International beliefs and head positioning practices in patients with spontaneous hyperacute intracerebral hemorrhage.

Background: Prior to the conduct of the Head Position in Stroke Trial (HeadPoST), an international survey (n = 128) revealed equipoise for selection of head position in acute ischemic stroke. Objectives: We aimed to determine whether equipoise exists for head position in spontaneous hyperacute intracerebral hemorrhage (ICH) patients following HeadPoST. Design: This is an international, web-distributed survey focused on head positioning in hyperacute ICH patients. Methods: A survey was constructed to examine clinicians' beliefs and practices associated with head positioning of hyperacute ICH patients. Survey items were developed with content experts, piloted, and then refined before distributing through stroke listservs, social media, and purposive snowball sampling. Data were analyzed using descriptive statistics and χ2 test. Results: We received 181 responses representing 13 countries on four continents: 38% advanced practice providers, 32% bedside nurses, and 30% physicians; overall, participants had median 7 [interquartile range (IQR) = 3-12] years stroke experience with a median of 100 (IQR = 37.5-200) ICH admissions managed annually. Participants disagreed that HeadPoST provided 'definitive evidence' for head position in ICH and agreed that their 'written admission orders include 30-degree head positioning', with 54% citing hospital policies for this head position in hyperacute ICH. Participants were unsure whether head positioning alone could influence ICH longitudinal outcomes. Use of serial proximal clinical and technology measures during the head positioning intervention were identified by 82% as the most appropriate endpoints for future ICH head positioning trials. Conclusion: Interdisciplinary providers remain unconvinced by HeadPoST results that head position does not matter in hyperacute ICH. Future trials examining the proximal effects of head positioning on clinical stability in hyperacute ICH are warranted.

High-resolution CT with arch/neck/head CT angiography on a mobile stroke unit.

BACKGROUND: Mobile stroke units (MSUs) performance dependability and diagnostic yield of 16-slice, ultra-fast CT with auto-injection angiography (CTA) of the aortic arch/neck/circle of Willis has not been previously reported. METHODS: We performed a prospective observational study of the first-of-its kind MSU equipped with high resolution, 16-slice CT with multiphasic CTA. Field CT/CTA was performed on all suspected stroke patients regardless of symptom severity or resolution. Performance dependability, efficiency and diagnostic yield over 365 days was quantified. RESULTS: 1031 MSU emergency activations occurred; of these, 629 (61%) were disregarded with unrelated diagnoses, and 402 patients transported: 245 (61%) ischemic or hemorrhagic stroke, 17 (4%) transient ischemic attack, 140 (35%) other neurologic emergencies. Total time from non-contrast CT/CTA start to images ready for viewing was 4.0 (IQR 3.5-4.5) min. Hemorrhagic stroke totaled 24 (10%): aneurysmal subarachnoid hemorrhage 3, hemorrhagic infarct 1, and 20 intraparenchymal hemorrhages (median intracerebral hemorrhage score was 2 (IQR 1-3), 4 (20%) spot sign positive). In 221 patients with ischemic stroke, 73 (33%) received alteplase with 31.5% treated within 60 min of onset. CTA revealed large vessel occlusion in 66 patients (30%) of which 9 (14%) were extracranial; 27 (41%) underwent thrombectomy with onset to puncture time averaging 141±90 min (median 112 (IQR 90-139) min) with full emergency department (ED) bypass. No imaging needed to be repeated for image quality; all patients were triaged correctly with no inter-hospital transfer required. CONCLUSIONS: MSU use of advanced imaging including multiphasic head/neck CTA is feasible, offers high LVO yield and enables full ED bypass.

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden.

Importance: Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations. Objective: To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group. Design, Setting, and Participants: The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020. Main Outcomes and Measures: Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location. Results: There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals. Conclusions and Relevance: This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.

Prognostication via early computed tomography head in patients treated with targeted temperature management after cardiac arrest.

BACKGROUND: We evaluated computed tomography head (CTH) imaging obtained prior to targeted temperature management (TTM) in patients after cardiac arrest, and its role in prognostication. METHODS: In this retrospective cohort study in a tertiary-care hospital, 341 adults presenting with out-of-hospital cardiac arrest received a CTH prior to TTM. Associations between outcomes and neuroimaging variables were evaluated with Chi-square analysis for significant associations that yielded a composite neuroimaging score-Tennessee Early Neuroimaging Score (TENS). Univariable and multivariable logistic regression analysis including TENS as an independent variable and the four outcome dependent variables were analyzed. RESULTS: Four of the neuroimaging variables-sulcal effacement, partial gray-white matter effacement, total gray-white matter effacement, deep nuclei effacement-had significant associations with each of the four outcome variables and yielded TENS. In multivariable logistic regression models adjusted for potential confounders, TENS was associated with poor discharge CPC (OR 2.15, 95%CI 1.16-3.98, p = .015), poor disposition (OR 2.62, 95%CI 1.37-5.02, p = .004), in-hospital mortality (OR 1.99, 95%CI 1.09-3.62, p = .024), and ICU mortality (OR 1.89, 95%CI 1.12-3.20, p = .018). CONCLUSION: Imaging prior to TTM may help identify post-cardiac arrest patients with severe anoxic brain injury and poor outcomes.

Hemicraniectomy for Malignant Middle Cerebral Artery Syndrome: A Review of Functional Outcomes in Two High-Volume Stroke Centers.

BACKGROUND AND PURPOSE: Despite recent landmark randomized controlled trials showing significant benefits for hemicraniectomy (HCT) compared with medical therapy (MT) in patients with malignant middle cerebral artery infarction (MMCAI), HCT rates have not substantially increased in the United States. We sought to evaluate early outcomes in patients with MMCAI who were treated with HCT (cases) in comparison to patients treated with MT due to the perception of procedural futility by families (controls). METHODS: We retrospectively evaluated consecutive patients with acute MMCAI treated in 2 tertiary care centers during a 7-year period. Pretreatment National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at 3 months were documented. Functional independence (FI) and survival without severe disability (SWSD) were defined as mRS of 0-2 and 0-4, respectively. RESULTS: A total of 66 patients (37 cases and 29 controls) fulfilled the study inclusion criteria (mean age 59 ± 15 years, 52% men, median admission NIHSS score: 19 points [interquartile range {IQR}: 16-22]). Cases were younger (51 ± 11 versus 68 ± 13 years; P < .001) and tended to have lower median admission NIHSS than controls (18 [IQR:16-20] versus 20 [IQR:18-23]; P = .072). The rates of FI and SWSD at 3 months were higher in cases than controls (16% versus 0% [P = .031] and 62% versus 0% [P < .001]), while 3-month mortality was lower (24% versus 77%; P < .001). Multivariable Cox regression analyses adjusting for potential confounders identified HCT as the most important predictor of lower risk of 3-month mortality (hazard ratio: .02, 95% confidence interval: .01-0.10; P < .001). CONCLUSIONS: HCT is a critical and effective therapy for patients with MMCAI but cannot provide a guarantee of functional recovery.

Sulfonylurea Pretreatment and In-Hospital Use Does Not Impact Acute Ischemic Strokes (AIS) Outcomes Following Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: Preliminary studies have indicated that sulfonylurea drugs (SUD) may confer protection against cerebral swelling and hemorrhagic transformation in severe acute ischemic stroke (AIS). We sought to determine whether pretreatment and in-hospital use of SUD may be associated with better outcomes in diabetic AIS patients treated with intravenous thrombolysis (IVT). SUBJECTS AND METHODS: We analyzed consecutive diabetic AIS patients treated with IVT during a 3-year period. Pretreatment with SUD, admission NIHSS (National Institutes of Health Stroke Scale) score, NIHSS at 48 hours, and modified Rankin Scale (mRS) at discharge were documented. Patients who discontinued SUD during hospitalization were excluded. Symptomatic intracranial hemorrhage (sICH) was defined as imaging evidence of ICH with NIHSS score increase of greater than or equal to 4 points within 72 hours. Early neurological improvement was defined as an NIHSS score decrease of greater than or equal to 4 points or NIHSS score of 0 at 48 hours. Cerebral edema was documented by neuroradiology reports. Favorable functional outcome (FFO) was defined as discharge mRS of 0-1. RESULTS: A total of 148 diabetic AIS patients were evaluated (mean age 64 ± 11 years, 49% men, median admission NIHSS score: 8 points). We identified 42 (28%) cases pretreated with SUD. The prevalence of complications and favorable outcomes did not differ (P > .1) between patients pretreated and nonpretreated with SUD: sICH (2% versus 5%), cerebral edema (5% versus 4%), early neurological improvement (42% versus 43%), in-hospital mortality (12% versus 5%), and FFO (22% versus 32%). CONCLUSIONS: Pretreatment and in-hospital use of SUD appears not to be associated with early favorable outcomes and lower likelihood of potential complications in diabetic AIS patients treated with IVT.

The value of transesophageal echocardiography for embolic strokes of undetermined source.

OBJECTIVE: Our aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS). METHODS: We prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups. RESULTS: We identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 ± 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3-8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%-65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%-28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%-10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%-9.6%]), ESUS (8.1% [95% CI: 3.4%-18.1%]), and IS (9.4% [95% CI: 7.5%-11.8%]). CONCLUSIONS: Abnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS.

Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series.

The safety and efficacy of intravenous thrombolysis (IVT) in dissection-related ischemic stroke (DRIS) has not been established. We sought to determine safety and recovery rates of IVT in DRIS using prospective, international, multicenter data and by conducting a comprehensive meta-analysis of reported case series. We analyzed consecutive DRIS patients treated with IVT according to national guidelines during a 5-year period at six tertiary-care stroke centers, and also conducted a comprehensive review and meta-analysis of all available case series reporting safety outcomes in DRIS treated with IVT according to PRISMA guidelines. A total of 39 DRIS patients (mean age 60 ± 18 years; 59% men; median NIHSS 13 points, IQR 9-17) received IVT in our multicenter study. Symptomatic intracranial hemorrhage (sICH), in-hospital mortality, complete recanalization, favorable functional outcome (FFO; mRS-score of 0-1) and functional independence (FI; mRS-score of 0-2) were 0% (adjusted Wald 95% CI 0-8%), 10% (3-24%), 55% (40-70%), 61% (45-74%) and 68% (52-81%). The pooled sICH and mortality rates in meta-analysis including 10 case series (234 IVT-DRIS patients) were 2% (0-5%) and 4% (0-8%). The pooled recanalization, FFO and FI rates were 45% (26-67%), 41% (29-54%) and 61% (48-72%), respectively. Substantial heterogeneity was only found for FFO (I(2) = 61%; p = 0.006). Subsequent meta-regression analysis identified baseline NIHSS and dissection in the posterior circulation as independent predictors of FFO (p < 0.05), accounting for FFO variance across different studies. Our prospective, international data coupled with comprehensive meta-analysis results underscore IVT safety in DRIS, while further independent validation is required in larger observational registries or RCTs.

Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis.

BACKGROUND AND PURPOSE: Shortening door-to-needle time may lead to inadvertent intravenous thrombolysis (IVT) administration in stroke mimics (SMs). We sought to determine the safety of IVT in SMs using prospective, single-center data and by conducting a comprehensive meta-analysis of reported case-series. METHODS: We prospectively analyzed consecutive IVT-treated patients during a 5-year period at a tertiary care stroke center. A systematic review and meta-analysis of case-series reporting safety of IVT in SMs and confirmed acute ischemic stroke were conducted. Symptomatic intracerebral hemorrhage was defined as imaging evidence of ICH with an National Institutes of Health Stroke scale increase of ≥4 points. Favorable functional outcome at hospital discharge was defined as a modified Rankin Scale score of 0 to 1. RESULTS: Of 516 consecutive IVT patients at our tertiary care center (50% men; mean age, 60±14 years; median National Institutes of Health Stroke scale, 11; range, 3-22), SMs comprised 75 cases. Symptomatic intracerebral hemorrhage occurred in 1 patient, whereas we documented no cases of orolingual edema or major extracranial hemorrhagic complications. In meta-analysis of 9 studies (8942 IVT-treated patients), the pooled rates of symptomatic intracerebral hemorrhage and orolingual edema among 392 patients with SM treated with IVT were 0.5% (95% confidence interval, 0%-2%) and 0.3% (95% confidence interval, 0%-2%), respectively. Patients with SM were found to have a significantly lower risk for symptomatic intracerebral hemorrhage compared with patients with acute ischemic stroke (risk ratio=0.33; 95% confidence interval, 0.14-0.77; P=0.010), with no evidence of heterogeneity or publication bias. Favorable functional outcome was almost 3-fold higher in patients with SM in comparison with patients with acute ischemic stroke (risk ratio=2.78; 95% confidence interval, 2.07-3.73; P<0.00001). CONCLUSIONS: Our prospective, single-center experience coupled with the findings of the comprehensive meta-analysis underscores the safety of IVT in SM.

Family presence during brain death evaluation: a randomized controlled trial*.

OBJECTIVE: To evaluate if a family presence educational intervention during brain death evaluation improves understanding of brain death without affecting psychological distress. DESIGN: Randomized controlled trial. SETTING: Four ICUs at an academic tertiary care center. SUBJECTS: Immediate family members of patients suspected to have suffered brain death. INTERVENTIONS: Subjects were group randomized to presence or absence at bedside throughout the brain death evaluation with a trained chaperone. All randomized subjects were administered a validated "understanding brain death" survey before and after the intervention. Subjects were assessed for psychological well-being between 30 and 90 days after the intervention. MEASUREMENTS AND MAIN RESULTS: Follow-up assessment of psychological well-being was performed using the Impact of Event Scale and General Health Questionnaire. Brain death understanding, Impact of Event Scale, and General Health Questionnaire scores were analyzed using Wilcoxon nonparametric tests. Analyses were adjusted for within family correlation. Fifty-eight family members of 17 patients undergoing brain death evaluation were enrolled: 38 family members were present for 11 brain death evaluations and 20 family members were absent for six brain death evaluations. Baseline understanding scores were similar between groups (median 3.0 [presence group] vs 2.5 [control], p = 0.482). Scores increased by a median of 2 (interquartile range, 1-2) if present versus 0 (interquartile range, 0-0) if absent (p < 0.001). Sixty-six percent of those in the intervention group achieved perfect postintervention "understanding" scores, compared with 20% of subjects who were not present (p = 0.02). Median Impact of Event Scale and General Health Questionnaire scores were similar between groups at follow-up (Impact of Event Scale: present = 20.5, absent = 23.5, p = 0.211; General Health Questionnaire: present = 13.5, absent = 13.0, p = 0.250). CONCLUSIONS: Family presence during brain death evaluation improves understanding of brain death with no apparent adverse impact on psychological well-being. Family presence during brain death evaluation is feasible and safe.

Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series.

BACKGROUND AND PURPOSE: Efforts to increase the availability and shorten the time delivery of intravenous thrombolysis in patients with acute ischemic stroke carry the potential for tissue plasminogen activator administration in patients with diseases other than stroke, that is, stroke mimics (SMs). We aimed to determine safety and to describe outcomes of intravenous thrombolysis in SM. METHODS: We retrospectively analyzed stroke registry data of consecutive acute ischemic stroke admissions treated with intravenous thrombolysis over a 6-year-period. The admission National Institutes of Health Stroke Scale score, vascular risk factors, ischemic lesions on brain MRI (routinely performed as part of diagnostic work-up), and discharge modified Rankin Scale scores were documented. Initial stroke diagnosis in the emergency department was compared with final discharge diagnosis. SM diagnosis was based on the absence of ischemic lesions on diffusion-weighted imaging sequences in addition to an alternate discharge diagnosis. Symptomatic intracranial hemorrhage was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by National Institutes of Health Stroke Scale score increase of ≥4 points. RESULTS: Intravenous thrombolysis was administered in 539 patients with acute ischemic stroke (55% men; mean age, 66 ± 15 years). Misdiagnosis of acute ischemic stroke was documented in 56 cases (10.4%; 95% CI, 7.9% to 13.3%). Conversion disorder (26.8%), complicated migraine (19.6%), and seizures (19.6%) were the 3 most common final diagnoses in SM. SMs were younger (mean age, 56 ± 13 years) and had milder baseline stroke severity (median National Institutes of Health Stroke Scale, 6; interquartile range, 4) compared with patients with confirmed acute ischemic stroke (mean age, 67 ± 14 years; median National Institutes of Health Stroke Scale, 8; interquartile range, 10; P<0.001). There was no case of symptomatic intracranial hemorrhage in SMs (0%; 95% CI, 0% to 5.5%); 96% of SMs were functionally independent at hospital discharge (modified Rankin Scale, 0 to 1). CONCLUSIONS: Our single-center data indicate favorable safety and outcomes of intravenous thrombolysis administered to SM.

Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage.

BACKGROUND AND PURPOSE: From small pilot studies, uncontrolled pretreatment systolic blood pressure >185 mm Hg and diastolic blood pressure >110 mm Hg in patients with acute ischemic stroke were introduced in the National Institute of Neurological Diseases and Stroke rtPA Stroke Study as a contraindication for thrombolysis. We sought to determine if pretreatment blood pressure protocol violations in patients with acute ischemic stroke receiving intravenous tissue plasminogen activator are related to the subsequent risk of symptomatic intracranial hemorrhage (sICH). METHODS: We reviewed medical records of consecutive ischemic stroke admissions treated with intravenous thrombolysis over a 10-year period at our tertiary care hospital. The National Institutes of Health Stroke Scale score on admission was used to determine baseline stroke severity. The closest documented blood pressure values to the time of tissue plasminogen activator bolus (range, 0 to 10 minutes) were considered as pretreatment blood pressure. Pretreatment blood pressure protocol violations were identified as systolic blood pressure >185 or diastolic blood pressure >110 mm Hg prebolus. sICH was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by the National Institutes of Health Stroke Scale score increase of >or=4 points. RESULTS: Among 510 patients with ischemic stroke treated with intravenous tissue plasminogen activator (282 men; mean age, 65+/-15 years), sICH occurred in 31 patients (6.1%). Blood pressure protocol violations were present in 63 patients (12.4%) and they were more frequent in patients with sICH (26% versus 12%; P=0.019). After adjusting for demographic characteristics, onset-to-treatment time, baseline National Institutes of Health Stroke Scale, stroke risk factors and medications, pretreatment blood pressure protocol violations were independently associated with a higher likelihood of sICH (OR, 2.59; 95% CI, 1.07 to 6.25; P=0.034). CONCLUSIONS: These data support current guidelines advising not to use intravenous tissue plasminogen activator when pretreatment blood pressure exceeds the prespecified thresholds by showing that blood pressure protocol violations are independently associated with a higher likelihood of sICH.

Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial.

OBJECTIVE: Microspheres (microS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of microS dose escalation with systemic thrombolysis. METHODS: Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to microS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA. RESULTS: Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24-36 hours following tPA bolus. INTERPRETATION: Perflutren lipid microS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with microS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28-38.

A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke.

BACKGROUND AND PURPOSE: Ultrasound transiently expands perflutren-lipid microspheres (muS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated muS with systemic tissue plasminogen activator (tPA). METHODS: Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL microS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by >or=4 NIHSS points within 72 hours. RESULTS: Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. muS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8+/-11.3 vs 28.8+/-13.8 cm/s, P<0.001. In 75% of subjects, microS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of microS infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P=0.456. CONCLUSIONS: Perflutren microS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further microS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.

Quantification of microspheres appearance in brain vessels: implications for residual flow velocity measurements, dose calculations, and potential drug delivery.

BACKGROUND AND PURPOSE: Characteristics of ultrasound-activated gaseous microspheres (muS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. METHODS: A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler microS traces included large (>8 micro) microS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5 micro) microS from acute patients without shunts receiving thrombolysis and perflutren-lipid microS. RESULTS: In 101 microS traces from 50 RLS-positive and 10 thrombolysis+microS treated patients, a large microS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0 ms), multi-gate travel time (MGTT) 58.6+/-19.3 ms versus small microS: duration 8.3 ms (IQR 4.3 ms), MGTT 43.2+/-13.9 ms, P<0.001. Small microS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P<0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265-588) small microS can produce continuous flow enhancement for 4 seconds. Small microS velocities on m-mode in obstructed vessels (39.8+/-11.3 cm/s) were similar to large microS in patent vessels (40.8+/-11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8+/-13.8 cm/s, P<0.001). CONCLUSIONS: With normal or reduced flow, activated muS passage duration through a small power motion Doppler gate can quantify the dose of delivered microS. Ultrasound can determine a minimum number of microS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of microS smaller than red blood cells may reflect plasma flow velocities around acute occlusions.

Applications and advantages of power motion-mode Doppler in acute posterior circulation cerebral ischemia.

BACKGROUND AND PURPOSE: Evaluation of posterior circulation with single-gate transcranial Doppler (TCD) is technically challenging and yields lower accuracy parameters in comparison to anterior circulation vessels. Transcranial power motion-mode Doppler (PMD-TCD), in addition to spectral information, simultaneously displays in real-time flow signal intensity and direction over 6 cm of intracranial space. We aimed to evaluate the diagnostic accuracy of PMD-TCD against angiography in detection of acute posterior circulation stenoocclusive disease. METHODS: Consecutive patients presenting to the emergency room with symptoms of acute (<24 hours) cerebral ischemia underwent emergent neurovascular evaluation with PMD-TCD and angiography (computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography). Previously published diagnostic criteria were prospectively applied for PMD-TCD interpretation independent of angiographic findings. RESULTS: A total of 213 patients (119 men; mean age 65+/-16 years; ischemic stroke 71%, transient ischemic attack 29%) underwent emergent neurovascular assessment. Compared with angiography, PMD-TCD showed 17 true-positive, 8 false-negative, 6 false-positive, and 182 true-negative studies in posterior circulation vessels (sensitivity 73% [55% to 91%], specificity 96% [93% to 99%], positive predictive value 68% [50% to 86%], negative predictive value 95% [92% to 98%], accuracy 93% [90% to 96%]). In 14 patients (82% of true-positive cases), PMD display showed diagnostic flow signatures complementary to the information provided by the spectral display: reverberating or alternating flow, distal basilar artery flow reversal, high-resistance flow, emboli tracks and, bruit flow signatures. CONCLUSIONS: PMD-TCD yields a satisfactory agreement with urgent brain angiography in the evaluation of patients with acute posterior circulation cerebral ischemia. PMD display can depict flow signatures that are complimentary to and can increase confidence in standard single-gate TCD spectral findings.

Detection of right-to-left shunts: comparison between the International Consensus and Spencer Logarithmic Scale criteria.

BACKGROUND: International Consensus Criteria (ICC) consider right-to-left shunt (RLS) present when Transcranial Doppler (TCD) detects even one microbubble (microB). Spencer Logarithmic Scale (SLS) offers more grades of RLS with detection of >30 microB corresponding to a large shunt. We compared the yield of ICC and SLS in detection and quantification of a large RLS. SUBJECTS AND METHODS: We prospectively evaluated paradoxical embolism in consecutive patients with ischemic strokes or transient ischemic attack (TIA) using injections of 9 cc saline agitated with 1 cc of air. Results were classified according to ICC [negative (no microB), grade I (1-20 microB), grade II (>20 microB or "shower" appearance of microB), and grade III ("curtain" appearance of microB)] and SLS criteria [negative (no microB), grade I (1-10 microB), grade II (11-30 microB), grade III (31100 microB), grade IV (101300 microB), grade V (>300 microB)]. The RLS size was defined as large (>4 mm) using diameter measurement of the septal defects on transesophageal echocardiography (TEE). RESULTS: TCD comparison to TEE showed 24 true positive, 48 true negative, 4 false positive, and 2 false negative cases (sensitivity 92.3%, specificity 92.3%, positive predictive value (PPV) 85.7%, negative predictive value (NPV) 96%, and accuracy 92.3%) for any RLS presence. Both ICC and SLS were 100% sensitive for detection of large RLS. ICC and SLS criteria yielded a false positive rate of 24.4% and 7.7%, respectively when compared to TEE. CONCLUSIONS: Although both grading scales provide agreement as to any shunt presence, using the Spencer Scale grade III or higher can decrease by one-half the number of false positive TCD diagnoses to predict large RLS on TEE.

Noninvasive detection of diffuse intracranial disease.

BACKGROUND AND PURPOSE: Intracranial arterial stenosis increases flow velocities on the upslope of the Spencer's curve of cerebral hemodynamics. However, the velocity can decrease with long and severely narrowed vessels. We assessed the frequency and accuracy for detection of focal and diffuse intracranial stenoses using novel diagnostic criteria that take into account increased resistance to flow with widespread lesions. METHODS: We evaluated consecutive patients referred to a neurovascular ultrasound laboratory with symptoms of cerebral ischemia. Transcranial Doppler mean flow velocities were classified as normal (30 to 99 cm/s), high and low. Pulsatility index >or=1.2 was considered high. Focal intracranial disease was defined as >or=50% diameter reduction by the Warfarin Aspirin in Symptomatic Intracranial Disease criteria. Diffuse disease was defined as stenoses in multiple intracranial arteries, multiple segments of one artery, or a long (>1 cm) stenosis in one major artery on contrast angiography (CT angiography or digital subtraction angiography) as the gold standard. RESULTS: One hundred fifty-three patients (96 men, 76% white, age 62+/-15 years) had previous strokes (n=135) or transient ischemic attack (n=18). Transcranial Doppler detection of focal and diffuse intracranial disease had sensitivity 79.4% (95% CI: 65.8% to 93%), specificity 92.4% (95% CI: 87.7% to 97.2%), positive predictive value 75.0% (95% CI: 60.9% to 89.2%), negative predictive value 94.0% (95% CI: 89.7% to 98.3%), and overall accuracy 89.5% (95% CI: 84.5% to 94.4%). After adjustment for stroke risk factors, transcranial Doppler findings of low mean flow velocities and high pulsatility index in a single vessel were independently associated with angiographically demonstrated diffuse single vessel intracranial disease, whereas low mean flow velocities/high pulsatility index in multiple vessels were related to multivessel intracranial disease (OR: 19.7, 95% CI: 4.8 to 81.2, P<0.001). CONCLUSIONS: Diffuse intracranial disease may have a higher than expected frequency in a select stroke population and can be detected with noninvasive screening.

Reversed Robin Hood syndrome in acute ischemic stroke patients.

BACKGROUND AND PURPOSE: Recurrent hemodynamic and neurological changes with persisting arterial occlusions may be attributable to cerebral blood flow steal from ischemic to nonaffected brain. METHODS: Transcranial Doppler monitoring with voluntary breath-holding and serial NIH Stroke Scale (NIHSS) scores were obtained in patients with acute middle cerebral artery or internal carotid artery occlusions. The steal phenomenon was detected as transient, spontaneous, or vasodilatory stimuli-induced velocity reductions in affected arteries at the time of velocity increase in normal vessels. The steal magnitude (%) was calculated as [(MFVm-MFVb)/MFVb]x100, where m=minimum and b=baseline mean flow velocities (MFV) during the 15- to 30-second period of a total 30 second of breath-holding. RESULTS: Six patients had steal phenomenon on transcranial Doppler (53 to 73 years, NIHSS 4 to 15 points). Steal magnitude ranged from -15.0% to -43.2%. All patients also had recurrent neurological worsening (>2 points increase in NIHSS scores) at stable blood pressure. In 3 of 5 patients receiving noninvasive ventilatory correction for snoring/sleep apnea, no further velocity or NIHSS score changes were noted. CONCLUSIONS: Our descriptive study suggests possibility to detect and quantify the cerebral steal phenomenon in real-time. If the steal is confirmed as the cause of neurological worsening, reversed Robin Hood syndrome may identify a target group for testing blood pressure augmentation and noninvasive ventilatory correction in stroke patients.

Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia.

BACKGROUND AND PURPOSE: Both transcranial Doppler (TCD) and spiral computed tomography angiography (CTA) are used for noninvasive vascular assessment tools in acute stroke. We aimed to evaluate the diagnostic accuracy of TCD against CTA in patients with acute cerebral ischemia. METHODS: Consecutive patients presenting to the Emergency Department with symptoms of acute (<24 hours) cerebral ischemia underwent emergent high-resolution brain CTA with a multidetector helical scanner. TCD was performed at bedside with a standardized, fast-track insonation protocol before or shortly (<2 hours) after completion of the CTA. Previously published diagnostic criteria were prospectively applied for TCD interpretation independent of angiographic findings. RESULTS: A total of 132 patients (74 men, mean+/-SD age 63+/-15 years) underwent emergent neurovascular assessment with brain CTA and TCD. Compared with CTA, TCD showed 34 true-positive, 9 false-negative, 5 false-positive, and 84 true-negative studies (sensitivity 79.1%, specificity 94.3%, positive predictive value 87.2%, negative predictive value 90.3%, and accuracy 89.4%). In 9 cases (7%), TCD showed findings complementary to the CTA (real-time embolization, collateralization of flow with extracranial internal carotid artery disease, alternating flow signals indicative of steal phenomenon). CONCLUSIONS: Bedside TCD examination yields satisfactory agreement with urgent brain CTA in the evaluation of patients with acute cerebral ischemia. TCD can provide real-time flow findings that are complementary to information provided by CTA.