Peter Brunecker

Transient Ischemic Attacks Before Ischemic Stroke: Preconditioning the Human Brain? A Multicenter Magnetic Resonance Imaging Study

Background and Purpose— We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. Methods— Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. Results— Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P =0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. Conclusions— The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.

Fluid-Attenuated Inversion Recovery Evolution Within 12 Hours From Stroke Onset A Reliable Tissue Clock?

Background and Purpose— It has recently been proposed that fluid-attenuated inversion recovery (FLAIR) imaging may serve as a surrogate marker for time of symptom onset after stroke. We assessed the hypothesis that FLAIR imaging could be used to decide if an MRI was performed within 4.5 hours from symptom onset or later. Methods— All consecutive patients with presumed stroke who underwent an MRI within 12 hours after known symptom onset were included regardless of stroke subtype and severity between May 2008 and May 2009. Blinded to time of symptom onset, 2 raters judged the visibility of lesions on FLAIR. Apparent diffusion coefficient values, lesion volume on diffusion-weighted imaging, and relative signal intensity of FLAIR lesions were determined. Results— In 94 consecutive patients with stroke, we found that median time from symptom onset for FLAIR-positive patients (189 minutes; interquartile range, 110 to 369 minutes) was significantly longer compared with FLAIR-negative patients (103 minutes; interquartile range, 75 to 183 minutes; P=0.011). Negative FLAIR had a sensitivity of 46% and a specificity of 79% for allocating patients to a time window of less than 4.5 hours. FLAIR positivity increased with diffusion-weighted imaging lesion volume (P<0.001) but showed no correlation with apparent diffusion coefficient values (P=0.795). There was no significant correlation between relative signal intensity and time from symptom onset (Spearman correlation coefficient −0.152, P=0.128). Conclusions— Based on our findings, we cannot recommend the use of FLAIR visibility as an estimate of time from symptom onset within the first 4.5 hours.

Number of Cerebral Microbleeds and Risk of Intracerebral Hemorrhage After Intravenous Thrombolysis

Background and Purpose— Cerebral microbleeds (CMBs) are found in a substantial proportion of patients with ischemic stroke eligible for treatment with intravenous thrombolysis. Until now, there is limited data on the impact of multiple CMBs on occurrence of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Methods— Between 2008 and 2013, all patients receiving MRI-based intravenous thrombolysis were identified within our prospective thrombolysis register. Number of CMBs was rated on pretreatment T2*-weighted MRI by a rater blinded to clinical data and follow-up. Outcomes of interest were occurrence of symptomatic ICH (sICH) and parenchymal hemorrhage (PH). Results— Among 326 included patients, 52 patients had a single CMB (16.0%), 19 had 2 to 4 CMBs (5.8%), and 10 had ≥5 CMBs (3.1%). Frequency of sICH/PH was 1.2%/5.7% in patients without CMBs, 3.8%/3.8% in patients with a single CMB, 10.5%/21.1% in patients with 2 to 4 CMBs, and 30.0%/30.0% in patients with ≥5 CMBs, respectively (each P for trend <0.01). The unadjusted odds ratio per additional CMB for sICH was 1.19 (95% confidence interval, 1.07–1.33; P<0.01) and for PH was 1.13 (95% confidence interval, 1.03–1.24; P=0.01). Compared with patients without CMBs, both patients with 2 to 4 CMBs (P=0.02/P=0.02) and patients with ≥5 CMBs (P<0.01/P<0.01) had significantly increased odds ratios for sICH and PH, whereas in patients with a single CMB, odds ratios were not significantly increased (P=0.21/P=0.59). The association of CMB burden with sICH/PH remained significant after adjustment for possible confounders (age, age-related white matter changes score, atrial fibrillation, onset-to-treatment time, prior statin use, and systolic blood pressure on admission). Conclusions— Our findings indicate a higher risk of sICH and PH after intravenous thrombolysis when multiple CMBs are present, with a graded relationship to increasing baseline CMB number.

Prospective study on the mismatch concept in acute stroke patients within the first 24 h after symptom onset - 1000Plus study

BackgroundThe mismatch between diffusion weighted imaging (DWI) lesion and perfusion imaging (PI) deficit volumes has been used as a surrogate of ischemic penumbra. This pathophysiology-orientated patient selection criterion for acute stroke treatment may have the potential to replace a fixed time window. Two recent trials - DEFUSE and EPITHET - investigated the mismatch concept in a multicenter prospective approach. Both studies randomized highly selected patients (n = 74/n = 100) and therefore confirmation in a large consecutive cohort is desirable. We here present a single-center approach with a 3T MR tomograph next door to the stroke unit, serving as a bridge from the ER to the stroke unit to screen all TIA and stroke patients. Our primary hypothesis is that the prognostic value of the mismatch concept is depending on the vessel status. Primary endpoint of the study is infarct growth determined by imaging, secondary endpoints are neurological deficit on day 5-7 and functional outcome after 3 months.Methods and design1000Plus is a prospective, single centre observational study with 1200 patients to be recruited. All patients admitted to the ER with the clinical diagnosis of an acute cerebrovascular event within 24 hours after symptom onset are screened. Examinations are performed on day 1, 2 and 5-7 with neurological examination including National Institute of Health Stroke Scale (NIHSS) scoring and stroke MRI including T2*, DWI, TOF-MRA, FLAIR and PI. PI is conducted as dynamic susceptibility-enhanced contrast imaging with a fixed dosage of 5 ml 1 M Gadobutrol. For post-processing of PI, mean transit time (MTT) parametric images are determined by deconvolution of the arterial input function (AIF) which is automatically identified. Lesion volumes and mismatch are measured and calculated by using the perfusion mismatch analyzer (PMA) software from ASIST-Japan. Primary endpoint is the change of infarct size between baseline examination and day 5-7 follow up.DiscussionsThe aim of this study is to describe the incidence of mismatch and the predictive value of PI for final lesion size and functional outcome depending on delay of imaging and vascular recanalization. It is crucial to standardize PI for future randomized clinical trials as for individual therapeutic decisions and we expect to contribute to this challenging task.Trial Registrationclinicaltrials.gov NCT00715533

Smoking-Thrombolysis Paradox Recanalization and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischemic Stroke

Background and Purpose— The so-called smoking-thrombolysis paradox of an improved outcome after thrombolysis was first described in smokers with myocardial infarction. We investigated whether reperfusion rates and clinical outcome differ between smokers and nonsmokers with ischemic stroke after intravenous tissue plasminogen activator. Methods— Consecutive acute ischemic stroke patients, who had magnetic resonance imaging before and 1 day after thrombolysis, were included for analysis. All of the patients received intravenous tissue plasminogen activator within 4.5 hours. Reperfusion was defined as a 75% reduction in perfusion deficit (mean transit time >6 s) after thrombolysis compared with baseline. Magnetic resonance angiography was used to evaluate arterial stenosis and occlusion. Functional outcome was assessed 3 months after stroke using the modified Rankin Score. Results— Of 148 patients, 21.6% were smokers (n=32). Smokers were younger (median, 61 years [SD, 9.4 years] versus 75 years [SD, 11.6 years]; P<0.001), less often women (28% versus 51%; P=0.03), had lower baseline glucose levels (median, 6.2 mmol/L [interquartile range, 5.7–6.8 mmol/L] versus 6.7 mmol/L [interquartile range, 6.1–8.2 mmol/L]; P<0.01) and higher baseline perfusion deficits (median, 53 mL [interquartile range, 13–141 mL] versus 17 mL [interquartile range, 2–66 mL]; P=0.04). In a backward stepwise regression analysis including age, sex, hypertension, glucose, perfusion deficit, and smoking, smoking had an odds ratio of 4 (95% confidence interval, 1–16; P=0.03) for reperfusion and 6 (95% confidence interval, 1–30; P=0.05) for recanalization (regression analysis for recanalization also included localization of arterial occlusion). Smokers had a better outcome (modified Rankin Score=0–2) than nonsmokers (77% versus 55%; P=0.05). Conclusions— Smoking is independently associated with recanalization and reperfusion, indicating that thrombolytic therapy acts more effectively in smokers; because of small numbers, these results should be considered preliminary. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique Identifier: NCT00715533.

Thalamic sensory strokes with and without pain: differences in lesion patterns in the ventral posterior thalamus

Objective Vascular lesions of the posterolateral thalamus typically result in a somatosensory syndrome in which some patients develop central neuropathic post-stroke pain (CPSP). Damage to the spinothalamic tract terminus is assumed to be a prerequisite for thalamic CPSP. At the nuclear level, it remains a matter of debate whether the ventral posterolateral nucleus (VPL) or the posterior portion of the ventral medial nucleus (VMpo) constitutes the decisive lesion site. The hypothesis of the study was that lesion location in thalamic CPSP patients differs from that in thalamic stroke patients without pain, and the aim was to identify whether this difference comprises the VPL and/or the VMpo. Design 30 patients with chronic thalamic stroke and a persistent contralateral somatosensory syndrome were examined. CPSP patients (n=18) were compared with non-pain control patients. By coregistration of a digitised thalamic atlas with T1 weighted MR images, lesion clusters were allocated to the thalamic nuclei. Results VPL was affected in both groups, but CPSP lesion clusters comprised the more posterior, inferior and lateral parts of the VPL compared with controls. Additional partial involvement of the VMpo was seen in only three pain patients. In three other pain patients, lesions involved neither the VPL nor the VMpo, but mainly affected the anterior pulvinar. Conclusion This study specifies the role of the VPL in thalamic CPSP and shows that the posterolateratal and inferior parts in particular are critically lesioned in pain patients. In this thalamic subregion, afferents of the spinothalamic tract are known to terminate. In contrast, the data do not support a pivotal impact of the VMpo on thalamic CPSP.

Fluid-Attenuated Inversion Recovery Images and Stroke Outcome After Thrombolysis

Background and Purpose— We investigated if hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences in arteries and parenchyma are associated with poor outcome 3 months after thrombolysis. Methods— Consecutive acute stroke patients with known time of symptom onset who had an MRI before and 1 day after thrombolysis were included in this study. Blinded to follow-up imaging and outcome, 2 raters independently judged the presence or absence of arterial and parenchymal FLAIR hyperintensities. Functional outcome (modified Rankin Scale) was assessed after 3 months. Results— Out of 90 patients, 22 had parenchymal FLAIR hyperintensities and 42 had hyperintense vessels. The combination of FLAIR hyperintensities in arteries and parenchyma occurred in 15 patients. Stepwise forward regression analysis revealed an adjusted odds ratio of 14.5 for a worse outcome (modified Rankin Scale score >2) in patients with FLAIR hyperintensities in arteries and parenchyma (95% confidence interval, 1.3–158.5; P=0.03). Conclusions— FLAIR hyperintensities in arteries and parenchyma are an easy-to-use MRI feature in acute ischemic stroke associated with poor outcome 3 months after thrombolysis.

Complete Early Reversal of Diffusion-Weighted Imaging Hyperintensities After Ischemic Stroke Is Mainly Limited to Small Embolic Lesions

Background and Purpose— Case reports have demonstrated complete early reversal of hyperintensities on diffusion-weighted imaging (DWI) after clinically diagnosed stroke. We aimed to investigate systematically the rate and characteristics of reversible diffusion hyperintensities (RDHs) in the first week after stroke. Methods— Patients with clinical diagnosis of an acute cerebrovascular event and evidence of ischemia on DWI were included. MRI scans were performed on admission, on the following day, and 4 to 7 days after onset of symptoms with DWI and fluid-attenuated inversion recovery. Baseline and follow-up DWIs were coregistered and examined for individual RDHs. Characteristics of patients and of hyperintensities associated with early reversal were identified. Results— We included 153 patients with a median National Institutes of Health Stroke Scale score of 4 (interquartile range, 2–8). In 3 patients (2%), MR images normalized completely. Thirty-seven patients (24%) displayed individual RDHs. Of 611 initial DWI hyperintensities, 97 (16%) reversed. Thirteen percent of the RDHs had corresponding abnormalities on fluid-attenuated inversion recovery images at the third measurement. Median size of the RDHs was 0.029 mL (interquartile range, 0.013–0.055). RDHs were associated with a multiple infarct pattern (odds ratio, 22.1; 95% confidence interval, 4.5–109.7) and symptomatic carotid stenosis (odds ratio, 5.5; 95% confidence interval, 1.4–21.5). Fifty-nine percent of the patients with RDHs had new additional lesions on follow-up DWI. RDHs were not associated with functional improvement on the National Institutes of Health Stroke Scale score. Conclusions— In this population of mainly minor to moderate stroke patients, complete normalization of MR images was rare. Complete reversal of individual DWI hyperintensities was limited to very small lesions and mostly occurred in embolic stroke patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715533.

FLAIR vascular hyperintensities in acute ICA and MCA infarction: a marker for mismatch and stroke severity?.

Background: Vascular hyperintensities of brain-supplying arteries on stroke FLAIR MRI are common and represent slow flow or stasis. FLAIR vascular hyperintensities (FVH) are discussed as an independent marker for cerebral hypoperfusion, but the impact on infarct size and clinical outcome in acute stroke patients is controversial. This study evaluates the association of FVH with infarct morphology, clinical stroke severity and infarct growth in patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion. Methods: MR images of 84 patients [median age 73 years (IQR 65–80), 56.0% male, median NIHSS 7 (IQR 3–13)] with acute stroke due to symptomatic ICA or MCA occlusion or stenosis were reviewed. Vessel occlusions were identified by MRA time of flight and graded with the TIMI score. Diffusion and perfusion deficit volumes on admission and FLAIR lesion volumes on discharge were assessed. The presence and number of FVH were evaluated according to MCA-ASPECT areas, and associations with MR volumes, morphology of infarction, recanalization status, presence of white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), stroke etiology and thrombolysis rate were analyzed. Results: FVH were detectable in 75 (89.3%) patients. The median number of FVH was 4 (IQR 2–7). Patients with FVH >4 presented with more severe strokes due to NIHSS (p = 0.021), had larger initial DWI lesions (p = 0.008), perfusion deficits (p = 0.001) and mismatch volumes/ratios (p = 0.005). The final infarct volume was larger (p = 0.005), and hemorrhagic transformation was more frequent (p = 0.029) in these patients. Conclusions: The presence of FVH indicates larger ischemic areas in brain parenchyma predominantly caused by proximal anterior circulation vessel occlusion. A high count of FVH might be a further surrogate marker for initial ischemic mismatch and stroke severity.

Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study.

Background— MRI-detected brain lesions are common after left atrial catheter ablation for symptomatic atrial fibrillation. The clinical relevance of these acute ischemic lesions is not fully understood, but ablation-related cerebral injury could contribute to cognitive dysfunction. Methods and Results— In the prospective Mesh Ablator versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation (MACPAF) study, serial 3-T brain MRIs and neuropsychological assessment were performed to analyze the rate of ablation-related brain lesions and their effect on cognitive function. Thirty-seven patients with paroxysmal atrial fibrillation (median age, 63.0 [interquartile range, 57–68] years; 41% female; median CHA2DS2VASc score 2 [interquartile range, 1–3]) underwent 41 ablation procedures according to study criteria. None of these patients had overt neurological deficits after ablation. High-resolution diffusion-weighted imaging, performed within 48 hours after ablation, showed that new brain lesions (range, 1–17) were present in 16 (43.2%) patients after 18 (43.9%) left atrial catheter ablation procedures. Follow-up MRI at 6 months (median, 6.5; interquartile range, 6–7) revealed that 7 (12.5%) of the 56 total acute brain lesions after ablation formed a persistent glial scar in 5 (31.3%) patients. Large diffusion-weighted imaging lesions and a corresponding fluid-attenuated inversion recovery lesion 48 hours after ablation predicted lesion persistence on 6-month follow-up. Neither persistent brain lesions nor the ablation procedure itself had a significant effect on attention or executive functions, short-term memory, or verbal and nonverbal learning after 6 months. Conclusions— Ablation-related acute ischemic brain lesions persist to some extent but do not cause cognitive impairment 6 months after the ablation procedure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061931.