Radiological investigation to exclude hemorrhage is essential in selecting patients for thrombolysis. It may also help to identify patients with large completed infarcts, a small ischemic penumbra or TIA, in whom thrombolysis would not be beneficial. The majority of centers currently rely on CT rather than MRI as the first-line investigation in stroke.
Retrospective analysis of CT scans has suggested that early signs of extensive infarction on CT, corresponding to a very poor ASPECTS score of 2 (Weir et al.2006) are associated with 85% mortality without thrombolysis and poor outcome, including hemorrhagic trans- formation, after thrombolysis (von Kummeret al.1994,1997; Hackeet al.1998; Dzialowski et al.2006). These observations have led to the introduction of the“one-third rule,” that is, patients with signs of infarction of greater than one-third of the middle cerebral artery
territory on CT should not receive thrombolytic therapy. However, overestimation of the degree of ischemic change on CT may lead to thrombolytic treatment being inappropriately withheld (Barberet al.1999). Initial small studies investigating cerebral microbleeds and the risk of hemorrhagic transformation after thrombolysis showed an uncertain relationship (Derexet al.2005; Koennecke2006; Cordonnieret al.2007), but more recent data do not show an increased thrombolysis risk (Fiehleret al.2007). In contrast, the presence of a large lesion on DWI (Singeret al.2007) or high permeability (Banget al.2007) is associated with hemorrhage. The theory that the ischemic penumbra represents salvageable tissue has led to the proposal that thrombolysis is likely to be most effective in those patients with diffusion– perfusion mismatch. Despite the fact that the area of diffusion–perfusion mismatch does not precisely delineate the penumbra, it appears reasonably robust in representing tissue at risk of infarction. Use of recombinant tissue plasminogen activator is associated with early resolution of perfusion-weighted imaging lesions in less than 36 hours, reduced DWI lesion growth, smaller final stroke volumes and better clinical outcome on follow-up (Hjortet al.
2005b). It has been suggested that diffusion–perfusion mismatch might be mirrored by a
clinical–diffusion mismatch, but current data suggest that this is not the case (Lansberg et al.2007; Messeet al.2007).
In patients with matched images by DWI and perfusion-weighted imaging, it is unclear whether reperfusion will be of benefit since it is uncertain whether the area detected by DWI still contains a significant penumbra. In these cases, MR angiographic findings and the clinical picture should be taken into account. A severe neurological deficit and middle cerebral artery occlusion predicts a malignant middle cerebral artery infarction. A DWI lesion with normal or increased perfusion indicates spontaneous recanalization and is inappropriate for thrombolysis.
Both MR and CT angiography have been used to assess patients in the acute phase after stroke and have been proposed as possible means of selecting patients for thrombolysis. It has been observed that patients with a patent middle cerebral artery typically have smaller perfusion-weighted imaging volumes than patients with evidence of large vessel occlusion: absent middle cerebral artery flow on MR angiogram is significantly associated with a greater perfusion–diffusion mismatch, larger acute DWI lesions, secondary lesion growth, larger final infarct size and worse final outcome (Barberet al.1999). However, a significant minority of the 30–35% of patients with middle cerebral artery occlusion do not show progressive lesion enlargement and patients without middle cerebral artery occlusion may show significant mismatch.
At present, there is no consensus on the exact criteria to use in patient selection for thrombolysis using multimodal MRI (Handet al.2006). Many centers offer thrombolytic therapy to selected patients within three hours of stroke onset according to local criteria, including brain imaging findings, often CT based. Beyond the three to six hour time window, there are few data to guide treatment decisions, although thrombolysis has been shown to be potentially effective when given three to nine hours after stroke onset (Furlan et al.2006). In the phase II Desmoteplase In Acute Ischemic Stroke trial (DIAS), patients with MRI evidence of perfusion–diffusion mismatch were randomized to escalating doses of desmoteplase administered three to nine hours after acute ischemic stroke (Hackeet al.
2005). High doses of desmoteplase were associated with unacceptably high intracerebral hemorrhage rates, but lower doses produced a higher rate of reperfusion and suggested better clinical outcome compared with placebo.
In the observational DEFUSE (Diffusion and Perfusion Imaging Evaluation for Under- standing Stroke Evolution) study, an MRI scan was obtained immediately before and three
Chapter 11: Brain imaging in major acute stroke
to six hours after treatment with intravenous tissue plasminogen activator, which was given three to six hours after symptom onset (Alberset al.2006). Baseline MRI profiles were used to categorize patients into subgroups, and clinical responses were compared based on whether early reperfusion was achieved. Early reperfusion was associated with significantly increased odds of achieving a favorable clinical response in patients with a perfusion– diffusion mismatch (odds ratio, 5.4;p¼ 0.039) and an even more favorable response in patients with the“target mismatch” profile (odds ratio, 8.7; p ¼ 0.011). Patients with the “no mismatch” profile did not appear to benefit from early reperfusion. Early reperfusion was associated with fatal intracranial hemorrhage in patients with the“malignant” profile.
The recent Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; Daviset al.
2008) randomly assigned 101 patients to receive alteplase or placebo three to six hours after onset of ischemic stroke. Perfusion and diffusion imaging were done before and three to five days after therapy, with T2-weighted MRI. The primary endpoint was infarct growth
between baseline diffusion imaging and the day 90 T2-weighted lesion in mismatch patients.
Major secondary endpoints were reperfusion, good neurological outcome and good func- tional outcome. Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch.
The DIAS, DEFUSE and EPITHET studies were small and used different thrombolytic agents (and different doses in DIAS), and further studies are needed before it is certain that diffusion–perfusion mismatch on MRI is a reliable surrogate for the presence of a penumbra that might benefit from thrombolysis beyond the three-hour time window.
Transcranial Doppler ultrasonography aimed at the occluded part of a vessel may help to expose thrombi to the effect of thrombolytic agents and thus augment the effect of thrombolysis. The CLOTBUST II (ultrasound-enhanced systemic thrombolysis for acute ischemic stroke) trial tested this hypothesis (Alexandrov et al.2004). Patients with acute ischemic stroke and middle cerebral artery occlusion presenting within three hours after stroke onset received intravenous tissue plasminogen activator and were randomized to receive additional transcranial Doppler ultrasonography or placebo. The treatment group showed a significantly higher rate of recanalization and a non-significant trend towards more favorable outcome, suggesting that transcranial Doppler ultrasonography may indeed enhance the effectiveness of intravenous thrombolysis. There are two ongoing trials assess- ing this technique further: MUST (Microbubbles and Ultrasound in Stroke Trial), and PULSE (Pilot UltraSound Lysis Early Treatment Study).
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