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Background: Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5-9 h after symptom onset benefit from intravenous thrombolysis compared to placebo., Methods: Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0-6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events., Results: The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63-2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53)., Conclusions: Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

Background: Established imaging methods are still not confident in the determination of stroke onset. Sodium imaging in animal models and lately in humans implicates that the sodium signal intensity within the ischemic lesion increases in a time-dependent fashion. Sodium imaging usually requires a time-consuming change of resonators or magnetic resonance imaging systems. To avoid this, we used a double-tuned (1) H/(23) Na birdcage head coil in combination with a protocol minimizing T1 - and T2 *-weighting effects for measurement of sodium intensity in acute stroke patients., Methods: Multinuclear (1) H/(23) Na data sets were obtained from 16 stroke patients [75 ± 9·9 (standard deviation) years old] 4-130 h after symptom onset. The protocol was acquired on a clinical 3T magnetic resonance imaging site using a double-tuned (1) H/(23) Na birdcage head coil. Sodium signal intensity within the lesion and homologous contralateral side was measured and compared., Results: With an acquisition time of the complete magnetic resonance imaging protocol of 22 min, a nonlinear sodium signal intensity increase within the lesion over time after stroke onset was acknowledged. Onset time within six-hours showed an increase of only 8% or less, whereas onset time beyond 8·5 h demonstrated increases of 36% or more reaching a maximum of 170% > 120 h. In addition, some patients showed a difference in sodium signal intensity compared with diffusion weighted imaging lesion., Conclusions: The use of a double-tuned (1) H/(23) Na birdcage head coil in a clinical setting 'allowed sodium intensity measurements' in a justifiable time also for acute stroke patients, and heterogenous sodium signal intensity in the diffusion weighted imaging lesion might represent differences in tissue damage or repair., (© 2015 World Stroke Organization.)

Background and Hypothesis: Functional improvement after middle cerebral artery ischaemia seems to depend on recanalization of large-vessel occlusion as early as possible. The only approved medical treatment for acute stroke is early IV tissue plasminogen activator administration. However, while some patients do not benefit from quick recanalization, others recover despite persistent middle cerebral artery occlusion. We wondered whether there are different effects of tissue plasminogen activator treatment on large artery and small artery reopening., Methods: We enrolled 55 acute stroke patients who showed persisting middle cerebral artery occlusion evidenced by transcranial colour-coded duplex ultrasonography in follow-up examination within 48 h postonset of middle cerebral artery stroke syndromes (mean 30·8 ± 5·4 h after admission). Twenty-two of 55 had been treated with tissue plasminogen activator and 33/55 had been treated without tissue plasminogen activator. We compared neurological (National Institutes of Health Stroke Scale) and functional (modified Rankin Scale) scores at baseline, after seven-days, and then after two-months. Risk factors, previous stroke prophylaxis, as well as clinical baseline characteristics were analysed to exclude significant differences between both groups., Results: Despite later admission to hospital (tissue plasminogen activator patients 1·6 ± 0·66 h vs. non-tissue plasminogen activator patients 7·4 ± 5·84 h; P < 0·001), there was no significant difference between both groups concerning demographic data, severity of symptoms on admission, risk factors, stroke prophylaxis, as well as basic laboratory values (international normalized ratio, leucocyte count, C-reactive protein) blood pressure and body temperature on admission. Irrespective of Doppler findings demonstrating persistent middle cerebral artery occlusion in all 55 patients, there was a significant neurological and functional improvement in tissue plasminogen activator patients compared to non-tissue plasminogen activator patients. Tissue plasminogen activator patients had a mean improvement on National Institutes of Health Stroke Scale within the first seven-days of 2·8 points, while non-tissue plasminogen activator patients deteriorated by 2·2 points (P < 0·001). Concerning modified Rankin Scale tissue plasminogen activator-treated patients showed a mean improvement within the first seven-days of 0·5 points, while non-tissue plasminogen activator patients deteriorated by 0·3 points (P = 0·019). A favourable overall short-term clinical course (i.e. improvement on National Institutes of Health Stroke Scale >3 points and/or modified Rankin Scale >1 point) was found in 36·4% of tissue plasminogen activator patients and in 6·1% of non-tissue plasminogen activator patients (P = 0·0047). At two-months follow-up, patients still showed a median modified Rankin Scale of 4 points after tissue plasminogen activator treatment and 5 points after non-tissue plasminogen activator treatment (P = 0·023)., Conclusion: Although the prognosis of patients with persisting middle cerebral artery occlusion after tissue plasminogen activator administration is known to be poor, patients do better if treated with tissue plasminogen activator vs. those who could not be treated - mainly for late presentation. This may be due to sufficient small vascular territory recanalization despite persistence of large artery occlusion after tissue plasminogen activator treatment., (© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.)

An upregulation of platelet CD40 ligand (CD40L) and CD62P has been described in atherosclerotic cardiovascular diseases and among patients with acute cerebral ischemia. Correlation between platelet and monocyte activation and the etiology of ischemic stroke were examined in 41 patients with acute ischemic stroke. Compared to 10 controls, all patients with stroke showed a significantly elevated platelet expression of CD40L (P < .001) and had significantly higher amounts of platelet-monocyte aggregates (P = .002). Plasma levels of interleukin 7 were significantly lower in patients with stroke compared to controls (P = .006). Patients with small artery disease had a significantly higher platelet CD40L expression than patients with cardioembolic stroke (P = .029). Plasma levels of soluble CD40L were significantly higher in patients with large artery disease compared to patients with cardioembolic stroke (P = .047). In conclusion, patients with acute ischemic stroke show an upregulation of platelet CD40L and an activation of cellular coagulation with highest activation in the large artery disease subgroup.

Ultrasound-induced opening of the blood-brain barrier (BBB) is an emerging technique for targeted drug delivery to the central nervous system. Gap junctions allow transfer of information between adjacent cells and are responsible for tissue homeostasis. We examined the effect of ultrasound-induced BBB opening on the structure of gap junctions in cortical neurons, expressing Connexin 36, and astrocytes, expressing Connexin 43, after focused 1-MHz ultrasound exposure at 1.25 MPa of one hemisphere together with intravenous microbubble (Optison, Oslo, Norway) application. Quantification of immunofluorescence signals revealed that, compared with non-insonicated hemispheres, small-sized Connexin 43 and 36 gap-junctional plaques were markedly reduced in areas with BBB breakdown after 3 to 6 hours (34.02+/-6.04% versus 66.49+/-2.16%, P=0.02 for Connexin 43; 33.80+/-1.24% versus 36.77+/-3.43%, P=0.07 for Connexin 36). Complementing this finding, we found significant increases in large-sized gap-junctional plaques (5.76+/-0.96% versus 1.02+/-0.84%, P=0.05 for Connexin 43; 5.62+/-0.22% versus 4.65+/-0.80%, P=0.02 for Connexin 36). This effect was reversible at 24 hours after ultrasound exposure. Western blot analyses did not show any change in the total connexin amount. These results indicate that ultrasound-induced BBB opening leads to a reorganization of gap-junctional plaques in both neurons and astrocytes. The plaque-size increase may be a cellular response to imbalances in extracellular homeostasis after BBB leakage.