Clinical Effi cacy of MRI in 17 2 Clinical Efficacy of MRI in Stroke

Rüdiger von Kummer

CONTENTS brain pathology depicted by MRI will be clinically effective. Subsequent chapters will describe the 2.1 Introduction 17 stroke pathology depicted by MRI in more detail 2.2 Hierarchy of Efficacy Levels for Diagnostic Imaging 17 and discuss its impact on stroke treatment and clini- 2.2.1 Feasibility and Technical Capacity of Stroke cal outcome. MRI 18 2.2.2 Diagnostic Accuracy 19 2.2.3 Diagnostic Impact 19 2.2.4 Therapeutic Impact 20 2.2 2.2.5 Impact on Patients’ Clinical Outcome 20 2.2.6 Impact on Health Care Costs 20 Hierarchy of Efficacy Levels for 2.3 Summary 20 Diagnostic Imaging References 21 In theory, MRI can be clinically effective in acute stroke patients on six different levels (Fryback and Thornbury 1991; Kent and Larson 1992; Sunshine 2.1 and Applegate 2004) (Table 2.1): (1) MRI will reduce Introduction health care costs, if it enables treatment that pre- vents disability and death in stroke victims. (2) MRI It is well established that computed will improve the clinical outcome of stroke patients (CT) identifies patients with acute cerebral ischemia if it can identify patients who will benefit from an among stroke syndrome patients and thus enables effective treatment, e.g. thrombolysis, and exclude effective thrombolytic therapy (The ATLAN- others who will not benefit. (3) To identify patients TIS, ECASS, and NINDS rt-PA Study Group who will benefit from a specific treatment, MRI Investigators 2004). It is a matter of debate, must provide relevant information for the choice of however, whether information provided by imag- treatment not available from other sources. (4) This ing other than the exclusion of hemorrhage, e.g. the could include MRI sequences that make it possible assessment of ischemic , arterial pathology, to exclude brain hemorrhage and other diseases that or perfusion deficit, can really improve the clinical mimic ischemic stroke, and assess ischemic edema, outcome of acute ischemic stroke patients and can perfusion disturbance, mass effect, arterial wall thus reduce health costs (Powers 2000; Powers and pathology, and obstruction. (5) The MRI sequence Zivin 1998; Hacke and Warach 2000) Moreover, should be sensitive and specific for stroke pathology new imaging technology like magnetic resonance early after symptom onset. (6) This requires that imaging (MRI) offers new insights into acute stroke the MRI sequence is technically capable of reliably pathology that may result in improved treatment for detecting the relevant stroke pathology and can be more patients. This book will provide arguments for feasibly performed in acute stroke patients. the question of whether MRI should be implemented It is important to bear in mind that diagnostic in acute stroke management or not. This chapter imaging is only clinically effective if an effective will outline the theoretical background needed to treatment is available, and the information provided understand under which conditions vascular and by imaging identifies conditions where such treat- ment is beneficial. The clinical efficacy at any level R. von Kummer, MD in this hierarchy is a precondition for the efficacy Department of Neuroradiology, University of Technology of a higher level, but is not sufficient to guarantee Dresden, Fetscherstrasse 74, 01307 Dresden, Germany improved clinical outcome. For example, the capac- 18 R. von Kummer

Table 2.1. Hierarchy of clinical effi cacy for MRI in acute stroke

Level Measures to quantify clinical effi cacy 1. Societal value Cost per hospital stay, proportion of patients going back to work, cost per gained quality- adjusted life years 2. Clinical outcome Mortality and disability 3. Impact on treatment Increase in the proportion of patients identifi ed by MRI that benefi t from treatment 4. Diagnostic impact Increase in the proportion of patients with a specifi c stroke pathology identifi ed by MRI 5. Diagnostic accuracy Sensitivity, specifi city, and prospective values of MRI for a specifi c stroke pathology compared to a reference standard, assessment of validity 6. Technical capacity, feasibility Interobserver agreement in assessing a specifi c stroke pathology on MRI, proportion of patients who can tolerate examination with MRI ity of T2*-weighted (T2*w) sequences in detecting bility was impaired by contraindications in about deposits within brain parenchyma may 10% of patients and medical instability in 23% identify patients with amyloid angiopathy, but does and 28% of patients, respectively. In both studies, not mean that stroke treatment can be improved with the MRI scanner was unavailable for about 20% of the knowledge of this finding. This finding would patients. Moreover, Hand et al.(2005) reported that have an impact on treatment only if it can be shown 11 of 61 patients (18%) scanned became hypoxic that patients with such hemosiderin deposits may be in the MRI scanner and 20% were non-compliant harmed by thrombolysis. Moreover, it is impossible during the scan. Even if 100% availability of MRI to assess the clinical efficacy of MRI for ischemic is assumed for stroke centers in the near future, it stroke patients in general. The different levels of would appear that 20%–30% of acute stroke patients clinical efficacy can be determined only with regard cannot tolerate this examination or take risks when to specific brain pathology as depicted by MRI like being scanned. This numbers may be reduced with arterial disease, perfusion deficit, vascular contrast new scanner technology with larger bores or smaller enhancement, disturbed water , increase in magnets allowing better control of patients. Never- brain tissue water content, and brain hemorrhage. theless, at the moment patient safety should be seri- ously taken into account, and oxygen saturation should be monitored in severely ill patients during 2.2.1 MRI. For patients with severe stroke, CT should be Feasibility and Technical Capacity of Stroke MRI considered as a useful alternative. Technical capacity of stroke MRI is its capabil- Feasibility and technical capacity of MRI represent ity to reproducibly display recognizable images that the basic condition for its clinical effectiveness in demonstrate specific stroke pathology with good acute stroke. MRI is suitable as a first line investiga- intra- and interobserver reliability (Powers 2000). tion for all acute stroke patients in clinical routine It is conventionally measured by the agreement if it can be applied in all patients with suspected among observers after definition of the pathology stroke, with only a few exceptions. that is sought. Cohen’s kappa is widely accepted as a The availability of scanning equipment and measure of chance adjusted agreement that is some- trained personal, specific contraindications, patient times difficult to interpret, however (Feinstein and claustrophobia, and the safety of the sometimes very Cicchetti 1990). ill or uncooperative stroke patients limit the feasibil- What is the specific stroke pathology that should ity of stroke MRI during the scan. To determine the be recognized as increasing the chances of stroke true feasibility of MRI requires a prospective study treatment being beneficial? So far, reperfusion strat- in all patients presenting with suspected stroke. egies have only been shown to be beneficial in acute Singer et al. (2004) found that only 80% of 144 stroke stroke (Hacke et al. 1995, 2005; The National patients recruited “at the hospital door” could be Institute of Neurological Disorders and examined with MRI. Others reported even smaller Stroke rt-PA Stroke Study Group 1995; Furlan numbers between 54% and 62% of the patients in et al. 1999), whereas neuroprotective drugs failed whom MRI was feasible (Barber et al. 2005; Hand to show any effect. The rationale of a reperfusion et al. 2005; Schramm et al. 2004). According to strategy like thrombolysis is the recanalization Barber et al. (2005) and Hand et al. (2005), feasi- of an occluded brain-supplying artery in order to Clinical Effi cacy of MRI in Stroke 19 restore blood flow into ischemic brain tissue that is 2.2.2 not yet irreversibly injured and can regain function. Diagnostic Accuracy Consequently, imaging modalities that can reliably exclude brain hemorrhage or assess arterial occlu- In-vivo neuroimaging bears an inherent problem: sion, cerebral perfusion deficit, or ischemic tissue The assessment of validity and diagnostic accuracy damage may identify patients who will benefit from requires a reference that is accepted as gold stan- thrombolysis. dard, but is hardly achievable. Digital subtracted Kidwell et al. (2004) have shown that MRI can is the accepted gold standard for MR detect primary brain hemorrhage as reliably as angiography (MRA) in assessing arterial obstruc- CT in acute stroke patients, but that it is superior tions (Chap. 5), but is inferior to MRI in detecting to CT in detecting old hemorrhages within brain arterial wall pathology like mural hematoma. Posi- parenchyma (see Chap. 10). The reliability of MRI tron emission tomography was used to validate MR in detecting arterial disease and cerebral perfusion perfusion imaging (PI) (Chap. 6). However, for the deficits is discussed in Chaps. 5 and 6 in detail. The most important findings in acute stroke, intracra- detection of ischemic damage early after arterial nial hemorrhage and ischemic edema, a reference occlusion is difficult even under experimental con- standard is not available in most cases. When study- ditions with the possibility to study ischemic brain ing the sensitivity of MRI for intracranial hemor- tissue under the microscope (Garcia et al. 1995). rhage, MRI can be compared with CT (Kidwell et al. Severely ischemic brain tissue with blood flow 2004), the number of true positive patients remains below the threshold of structural integrity takes up unclear, however, because CT may miss the same water, however, immediately after arterial occlusion as MRI, and surgery or autopsy is fortu- (Schuier and Hossmann 1980; Todd et al. 1986). nately not performed in most of these patients. The CT can detect and measure the change in brain same is true for acute ischemic edema: The sensitiv- tissue water content and thus identify the volume ity and specificity of brain imaging can be evaluated of irreversibly injured brain tissue (Dzialowski under experimental conditions only (Dzialowski et al. 2004; von Kummer et al. 2001). The signal et al. 2004). If one accepts that ischemic necrosis is of MRI sequences is relatively insensi- represented by a well demarcated, hypoattenuating tive for brain tissue water content and cannot be arterial territory on CT or a brain tissue volume with used to define ischemic damage early on. As dis- increased signal on T2w sequences on follow-up cussed by Back and Neumann-Haefelin in Chaps. 3 images, one could use this as a reference and assess and 7, diffusion weighted imaging (DWI) also does the positive and negative predictive values of acute not directly show the volume of brain tissue that CT or MRI findings for the development of brain cannot recover from ischemia. The apparent dif- . Again, this approach suffers from the fusion coefficient (ADC) declines at cerebral blood same methodical problem: The sensitivity and spec- flow (CBF) values of 0.35–0.45 ml/g/min in animal ificity of CT and MRI findings for subacute or old studies and at 0.15–0.24 ml/g/min in humans, at the brain are not yet assessed. It is evident CBF threshold where the extracellular fluid space that MRI shows more than CT does (Chaps. 7–10); it shrinks due to ischemic cell swelling (Kohno et is not clear, however, what MRI fails to detect. al. 1995; Lin et al. 2003; The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group et al. 1995; Schuier and 2.2.3 Hossmann 1980; Wang et al. 2000). That means Diagnostic Impact that brain tissue volume with increased signal on DWI and associated decreased ADC may include The diagnostic impact of stroke MRI can be mea- both brain tissue that is irreversibly injured and sured by the percentage of patients in whom the tissue that can recover if CBF is restored. It appears diagnosis made without MRI is altered when the as if MRI has the technical capacity to exclude information from MRI is received (Albers et al. brain hemorrhage and to assess arterial pathology 2000). In acute hemorrhagic stroke, MRI does and perfusion deficits, but cannot reliably define not increase the frequency of this diagnosis, if all ischemic brain damage within the first hours after patients were examined with CT, but MRI may clar- stroke onset. Prediction of ischemic damage may be ify the cause of brain hemorrhage if gradient echo possible by combining the information of DWI and sequences are applied and detect, for example, signs PI in a multimodal approach (Chap. 8). of amyloid angiopathy or cavernous hemangioma. 20 R. von Kummer

MR angiography and PI do not add much to the with perfusion-diffusion mismatch up to 9 h after diagnostic information that can be provided by CT symptom onset (Hacke et al. 2005). Part 1 of this angiography and CT PI. DWI is highly sensitive for study was terminated prematurely because of high ischemic brain tissue even above the CBF level of rates of symptomatic brain hemorrhages in patients the and indicates brain tissue at high risk treated with desmoteplase. The upper limit of the if not already irreversibly injured, whereas hypoat- “DWI lesion” at baseline was reduced from two tenuation on CT depicts ischemic edema and tissue thirds to one third of the middle cerebral artery damage with high specificity within the first 6 h of territory. This adjustment of the protocol did not stroke onset (von Kummer et al. 2001). The pattern reduce the incidence of brain hemorrhages. The of areas with high signal on DWI may thus enable rate of symptomatic hemorrhages was considerably assessment of the affected brain territory and the reduced after lowering the dose of desmoteplase cause of stroke early on (Chaps. 13–16). in 57 patients (part 2). Part 2 of this study showed a beneficial effect of desmoteplase on reperfusion and on clinical outcome. Patients without perfu- 2.2.4 sion-diffusion mismatch were not studied. Conse- Therapeutic Impact quently, the impact of MRI findings on patients’ clinical outcome remains unclear. The study shows, The therapeutic impact of stroke MRI is measured however, that beneficial treatment can be achieved by the percentage of patients in whom MRI changes based on MRI imaging alone. treatment planned without MRI. As shown in Chap. 3, the MRI finding of extended brain perfusion defi- cit, but relatively small tissue volume with impaired 2.2.6 water diffusion (perfusion-diffusion mismatch) may Impact on Health Care Costs allow the treatment beyond currently accepted time windows. Parsons et al. (2002) showed a beneficial Although MRI is promising in that it provides spe- outcome after thrombolysis in patients with perfu- cific information which could improve treatment sion-diffusion mismatch within 6 h of stroke onset, in ischemic stroke, there is no scientific proof that but did not compare the effect of recombinant tissue it actually does improve patients’ clinical outcome. plasminogen activator (rt-PA) with placebo treat- Consequently, based on current knowledge, the ment. It is evident – though without scientific proof recommendation to base acute stroke management – that reperfusion strategies are clinically effective solely on MRI means a big investment without a only if a perfusion deficit is present. It was shown guaranteed return in the form of reduced health with CT-PI, that stroke patients without cerebral care costs. perfusion disturbance did not develop brain infarc- tions (Schramm et al. 2004). It is debatable whether PI is required in all stroke patients or whether the image of arterial obstruction or the clinical syn- drome is sufficient to justify reperfusion strategies 2.3 after brain hemorrhage and other stroke mimics Summary have been excluded. With a view to the high sen- sitivity of DWI for even relatively mild degrees of MRI has the specific capability to detect brain areas brain ischemia, the risk of ischemic damage appears with ischemic cell swelling and to identify deposits minimal in patients with small “DWI lesions”. It is of degradation products within brain still unclear, however, which extent of “DWI lesion” parenchyma. It can easily be combined with angi- is associated with a reduced chance to benefit from ography and PI and thus assess important aspects thrombolysis. of acute stroke pathology. MRI has the disadvan- tage that not all patients with suspected stroke can tolerate the examination. It will be discussed in the 2.2.5 following chapters whether the diagnostic informa- Impact on Patients’ Clinical Outcome tion provided by MRI has an impact on acute stroke treatment and can improve patients’ clinical out- The Desmoteplase in Acute Ischemic Stroke Trial come compared to patients being examined with (DIAS) was based on MRI and included patients CT. Clinical Effi cacy of MRI in Stroke 21

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