worse. Post hoc analysis
suggests that a cutoff volume of > 100 mL may identify ‘poor’ outcome patients.”
Kloska et al. (2004) evaluated the efficacy of multimodal CT evaluation (i.e., non-contrast CT, perfusion
CT, and CTA) to assess detection of stroke and prediction of extent of infarction in 44 patients suspected
of having acute stroke. CT imaging was performed 0.5–8.0 hours after onset of symptoms. Results were
compared to follow-up imaging performed with CT (n=28) or MR imaging (n=16) within 1–11 days of
admission. Multimodal CT revealed true-positive findings in 30 of 41 patients and true-negative findings in
three, resulting in a sensitivity of 78.9%. Unenhanced (i.e., non-contrast) CT, CTA, and perfusion CT
demonstrated sensitivities of 55.3%, 57.9%, and 76.3%, respectively. The authors stated that the
presented multimodal CT evaluation improved detection rate and prediction of the final size of infarction in
comparison with unenhanced CT, CTA, and perfusion CT alone. The authors concluded that multimodal
CT evaluation can aid decision-making for treatment of patients suspected of having a stroke. The
authors noted that follow-up imaging modality and timeframe varied.
Schramm et al. (2004) evaluated the diagnostic value of perfusion CT, CTA including CTA source images
(CTA-SI), PWI and DWI in 22 patients with symptoms of acute stroke lasting < 6 hours. Ischemic lesion
volumes on patients’ arrival as shown on perfusion CT, CTA-SI, DWI, and PWI were compared to the
infarct extent as shown on day five with non-enhanced CT. Perfusion CT TTP volumes did not differ from
PWI-TTP, nor did perfusion CT CBV differ from PWI-CBV. Lesion volumes measured in perfusion CT
maps significantly correlated with lesion volumes on PWI. Also, perfusion CT CBV lesion volumes
significantly correlated with follow-up CT lesion volumes. The authors concluded that “the combination of
non-contrast CT, perfusion CT, and CTA can render additional information within < 15 minutes and may
Page 7 of 18
Coverage Position Number: 0442
help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific
patients.”
Cohnen et al. (2006) assessed patient radiation exposure in comprehensive stroke imaging using
multidetector-row CT (MDCT) combining standard CT of the head, cerebral perfusion and CTA studies. In
comprehensive stroke imaging, “critical doses for organ damage (e.g., cataract formation or hair loss) are
not reached; however, physicians need to be aware of possible radiation-induced sequelae, particularly in
repetitive examinations. Specifically, limited coverage of CT perfusion studies, the impossibility of
delineating early cytotoxic edema, and radiation exposure, particularly in case of repeated examinations,
should alert physicians to reflect on which method may be more adequate for patients with acute stroke.”
Literature Review: Other
After Subarachnoid Hemorrhage: Pham et al. (2007) assessed the diagnostic accuracy of perfusion CT
and transcranial Doppler sonography (TCD) for the prediction of secondary cerebral infarction (SCI) after
aneurismal subarachnoid hemorrhage (SAH) in a prospective cohort study of 38 patients. Control data
were the perfusion CT and TCD examinations of the patients not developing SCI at comparable time
points after admission. An average of 3.5 CT/perfusion CT and 10.7 TCD examinations were performed
per patient. The target condition was SCI defined as complete late infarction on CT between three and 14
days after SAH. SCI developed in n =14 patients (n = 24 without SCI). The median interval between the
predictive perfusion CT session before complete SCI on native CT was three days (range two to five
days). Visual assessment of TTP color maps predicted SCI with 0.93 sensitivity, 0.67 specificity, 0.94
NPV, and 0.62 PPV. For CBF, sensitivity was 0.29, specificity 0.96, NPV 0.7, and PPV 0.67. CBV showed
0.21 sensitivity, 0.96 specificity, 0.68 NPV, and 0.75 PPV. Any combination of perfusion CT measures did
not improve diagnostic performance. Daily TCD measures were not significantly related to SCI at any time
before complete infarction on native CT. The authors state that “time to peak as indicated by CT perfusion
is a sensitive and early predictor of secondary cerebral infarction.” The authors concluded that their
“results help to further specify the usefulness of this widely available technology in that secondary
infarctions as one important complication after SAH are predictable with high sensitivity. A further
increase in its diagnostic performance may be achieved in the future through the coverage of wider
anatomic regions and improved validity of quantitative measures. At present already, even though
perfusion CT examines only confined regions, especially the employment of perfusion CT during early
observation seems reasonable and is supported by this study. During this period, particularly the patients
with clinical findings difficult to interpret and inconclusive TCD will benefit in that the impending risk for
later infarction may be better assessed. The very sensitive and early prediction of SCI by perfusion CT
may improve the timely indication of invasive angiography and prompt early therapy of potentially
underlying vasospasm.”
Sviri et al. (2006a) evaluated 46 patients with vasospasm after aneurysmal subarachnoid hemorrhage
(SAH). Patients underwent perfusion CT 2–17 days after the initial hemorrhage and transcranial Doppler
(TCD) within the first 48 hours after onset of SAH. A total of 28 had an angiography study, and 38 had
technetium-99m-labeled (Tc-99m) ethyl cysteinate dimer (ECD) SPECT imaging performed within 72
hours of the initial hemorrhage. The authors stated that “almost all patients with severe hypoperfusion on
SPECT imaging showed reduced rCBF and prolonged relative MTT on perfusion CT in the same vascular
territory. Most regions with unimpaired perfusion or mildly impaired rCBF on SPECT imaging were
unimpaired or mildly impaired on perfusion CT scans.” The authors stated that their study “suggests that,
in general, absolute measurements of CBF and MTT by perfusion CT scanning show high concordance
rates with the clinical course, vasospasm severity, and SPECT imaging. Further studies should be
performed to evaluate the role of perfusion CT scans in the diagnosis of cerebral vasospasm.” The
authors noted that perfusion CT methods have many limitations, “related to the deconvolution algorithm
used for calculation and assuming normal cerebral hemodynamic physiology and intact blood-brain
barrier, which are not necessarily intact after aneurysmal SAH. Furthermore, perfusion values are highly
dependent on the arterial input function chosen for the measurements.”
Sviri et al. (2006b) compared dynamic perfusion CT with Tc-99m ECD SPECT in 35 patients with cerebral
vasospasm following aneurysmal SAH. The CBF and MTT values using perfusion CT scans were
compared with CBF estimated on SPECT images. Qualitative relative (r)CBF estimated on SPECT
images in brain regions with normal, mild (rCBF 71–85%), moderate (rCBF 50–70%), and severe
Page 8 of 18
Coverage Position Number: 0442
(rCBF< 50%) hypoperfusion were compared with the mean rCBF values measured on perfusion CT.
Perfusion CT results were 1.01, 0.82, 0.6, and 0.32, respectively. The authors concluded that “relative
CBF (rCBF) and MTT values on perfusion CT showed a high concordance rate with estimated rCBF on
SPECT in patients with vasospasm following aneurysmal SAH. Given its logistical advantages, perfusion
CT may be a valuable method of assessing perfusion abnormality in the acute setting of vasospasm and
in patients with an unstable condition following aneurysmal SAH.” The authors noted that their results are
from treated patients and “do not necessarily show the variability of relative perfusion abnormalities in all
patients with aneurysmal SAH, particularly those in whom treatment was not administered.” The authors
noted that “perfusion CT is limited to select brain areas visualized in chosen axial slices (unlike global
SPECT), and does not provide information in all brain regions (e.g., thalamic nuclei, brainstem, and
cerebellum).”
Schaaf et al. (2006) performed perfusion CT on 69 patients within 72 hours after subarachnoid
hemorrhage to determine if perfusion CT provided any additional prognostic value than three established
predictors (age, clinical condition on admission, and amount of subarachnoid blood) for the development
of delayed cerebral ischemia. Non-contrast CT was performed initially and as needed for follow-up. CTA
was also performed initially. The CBF ratio was an independent predictor for the development of delayed
cerebral ischemia as was clinical condition. By adding the CBF ratio to the model with the three
established predictors, the area under the receiver operating characteristic curve (AUC) increased from
0.76 to 0.81. This trend toward an increased AUC suggests an improved predictive value. The authors
stated that CBF ratio measured in the acute stage after SAH is a good predictor for the development of
delayed cerebral ischemia. The lower the CBF ratio (indicating more asymmetry between the perfusion of
both hemispheres), the higher the risk of developing delayed cerebral ischemia. CBF ratio can contribute
to a better identification of patients at high risk for delayed cerebral ischemia. The authors did note that
“the interpretation of quantitative perfusion values as measured by perfusion CT has some restrictions.
Although the accuracy of perfusion CT has been validated many times in animal and human models,
controversies exist to the quantification of perfusion CT.” The authors stated they avoided this problem by
“analyzing the data in a semiquantitative manner. A disadvantage of this method is that bilateral
decreased perfusion can be missed. In future studies, this can be tested by comparing quantitative
perfusion values in different flow territories. Another limitation of brain perfusion measurements by means
of perfusion CT is the limited brain volume included in the analyses, which may underestimate the relation
between perfusion asymmetry and development of delayed cerebral ischemia.”
Wintermark et al. (2006b) evaluated 27 patients with aneurysmal SAH to determine whether a
CTA/perfusion CT combination could represent a noninvasive alternative to conventional DSA for the
diagnosis of vasospasm and for the capability to predict which patients will require endovascular
treatment. Results demonstrated CTA qualitative assessment and perfusion CT MTT with a threshold at
6.4 seconds represented the most accurate (93%) combination for the diagnosis of vasospasm, whereas
MTT considered alone represented the most sensitive parameter (NPV, 98.7%). A cortical regional
cerebral blood flow value ≤ 39.3 (mL X 100 g-1 X min-1) represented the most accurate (94.8%) indicator
for endovascular therapy. The authors propose “MTT maps should be reviewed for arterial territories with
MTT values superior to 6.4 seconds. These territories should be considered at risk for vasospasm. The
corresponding artery supplying this territory should then be evaluated by CTA for vasospasm. If CTA of
the corresponding artery is abnormal, the diagnosis of vasospasm is highly suggestive. The arterial
territories at risk of or with positive vasospasm should be followed carefully and a decrease in cortical
rCBF values should prompt DSA for possible endovascular treatment. This approach may help eliminate
unnecessary invasive DSA in selected lower-risk patients and should be validated in future prospective
studies.” The authors noted that the decision to perform endovascular treatment or not was made
independent of this retrospective study. Future prospective longitudinal studies will be able to compare
the CTA and perfusion CT results measured when vasospasm is suspected to the results measured on
admission. “This will allow one to distinguish between vasospastic and hypoplastic arteries of the circle of
Willis and also to assess the correlation between the evolution of perfusion CT and DSA results with more
significant statistical power.”
Epilepsy: A pilot study of 15 patients “suggests perfusion CT may help to identify patients with subtle
status epilepticus (SSE) during emergency workup. This technique provides important information to
neurologists or emergency physicians in the difficult clinical differential diagnosis of altered mental status
due to subtle status epilepticus” (Wiest, et al., 2006).
Page 9 of 18
Coverage Position Number: 0442
Head Injury: Metting et al. (2007) reviewed various structural and functional imaging techniques
(including different MRI sequences, single photon emission computed tomography, perfusion-weighted
MRI, perfusion CT, PET, magnetic resonance spectroscopy, functional MRI and magnetic
encephalography) in patients with mild-to-moderate head injury. The authors state that “the use of
perfusion MRI and perfusion CT is not extensively investigated in traumatic head injury. Perfusion MRI
provides better brain coverage than does perfusion CT, although this latter technique has some promising
qualities, despite its radiation exposure, as it has a low exposure time and is readily available in most
emergency departments.”
Tumor: Jain et al. (2007) prospectively evaluated 22 patients with previously treated brain tumors who
showed recurrent or progressive enhancing lesions on follow-up MRI and had a histopathological
diagnosis underwent first-pass perfusion CT. Another eight patients with treatment-naïve, high-grade
tumors (control group) also underwent perfusion CT assessment. The mean time period between the
radiation therapy and the appearance of recurrent enhancing lesion on follow-up MRI scans was 22.6
months. The authors stated that according to their “small preliminary data, recurrent tumors show higher
normalized (n)CBV and nCBF and a lower nMTT compared with radiation necrosis. This needs to be
evaluated further with a larger number of patients. Most of the recurrent enhancing lesions have a mixture
of tumor and necrosis, and, according to the composition of this mixed lesion, there could be an overlap
of the perfusion parameters. However, perfusion CT maps may be useful, particularly for surgical biopsy
or radiosurgery planning to target ‘hot spots’ with a better yield and better response to treatment.”
Ding et al. (2006) evaluated 22 patients with suspected intracranial gliomas, comparing perfusion CT
values of regional CBV and regional permeability surfaces to histological grade. A significant correlation
between regional CBV and regional permeability surfaces was only observed in high-grade gliomas. The
authors noted that “limitations of perfusion CT include the exposure to ionizing radiation, less tissue
resolution and restricted anatomic coverage compared with MR, for evaluation of the microvasculature.
With the rapid development of volume CT scanning, the last two of these limitations will hopefully be
ameliorated.” The authors also noted that MR images were used as a guide for the location of the tumor
because on some perfusion parameter maps showing relatively normal vascularity and permeability in
tumors, the tumor was not obvious against a normal background.
Professional Societies/Organizations
American Heart Association (AHA)/American Stroke Association (ASA)/American Academy of
Neurology (AAN): The Guidelines for the Early Management of Adults with Ischemic Stroke was
published by the AHA, ASA 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, the AAN affirms the value of this guideline as an
educational tool for neurologists (Adams, et al., 2007).
Under the section heading ‘Early Diagnosis: Brain and Vascular Imaging’, the AHA/ASA discusses:
non–contrast-enhanced CT scan of the brain, multimodal CT, multimodal MRI, and other brain imaging
techniques (e.g., oxygen-15 positron-emission tomography, xenon-enhanced CT, SPECT). Under Non–
Contrast-Enhanced CT Scan of the Brain, the AHA/ASA states that “it is agreed that emergency, non–
contrast-enhanced CT scanning of the brain accurately identifies most cases of intracranial hemorrhage
and helps discriminate nonvascular causes of neurological symptoms (e.g., brain tumor).” Under the
section heading ‘Early Diagnosis: Brain and Vascular Imaging,’ under Multimodal CT, the AHA/ASA
states that “recent technological advances have led to increased interest in more sophisticated
multimodal approaches to acute stroke imaging. The multimodal CT approach may include noncontrast
CT, perfusion CT, and CT angiography studies. Two types of perfusion techniques are currently available.
Whole-brain perfusion CT provides a map of cerebral blood volume, and it is postulated that regions of
hypoattenuation on these cerebral blood volume maps represent the ischemic core (Ezzeddine, et al.,
2002). Although this technique has the advantage of providing whole-brain coverage, it is limited by its
inability to provide measures of cerebral blood flow or mean transit time. Alternatively, the second
technique, dynamic perfusion CT, has the potential to provide absolute measures of cerebral blood flow,
mean transit time, and cerebral blood volume. Dynamic perfusion CT is currently limited to 2 to 4 brain
slices and provides incomplete visualization of all pertinent vascular territories. Recent reports
Page 10 of 18
Coverage Position Number: 0442
demonstrate a high degree of sensitivity and specificity for detecting cerebral ischemia with both of these
perfusion CT techniques (Kloska, et al., 2004; Wintermark, et al., 2005a; Schramm, et al., 2004). In
addition, several studies have suggested that “perfusion CT may be able to differentiate thresholds of
reversible and irreversible ischemia and thus identify the ischemic penumbra” (Klotz and König, 1999;
Wintermark, et al., 2002b). The AHA/ASA concludes the Multimodal CT section by noting that “these
techniques have the advantage of relatively rapid data acquisition and can be performed with
conventional CT equipment. Disadvantages include iodine contrast and additional radiation exposure.
The role of perfusion CT and CT angiography in making acute treatment decisions has not yet been
established.”
The AHA concludes the ‘Early Diagnosis: Brain and Vascular Imaging’ section by stating that “brain
imaging remains a required component of the emergency assessment of patients with suspected stroke.
Both CT and MRI are options for imaging the brain, but for most cases and at most institutions, CT
remains the most practical initial brain imaging test. A physician skilled in assessing CT or MRI studies
should be available to examine the initial scan. In particular, the scan should be evaluated for evidence of
early signs of infarction. Baseline CT findings, including the presence of ischemic changes involving more
than one third of a hemisphere, have not been predictors of responses to treatment with rtPA when the
agent is administered within the 3-hour treatment window. Information about multimodal CT and MRI of
the brain suggests that these diagnostic studies may help in the diagnosis and treatment of patients with
acute stroke. Imaging of the intracranial or extracranial vasculature in the emergency assessment of
patients with suspected stroke is useful at institutions providing endovascular recanalization therapies.
The usefulness of vascular imaging for predicting responses to treatment before intravenous
administration of thrombolytic agents has not been demonstrated.”
Under the section heading ‘Early Diagnosis: Brain and Vascular Imaging’ the AHA recommends:
Class I Recommendations
1. Imaging of the brain is recommended before initiating any specific therapy to treat acute ischemic
stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous
guideline.
2. In most instances, CT will provide the information to make decisions about emergency
management (Class I, Level of Evidence A). This recommendation has not changed from the
previous guideline.
3. The brain imaging study should be interpreted by a physician with expertise in reading CT or MRI
studies of the brain (Class I, Level of Evidence C). This recommendation has been added since
the previous guideline.
4. Some findings on CT, including the presence of a dense artery sign, are associated with poor
outcomes after stroke (Class I, Level of Evidence A). This recommendation has not changed from
the previous guideline.
5. Multimodal CT and MRI may provide additional information that will improve diagnosis of
ischemic stroke (Class I, Level of Evidence A). This recommendation has been added since the
previous guideline.
Class II Recommendations
1. Nevertheless, data are insufficient to state that, with the exception of hemorrhage, any specific
CT finding (including evidence of ischemia affecting more than one third of a cerebral
hemisphere) should preclude treatment with rtPA within three hours of onset of stroke (Class IIb,
Level of Evidence A). This recommendation has not changed from the previous guideline.
2. Vascular imaging is necessary as a preliminary step for intra-arterial administration of
pharmacological agents, surgical procedures, or endovascular interventions (Class IIa, Level of
Evidence B). This recommendation has not changed from the previous guideline.
Class III Recommendations
1. Emergency treatment of stroke should not be delayed in order to obtain multimodal imaging
studies (Class III, Level of Evidence C). This recommendation has been added since the previous
guideline.
Page 11 of 18
Coverage Position Number: 0442
2. Vascular imaging should not delay treatment of patients whose symptoms started <3 hours ago
and who have acute ischemic stroke (Class III, Level of Evidence B). This recommendation has
been added since the previous guideline.
Under the section heading ‘Intravenous Thrombolysis,’ the AHA lists ‘Characteristics of Patients With
Ischemic Stroke Who Could Be Treated With Recombinant Tissue-type Plasminogen Activator (rtPA).
These include, but are not limited to:
• diagnosis of ischemic stroke causing measurable neurological deficit
• onset of symptoms < 3 hours before beginning treatment
• CT does not show a multilobar infarction (hypodensity >1/3 cerebral hemisphere)
Other Class I Recommendations
• Intravenous rtPA is recommended for selected patients who may be treated within three hours of
onset of ischemic stroke (Class I, Level of Evidence A). This recommendation has not changed
from previous statements.
• Intra-arterial thrombolysis is an option for treatment of selected patients who have major stroke of
<6 hours’ duration due to occlusions of the middle cerebral artery and who are not otherwise
candidates for intravenous rtPA (Class I, Level of Evidence B). This recommendation has not
changed since previous guidelines.
*Definition of Classes and Levels of Evidence Used in AHA Recommendations
Classification:
Class I: Conditions for which there is evidence for and/or general agreement that the procedure
or treatment is useful and effective
Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about
the usefulness/efficacy of a procedure or treatment
Class IIa: The weight of evidence or opinion is in favor of the procedure or treatment.
Class IIb: Usefulness/efficacy is less well-established by evidence or opinion.
Class III: Conditions for which there is evidence and/or general agreement that the procedure or
treatment is not useful/effective and in some cases may be harmful
Level of evidence:
A: Data derived from multiple randomized clinical trials
B: Data derived from a single randomized trial or nonrandomized studies
C: Consensus opinion of experts
Level of evidence for diagnostic recommendation:
A: Data derived from multiple prospective cohort studies that used a reference standard applied
by a masked evaluator
B: Data derived from a single grade A study or one or more case control studies or studies that
used a reference standard applied by an unmasked evaluator
C: Consensus opinion of experts (Adams, et al., 2007).
American College of Radiology (ACR)/American Society of Neuroradiology (ASNR):
The ACR/ASNR Practice Guideline for the performance of CT Perfusion in Neuroradiologic Imaging
(October, 2007) states that indications for perfusion CT in neuroradiology include, but are not limited to:
• Brain primary indications: acute neurological change suspicious for stroke, suspected vasospasm
following subarachnoid hemorrhage, cerebral hemorrhage with secondary local ischemia, and
intracranial tumors.
• Brain secondary indications: follow-up of acute cerebral ischemia or infarction in the subacute or
chronic phase of recovery; to assist in planning, and evaluating the effectiveness of, therapy for
arterial occlusive disease; and in patients with contraindication to magnetic resonance imaging
(MRI) or with devices or material in or close to the field of view that would result in nondiagnostic
MRI scans. Perfusion CT scanning may also be helpful in the setting of acute trauma.
• Head and neck primary indications: evaluation of the vascular status of solid tumors where MRI is
degraded due to susceptibility artifact from air-containing spaces or from surgical clips or dental
work.
Page 12 of 18
Coverage Position Number: 0442
•
•
Head and Neck secondary indications: Follow-up of tumor response to therapy.
Prior documented major allergic reaction to iodinated contrast material is an absolute
contraindications.
Agency for Healthcare Research and Quality: The Agency for Healthcare Research and Quality’s
(AHRQ) Evidence Report/Technology Assessment “Acute Stroke: Evaluation and Treatment” (Sharma, et
al., 2005) addressed numerous issues, including whether perfusion CT/angiography affects the safety
and efficacy of thrombolytic therapy for acute ischemic stroke. The report stated that “prospective use of
perfusion CT and angiography techniques in patient selection for thrombolysis was not identified.”
Summary
A non-contrast computed tomography (CT) scan is regarded as the most important diagnostic tool in the
assessment of patients with a suspected acute stroke to exclude hemorrhage and demonstrate early
infarct signs. Studies suggest that additional perfusion imaging techniques may provide information to
differentiate patient subgroups that will be more likely to benefit from early reperfusion from those who are
unlikely to benefit or may be harmed. Perfusion studies also suggest a significant association between
early reperfusion and favorable clinical outcomes.
There is a lack of evidence to support cerebral perfusion CT for any other indication, including, but not
limited to, following subarachnoid hemorrhage, or for use with epilepsy, head injury or tumor.
Coding/Billing Information
Note: This list of codes may not be all-inclusive.
Covered when medically necessary:
CPT* Codes
0042T
Description
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
HCPCS
Codes
Description
No specific codes
ICD-9-CM
Diagnosis
Codes
434.01
434.11
434.19
Description
Cerebral thrombosis, with cerebral infarction
Cerebral embolism, with cerebral infarction
Cerebral artery occlusion, unspecified, with cerebral infarction
Multiple/Varied
Experimental/Investigational/Unproven/Not Covered:
CPT* Codes
Description
No specific codes
HCPCS
Codes
Description
No specific codes
ICD-9-CM
Diagnosis
Codes
Description
Page 13 of 18
Coverage Position Number: 0442
Multiple/Varied
*Current Procedural Terminology (CPT®) ©2007 American Medical Association: Chicago, IL.
References
1. Acker JE 3rd, Pancioli AM, Crocco TJ, Eckstein MK, Jauch EC, American Heart Association,
American Stroke Association Expert Panel on Emergency Medical Services Systems, Stroke
Council, et al. Implementation strategies for emergency medical services within stroke systems of
care: a policy statement from the American Heart Association/American Stroke Association
Expert Panel on Emergency Medical Services Systems and the Stroke Council. Stroke. 2007
Nov;38(11):3097-115.
2. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, 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: the
American Academy of Neurology affirms the value of this guideline as an educational tool for
neurologists. Stroke. 2007 May;38(5):1655-711. Epub 2007 Apr 12. Erratum in: Stroke. 2007
Jun;38(6):e38. Stroke. 2007 Sep;38(9):e96.
3. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy
for ischemic stroke: the Seventh American College of Chest Physicians (ACCP) Conference on
Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):483S-512S.
4. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, DEFUSE Investigators, et al. Magnetic
resonance imaging profiles predict clinical response to early reperfusion: the diffusion and
perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol.
2006 Nov;60(5):508-17.
5. American College of Cardiology Foundation/American Heart Association/American College of
Physicians Task Force on Clinical Competence and Training, Society of Atherosclerosis Imaging
and Prevention, Society for Cardiovascular Angiography and Interventions, Society of
Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, Society
for Vascular Medicine and Biology, Kramer CM, Budoff MJ, et al. ACCF/AHA 2007 clinical
competence statement on vascular imaging with computed tomography and magnetic resonance:
a report of the American College of Cardiology Foundation/American Heart Association/American
College of Physicians Task Force on Clinical Competence and Training: developed in
collaboration with the Society of Atherosclerosis Imaging and Prevention, the Society for
Cardiovascular Angiography and Interventions, the Society of Cardiovascular Computed
Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society for Vascular
Medicine and Biology. Circulation. 2007 Sep 11;116(11):1318-35.
6. American College of Radiology (ACR) and the American Society of Neuroradiology (ASNR).
Practice Guideline for the performance of CT Perfusion in Neuroradiologic Imaging. October,
2007. Accessed December 2007. Available at URL address:
http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guidelines/dx/headneck/ct_perfusion.aspx
7. Chalela JA, Kidwell CS, Nentwich LM, Luby M, Butman JA, Demchuk AM, et al. Magnetic
resonance imaging and computed tomography in emergency assessment of patients with
suspected acute stroke: a prospective comparison. Lancet. 2007 Jan 27;369(9558):293-8.
Page 14 of 18
Coverage Position Number: 0442
8. Cohnen M, Wittsack HJ, Assadi S, Muskalla K, Ringelstein A, Poll LW, et al. Radiation exposure
of patients in comprehensive computed tomography of the head in acute stroke. AJNR Am J
Neuroradiol. 2006 Sep;27(8):1741-5.
9. Ding B, Ling HW, Chen KM, Jiang H, Zhu YB. Comparison of cerebral blood volume and
permeability in preoperative grading of intracranial glioma using CT perfusion imaging.
Neuroradiology. 2006 Oct;48(10):773-781.
10. Eastwood JD, Lev MH, Provenzale JM. Perfusion CT with iodinated contrast material. AJR Am J
Roentgenol. 2003a Jan;180(1):3-12.
11. Eastwood JD, Lev MH, Wintermark M, Fitzek C, Barboriak DP, Delong DM, et al. Correlation of
early dynamic CT perfusion imaging with whole-brain MR diffusion and perfusion imaging in acute
hemispheric stroke. AJNR Am J Neuroradiol 24: 1869–1875, 2003b.
12. Ezzeddine MA, Lev MH, McDonald CT, Rordorf G, Oliveira-Filho J, Aksoy FG, et al. CT
angiography with whole brain perfused blood volume imaging: added clinical value in the
assessment of acute stroke. Stroke. 2002 Apr;33(4):959-66.
13. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of populationbased studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol.
2003 Jan;2(1):43-53. Review.
14. Gomori JM, Cohen JE. Imaging of cerebral perfusion in acute stroke. Neurol Res. 2005;27 Suppl
1:S50-2.
15. Grainger RG, Allison D, editors. Grainger & Allison's Diagnostic Radiology: A Textbook of Medical
Imaging 4th Ed., London: Churchill Livingstone, Inc.; 2001.
16. Hacke W, Donnan G, Fieschi C, ATLANTIS Trials Investigators, ECASS Trials Investigators,
NINDS rt-PA Study Group Investigators, et al. Association of outcome with early stroke treatment:
pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004 Mar
6;363(9411):768-74.
17. Higashida RT, Furlan AJ, Roberts H, Technology Assessment Committee of the American
Society of Interventional and Therapeutic Neuroradiology, Technology Assessment Committee of
the Society of Interventional Radiology, et al. Trial design and reporting standards for intra-arterial
cerebral thrombolysis for acute ischemic stroke. Stroke. 2003 Aug;34(8):e109-37. Erratum in:
Stroke. 2003 Nov;34(11):2774.
18. Hoeffner EG. Cerebral perfusion imaging. J Neuroophthalmol. 2005 Dec;25(4):313-20.
19. Hoeffner EG, Case I, Jain R, Gujar SK, Shah GV, Deveikis JP, et al. Cerebral perfusion CT:
technique and clinical applications. Radiology. 2004 Jun;231(3):632-44.
20. Jain R, Scarpace L, Ellika S, Schultz LR, Rock JP, Rosenblum ML, et al. First-pass perfusion
computed tomography: initial experience in differentiating recurrent brain tumors from radiation
effects and radiation necrosis. Neurosurgery. 2007 Oct;61(4):778-86; discussion 786-7.
21. Kloska SP, Nabavi DG, Gaus C, Nam EM, Klotz E, Ringelstein EB, Heindel W. Acute stroke
assessment with CT: do we need multimodal evaluation? Radiology. 2004 Oct;233(1):79-86.
22. Klotz E, König M. Perfusion measurements of the brain: using dynamic CT for the quantitative
assessment of cerebral ischemia in acute stroke. Eur J Radiol. 1999 Jun;30(3):170-84.
23. Koenig M, Kraus M, Theek C, Klotz E, Gehlen W, Heuser L. Quantitative assessment of the
ischemic brain by means of perfusion-related parameters derived from perfusion CT. Stroke.
2001 Feb;32(2):431-7.
Page 15 of 18
Coverage Position Number: 0442
24. Köhrmann M, Jüttler E, Huttner HB, Nowe T, Schellinger PD. Acute stroke imaging for
thrombolytic therapy--an update. Cerebrovasc Dis. 2007;24(2-3):161-9. Review.
25. Lad SP, Guzman R, Kelly ME, Li G, Lim M, Lovbald K, Steinberg GK. Cerebral perfusion imaging
in vasospasm. Neurosurg Focus. 2006 Sep 15;21(3):E7.
26. Latchaw RE, Yonas H, Hunter GJ, Yuh WT, Ueda T, Council on Cardiovascular Radiology of the
American Heart Association et al. Guidelines and recommendations for perfusion imaging in
cerebral ischemia: A scientific statement for healthcare professionals by the writing group on
perfusion imaging, from the Council on Cardiovascular Radiology of the American Heart
Association. Stroke. 2003 Apr;34(4):1084-104.
27. Lev MH, Segal AZ, Farkas J, Hossain ST, Putman C, Hunter GJ, et al. Utility of perfusionweighted CT imaging in acute middle cerebral artery stroke treated with intra-arterial
thrombolysis: prediction of final infarct volume and clinical outcome. Stroke. 2001
Sep;32(9):2021-8.
28. Maruya J, Yamamoto K, Ozawa T, Nakajima T, Sorimachi T, Kawasaki T et al. Simultaneous
multi-section perfusion CT and CT angiography for the assessment of acute ischemic stroke.
Acta Neurochir (Wien). 2005 Apr;147(4):383-91; discussion 391-2.
29. Masdeu JC, Irimia P, Asenbaum S, Bogousslavsky J, Brainin M, Chabriat H, et al. EFNS
guideline on neuroimaging in acute stroke. Report of an EFNS task force. Eur J Neurol. 2006
Dec;13(12):1271-83. Review.
30. Metting Z, Rödiger LA, De Keyser J, van der Naalt J. Structural and functional neuroimaging in
mild-to-moderate head injury. Lancet Neurol. 2007 Aug;6(8):699-710. Review.
31. Miyazawa N, Arbab AS, Umeda T, Akiyama I. Perfusion CT investigation of chronic internal
carotid artery occlusion: comparison with SPECT. Clin Neurol Neurosurg. 2005 Dec;108(1):11-7.
32. Mullins ME. Stroke imaging with xenon-CT. Semin Ultrasound CT MR. 2006 Jun;27(3):219-20.
33. Murphy BD, Fox AJ, Lee DH, Sahlas DJ, Black SE, et al. Identification of penumbra and infarct in
acute ischemic stroke using computed tomography perfusion-derived blood flow and blood
volume measurements. Stroke. 2006 Jul;37(7):1771-7.
34. No authors listed. Tissue plasminogen activator for acute ischemic stroke. The National Institute
of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995 Dec
14;333(24):1581-7.
35. Parsons MW, Pepper EM, Bateman GA, Wang Y, Levi CR. Identification of the penumbra and
infarct core on hyperacute noncontrast and perfusion CT. Neurology. 2007 Mar 6;68(10):730-6.
36. Pexman JH, Barber PA, Hill MD, Sevick RJ, Demchuk AM, Hudon ME et al. Use of the Alberta
Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute
stroke. AJNR Am J Neuroradiol. 2001 Sep;22(8):1534-42.
37. Pham M, Johnson A, Bartsch AJ, Lindner C, Müllges W, Roosen K, et al. CT perfusion predicts
secondary cerebral infarction after aneurysmal subarachnoid hemorrhage. Neurology. 2007 Aug
21;69(8):762-5.
38. Sacco RL, Adams R, American Heart Association/American Stroke Association Council on
Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology.
Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a
statement for healthcare professionals from the American Heart Association/American Stroke
Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and
Page 16 of 18
Coverage Position Number: 0442
Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation.
2006 Mar 14;113(10):e409-49.
39. Sá de Camargo EC, Koroshetz WJ. Neuroimaging of ischemia and infarction. NeuroRx. 2005
Apr;2(2):265-76.
40. Schaefer PW, Roccatagliata L, Ledezma C, Hoh B, Schwamm LH, et al. First-pass quantitative
CT perfusion identifies thresholds for salvageable penumbra in acute stroke patients treated with
intra-arterial therapy. AJNR Am J Neuroradiol. 2006 Jan;27(1):20-5.
41. Schramm P, Schellinger PD, Klotz E, Kallenberg K, Fiebach JB, Kulkens S, 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 Jul;35(7):1652-8.
42. Schumacher HC, Bateman BT, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, et al. Use of
thrombolysis in acute ischemic stroke: analysis of the Nationwide Inpatient Sample 1999 to 2004.
Ann Emerg Med. 2007 Aug;50(2):99-107.
43. Sharma M, Clark H, Armour T, Stotts G, Cote R, Hill MD et al. Acute stroke: evaluation and
treatment. Evid Rep Technol Assess (Summ). 2005 Jul;(127):1-7. Accessed January 2008.
Available at URL address:
http://www.ahrq.gov/downloads/pub/evidence/pdf/acutestroke/acstroke.pdf
44. Shetty SK, Lev MH. CT Perfusion in Acute Stroke. Neuroimaging Clin N Am. 2005 Aug;15(3):481501.
45. Sims J, Schwamm LH. The evolving role of acute stroke imaging in intravenous thrombolytic
therapy: patient selection and outcomes assessment. Neuroimaging Clin N Am. 2005
May;15(2):421-40, xii.
46. Smith WS, Roberts HC, Chuang NA, Ong KC, Lee TJ, Johnston SC et al. Safety and feasibility of
a CT protocol for acute stroke: combined CT, CT angiography, and CT perfusion imaging in 53
consecutive patients. AJNR Am J Neuroradiol. 2003 Apr;24(4):688-90.
47. Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006
Jan 26;354(4):387-96. Review.
48. Sviri GE, Britz GW, Lewis DH, Newell DW, Zaaroor M, Cohen W. Dynamic perfusion computed
tomography in the diagnosis of cerebral vasospasm. Neurosurgery. 2006a Aug;59(2):319-25;
discussion 319-25.
49. Sviri GE, Mesiwala AH, Lewis DH, Britz GW, Nemecek A, et a. Dynamic perfusion computerized
tomography in cerebral vasospasm following aneurysmal subarachnoid hemorrhage: a
comparison with technetium-99m-labeled ethyl cysteinate dimer-single-photon emission
computerized tomography. J Neurosurg. 2006b Mar;104(3):404-10.
50. Tan JC, Dillon WP, Liu S, Adler F, Smith WS, Wintermark M. Systematic comparison of
perfusion-CT and CT-angiography in acute stroke patients. Ann Neurol. 2007 Jun;61(6):533-43.
51. Thurnher MM, Castillo M. Imaging in acute stroke. Eur Radiol. 2005 Mar;15(3):408-15. Epub
2005 Jan 21.
52. Tomandl BF, Klotz E, Handschu R, Stemper B, Reinhardt F, Huk WJ et al. Comprehensive
imaging of ischemic stroke with multisection CT. Radiographics. 2003 May-Jun;23(3):565-92.
Page 17 of 18
Coverage Position Number: 0442
53. U.S. Food and Drug Administration. Summary of 510(k) safety and effectiveness. Syngo Neuro
PBV CT software package. Nov 30, 2006. Accessed January 2008. Available at URL address:
http://www.fda.gov/cdrh/pdf6/K063507.pdf
54. van der Worp HB, van Gijn J. Clinical practice. Acute ischemic stroke. N Engl J Med. 2007 Aug
9;357(6):572-9. Review.
55. Wiest R, von Bredow F, Schindler K, Schauble B, Slotboom J, et al. Detection of regional blood
perfusion changes in epileptic seizures with dynamic brain perfusion CT-A pilot study. Epilepsy
Res. 2006 Dec;72(2-3):102-10. Epub 2006 Nov 21.
56. Wintermark M, Fischbein NJ, Smith WS, Ko NU, Quist M, Dillon WP. Accuracy of dynamic
perfusion CT with deconvolution in detecting acute hemispheric stroke. AJNR Am J Neuroradiol.
2005a Jan;26(1):104-12.
57. Wintermark M, Flanders AE, Velthuis B, Meuli R, van Leeuwen M, Goldsher D, et al. PerfusionCT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in
130 patients suspected of acute hemispheric stroke. Stroke. 2006a Apr;37(4):979-85.
58. Wintermark M, Meuli R, Browaeys P, Reichhart M, Bogousslavsky J, Schnyder P, et al.
Comparison of CT perfusion and angiography and MRI in selecting stroke patients for acute
treatment. Neurology. 2007 Feb 27;68(9):694-7.
59. Wintermark M, Ko NU, Smith WS, Liu S, Higashida RT, Dillon WP. Vasospasm after
subarachnoid hemorrhage: utility of perfusion CT and CT angiography on diagnosis and
management. AJNR Am J Neuroradiol. 2006b Jan;27(1):26-34.
60. Wintermark M, Reichhart M, Cuisenaire O, Maeder P, Thiran JP, Schnyder P et al. Comparison
of admission perfusion computed tomography and qualitative diffusion- and perfusion-weighted
magnetic resonance imaging in acute stroke patients. Stroke. 2002a Aug;33(8):2025-31.
61. Wintermark M, Reichhart M, Thiran JP, et al. Prognostic accuracy of cerebral blood flow
measurement in perfusion computed tomography, at the time of emergency room admission, in
acute stroke patients. Ann Neurol 2002b;55:417-432.
62. Wintermark M, Sesay M, Barbier E, Borbely K, Dillon WP, Eastwood JD et al. Comparative
overview of brain perfusion imaging techniques. Stroke. 2005b Sep;36(9):2032-3.
63. Zimmerman RD. Stroke wars: episode IV CT strikes back. AJNR Am J Neuroradiol 2004;25:1304
–1309. The National Institute of Neurological Disorders.
Page 18 of 18
Coverage Position Number: 0442