radiofrequency pulse can be used as an endogenous contrast agent. ASL should be focused on patients with contraindications to gadolinium contrast agents.
Susceptibility weighted imaging (SWI) and intracerebral hemorrhage
For the evaluation of intracerebral hemorrhage, clin- icians have traditionally relied on CT, in fear of miss- ing or misdiagnosing an intracerebral hemorrhage by utilizing MRI only. Thrombolysis as the most effect- ive treatment of ischemic stroke requires a rapid and reliable imaging assessment to exclude hemorrhage.
Systematic studies suggest that MRI identifies intra- cranial hemorrhages rapidly and reliably, in particular if appropriate sequences are performed such as SWI (or gradient echo [GRE] or T2*) for intracerebral hemorrhage [88] and FLAIR for subdural hematomas (SDHs) and subarachnoid hemorrhage (SAH).
MRI in fact may be superior to CT, especially for the detection of small chronic hemorrhages, the cere- bral microbleeds (CMBs). CMBs in the brain paren- chyma diagnosed in T2*-weighted MRI should be interpreted in the light of the patient’s history as well as the location, number, and distribution of the lesions and associated imaging findings. The retro- spective BRASIL study does not support the hypoth- esis that CMBs are associated with a higher risk for a clinically relevant intracerebral hemorrhage after anticoagulation/antiaggregation therapy or after thrombolytic therapy in stroke patients, and thus does not support the general exclusion of patients from therapy based on the presence of CMBs [89, 90].
SDHs can also be identified reliably with MRI. In the hyperacute setting, SDHs are best demonstrated on FLAIR sequences since FLAIR imaging nulls the effect of cerebrospinal fluid. On DWI, SDHs appear hyperintense and on T2*-weighted images they tend to be hypointense. The presence of mixed signal intensity within the SDH may indicate the presence of blood with different ages and MRI may emerge as a tool in selecting the therapeutic approach to SDHs [91]. Proton density-weighted images may add fur- ther value to the diagnosis of SDH [92].
For SAH detection, the best imaging sequences on MRI are FLAIR and proton density-weighted images.
MRI identifies intracranial hemorrhages rapidly and reliably, in particular if appropriate sequences are performed.
PART C: MULTIMODAL IMAGING-
radiation seems acceptable [102], it prohibits fre- quent use of PCT and CTA because of a probable risk of inducing cancer by radiation, particularly in younger subjects and with multiple exposures [103].
There are reports of radiation overdosing from wrongly calibrated scanners. Iodinated contrast can occasionally be associated with allergy, hyperthy- roidism, or renal failure, although the last seems to occur rarely [104]. These drawbacks are counter- balanced by the availability of CT in most emergency rooms, its easy accessibility, and the easy monitoring of patients. Patients with known severe renal failure (creatinine clearance <30 ml/min) should probably receive neither iodinated contrast agents nor gado- linium [105].
Both CT- and MR-based perfusion and arterial imaging are feasible in the emergency setting. Both detect intracranial hemorrhage with high accuracy, and exclude the major contraindications for throm- bolysis. Decisions for endovascular therapy based on non-invasive arterial imaging can be obtained by both methods with a sufficient degree of confidence.
Advantages of MRI of a higher sensitivity to detect acute ischemic stroke (DWI) have to be balanced with the somewhat easier accessibility of CT. Both methods have certain limitations in patients with agitation and renal failure, as described below. Ideally, a stroke-receiving hospital offers both CT- and MRI-based imaging on an emergency basis, allowing physicians to choose the most appropriate one for a clinical question and situation. More realistically, most hospitals will chose one method as their first-line imaging, where indications and contraindi- cations to multimodal sequences should be integrated in standard operating procedures of hyperacute stroke care.
With regard to information about brain perfusion, PCT appears at least equivalent to MRI, but both imaging methods still need better standardization. DWI has the advantage of widespread availability and relative robustness. On the other hand, the linear relationship between contrast concentration and signal intensity may be an advantage of CT perfusion imaging over
gadolinium-based MR perfusion imaging.
Advantages of CT: available in most emergency rooms, easily accessible, and the monitoring of patients is easy. Disadvantages: iodinated contrast can be associated with allergy, hyperthyroidism, or renal failure.
Advantages of MRI: higher sensitivity to detect acute ischemic stroke (DWI). Disadvantages: higher costs,
limited availability, more difficult patient monitoring, pacemaker incompatibility, and the longer time required for scanning.
Treatment decisions based on multimodal imaging
The concept of using advanced imaging for treatment decisions is similar for MR- and CT-based imaging.
Through the above-mentioned systematic work, sev- eral important markers for benefit from acute revas- cularization treatment have been identified: low core volumes, large penumbra volumes accompanied by reperfusion, reperfusion (mostly through recanaliza- tion of large arteries), good collateral blood flow. In general, there are important relationships and code- pendence between such multimodal imaging param- eters [51], and the most reliable and simple combination of variables for each clinical question still needs to be determined. In addition, generally applied thresholds in perfusion imaging might be inappropriate because the same degree of perfusion impairment might have a different impact on the tissue depending on patient age, the anatomic loca- tion, and time from stroke onset.
Analysis of multimodal MR-based treatment trials assessing the predictive value of multimodal imaging has shown its added value in some [77, 82], but not in others [78, 106], or only after reanalysis [69, 107]. The combination on MRI-based imaging of a core
<70 ml, a significant hypoperfusion of<100 ml, and a mismatch ratio of 1.8 has been labeled “target mismatch”by the DEFUSE group in order to describe the patient with an increased benefit from acute revascularization [65].
Some [108, 109] but not all [69, 106, 110] retro- spective analyses of recanalization treatments incorp- orating multimodal CT show a potential benefit.
Given the proven benefits in the first 2–3 hours after stroke onset and the high likelihood of substantial pen- umbra and limited infarct size very early on, intraven- ous thrombolytics should probably be given immediately after exclusion of major contraindications.
Multimodal imaging may then be added during throm- bolysis and guide further treatment decisions such as:
adding or not mechanical revascularization treatment
treating patients arriving late or with unknown
stroke onset
55
selecting the best treatment modality to achieve rapid reperfusion
avoiding overtreatment that is likely futile or harmful.
Several important markers for benefit from
acute revascularization treatment can be identified by multimodal CT and MRI investigations: low
core volumes, large penumbra volumes accompanied by reperfusion, reperfusion (mostly through recanalization of large arteries), and good collateral blood flow.
Patient selection for clinical trials based on multimodal imaging
Several important markers for benefit from acute revascularization treatment can be identified by mul- timodal CT and MRI investigations, as described above. Such knowledge was gained in randomized and non-randomized trials applying multimodal imaging systematically before revascularization trials, with various results:
DEFUSE-1: non-randomized trial of intravenous rtPA at 0–6 hours. Finding: if mismatch pattern was present and reperfusion was achieved, clinical outcome was improved [77]
EPITHET: randomized trial using intravenous rtPA vs. placebo at 3–6 hours. Findings: initial analysis negative [78]. Post-hoc analysis of target mismatch patients, using coregistration
techniques: less infarct growth was observed with rtPA [79].
DEFUSE-2: non-randomized trial of standard treatment vs. endovascular reperfusion treatment.
Findings: if mismatch pattern was present and reperfusion was achieved, clinical outcome was improved [82]
MR RESCUE: randomized trial using
standard treatment (including intravenous rtPA) vs. endovascular recanalization up to 8 hours.
Findings: mismatch pattern was not associated with outcome [106].
Several randomized revascularization trials using advanced neuroimaging for treatment selection have been completed:
DIAS-2: intravenous desmoteplase vs. placebo in the 3–9-hour window if20% mismatch on PWI or PCT
:
Overall result negative regarding 3 months handicap:
Subgroup of occlusion patients had benefit [69]:
Subgroup of patients with60% mismatch had benefit [80]:
Intravenous tenecteplase vs. rtPA in the 0–6- hour window if20% mismatch on PCT! tenecteplase was superior to rtPA regarding 3 months handicapWake-up pilot trial: n¼12 based on PCT mismatch
:
PCT-based wake-up study is feasible:
Number of patients too small to make conclusions on efficacy.Knowledge from such trials can be combined with insight obtained from case series and randomized recanalization trials that did not use multimodal imaging, such as PROACT-2 [111], IMS-3 [112], and SYNTHESIS [113]. Such lessons include:
Presence of initial arterial occlusion matters: if there is visible occlusion, revascularization treatments are more likely to work
Time is brain also for endovascular treatment [114]
Completeness of recanalization matters, in addition to speed.
Reperfusion trials using multimodal imaging are now under way, selecting patients based on tissue viability, occlusion patterns, or both (see Table 3.C.1). All these trials are using non-invasive arterial information for patient selection, and all CT-based trials set an upper limit for the volume of early ischemic changes.
Automated mismatch analyzer software in acute ischemic stroke is part of some of these trials and needs further validation; at this stage, such programs cannot be recommended for routine clinical use because of limited knowledge about their limitations and accur- acy. Further work on methodological standardization and thresholds is needed for a practical and operation core/penumbra definition [115]. Other acute imaging parameters such as site of arterial occlusion, thrombus length or load, and degree of collateralization also need to be integrated in patient selection models.
Reperfusion trials using multimodal imaging are now under way, selecting patients based on tissue viability, occlusion patterns, or both.
56
Chapter summary
CT, perfusion CT, CT angiography
Non-contrast CT (NCCT) is considered sufficient to select patients for intravenous thrombolysis with intravenous RTPA within 4.5 hours, or endovascular treatment within 6 hours. It is a highly accurate method for identifying acute intracerebral hemor- rhage and subarachnoid hemorrhage, but quite insensitive for detecting acute ischemia. Early ische- mic changes (EIC) on NCCT predict post-thrombolysis symptomatic ICH independently of other factors.
Perfusion CT (PCT) with iodinated contrast can be used to create parametric maps of regional cerebral blood volume, mean transit time, and regional cere- bral blood flow. PCT has an overall sensitivity of about 75% for ischemic stroke, above 85% for
non-lacunar supratentorial infarcts, and a high speci- ficity for ischemia, but diffusion-weighted MRI (DWI) remains more sensitive for small and infratentorial lesions. Still, in the absence of an abnormality on PCT in a patient with stroke symptoms, acute recanaliza- tion treatments might be inappropriate.
CT angiography (CTA) has been shown to identify the site of arterial occlusion in acute ischemic stroke patients, with similar accuracy as DSA and probably better than MRA. Clot length can be assessed by thin-sliced NCCT and CTA. Clot presence, localization, length, and burden seem to predict clinical outcome and clot length and site seem to predict recanaliza- tion after intravenous thrombolysis.
Hyperintensity in acute intracranial hemorrhage (ICH) is present on NCCT from its onset in virtually all patients, but one main advantage of adding Table 3.C.1. Ongoing randomized phase IIB or III acute stroke revascularization trials
Name Arterial criteria Tissue viability Treatment tested
DIAS-3/4 √ CT : EIC IV desmoteplase (3–9 h)
BASICS √ CT : EIC IV rtPA vs. bridging (0–6 h)
THRACE √ CT : EIC Endovascular vs. IV rtPA
PISTE √ CT : EIC IV rtPA vs. bridging
MR CLEAN √ CT : EIC Endovascular vs. standard
THERAPY √ CT : EIC IV rtPA vs. bridging (<8 h)
POSITIVE √ CT : EIC Endovascular vs. standard for
IV thrombolysis ineligible (<12 h)
°* WAKE-UP – DWI/FLAIR IV rt-PA vs. placebo for wake-up
° DAWN √ DWI or PCT
(max. core)
Endovascular vs. standard for wake-up or late (<24 h)
° REVASCAT √ DWI or PCT
(max. core)
Endovascular vs. standard (<8 h)
° ESCAPE √ CT or PCT
(max. core)
Endovascular vs. standard (<12 h)
°* EXTEND/ ECASS-4 – PWI (or PCT) IV rtPA vs. placebo (4.5–9 h)
°* DEFUSE-3 √ PWI/DWI Endovascular vs. standard (<15 h)
°* SWIFT-PRIME √ PWI/DWI
or PCT
IV rtPA vs. bridging (0–4.5 h)
°* EXTEND-IA √ PWI/DWI or PCT IV rtPA vs. bridging (0–4.5 h)
° indicates that multimodal imaging core information based on advanced imaging is required as a selection criterion for the trial.
* indicates that some form of radiological mismatch information is required.
EIC¼early ischemic changes on non-contrast CT; IV¼intravenous; Bridging¼IV rtPA followed rapidly by an endovascular revascularization procedure.
57
iodinated contrast in ICH is that contrast extravasa- tion (“leakage”) is an independent predictor of hema- toma growth and poorer clinical outcome.
MRI and MR angiography
Sensitivity of diffusion-weighted imaging (DWI) at standard slice thickness of 5–6 mm is 80–90%, which is about twice the sensitivity of acute non-contrast CT examinations. DWI lesions represent infarction in the majority of stroke patients but are not com- pletely specific for infarction–hyperintensities have also been reported after seizures and in multiple sclerosis plaques. A normal DWI exam in a patient with suspected stroke may also indicate a stroke imitator such as epileptic seizures, hypoglycemia, and migraine with aura. Such patients presenting with stroke-like symptoms but showing neither infarction/ischemia nor vessel obstruction are unlikely to benefit from thrombolysis.
The so-called DWI-FLAIR mismatch with FLAIR (fluid attenuated inversion recovery) negative DWI lesions identified patients within 4.5 hours of symp- tom onset with 62% sensitivity and 83% positive predictive value. FLAIR imaging may be used as a substitute for the time clock in patients with unknown stroke onset as it seems to separate with reasonable accuracy the patient within and outside the 4.5-hour (thrombolysis) window.
MRA directly reveals the location of the vessel occlusion. Patients presenting with a major vessel occlusion or severe stenosis seem more likely to bene- fit from thrombolytic treatment.
The extension of hypoperfusion on perfusion imaging (PWI) beyond the corresponding DWI boundary represents penumbra. This PWI > DWI mismatch has been used to identify patients that are likely to benefit from reperfusion therapies.
Arterial spin labeling (ASL) enables imaging of perfusion without contrast agent. Blood labeled with a radiofrequency pulse can be used as an endogenous contrast agent. ASL should be focused
on patients with contraindications to gadolinium contrast agents.
MRI identifies intracranial hemorrhages rapidly and reliably, in particular if appropriate sequences are performed. MRI in fact may be superior to CT for the detection of small chronic hemorrhages, the cere- bral microbleeds. Subdural hematomas can also be identified reliably with MRI and are best demon- strated on FLAIR sequences. For subarachnoidal hem- orrhage detection, the best imaging sequences on MRI are FLAIR and proton density-weighted images.
Comparison of MR- and CT-based acute stroke imaging
With regard to information about brain perfusion, PCT appears at least equivalent to MRI, but both imaging methods still need better standardization. DWI has the advantage of widespread availability and relative robustness. On the other hand, the linear relationship between contrast concentration and signal intensity may be an advantage of CT perfusion imaging over gadolinium-based MR perfusion imaging.
Iodinated contrast can occasionally be associated with allergy, hyperthyroidism, or renal failure. On the other hand, CT is available in most emergency rooms, is easily accessible, and the monitoring of patients is easy.
Advantages of MRI of a higher sensitivity to detect acute ischemic stroke (DWI) have to be bal- anced with its cost, limited availability, more difficult patient monitoring, pacemaker incompatibility, and the longer time required for scanning.
Several important markers for benefit from acute revascularization treatment can be identified by multimodal CT and MRI investigations: low core volumes, large penumbra volumes accompanied by reperfusion, reperfusion (mostly through recanalization of large arteries), and good collateral blood flow. Reperfusion trials using multimodal imaging are now under way, selecting patients based on tissue viability, occlusion patterns, or both.
References
1. Krol AL, Dzialowski I, Roy J,et al.
Incidence of radiocontrast nephropathy in patients
undergoing acute stroke computed tomography angiography.Stroke 2007;38:2364–6.
2. Michel P, Odier C, Rutgers M,et al.
The Acute STroke Registry and
Analysis of Lausanne (ASTRAL):
design and baseline analysis of an ischemic stroke registry
including acute multimodal imaging.Stroke2010;
41:2491–8.
3. Na DG, Kim EY, Ryoo JW,et al.
CT sign of brain swelling without concomitant parenchymal hypoattenuation: comparison
with diffusion- and perfusion- weighted MR imaging.Radiology 2005;235:992–48.
4. Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group.
58
Alberta Stroke Programme Early CT Score.Lancet2000;
355:1670–4.
5. Puetz V, Dzialowski I, Hill MD, Demchuk AM. The Alberta Stroke Program Early CT Score in clinical practice: what have we learned?Int J Stroke2009;
4:354–64.
6. Hill MD, Rowley HA, Adler F, et al. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS.Stroke2003;
34:1925–31.
7. Demchuk AM, Hill MD, Barber PA,et al. Importance of early ischemic computed tomography changes using ASPECTS in NINDS rtPA Stroke Study.Stroke 2005;36:2110–15.
8. Strbian D, Engelter S, Michel P, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score.
Ann Neurol2012;71:634–41.
9. Nezu T, Koga M, Nakagawara J, et al. Early ischemic change on CT versus diffusion-weighted imaging for patients with stroke receiving intravenous recombinant tissue- type plasminogen activator therapy: stroke acute management with urgent risk-factor assessment and improvement (SAMURAI) rt-PA registry.Stroke2011;
42:2196–200.
10. Latchaw RE, Yonas H, Hunter GJ, et al. Guidelines and
recommendations for perfusion imaging in cerebral ischemia: a scientific statement for healthcare professionals by the writing group on perfusion imaging, from the Council on Cardiovascular Radiology of the American Heart Association.Stroke2003;
34:1084–104.
11. Koenig M, Kraus M, Theek C, et al. Quantitative assessment of the ischemic brain by means of perfusion-related parameters derived from perfusion CT.Stroke 2001;32:431–7.
12. Eastwood JD, Lev MH, Azhari T, et al. CT perfusion scanning with deconvolution analysis: pilot study in patients with acute middle cerebral artery stroke.
Radiology2002;222:227–36.
13. Murphy BD, Fox AJ, Lee DH, et al. White matter thresholds for ischemic penumbra and infarct core in patients with acute stroke:
CT perfusion study.Radiology 2008;247:818–25.
14. Wintermark M, Reichhart M, Thiran JP,et al. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients.Ann Neurol2002;
51:417–32.
15. Wintermark M, Fischbein NJ, Smith WS,et al. Accuracy of dynamic perfusion CT with deconvolution in detecting acute hemispheric stroke.AJNR Am J Neuroradiol2005;26:104–12.
16. Youn SW, Kim JH, Weon YC, et al. Perfusion CT of the brain using 40-mm-wide detector and toggling table technique for initial imaging of acute stroke.AJR Am J Roentgenol2008;191:W120–6.
17. Wintermark M, Flanders AE, Velthuis B,et al. Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric stroke.Stroke2006;
37:979–85.
18. Bivard A, Spratt N, Levi C, Parsons M. Perfusion computer tomography: imaging and clinical validation in acute ischaemic stroke.Brain2011;134:3408–16.
19. Campbell BC, Christensen S, Levi CR,et al. Cerebral blood flow is the optimal CT perfusion parameter for assessing infarct core.Stroke2011;42:3435–40.
20. Michel P, Reichhart M, Wintermark M, Maeder Ph,
Bogousslavsky R. Perfusion-CT in transient ischemic attacks (abstract).Stroke2005;36:484.
21. Gelfand JM, Wintermark M, Josephson SA. Cerebral perfusion- CT patterns following seizure.Eur J Neurol2010;17:594–601.
22. Bezerra DC, Michel P, Reichhart M,et al. Perfusion-CT guided acute thrombolysis in patients with seizures at stroke onset (abstract).Stroke2005;36:484.
23. Gonzalez-Delgado M, Michel P, Reichhart M,et al. The significance of focal
hypoperfusion during migraine with aura (abstract).Stroke2005;
36:444.
24 Furtado AD, Smith WS, Koroshetz W,et al. Perfusion CT imaging follows clinical severity in left hemispheric strokes.Eur Neurol2008;60:244–52.
25. Zhu G, Michel P, Aghaebrahim A, et al. Computed tomography workup of patients suspected of acute ischemic stroke: perfusion computed tomography adds value compared with clinical evaluation, noncontrast computed
tomography, and computed tomography angiogram in terms of predicting outcome.Stroke 2013;44:1049–55.
26. Zhu G, Michel P, Aghaebrahim A, et al. Prediction of recanalization trumps prediction of tissue fate:
the penumbra: a dual-edged sword.Stroke2013;
44:1014–19.
27. Silvennoinen HM, Hamberg LM, Lindsberg PJ, Valanne L, Hunter GJ. CT perfusion identifies increased salvage of tissue in patients receiving intravenous recombinant tissue plasminogen activator within 3 hours of stroke onset.AJNR Am J Neuroradiol 2008;29:1118–23.
28. Psychogios MN, Schramm P, Frölich AM,et al. Early CT scale evaluation of multimodal computed tomography in
predicting clinical outcomes of