Advances in Stroke: Imaging 2013 Wolf-Dieter Heiss and Chelsea S. Kidwell Stroke. 2014;45:363-364; originally published online January 16, 2014; doi: 10.1161/STROKEAHA.113.004102 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628

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Advances in Stroke Imaging 2013 Wolf-Dieter Heiss, MD; Chelsea S. Kidwell, MD


ubstantial advances have been made during the past 2 years in various applications of neuroimaging in stroke. Because of limited space, a few major areas in imaging are highlighted here, including developments in selection for acute stroke therapies, hemorrhage, and recovery. Results from several clinical trials have provided important data about imaging selection, including the mismatch concept, for acute stroke reperfusion therapies. A post hoc analysis of the pooled EPITHET-DEFUSE (Echoplanar Imaging Thrombolytic Evaluation Trial and Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study) datasets found that alteplase in the 3- to 6-hour window attenuated infarct growth and increased reperfusion in mismatch patients compared with placebo. Clinical outcomes were associated with degree of reperfusion; however, there was no difference in mortality or outcome between treatment groups and no comparison with nonmismatch patients.1,2 Another secondary pooled analysis from all 3 of the desmoteplase trials suggested that defining mismatch with a minimum volume of 60 cc based on magnetic resonance imaging (MRI) alone showed a significant treatment effect for desmoteplase.3 Additionally, in patients with a visible occlusion on noninvasive vessel imaging at baseline, the desmoteplase groups had greater rates of good clinical response.4 A phase IIb, prospective, randomized, open-label blinded end point trial tested 2 doses of intravenous tenecteplase compared with alteplase within 6 hours of onset.5 Only patients with a demonstrated target vessel occlusion and >20% mismatch on perfusion computed tomography were enrolled. Both coprimary end points were positive, with greater rates of reperfusion and greater improvement at 24 hours on the National Institute of Health Stroke Scale (NIHSS) score in the tenecteplase groups. DEFUSE 2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2) was a prospective, cohort study of thrombectomy in patients with and without target mismatch.6 In this study, patients with target mismatch had a greater likelihood of favorable clinical response, which was associated with reperfusion. In contrast, MR RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy) was a randomized, controlled trial of thrombectomy versus standard care up to 8 hours from onset, with enrollment stratified by

favorable penumbral or nonpenumbral pattern based on multimodal computed tomography or MRI.7 The trial failed to demonstrate that penumbral imaging selection improved outcomes for patients undergoing endovascular therapy for acute ischemic stroke. Neutral results may have been partly because of low recanalization rates with first-generation thrombectomy devices and relatively large predicted infarct cores compared with other studies. Several recent studies have suggested that arterial spin labeling might be applied similarly to perfusion weighted imaging for detection of perfusion deficits in acute stroke; however, arterial spin labeling often overestimates the lesion volume.8,9 Imaging continues to play an increasingly prominent role not only in understanding the underlying pathophysiology of brain hemorrhage, but also in predicting outcome. A series of studies have reported ischemic lesions visualized on diffusion weighted imaging that are remote from the index hemorrhage occurring in approximately one fourth to one third of patients with primary intracerebral hemorrhage.10 Several of the studies have found an association with blood pressure reductions as well as an association with poor outcomes in patients with lesions. Prospective studies have also now confirmed the prognostic value of the spot sign (contrast extravasation on computed tomographic angiography) in predicting hematoma expansion and poor clinical outcome in primary hemorrhage.11,12 The spot sign is currently being introduced as an outcome biomarker in clinical trials of acute interventions, although limitations of this application have been noted.13 Several studies have examined changes in bihemispheric networks and their impact on stroke recovery and functional impairment. Several studies of diffusion tensor imaging have demonstrated the impact of a focal lesion on the integrity of fiber tracts in the motor system. Strength of handgrip was positively correlated with the integrity of the corticospinal tract.14 The fractional anisotropy of the corticospinal tract at day 30 after stroke was found to be an independent predictor of motor outcome at 2 years.15 After subcortical stroke affecting the pyramidal tract, a progressive degenerative transsynaptic effect on transcallosal motor fibers was observed by diffusion tensor imaging, which could be a morphological correlate of transcallosal disinhibition increasing contralesional functional activity and thereby interacting with

Received December 3, 2013; accepted December 4, 2013. From the Max Planck Institute for Neurological Research, Cologne, Germany (W.-D.H.); and Departments of Neurology and Medical Imaging, University of Arizona, Tucson, AZ (C.S.K.). Correspondence to Wolf-Dieter Heiss, MD, Max Planck Institute for Neurological Research, Gleueler Str 50, D-50931 Cologne, Germany. E-mail [email protected] (Stroke. 2014;45:363-364.) © 2014 American Heart Association, Inc. Stroke is available at

DOI: 10.1161/STROKEAHA.113.004102

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364  Stroke  February 2014 recovery.16 In a study, diffusion tensor imaging–derived measures of corticospinal and transcallosal tracts were used to predict the potential for subsequent motor recovery after transcranial direct current stimulations and physical therapy.17 In poststroke patients with aphasia, repetition impairments were associated with lesions in the posterior temporoparietal region, whereas comprehension deficits were related to temporofrontal lesions, indicating that language is organized along 2 segregated dorsal-ventral streams.18 In a recent trial, inhibitory repetitive transcranial magnetic stimulation improved language recovery in patients with subacute ischemic stroke when combined with speech therapy.19 Repetitive transcranial magnetic stimulation also significantly increased recruitment of language areas in the dominant hemisphere. Similarly, inhibitory repetitive transcranial magnetic stimulation to areas most activated on functional magnetic resonance imaging (fMRI) improved language performance in chronic poststroke aphasics.20 Recent resting-state fMRI studies have demonstrated disturbances after stroke not only in the vicinity of the lesion, but also between remote cortical areas in the affected and unaffected hemispheres, suggesting that recovery requires reorganization by restoration of interhemispheric functional coherence.21 Changes in connectivity of networks were shown to significantly correlate with changes in NIHSS.22 These studies suggest that resting-state fMRI might prove valuable for predicting prognosis and for selecting rehabilitation strategies.

Disclosures Dr Heiss is supported by the Wolf-Dieter Heiss Foundation at the Max Planck Society. Dr Kidwell is supported by the National Institutes of Health grants U01 NS069763 and P60 MD006920.

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5. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366:1099–1107. 6. Lansberg MG, Straka M, Kemp S, Mlynash M, Wechsler LR, Jovin TG, et al; DEFUSE 2 study investigators. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol. 2012;11:860–867. 7. Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, et al; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914–923. 8. Nael K, Meshksar A, Liebeskind DS, Coull BM, Krupinski EA, Villablanca JP. Quantitative analysis of hypoperfusion in acute stroke: arterial spin labeling versus dynamic susceptibility contrast. Stroke. 2013;44:3090–3096. 9. Zaharchuk G, El Mogy IS, Fischbein NJ, Albers GW. Comparison of arterial spin labeling and bolus perfusion-weighted imaging for detecting mismatch in acute stroke. Stroke. 2012;43:1843–1848. 10. Prabhakaran S, Naidech AM. Ischemic brain injury after intracerebral hemorrhage: a critical review. Stroke. 2012;43:2258–2263. 11. Romero JM, Brouwers HB, Lu J, Delgado Almandoz JE, Kelly H, Heit J, et al. Prospective validation of the computed tomographic angiography spot sign score for intracerebral hemorrhage. Stroke. 2013;44:3097–3102. 12. Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Blas YS, Dzialowski I, et al; PREDICT/Sunnybrook ICH CTA study group. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol. 2012;11:307–314. 13. Wardlaw JM. Prediction of haematoma expansion with the CTA spot sign: a useful biomarker? Lancet Neurol. 2012;11:294–295. 14. Schulz R, Park CH, Boudrias MH, Gerloff C, Hummel FC, Ward NS. Assessing the integrity of corticospinal pathways from primary and secondary cortical motor areas after stroke. Stroke. 2012;43:2248–2251. 15. Puig J, Blasco G, Daunis-I-Estadella J, Thomalla G, Castellanos M, Figueras J, et al. Decreased corticospinal tract fractional anisotropy predicts long-term motor outcome after stroke. Stroke. 2013;44:2016–2018. 16. Radlinska BA, Blunk Y, Leppert IR, Minuk J, Pike GB, Thiel A. Changes in callosal motor fiber integrity after subcortical stroke of the pyramidal tract. J Cereb Blood Flow Metab. 2012;32:1515–1524. 17. Lindenberg R, Zhu LL, Rüber T, Schlaug G. Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging. Hum Brain Mapp. 2012;33:1040–1051. 18. Kümmerer D, Hartwigsen G, Kellmeyer P, Glauche V, Mader I, Klöppel S, et al. Damage to ventral and dorsal language pathways in acute aphasia. Brain. 2013;136(Pt 2):619–629. 19. Thiel A, Hartmann A, Rubi-Fessen I, Anglade C, Kracht L, Weiduschat N, et al. Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia. Stroke. 2013;44:2240–2246. 20. Abo M, Kakuda W, Watanabe M, Morooka A, Kawakami K, Senoo A. Effectiveness of low-frequency rTMS and intensive speech therapy in poststroke patients with aphasia: a pilot study based on evaluation by fMRI in relation to type of aphasia. Eur Neurol. 2012;68:199–208. 21. Rehme AK, Grefkes C. Cerebral network disorders after stroke: evidence from imaging-based connectivity analyses of active and resting brain states in humans. J Physiol. 2013;591(Pt 1):17–31. 22. Ovadia-Caro S, Villringer K, Fiebach J, Jungehulsing GJ, van der Meer E, Margulies DS, et al. Longitudinal effects of lesions on functional networks after stroke. J Cereb Blood Flow Metab. 2013;33:1279–1285. Key Words: diagnostic imaging ◼ hemorrhage ◼ magnetic resonance imaging ◼ penumbra ◼ recovery ◼ stroke

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Advances in stroke: Imaging 2013.

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