Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. METHODS: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. RESULTS: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03-4.54]; adjusted OR, 2.33 [95% CI, 1.02-5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68-6.11]; adjusted OR, 2.55 [95% CI, 0.76-8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. CONCLUSIONS: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.

Clot Formation in the Presence of Acetylsalicylic Acid Leads to Increased Lysis Rates Regardless of the Chosen Thrombolysis Strategy.

BACKGROUND: Patients with acute ischemic strokes frequently take an acetylsalicylic acid (ASA) premedication. We determined the impact of ASA on different thrombolysis strategies in vitro. METHODS: For two clot types made from platelet-rich plasma (one with and one without ASA) lysis rates were measured by weight loss after 1 h for five different groups: in control group A clots were solely placed in plasma; in groups B and C clots were treated with rt-PA (60 kU/ml), and in groups D and E clots were treated with desmoteplase (DSPA; 2 µg/ml). Ultrasound (2 MHz, 0.179 W/cm2) was included in groups C and E. The fibrin mesh structures of the clots were investigated by electron microscopy. RESULTS: For both clot types lysis rates increased significantly for all treatment strategies compared to their control group (each p < 0.001). The addition of ASA significantly increased the lysis rate in all 5 groups (each p < 0.001) and led to a ceiling effect concerning the treatment. A semiquantitative analysis of transmission electron micrographs revealed a decreased fibrin density for clots with ASA. For both clot types DSPA and ultrasound led to a significant dissolution of the fibrin mesh (both p = 0.029). CONCLUSIONS: In vitro ASA pretreatment leads to significantly increased lysis rates due to a weaker fibrin mesh in platelet-rich plasma clots.

Acute brain infarction detected by CCT and stroke risk in patients with transient ischemic attack lasting <1 hour.

BACKGROUND AND PURPOSE: This study aimed to determine the frequency and associated factors of acute brain infarction (ABI) detected by noncontrast cranial computed tomography (CCT) in patients with transient ischemic attack (TIA) of symptom duration <1 h and to investigate the association between evidence of ABI and short-term risk of stroke. METHODS: During a 54-month period (starting November 2007), consecutive patients with TIA (symptom duration <1 h) admitted and imaged with CCT were prospectively evaluated. Adjusted logistic regression was used to estimate odds ratios (ORs). RESULTS: Of 1021 patients (mean age, 74.5 ± 11 years; 52% female) with TIA (symptom duration <1 h) imaged with CCT at admission, 68 patients (6.7%; 95% CI, 5.3-8.3%) exhibited TIA-related ABI. Adjusted logistic regression showed that ABI was independently correlated with atrial fibrillation (AF) (OR, 3.3; 95% CI, 1.4-7.9; p = 0.006) and time between onset and CT assessment >6 h (OR, 2.5; 95% CI, 1.1-6.1; p = 0.034). During hospitalization (5 ± 3 d), 22 patients (2.2%; 95% CI, 1.4-3.1%) developed a stroke. Patients with ABI had higher stroke rates than those without (10.3% and 1.6%, respectively; p < 0.001). Adjusted logistic regression revealed that stroke risk was independently correlated with ABI (OR, 5.3; 95% CI, 1.8-15.0; p = 0.002) and AF (OR, 2.6; 95% CI, 1.1-6.4; p = 0.026). CONCLUSIONS: Detection of ABI by CCT in TIA patients with symptom duration <1 h may depend on timing of CCT assessment and presence of AF. Evidence of ABI indicates an elevated stroke risk during hospitalization.

Prognosis of intracerebral hemorrhage after conservative treatment.

BACKGROUND: The aim of this population-based study was to determine the short-term prognosis of patients treated conservatively for spontaneous intracerebral hemorrhage (ICH), a disease with a high rate of mortality. METHODS: During a 39-month period beginning in October 2007, 594 patients (mean age 72 ± 12 years; 52% female; median National Institutes of Health Stroke Scale [NIHSS] score 9) with spontaneous ICH were enrolled in this prospective, population-based study. RESULTS: Of 594 patients, 74 (12%) died during hospitalization (10.3 ± 7 days). Adjusted logistic regression analyses revealed that the in-hospital mortality rate was significantly associated with age >80 years (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.3-7.5; P = .01), NIHSS score >15 (OR 3.3; 95% CI 1.4-9.7; P = .007), unconsciousness at admission (OR 5.3; 95% CI 2.0-13.6; P = .001), and cerebral edema detected by cranial computed tomography at admission (OR 14.7; 95% CI 6.2-34.6; P < .001). At hospital discharge, 329 patients (63%) agreed to participate in the inquiry. At 3 months of follow-up, 55 (18%) of 309 patients died. The 3-month mortality rate correlated significantly with age >80 years (OR 3.5; 95% CI 1.4-8.7; P = .008), previous stroke (OR 4.1; 95% CI 1.6-10.3; P = .002), unconsciousness at admission (OR 5.7; 95% CI 2.4-13.9; P = .001), pneumonia suffered during hospitalization (OR 3.3; 95% CI 1.2-9.6; P = .02), and cerebral edema (OR 5.7; 95% CI 2.3-13.8; P < .001). CONCLUSIONS: Our study may help clinicians estimate the short-term prognosis of patients treated conservatively for ICH.

Early hospitalization of patients with TIA: a prospective, population-based study.

BACKGROUND: The German Stroke Society (GSS) recommends early hospitalization of patients with transient ischemic attack (TIA) regardless of ABCD(2) score. This population-based study determined the rate of stroke during hospitalization and within 3 months after discharge, as well as the rates of mortality and readmission during the 3 months after discharge in patients with TIA. METHODS: During a 36-month period (starting November 2007), 2200 consecutive patients (mean age, 70.6 ± 12.8 years; 49% women) with TIA from 15 hospitals in the Federal State of Schleswig-Holstein (1 of the 16 states in Germany) were prospectively evaluated during hospitalization and a follow-up time of 3 months after discharge. The primary outcomes were stroke during hospitalization and 3 months after discharge, as well as readmission and mortality at 3 months. Odds ratios (ORs) were calculated by the adjusted logistic regression analysis. RESULTS: Of 2200 patients (median time of admission, 6 hours from symptom onset), 24 patients (1.1%; 95% confidence interval [CI], 0.7%-1.5%) experienced a stroke during hospitalization (mean, 6 days), and of 1335 patients, 38 (2.8%; 95% CI, 2.1%-3.8%) experienced a stroke during the 3 months after discharge. Stroke during hospitalization was independently correlated with male sex (OR, 3.5) and acute brain infarction detected by brain imaging (OR, 2.6), whereas stroke within 3 months correlated with age greater than 65 years (OR, 3.0). The readmission rate (11.1%; 95% CI, 9.3%-12.7%) was increased in patients who had had previous stroke (OR, 1.7) but decreased in patients who were discharged with statin medication (OR, 0.6). The 3-month mortality (1.4%; 95% CI, 0.9%-1.9%) was independently correlated with unilateral weakness (OR, 2.6) and atrial fibrillation (AF) (OR, 2.6). CONCLUSIONS: These findings may help clinicians to estimate the TIA prognosis in patients who were hospitalized early with TIA.

Predictors of in-hospital mortality and the risk of symptomatic intracerebral hemorrhage after thrombolytic therapy with recombinant tissue plasminogen activator in acute ischemic stroke.

Recombinant tissue-plasminogen activator (rt-PA) therapy improves functional outcome in patients with acute ischemic stroke (AIS) but is associated with serious complications, including symptomatic intracerebral hemorrhage (sICH). This study aimed to determine the independent predictors of in-hospital mortality (IHM) and the risk of sICH after rt-PA therapy. A total of 1007 patients (mean age, 72 ± 12 years; 52% women; mean National Institutes of Health Stroke Scale [NIHSS] score, 11.6 ± 5.6) with AIS treated with rt-PA were enrolled in this study during a 42-month period beginning in November 2007. Univariate and multivariate regression analyses were performed to estimate the predictors of IHM. Eighty-three of the 1007 patients (8.2%) died during hospitalization (mean duration of hospitalization, 10 ± 1.8 days). Logistic regression estimated the following independent predictors for IHM: age ≥80 years (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1-3.0; P = .031), aphasia (OR, 2.0; 95% CI, 1.1-3.4; P = .017), altered consciousness (OR, 3.6; 95% CI, 2.0-6.2; P < .001), hypertension (OR, 4; 95% CI, 1.4-11.6; P = 0.012), sICH (OR, 5.9; 95% CI, 2.9-11.9; P < 0.001), and pneumonia during hospitalization (OR, 3.0; 95% CI, 1.8-5.0; P < .001). After rt-PA therapy, 58 patients (5.8%) sustained sICH, 16 (28%) of whom died. Increased age (P = .008), higher NIHSS score (P = .011), and atrial fibrillation (P = .025) were correlated with sICH. The findings from this study may help clinicians estimate the prognosis and risk of sICH in patients with AIS treated with rt-PA.

Validation of the transcranial Doppler rescue criteria for mechanical thrombectomy.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) identifies acute stroke patients with arterial occlusion where treatment may not effectively open the blocked vessel. This study aimed to examine the clinical utility and prognostic value of TCD flow findings in patients enrolled in a multicenter prospective study (CLOTBUST-PRO). METHODS: Patients enrolled with intracranial occlusion on computed tomography angiography (CTA) who underwent urgent TCD evaluation before intravenous thrombolysis was included in this analysis. TCD findings were assessed using the mean flow velocity (MFV) ratio, comparing the reciprocal ratios of the middle cerebral artery (MCA) depths bilaterally (affected MCA-to-contralateral MCA MFV [aMCA/cMCA MFV ratio]). RESULTS: A total of 222 patients with intracranial occlusion on CTA were included in the study (mean age: 64 ± 14 years, 62% men). Eighty-eight patients had M1 MCA occlusions; baseline mean National Institutes of Health Stroke Scale (NIHSS) score was 16, and a 24-hour mean NIHSS score was 10 points. An aMCA/cMCA MFV ratio of <.6 had a sensitivity of 99%, specificity of 16%, positive predictive value (PV) of 60%, and negative PV of 94% for identifying large vessel occlusion (LVO) including M1 MCA, terminal internal carotid artery, or tandem ICA/MCA. Thrombolysis in Brain Ischemia scale, with (grade ≥1) compared to without flow (grade 0), showed a sensitivity of 17.1%, specificity of 86.9%, positive PV of 62%, and negative PV of 46% for identifying LVO. CONCLUSIONS: TCD is a valuable modality for evaluating arterial circulation in acute ischemic stroke patients, demonstrating significant potential as a screening tool for intravenous/intra-arterial lysis protocols.

The incidence and clinical predictors of acute infarction in patients with transient ischemic attack using MRI including DWI.

INTRODUCTION: According to the most recent definition of transient ischemic attack (TIA) and the recommendations of the American Heart Association, magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) is considered a mandatory tool in evaluating and treating patients with TIA. This study aims to determine the incidence of TIA-related acute infarction, identify the independent predictors of acute infarction, and investigate the correlation between acute infarction detected by DWI-MRI and stroke risk during hospitalization. METHODS: Over a 36-month period (starting November 2007), all TIA patients (symptom duration of <24 h) who were admitted to hospital within 48 h of symptom onset and who underwent DWI-MRI were included in this population-based prospective study. The incidence of acute infarction, clinical predictors, and association with stroke recurrence during hospitalization were studied. RESULTS: Of 1,910 patients (mean age, 66.7 ± 13 years; 46 % women), 1,862 met the inclusion criteria. A TIA-related acute infarction was detected in 206 patients (11.1 %). Several independent predictors were identified with logistic regression analysis: motor weakness [odds ratio (OR), 1.5], aphasia (OR, 1.6), National Institutes of Health Stroke Scale (NIHSS) score of ≥10 at admission (OR, 3.2), and hyperlipidemia (OR, 0.6). Of 24 patients (1.3 %) who suffered a stroke during hospitalization (mean, 6 ± 4 days), five had positive DWI. Stroke rate during hospitalization was nonsignificantly higher in patients with positive DWI than those with negative DWI (2.4 vs 1.1 %, respectively; P = 0.12). CONCLUSION: The evidence of acute infarction by DWI-MRI in TIA patients was detected in 11.1 % of patients and associated with motor weakness, aphasia, and NIHSS score of ≥10 at admission.

Introduction of a new model for time-continuous and non-contact investigations of in-vitro thrombolysis under physiological flow conditions.

BACKGROUND: Thrombolysis is a dynamic and time-dependent process influenced by the haemodynamic conditions. Currently there is no model that allows for time-continuous, non-contact measurements under physiological flow conditions. The aim of this work was to introduce such a model. METHODS: The model is based on a computer-controlled pump providing variable constant or pulsatile flows in a tube system filled with blood substitute. Clots can be fixed in a custom-built clot carrier within the tube system. The pressure decline at the clot carrier is measured as a novel way to measure lysis of the clot. With different experiments the hydrodynamic properties and reliability of the model were analyzed. Finally, the lysis rate of clots generated from human platelet rich plasma (PRP) was measured during a one hour combined application of diagnostic ultrasound (2 MHz, 0.179 W/cm2) and a thrombolytic agent (rt-PA) as it is commonly used for clinical sonothrombolysis treatments. RESULTS: All hydrodynamic parameters can be adjusted and measured with high accuracy. First experiments with sonothrombolysis demonstrated the feasibility of the model despite low lysis rates. CONCLUSIONS: The model allows to adjust accurately all hydrodynamic parameters affecting thrombolysis under physiological flow conditions and for non-contact, time-continuous measurements. Low lysis rates of first sonothrombolysis experiments are primarily attributable to the high stability of the used PRP-clots.

Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies.

BACKGROUND AND PURPOSE: Ultrasound-enhanced thrombolysis is a promising new approach to facilitate reperfusion therapies for acute ischemic stroke. So far, 3 different ultrasound technologies were used to increase the thrombolytic activity of tissue plasminogen activator (tPA), including transcranial Doppler (TCD), transcranial color-coded duplex (TCCD), and low-frequency ultrasound. We performed a meta-analysis to evaluate the safety and efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous tPA). SUBJECTS AND METHODS: Through Medline, Embase, and Cochrane database search, we identified and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia. Principal investigators were contacted if data not available through peer-reviewed publication were needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were compared between tPA, tPA+TCD+/-microspheres (microS), tPA+TCCD+/-microS, and tPA+low-frequency ultrasound. RESULTS: A total of 6 randomized (n=224) and 3 nonrandomized (n=192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPA+TCD, 3.8% (95% CI, 0%-11.2%); tPA+TCCD, 11.1% (95% CI, 0%-28.9%); tPA+low-frequency ultrasound, 35.7% (95% CI, 16.2%- 61.4%); and tPA alone, 2.9% (95% CI, 0%-8.4%). Complete recanalization rates were higher in patients receiving combination of TCD with tPA 37.2% (95% CI, 26.5%- 47.9%) compared with patients treated with tPA alone 17.2% (95% CI, 9.5%-24.9%). In 8 trials of high-frequency (TCD/TCCD) ultrasound-enhanced thrombolysis, tPA+TCD/TCCD+/-microS was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70-5.25; P=0.0001) when compared to tPA alone. High-frequency ultrasound-enhanced thrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled OR, 1.26; 95% CI, 0.44-3.60; P=0.67). CONCLUSIONS: The present safety and signal-of-efficacy data of high-frequency ultrasound-enhanced thrombolysis should be taken into account in the design of future randomized controlled trials.

Timing of Recanalization and Functional Recovery in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Although onset-to-treatment time is associated with early clinical recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (tPA), the effect of the timing of tPA-induced recanalization on functional outcomes remains debatable. METHODS: We conducted a multicenter, prospective observational cohort study to determine whether early (within 1-hour from tPA-bolus) complete or partial recanalization assessed during 2-hour real-time transcranial Doppler monitoring is associated with improved outcomes in patients with proximal occlusions. Outcome events included dramatic clinical recovery (DCR) within 2 and 24-hours from tPA-bolus, 3-month mortality, favorable functional outcome (FFO) and functional independence (FI) defined as modified Rankin Scale (mRS) scores of 0-1 and 0-2 respectively. RESULTS: We enrolled 480 AIS patients (mean age 66±15 years, 60% men, baseline National Institutes of Health Stroke Scale score 15). Patients with early recanalization (53%) had significantly (P<0.001) higher rates of DCR at 2-hour (54% vs. 10%) and 24-hour (63% vs. 22%), 3-month FFO (67% vs. 28%) and FI (81% vs. 39%). Three-month mortality rates (6% vs. 17%) and distribution of 3-month mRS scores were significantly lower in the early recanalization group. After adjusting for potential confounders, early recanalization was independently associated with higher odds of 3-month FFO (odds ratio [OR], 6.19; 95% confidence interval [CI], 3.88 to 9.88) and lower likelihood of 3-month mortality (OR, 0.34; 95% CI, 0.17 to 0.67). Onset to treatment time correlated to the elapsed time between tPA-bolus and recanalization (unstandardized linear regression coefficient, 0.13; 95% CI, 0.06 to 0.19). CONCLUSIONS: Earlier tPA treatment after stroke onset is associated with faster tPA-induced recanalization. Earlier onset-to-recanalization time. RESULTS: in improved functional recovery and survival in AIS patients with proximal intracranial occlusions.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Sonothrombolysis with transcranial color-coded sonography and recombinant tissue-type plasminogen activator in acute middle cerebral artery main stem occlusion: results from a randomized study.

BACKGROUND AND PURPOSE: Sonothrombolysis is a new treatment approach in acute ischemic stroke. The results of a monocenter, randomized clinical study are presented. METHODS: Subjects with acute middle cerebral artery main stem occlusion were randomized into a target group receiving 1-hour transcranial continuous insonation using a 1.8-MHz Doppler ultrasound (US) probe or a control group. All underwent standard thrombolysis with intravenous recombinant tissue-type plasminogen activator. RESULTS: Thirty-seven subjects were included; 19 subjects were treated in the target (US) group and 18 in the control (no-US) group, all with no residual flow in the middle cerebral artery main stem occlusion (Thrombolysis in Brain Ischemia recanalization grade 0). Compared with the no-US group, the US group showed greater improvement in National Institutes of Health Stroke Scale values at days 1 and 4 and a higher median Thrombolysis in Brain Ischemia grade 1 hour after recombinant tissue-type plasminogen activator initiation. Recanalization (complete or partial) after 1 hour occurred in 57.9% of the US group and 22.2% of the no-US group (P=0.045). After 90 days, 4 subjects from the US group had a modified Rankin Score or=95 (none from the no US group; P=0.106 and P=0.003, respectively). Three subjects from the US group (15.8%) developed a symptomatic intracranial hemorrhage as did one (5.6%) in the no-US group (P=0.60). CONCLUSIONS: This small randomized study indicates a beneficial impact of transcranial ultrasound on recanalization and short-term outcome in subjects with middle cerebral artery main stem occlusion and recombinant tissue-type plasminogen activator treatment.

In Vitro Examination of the Thrombolytic Efficacy of Desmoteplase and Therapeutic Ultrasound Compared with rt-PA.

The aim of the study described here was to evaluate the thrombolytic efficacy of combined treatment with the fibrin-selective plasminogen activator desmoteplase (DSPA) and therapeutic ultrasound (sonothrombolysis [STL]) compared with conventional rt-PA (recombinant tissue plasminogen activator) treatment in vitro. Lysis rates were determined by the weight loss of platelet-rich plasma (PRP) clots treated with rt-PA (60 kU/mL) or DSPA (2 µg/mL) combined with pulsed wave ultrasound (2 MHz, 0.179 W/cm(2)). To reveal the individual effects of medication and ultrasound, lysis rates were also determined for DSPA monotherapy and for combined treatment with rt-PA and ultrasound. Clots solely placed in plasma served as the control group. Lysis increased significantly with rt-PA (26.5 ± 7.8%) and DSPA (30.5 ± 6%) compared with the control group (18.2 ± 5.9%) (each p < 0.001). DSPA lysis was more effective than rt-PA lysis (without STL: p = 0.015, with STL: p = 0.01). Combined treatment with DSPA and 2-MHz STL significantly exceeded rt-PA lysis (32.8% vs. 26.5%, p < 0.001).

Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease.

BACKGROUND: Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. Beta-galactocerebrosidase (GALC) is a specific beta-galactosidase which is defective in GLD. About 90% of GLD patients have an infantile course by fatal cerebral demyelination, but 10% have a later onset (LOGLD) of symptoms and survive for one or several decades. METHODS: Activities of GALC towards galactosylceramide (GC) and galactosylsphingosine (psychosine; PS) were determined in white blood cells and cultured fibroblasts derived from GLD patients and controls using tritium-labelled natural substrates. In the galactosylsphingosine (psychosine) beta-galactosidase (GALC-PS) assay, a thin layer chromatographic technique was used to separate enzymatically released radioactive galactose. RESULTS: Both galactosylceramide beta-galactosidase (GALC-GC) and GALC-PS activities were reduced by at least 85% of the normal in all but 2 of the 10 GLD patients studied. In particular, one 23-year-old severely demyelinated LOGLD patient was strongly deficient (11% of the normal) in GALC-GC but apparently normal for GALC-PS activity. This patient's GALC genotype was the 30-kb-deleted/502T allele combined with a wild-type allele in the 1637C background known to slightly reduce GALC-GC activity. Further, of six LOGLD patients, both of 62- and 63-year-old brothers had the deleted allele combined with an 809G>A mutated 1637C allele. The sibs had strongly reduced GALC-GC and GALC-PS activities but became clinically remarkable only in their 50s with a severe mental downhill course in one of them. CONCLUSIONS: A GALC genotype with one deleted and one polymorphic GALC activity-reducing allele can lead to enzymatic and clinical signs of LOGLD in the absence of marked GALC-PS deficiency. If an active PS hydrolysis in the fibroblasts of a LOGLD patient also reflected such hydrolysis in the brain, the psychosine hypothesis for GLD may need to be revised.

Statin treatment in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: We aimed to investigate the association of statin treatment with outcomes in patients with acute ischemic stroke. METHODS: Over a 4.5-year period (starting November 2007), 12 781 patients (mean age, 72·8 ± 12·6 years; 48·6% women) with acute ischemic stroke from 15 hospitals in Schleswig-Holstein, Germany, were enrolled in a population-based study and prospectively evaluated. The primary outcomes were the mortality during hospitalization and the disability (modified Rankin Scale score ≥2) at discharge from hospital. The secondary outcomes were the mortality and disability at three-months after discharge. RESULTS: A total of 7535 patients (59%) with acute ischemic stroke were treated with statins. During hospitalization (mean, nine-days), the in-hospital mortality rate (4·7%; 95% confidence interval, 4·3-5·1%) was lower in patients treated with statins than in those without statins (2·3% vs. 7·9%, respectively; P < 0·001). At three-months after discharge, the mortality rate (6·9%; 95% confidence interval, 6·4-7·5%) was lower in patients treated with statins than in those without statins (5·0% vs. 10·6%, respectively; P < 0·001). Adjusted logistic regression analysis showed that statin treatment was associated with reduced rates of in-hospital mortality (odds ratio, 0·39; 95% confidence interval, 0·31-0·48; P < 0·001) and three-month mortality (odds ratio, 0.47; 95% confidence interval, 0·34-0·63; P < 0·001). A comparison of the patient groups revealed that patients on statins were likely to have lower disability rates at discharge (59% vs. 67%, respectively; P < 0·001) and after three-months (33% vs. 42%, respectively; P < 0·001) in patients who had survived the stroke. CONCLUSION: Statin treatment may improve the outcomes in patients with acute ischemic stroke. Further studies are necessary to confirm this finding.

The role of sonolysis and sonothrombolysis in acute ischemic stroke: a systematic review and meta-analysis of randomized controlled trials and case-control studies.

OBJECTIVES: To assess the evidence on the safety and efficacy of sonothrombolysis in acute stroke. SEARCH METHODS: Electronic databases and grey literature were searched under different MeSH terms from 1970 to present. SELECTION CRITERIA: Randomized control trials (RCTs) and case control studies (CCSs) on sonolysis and sonothrombolysis alone or with microsphere in acute stroke patients (>18 old). Outcome measures included complete recanalization (CR) at 1-2 and 24 hours, 3 months modified Rankin Scale (mRS), and symptomatic intracerebral hemorrhage (sICH). Data was extracted to Review Manager software. RESULTS: Fifty-seven studies were retrieved and analyzed. Ten studies (7 RCTs and 3 CCSs) were included in our meta-analysis, which revealed that sonolysis and sonothrombolysis are safe (OR of sICH: 1.14; 95% confidence interval (CI): 0.56- 2.34;P=0.71) and effective (OR of CR at 1-2 hours: 2.95;95% CI: 1.81-4.81;P<0.00001) and have more than two-fold higher likelihood of favourable long-term outcome (3-month mRS 0-2; OR: 2.20; CI:1.52-3.19;P<0.0001). Further subgroup analysis based on the presence of microsphere revealed that it is safe (OR of sICH: 1.18; CI:0.433.24;P=0.75) and effective (OR of CR: 2.61; CI: 1.36-4.99;P=0.004). Subgroup analysis based on sonolysis revealed to be safe and effective. CONCLUSIONS: This novel treatment appears safe and effective. The evidence of microsphere as an enhancement of sonothrombolysis is evolving.

MRI findings and stroke risk in TIA patients with different symptom durations.

OBJECTIVE: To determine the frequency of acute infarction detected by diffusion-weighted imaging (DWI)-MRI and stroke risk in TIA patients with different symptom duration in a population-based study. METHODS: During a 54-month period (starting November 2007), 3,724 admitted patients (mean age, 67 ± 14 years; 45% women) with transient neurologic symptoms lasting <24 hours from 15 hospitals were included. All patients underwent DWI-MRI during hospitalization. RESULTS: Of 3,724 patients, 1,166 showed an acute infarction (32.2%; 95% confidence interval [CI], 30.8%-33.8%) and 88 (2.4%; 95% CI, 1.9%-2.9%) had a stroke during hospitalization (7 days). Stroke risk was higher in patients with tissue-positive DWI than in those with tissue-negative DWI (4.5% vs. 1.5%, respectively; p < 0.001). Logistic regression analysis revealed that stroke risk was correlated with positive DWI (odds ratio [OR], 3.1; 95% CI, 2.0-4.8; p < 0.001), atrial fibrillation (OR, 2.1; 95% CI, 1.3-3.5; p = 0.001), and symptom duration <1 hour (OR, 1.5; 95% CI, 1.0-2.4; p = 0.042). Patients with symptoms lasting <1 hour had a lower rate of acute infarction than those with symptoms lasting ≥1 hour (24% vs. 36%, respectively; p < 0.001), whereas stroke risk did not differ between the groups (2.8% vs. 2.1%, respectively; p = 0.22). Stroke risk was higher after tissue-positive events than tissue-negative ones in patients with symptom duration <1 hour (5.2% vs 2.0%, respectively; p = 0.002) and in those with symptom duration ≥1 hour (4.1% vs. 1.1%, respectively; p < 0.001). CONCLUSION: Stroke risk was higher after tissue-positive events than tissue-negative ones in TIA patients with different symptom duration.