Tomohisa Nezu

Pretreatment ASPECTS on DWI predicts 3-month outcome following rt-PA: SAMURAI rt-PA Registry

Objective: To evaluate whether the pretreatment Alberta Stroke Programme Early CT Score (ASPECTS) assessed using diffusion-weighted imaging (DWI) predicts stroke outcomes at 3 months following IV recombinant tissue-type plasminogen activator (rt-PA) therapy. Methods: Stroke patients treated with rt-PA (0.6 mg/kg alteplase) in 10 stroke centers in Japan were retrospectively studied. ASPECTS was assessed on DWI just prior to rt-PA injection. The primary outcome was a modified Rankin Scale (mRS) score of 0–2 at 3 months. Secondary outcomes included death at 3 months and symptomatic intracerebral hemorrhage (sICH) within 36 hours. Results: For the 477 patients (316 men, 71 ± 11 years old) enrolled, the median NIH Stroke Scale score was 13 (interquartile range 7–18.5), the median ASPECTS on DWI was 8 (7–10), and sICH was identified in 15 patients (3.1%). At 3 months, 245 (51.4%) had an mRS score of 0–2, and 29 (6.1%) had died. Patients with an mRS score of 0–2 had higher median ASPECTS (9; interquartile range 8–10) than other patients (8; 6–9, p < 0.001). Using receiver operating characteristic curves, the optimal cutoff ASPECTS to predict an mRS score of 0–2 was ≥7. On multivariate regression analysis, ASPECTS ≥7 was related to an mRS score of 0–2 (odds ratio 1.85; 95% confidence interval 1.07–3.24), ASPECTS ≤4 was related to death (3.61; 1.23–9.91), and ASPECTS ≤5 was related to sICH (4.74; 1.54–13.64). Conclusion: ASPECTS on DWI was independently predictive of functional and vital outcomes at 3 months, as well as sICH within 36 hours, following rt-PA therapy for stroke patients.

Carotid Intima-Media Thickness for Atherosclerosis.

The carotid intima-media thickness (IMT) is a widely used surrogate marker for atherosclerosis worldwide. The carotid IMT can be simply, noninvasively, and reproducibly measured through B-mode carotid ultrasound. The carotid IMT is also a strong predictor of future cerebral and cardiovascular events. In addition, regressions of increased carotid IMT by lipid-lowering and antihypertensive drugs have been reported. Despite the strong association between increased carotid IMT and cardiovascular disease, it remains unclear whether routine carotid IMT measurement is useful for the detection of subclinical atherosclerosis in clinical practice. Researches should consider other methodological aspects, such as the definition of carotid plaques, the choice of measurement sites on the common or internal carotid artery, and the assessment of maximum or minimum IMT. The detailed guidelines for measuring carotid IMT vary by county. Thus, the usefulness of the carotid IMT may be assessed in different countries taking racial differences into account. Other important parameters revealed by carotid ultrasound, such as artery stenosis and the characteristics and size of plaques, should also be considered. Physicians should comprehensively interpret the results of carotid ultrasonography. Therefore, carotid ultrasonography is an essential tool for assessing cardiovascular risk in clinical settings.

Early Ischemic Change on CT Versus Diffusion-Weighted Imaging for Patients With Stroke Receiving Intravenous Recombinant Tissue-Type Plasminogen Activator Therapy: Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) rt-PA Registry

Background and Purpose— Alberta Stroke Programme Early CT Score (ASPECTS) is a quantitative topographical score to evaluate early ischemic change in the middle cerebral arterial territory on CT as well as on diffusion-weighted imaging (DWI). The aim of the present study was to elucidate the relationship between CT-ASPECTS and DWI-ASPECTS for patients with hyperacute stroke and their associations with outcomes after recombinant tissue-type plasminogen activator therapy based on a multicenter registry. Methods— ASPECTS was assessed on both CT and DWI before intravenous 0.6 mg/kg alteplase in 360 patients with stroke (119 women, 71±11 years old). The outcomes were symptomatic intracerebral hemorrhage within 36 hours and independence at 3 months defined by a modified Rankin Scale score of 0 to 2. Results— DWI-ASPECTS was positively correlated with CT-ASPECTS (&rgr;=0.511, P<0.001) and was lower than CT-ASPECTS (median 8 [interquartile range, 6 to 9] versus 9 [8 to 10], P<0.001). Higher baseline National Institutes of Health Stroke Scale score (standardized partial regression coefficient [&bgr;] 0.061, P<0.001) and cardioembolic stroke (&bgr; 0.35, P<0.001) were related to this discrepancy. The area under the receiver operating characteristic curve for predicting sICH (12 patients) using ASPECTS was 0.673 (95% CI, 0.503 to 0.807) by CT and 0.764 (95% CI, 0.635 to 0.858) by DWI (P=0.275). The area for predicting independence at 3 months (192 patients) was 0.621 (0.564 to 0.674) by CT and 0.639 (0.580 to 0.694) by DWI (P=0.535). Conclusions— For patients with hyperacute stroke, DWI-ASPECTS scored approximately 1 point lower than CT-ASPECTS. Both CT-ASPECTS and DWI-ASPECTS were useful predictors of symptomatic intracerebral hemorrhage and independence at 3 months after recombinant tissue-type plasminogen activator.

Association of Serum Anti-Periodontal Pathogen Antibody with Ischemic Stroke

Background: Periodontitis increases the risk of atherosclerotic cardiovascular disease and ischemic stroke. In this study, we evaluated whether serum antibody levels against individual periodontal pathogens are significantly associated with ischemic stroke subtypes and their risk factors. Methods: Patients with acute ischemic stroke (n = 132; 74 male and 58 female, 71.3 ± 10.7 years) and patients with no previous stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. Stroke subtype was evaluated based on the Trial of Org 10172 in Acute Stroke Treatment classification. Serum was obtained from each patient after obtaining their consent to participate in the study. The levels of serum antibodies against Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg) and Prevotella intermedia (Pi) were evaluated by ELISA. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured by nephelometry. Results: Serum hs-CRP levels were significantly associated with acute ischemic stroke even after controlling for acute ischemic stroke, hypertension, diabetes mellitus and bulb/ internal carotid artery (ICA) atherosclerosis which were statistically selected (coefficient 0.245, 95% CI 0.142–0.347, p < 0.0001). The serum-antibody level of Pi was significantly higher in atherothrombotic-stroke patients than in patients with no previous stroke (p = 0.0035). Detectable serum anti-Pg antibody was significantly associated with atrial fibrillation (overall χ2 = 35.5, R2 = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 4.36, 95% CI 1.71–12.10, p = 0.0017), and detectable serum anti-Pi antibody was significantly associated with bulb/ICA atherosclerosis after controlling for the statistically selected associated factors (overall χ2 = 46.1, R2 = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 16.58, 95% CI 3.96–78.93, p < 0.0001). The levels of serum anti-Pi antibody were significantly associated with atherothrombotic stroke with the statistically selected associated factors excluding bulb/ICA atherosclerosis (overall χ2 = 77.0, R2 = 0.44, n = 129, p < 0.0001; anti-Pi antibody: OR 23.6, 95% CI 2.65–298.2, p = 0.008). However, when we included bulb/ICA atherosclerosis in this model, the levels of serum anti-Pi antibody were no longer significantly associated with atherothrombotic stroke (overall χ2 = 98.0, R2 = 0.56, n = 129, p < 0.0001; anti-Pi antibody: p = 0.107). Conclusions: Our results suggest that anti-Pg antibody is associated with atrial fibrillation and that anti-Pi antibody is associated with carotid artery atherosclerosis. In addition, anti-Pi antibody may be associated with atherothrombotic stroke through its association with carotid artery atherosclerosis. Thus, periodontitis may lead to serious systemic diseases.

Nationwide survey of neuro-specialists' opinions on anticoagulant therapy after intracerebral hemorrhage in patients with atrial fibrillation

PURPOSE A nationwide survey was conducted regarding anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) on warfarin with nonvalvular atrial fibrillation (NVAF). METHODS A questionnaire on standard therapeutic strategy for warfarin-related ICH in patients with NVAF was mailed to 416 institutes. RESULTS A total of 329 physicians (79%) responded with a completed questionnaire. On admission, all respondents stopped warfarin medication and 94% normalized the international normalized ratio (INR) mainly by Vitamin K (63%), followed by fresh frozen plasma (20%), and prothrombin complex concentrate (10%). Afterwards, 91% of the respondents restarted anticoagulation and 3% used antiplatelet for prevention of thromboembolism, but the remaining 6% disagreed with restarting antithrombotic therapy. As contraindications for resuming anticoagulation, recurrent ICH (59%) and poor functional condition (59%) were often chosen. Of those who restarted anticoagulation, the timing was within 4 days in 7%, 5 to 7 days in 21%, 8 to 14 days in 25%, 15 to 28 days in 28% and 29 days or later in 18%. The major key finding on follow-up CT to restart anticoagulation was the absorption tendency of hematomas (47%). When restarting anticoagulation, 76% of the respondents used warfarin alone and 20% used either unfractionated heparin plus warfarin or heparin alone. CONCLUSION A large majority of respondents responsible for ICH management stopped oral warfarin medication and normalized INR on admission, and restarted anticoagulation after acute ICH in patients with NVAF. However, the strategies to normalize INR and to restart anticoagulant therapy varied greatly and depended on each individual physicians decision.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

Background Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. Methods This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. Finding Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. Interpretation Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. Funding This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Endothelial dysfunction is associated with the severity of cerebral small vessel disease.

The pathogenesis of cerebral small vessel disease, a disease that involves white matter lesions (WMLs) and cerebral microbleeds (CMBs), is thought to be associated with endothelial dysfunction. Flow-mediated dilation (FMD) has been used to measure endothelium-dependent vasodilation. The aim of this study was to investigate the association between endothelial function (as measured by FMD) and cerebral small vessel disease. Patients with a history of cerebrovascular disease and comorbidities were enrolled in this study (n=102; 69 males, 70.1±9.2 years). The patients were divided into two groups according to the severity of WMLs, which were assessed by Fazekas classification; grades 0 to 1 as mild WMLs group and grades 2 to 3 as severe WMLs group. A gradient-echo MRI was performed in 96 patients (94.1%) to evaluate whether CMBs were present. The patients in the severe WMLs group (n=40) were older (P=0.001), more frequently exhibited hypertension (P=0.045) and diabetes mellitus (P=0.026) and possessed lower FMD values (P<0.001) than the patients in the mild WMLs group (n=62). CMBs were observed in 30 patients (31.3%). Using receiver operating characteristic curves, the optimal FMD cutoff values for predicting the presence of severe WMLs and CMBs were 3.9% and 3.7%, respectively. On multivariate logistic analysis, FMD <4.0% (odds ratio 9.50; 95% confidence interval 3.55–28.83) was independently associated with severe WMLs. Additionally, FMD <3.8% (5.82; 2.23–16.50) was also associated with the presence of CMBs. Endothelial dysfunction as evaluated by FMD may be predictive of the severity of cerebral small vessel disease.

Effects of hyperacute blood pressure and heart rate on stroke outcomes after intravenous tissue plasminogen activator.

Background and purpose The present study clarifies associations between stroke outcomes after intravenous tissue plasminogen activator (tPA) and blood pressure (BP) as well as heart rate (HR) profiles. Methods We assessed 125 patients with stroke who received tPA within 3 h of onset. We obtained baseline, mean, maximum, minimum, and coefficient of variation values for BP and HR during the initial 24 h. The primary outcome was independence at 3 months corresponding to a modified Rankin Scale score of 2 or less. The secondary outcomes were early neurological improvement at 24 h and intracerebral hemorrhage (ICH) within 36 h. Results Among the patients, 64 (51%) achieved independence, 66 (53%) early improvement, and 26 (21%) developed ICH. The 24-h time courses of SBP (P = 0.033), pulse pressure (PP, P = 0.007), and HR (P < 0.001) were lower among patients who reached independence than among those who did not. After multivariate adjustment, 24-h mean levels of SBP (odds ratio 0.69, 95% confidence interval 0.48–0.97, per 10-mmHg increase), PP (0.63, 0.41–0.94), and HR (0.59, 0.42–0.80, per 10-bpm increase) were inversely associated with independence, as were their maximum and minimum values. In particular, mean SBP values were inversely associated with independence at 8–16 and 16–24 h (0.73, 0.54–0.97 and 0.66, 0.47–0.91, respectively), but not at 0–8 h (0.79, 0.57–1.07). Baseline and maximum SBP were inversely associated with early improvement. Maximum and coefficient of variation of SBP were associated with ICH. Conclusion Lower SBP, PP, and HR values during the initial 24 h after tPA, especially at 8 h thereafter, were associated with independence at 3 months.

Greater Severity of Neurological Defects in Women Admitted With Atrial Fibrillation-Related Stroke.

BACKGROUND The magnitude of the CHA2DS2-VASc score is associated with not only stroke incidence but also long-term outcomes. The association between sex and initial stroke severity in AF-related cardioembolic stroke patients has not been clarified. The present study aimed to elucidate the risk factors for initial stroke severity among patients with cardioembolic stroke enrolled in a multicenter registry. METHODS AND RESULTS We selected 12,701 patients (age, 77±10 years; 5,653 women) with AF-related cardioembolic stroke from the Japan Standard Stroke Registry Study between January 2000 and July 2013. Indicators of National Institutes of Health Stroke Scale (NIHSS) scores at admission were identified using a multiple linear regression. Increased NIHSS scores positively correlated with CHA2DS2-VASc score (ρ=0.197; P<0.001). The initial neurological deficits were more severe in women than in men (NIHSS scores, median [interquartile range] 14 [5-22] vs. 8 [3-18]; P<0.001). Multiple regression analysis revealed that higher age (standardized partial regression coefficient [β] 0.162; P<0.001), female sex (β 0.120; P<0.001), diabetes mellitus (β 0.020; P=0.019), dyslipidemia (β -0.076; P<0.001), congestive heart failure (β 0.039; P<0.001), vascular disease (β 0.030; P=0.001), prior stroke/TIA (β 0.085; P<0.001) and prior anticoagulant use (β -0.020; P=0.028) were associated with the NIHSS score at admission. CONCLUSIONS Female sex was independently associated with the initial neurological severity among AF-related cardioembolic stroke patients.

Preserved Acetazolamide Reactivity in Lacunar Patients with Severe White-Matter Lesions: 15O-Labeled Gas and H2O Positron Emission Tomography Studies:

Limited evidence exists on the relationships between severity of white-matter lesions (WMLs) and cerebral hemodynamics in patients without major cerebral artery disease. To examine changes of cerebral blood flow (CBF), oxygen metabolism, and vascular reserve capacity associated with severity of WML in patients with lacunar stroke, we used a positron emission tomography (PET). Eighteen lacunar patients were divided into two groups according to the severity of WMLs, assessed by Fazekas classification; grades 0 to 1 as mild WML group and grades 2 to 3 as severe WML group. Rapid dual autoradiography was performed with 15O-labeled gas-PET followed by 15O-labeled water-PET with acetazolamide (ACZ) challenge. Compared with the mild WML group, the severe WML group showed lower CBF (20.6 ± 4.4 versus 29.9 ± 8.2 mL/100 g per minute, P = 0.008), higher oxygen extraction fraction (OEF) (55.2 ± 7.4 versus 46.7 ± 5.3%, P = 0.013), and lower cerebral metabolic rate of oxygen (CMRO2) (1.95 ± 0.41 versus 2.44 ± 0.42 mL/100 g per minute, P = 0.025) in the centrum semiovale. There were no significant differences in the ACZ reactivity between the two groups (48.6 ± 22.6% versus 42.5 ± 17.2%, P = 0.524). Lacunar patients with severe WMLs exhibited reduced CBF and CMRO2, and increased OEF in the centrum semiovale. The ACZ reactivity was preserved in both patients with severe and mild WMLs in each site of the brain.