Intravenous tissue plasminogen activator (TPA) improves patient chances to recover from stroke by inducing mostly partial recanalization of large intracranial thrombi. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. The international multi-center CLOTBUST trial showed that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming multi-disciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA+TCD compared to 8% who received TPA alone (p=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the Target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, subject for a pivotal trial. However, different results were achieved in a small TRUMBI trial and another study that used Transcranial Color-Coded Duplex Sonography (TCCD). Adverse bio-effects of mid-KHz (300) ultrasound promote bleeding, including brain areas not-affected by ischemia while exposure to multi-frequency / multi-element duplex ultrasound resulted in a trend towards higher risk of hemorrhagic transformations. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of a single beam 2 MHz TCD with perflutren-lipid microspheres. Enhancement of intra-arterial TPA delivery is being clinically tested with 1.7-2.1 MHz pulsed wave ultrasound (EKOS catheter). Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.
Brain ; Brain Ischemia* ; Hemorrhage ; Humans ; Ischemia ; Microspheres ; Perfusion ; Stroke ; Thrombosis ; Tissue Plasminogen Activator ; Ultrasonography*

On page 149, 9th line of the third paragraph in ‘Antiplatelet therapy,’‘without’ was misspelled. The correct word is ‘with.’

Atherosclerosis is a major cause of ischemic stroke that can be effectively prevented with appropriate lifestyle modifications and control of cardiovascular risk factors. Medical advances in recent years along with aggressive cardiovascular risk factor modifications have resulted in decreased recurrence rates of atherosclerotic stroke. Non-statin lipid-lowering molecules have recently shown clinical benefit and are recommended for very high-risk patients to reduce their risk of stroke. Aggressive hypertension treatment is crucial to reduce atherosclerotic stroke risk. Advances in antithrombotic treatments include combinations of antiplatelets and new antiplatelet agents in the acute phase post-stroke, which carries a high risk of recurrence. Intensive medical treatment has also limited the indications for carotid interventions, especially for asymptomatic disease. Intracranial atherosclerotic disease may provoke stroke through various mechanisms; it is increasingly recognized as a cause of ischemic stroke with advanced imaging and is best managed with lifestyle modifications and medical therapy. The diagnostic search for the vulnerable culprit atherosclerotic plaque is an area of intense research, from the level of the intracranial arteries to that of the aortic arch. Ultrasonography and novel magnetic resonance imaging techniques (high-resolution vessel-wall imaging) may assist in the identification of vulnerable atherosclerotic plaques as the underlying cause in cryptogenic or misdiagnosed non-atherosclerotic ischemic stroke. Vertebrobasilar atherosclerotic disease is less common than carotid artery disease; thus, high-quality data on effective prevention strategies are scarcer. However, aggressive medical treatment is also the gold standard to reduce cerebrovascular disease located in posterior circulation.
Aorta, Thoracic ; Arteries ; Asymptomatic Diseases ; Atherosclerosis ; Carotid Artery Diseases ; Cerebrovascular Disorders ; Dyslipidemias ; Humans ; Hypertension ; Life Style ; Magnetic Resonance Imaging ; Plaque, Atherosclerotic ; Platelet Aggregation Inhibitors ; Recurrence ; Risk Factors ; Secondary Prevention* ; Stroke* ; Ultrasonography

BACKGROUND AND PURPOSE: Although arbitrary blood pressure (BP) thresholds exist for acute ischemic stroke (AIS) patients eligible for intravenous thrombolysis (IVT), current international recommendations lack clarity on the impact of mean pre- and post-IVT BP levels on clinical outcomes. METHODS: Eligible studies involving IVT-treated AIS patients were identified that reported the association of mean systolic BP (SBP) or diastolic BP levels before and after IVT with the following outcomes: 3-month favorable functional outcome (modified Rankin Scale [mRS] scores of 0–1) and 3-month functional independence (mRS scores of 0–2), 3-month mortality and symptomatic intracranial hemorrhage (sICH). Unadjusted analyses of standardized mean differences and adjusted analyses of studies reporting odds ratios (ORadj) per 10 mm Hg BP increment were performed using random-effects models. RESULTS: We identified 26 studies comprising 56,513 patients. Higher pre- (P=0.02) and posttreatment (P=0.006) SBP levels were observed in patients with sICH. Patients with 3-month functional independence had lower post-treatment (P < 0.001) SBP whereas trended towards lower pre-treatment (P=0.06) SBP. In adjusted analyses, elevated pre- (ORadj, 1.08; 95% confidence interval [CI], 1.01 to 1.16) and post-treatment (ORadj, 1.13; 95% CI, 1.01 to 1.25) SBP levels were associated with increased likelihood of sICH. Increasing pre- (ORadj, 0.91; 95% CI, 0.84 to 0.98) and post-treatment (ORadj, 0.70; 95% CI, 0.57 to 0.87) SBP values were also related to lower odds of 3-month functional independence. CONCLUSIONS: We found that elevated BP levels adversely impact AIS outcomes in patients receiving IVT. Future randomized-controlled clinical trials will provide definitive data on the aforementioned association.
Blood Pressure ; Humans ; Intracranial Hemorrhages ; Mortality ; Odds Ratio ; Stroke ; Thrombolytic Therapy

BACKGROUND AND PURPOSE: Sickle cell disease (SCD) is strongly linked to stroke across all haplotypes in the pediatric population. Transcranial Doppler (TCD) ultrasound is known to identify the highest risk group in African-Americans who need to receive and stay on blood transfusions, but it is unclear if the same flow velocity cut-offs can be applied to the Iranian population. We aimed to evaluate baseline TCD findings in Iranian children with SCD and no prior strokes. METHODS: Children with genetically confirmed SCD (Arabian haplotype, homozygote) and without SCD (controls) were prospectively recruited from pediatric outpatient clinic over a period of 9 months. We performed TCD in both groups to determine flow velocities in the middle cerebral (MCA) and terminal internal carotid arteries (TICA). RESULTS: Of 74 screened children, 60 met the inclusion/exclusion criteria (62% female; mean age 10+/-4 years). Baseline characteristics did not differ between the cases and controls, except hemoglobin (Hb) which was significantly lower in the SCD group (P<0.001). The right MCA TAMM (Time Averaged Maximum Mean) was significantly higher than in controls (125+5.52 cm/s vs. 92.5+1.63 cm/s, P<0.001). Left MCA did not show differences. The TICA TAMM was also different between cases and controls (P<0.05). CONCLUSIONS: Among Iranian children with asymptomatic SCD and without receiving recent transfusion TCD velocities are higher as compared to healthy controls but appear much lower than those observed in STOP (Stroke Prevention Trial in Sickle Cell Anemia) studies. We hypothesize that some children at high risk may be present with velocities lower than 170-200 cm/s thresholds. A prospective validation of ethnicity-specific prognostic criteria is warranted.
Ambulatory Care Facilities ; Anemia, Sickle Cell* ; Blood Transfusion ; Carotid Artery, Internal ; Child* ; Female ; Haplotypes ; Humans ; Prospective Studies ; Stroke ; Ultrasonography

BACKGROUND AND PURPOSE: Current guidelines do not provide firm directions on atrial fibrillation (AF) screening after ischemic stroke (IS). We sought to investigate the association of implantable cardiac monitoring (ICM) duration with the yield of AF detection in IS patients. METHODS: We included studies reporting AF detection rates by ICM in IS patients with negative initial AF screening. We excluded studies reporting prolonged cardiac monitoring with devices other than ICM, not providing AF detection rates or monitoring duration, and reporting overlapping data for the same population. The random-effects model was used for all pooled estimates and meta-regression analyses. RESULTS: We included 28 studies (4,531 patients, mean age 65 years). In meta-regression analyses, the proportion of AF detection by ICM was independently associated with monitoring duration (coefficient=0.015; 95% confidence interval [CI], 0.005 to 0.024) and mean patient age (coefficient=0.009; 95% CI, 0.003 to 0.015). No associations were detected with other patient characteristics, including IS subtype (cryptogenic vs. embolic stroke of undetermined source) or time from IS onset to CM implantation. In subgroup analyses, significant differences (P<0.001) in the AF detection rates were found for ICM duration (<6 months: 5% [95% CI, 3% to 6%]; ≥6 and ≤12 months: 21% [95% CI, 16% to 25%]; >12 and ≤24 months: 26% [95% CI, 22% to 31%]; >24 months: 34% [95% CI, 29% to 39%]). CONCLUSIONS: Extended duration of ICM monitoring and increased patient age are factors that substantially increase AF detection in IS patients with initial negative AF screening.
Atrial Fibrillation ; Humans ; Mass Screening ; 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.