Perfusion Imaging in Cerebral Ischemia

Guidelines and Recommendations for Perfusion Imaging inCerebral Ischemia

A Scientific Statement for Healthcare Professionals by the Writing Groupon Perfusion Imaging, From the Council on Cardiovascular Radiology of

the American Heart Association

Richard E. Latchaw, MD, Chair; Howard Yonas, MD; George J. Hunter, MD;William T.C. Yuh, MD, MSEE; Toshihiro Ueda, MD, PhD; A. Gregory Sorensen, MD;

Jeffrey L. Sunshine, MD, PhD; Jose Biller, MD; Lawrence Wechsler, MD;Randall Higashida, MD; George Hademenos, PhD

A number of techniques have been developed during thepast four decades to evaluate cerebral perfusion. The

oldest used 133Xe, a lipophilic radioactive tracer that easilydiffuses through the blood-brain barrier (BBB). It was eitherinjected or inhaled, and probes placed over the scalp wereused to measure perfusion to the cerebral cortex.1,2 In themid-1970s, the development of a scanner to detect theemission of positrons led to positron emission tomography(PET) in humans.3 Using a number of radioisotopes, thistechnology can measure cerebral blood flow (CBF) andvarious metabolic processes, but until recently it has beenprimarily used as a research tool. Stable (“cold”) xenon wasfound to attenuate x-rays in a manner similar to iodine, andthere were a number of projects in the 1970s to use this gasas a contrast agent for the rapidly emerging technology ofcomputed tomography (CT), particularly as a perfusion trac-er.4 This resulted in the development of the xenon-enhancedCT (XeCT) technique to calculate CBF in patients.5 Withimprovements in single photon emission CT (SPECT) duringthe 1980s, a number of compounds that are metabolized in thecentral nervous system (CNS) were found to be appropriatefor perfusion imaging.6,7 Perfusion-weighted and diffusion-weighted magnetic resonance (MR) imaging (PWI and DWI)were developed in the late 1980s,8,9 and that technology hascontinued to improve. Finally, with the evolution of helicaland spiral multislice CT technology, CT perfusion (CTP)imaging is becoming a potentially important clinicaltechnique.10

Although the development of these technologies has beenfascinating, their role in evaluating a variety of diseases of theCNS is controversial. It might seem obvious that a disorder of

blood flow, such as acute stroke or chronic vascular occlusivedisease, should be studied with a perfusion imaging tech-nique. The accuracy, reproducibility, and reliability of thedata from these techniques have been evaluated in animalmodels and in general have been found to be of very highquality. Their roles in predicting patient outcome and theiruse in planning treatment have received varying levels ofscientific scrutiny. One of the purposes of this report is toassess the quality of such studies to determine the grade ofrecommendation that can be made for their use today and toguide the direction of future research. The rules of evidencefor evaluating the quality and reliability of diagnostic testssuch as perfusion imaging must obviously differ from thoseused to evaluate clinical studies. A committee of the Amer-ican Academy of Neurology developed a scheme of evidenceclassification for diagnostic testing to evaluate reports oftechniques that test the vestibular system.11 However, imag-ing studies differ from other types of diagnostic tests inimportant ways, because the data must often be interpreted bysubjective rather than purely objective criteria. In addition,adequate clinical history is often necessary for an appropriateinterpretation to be made. One way to assess the accuracy ofan imaging study such as perfusion imaging is to gauge itsability to predict outcome, with or without subsequent treat-ment. This outcome may not be actual patient outcome butmay be an outcome related to the tissue in question, such asthe development of infarction. Another method of evaluation,possibly of even more importance, is an assessment of theability of the information derived from the imaging test toinfluence the selection of subsequent medical management.For perfusion imaging, the ideal impartial assessment of the

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outsiderelationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are requiredto complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in December 2002. A single reprintis available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX75231-4596. Ask for reprint No. 71-0252. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000or more copies, call 410-528-4426, fax 410-528-4264, or e-mail [email protected]. To make photocopies for personal or educational use, call theCopyright Clearance Center, 978-750-8400.

(Stroke. 2003;34:1084-1104.)© 2003 American Heart Association, Inc.

Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000064840.99271.9E

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accuracy and influence of a given technique would requirethat the interpreters of the test be blinded, prospectively orretrospectively, to both the subsequent subject managementand outcome and that the individuals making treatmentdecisions and outcome assessments be blinded to the resultsof the imaging study. A scheme to evaluate the perfusionliterature has been developed with these considerations inmind (Table), representing a modification of that found in thereport by Fife et al.11

This report is intended to summarize what is known aboutthe clinically available perfusion technologies, specificallyXeCT, CTP, SPECT, and PWI (and the associated DWI), intheir role of evaluating acute and chronic cerebral ischemicconditions. Major goals are to indicate the strengths andweaknesses of each technique, make recommendations as tothe use of each, and indicate the need for future research. PETscanning is excluded because it is primarily a research tool inacademic institutions. Traumatic head injury is includedbecause of its close relationship to ischemic injury, but theuse of perfusion imaging in other diseases, such as neoplasmsand inflammatory conditions, has not been evaluated. Thisreview should give impetus to the improvement and perfec-tion of these techniques, the direct comparison of their abilityto provide significant information, and the formation ofstudies to prove that perfusion imaging has a role in improv-ing patient outcomes.

Roles of Perfusion ImagingAcute StrokeTherapy for acute stroke depends on ensuring the diagnosisand excluding diseases that mimic cerebral ischemia, such ashypoglycemia, hyponatremia, a seizure, or a mass lesion suchas a tumor or subdural hematoma. The exclusion of ahemorrhagic rather than ischemic stroke can be determined

rapidly and accurately with CT or MR imaging. The differ-entiation of a transient ischemic attack (TIA) from ischemiapotentially producing infarction often can be made clinically,with the former lasting only a matter of minutes. It is moredifficult to clinically differentiate those neurological deficitsdue to ischemia that are likely to improve or reverse sponta-neously from those that are likely to persist or worsen, andthis is a significant value of perfusion imaging.12–17 Thedemonstration of a normal level of CBF suggests thatreperfusion has occurred spontaneously and that no acutevascular thrombolysis or flow augmentation is necessary.18–20

The level of perfusion to the ischemic tissues may help todetermine the relative benefits and risks of a given therapy.Neurological dysfunction occurs in a tissue after CBF fallsbelow approximately 18 to 20 mL/100 g of tissue per minute.Given this dysfunction, it is impossible to determine byclinical examination alone the level of the persisting perfu-sion. CBF of less than 10 mL/100 g of tissue per minutecannot be tolerated beyond a few minutes before infarctionoccurs, but between 10 and 20 mL · 100 g�1 · min�1, cell deathrequires many minutes to hours.21–30 Theoretically, tissueswith flow values in this intermediate zone might be salvagedif flow restoration occurred quickly, either spontaneously byclot fragmentation and dissolution31,32 or by therapeuticmeans such as arterial thrombolysis. While some tissuesmight be dead at the core of the ischemic process, the moreperipheral tissues (the “penumbra”) might still be salvage-able.33–42 However, recanalization of arteries serving tissuesthat are severely ischemic or infarcted may increase the riskof edema and hemorrhage, which can produce enough masseffect that herniation and death ensue.22,43–47 Hence, thepotential benefits of recanalization of arteries supplyinginjured but viable tissue must be weighed against the poten-tially increased morbidity and mortality.

Quality of Evidence Ratings for Perfusion Imaging

Level of evidence

Class I Evidence provided by a prospective study in a broad spectrum of subjects with the suspected condition, using a “goldstandard” for case definition. The interpreters of the test and those providing treatment decisions and assessing outcome areeach blinded to any data from the other, enabling assessment of the diagnostic accuracy of the test.

Class II Evidence provided by a prospective study in a narrow spectrum of subjects with the suspected condition, or a well-designedretrospective study of a broad spectrum of subjects with an established condition (using a “gold standard”) compared with abroad spectrum of control subjects. The interpreters of the test and those providing treatment decisions and assessingoutcome are each blinded to any data from the other, enabling assessment of the diagnostic accuracy of the test.

Class III Evidence supplied by a retrospective study in which either the subjects with an established condition or the controls are of anarrow spectrum. The interpreters of the test and those providing treatment decisions and assessing outcome are eachblinded to any data from the other, enabling assessment of the diagnostic accuracy of the test.

Class IV Any study design in which the interpretation of the test is not blinded relative to any treatment decision or outcomeassessment, the treatment decision or outcome assessment is not blinded to the test interpretation, the evidence is providedby “expert opinion” alone, or there is only a descriptive series without controls.

Strength of recommendation

Grade A Established as a useful/predictive or not useful/predictive test for the given condition in the specified population. Requires atleast one class I study or two class II studies.

Grade B Probably useful/predictive or not useful/predictive test for the given condition in the specified population. Requires at leastone class II study or three class III studies.

Grade C Possibly useful/predictive or not useful/predictive test for the given condition in the specified population. Requires at least twoclass III studies.

Grade D Data are inadequate or conflicting. Given current knowledge, the test is unproven.

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The risks of recanalization might be based on the relativevolume of dead versus injured but viable tissue and thedegree of that injury. Unfortunately, a precise relationship ofCBF level to the time available for tissue salvage has not beendetermined, and so the benefit of quantification of CBF inacute stroke has not been proven.48 In a given case, this“therapeutic window” depends to a large degree on theamount of collateral circulation beyond the primary occlusionproviding enough perfusion to keep the tissue viable.22,41

However, because the neurological examination cannot fullydifferentiate the status of the tissue, some type of rapid andaccurate technique may help to distinguish potentially revers-ible from irreversible ischemia, which, in turn, may aid in thedecision to undertake risky but potentially life-savingtherapies.22,36–44,49–51

Other benefits of perfusion imaging in acute stroke are thedetermination of the volume of tissue at risk and the vasculardistribution of the ischemia.14,16,17,52–60 Anatomic imagingprovided by CT and MR demonstrates the changes in tissuedensity or intensity based on the presence of cytotoxic andvasogenic edema after the onset of ischemia.61 However,these tissue changes require hours to fully develop, and henceit is difficult or impossible to adequately determine thevolume of tissue at risk on the initial CT or MR. This volumehas a substantial effect on the morbidity and mortality oftherapy using thrombolytic drugs.37,43,44 The specific vasculardistribution of ischemia cannot always be determined withaccuracy from the clinical presentation alone. In addition, theprognosis and outcome of ischemia in one vascular distribu-tion differ from those of another. Unfortunately, the largemulti-center trials of tissue plasminogen activator (tPA) didnot include any vascular imaging to accurately determinewhether arterial obstruction persisted or define the site of thatarterial obstruction prior to thrombolysis, so that the relativerisks of the therapy and the outcome of the disease could notbe stratified on the basis of the site and extent of the vascularocclusive disease.62,63

Chronic IschemiaStenoses and occlusions may lead to intermittent neurologicalsymptoms, either because of hypoperfusion secondary toinadequate collateral circulation or because of emboli fromthe affected arteries. Cerebral angiography demonstrates apotential embolic source and the presence of the collateralcirculation but cannot reliably determine whether that collat-eral is “adequate.” Perfusion imaging permits a rapid differ-entiation of these conditions so that a decision can be made toeliminate an embolic source or augment a low-flow condi-tion. A rough comparison of the perfusion to part or all of ahemisphere relative to other parts or to the opposite hemi-sphere can be obtained at angiography by comparing the timeof appearance of the capillary phase.64 Improvements in this“poor man’s blood flow study” are provided by the dedicatedperfusion imaging methodologies discussed in this report.

The concepts of tissue demand, “autoregulation,” and“vascular reserves” must be understood to appreciate thecomplexities in the interpretation of perfusion images, partic-ularly in patients who have chronic cerebrovascular diseasewith previous infarction. A patient may present with an old

vascular occlusion and new symptoms of transient neurolog-ical deficit. Progressive occlusive disease increases the risk ofmajor stroke in the distribution of the marginal perfusion.However, if the previous ischemic process has led to tissueinjury, the demand for blood flow to the territory in questionmay be diminished, and a single measurement of CBF will bemisleading.65–69 Conversely, CBF may normalize in a regiondistal to the occlusive disease because of both collateral flowand dilation of regional arteries to increase blood volume(autoregulation), both of which contribute to the vascularreserves.68–73 However, maximally dilated arteries are unableto increase their capacity from a stress such as hypotension ordecreased cardiac output, and acute stroke may occur. Asingle perfusion study at rest is insufficient to evaluate thetissue need and ability of the vascular reserves to respond tothat need, particularly during an additional stress.72,73 There-fore, “challenge tests” to determine the ability of the vascularbed to respond to a stress must be an integral part of anyperfusion imaging methodology that seeks to evaluatechronic cerebral ischemia.68–70,72–75 Perfusion imaging with achallenge test may help to identify those patients with chronicischemia who are at high risk for future stroke.69

These challenge tests include the intravenous injection of1 g of the vasodilating agent acetazolamide (Diamox).70,72–75

This produces an increase in CBF of 50% to 100% within 20to 30 minutes. The lack of such flow augmentation indicatesa loss of autoregulation and inadequate vascular reserves.68

Other types of challenge tests include the measurement ofCBF at 2 levels of blood pressure or at 2 tissue pH levels; thelatter can be achieved by altering the ventilation rate of theintubated patient.76–78

Perfusion imaging with a challenge test may be able toselect those patients who would benefit from an extracranial-to-intracranial (EC-IC) bypass to augment CBF. A newnational trial using the oxygen extraction fraction (OEF) asmeasured with PET scanning will attempt to define thepatient population with occlusive vascular disease at risk forstroke and the potential of an EC-IC bypass to decrease thatrisk.79–81 Other types of perfusion imaging with challengetests may act as surrogate techniques for the more elaborateand expensive PET-OEF technique; the Xe/CT method withan acetazolamide challenge has already demonstrated itsability to detect such patients.70 Perfusion imaging might beused to determine when a patient with moyamoya disease orsyndrome should undergo a procedure to augment flow.82,83

Conceivably, such tests could be used to select those patientsfor carotid endarterectomy or angioplasty and stenting whohave multiple vascular stenoses and occlusions but who donot now qualify for such procedures by demonstrating focalneurological symptoms and a 70% or greater stenosis. How-ever, this will take large, well-planned studies utilizingcontrol groups to compare natural history data with postpro-cedural outcomes.

Ischemia From VasospasmSubarachnoid hemorrhage (SAH) leads to vasospasm, whichis a major determinant of morbidity and mortality in thosepatients who survive the initial event. Vasospasm producesischemia and infarction in the territory distal to the involved

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vessels because of low flow. Perfusion imaging helps toestablish the diagnosis of ischemia and differentiate it fromother complications that produce neurological deficits, suchas recurrent hemorrhage or metabolic disorders. The initialtreatment of vasospasm is by medical means, includingsystemic hypertension, hemodilution, and hypervolemia(“triple-H therapy”). If not successful, endovascular methodsmay be employed, including intracranial angioplasty and theinfusion of vasodilators. It appears that outcomes are im-proved if these treatments are instituted as early as possible.Perfusion imaging may aid in this early diagnosis andtherapeutic intervention.19,33,34,84–88

Prevention of Stroke Following TherapeuticCarotid OcclusionApproximately 10% of patients cannot tolerate carotid occlu-sion because of inadequate collateral circulation to the af-fected hemisphere. There is another large group of patientswho will have a low-flow state after vascular sacrifice,leading to ischemia and possibly infarction unless adequateblood pressure is maintained to permit perfusion throughcollateral channels. By identifying those patients at riskpreoperatively, decisions can be made to augment cerebralperfusion before vascular sacrifice using a bypass graft or toavoid the vascular occlusion.88

Temporary occlusion of the vessel to be sacrificed with aninflatable balloon for a number of minutes, during whichneurological examinations are performed (the balloon occlu-sion test [BOT]), is the traditional method to identify theat-risk patient. However, the lack of neurological symptomsduring temporary arterial occlusion only means that CBF tothe cerebral tissue distal to the occluded vessel is �20 mL ·100 g�1 · min�1. An assessment of the actual CBF to thetissues may help to determine the relative risk of vascularocclusion, especially if postoperative hypotension or de-creased cardiac output were to occur. Performing a CBF testduring carotid occlusion, assuming the BOT with neurologi-cal examination has not produced symptoms of ischemia, canprovide objective data.88 The CBF in the distribution of thetemporarily occluded vessel is compared with that of the“normal” contralateral hemisphere.89 Although a ratio offlows can be calculated, the degree of asymmetry thatindicates the need for preoperative flow augmentation is amatter of continuing research.18,68,90

Aid in Patient Management Following Head TraumaManagement of significant head trauma frequently involveshyperventilation to decrease the small intracranial volumerequired for the blood volume (approximately 4%) in anattempt to provide more space for the swelling brain. How-ever, when autoregulation of the arterial supply to the injuredtissue is lost, hyperventilation leads to vasoconstriction of thenormal vessels and potential ischemia of normal brain, with aparadoxical increased flow in those arteries feeding theinjured tissues, followed by increased swelling.91,92 Hence,perfusion imaging may provide information on appropriateventilation management.76,92,93 In addition, significant loss ofthis chemoregulation is indicative of irreversible tissue inju-ry.76–78 Therefore, perfusion imaging with tests of vascular

and tissue response provides important information on poten-tial patient outcome.

Determination of Brain DeathA surrogate of clinical brain death determination is thedemonstration of inadequate cerebral perfusion to maintaintissue viability. Perfusion imaging may be of aid in cases inwhich the clinical determination cannot be made; eg, when anaccurate clinical examination is hampered by the presence ofhypnotics or sedatives.94,95

Perfusion TechnologiesThere are 2 major classes of perfusion techniques: those thatutilize a diffusible tracer and those that rely on a nondiffusibleagent. The physiological principles underlying these 2 classesof techniques and the mathematical models used to attemptquantification of their data are different.

A diffusible tracer technique relies on the ability of alipophilic molecule to rapidly pass the BBB and pass into thecerebral parenchyma. The measurement of CBF is a determi-nation of both the amount of agent in the feeding arteries andthe uptake of that agent by the tissues. Quantification of CBFrequires knowledge of the arterial (arterial input function[AIF]) and tissue concentrations of the agent, or the partitioncoefficient between these spaces at equilibrium.

The nondiffusible tracer technique uses an agent thatremains within the vasculature. The central volume principlestates that CBF is the ratio of the blood volume within allblood vessels in a given volume of tissue (cerebral bloodvolume [CBV] in milliliters per gram) to the mean transittime (MTT, in seconds) of the agent from the arterial input tothe venous drainage within the volume being evaluated(CBF�CBV:MTT).96–98 After intravenous contrast injection,a time-density curve is constructed that indicates the changein CT density or MR intensity of the imaged tissues as theagent passes through the vasculature, and the area under thatcurve is the CBV.99–101 Calculation of MTT and CBFrequires knowledge of the agent concentration in the feedingarteries (AIF) and draining veins related to the volume oftissue. Using mathematical models—“deconvolution” tech-niques—the MTT and CBF can be approximated. Thesemodels assume an intact BBB, so that the agent stays in thevasculature.102–107

Diffusible Tracer Techniques

Xenon-Enhanced CT

Rationale of TechniqueXenon is a small, biologically inert molecule that is soluble inboth lipid and water and is freely diffusible. These attributesmake it an ideal tracer for evaluation of cerebral perfusion,because the gas dissolves in blood after inhalation and freelycrosses the lipid-rich BBB. A measure of its tissue concen-tration reflects both arterial input to and uptake by the targettissue. The radioactive form (133Xe) has been used for cerebralperfusion evaluation for over 40 years.1 Because x-rayattenuation by xenon is similar to that by iodine, it can beused as a contrast agent for a sensitive x-ray–based technol-ogy such as CT.4 Therefore, the nonradioactive form is used




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as an inhaled diffusible tracer during CT scanning to measuretissue perfusion in patients.5

Method of PerformanceThe technique requires the inhalation of a mixture of stablexenon gas and oxygen. With improvements in CT scannertechnology, including both speed and contrast resolution, theamount of xenon required for an adequate contrast-to-noiseratio has decreased, which also decreases the neurologicaleffects of the gas. Currently, a mixture of 28% xenon and72% oxygen is most commonly used, with inhalation over aperiod of 4.33 minutes. Following the acquisition of anon-enhanced baseline scan of the entire head, 6 contiguous10-mm-thick levels are selected for study. Each level isscanned 6 times during the inhalation period, requiring exacttable relocation. As the xenon accumulates in the cerebraltissues, the patient experiences a sedative effect, which isrelatively mild given the percentage of xenon used today.After gas inhalation ceases, a few minutes are required for thegas to be washed out of the cerebral tissues and the patient toreturn to baseline attentiveness. This test is easily performedin an outpatient setting.108

Quantification, Accuracy, and ReproducibilityThe CT scanner measures the x-ray attenuation coefficient(Hounsfield units) of every voxel during each acquisitionperiod. By subtracting the baseline values from those ac-quired during xenon inhalation, a build-up curve of traceraccumulation over time is calculated for each voxel. The AIFis estimated by measuring the xenon concentration duringexpiration. The Kety-Schmidt equation for perfusion issolved in an iterative manner for each of the 24 000 voxels ineach CT slice, yielding both CBF in mL · 100 g tissue�1 ·min�1 and the partition coefficient, lambda, between bloodand tissue.109 The integration of the partition coefficient to theflow data adds another parameter to ensure accuracy, even in

disease states. Superimposition of the numerical data on theanatomic image yields a high-resolution (Full Width HalfMaximum [FWHM] �4 mm) map of quantitative flow datathat is tightly coupled to cerebral anatomy.109 With theaddition of a gray or color scale, the data are converted to amap for visual inspection (Figure 1), on which regions ofinterest (ROIs) can be drawn for regional quantitative assess-ment. A confidence map is also produced to demonstrate theeffects of any patient motion and other artifacts on the data.The data processing requires approximately 10 minutes be-fore the flow maps are available for inspection and analysis.

There is a high degree of correlation between CBF valuesacquired with the XeCT technique and 133Xe,110 iodoan-tipyrine,111 and microsphere embolization112–114 in prospec-tive, comparative studies using animal models in tightlycontrolled laboratory experiments. Although the stability ofthe flow value in a single voxel of 10 mm3 is poor, thereliability of the data from an ROI of �100 voxels isapproximately 12%.115 This reliability in spite of the phar-macological property of xenon to directly increase CBF by20% to 30% is explained by the fact that nearly all of theimportant flow data are acquired prior to this flow activation,which does not become significant until after 2.5 minutes ofinhalation.116 The use of a flow phantom not only allows eachscanner to be calibrated between studies, but its universal useby all sites performing XeCT examinations permits standard-ization of the data between scanners of different manufactur-ers and the potential integration and comparison of the datafor multi-institutional studies.

Significant Issues in Study PerformanceHead motion is the major problem, because each voxel in aslice that is studied must remain in its location throughout the4 minutes of scanning. Head stabilization with inflatablerestraints is necessary. The sedative effect, particularly in aneurologically impaired patient, can lead to increased motion.

Figure 1. XeCT CBF analysis. A right-handed male had acute onset of righthemiparesis and aphasia 3 hours previ-ously. This 4-level study demonstrates anormal plain CT scan (top row), butdecreased CBF throughout much of theleft temporal, frontal and parietal lobes(middle row). Many areas have CBF inthe ‘teens, and there are areas with CBFin the single digits. A confidence map(lower row) shows that there was littlemotion, so that the absolute values ofCBF, as determined from the color scaleto the right, are accurate.




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Lowering the xenon concentration to 28% has lessened theincidence of significant patient agitation and sedation to�5%. Interpretable studies have been obtained in 87% ofnonintubated acute stroke victims in whom the xenon/oxygenmixture was delivered with a tightly fitting face mask,although 30% did require intravenous sedation (class IV). Inmore impaired patients, intubation is required, which yieldsdiagnostic studies in 100% of patients.102 Adverse reactionsto a 32% concentration of xenon have been reported in�0.1% of cases117 (class II).

Diversity of Data and Ability to Perform Challenge Tests

Acute StrokeIt has been demonstrated in numerous studies using bothanimal and human subjects, and both normal controls andsubjects with ischemia, that CBF values attained with thistechnique are accurate, especially in the flow ranges thatdistinguish low but nonischemic regions from reversibly andirreversibly ischemic areas (Figure 1)110–114,118,119 (class I). Inacute ischemia, flow values above 20 mL · 100 g�1 · min�1

have been consistent with sustained viability and reversibleneurological deficits without the immediate need for vascularrecanalization or augmentation.18–20 CBF in the range of 10 to20 mL · 100 g�1 · min�1 has been consistent with the onset ofneurological deficits that have been reversible using aggres-sive revascularization techniques, or with infarction if there isno revascularization, depending on the duration of theishemia.19,20,33–37 Flow values below 10 mL · 100 g�1 · min�1

within a major vascular territory have correlated with thevolume of eventual infarction,35–37 and global flow valuesnear zero have been utilized for the diagnosis of braindeath.94,95 Of particular note are the multiple retrospectivestudies that have demonstrated an increased risk of hemor-rhage, edema formation, and herniation due to massive edemawith CBF values below 15 and especially below 10 mL · 100g�1 · min�1, in spite of or due to reperfusion.43,44 Theseclinical studies with a data quality of class II-III, because oftheir retrospective nature, demonstrate the value of highlyaccurate quantification of CBF within a narrow range.

Chronic IschemiaIn chronic vascular occlusive disease, the XeCT technique

yields quantitative CBF data but does not measure directlyany metabolic functions, such as oxygen and glucose utiliza-tion, which are important to understand both the arterialsupply of oxygen and nutrients, and the demand of the tissuesfor them. However, because of the coupling of blood flowand metabolism in chronic ischemia, measuring the ability tomaintain or augment vascular reserves allows an assessmentof the underlying tissue metabolism and the risk of subse-quent infarction.68,69 Performance of 2 XeCT studies withdifferent blood pressures following pharmacologic manipu-lation has defined an important subset of patients whodevelop a paradoxical lowering of flow to blood pressureelevation, an indication of the loss of autoregulation.120,121

The PCO2 levels can be manipulated by changing the ventila-tion rate in an intubated patient,76–78 or by injecting acetazol-amide intravenously. The resulting vasodilation produces anincreased CBF of 50% to 100% in normal tissues.73 The lack

of flow augmentation is indicative of maximal vasodilatationand a lack of vascular reserves.69,73 A paradoxical decrease ofregional CBF has proven to be diagnostic of a subgroup athigh risk for future infarction69 (class I). No prospective studyhas been undertaken to determine whether that risk can beminimized by a flow augmentation procedure, such as anEC-IC bypass.

VasospasmThe XeCT method has been used to determine which

patients developing neurological deficits after SAH are suf-fering from vasospasm-induced slow flow and cerebral ische-mia and to differentiate this condition from other causes ofdeterioration33,34,84 (class IV). If vasospasm is present, med-ical therapy can be instituted initially, and, if this fails,intracranial angioplasty and/or the infusion of a vasodilatorcan be performed with a higher risk of vascular and neuro-logical injury. XeCT can establish the presence of ische-mia,33,34,84 and both medical and endovascular techniques canbe used to increase CBF, as demonstrated on subsequentXeCT studies33,34 (class IV). However, it has not been proventhat such treatments improve patient outcome.

Head InjuryThe XeCT technique can be used in the intubated head

injury patient to determine the appropriate rate of assistedventilation that seeks to balance the need to lower intracranialvascular volume while maintaining adequate blood flow.91–93

The loss of normal chemoregulation (a 3% lowering of CBFin response to a 1-mm Hg lowering of PCO2 during a doubleXeCT study) is a significant indicator of irreversible cerebralinjury, and the level and pattern of CBF reduction in theinjured tissues have been prognostic of poor outcome81–83

(class II).

Balloon Occlusion TestCBF maps can be made before and after temporary

occlusion of a carotid or vertebral artery with an inflatableballoon during a XeCT test if no neurological deficit hasoccurred during prolonged balloon inflation under fluoro-scopic control.88 Such flow studies provide assessment of thepotential for collateral circulation, and of the potential risk ofarterial sacrifice, possibly much better than just the neurolog-ical examination90 (class IV).

Marker of Seizure FocusXeCT CBF has also been used to demonstrate a region of

increased flow as a marker for the site of seizure activity inpatients with chronic epilepsy122,123 (class IV).

Availability of the System, Cost, and ReimbursementThere are only 30 systems in the United States at this time,

and 40 in Europe, but there are more than 700 in Japan.Although there has been a hiatus in the supply of medical-grade xenon in the US, the agent is currently available underan Investigational New Drug (IND) authorization until theFood and Drug Administration reviews a new NDA applica-tion for safety and efficacy.

The hardware and software cost approximately $150 000.Reimbursement in the United States is currently for a CT scanwith and without contrast enhancement, and a charge for




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computer manipulation of the data might be added. Theconsistency of this reimbursement in each state is unknown.

Advantages and Disadvantages Relative to OtherTechniques

The advantages are the following:

1. The technique is based on CT, which is a ubiquitoustechnology.

2. CBF analysis can be added to other CT studies, such asnonenhanced CT and CT angiography (CTA), in thesame imaging session.

3. This is a quantitative technique, with CBF given inabsolute values.

4. The hardware and software are relatively inexpensive inrelation to other types of imaging equipment.

5. The examinations are standardized for a given CTsystem and between different systems.

6. Challenge tests can be performed to study cerebrovas-cular physiology.

7. The literature describes numerous studies ranging fromclass I to IV in quality that used the technique in bothanimals and humans for diversity of diseases.

The disadvantages are the following:

1. Patient motion can produce artifacts, making interpre-tation difficult and inaccurate.

2. It directly measures only one parameter, CBF (with theexception of the partition coefficient). Other vascularand tissue parameters must be evaluated by performingchallenge tests to derive surrogate endpoints.

3. There is no ability to evaluate cell viability or function-ality, such as with diffusion-weighted MR; these param-eters are assumed, given the level of CBF and theduration of the insult. Concurrent changes in CT imagesdo provide the ability to integrate CBF data withCT-defined evidence of infarction.

Recommendations

1. With increased availability of stable xenon gas, it isimperative that more centers evaluate the utility of thistechnology in numerous clinical conditions.

2. Quantitative data, especially absolute values of perfu-sion, may be helpful as an aid in determining the risksand benefits of revascularization of the acute strokepatient, including post-thrombolysis hemorrhage, andXeCT can be used to acquire such information (gradeA).

3. Prospective controlled outcome studies of acute strokepatients treated with revascularization after XeCT stud-ies, with blinding of their CBF values, must be under-taken in order to prove the predictability of the quanti-tative data.

4. Prospective outcome studies following the recanaliza-tion of acute stroke patients, with and without XeCTperfusion imaging and blinded to specific CBF levels ifacquired, must be undertaken to evaluate the relativebenefits of earlier treatment versus the time-consumingacquisition of physiological data that may predict out-come and risk.

5. XeCT perfusion imaging with an acetazolamide chal-lenge test can be used to define a group of patients withchronic ischemia who are at significant risk for infarc-

tion (grade A). Larger prospective studies are necessary,along with prospective comparative studies, to deter-mine whether a flow augmentation bypass can reducethe risk predicted by XeCT.

6. CBF levels obtained with XeCT, combined with studiesof autoregulation and the responses to physiologicalchallenges, can probably be used to accurately predictoutcome following head trauma (grade B). Largerprospective and comparative studies should be under-taken to prove the validity of this utilization.

Single Photon Emission CT

Rationale of TechniqueA radioisotope such as technitium-99m (99mTc) is attached

to a delivery compound that passes through the BBB afterintravenous injection and is metabolized by neuronal andglial cells. Hence, this radioactive compound “sticks” duringfirst passage, with uptake proportional to CBF at the momentof passage,124 rather than the progressive tissue uptake that ischaracteristic of the xenon methods. Imaging can be per-formed anytime within a few hours after injection.

Method of PerformanceThe radioisotope, 99mTc, must be attached to the delivery

compound, hexamethylpropyleneamine oxime (HMPAO) orethyl cysteinate dimer (ECD), before injection. Combining99mTc and HMPAO can be done in-house, using a commer-cially available kit, and requires approximately 20 to 30minutes.7

Once the compound is injected, circulation to and local-ization within the cerebral tissues occurs within 1 minute.Scanning of the head can be performed within the next fewhours,124 preferably using a system that provides maximumspatial resolution, such as a 2-headed or, even better, a3-headed SPECT imaging system. Data acquisition starts 5 to10 minutes after injection and is acquired in a 64�64 or128�128 matrix through a 360-degree rotation that requiresapproximately 5 minutes to complete. Reconstruction is bystandard filtered back-projection techniques using a 2D But-terworth filter.

Quantification, Accuracy, and ReproducibilityAbsolute quantification of the flow kinetics requires know-

ing the AIF, but this requires an indwelling arterial line.125–128

However, an alternative method that obviates the need forarterial blood sampling uses graphical analysis of the time-activity curves between the aortic arch and the brain.129–132

Usually a semiquantitative approach is taken by comparingthe counts in a given ROI with those in a comparable ROI inthe opposite, and presumably normal, hemisphere or inanother region such as the cerebellum (the “control” region).For example, in a case of acute embolus to a middle cerebralartery (MCA), the relative perfusion in the frontotemporalregion distal to the embolus can be determined by drawing anelliptical ROI in the ROI, measuring the counts in that region,moving the ROI to a control area and determining thosecounts, then dividing the former number by the latter toobtain the ratio (relative cerebral blood flow [rCBF]). Ofcourse, this assumes that the CBF to the unaffected hemi-sphere is normal, which is frequently not the case. Thisassumption is obviously fallacious for patients with chronic




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cerebrovascular disease, which is usually multifocal, or withvasospasm. Even in acute stroke, there are complicatedalterations of CBF in distant territories, even in the presum-ably unaffected hemisphere, which will produce errors whensuch ratios are calculated.133,134

The accuracy and reliability of SPECT CBF determinationare indicated by comparisons to other techniques. There is alinear relationship between rCBF measured by ECD-SPECTand that measured with PWI, which has a linear relationshipwith absolute CBF measured with PET. The volume ofhypoperfusion detected by HMPAO-SPECT has been shownto correlate significantly with that demonstrated byPWI50,135,136 (class II).

This is a relatively low-resolution method for imagingcerebral perfusion (Figure 2), without the inherently highspatial resolution of CT or MR. However, the counts in agiven region are very high, so that a large amount of data areprovided rapidly, obviating the effects of minor head motion.

Significant Issues in Study PerformancePreparation of the compound is rapid and can be done

while the patient is undergoing a CT scan to excludehemorrhage. The only problem may be the availability of thekit to make the compound. The ratio of the counts of uptaketo background is so high that data acquisition is rapid, headmotion is not an issue, and sedation is not necessary. Thesemiquantitative method is extremely simple; ratios of countsin the ROIs, indicative of relative blood flow, are determinedwith a calculator, and no special software is required.

Availability of the System, Cost, and ReimbursementEssentially all radiology departments in hospitals of 250

beds or more in the United States have 2- and 3-headedSPECT imaging systems that are used for a variety ofprocedures. No special software is needed for CBF analysis.There is no problem with reimbursement, which is sufficientto cover the cost of the procedure, including multiplanarreformations.

Diversity of the Data and Ability to Perform Challenge Tests

Acute StrokeNo treatment: Numerous reports demonstrate the ability of

HMPAO-99mTc SPECT imaging to detect hypoperfusion afterthe onset of acute stroke symptoms.31,38,45,54–59,135–144 Twoprospective, blinded, controlled trials demonstrated a sensi-tivity of the technique to abnormal perfusion in acute strokeranging from 61% to 74%, with a specificity of 88% to98%140 (class I). Of course, focal or regional ischemia of graymatter supplied by the larger pial vessels with more rapidflow was much more apparent than decreased flow to whitematter supplied by the smaller perforating vessels at a slowerrate. Findings on these studies have been shown to correlatewith the severity of neurological deficit, infarct size, andclinical outcome in untreated patients without evidence ofspontaneous recanalization54 –59,135,136,143,144 (class I-III).Early severe hypoperfusion within 6 hours after onset ofsymptoms was highly predictive (up to 92%) of poor neuro-logical outcome54–58,145 (class I). SPECT imaging is betterthan the neurological deficit score at predicting short-termoutcome if performed within 72 hours of symptom onset; ifperformed later, the improved flow after spontaneous recan-alization gives false-negative information.54 The size of theinfarct predicted by SPECT has been shown to correlatesignificantly with that measured by CT.59 The threshold ofrCBF on SPECT imaging between infarction and sustainedviability over time without thrombolysis has been shown tobe 0.52.136 Improvement in the perfusion abnormality due tospontaneous recanalization has been shown to correlate withimproved clinical outcome31,32 (class II).

With thrombolytic treatment: Based on 42 lesions in 30patients, Ueda et al22 reported that the rCBF threshold forreversibility of the ischemic process with intra-arterialthrombolysis was 0.55, and the threshold for hemorrhagefollowing this thrombolytic treatment was 0.35 (Figure 2).22

These imaging parameters predicted the treatment outcome,which was not influenced by the duration of the ischemicprocess, the location of the vascular occlusion, the sex of thepatient, or the dosage of thrombolytic drug22 (class I).Relative CBF on SPECT imaging has also been shown tocorrelate with response to intravenous tPA therapy andclinical outcome.38,143 These studies provide strong evidencefor the role of collateral circulation in maintaining viabilityuntil treatment can be performed. Like the studies using theXeCT technique, they demonstrate the value of determiningthe degree of perfusion to the ischemic tissue in makingtreatment decisions rather than simply using the time betweensymptom onset and potential treatment. Demonstrating thedegree of tissue viability may allow a prediction of theresponse to treatment, no matter the time from symptomonset. Again as in the XeCT studies, the degree of pretreat-ment perfusion predicts the potential for hemorrhage afterthrombolytic treatment, thereby aiding in the decision to under-take the risk of chemical recanalization22,38,45,143 (class I).

Not only does SPECT perfusion imaging help to determinethe relative risks and benefits of treatment, these studiesdemonstrate the value of data that are semiquantitative, incontradistinction to the more quantitative approach that is

Figure 2. SPECT-HMPAO CBF study. A right-handed femalehad the acute onset of right hemiparesis and aphasia 5 hourspreviously. This study demonstrates decreased levels of CBF inthe left frontotemporal region, but when comparing them to sim-ilar areas on the right, the ratio of counts suggests that the tis-sue is still viable, and thrombolysis may be of benefit.




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provided by the XeCT method.22,38,45,143 Whether such semi-quantification is sufficient to make difficult clinical decisions,or a more quantitative approach is necessary is a significantfocus of clinical research in perfusion imaging.

Chronic IschemiaSPECT imaging has been used to evaluate rCBF in patients

with symptoms of chronic cerebral ischemia. As previouslydiscussed, a single measurement of rCBF may be misleading.Determining the ratio of CBF in the symptomatic regionrelative to a control area may also be misleading, because thelatter values are considered to be normal, which may not becorrect. In addition, such a test does not provide dataregarding tissue demand, autoregulation, and vascular re-serves.67 Therefore, the need for a challenge test to providedata points under different physiological conditions isapparent.70

SPECT imaging before and after the administration ofacetazolamide has been used to demonstrate impaired vascu-lar reserves and maximum vasodilation in a territory referableto the presenting symptoms.67,70,72,73,145 This challenge testrequires the performance of 2 procedures separated by 1 ormore days and assumes that CBF does not change substan-tially between tests. The ratio of CBF values before and afteracetazolamide is obtained in the ROI and also between thearea in question and that in the control area. A lack ofsignificant change in CBF after acetazolamide within tissueshaving low flows on the pre-acetazolamide test is indicativeof a low-flow state with maximum vasodilation. Tissuedemand is present, autoregulatory mechanisms have beenexhausted, and there are no vascular reserves67,70,72,74 (classIII and IV data). However, such ratios assume a normal statein the comparative tissues. Validation of this qualitativemethodology relative to more quantitative techniques iscurrently lacking. The precise ratios of rCBF that suggest anincreased risk for future stroke and the potential need forsurgical flow augmentation have not been determined.

VasospasmRegional hypoperfusion on SPECT due to vasospasm after

SAH correlates with the presence and severity of delayedneurological deficits.86 SPECT can provide the early evidenceof vasospasm-induced hypoperfusion and may help to differ-entiate this hypoperfusion from other causes of neurologicaldeterioration, such as edema, hydrocephalus, elevated intra-cranial pressure, and metabolic etiologies. SPECT combinedwith transcranial Doppler may prove to be sensitive enoughfor the early detection of vasospasm and delayed ischemicdeficits to obviate other more invasive techniques87 (classIV).

Potential Ischemia Following Carotid Artery SacrificeDuring temporary carotid occlusion with a balloon,

HMPAO-99mTc is injected intravenously in order for thedistribution of CBF at the time of occlusion to be docu-mented. After the balloon has been deflated, the patient canbe scanned within the succeeding few hours, and the imageswill demonstrate the CBF at the time of occlusion.89 Ratios ofthe counts in an ROI of the cerebral hemisphere supplied bythe temporarily occluded ICA relative to an ROI in a control

area can be calculated, similar to the method for the acutestroke patient. However, the threshold of lowered CBF thatindicates the collateral circulation is inadequate to preventcerebral ischemia after permanent ICA occlusion has notbeen determined (class IV).

Evaluation After Head TraumaSPECT scanning is used following head trauma, especially

in patients with persistent neurobehavioral abnormalities aftermild degrees of trauma when the CT and MR studies arenormal. Areas of hypoperfusion may be seen in patients whohave abnormal neuropsychological tests146 (class IV). How-ever, the pathophysiology of these abnormalities and theirrole in predicting patient outcome and patient managementremain elusive.

Advantages and Disadvantages Relative to Other Techniques


1. The SPECT imaging is easy to perform, requiring onlyan intravenous injection.

2. Most large radiology departments have adequate hard-ware and software.

3. The software provides 3 orthogonal views of CBF incolor.

4. Semiquantitative measurements can be obtained rap-idly, requiring only a calculator.


1. Acquisition of the kit to make the injected compoundmay be difficult on short notice.

2. The data are nonanatomic, so that correlation must bemade with either a CT or MR scan acquired at anothertime. Coregistration with a CT or MR scan can beperformed, overlaying the SPECT data on the anatom-ical substrate, but this is a tedious, time-consumingprocedure.

3. The technique has low spatial resolution compared withCT and MR scans.

4. Because the arterial concentration of the isotope isusually not known, only semiquantitative analysis canbe made, such as the comparison of counts in analogousROIs.

5. There is no standard with which to compare the countsin a given ROI. Comparison to the uptake in anotherregion assumes that the CBF in the comparison ROI isnormal.

6. Comparison of studies performed on different daysassumes that CBF does not change. Comparison ofstudies in different patients and between institutionsrequires many assumptions and may be misleading.

7. The ability to perform challenge tests is limited becausethe baseline examination and the study during thechallenge usually must be performed on different days,and stable CBF must be assumed. Hence, the acquisi-tion of accurate data that may act as surrogates forcerebral metabolism or physiology is very difficult.

Recommendations

1. SPECT CBF studies can be used to determine therelative risks of hemorrhage following thrombolysis of




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acute stroke patients, whatever the time after onset ofsymptoms (grade A).

2. Because both the quantitative (XeCT) and semiquanti-tative (SPECT) methods provide class I data regardingthe risks of hemorrhage following thrombolysis, andboth may be helpful in identifying patients at greaterrisk of hemorrhage after thrombolysis, comparativestudies must be undertaken to determine the relativemerits of the 2 methodologies. Studies should also beperformed to determine the value of the time expendi-ture in obtaining such data.

3. Because the SPECT data obtained with challenge testscannot be controlled, the reliability of this technique toevaluate patients with chronic ischemia is unproven(grade D). These techniques should be compared withmore stable, quantitative methodologies to determinetheir role in such assessment.

4. The SPECT CBF technique is unproven (class IV data)in determining the presence of clinically significantvasospasm and for predicting infarction following ca-rotid artery sacrifice (grade D). These techniques shouldbe compared with more rigorous, quantitativemethodologies.

5. The value of SPECT CBF in head-injured patients isunproven (grade D).

Nondiffusible Tracer Techniques

CT Perfusion

Rationale of TechniqueThe Central Volume Principle relates CBV, MTT, and

CBF.96–98 CT can measure the integrated change in tissuedensity following the intravascular injection of a contrastagent to calculate CBV.147 MTT and CBF are time-relatedvalues and require rapid imaging of a limited volume ofimaged slices to determine the density change over time,arterial input and venous outflow values, and the use ofmathematical models that assume that the contrast stayswithin the vasculature.102–107 Although the concept of perfu-sion CT is not new,148 the ability to measure these perfusionparameters with accuracy has been made possible with thedevelopment of high-speed helical/spiral CT scanners havingsolid-state detectors and a gantry design to contain the veryhigh gravitational forces generated by high-speed rotation ofthe x-ray tube.10 Software development has been a crucialpart of this development, allowing rapid electronic transfer ofdata from the detector arrays and rapid image reconstructionfor perfusion analysis.39,85,100,149–164

Methods of Performance

There are 2 methods of CTP, which differ in the amount ofbrain that can be imaged, the rate and volume of contrastinjected, the type of data that are acquired, and the degreeof quantification that is possible.

Slow-Infusion/Whole-Brain TechniqueTechnique: First, a nonenhanced CT of the head is ob-

tained. Then, a typical intravenous iodinated contrast infusionprotocol is 3 mL/s of a nonionic agent over 40 seconds, for atotal of 120 mL. A delay of 25 seconds permits a peak ofcontrast enhancement of the entire brain and vasculature to beachieved before the start of scanning. The CT table move-ment and scanner rotation speed are adjusted so that scanthickness is 1 to 1.25 mm from vertex to skull base. Image

reconstruction yields 3- to 5-mm-thick images of the entirebrain parenchyma for the determination of relative CBV, and1- to 1.25-mm-thick images for the simultaneous reconstruc-tion of a CTA of the vessels at the skull base.39,53,101,154

Relative quantification: Pixel-by-pixel subtraction of theunenhanced from the enhanced scans is performed to yieldmaps of contrast concentrations only, minus the underlyingbrain density. Normalization of brain values with densitymeasurements in a large vein such as the superior sagittalsinus yields relative “perfused CBV” maps.100 MTT and CBFcannot be determined with this method because there are notimed data and no AIF. Low-density changes on the nonen-hanced CT are assumed to represent infarction, and changeson the CBV map are correlated with these parenchymalabnormalities to differentiate reversible from nonreversibleischemia. In addition, it may be possible to generate maps ofthe risks of infarction using CBV values only.165

Utilization, accuracy, and reproducibility: Recent paperssuggest that the combination of CTA and the relativelysimple CTP CBV maps is a fast and effective way ofevaluating the acute stroke patient. The CTA can demonstratea clot in a large vessel that might respond better to IA than IVthrombolysis. The combination of the nonenhanced CT show-ing the parenchymal changes that have already occurred, theCBV map showing the tissue at risk, and the location andlength of the vascular obstruction is used to make thedetermination to undertake thrombolysis39,53,100,101,161 (classIII and IV data). However, the actual level of ischemia and abetter distinction between reversible and nonreversible ische-mia may not be possible without the use of a more rigorous,time-dependent quantitative method.166 In addition, evalua-tion of physiological parameters such as vascular reserves ina patient with chronic ischemia is probably not possible withthis limited technique.

First-Pass Bolus-Tracking MethodologyTechnique: The requirement for multiple data points from

a given volume of tissue and the limited ability of currentscanners to move quickly back and forth from one slice to thenext mean that at this time, only a limited amount of the braincan be imaged during a CTP study, usually 2 sections up to10 mm in thickness each, covering 2 to 3 cm of the brain. Thisrequires the physician to determine the most likely location ofthe ischemic process, either on the basis of the initialnonenhanced CT scan or on clinical grounds. Usually one ofthe slices passes through the basal ganglia, so that portions ofthe middle, anterior, and posterior cerebral distributions areevaluated.10,49,100,167–170 The advent of multislice scanners haspermitted the acquisition of 2 contiguous 10-mm slices, 4 0.5-to 0.8-mm slices, or even 8 0.25-mm slices, but no significantincrease in the overall volume of scanned tissue. Although itis possible to move (“toggle”) the scanner between 2 moreseparated locations during the scanning protocol,155 fewerdata points are acquired at each location, leading to signal-to-noise limitations and lower-quality, less-accurate perfusionmaps.

An indwelling catheter of at least 18-gauge is inserted intothe brachial or cephalic vein, preferably on the right. Aprecontrast scan provides the baseline of attenuation valuesthat will be subtracted, voxel by voxel, from the enhancedscan. An injection of a contrast agent is performed, usually anon-ionic agent to minimize any sensations that might resultin movement. From 3 to 10 mL/s, for a total of 40 to 80 mL,has been reported. A 40-mL injection delivered at 5 mL/s willyield a “bolus width” in the brain of 16 to 20 seconds. An




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80-mL bolus delivered at 10 mL/s, requiring a 16-gaugeindwelling catheter, will also result in a bolus width of 16 to20 seconds, but approximately twice the peak opacity will beachieved, resulting in improved signal-to-noise ratio, relativeto the smaller dose.10,100,149–152,157–159

If a combination of the slow/whole-brain and the quanti-tative bolus-tracking methods is desired, the initial contrastinjection to acquire the CTA and CBV maps is slowed to 2.5mL/s for a total of 90 to 95 mL. The bolus-tracking study isperformed with 4 to 6 mL/s for a total of 45 mL, making atotal of 140 mL for the entire study. The contrast from thefirst study can be allowed to wash out before the second, orthe density from the first study represents the baseline for thesecond.53,101

A recent publication suggests another way to evaluatemore brain tissue. Two studies are performed 5 minutes apart,centered at 2 different levels, each study consisting of two10-mm slides so that a total of 4 cm of brain is scanned. Eachstudy requires 50 mL of contrast material, injected at 5 mL/s.A CTA can also be obtained in the same sitting, requiring anadditional 50 mL of contrast. Thus, the 150 mL of contrastthat is typical of an enhanced cerebral CT study yields both ahigh-resolution study of the extracranial and intracranialvessels and a perfusion study of much of the brain.171

Quantification of the bolus technique: The deconvolutionmethod requires that attenuation values of an artery in thefield of view, such as the horizontal MCA or the verticalACA, and of a major venous sinus such as the SSS, arecombined with the time-density information to calculaterMTT, rCBV, and rCBF (Figure 3). The accuracy of thismethod requires an intact BBB, so that the contrast materialstays within the intravascular space; leakage into the tissuesresults in spuriously high values of the flow parameters.Although the goal is to obtain absolute values of MTT, CBV,and CBF, most investigators have relied on relative maps ofperfusion, with a mismatch between the rMTT and the rCBVor rCBF maps indicating the presence of ischemic butpotentially salvageable brain.149–152,167–170,172–174

An analysis of the “time to peak” does not require thecomplexity of the deconvolution method. Maps of the relativespeed of the contrast agent reaching each voxel of the singleslice can be quickly constructed from the time-density da-ta.173 Obviously, this type of analysis does not address thevolume of blood that reaches the destination, whether bydirect or collateral channels, just the relative speed. A

vascular distribution far from the ICA, fed primarily bycollateral channels, would have a significantly delayed time-to-peak value yet might be adequately perfused. The role ofthis method in triaging patients with acute ischemia fortreatment is under investigation.167,174

A recent article suggests that truly quantitative CBV andCBF values can be obtained with CTP and that they maydifferentiate reversible from non-reversible ischemia.171 Theunderlying concept is that as CBF falls, CBV is initiallyunchanged or increases slightly, reflecting vasodilation, aspart of the autoregulatory process. As CBF continues to fall tolevels of irreversible ischemia, CBV drops, too. The authorsused a CBV level of �2.5 mL/100 g to define infarcted tissueand CBF �34% of the analogous tissues in the oppositehemisphere to define the combined reversible and irreversibleischemic tissues (infarct plus penumbra). Some of the patientsunderwent thrombolysis with salvage of tissue. There was ahighly significant correlation between the defined values andthe outcome of the at-risk tissues on subsequent CT anddiffusion-weighted MR studies. The authors’ use of “prog-nostic maps,” with the very low CBV map analogous to theMR DWI map, parallels the MR perfusion/diffusion mis-match concept.175 There are no data as to how knowledge ofthe perfusion as demonstrated with CTP may aid in theassessment of the risk of hemorrhage following thrombolysis.

Issues regarding accuracy and reproducibility: The accu-racy of the Central Volume Principle has been validatedmany times over the past 100 years since its proposal96–98

(class I). The accuracy of the deconvolution method ofquantification of CTP has been validated relative to othermethods of blood flow analysis, including injected micro-spheres in the experimental animal and the diffusible tracer,xenon149–152,176 (class I). However, there are significant issuesregarding the quantification of CTP as used clinically with aCT scanner. Many problems exist with the accuracy ofmeasuring the AIF. First, the horizontal portion of the MCAis only 3 mm in diameter and the ACA 2 mm, which permitspartial volume effects in their density measurements. Second,which MCA should be chosen for the AIF? That on the sideof the ischemia will probably have a slower flow rate than thenormal contralateral one. Third, a significant problem occursif the slice of interest is higher than the usual one through thebasal ganglia and a smaller vessel must be chosen for the AIFmeasurement, so that the accuracy in density measurement iseven less than for the MCA or ACA. Fourth, the desired MTTparameter is transit time through the same volume in whichthe CBV is determined, not between the MCA and a venoussinus, but transit time to and from that tissue volume cannotbe determined with current methodology. Finally, the pres-ence of large vessels in the analyzed volume overestimatesCBF.177

Diversity of Data From Both Methods and Ability toPerform Challenge Tests

Most of the reports discussing this new and evolvingtechnology deal with evaluating the acute stroke patient. Theslow infusion method provides both CBV maps and ahigh-resolution CTA of the large vessels at the skullbase39,53,100,101,161 (class III and IV data). However, there is aquestion whether this technique provides the ability to dis-tinguish reversible from non-reversible ischemia.166 Thebolus-tracking method seeks to provide such discriminationby acquiring quantifiable data, albeit in a limited volume oftissue10,49,100,167–175 (class III and IV). A combination of these

Figure 3. CT Perfusion study. Acute left hemiparesis broughtthis middle-aged man to seek emergency treatment. A quantita-tive CTP study through the MCA distributions permitted perfu-sion maps to be produced for rCBV, rCBF, and rMTT. The colorscale can be used to determine relative flow values, which canbe compared with those of the contralateral hemisphere.




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2 techniques may be necessary to determine the correct levelfrom which to obtain quantified data, or the approach of 2 ormore injections may suffice. Whether the extra time forperforming these studies leads to better decision-making fortherapy and better patient outcomes will be determined byfuture research.53,101,171,175

For the study of chronic ischemic disease, there are fewarticles evaluating cerebrovascular reserves,71 such as with anacetazolamide challenge test75,176,177 or by varying PCO2

levels in the intubated subject160 (class IV). Performance of 2studies during the same imaging session requires morecontrast material, but the use of non-ionic agents decreasesthe risk of a contrast reaction significantly.176–183 Study of thepatient with vasospasm using CTP has been limited85 (classIV). There are no data on its use in head injury, as part of theBOT, or as an aid in brain death determination.

Availability of the System, Cost, and ReimbursementThe use of helical and spiral CT scanners is increasing rapidly

in the United States, and most urban hospitals and imagingcenters now have such equipment for many other uses. Multi-detector systems are becoming common, and the newest scan-ners have 16 detector arrays. Thus, the performance and the costof CTP are limited only by the purchase of an independentworkstation, which can be used for many software processingapplications, and appropriate CTP software (�$60 000 to$80 000). Reimbursement for CTA exists, and should be forth-coming for CTP as the necessary codes evolve to cover complexdata processing applications for both CT and MR.



1. The technique is based on the use of helical and spiralCT scanners, the numbers and scanning capabilities ofwhich are rapidly increasing.

2. Because the technique is CT-based, any other CTtechnique, such as nonenhanced CT and CTA, can beperformed during the same imaging session.

3. The method of performance is rapid, requiring only 60seconds or less of contrast infusion.

4. The slow-infusion CBV technique is very easy, requir-ing a minimum of software.

5. The slow-infusion technique also provides a CTA tovisualize the obstructed artery.

6. Perfusion parameters can be quantified to characterizevarious degrees of tissue ischemia.

7. Maps of probably irreversible ischemia (very low CBV)and tissue at risk (lowered CBF, reflecting both infarctand penumbra) may improve analysis of a large amountof complex data.

8. A combination of both the qualitative slow infusionCBV method to demonstrate the area of ischemia andthe status of the vasculature and the quantitative tech-nique to more fully characterize the tissue could beperformed without an overdose of injected contrastmaterial.


1. The amount of brain that is imaged with the bolus-tracking method is limited, and the newest multisliceCT systems do not improve this volume of coverage.

2. Even with a multislice CT system, the speed of imageacquisition is significantly slower than with echoplanarMR. This may directly affect the number of slices thatcan be studied, the amount of data per slice, and,therefore, the accuracy of the data.

3. The radiation dose to the volume of tissue studied withthe bolus-tracking method is relatively high comparedwith other perfusion techniques.

4. Although the slow-infusion technique can demonstratedecreased blood volume in the ischemic tissue, theability to differentiate between reversible and irrevers-ible ischemia is probably not as great as with thequantifiable techniques.

5. The accuracy and reproducibility of the quantifiablebolus-tracking method requires a more robust way tomeasure the AIF.

6. The ability to assess the risk of hemorrhage followingthrombolysis, as demonstrated with both the XeCT andSPECT methods, has not been demonstrated by acquir-ing quantified CTP perfusion parameters.

7. The accuracy of the quantified data depends on an intactBBB, which is frequently not the case if the ischemicevent has been ongoing for a few days.

8. The role of quantitative CTP in patients with chroniccerebral ischemia, vasospasm, or head injury as part ofthe BOT and as a surrogate for brain death determina-tion has not been demonstrated.

9. The number of repeated examinations, including thosefor challenge tests, is limited by the amount of contrastthat can be tolerated systemically.

Recommendations

1. Quantitative CTP may possibly be useful to differenti-ate between reversibly and irreversibly ischemic tissuesin the acute stroke patient (grade C). Large prospectiveand appropriately blinded studies will be necessary todetermine the value of this technique. There are no dataregarding the ability of this technique to predict thepotential for hemorrhage following thrombolysis, asthere is for the diffusible tracer techniques.

2. Qualitative mapping of CBV with the slow-infusionmethod, in combination with the acquisition of CTA,may possibly be of value to determine emergent formsof therapy for the acute stroke patient (grade C). Again,larger prospective studies are needed.

3. No recommendation can be made for the use of thistechnique in patients with chronic ischemia, vasospasm,head trauma, or as part of the BOT (grade D).

Perfusion and Diffusion MRAlthough PWI and DWI are distinctly different techniques,they will be considered together in this section because theyare interrelated physiological parameters, and both are usu-ally performed during the same imaging examination.

Rationales of the Techniques

Perfusion MRThere are 2 types of perfusion MR, the First Pass Bolus

Tracking technique (also called dynamic susceptibility con-trast [DSC] imaging), analogous to CTP, and the arterial




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spin-labeling (ASL) method. In DSC imaging, a paramag-netic contrast agent produces dephasing of protons in an areaequal to the radius of the blood vessel as the agent movesthrough the vasculature, leading to an alteration of T2*relaxation in the adjoining tissues. The degree of T2* effect isproportional to the perfusion.9,12–14,60,99,184–187

In the ASL method, water proton spins in the extracranialblood are saturated and inverted electromagnetically, andthese labeled protons mix with extravascular water in thebrain. Intracranial imaging before and after spin inversiondetects the difference in tissue magnetization, which isproportional to local perfusion.188–191 The method suffersfrom a relatively low signal-to-noise ratio, requiring longimaging times as compensation, but may provide quantifiabledata.192 However, because this is an experimental methodwith few data regarding its utilization in acute or chronicischemia, there will be no further discussion of this technique.

Diffusion MRThe ability of water molecules to diffuse can be evaluated

by the use of powerful gradient coils that undergo rapidswitching in polarity on either side of a 180-degree excitationpulse. The random motion of diffusion leads to phase shiftsand relative signal loss, whereas decreased or no motionproduces little or no signal loss and a relatively brightappearance on the diffusion-weighted image. The degree ofdiffusion weighting can be varied, with different valuesapplied so that an apparent diffusion coefficient (ADC) canbe calculated. Because the actual route of the diffusingmolecule is not measured, only its origin and final destina-tion, and because there are unmeasured variables that influ-ence the rate of diffusion, such as the temperature of thetissue, the ADC value is only “apparent” or “relative,” notabsolute, and must be compared with those obtained in otherareas during that DWI sequence. Diffusion is normallyaltered by the presence of membranes or the increasedconcentration of large molecules. In acute ischemia, the bulkmovement of water into the intracellular environment, con-taining many membranes and macromolecules, is a majorreason for the observed decrease in the rate of diffusion.Another is cell swelling, which increases the tortuosity of thepath that extracellular water protons must traverse and there-fore increases the diffusion time. After the dead tissue hasbeen absorbed, fewer obstructing membranes are present, andthe diffusion coefficient increases.8,193–196

Method of Performance of DSCTen to 13 brain slices are usually imaged, using a T2*–

weighted pulse sequence. Ten to 15 images per slice areobtained before contrast injection and averaged to provide abaseline intensity of each pixel in that slice. A gadolinium-containing contrast agent is injected into a peripheral vein,usually at 5 mL/s. If the gradient-echo echoplanar imaging(EPI) technique is used for image acquisition, a dose similarto T1 contrast enhancement (ie, 0.1 mmol/kg body weight) isused. If the spin-echo EPI technique is used, that concentra-tion is doubled. Imaging of the 10 to 13 brain slices isrepeated for 70 to 80 seconds after contrast injection, with 20to 40 images per slice obtained. Rapid imaging methods suchas EPI permit tracking of the bolus through the entire brain.The alterations of the signal intensity (SI) of the tissues aremeasured, and a time-SI curve is calculated for each voxel.The information provided by the gradient-echo technique

relates more to the magnetic susceptibility effects from thecontrast agent within large blood vessels, whereas the spin-echo technique provides more information regarding signalalterations from small vessels, which is more important whenstudying tissue perfusion and metabolism.14,185

QuantificationQuantification depends on measuring the signal intensity

change within the tissues, which is a function of the suscep-tibility effect of the contrast agent rather than directly relatedto the contrast concentration in the tissues, as it is withCTP.175 Relative quantification of CBV is straightforward,because it represents a simple change of intensity relative tothe nonenhanced images. The multiple images per voxel areused to calculate the time-intensity curve for that voxel, withthe area under the curve approximating the CBV of that voxel(rCBV).184–187 Quantification of MTT and CBF, which aretime-dependent parameters, is much more complex. Thehighest degree of quantification utilizes the deconvolutionmethod, similar to CTP, and requires knowledge of an AIF.This is obtained by highlighting a few voxels near but not ina well-visualized major artery at the skull base, such as anMCA. A relative value of CBF is calculated; then,rMTT�rCBV/rCBF. Unfortunately, these are still relativevalues. Absolute values cannot be calculated because thereare variables such as the dispersion of the contrast materialfollowing IV injection, cardiac output, and the preciseamount of contrast entering and leaving an ROI at a givenpoint in time that cannot be measured.185,197–201

Because the deconvolution method is computationallyintensive, a simpler, more approximate method can be used.Once the time-SI kinetic curve has been calculated for eachvoxel, the value of the width of the curve when it reaches onehalf of its maximum value (full width-half maximum) isproportional to the rMTT, whereas the slope of the increase inSI after contrast arrival is proportional to rCBF.185

Accuracy and Reproducibility of PWI Perfusion ParametersThere are significant issues regarding the ability to obtain

an AIF. The measurements of SI around an artery at the skullbase may be even less accurate than simply measuring arterialdensity as in the CTP methodology. In addition, tissue SI isnot in a direct linear relationship to tissue contrast concen-tration, as in CTP.175

There are a few reports comparing the perfusion parame-ters obtained with PWI to those acquired with PET scanningin both animals and humans that demonstrate the positivecorrelation between the 2 techniques.202–204 A few demon-strate the positive correlation between PWI and SPECT inhuman acute cerebral ischemia.135,143,205 One shows the pos-itive correlation between PWI and the XeCT technique.206

Interrelationship With DWIMost reports focus on the perfusion/diffusion “mismatch.”

The areas of DWI abnormalities with decreased ADCs areassumed to have suffered irreversible injury, at least by thetime the patient is scanned. The area of lowered perfusionvalues is usually larger than the DWI abnormality (Figure 4),and it has been shown that unless there is an increase in flowto this tissue in jeopardy, the DWI abnormality increases to




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match the perfusion abnormality. Hence, this area of loweredPWI and normal DWI is an index of the penumbra, or tissuethat has potentially reversible ischemia (Figure 4). PWI-DWImismatch does not precisely correlate with the physiologicalpenumbra. The DWI lesion overestimates the volume of theirreversibly ischemic tissue—the infarct—early after theonset of ischemia. The rMTT map appears to overestimate thesize of the penumbra, but whether rCBF also overestimates oris an accurate predictor of the tissue in jeopardy differsamong reports. CBV varies during the ischemic process. It isincreased initially after vascular occlusion via vasodilationand collateral flow, in conjunction with a prolonged rMTT,but a decreased rCBV probably indicates that these autoreg-ulatory mechanisms are exhausted and are inadequate toprevent infarction, and may be the best predictor of the size ofthe eventual infarct in the untreated patient. Despite thesecomplexities, diffusion-perfusion mismatch does appear toprovide a good indication of the presence of salvageablepenumbral tissue. Conversely, a pattern in which the diffusionabnormality is equal to or larger than that for perfusion indicatesthat there is no penumbra to salvage.8,14,16,17,41,42,60,185,201,207–210

It must be stressed that all perfusion and diffusion param-eters are relative, and no specific thresholds between revers-ible and irreversible ischemia have been defined. In addition,the validity of “irreversibility” can only be determined bymeasuring these parameters in a large group of patientsbefore and after some form of treatment, such asthrombolysis, or in patients who undergo early spontaneousrecanalization.40,41,211–213

Diversity of Data and Ability to Perform Challenge Tests

Acute StrokeMany controlled trials of perfusion and diffusion MR in the

experimental animal with induced ischemia have demonstratedthe ability of these techniques to define ischemic tissue (class Idata). Numerous retrospective trials in humans have demon-strated the ability of these methods not only to define ischemictissue but also to predict its death if no treatment is possible orsuccessful12–16,184–196,201,206–210 (class II).

The ability to use these data to guide the use of intra-ar-terial41 and intravenous42 thrombolytic therapy was reportedin 1999. Recent reports suggest that a significant portion ofthe abnormal DWI signal may normalize with flow restora-tion, indicating that this DWI abnormality is a combination ofboth reversible and nonreversible ischemia.40,212 Although“pseudo-normalization” of the DWI parameter may occurduring the process of infarction and tissue absorption,214

recent observations suggest that patients with a significanttrue normalization of their pretreatment DWI abnormalitydemonstrate significant clinical improvement.212,215 One re-port demonstrates the use of perfusion MR to monitor theeffects of hypertensive therapy to augment blood flow afteran acute stroke, improving the language deficits216 (all classIV data).

The ability of perfusion and diffusion MR to be as accuratein their predictive ability when treatment is a possibility andto guide those patient management decisions appears to beless clear than in the studies in which no treatment waspossible. Quantitative threshold values of DWI and PWIparameters differentiating reversible and irreversible ische-mia have not been determined. The fate of cerebral tissue

subjected to ischemia is a complex, multifactorial process,which includes factors of time from occlusion, hemodynam-ics, tissue susceptibility, and types of intervention. It may bedifficult to determine which of the perfusion and diffusionparameters, or a combination of them, adequately predict thepotential success of treatment strategies to salvage tissue injeopardy.213 In addition, there are no data at this time onthreshold values or even patterns of perfusion and diffusionparameters that would define the risk of inducing hemorrhagewith thrombolysis, as with both the XeCT and SPECTtechniques.22,43

Other UsesThere are a few reports regarding the use of PWI in chronic

ischemia,65,66,217 and some demonstrating the use of acetazol-amide and DSC scanning to evaluate vascular reserves.218

There is no substantial experience with the use of PWI todetermine the relative degree of ischemia from vasospasm orits use after head injury, to supplement the BOT, or to aid inbrain death determination.

Difficulties in Study PerformanceAlthough the perfusion and diffusion MR sequences are

relatively short, they are usually combined with othersequences, making for a lengthy examination (30 to 45minutes) on a sick patient. However, many institutionshave developed limited, stroke-specific protocols that canbe accomplished within 15 to 20 minutes of actual “in-room” time.

MR studies are performed in a relatively “closed” scanningenvironment, where it is difficult to monitor the patient. Inaddition, with the relative lack of MR scanning resourcescompared with those of CT, many institutions are reluctant toinsert an acute stroke patient into the already-busy MRschedule.

Finally, manufacturers have not made the calculations ofthe parametric perfusion maps as easy or rapid as necessary tomake them an integral part of the MR examination. Rather,the imager frequently must download the scanning data to aseparate console to obtain the maps. The diffusion images,however, are obtained quickly and easily and have becomeroutine in most institutions. Because of this, DWI scans arefrequently obtained without PWI maps. If the DWI scan isnormal, an inexperienced observer may make a diagnosis of“no stroke,” even when there is a neurological deficit, only tofind that the DWI scan becomes abnormal at a later time,beyond the window for thrombolytic treatment (Figure4).209,219,220 It is not appreciated that collateral circulation orother factors may prevent the DWI image from becomingabnormal as quickly as expected but that ADC mapping mayhave demonstrated an abnormality, and PWI would showfocally abnormal perfusion. The best patient to treat withthrombolysis has normal DWI and abnormal PWI, ie, de-creased perfusion without irreversible injury.211 Making theparametric perfusion and ADC maps readily accessible and“user-friendly” will decrease this source of confusion.

Availability of the System, Cost, and ReimbursementPWI currently requires a 1.5T system and expensive

modifications of both hardware (especially high-performancegradient coils) and software to permit EPI scanning. Although




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field strength is not an issue for the performance of DWI, itrequires expensive gradient coils. Diffusion and perfusionMR are usually added together to a 1.5T system. The cost ofthese MR modifications is in the hundreds of thousands ofdollars and is significantly greater than with any of the otherperfusion technologies. Even so, PWI is the most frequentlyused perfusion technology in the United States today. Reim-bursement for DWI is not an issue in most states, but paymentfor PWI is variable.



1. The ability to image not only cerebral perfusion, butalso the status of the tissue (diffusion), the patency ofthe vasculature (MR angiography), and the anatomicalsubstrate during the same imaging session.

2. The potential for differentiating reversibly and irrevers-ibly ischemic tissue by defining the status of the tissuevia DWI relative to its perfusion.

3. The rapidity of imaging the entire brain during theperfusion study, rather than a limited volume of braintissue.

4. The acquisition of many data points per voxel, increas-ing the quality of the time-dependent calculations.


1. The expense of the equipment2. The time of the examination3. The inhospitable MR scanning environment4. It is not clear that using only relative parametric maps of

the various forms of perfusion, in combination withdiffusion and ADC maps, provides enough predictivevalue regarding the ability to reverse the ischemicprocess.

5. The accuracy of the quantification of DSC imaging isextremely difficult and requires a far more robustmethod of determining the AIF.

6. The assumptions underlying the mismatch method ofdefining the amount of salvageable tissue are still beinginvestigated.

7. There is no information regarding the potential forhemorrhage following thrombolysis using either perfu-sion maps alone or the combination of diffusion andperfusion mapping, as there is with the diffusible tracertechniques.

8. There is no standardization between MR machines,even those of the same field strength. Thus, there is noability to compare any objective parameters betweensites, only relative data.

9. The ability to perform challenge tests to study cerebro-vascular physiology has not been defined. Using DSCimaging, challenge tests may be limited by the volumeof contrast material that can be injected. However, theymay be possible using the ASL technique.

Recommendations

1. Perfusion and diffusion MR can be recommended astechniques that have been proven capable of demon-strating severely ischemic tissue in the acute stroke

Figure 4. MR Perfusion and Diffusion Studies. This 70-year-old manpresented with acute onset of right leg weakness. An emergency MRstudy was performed, with a normal DWI sequence (A), especially inthe left ACA distribution. However, the MTT map of the perfusionstudy demonstrated markedly slow flow in the medial left posteriorfrontal and anterior parietal lobes (B). It was elected not to performthrombolysis. The DWI study the next day (C) demonstrated infarctionin the same distribution as the MTT abnormality.




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patient. These techniques are probably useful at differ-entiating between reversibly and irreversibly ischemictissues (grade B), although the issue of reversibility of adiffusion abnormality, especially in the early stages ofischemia, requires more study.

2. No recommendation can be given for the ability of thesetechniques to guide the use of treatment modalities suchas thrombolysis in the acute stroke patient, nor in theiruse to predict complications from that treatment, suchas postthrombolytic hemorrhage (grade D).

3. No recommendation can be made regarding the abilityof these techniques to provide accurate information onthe status of vascular reserves in patients with chronicischemia or in patients with vasospasm or head trauma.No information is available regarding their use as partof the BOT (grade D).

Summary Statement

1. More comparison testing of the different techniquesmust be performed in experimental ischemia modelsand in humans to determine the relative abilities of thesetechnologies to differentiate tissues having normal per-fusion, reversibly ischemic, and irreversibleischemia/infarction.

2. Quantifiable data are a laudable goal. Although theXeCT technique provides such data, and CTP may,obtaining such quantification with SPECT and Perfu-sion/Diffusion MR is much more complex. More re-search must be conducted to make these techniques,especially the MR-based methods, quantifiable. In ad-dition, the accuracy of the quantification must beimproved for all methods.

3. Outcome studies must determine not only the ability ofeach technology to predict the potential for infarctionand for reversibility but also the need for quantifiabledata to make those predictions. The use of perfusionpatterns, mismatches, and multi-parametric maps ofrelative data may be appropriate surrogates and muchmore rapid to acquire than quantified data.

4. Controlled outcome studies must determine whetherperfusion data help to define the risks and benefits oftreatment for acute ischemia and the ability to triagepatients into treatment groups. Are the data worth thedelay in time to treatment and the expense of thetechnology?

5. Are physiological challenge tests of vascular reserves inpatients with chronic ischemia an adequate surrogate fortissue metabolic data, like that derived from PET? Cansuch tests adequately predict potential infarction unlessflow augmentation is undertaken?

6. Reproducibility of the data is essential if patients withchronic ischemia are to be followed and if data betweencenters are to be compared. Scanning of a standardphantom has permitted reproducibility for the XeCTtechnique, and the reproducibility of the other methodsmust also be ensured.

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KEY WORDS: procedures and tests � stroke � AHA Scientific Statement




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George HademenosGregory Sorensen, Jeffrey L. Sunshine, Jose Biller, Lawrence Wechsler, Randall Higashida and Richard E. Latchaw, Howard Yonas, George J. Hunter, William T.C. Yuh, Toshihiro Ueda, A.

AssociationImaging, From the Council on Cardiovascular Radiology of the American Heart

Scientific Statement for Healthcare Professionals by the Writing Group on Perfusion Guidelines and Recommendations for Perfusion Imaging in Cerebral Ischemia: A

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