Aetna considers cerebral computed tomography (CT) perfusion studies medically necessary as a supplement to non-contrast head CT or when magnetic resonance imaging (MRI) is unavailable or contraindicated for the evaluation of acute cerebral ischemia.

Aetna considers cerebral CT perfusion studies experimental and investigational for the following indications because there is inadequate scientific evidence to support its use for these indications (not an all-inclusive list):

Aetna considers cerebral MRI perfusion studies (diffusion-weighted or perfusion-weighted) medically necessary for the evaluation of acute cerebral ischemia.

Aetna considers cerebral MRI perfusion studies experimental and investigational for assessment of response to angiogenesis inhibitors in persons with glioblastomas and evaluation of persistent pain because its effectiveness for these indications has not been established.

Computed Tomography Perfusion Studies:

Computed tomography (CT) perfusion imaging provides a quantitative measurement of regional cerebral blood flow.  A perfusion CT study involves sequential acquisition of CT sections during intravenous administration of an iodinated contrast agent.  Analysis of the results allows the physician to calculate the regional cerebral blood volume, the blood mean transit time through the cerebral capillaries, and the regional cerebral blood flow.

Currently, non-contrast computed tomography is used to detect intracerebral hemorrhage in stroke patients who are being considered for thrombolytic therapy.

Computed tomography perfusion imaging has been proposed to be used primarily as a method of evaluating patients suspected of having an acute stroke whenever thrombolysis is considered.  Computed tomography perfusion imaging may provide information about the presence and site of vascular occlusion, the presence and extent of ischemia, and about tissue viability.  This information may help the clinician determine whether thrombolysis is appropriate.

Potential advantages of CT perfusion imaging are that it can be performed using standard CT scanners, which are more widely available and less expensive than magnetic resonance imaging (MRI), and it is less invasive than CT angiography.  Computed tomography perfusion imaging can be performed rapidly, and involves injection of a relatively small amount of contrast agent.

Current literature on CT perfusion imaging has focused on its feasibility and technical capabilities.  Prospective clinical studies are needed to determine the clinical value of CT perfusion imaging over standard non-contrast computed tomography in the assessment of patients with symptoms suggestive of acute stroke, and in the triage of patients in whom thrombolytic therapy is contemplated.

The Council on Cardiovascular Radiology of the American Heart Association provided guidelines and recommendations for perfusion imaging in cerebral ischemia (Latchaw et al, 2003).  It stated that quantitative CT perfusion may possibly be useful to differentiate between reversibly and irreversibly ischemic tissues in patients with acute stroke.  However, large prospective and appropriately blinded studies are needed to ascertain the value of this technique.  There are no data regarding the ability of this technique to predict the potential for hemorrhage following thrombolysis, as there is for the diffusible tracer techniques.  Furthermore, no recommendation can be made for the use of CT perfusion in patients with chronic ischemia, vasospasm, head trauma, or as part of the balloon occlusion test, the traditional method for identifying patients at risk for stroke.

In a review on imaging viable brain tissue with CT scan during acute stroke, Meuli (2004) stated that perfusion CT is now ready to be used in clinical trials as a decision-making tool to tailor more precisely the thrombolytic therapy to the individual patient.

Ding et al (2006) simultaneously examined regional cerebral blood volume (rCBV) and permeability surfaces (rPS) in glioma patients to determine their correlation with histological grade using CT perfusion imaging.  A total of 22 patients with gliomas underwent multi-slice CT perfusion imaging pre-operatively.  Low-grade and high-grade groups were categorized corresponding to World Health Organization (WHO) grade II gliomas and WHO grade III or IV gliomas, respectively, as determined by histopathological examination.  Regional cerebral blood volume and rPSs were obtained from regions of maximal abnormality in tumor parenchyma on CBV and PS color perfusion maps.  Perfusion parameters were compared using the Kruskal-Wallis test in order to evaluate the differences in relation to tumor grade.  The Pearson coefficients of rCBV and rPS for each tumor grade were assessed using SPSS 13.0 software.  Regional cerebral blood volume and rPS provided significant P-value in differentiating glioma grade (low-grade gliomas 3.28 +/- 2.01 versus 2.12 +/- 3.19 ml/100 g/min, high-grade gliomas 8.87 +/- 4.63 versus 12.11 +/- 3.18 ml/100 g/min, p < 0.05).  Receiver operating characteristic (ROC) curves revealed better specificity and sensitivity in PS than in CBV for glioma grade.  A significant correlation between rCBV and rPS was observed in high-grade gliomas (r = 0.684).  Regional cerebral blood volume in oligodendrogliomas were higher than in other low-grade gliomas, whereas their rPS values did not show a parallel difference.  The authors concluded that perfusion CT provides useful information for glioma grading and might have the potential to significantly impact clinical management and follow-up of cerebral gliomas.

Marco de Lucas et al (2006) noted that an early diagnosis is crucial in herpes simplex virus encephalitis patients in order to institute acyclovir therapy and reduce mortality rates.  Magnetic resonance imaging is considered the gold standard for evaluation of these patients, but is frequently not available in the emergency setting.  These investigators reported the first case of a CT perfusion study that helped to establish a prompt diagnosis revealing abnormal increase of blood flow in the affected temporo-parietal cortex at an early stage.

Sajjad (2008) noted that cerebral perfusion imaging allows blood flow to the cerebral tissue to be imaged.  It has been used in the management of acute ischemic stroke.  Using either CT or MRI techniques, perfusion maps can be created in a short enough time to allow their routine use in clinical practice.  Perfusion imaging enables physicians to directly estimate the tissue at risk, which can be salvaged with reperfusion, enabling appropriate patient selection.  However, perfusion imaging has its limitations that need to be kept in mind when these studies are interpreted.  Although perfusion imaging is widely used, the evidence to support its routine use in acute stroke is somewhat sparse and therefore there are no clear cut guidelines as to its role in this context.

Parsons (2008) stated that combining perfusion CT with CT angiography (CTA) and non-contrast CT (NCCT) provides much more information about acute stroke pathophysiology than NCCT alone.  This multi-modal CT approach adds only a few minutes to the standard NCCT and is more accessible and rapidly available in most centers than MRI.  Perfusion CT can distinguish between infarct core and penumbra, which is not possible with NCCT alone.  A small infarct core and large penumbra, plus the presence of vessel occlusion on CTA may be an ideal imaging "target" for thrombolysis.  To date, multi-modal CT has predominantly been assessed in hemispheric stroke due to its limited spatial coverage.  This will become less of an issue as slice coverage continues to improve with new generation CT scanners.  Apart from the concepts above, more specific perfusion CT and CTA criteria that increase (or decrease) probability of response to thrombolytic treatment are yet to be determined. Nonetheless, perfusion CT thus has the potential to improve patient selection for thrombolysis.

Provenzale et al (2008) performed a meta-analysis on perfusion imaging to determine its role in clinical decision making for patients with acute cerebral ischemia.  These investigators searched Medline by using a strategy that combined terms related to perfusion imaging with terms related to acute cerebral ischemia and brain tumors.  They identified 658 perfusion imaging articles and classified them according to the clinical usefulness criteria of Thornbury and Fryback; and found 59 articles with promise of indicating usefulness in clinical decision making.  These researchers devised and implemented a clinical decision-making scoring scale more appropriate to the topic of acute cerebral ischemia.  Several articles provided important insights into the physiological processes underlying acute cerebral ischemia by correlation of initial perfusion imaging deficits with clinical outcome or ultimate size of the infarct.  However, most articles showed relatively low relevance to influencing decisions in implementing treatment.  The authors concluded that most perfusion imaging articles were oriented toward important topics such as optimization of imaging parameters, determination of ischemia penumbra, and prediction of outcome.  However, information as to the role of perfusion imaging in clinical decision-making is lacking.  They stated that studies are needed to demonstrate that use of perfusion imaging changes outcome of patients with acute cerebral ischemia.

Wang et al (2010) noted that CT perfusion (CTP) mapping has been reported to be useful in the differentiation of the infarct core and ischemic penumbra.  However, the value of the CTP source imaging (CTP-SI) during the arterial and venous phases has not been fully investigated.  These researchers developed a CTP-SI methodology for acute ischemic stroke and compared its effectiveness with cerebral blood flow (CBF) and cerebral blood volume (CBV) in predicting infarct core and penumbra.  Computed tomographic examinations, including NCCT, CTP, and CTA, were performed in 42 patients with symptoms of stroke for less than 9 hours.  The Alberta Stroke Program Early CT Score (ASPECTS) was analyzed on the arterial phase CTP-SI and venous phase CTP-SI and then compared with the ASPECTS on CBF and CBV for effectiveness assessment.  The ASPECTS on the arterial phase CTP-SI was closely correlated with the ASPECTS on CBF, the Pearson correlation coefficient was 0.88 (p < 0.001), and the concordance correlation coefficient was 0.7603 (95 % confidence interval [CI]: 0.6331 to 0.8476).  The ASPECTS on the venous phase CTP-SI revealed a significant correlation with the ASPECTS on CBV, the Pearson correlation coefficient was 0.92 (p < 0.001), and the concordance correlation coefficient was 0.8880 (95 % CI: 0.8148 to 0.9334).  Significant differences were shown between the arterial phase CTP-SI/ venous phase CTP-SI (p < 0.001) and CBF/CBV (p < 0.001).  The authors concluded that this study provides preliminary evidence that the arterial phase and venous phase CTP-SI mis-match model could possibly be applied to ischemic regions in the acute stage of stroke to determine penumbra and infarct core.

In a prospective, pilot series, Schichor et al (2010) analyzed the feasibility of intra-operative CTA and brain perfusion mapping using an up-to-date multi-slice CT scanner.  A total of 10 patients with unruptured aneurysms underwent intra-operative scanning with a 40-slice sliding-gantry CT scanner.  Multi-modal CT acquisition was obtained in 8 patients consisting of dynamic CTP scanning followed by intra-cranial CTA.  Two of these patients underwent CTA and CTP 2 times in 1 session as a control after re-positioning cerebral aneurysm clips.  In another 2 patients, CTA was performed alone.  The quality of all imaging obtained was assessed in a blinded consensus reading performed by an experienced neurosurgeon and an experienced neuroradiologist.  A 6-point scoring system ranging from excellent to insufficient was used for quality evaluation of CTP and CTA.  In 9 of 10 CTP data sets, the quality was rated excellent or good.  In the remaining case, the quality was rated insufficient for diagnostic evaluation due to major streak artifacts induced by the titanium pins of the head clamp.  In this particular case, the quality of the related CTA was rated good and sufficient for intra-operative decision making.  The quality of all 12 CTA data sets was rated excellent or good.  In 1 patient with an anterior communicating artery aneurysm, CTP scanning led to a re-positioning of the clip because of an ischemic pattern of the perfusion parameter maps due to clip stenosis of an artery.  The subsequent CTP scan obtained in this patient revealed an improved perfusion of the related vascular territory, and follow-up MRI showed only minor ischemia of the anterior cerebral artery territory.  The authors concluded that intra-operative CTA and CTP scanning were shown to be feasible with short acquisition time, little interference with the surgical workflow, and very good diagnostic imaging quality.  Thus, these modalities might be very helpful in vascular neurosurgery.  They stated that having demonstrated their feasibility, the impact of these methods on patients' outcomes has now to be analyzed prospectively in a larger series.

Silvennoinen et al (2010) stated that the routine diagnostic tool of acute ischemic stroke is NCCT.  Modern multi-slice CT scanners also allow functional imaging with brain perfusion and CTA.  Wider adoption of thrombolytic therapy in acute stroke have advanced their application.  Computed tomography perfusion is fast and widely available.  It allows verification of cerebral ischemia, and may potentially assist in determining the extent of the ischemic tissue that still is salvageable with thrombolytic therapy.  Major cerebral arteries can also be visualized to detect occlusions or stenosis, which also assists in clinical decision making.  Non-contrast CT still remains the mainstay of acute stroke imaging.  Furthermore, Warren et al (2010) noted that integrated stroke imaging, including demonstration of potentially salvageable tissue with either MR perfusion/diffusion studies or CT perfusion, is increasingly likely to play a central role in future management strategies and widening of the potential therapeutic window.

Lovblad and Baird (2010) noted that over the past 10 years, there has been a parallel in progress in techniques in both diagnostic and therapeutic options for acute cerebral ischemia.  While previously only used for excluding hemorrhage, imaging now has the possibility to detect ischemia, vascular occlusion, and tissue at risk in one setting.  It also allow clinicians to monitor treatment and predict/exclude therapeutic complications.  Parallel to advances in MRI of stroke, CT has markedly improved over the past 10 years as a result of the development of faster CT scanners, which allow clinicians to acquire CTP or CTA in a reliable way. Computed tomography can detect many signs that might help clinicians detect impending signs of massive infarction, but there is still a lack of experience in the use of these techniques to guide possible therapy.

In a pilot study, Michel and colleagues (2012) examined the feasibility of a trial of perfusion computed tomography (PCT)-guided thrombolysis in patients with ischemic tissue at risk of infarction and unknown stroke onset.  Patients with a supra-tentorial stroke of unknown onset in the middle cerebral artery territory and significant volume of at-risk tissue on PCT were randomized to intravenous thrombolysis with alteplase (0.9 mg/kg) or placebo.  Feasibility endpoints were randomization and blinded treatment of patients within 2 hrs after hospital arrival, and the correct application (estimation) of the perfusion imaging criteria.  At baseline, there was a trend towards older age [69.5 (57 to 78) versus 49 (44 to 78) years] in the thrombolysis group (n = 6) compared to placebo (n = 6).  Regarding feasibility, hospital arrival to treatment delay was above the allowed 2 hrs in 3 patients (25 %).  There were 2 protocol violations (17 %) regarding PCT, both under-estimating the predicted infarct in patients randomized in the placebo group.  No symptomatic hemorrhage or death occurred during the first 7 days.  Three of the 4 (75 %) and 1 of the 5 (20 %) patients were re-canalized in the thrombolysis and placebo group respectively.  The volume of non-infarcted at-risk tissue was 84 (44 to 206) cm(3) in the treatment arm and 29 (8 to 105) cm(3) in the placebo arm.  The authors concluded that this pilot study shoeds that a randomized PCT-guided thrombolysis trial in patients with stroke of unknown onset may be feasible if issues such as treatment delays and reliable identification of tissue at risk of infarction tissue are resolved.  Safety and efficiency of such an approach need to be established.

Recent guidelines regarding CT perfusion for evaluating acute cerebral ischema included the following:

• The European Federation of Neurological Societies' guideline on neuroimaging in acute stroke (Masdeu et al, 2006) stated that perfusion CT is helpful when MRI is not available and for the study of stroke patients for whom MRI is contraindicated (class IV, level GCPP).  Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).  Good clinical practice point (GCPP) supported primarily by expert opinion.
• The American Heart Association, American Stroke Association Stroke Council, and Clinical Cardiology Council's guidelines for the early management of adults with ischemic stroke (Adams et al, 2007) stated multi-modal CT and MRI may provide additional information that will improve diagnosis of ischemic stroke (Class I, Level of Evidence A).  Class I Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful and effective.  Level of Evidence "A" Data derived from multiple randomized clinical trials
• The American Association of Neuroscience Nurses' guide to the care of the hospitalized patient with ischemic stroke (2008) stated that the use of CT angiography (CTA) and CT perfusion (CTP) is growing in popularity and usefulness for acute stroke management.  CTA/CTP imaging at admission assists in evaluating the cervical vessels and determining infarct localization and site of vascular occlusion.  As this technology improves and is studied further, the use of CTA and CTP may increase.
• The American College of Radiology's Appropriateness Criteria on cerebrovascular disease (De La Paz et al, 2010) noted that advanced CTP methods improve sensitivity to acute ischemia and are increasingly used with CTA to evaluate acute stroke as a supplement to the non-contrast head CT.
• The Institute for Clinical Systems Improvement's guideline on the diagnosis and treatment of ischemic stroke (2010) stated that although ischemic brain swelling typically peaks between 3 and 5 days after stroke onset, marked early swelling (in the first 24 to 48 hours) causing mass effect and tissue shift can occur in the most severe cases ("malignant" ischemic brain edema).  Low attenuation changes exceeding 2/3 of the middle cerebral artery territory and large areas of hypoperfusion on perfusion scans (CT perfusion or MRI perfusion) on initial radiological evaluation are associated with high risk of developing malignant brain edema.  Patients with these features should be strictly monitored with serial neurological examinations, ideally in a stroke unit.  Repeating CT scan of the brain to evaluate for progression of regional mass effect is indicated if the patient develops any signs of neurological deterioration.  The value of serial CT scans of the brain in the absence of clinical changes remains to be established.

An UpToDate review on “Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage” (Singer et al, 2013) stated that “Preliminary but accumulating data suggest that brain perfusion asymmetry demonstrated on CT perfusion (CTP) scanning in the acute stage of SAH may be a useful and highly sensitive method for predicting delayed cerebral ischemia, which is most cases, is presumably due to vasospasm.  A finding of perfusion-diffusion mismatch on MRI may be another method of detecting brain areas at risk of infarction in this setting.  However, the clinical utility of either of these methods remains to be established".

Shibamoto et al (2012) reported the case of a 31-year old male presenting with intra-cranial hemorrhage manifesting as deep coma and anisocoria underwent immediate emergency surgery.  Three-dimensional computed tomography (CT) angiography revealed stenosis of the right middle cerebral artery (MCA) and perfusion CT immediately after the surgery suggested severe hypo-perfusion in the right MCA territory.  Post-operative angiography demonstrated right unilateral moyamoya disease.  These researchers predicted that brain edema and intra-cranial pressure (ICP) elevation occurring after the hemorrhage might result in cerebral infarction.  Hyper-osmotic drugs were contraindicated by dehydration.  Therefore, therapeutic hypothermia was induced that controlled the ICP.  These researchers considered that the increased ICP, dehydration, vasospasm, and shrinkage of the ruptured vessel comprised the pathogenesis of acute cerebral ischemia after intra-cranial bleeding.  They stated that cerebral hemodynamics should be evaluated during the acute phase of cerebral hemorrhage to prevent subsequent cerebral infarction.

Furthermore, an UpToDate review on “Moyamoya disease: Prognosis and treatment” (Suwanwela, 2013) stated that “Preoperative cerebral angiography with bilateral injections of the internal and external carotid arteries and vertebral arteries is generally recommended to evaluate the sites of occlusion and collateral circulation and to identify donor vessels.  Cerebral perfusion and autoregulation studies using xenon CT, perfusion CT, and/or perfusion MRI, with or without acetazolamide, may also be helpful in evaluating cerebrovascular reserve".

While CT perfusion may be useful for the evaluation of moyamoya disease patients who present with acute cerebral ischemic attacks, there is inadequate evidence to support CT perfusion for monitoring of the disease.

Magnetic Resonance Imaging Perfusion Studies:

Stroke is one of the most common causes of permanent disability and/or death in the Western world.  The majority of strokes is caused by acute ischemia as a consequence of occlusion of the cerebral artery by a clot.  The minority of strokes is related to intra-cerebral hemorrhage or other sources.  Transient ischemic attack (TIA) is defined as symptom duration of less than 24 hrs.  Time from onset of symptoms to treatment is considered to be the key variable that influences the indication of re-canalization therapy for treatment of acute brain infarction.  Early reperfusion has been reported to improve clinical outcomes, yet the majority of patients with acute stroke do not attend in time for thrombolysis, which is the only approved treatment.  To extend the time window for thrombolysis, several imaging parameters in computed tomography and magnetic resonance imaging (MRI) have been investigated.  In particular, multi-modal neuroimaging is increasingly employed in the initial evaluation and management of acute stroke patients in parallel with the expansion of therapeutic options.  Multi-modal MRI can identify the type of stroke (ischemia or hemorrhage), severity and location of the lesion, the patency of the intra-cranial vessels, the degree of cerebral perfusion, as well as the presence and size of the ischemic penumbra (tissue).  This information can be used to guide both acute and long-term treatment decisions for stroke patients (Kloska et al, 2010 ;  Warren et al, 2010; Burgess and Kidwell, 2011; Olivot and Albers, 2011).

Olivot and Albers (2011) noted that preliminary studies suggested that stroke victims with a significant penumbra estimated by the diffusion/perfusion mismatch on MRI benefit from thrombolysis beyond the currently recommended time window of 4.5 hrs.  New software programs can automatically produce reliable perfusion and diffusion maps for use in clinical practice.  Combined diffusion and perfusion MRI reveals an acute ischemic lesion in about 60 % of TIA patients.  Patients with transient symptoms and a restricted diffusion lesion on MRI are considered by the American Heart Association (AHA) scientific committee to have suffered a brain infarction and have a very high risk of early stroke recurrence.  The authors concluded multi-modal MRI provides critical real-time information about ongoing tissue injury as well as the risk of additional ischemic damage.  It is becoming an essential tool for the diagnosis, management and triage of acute TIA and brain infarction (Olivot and Albers, 2011).

Straka et al (2010) noted that diffusion-perfusion mismatch can be used to identify acute stroke patients that could benefit from re-perfusion therapies.  Early assessment of the mismatch facilitates necessary diagnosis and treatment decisions in acute stroke.  These researchers developed the RApid processing of PerfusIon and Diffusion (RAPID) for unsupervised, fully automated processing of perfusion and diffusion data for the purpose of expedited routine clinical assessment.  The RAPID system computes quantitative perfusion maps (CBV, CBF, mean transit time [MTT], and the time until the residue function reaches its peak [T(max)] using deconvolution of tissue and arterial signals.  Diffusion-weighted imaging/perfusion-weighted imaging (DWI/PWI) mismatch is automatically determined using infarct core segmentation of ADC maps and perfusion deficits segmented from T(max) maps.  The performance of RAPID was evaluated on 63 acute stroke cases, in which diffusion and perfusion lesion volumes were outlined by both a human reader and the RAPID system.  The correlation of outlined lesion volumes obtained from both methods was r(2) = 0.99 for DWI and r(2) = 0.96 for PWI.  For mismatch identification, RAPID showed 100 % sensitivity and 91 % specificity.  The mismatch information is made available on the hospital's PACS within 5 to 7 mins.  Results indicate that the automated system is sufficiently accurate and fast enough to be used for routine care as well as in clinical trials.

Kim et al (2010) developed fully automated software for dynamic susceptibility contrast (DSC) MR PWI to efficiently and reliably derive critical hemodynamic information for acute stroke treatment decisions.  Brain MR PWI was performed in 80 consecutive patients with acute non-lacunar ischemic stroke within 24 hrs after onset of symptom.  These studies were automatically processed to generate hemodynamic parameters that included CBF and CBV, and MTT.  To develop reliable software for PWI analysis, these investigators used computationally robust algorithms including the piecewise continuous regression method to determine bolus arrival time (BAT), log-linear curve fitting, arrival time independent de-convolution method as well as sophisticated motion correction methods.  An optimal arterial input function (AIF) search algorithm using a new artery-likelihood metric was also developed.  Anatomical locations of the automatically determined AIF were reviewed and validated.  The automatically computed BAT values were statistically compared with estimated BAT by a single observer.  In addition, gamma-variate curve-fitting errors of AIF and inter-subject variability of AIFs were analyzed.  Lastly, 2 observers independently assessed the quality and area of hypo-perfusion mismatched with restricted diffusion area from motion corrected MTT maps and compared that with time-to-peak (TTP) maps using the standard approach.  The AIF was identified within an arterial branch and enhanced areas of perfusion deficit were visualized in all evaluated cases.  Total processing time was 10.9 +/- 2.5 s (mean +/- S.D.) without motion correction and 267 +/- 80 s (mean +/- S.D.) with motion correction on a standard personal computer.  The MTT map produced with the authors' software adequately estimated brain areas with perfusion deficit and was significantly less affected by random noise of the PWI when compared with the TTP map.  Results of image quality assessment by 2 observers revealed that the MTT maps exhibited superior quality over the TTP maps (88 % good rating of MTT as compared to 68 % of TTP).  The authors' software allowed fully automated de-convolution analysis of DSC PWI using proven efficient algorithms that can be applied to acute stroke treatment decisions.

Recent guidelines regarding MRI perfusion for evaluating acute cerebral ischema included the following:

• The European Federation of Neurological Societies' guideline on neuroimaging in acute stroke (Masdeu et al, 2006) stated that MR PWI and MR DWI are very helpful for the evaluation of patients with acute ischemic stroke (class I, level A).
• The American Heart Association, American Stroke Association Stroke Council, and Clinical Cardiology Council's guidelines for the early management of adults with ischemic stroke (Adams et al, 2007) stated that multi-modal MRI may provide additional information that will improve diagnosis of ischemic stroke (Class I, Level of Evidence A).
• The American College of Radiology's Appropriateness Criteria on cerebrovascular disease (De La Paz et al, 2010) noted that MR DWI are highly sensitive and specific for acute cerebral ischemia and, when combined with MR PWI, may be used to identify potentially salvageable ischemic tissue, especially in the period greater than 3 hours after symptom onset.
• The Institute for Clinical Systems Improvement (ICSI)'s guideline on the diagnosis and treatment of ischemic stroke (ICSI, 2010) reported that MRI scans of the brain with diffusion- and susceptibility-weighted sequences are much more sensitive than CT in detecting new infarction and chronic hemorrhage as well as of equal sensitivity for acute hemorrhage.  If the patient is not having symptoms at the time of presentation, a MR DWI is preferred because diffusion-weighted sequences may identify patients at particularly high risk of early major recurrence.
• On behalf of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN), Schellinger et al (2010) evaluated the evidence for the use of MR DWI and MR PWI in the diagnosis of patients with acute ischemic stroke.  These investigators systematically analyzed the literature from 1966 to January 2008 to address the diagnostic and prognostic value of DWI and PWI.  Diffusion-weighted MRI is established as useful and should be considered more useful than non-contrast CT for the diagnosis of acute ischemic stroke within 12 hours of symptom onset.  Diffusion-weighted MRI should be performed for the most accurate diagnosis of acute ischemic stroke (Level A); however, the sensitivity of MR DWI for the diagnosis of ischemic stroke in a general sample of patients with possible acute stroke is not perfect.  On the basis of Class II and III evidence, baseline MR DWI volumes probably predict baseline stroke severity in anterior territory stroke (Level B) but possibly do not in vertebro-basilar artery territory stroke (Level C).  Baseline MR DWI lesion volumes probably predict (final) infarct volumes (Level B) and possibly predict early and late clinical outcome measures (Level C).  Baseline MR PWI volumes predict to a lesser degree the baseline stroke severity compared with DWI (Level C).  There is insufficient evidence to support or refute the value of MR PWI in diagnosing acute ischemic stroke.

Howard et al (2011) stated that development of treatments for acute and chronic pain conditions remains a challenge, with an unmet need for improved sensitivity and reproducibility in measuring pain in patients.  These investigators used pulsed-continuous arterial spin-labeling [pCASL], a relatively novel perfusion MRI technique, in conjunction with a commonly-used post-surgical model, to measure changes in regional cerebral blood flow [rCBF] associated with the experience of being in ongoing pain.  They demonstrated repeatable, reproducible assessment of ongoing pain that is independent of patient self-report.  In a cross-over trial design, 16 participants requiring bilateral removal of lower-jaw 3rd molars underwent pain-free pre-surgical pCASL scans.  Following extraction of either left or right tooth, repeat scans were acquired during post-operative ongoing pain.  When pain-free following surgical recovery, the pre/post-surgical scanning procedure was repeated for the remaining tooth.  Voxel-wise statistical comparison of pre and post-surgical scans was performed to reveal rCBF changes representing ongoing pain.  In addition, rCBF values in pre-defined pain and control brain regions were obtained.  Regional CBF increases (5 to 10 %) representing post-surgical ongoing pain were identified bilaterally in a network including primary and secondary somatosensory, insula and cingulate cortices, thalamus, amygdala, hippocampus, midbrain and brainstem (including trigeminal ganglion and principal-sensory nucleus), but not in a control region in visual cortex.  Regional CBF changes were reproducible, with no rCBF differences identified across scans within-session or between post-surgical pain sessions.  This was the first report of the cerebral representation of ongoing post-surgical pain without the need for exogenous tracers.  Regions of rCBF increases are plausibly associated with pain and the technique is reproducible, providing an attractive proposition for testing interventions for on-going pain that do not rely solely on patient self-report.  The authors concluded that these findings have the potential to improve the understanding of the cerebral representation of persistent painful conditions, leading to improved identification of specific patient sub-types and implementation of mechanism-based treatments.

Howard et al (2012) determined rCBF changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and examined rCBF variability across sessions.  These researchers used pCASL, a perfusion MRI technique.  The study included 16 patients with CMC OA and 17 matched controls.  Two pCASL scans and numerical rating scale (NRS) estimates of ongoing pain were acquired in each of 2 identical sessions.  Voxel-wise general linear model analyses were performed to determine rCBF differences between OA and control groups, rCBF differences between sessions within each group, and whether session-wise rCBF differences were related to variability in perceived ongoing pain.  In the OA group, rCBF increases representing ongoing pain were identified in the primary and secondary somatosensory, insula, and cingulate cortices; thalamus; amygdala; hippocampus; and dorsal midbrain/pontine tegmentum, including the peri-aqueductal gray/nucleus cuneiformis.  Session-wise rCBF differences in the OA group in the post-central, rostral/subgenual cingulate, mid/anterior insula, prefrontal, and premotor cortices were related to changes in perceived ongoing pain.  No significant session-wise rCBF differences were observed in controls.  The authors concluded that this was the first quantitative endogenous perfusion MRI study of the cerebral representation of ongoing, persistent pain due to OA.  Observed rCBF changes potentially indicate dysregulated central nervous system appraisal and modulation of pain, most likely the maladaptive neuroplastic sequelae of living with painful OA.  Moreover, the clinical value of cerebral MRI perfusion studies for evaluating persistent pain has yet to be established.

Liu and colleagues (2013) examined the effects of post-herpetic neuralgia (PHN) on resting-state brain activity utilizing ASL techniques.  Features of static and dynamic CBF were analyzed to reflect the specific brain response to PHN pain.  A total of 11 consecutive patients suffering from PHN and 11 age- and gender-matched control subjects underwent perfusion functional MRI brain scanning during the resting state.  Group comparison was conducted to detect the regions with significant changes of CBF in PHN patients.  Then these investigators chose those regions that were highly correlated with the self-reported pain intensity as "seeds" to calculate the functional connectivity of both groups.  Absolute CBF values of these regions were also compared across PHN patients and control subjects.  Significant increases in CBF of the patient group were observed in left striatum, right thalamus, left primary somatosensory cortex (S1), left insula, left amygdala, left primary somatomotor cortex, and left inferior parietal lobule.  Significant decreases in CBF were mainly located in the frontal cortex.  Regional CBF in the left caudate, left insula, left S1, and right thalamus was highly correlated with the pain intensity, and further comparison showed that the regional CBF in these regions is significantly higher in PHN groups.  Functional connectivity results demonstrated that the reward circuitry involved in striatum, prefrontal cortex, amygdala, and parahippocampal gyrus and the circuitry among striatum, thalamus, and insula were highly correlated with each element in PHN patients.  The authors stated that non-invasive brain perfusion imaging at rest may provide novel insights into the central mechanisms underlying PHN pain.

Aquino et al (2014) stated that PWI can be used to measure key aspects of tumor vascularity in-vivo and recent studies suggested that perfusion imaging may be useful in the early assessment of response to angiogenesis inhibitors.  These investigators compared Parametric Response Maps (PRMs) with the Region of Interest (ROI) approach in the analysis of tumor changes induced by bevacizumab and irinotecan in recurrent glioblastomas (rGBM), and evaluated if changes in tumor blood volume measured by perfusion MRI may predict clinical outcome.  A total of 42 rGBM patients with KPS greater than or equal to 50 were treated until progression, as defined by MRI with RANO criteria.  Relative CBV variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline.  Alternatively, relative CBV variations with respect to baseline were calculated into the evolving tumor region using a voxel-by-voxel difference.  Parametric Response Maps were created showing where relative CBV significantly increased, decreased or remained unchanged.  An increased blood volume in PRM (PRMCBV+) higher than 18 % (1st quartile) after 8 weeks of treatment was associated with increased progression free survival (PFS; 24 versus 13 weeks, p = 0.045) and overall survival (OS; 38 versus 25 weeks, p = 0.016).  After 8 weeks of treatment ROI analysis showed that mean relative CBV remained elevated in non-responsive patients (4.8 ± 0.9 versus 5.1 ± 1.2, p = 0.38), whereas decreased in responsive patients (4.2 ± 1.3 versus 3.8 ± 1.6 p = 0.04), and re-increased progressively when patients approached tumor progression.  The authors concluded that these findings suggested that PRMs can provide an early marker of response to anti-angiogenic treatment and warrant further confirmation in a larger cohort of GBM patients.