Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study.

BACKGROUND: Clinical and subclinical (covert) stroke is a cause of cognitive loss and functional impairment. In the AVERROES trial, we performed serial brain magnetic resonance imaging (MRI) scans in a subgroup to explore the effect of apixaban, compared with aspirin, on clinical and covert brain infarction and on microbleeds in patients with atrial fibrillation. METHODS: We performed brain MRI (T1, T2, fluid-attenuated inversion recovery, and T2* gradient echo sequences) in 1,180 at baseline and in 931 participants at follow-up. Mean interval from baseline to follow-up MRI scans was 1.0 year. The primary outcome was a composite of clinical ischemic stroke and covert embolic pattern infarction (defined as infarction >1.5 cm, cortical-based infarction, or new multiterritory infarction). Secondary outcomes included new MRI-detected brain infarcts and microbleeds and change in white matter hyperintensities. RESULTS: Baseline MRI scans revealed brain infarct(s) in 26.2% and microbleed(s) in 10.5%. The rate of the primary outcomes was 2.0% in the apixaban group and 3.3% in the aspirin group (hazard ratio [HR] 0.55; 0.27-1.14) from baseline to follow-up MRI scan (mean duration of follow-up: 1 year). In those who completed baseline and follow-up MRI scans, the rate of new infarction detected on MRI was 2.5% in the apixaban group and 2.2% in the aspirin group (HR 1.09; 0.47-2.52), but new infarcts were smaller in the apixaban group (P = .03). There was no difference in proportion with new microbleeds on follow-up MRI (HR 0.92; 0.53-1.60) between treatment groups. CONCLUSIONS: Apixaban treatment was associated with a nonsignificant trend toward reduction in the composite of clinical ischemic stroke and covert embolic-pattern infarction and did not increase the number of microbleeds in patients with atrial fibrillation compared with aspirin.

Longitudinal assessment of infarct progression, brain metabolism and behavior following anterior cerebral artery occlusion in rats.

BACKGROUND: Stroke patients suffering from occlusion of the anterior cerebral artery (ACAo) develop cognitive and executive deficits. Experimental models to investigate such functional impairments and recovery are rare and not satisfyingly validated. NEW METHOD: We stereotactically injected the vasoconstrictor endothelin-1 (ET-1) close to the ACA of rats and assessed magnitude and course of CBF reduction using [(14)C]iodoantipyrine autoradiography and [(15)O]H2O-PET. [(18)F]FDG-PET and T2-weighted MRI determined regional metabolic and structural alterations. To test cognitive and executive functions, we analyzed decision-making in a food-carrying task, spatial working memory in a spontaneous alternation task and anxiety in an elevated plus maze test before and 1 month after ACAo. RESULTS: CBF decreased immediately after ET-1 injection, started to recover 1-2h and returned to control 4h thereafter. Metabolic and structural lesions developed permanently in the ACA territory. Hypometabolism occurring bilaterally in the piriform region may reflect diaschisis. Behavioral testing after ACAo revealed context-dependent changes in decision making, exploratory activity and walking speed, as well as decreased anxiety and spatial working memory. COMPARISON WITH EXISTING METHOD(S): Aside from modeling a known entity of stroke patients, ACAo in rats allows to longitudinally study deterioration of cognitive and executive function without major interference by disturbed primary motor function. It complements therefore stroke research since common models using middle cerebral artery occlusion (MCAo) all affect motor function severely. CONCLUSION: The established ACAo model in rats effectively reflects deficits characteristic for ACA stroke in humans. It is furthermore highly suitable for longitudinal assessment of cognitive and executive functions.

Surgically acquired deficits and diffusion weighted MRI changes after glioma resection--a matched case-control study with blinded neuroradiological assessment.

BACKGROUND: Acquired deficits following glioma resection may not only occur due to accidental resection of normal brain tissue. The possible importance of ischemic injuries in causing neurological deficits after brain tumor surgery is not much studied. We aimed to study the volume and frequency of early postoperative circulatory changes (i.e. infarctions) detected by diffusion weighted resonance imaging (DWI) in patients with surgically acquired neurological deficits compared to controls. METHODS: We designed a 1 ∶ 1 matched case-control study in patients with diffuse gliomas (WHO grade II-IV) operated with 3D ultrasound guided resection. 42 consecutive patients with acquired postoperative dysphasia and/or new motor deficits were compared to 42 matched controls without acquired deficits. Controls were matched with respect to histopathology, preoperative tumor volumes, and eloquence of location. Two independent radiologists blinded for clinical status assessed the postoperative DWI findings. RESULTS: Postoperative peri-tumoral infarctions were more often seen in patients with acquired deficits (63% versus 41%, p = 0.046) and volumes of DWI abnormalities were larger in cases than in controls with median 1.08 cm3 (IQR 0-2.39) versus median 0 cm3 (IQR 0-1.67), p = 0.047. Inter-rater agreement was substantial (67/82, κ = 0.64, p<0.001) for diagnosing radiological significant DWI abnormalities. CONCLUSION: Peri-tumoral infarctions were more common and were larger in patients with acquired deficits after glioma surgery compared to glioma patients without deficits when assessed by early postoperative DWI. Infarctions may be a frequent and underestimated cause of acquired deficits after glioma resection. DWI changes may be an attractive endpoint in brain tumor surgery with both good inter-rater reliability among radiologists and clinical relevance.

The myth of the 'unaffected' side after unilateral stroke: is reorganisation of the non-infarcted corticospinal system to re-establish balance the price for recovery?

BACKGROUND: Bilateral changes in the hemispheric reorganisation have been observed chronically after unilateral stroke. Our hypotheses were that activity dependent competition between the lesioned and non-lesioned corticospinal systems would result in persisting asymmetry and be associated with poor recovery. METHODS: Eleven subjects (medium 6.5 years after stroke) were compared to 9 age-matched controls. The power spectral density (PSD) of the sensorimotor electroencephalogram (SM1-EEG) and electromyogram (EMG) and corticomuscular coherence (CMC) were studied during rest and isometric contraction of right or left opponens pollicis (OP). Global recovery was assessed using NIH score. FINDINGS: There was bilateral loss of beta frequency activity in the SM1-EEGs and OP-EMGs in strokes compared to controls. There was no difference between strokes and controls in symmetry indices estimated between the two corticospinal systems for SM1-EEG, OP-EMG and CMC. Performance correlated with preservation of beta frequency power in OP-EMG in both hands. Symmetry indices for the SM1-EEG, OP-EMG and CMC correlated with recovery. INTERPRETATION: Significant changes occurred at both cortical and spinomuscular levels after stroke but to the same degree and in the same direction in both the lesioned and non-lesioned corticospinal systems. Global recovery correlated with the degree of symmetry between corticospinal systems at all three levels - cortical and spinomuscular levels and their connectivity (CMC), but not with the absolute degree of abnormality. Re-establishing balance between the corticospinal systems may be important for overall motor function, even if it is achieved at the expense of the non-lesioned system.

DL-3-n-Butylphthalide, an anti-oxidant agent, prevents neurological deficits and cerebral injury following stroke per functional analysis, magnetic resonance imaging and histological assessment.

DL-3-n-Butylphthalide (NBP) is a synthetic compound based on L-3-n-Butylphthalide which was isolated from seeds of Apium graveolens. The present study aims at evaluating the outcome of NBP given prior to and after the onset of ischemic stroke in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Stroke was induced by the middle cerebral artery occlusion (MCAO) in SHR and WKY. For pre-treatment, NBP was administered to SHR and WKY daily for two months prior to MCAO. For post-treatment, NBP was given daily for seven consecutive days after MCAO. Seven days post-surgery, rats were tested for the presence of neurological deficits. Magnetic resonance imaging (MRI) and 2,3,5-triphenyltetrazolium chloride (TTC) staining were employed to calculate the infarct volume. The cerebral cortex and corpus striatum in the ischemic penumbra area were examined microscopically for pathological changes. In SHR, NBP pre- and post-treatment significantly lowered neurological deficit scores, reduced infarct volume, and minimized pathological changes in the penumbra area when compared to oil-vehicle treated controls. In WKY, these beneficial effects were observed only in the post-treatment group. The beneficial effects of NBP post-treatment were greater in WKY than in SHR. Results indicated that NBP could exert both preventive and therapeutic effects on ischemic stroke in SHR, but only exerted therapeutic effect in WKY.

Compromise of brain tissue caused by cortical venous reflux of intracranial dural arteriovenous fistulas: assessment with diffusion-weighted magnetic resonance imaging.

BACKGROUND AND PURPOSE: Cortical venous reflux (CVR) is a high risk factor for aggressive behavior of intracranial dural arteriovenous fistulas (DAVF). The pathological conditions in brain tissue affected by CVR were investigated by diffusion-weighted magnetic resonance imaging. METHODS: A retrospective review identified 56 patients with DAVFs who underwent diffusion-weighted imaging before treatment. Twenty patients had neurological symptoms corresponding to the brain area affected by CVR (Group I), 21 patients with CVR had no focal brain dysfunctions (Group II), and 15 patients had no CVR (Group III). Apparent diffusion coefficient (ADC) was measured for 11 brain areas predefined based on normal venous drainage patterns in the 56 patients and in 21 normal volunteers. The mean ADC ratio was calculated for each area by dividing the ADC value of patients by that of normal volunteers. RESULTS: Areas affected by CVR in Group I showed a mean ADC-to-control ratio of 0.72, which was significantly lower than that of Group II (0.96, P<0.01). Follow-up studies demonstrated significantly increased ADC ratios in brain areas affected by CVR after the DAVFs were treated successfully. The mean ADC ratio of an affected area remained low, with persistent symptoms in 1 patient who underwent palliative treatment. CONCLUSIONS: Decreased ADC was observed in the brain parenchyma affected by CVR and was associated with regional brain dysfunction. Successful treatment of the DAVF increased the ADC toward normal levels. The ADC may be a useful indicator of the severity of CVR.

Association of aortic arch pulse wave velocity with left ventricular mass and lacunar brain infarcts in hypertensive patients: assessment with MR imaging.

PURPOSE: To assess the possible association between aortic arch stiffness, which may cause hypertensive cardiovascular disease, and cardiac and cerebral end-organ damage in patients with hypertension by using magnetic resonance (MR) imaging. MATERIALS AND METHODS: Approval from the local institutional review board was obtained, and patients gave informed consent. Fifty patients with hypertension (31 women and 19 men; mean age +/- standard deviation, 49.2 years +/- 12.7; mean systolic blood pressure, 152.1 mm Hg +/- 22.3; mean diastolic blood pressure, 88.0 mm Hg +/- 13.1), compliant for treatment with antihypertensive medication, were prospectively enrolled for MR examinations of the aorta, heart, and brain with standard pulse sequences. Aortic arch pulse wave velocity (PWV), left ventricular (LV) mass, LV systolic and diastolic function, lacunar brain infarcts, and periventricular and deep white matter hyperintensities (WMHs) were assessed. Univariable and multiple linear and logistic regression analyses were used for statistical analyses. RESULTS: Mean aortic arch PWV was 7.3 m/sec +/- 2.5. Aortic arch PWV was statistically significantly associated with LV mass (r = 0.30, P = .03, beta = 1.73); indexes of systolic function, including ejection fraction (r = -0.38, P = .01, beta = -1.12); indexes of diastolic function, including the ratio of early diastolic to atrial contraction peak filling rates (r = -0.44, P < .01, beta = -0.11); lacunar brain infarcts (odds ratio [OR] = 1.8, P < .01); and periventricular (OR = 1.5, P = .01) and deep (OR = 1.6, P = .01) WMHs. Aortic arch PWV was statistically significantly associated with LV mass (r = 0.37, P = .03, beta = 2.11) and lacunar brain infarcts (OR = 1.8, P = .04), independent of age, sex, and hypertension duration, but not with indexes of diastolic and systolic function and WMHs. CONCLUSION: Aortic arch stiffness is associated with LV mass and lacunar brain infarcts in hypertensive patients, independent of age, sex, and hypertension duration; these manifestations of end-organ damage may help to risk stratify hypertensive patients.

Fast multimode MRI based emergency assessment of hyperacute stroke thrombolysis.

OBJECTIVE: To investigate the value of fast multimode magnetic resonance imaging (MRI) based emergency assessment hyperacute stroke thrombolysis. METHODS: One hundred and twenty four patients with 12 hour window acute ischemic strokes were examined by fast multimode MRI, and among them, 46 patients with hyperacute cerebral infarction confirmed by fast multimode MRI were treated by recombinant tissue plasminogen activator and followed up periodically by MRI. RESULTS: The 46 patients selected by fast multimode MRI to receive thrombolytics demonstrated clinical improvement with 90 days modified Rankin scale scores < or =2 and life quality Barthal index of 80-100. Six patients developed asymptomatic intracranial hemorrhage (13.0%) 1-7 days after receiving thrombolytics. CONCLUSIONS: Patients suffering from hyperacute ischemic cerebral infarction that are strong candidates for intravenous thrombolytic therapy can be identified by multimode MRI, especially for those whose time windows were undefined or beyond 3 hours after symptom onset. Fast multimodal MRI based selection of the hyperacute stroke model is more feasible compared with the traditional diffusion weighted imaging/perfusion weighted imaging mismatch model for the emergency assessment of hyperacute stroke thrombolysis.

Computed tomography perfusion source images assessment of infarct core and penumbra in acute stroke.

OBJECTIVE: The purpose of this study was to develop a methodology on computed tomography (CT) perfusion source images for an acute ischemic stroke in predicting infarct core and penumbra. METHODS: Computed tomography examinations, including non-contrast enhanced CT, CT perfusion and CT angiography, were performed on 24 patients with symptoms of stroke in less than 9 hours. The Alberta Stroke Program Early CT Score (ASPECTS) was analysed on arterial and venous phase CT perfusion source images and then compared with the ASPECTS on follow-up imaging for an efficacy assessment. RESULTS: The ASPECTS on arterial phase CT perfusion source images was significantly different from venous phase CT perfusion source images (z=-2.812, p=0.005); linear regression analysis revealed that there was a statistically significant relationship between venous phase CT perfusion source images and the follow-up imaging (beta=0.715, p=0.003). CONCLUSION: The limited data suggested that CT perfusion source images of both arterial and venous phases may have the potential of being used as an assessment for infarct core and penumbra in acute ischemic stroke.

Window narrowing: a new method for standardized assessment of the tissue at risk-maximum of infarction in CT based brain perfusion maps.

BACKGROUND: Mapping of brain perfusion using bolus tracking methods is increasingly used to assess the amount and severity of cerebral ischemia in acute stroke. Using relative perfusion maps, however, it is difficult to identify the tissue at risk-maximum (TARM) of infarction with sufficient reliability and reproducibility. METHODS: We analysed 76 perfusion computed tomography (PCT) derived maps of cerebral blood flow (CBF), cerebral blood volume (CBV) and time-to-peak (TTP) in 40 acute stroke patients using multidetector row technology and standard software (Somatom VolumeZoom, Siemens, Germany). 'Window narrowing' of the color maps was performed until color homogenisation of the contralateral unaffected hemisphere was reached. Tissue still depictable on the affected hemisphere after sufficient window narrowing was defined as the TARM. We analysed presence and size of the TARM on PCT maps, its relative perfusion values by comparison with contralateral, mirrored tissue, and its correlation with occurrence and final size of cerebral infarction on follow-up imaging. RESULTS: An ischemic area was visible in 64, 58.9 and 72.6% on the conventional CBF, CBV and TTP maps, respectively. After window narrowing, a TARM was present in 56.8, 54.1 and 63.0% of slices comprising 11.9, 11.6 and 21.1% of the ipsilateral hemisphere (CBF, CBV and TTP), respectively. The relative perfusion values were 38.7 (CBF) and 43.0% (CBV) for the entire ischemic area and 11.3 (CBF) and 13.3% (CBV) for the TARM. Definite cerebral infarction was visible on 68.1% of the target slices comprising 23.7 +/- 22.9% of the ipsilateral hemisphere. The size of the TARM correlated slightly better with the final infarction size (r=0.74-0.82) than the entire ischemic area (r=0.61-0.79). With respect to the occurrence of cerebral infarction, the presence of a TARM on CBF maps showed the best positive (97.9%) and negative (72.7%) predictability. DISCUSSION: On PCT maps, window narrowing provides a standardized display of the TARM in peracute stroke. The severely reduced values of relative CBF and CBV suggest the TARM to indicate tissue most prone to infarction.

Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia.

Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.

Common carotid artery intima-media thickness for the risk assessment of lacunar infarction versus intracerebral haemorrhage.

BACKGROUND AND PURPOSE: Arterial hypertension is the major risk factor for intracerebral haemorrhage (ICH) and lacunar infarction (LI) and both types of cerebral lesions originate from pathology of the same deep perforating small arteries. We aimed to evaluate the relationship between vascular risk factors including common carotid artery intima-media thickness (CCA-IMT) with LI versus ICH. METHODS: We prospectively collected data from 159 first ever stroke patients (67 cases with ICH and 92 cases with LI) with documented history of hypertension. All subjects underwent B-mode ultrasonographic measurements of the CCA-IMT. Logistic regression modelling was used to determine the factors (established vascular risk factors, severity and duration of hypertension, concomitant medications and CCA-IMT) that may significantly differentiate LI from ICH. RESULTS: Patients with LI had significantly (p=0.002) larger CCA-IMT values (0.926 mm, 95% CI: 0.881-0.971) than subjects with ICH (0.815 mm, 95% CI: 0.762-0.868) even after adjusting for baseline characteristics and cardiovascular medications. The multivariate logistic regression procedure selected CCA-IMT, diabetes mellitus and hypercholesterolaemia as the only independent factors able to discriminate between LI and ICH. The risk for LI versus ICH increased continuously with increasing CCA-IMT. For each increment of 0.1 mm in CCA-IMT the probability of suffering from LI versus ICH increased by 36.6% (95 % CI: 13%-65.2%, p=0.001) even after adjustment for cardiovascular risk factors. CONCLUSIONS: Increased CCA-IMT values are a factor favouring LI over ICH in hypertensive patients. The measurement of CCA-IMT may be a useful non-invasive diagnostic tool for the risk assessment of LI with respect to ICH in such patients.