Neurovascular Complications of Iatrogenic Fusarium solani Meningitis.

A multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with symptoms after a median delay of 39 days.

Recruitment in Acute Stroke Trials: Challenges and Potential Solutions.

Randomized clinical trials of acute stroke have led to major advances in acute stroke therapy over the past decade. Despite these successes, recruitment in acute trials is often difficult. We outline challenges in recruitment for acute stroke trials and present potential solutions, which can increase the speed and decrease the cost of identifying new treatments for acute stroke. One of the largest opportunities to increase the speed of enrollment and make trials more generalizable is expansion of inclusion criteria whose impact on expected recruitment can be assessed by epidemiologic and registry databases. Another barrier to recruitment besides the number of eligible patients is availability of study investigators limited to business hours, which may be helped by financial support for after-hours call. The wider use of telemedicine has accelerated quicker stroke treatment at many hospitals and has the potential to accelerate research enrollment but requires training of clinical investigators who are often inexperienced with this approach. Other potential solutions to enhance recruitment include rapid prehospital notification of clinical investigators of potential patients, use of mobile stroke units, advances in the process of emergency informed consent, storage of study medication in the emergency department, simplification of study treatments and data collection, education of physicians to improve equipoise and enthusiasm for randomization of patients within a trial, and clear recruitment plans, and even potentially coenrollment, when there are competing trials at sites. Without successful recruitment, scientific advances and clinical benefit for acute stroke patients will lag.

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.

Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT): A Prospective, Multicenter Cohort Study of Imaging Selection.

OBJECTIVE: The primary imaging modalities used to select patients for endovascular thrombectomy (EVT) are noncontrast computed tomography (CT) and CT perfusion (CTP). However, their relative utility is uncertain. We prospectively assessed CT and CTP concordance/discordance and correlated the imaging profiles on both with EVT treatment decisions and clinical outcomes. METHODS: A phase 2, multicenter, prospective cohort study of large-vessel occlusions presented up to 24 hours from last known well was conducted. Patients received a unified prespecified imaging evaluation (CT, CT angiography, and CTP with Rapid Processing of Perfusion and Diffusion software mismatch determination). The treatment decision, EVT versus medical management, was nonrandomized and at the treating physicians' discretion. An independent, blinded, neuroimaging core laboratory adjudicated favorable profiles based on predefined criteria (CT:Alberta Stroke Program Early CT Score ≥ 6, CTP:regional cerebral blood flow (<30%) < 70ml with mismatch ratio ≥ 1.2 and mismatch volume ≥ 10ml). RESULTS: Of 4,722 patients screened from January 2016 to February 2018, 361 patients were included. Two hundred eighty-five (79%) received EVT, of whom 87.0% had favorable CTs, 91% favorable CTPs, 81% both favorable profiles, 16% discordant, and 3% both unfavorable. Favorable profiles on the 2 modalities correlated similarly with 90-day functional independence rates (favorable CT = 56% vs favorable CTP = 57%, adjusted odds ratio [aOR] = 1.91, 95% confidence interval [CI] = 0.40-9.01, p = 0.41). Having a favorable profile on both modalities significantly increased the odds of receiving thrombectomy as compared to discordant profiles (aOR = 3.97, 95% CI = 1.97-8.01, p < 0.001). Fifty-eight percent of the patients with favorable profiles on both modalities achieved functional independence as compared to 38% in discordant profiles and 0% when both were unfavorable (p < 0.001 for trend). In favorable CT/unfavorable CTP profiles, EVT was associated with high symptomatic intracranial hemorrhage (sICH) (24%) and mortality (53%) rates. INTERPRETATION: Patients with favorable imaging profiles on both modalities had higher odds of receiving EVT and high functional independence rates. Patients with discordant profiles achieved reasonable functional independence rates, but those with an unfavorable CTP had higher adverse outcomes. Ann Neurol 2020;87:419-433.

Alteplase and Adjuvant Therapies for Acute Ischemic Stroke.

Acute ischemic stroke (AIS) is a time sensitive medical emergency and a leading cause of morbidity and mortality worldwide. Intravenous (IV) recombinant tissue plasminogen activator (IV alteplase) is currently the only proven effective medication for the treatment of AIS with promising adjuvant medications currently under investigation. Recent advances in endovascular thrombectomy have broadened therapeutic options in specific patient populations, with modern treatment strategies utilizing advanced imaging modalities to extend the window for treatment. In all cases, rapid treatment remains a priority. The future of IV alteplase and the changing standard for treatment of AIS remain unwritten with the increasing evidence for imaging selection for both endovascular thrombectomy and IV alteplase, while novel adjuncts are under investigation. In this article, we review the history of IV alteplase investigations for stroke, evidence for thrombectomy as an adjunct to IV alteplase, and the potential of novel adjuvant therapeutics currently under investigation.

Leveraging Multimedia Patient Engagement to Address Minority Cerebrovascular Health Needs: Prospective Observational Study.

BACKGROUND: Social inequities affecting minority populations after Hurricane Katrina led to an expansion of environmental justice literature. In August 2017, Hurricane Harvey rainfall was estimated as a 3000- to 20,000-year flood event, further affecting minority populations with disproportionate stroke prevalence. The Stomp Out Stroke initiative leveraged multimedia engagement, creating a patient-centered cerebrovascular health intervention. OBJECTIVE: This study aims to address social inequities in cerebrovascular health through the identification of race- or ethnicity-specific health needs and the provision of in-person stroke prevention screening during two community events (May 2018 and May 2019). METHODS: Stomp Out Stroke recruitment took place through internet-based channels (websites and social networking). Exclusively through web registration, Stomp Out Stroke participants (aged >18 years) detailed sociodemographic characteristics, family history of stroke, and stroke survivorship. Participant health interests were compared by race or ethnicity using Kruskal-Wallis or chi-square test at an α=.05. A Bonferroni-corrected P value of .0083 was used for multiple comparisons. RESULTS: Stomp Out Stroke registrants (N=1401) were 70% (973/1390) female (median age 45 years) and largely self-identified as members of minority groups: 32.05% (449/1401) Hispanic, 25.62% (359/1401) African American, 13.63% (191/1401) Asian compared with 23.63% (331/1401) non-Hispanic White. Stroke survivors comprised 11.55% (155/1401) of our population. A total of 124 stroke caregivers participated. Approximately 36.81% (493/1339) of participants had a family history of stroke. African American participants were most likely to have Medicare or Medicaid insurance (84/341, 24.6%), whereas Hispanic participants were most likely to be uninsured (127/435, 29.2%). Hispanic participants were more likely than non-Hispanic White participants to obtain health screenings (282/449, 62.8% vs 175/331, 52.9%; P=.03). Asian (105/191, 54.9%) and African American (201/359, 55.9%) participants were more likely to request stroke education than non-Hispanic White (138/331, 41.6%) or Hispanic participants (193/449, 42.9%). African American participants were more likely to seek overall health education than non-Hispanic White participants (166/359, 46.2% vs 108/331, 32.6%; P=.002). Non-Hispanic White participants (48/331, 14.5%) were less likely to speak to health care providers than African American (91/359, 25.3%) or Asian participants (54/191, 28.3%). During the 2018 and 2019 events, 2774 health screenings were completed across 12 hours, averaging four health screenings per minute. These included blood pressure (1031/2774, 37.16%), stroke risk assessment (496/2774, 17.88%), bone density (426/2774, 15.35%), carotid ultrasound (380/2774, 13.69%), BMI (182/2774, 6.56%), serum lipids (157/2774, 5.65%), and hemoglobin A1c (102/2774, 3.67%). Twenty multimedia placements using the Stomp Out Stroke webpage, social media, #stompoutstroke, television, iQ radio, and web-based news reached approximately 849,731 people in the Houston area. CONCLUSIONS: Using a combination of internet-based recruitment, registration, and in-person assessments, Stomp Out Stroke identified race- or ethnicity-specific health care needs and provided appropriate screenings to minority populations at increased risk of urban flooding and stroke. This protocol can be replicated in Southern US Stroke Belt cities with similar flood risks.

Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial.

Cellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24-72 hours of onset. A target dose of 10 million cells per kilogram was chosen based on preclinical data. Patients were followed up daily during hospitalization and at 1, 3, 6, 12, and 24 months for incidence of adverse events using laboratory, clinical (12 months), and radiological (24 months) parameters. The trial was powered to detect severe adverse events (SAEs) with incidences of at least 10% and planned to enroll 30 patients. Primary outcomes were study-related SAEs and the proportion of patients successfully completing study intervention. A propensity score-based matched control group was used for the estimation of effect size (ES) for day-90 modified Rankin score (mRS). There were no study-related SAEs and, based on a futility analysis, enrolment was stopped after 25 patients. All patients successfully completed study intervention and most received the target dose. Secondary analysis estimated the ES to be a reduction of 1 point (95% confidence interval: 0.33-1.67) in median day-90 mRS for treated patients as compared with the matched control group. Bone marrow harvest and infusion of MNCs is safe and feasible in patients with AIS. The estimated ES is helpful in designing future randomized controlled trials. Stem Cells 2019;37:1481-1491.

Safety and Feasibility of Argatroban, Recombinant Tissue Plasminogen Activator, and Intra-Arterial Therapy in Stroke (ARTSS-IA Study).

BACKGROUND: A randomized trial of concurrent recombinant tissue-type plasminogen activator (r-tPA) + thrombin-inhibition with Argatroban in stroke patients recently demonstrated safety and signal of efficacy compared to r-tPA alone, but patients having endovascular therapy (EVT) were excluded. The current study intended to study feasibility and safety of concurrent r-tPA and Argatroban in patients undergoing EVT. METHODS: We conducted a single-arm, feasibility, and safety study of patients that received standard-dose r-tPA, had intracranial large vessel occlusions, and underwent EVT within 6 hours of stroke onset. During r-tPA, a 100 µg/kg Argatroban bolus, followed by 12-hour infusion, targeted an activated Partial Thromboplastin Time (aPTT) 2.25 timesbaseline. Feasibility was defined as ability to combine treatments without EVT time-metric delays, compared to cotemporaneous r-tPA + EVT treatments. Safety was incidence of symptomatic intracerebral hemorrhage (sICH), systemic hemorrhage, or EVT complications. RESULTS: All preplanned 10 patients were enrolled. Arterial occlusions were middle cerebral artery (n = 8), internal carotid artery (n = 1), and posterior cerebral artery (n = 1). All received Argatroban before EVT and completed infusions. There were no delays in time-metrics compared to nonstudy patients during the same period. Nine patients achieved excellent angiographic reperfusion (Thrombolysis In Cerebral Ischemia [TICI] ≥2b); with 7 complete (TICI = 3). There were no sICH, systemic hemorrhage, or EVT complications. At 90 days, 6 (60%) patients had a modified Rankin Scale of 0-2 and none died. CONCLUSIONS: In patients treated with r-tPA and EVT, concomitant Argatroban is feasible, does not delay EVT provision, produces high rates of recanalization, is probably safe, and warrants further study.

Predictors of Percutaneous Endoscopic Gastrostomy Placement in Acute Ischemic Stroke.

BACKGROUND: Dysphagia is a common complication of stroke and can have a lasting impact on morbidity and mortality; yet there are no standards to guide dysphagia management in stroke patients. We assessed predictors of percutaneous endoscopic gastrostomy (PEG) placement in an ischemic stroke cohort and sought to determine the utility of an objective scale in predicting PEG placement in a high-risk sub-set. METHODS: Consecutive cases of ischemic stroke were retrospectively, identified and demographic and clinical variables were collected. Penetration-Aspiration (PAS) scores (1-2 normal; 3-5 penetration; 6-8 aspiration) were calculated for patients undergoing Fiberoptic Endoscopic Evaluation of Swallowing (FEES) or Modified Barium Swallowing Studies (MBSS). Multiple logistic regression analysis was used to assess predictors of PEG placement. RESULTS: Among 724 patients, 131 underwent PEG placement. In univariate analysis of the overall cohort, sex, age, insured payer status, arrival National Institute of Health Stroke Scale (NIHSS), NIHSS level of consciousness severity, NIHSS dysarthria severity, diabetes mellitus, and prior International Conference for Harmonization (ICH) were all significantly associated with PEG placement. Among 197 high-risk patients undergoing FEES or MBSS, the multivariate logistic regression analysis showed that PAS scores 6-8 versus 1-2 (odds ratio [OR] 13.2; 95% confidence interval [CI] 4.58, 38.2), PAS score 3-5 versus 1.2 (OR 33.8; 95% CI 11.6, 98.3), Hispanic race (OR, 5.73; 95% CI 1.82, 18.0), male sex (OR, 2.59; 95% CI 1.05, 6.34), and arrival NIHSS (OR, 1.11; 95% CI 1.05, 1.18) were associated with PEG placement. CONCLUSIONS: Use of an objective dysphagia scale simplified the prediction model among acute ischemic stroke patients undergoing instrumental assessments of dysphagia with FEES or MBSS. Male sex and Hispanic race were also significantly associated with PEG placement in this analysis. These findings support the need for rigorously designed prospective studies to assess biological and social factors that influence PEG placement and to determine, how to best evaluate and manage patients with dysphagia.

Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke).

BACKGROUND AND PURPOSE: We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients. METHODS: Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 µg/kg bolus) followed by infusion of either 1 (low dose) or 3 µg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0). RESULTS: Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. CONCLUSIONS: In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.

Prospective, open-label safety study of intravenous recombinant tissue plasminogen activator in wake-up stroke.

OBJECTIVE: It is estimated that one of four ischemic strokes are noticed upon awakening and are not candidates for intravenous recombinant tissue plasminogen activator (rtPA) because their symptoms are >3 hours from last seen normal (LSN). We tested the safety of rtPA in a multicenter, single-arm, prospective, open-label study (NCT01183533) in patients with wake-up stroke (WUS). METHODS: We aimed to enroll 40 WUS patients with disabling deficits. Patients were 18 to 80 years of age, National Institutes of Health Stroke Scale (NIHSS) ≤25, and selected only on the appearance of noncontrast computed tomography (ie, over one-third middle cerebral artery territory hypodensity). Standard-dose (0.9mg/kg) intravenous rtPA had to be started ≤3 hours of patient awakening. The primary safety outcome was symptomatic intracerebral hemorrhage (sICH) with preplanned stopping rules and data safety board oversight. Other endpoints included: asymptomatic intracerebral hemorrhage; clinical improvement in NIHSS; and 90-day modified Rankin Scale (mRS) score. RESULTS: Between October 2010 and October 2013, all 40 preplanned patients were enrolled (50% men) at five stroke centers. Four patients (10%) were subsequently determined to be mimics. Patients had a mean age of 60.8, median NIHSS of 6.5 (range, 2-24), and received thrombolysis at a mean time of 10.3 ± 2.6 LSN and 2.6 ± 0.6 hours from awakening with deficits. No sICH or parenchymal hematomas occurred. At 3 months, 20 of 38 (52.6%) patients achieved excellent recovery with mRS scores of 0 or 1 (2 patients were lost to follow-up). INTERPRETATION: Intravenous thrombolysis was safe in this prospective WUS study of patients selected by noncontrast CT. A randomized effectiveness trial appears feasible using a similar, pragmatic design. Ann Neurol 2016;80:211-218.

Higher prehospital blood pressure prolongs door to needle thrombolysis times: a target for quality improvement?

BACKGROUND: Per the American Heart Association guidelines, blood pressure (BP) should be less than 185/110 to be eligible for stroke thrombolysis. No studies have focused on prehospital BP and its impact on door to needle (DTN) times. We hypothesized that DTN times would be longer for patients with higher prehospital BP. METHODS: We conducted a retrospective review of acute ischemic stroke patients who presented between January 2010 and December 2010 to our emergency department (ED) through emergency medical services within 3 hours of symptom onset. Patients were categorized into 2 groups: prehospital BP greater than or equal to 185/110 (group 1) and less than 185/110 (group 2). Blood pressure records were abstracted from emergency medical services run sheets. Primary outcome measure was DTN time, and secondary outcome measures were modified Rankin Score at discharge, symptomatic intracranial hemorrhage, length of stay in stroke unit, and discharge disposition. RESULTS: A total of 107 consecutive patients were identified. Of these, 75 patients (70%) were thrombolysed. Mean DTN times were significantly higher in group 1 (adjusted mean [95% confidence interval], 86minutes [76-97] vs 56minutes [45-68]; P<.0001). A greater number of patients required antihypertensive medications before thrombolysis in the ED in group 1 compared to group 2 (54% vs 27%; P=.02). CONCLUSION: Higher prehospital BP is associated with prolonged DTN times and DTN time remains prolonged if prehospital BP greater than or equal to 185/110 is untreated before ED arrival. Prehospital BP control could be a potential area for improvement to reduce DTN times in patients with acute ischemic stroke.

Adopting a Patient-Centered Approach to Primary Outcome Analysis of Acute Stroke Trials Using a Utility-Weighted Modified Rankin Scale.

BACKGROUND AND PURPOSE: Although the modified Rankin Scale (mRS) is the most commonly used primary end point in acute stroke trials, its power is limited when analyzed in dichotomized fashion and its indication of effect size challenging to interpret when analyzed ordinally. Weighting the 7 Rankin levels by utilities may improve scale interpretability while preserving statistical power. METHODS: A utility-weighted mRS (UW-mRS) was derived by averaging values from time-tradeoff (patient centered) and person-tradeoff (clinician centered) studies. The UW-mRS, standard ordinal mRS, and dichotomized mRS were applied to 11 trials or meta-analyses of acute stroke treatments, including lytic, endovascular reperfusion, blood pressure moderation, and hemicraniectomy interventions. RESULTS: Utility values were 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. For trials with unidirectional treatment effects, the UW-mRS paralleled the ordinal mRS and outperformed dichotomous mRS analyses. Both the UW-mRS and the ordinal mRS were statistically significant in 6 of 8 unidirectional effect trials, whereas dichotomous analyses were statistically significant in 2 to 4 of 8. In bidirectional effect trials, both the UW-mRS and ordinal tests captured the divergent treatment effects by showing neutral results, whereas some dichotomized analyses showed positive results. Mean utility differences in trials with statistically significant positive results ranged from 0.026 to 0.249. CONCLUSIONS: A UW-mRS performs similar to the standard ordinal mRS in detecting treatment effects in actual stroke trials and ensures the quantitative outcome is a valid reflection of patient-centered benefits.

Chronic cerebrospinal venous insufficiency: case-control neurosonography results.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine whether neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS. METHODS: This was a single-center, prospective case-control study of volunteer MS and non-MS participants. A neurosonologist, blind to the subjects' diagnosis, used high-resolution B-mode imaging with color and spectral Doppler to systematically investigate, capture, and record extracranial and intracranial venous drainage. These neuroimaging results were evaluated and scored by an expert blinded to subjects' information and with no interactions with the participants. RESULTS: Altogether, 276 subjects were studied: 206 with MS and 70 non-MS. MS patients were older than non-MS subjects (48.3±9.9 vs 44.3±11.8 years, p<0.007), with durations from first symptoms and diagnosis of 13.7±10 and 9.9±7.8 years, and Expanded Disability Status Scale of 2.6±2.0. Overall, 82 subjects (29.7%) fulfilled 1 of 5 NS criteria proposed for CCSVI; 13 (4.7%) fulfilled 2 criteria required for diagnosis, and none fulfilled >2 criteria. The distribution of subjects with 0, 1, or 2 criteria did not differ significantly across all diagnostic groupings, between MS and non-MS subjects, or within MS subgroups. CCSVI was present in 7.14% of non-MS and 3.88% of MS patients (p=0.266). No significant differences emerged between MS and non-MS subjects for extracranial or intracranial venous flow rates. INTERPRETATION: NS findings described as CCSVI are much less prevalent than initially reported, and do not distinguish MS from other subjects. Our findings do not support the hypothesis that CCSVI is causally associated with MS.

Contrast enhanced MR venography with gadofosveset trisodium: evaluation of the intracranial and extracranial venous system.

PURPOSE: To demonstrate the efficacy of contrast enhanced magnetic resonance venography (CEMRV) using gadofosveset trisodium in the comprehensive evaluation of the intracranial and extracranial venous system. MATERIALS AND METHODS: Temporal signal decay, in-plane saturation and flow artifacts were assessed in an institutional review board approved, HIPAA compliant CEMRV study of 99 subjects. In a 39 subject subset, percent diameter narrowing of the internal jugular (IJ), brachiocephalic and azygous veins were coded according to the following ordinal grades for both catheter venography (CV) and CEMRV: grade 0 ≤ 50%, grade 1 >50% and ≤ 75%, grade 2 >75% and <100% and grade 3 = 100% and compared with pressure gradient measurements obtained during CV. RESULTS: There was no significant signal decay, in-plane saturation or flow artifacts identified on CEMRV or hemodynamically significant pressure gradients identified on CV. All brachiocephalic and azygous veins had matched grade 0 narrowing on both modalities. Discrepancy between modalities occurred in the IJ veins at the level of thyroid gland where 15% of IJ veins had CEMRV grade ≥ 1 narrowing compared with 4% for CV or below the thyroid gland where 5% of IJ veins had CEMRV grade ≥ 1 narrowing compared with 20% for CV. There was fair agreement (κ = 0.24) between modalities for grade of narrowing in the combined data set of all coded veins. CONCLUSION: CEMRV using gadofosveset trisodium is accurate in the evaluation of the venous system.

CLOTBUST-hands free: initial safety testing of a novel operator-independent ultrasound device in stroke-free volunteers.

BACKGROUND AND PURPOSE: We aimed to evaluate safety and tolerability of a novel operator-independent ultrasound device among stroke-free volunteers. METHODS: A headframe containing 18 ultrasound transducers (each operating at 2 MHz, pulsed-wave) was used to expose both temporal windows and the suboccipital window. The transmission characteristics were set to emulate the acoustic characteristics of the exposure levels in the Combined Lysis of Thrombus in Brain Ischemia using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial and to never exceed Food and Drug Administration mandated diagnostic ultrasound exposure limits. Volunteers underwent 2 hours of insonation with transducer activation one at a time. Safety was captured using serial neurological examinations and pre- and postinsonation MRI for detection of the blood brain barrier permeability. RESULTS: A total of 15 volunteers (40% men; 49 ± 16 years; 27% black; all pre-exposure National Institutes of Health Stroke Scale scores 0) were enrolled. Five volunteers received pulsed-wave ultrasound via the best pair temporal transducers, 5 via sequential activation of the suboccipital transducers, and 5 via sequential activation of all bilateral temporal and suboccipital transducers. All subjects were safely insonated with no adverse effects as indicated by the neurological examinations during, immediately after the exposure, and at 24 hours, and no abnormality of the blood brain barrier was found on any of the MRIs. CONCLUSIONS: Our novel device was well tolerated by stroke-free volunteers and did not cause any neurological dysfunction nor did it affect blood brain barrier integrity. The safety and efficacy of the device are now being tested in stroke patients receiving intravenous tissue-type plasminogen activator in phase II-III clinical trials.

CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health-sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. METHODS: All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. RESULTS: Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5-29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%-64%) complete and 2 of 20 (10%; 95% confidence interval, 1%-32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%-82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%-49) patients had a modified Rankin scale of 0 to 1. CONCLUSIONS: Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.

Optimizing prediction scores for poor outcome after intra-arterial therapy in anterior circulation acute ischemic stroke.

BACKGROUND AND PURPOSE: Intra-arterial therapy (IAT) promotes recanalization of large artery occlusions in acute ischemic stroke. Despite high recanalization rates, poor clinical outcomes are common. We attempted to optimize a score that combines clinical and imaging variables to more accurately predict poor outcome after IAT in anterior circulation occlusions. METHODS: Patients with acute ischemic stroke undergoing IAT at University of Texas (UT) Houston for large artery occlusions (middle cerebral artery or internal carotid artery) were reviewed. Independent predictors of poor outcome (modified Rankin Scale, 4-6) were studied. External validation was performed on IAT-treated patients at Emory University. RESULTS: A total of 163 patients were identified at UT Houston. Independent predictors of poor outcome (P≤0.2) were identified as score variables using sensitivity analysis and logistic regression. Houston Intra-Arterial Therapy 2 (HIAT2) score ranges 0 to 10: age (≤59=0, 60-79=2, ≥80 years=4), glucose (<150=0, ≥150=1), National Institute Health Stroke Scale (≤10=0, 11-20=1, ≥21=2), the Alberta Stroke Program Early CT Score (8-10=0, ≤7=3). Patients with HIAT2≥5 were more likely to have poor outcomes at discharge (odds ratio, 6.43; 95% confidence interval, 2.75-15.02; P<0.001). After adjusting for reperfusion (Thrombolysis in Cerebral Infarction score≥2b) and time from symptom onset to recanalization, HIAT2≥5 remained an independent predictor of poor outcome (odds ratio, 5.88; 95% confidence interval, 1.96-17.64; P=0.02). Results from the cohort of Emory (198 patients) were consistent; patients with HIAT2 score≥5 had 6× greater odds of poor outcome at discharge and at 90 days. HIAT2 outperformed other previously published predictive scores. CONCLUSIONS: The HIAT2 score, which combines clinical and imaging variables, performed better than all previous scores in predicting poor outcome after IAT for anterior circulation large artery occlusions.