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Background@#and Purpose Intracranial arterial stenosis (ICAS)-related stroke occurs due to three primary mechanisms with distinct infarct patterns: (1) borderzone infarcts (BZI) due to impaired distal perfusion, (2) territorial infarcts due to distal plaque/thrombus embolization, and (3) plaque progression occluding perforators. The objective of the systematic review is to determine whether BZI secondary to ICAS is associated with a higher risk of recurrent stroke or neurological deterioration. @*Methods@#As part of this registered systematic review (CRD42021265230), a comprehensive search was performed to identify relevant papers and conference abstracts (with ≥20 patients) reporting initial infarct patterns and recurrence rates in patients with symptomatic ICAS. Subgroup analyses were performed for studies including any BZI versus isolated BZI and those excluding posterior circulation stroke. The study outcome included neurological deterioration or recurrent stroke during follow-up. For all outcome events, corresponding risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated. @*Results@#A literature search yielded 4,478 records with 32 selected during the title/abstract triage for full text; 11 met inclusion criteria and 8 studies were included in the analysis (n=1,219 patients; 341 with BZI). The meta-analysis demonstrated that the RR of outcome in the BZI group compared to the no BZI group was 2.10 (95% CI 1.52–2.90). Limiting the analysis to studies including any BZI, the RR was 2.10 (95% CI 1.38–3.18). For isolated BZI, RR was 2.59 (95% CI 1.24–5.41). RR was 2.96 (95% CI 1.71–5.12) for studies only including anterior circulation stroke patients. @*Conclusion@#This systematic review and meta-analysis suggests that the presence of BZI secondary to ICAS may be an imaging biomarker that predicts neurological deterioration and/or stroke recurrence.
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Background@#and Purpose The optimal management of patients with acute basilar artery occlusion (BAO) is uncertain. We aimed to evaluate the safety and efficacy of endovascular thrombectomy (EVT) compared to medical management (MM) for acute BAO through a meta-analysis of randomized controlled trials (RCTs). @*Methods@#We performed a systematic review and meta-analysis of RCTs of patients with acute BAO. We analyzed the pooled effect of EVT compared to MM on the primary outcome (modified Rankin Scale [mRS] of 0–3 at 3 months), secondary outcome (mRS 0–2 at 3 months), symptomatic intracranial hemorrhage (sICH), and 3-month mortality rates. For each study, effect sizes were computed as odds ratios (ORs) with random effects and Mantel-Haenszel weighting. @*Results@#Four RCTs met inclusion criteria including 988 patients. There were higher odds of mRS of 0-3 at 90 days in the EVT versus MM group (45.1% vs. 29.1%, OR 1.99, 95% confidence interval [CI] 1.04–3.80; P=0.04). Patients receiving EVT had a higher sICH compared to MM (5.4% vs. 0.8%, OR 7.89, 95% CI 4.10–15.19; P<0.01). Mortality was lower in the EVT group (35.5% vs. 45.1%, OR 0.64, 95% CI 0.42–0.99; P=0.05). In an analysis of two trials with BAO patients and National Institutes of Health Stroke Scale (NIHSS) <10, there was no difference in 90-day outcomes between EVT versus MM. @*Conclusion@#In this systematic review and meta-analysis, EVT was associated with favorable outcome and decreased mortality in patients with BAO up to 24 hours from stroke symptoms compared to MM. The treatment effect in BAO patients with NIHSS <10 was less certain. Further studies are of interest to evaluate the efficacy of EVT in basilar occlusion patients with milder symptoms.
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Numerous observational studies have identified a decline in cerebro-/cardiovascular (CV) admissions during the initial phase of the COVID-19 pandemic. Recent studies and meta-analyses indicated that the overall decrease was smaller than that found in initial studies during the first months of 2020. Two years later we still do not have clear evidence about the potential causes and impacts of the reduction of CV hospitalizations during the COVID-19 pandemic. It has becoming increasingly evident that collateral damage (i.e., incidental damage to the public and patients) from the COVID-19 outbreak is the main underlying cause that at least somewhat reflects the effects of imposed measures such as social distancing and self-isolation. However, a smaller true decline in CV events in the community due to a lack of triggers associated with such acute syndromes cannot be excluded. There is currently indirect epidemiological evidence about the immediate impact that the collateral damage had on excess mortality, but possible late consequences including a rebound increase in CV events are yet to be observed. In the present narrative review, we present the reporting milestones in the literature of the rates of CV admissions and collateral damage during the last 2 years, and discuss all possible factors contributing to the decline in CV hospitalizations during the COVID-19 pandemic. Healthcare systems need to be prepared so that they can cope with the increased hospitalization rates for CV events in the near future.
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Background@#and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. @*Methods@#We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). @*Results@#There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. @*Conclusions@#During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.
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Background@#and Purpose Substantial uncertainty exists on the benefit of organizational paradigms in stroke networks. Here we systematically reviewed and meta-analyzed data from studies comparing functional outcome between the mothership (MS) and the drip and ship (DS) models. @*Methods@#The meta-analysis protocol was registered international prospective register of systematic reviews (PROSPERO) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, EMBASE, and Cochrane Central databases were searched for randomized-controlled clinical trials (RCTs), retrospective and prospective studies comparing MS versus DS. Primary endpoints were functional independence at 90 days (modified Rankin Scale 2a); secondary endpoints were 3-month mortality and symptomatic intracranial haemorrhage (sICH). Odds ratios for endpoints were pooled using the random effects model and were compared between the two organizational models. @*Results@#Overall, 18 studies (n=7,017) were included in quantitative synthesis. MS paradigm was superior to DS model for functional independence (odds ratio, 1.34; 95% confidence interval, 1.16 to 1.55; I2=30%). Meta-regression analysis revealed association between onset-to-needle time and good functional outcome, with longer onset-to-needle time being detrimental. Similar rates of recanalization, sICH and mortality at 90 days were documented between MS and DS. @*Conclusions@#Patients with acute ischemic stroke eligible for reperfusion strategies might benefit more from MS paradigm as compared to DS. RCTs are needed to further refine best management taking into account logistics, facilities and resources.
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Background@#and Purpose Left ventricular hypertrophy (LVH) is associated with the risk of stroke and dementia independently of other vascular risk factors, but its association with cerebral small vessel disease (CSVD) remains unknown. Here, we employed a systematic review and meta-analysis to address this gap. @*Methods@#Following the MOOSE guidelines (PROSPERO protocol: CRD42018110305), we systematically searched the literature for studies exploring the association between LVH or left ventricular (LV) mass, with neuroimaging markers of CSVD (lacunes, white matter hyperintensities [WMHs], cerebral microbleeds [CMBs]). We evaluated risk of bias and pooled association estimates with random-effects meta-analyses. @*Results@#We identified 31 studies (n=25,562) meeting our eligibility criteria. In meta-analysis, LVH was associated with lacunes and extensive WMHs in studies of the general population (odds ratio [OR]lacunes, 1.49; 95% confidence interval [CI], 1.12 to 2.00) (ORWMH, 1.73; 95% CI, 1.38 to 2.17) and studies in highrisk populations (ORlacunes: 2.39; 95% CI, 1.32 to 4.32) (ORWMH, 2.01; 95% CI, 1.45 to 2.80). The results remained stable in general population studies adjusting for hypertension and other vascular risk factors, as well as in sub-analyses by LVH assessment method (echocardiography/electrocardiogram), study design (cross-sectional/cohort), and study quality. Across LV morphology patterns, we found gradually increasing ORs for concentric remodelling, eccentric hypertrophy, and concentric hypertrophy, as compared to normal LV geometry. LVH was further associated with CMBs in high-risk population studies. @*Conclusions@#LVH is associated with neuroimaging markers of CSVD independently of hypertension and other vascular risk factors. Our findings suggest LVH as a novel risk factor for CSVD and highlight the link between subclinical heart and brain damage.
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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.
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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 (P12 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.
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Humanos , Fibrilação Atrial , Programas de Rastreamento , Acidente Vascular CerebralRESUMO
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.
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Humanos , Pressão Sanguínea , Hemorragias Intracranianas , Mortalidade , Razão de Chances , Acidente Vascular Cerebral , Terapia TrombolíticaRESUMO
On page 149, 9th line of the third paragraph in ‘Antiplatelet therapy,’‘without’ was misspelled. The correct word is ‘with.’
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The authors review the current status of percutaneous left atrial appendage (LAA) occlusion therapy in patients with atrial fibrillation with the goal to prevent ischemic stroke and systemic embolism and to reduce oral anticoagulation associated bleeding. While we cover the historical and also surgical background, and all tested devices, the main focus rests on the single currently U.S. Food and Drug Administration (FDA) approved LAA occluder, the WATCHMAN device, and its approval process. The authors also give a critical appraisal beyond the review of mere facts, trying to put the current data into perspective.
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Humanos , Apêndice Atrial , Fibrilação Atrial , Isquemia Encefálica , Embolia , Hemorragia , Hemorragias Intracranianas , Acidente Vascular Cerebral , United States Food and Drug AdministrationRESUMO
Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.
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Humanos , Anticoagulantes , Antídotos , Avena , Hemorragia Cerebral , Dabigatrana , Hemorragia , Mortalidade , Tempo de Tromboplastina Parcial , Protrombina , Tempo de Protrombina , Rivaroxabana , Vitamina KRESUMO
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.
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Humanos , Aorta Torácica , Artérias , Doenças Assintomáticas , Aterosclerose , Doenças das Artérias Carótidas , Transtornos Cerebrovasculares , Dislipidemias , Hipertensão , Estilo de Vida , Imageamento por Ressonância Magnética , Placa Aterosclerótica , Inibidores da Agregação Plaquetária , Recidiva , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral , UltrassonografiaRESUMO
No abstract available.
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Aneurisma , Artéria Carótida Interna , Infarto da Artéria Cerebral Média , Artéria Cerebral Média , TrombectomiaRESUMO
BACKGROUND AND PURPOSE: The potential association between the severity of autonomic dysfunction and peripheral neuropathy has not been extensively investigated, with the few studies yielding inconsistent results. We evaluated the relationship between autonomic dysfunction and peripheral neuropathy in chronic hemodialysis patients in a cross-sectional study. METHODS: Cardiovascular autonomic function was assessed in 42 consecutive patients with chronic renal failure treated by hemodialysis, using a standardized battery of 5 cardiovascular reflex tests. Symptoms of autonomic dysfunction and of peripheral neuropathy were evaluated using the Autonomic Neuropathy Symptom Score (ANSS) and the Neuropathy Symptoms Score. Neurological deficits were assessed using the Neuropathy Disability Score. Conduction velocities along the sensory and motor fibers of the sural and peroneal nerves were measured. Thermal thresholds were documented using a standardized psychophysical technique. RESULTS: Parasympathetic and sympathetic dysfunction was prevalent in 50% and 28% of cases, respectively. Peripheral neuropathy was identified in 25 cases (60%). The prevalence of peripheral neuropathy did not differ between patients with impaired (55%) and normal (75%) autonomic function (p=0.297; Fisher's exact test). The electrophysiological parameters for peripheral nerve function, neuropathic symptoms, abnormal thermal thresholds, age, gender, and duration of dialysis did not differ significantly between patients with and without autonomic dysfunction. Patients with autonomic dysfunction were more likely to have an abnormal ANSS (p=0.048). The severity of autonomic dysfunction on electrophysiological testing was positively correlated with ANSS (r=0.213, p=0.036). CONCLUSIONS: The present data indicate that although cardiovascular autonomic dysfunction is prevalent among patients with chronic renal failure, it is not associated with the incidence of peripheral neuropathy.
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Humanos , Estudos Transversais , Diálise , Incidência , Falência Renal Crônica , Compostos Orgânicos , Nervos Periféricos , Doenças do Sistema Nervoso Periférico , Nervo Fibular , Prevalência , Reflexo , Diálise RenalRESUMO
BACKGROUND AND PURPOSE: There are no data regarding psychometrically validated, health-related quality-of-life instruments designed specifically for patients with multiple sclerosis (MS) in Greece. Recently, the MS International Quality-of-Life questionnaire (MusiQoL), a multidimensional, self-administered questionnaire, which is available in 14 languages (including Greek), has been validated using a large international sample. We investigated the validity and reliability of the Greek version of the MusiQoL. METHODS: Consecutive patients with different types and severities of MS were recruited from two tertiary-care centers in Greece. All patients completed the MusiQoL, the Short-Form-36 quality-of-life questionnaire (SF-36), and a symptom checklist at baseline and 21+/-7 days (mean+/-SD) later. Data regarding sociodemographic status, MS history, and functional outcome were also collected prospectively. Construct validity, internal consistency, reproducibility, and external consistency were tested. RESULTS: A total of 92 patients was evaluated. The construct validity was confirmed in terms of satisfactory item-internal consistency correlations and scaling success (87.5-100%) of item-discriminant validity. The dimensions of the MusiQoL exhibited high internal consistency (Cronbach's alpha: 0.63-0.96), and reproducibility was satisfactory (intraclass correlation coefficients: 0.69-0.99). External validity testing indicated that the MusiQoL correlated significantly with all SF-36 dimension scores (Spearman's correlation: 0.43-0.76). CONCLUSIONS: The Greek version of the MusiQoL appears to be a valid and reliable instrument for measuring quality of life in Greek MS patients.
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Humanos , Lista de Checagem , Epilepsia , Grécia , Esclerose Múltipla , Estudos Prospectivos , Qualidade de Vida , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
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.