Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies.

BACKGROUND AND PURPOSE: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. METHODS: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. RESULTS: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. CONCLUSIONS: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.

Prognostic Factors and Pattern of Long-Term Recovery with MLC601 (NeuroAiD™) in the Chinese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study.

BACKGROUND: The Chinese Medicine NeuroAiD Efficacy on Stroke recovery - Extension (CHIMES-E) study is among the few acute stroke trials with long-term outcome data. We aimed to evaluate the recovery pattern and the influence of prognostic factors on treatment effect of MLC601 over 2 years. METHODS: The CHIMES-E study evaluated the 2 years outcome of subjects aged ≥18 years with acute ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score 6-14, pre-stroke modified Rankin Scale (mRS) score ≤1 included in a multicenter, randomized, double-blind, placebo-controlled trial of MLC601 for 3 months. Standard stroke care and rehabilitation were allowed during follow-up with mRS score being assessed in-person at month (M) 3 and by telephone at M1, M6, M12, M18 and M24. RESULTS: Data from 880 subjects were analyzed. There was no difference in baseline characteristics between treatment groups. The proportion of subjects with mRS score 0-1 increased over time in favor of MLC601 most notably from M3 to M6, thereafter remaining stable up to M24, while the proportion deteriorating to mRS score ≥2 remained low at all time points. Older age (p < 0.01), female sex (p = 0.06), higher baseline NIHSS score (p < 0.01) and longer onset to treatment time (OTT; p < 0.01) were found to be predictors of poorer outcome at M3. Greater treatment effect, with more subjects improving on MLC601 than placebo, was seen among subjects with 2 or more prognostic factors (OR 1.65 at M3, 1.78 at M6, 1.90 at M12, 1.65 at M18, 1.39 at M24), especially in subjects with more severe stroke or longer OTT. CONCLUSIONS: The sustained benefits of MLC601 over 2 years were due to more subjects improving to functional independence at M6 and beyond compared to placebo. Selection of subjects with poorer prognosis, particularly those with more severe NIHSS score and longer OTT delay, as well as a long follow-up period, may improve the power of future trials investigating the treatment effect of neuroprotective or neurorestorative therapies.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, randomized study.

BACKGROUND AND PURPOSE: Previous clinical studies suggested benefit for poststroke recovery when MLC601 was administered between 2 weeks and 6 months of stroke onset. The Chinese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study tested the hypothesis that MLC601 is superior to placebo in acute, moderately severe ischemic stroke within a 72-hour time window. METHODS: This multicenter, double-blind, placebo-controlled trial randomized 1100 patients with a National Institutes of Health Stroke Scale score 6 to 14, within 72 hours of onset, to trial medications for 3 months. The primary outcome was a shift in the modified Rankin Scale. Secondary outcomes were modified Rankin Scale dichotomy, National Institutes of Health Stroke Scale improvement, difference in National Institutes of Health Stroke Scale total and motor scores, Barthel index, and mini-mental state examination. Planned subgroup analyses were performed according to age, sex, time to first dose, baseline National Institutes of Health Stroke Scale, presence of cortical signs, and antiplatelet use. RESULTS: The modified Rankin Scale shift analysis-adjusted odds ratio was 1.09 (95% confidence interval, 0.86-1.32). Statistical difference was not detected between the treatment groups for any of the secondary outcomes. Subgroup analyses showed no statistical heterogeneity for the primary outcome; however, a trend toward benefit in the subgroup receiving treatment beyond 48 hours from stroke onset was noted. Serious and nonserious adverse events rates were similar between the 2 groups. CONCLUSIONS: MLC601 is statistically no better than placebo in improving outcomes at 3 months when used among patients with acute ischemic stroke of intermediate severity. Longer treatment duration and follow-up of participants with treatment initiated after 48 hours may be considered in future studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

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.

A spectrum of knock-type Doppler signals in the intracranial vessels.

BACKGROUND AND PURPOSE: Knock-type Doppler signals (KTDS) are detectable by transcranial Doppler, and it has been hypothesized that they are related to an occlusion of a small perforating artery and microvascular ischemia. However, the nature of KTDS has not been prospectively defined. We aimed at describing the spectral and power motion Doppler characteristics of KTDS and ultrasound exposure conditions that lead to their appearance. METHODS: Consecutive patients referred with symptoms of stroke or transient ischemic attacks to our cerebrovascular ultrasound laboratory were screened for the presence of KTDS. The presence of microvascular ischemia was assessed using brain MRI. RESULTS: Among 327 patients with cerebrovascular symptoms, 46 (14%) had KTDS. KTDS were found more frequently in posterior circulation vessels (55% vertebral artery, 21.5% basilar artery, and 6% posterior cerebral artery). There was no association between ultrasound identification of KTDS and the presence of brain ischemia in the distribution of any vessel (OR, 0.37; 95% CI, 0.09-1.53; P=0.171) on univariate logistic regression analyses. KTDS was not related to the presence of microvascular ischemia on brain MRI (OR, 1.12; 95% CI, 0.55-2.29; P=0.761). We described the range of spectral and power motion Doppler appearances of KTDS and experimentally demonstrated the most likely underlying mechanism being a large vessel wall movement artifact. CONCLUSIONS: Although KTDS can be distinguished from other spectral flow signals, they can be found in normal vessels, they do not seem to be associated with the vessel affected by ischemia, and they should not be overinterpreted.

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.

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.

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.

Association of pretreatment ASPECTS scores with tPA-induced arterial recanalization in acute middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: The Alberta Stroke Program Early CT-Score (ASPECTS) assesses early ischemic changes within the middle cerebral artery (MCA) and predicts poor outcome and increased risk for thrombolysis-related symptomatic ICH. We evaluated the potential relationship between pretreatment ASPECTS and tPA-induced recanalization in patients with MCA occlusions. SUBJECTS & METHODS: Consecutive patients with acute ischemic stroke due to MCA occlusion were treated with standard IV-tPA and assessed with transcranial Doppler (TCD) for arterial recanalization. Early recanalization was determined with previously validated Thrombolysis in Brain Ischemia (TIBI) flow-grading system at 120 minutes after tPA-bolus. All pretreatment CT-scans were prospectively scored by trained investigators blinded to TCD findings. Functional outcome at 3 months was evaluated using the modified Rankin Scale (mRS). RESULTS: IV-tPA was administered in 192 patients (mean age 68 +/- 14 years, median NIHSS-score 17). Patients with complete recanalization (n= 51) had higher median pretreatment ASPECTS (10, interquartile range 2) than patients with incomplete or absent recanalization (n= 141; median ASPECTS 9, interquartile range 3, P= .034 Mann-Whitney U-test). An ASPECTS < or =6 was documented in 4% and 17% of patients with present and absent recanalization, respectively (P= .019). Pretreatment ASPECTS was associated with complete recanalization (OR per 1-point increase: 1.54; 95% CI 1.06-2.22, P= .023) after adjustment for baseline characteristics, risk factors, NIHSS-score, pretreatment TIBI grades and site of arterial occlusion on baseline TCD. Complete recanalization (OR: 33.97, 95% CI 5.95-185.99, P < .001) and higher ASPECTS (OR per 1-point increase: 1.91; 95% CI 1.17-3.14, P= .010) were independent predictors of good functional outcome (mRS 0-2). CONCLUSIONS: Higher pretreatment ASPECT-scores are associated with a greater chance of complete recanalization and favorable long-term outcome in tPA-treated patients with acute MCA occlusion.

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.

Association of pretreatment blood pressure with tissue plasminogen activator-induced arterial recanalization in acute ischemic stroke.

BACKGROUND AND PURPOSE: Elevated systolic blood pressure (SBP) and lack of early vessel recanalization are predictors of poor outcome among patients with stroke treated with systemic tissue plasminogen activator (tPA). We aimed to evaluate the potential relationship between pretreatment SBP and tPA-induced recanalization. METHODS: Consecutive patients with acute ischemic stroke resulting from intracranial artery occlusion were treated with standard intravenous tPA and assessed with 2-MHz transcranial Doppler for arterial recanalization. Early arterial recanalization was determined with previously validated Thrombolysis in Brain Ischemia flow grading system at 120 minutes after tPA bolus. Functional outcome at 3 months was evaluated using the modified Rankin Scale. RESULTS: A total of 351 patients received intravenous tPA (mean age: 68.7+/-13.4 years, median National Institutes of Health Stroke Scale score 16.5). Patients with complete recanalization (n=94) had lower mean pretreatment SBP values (152+/-23 mm Hg) than patients with incomplete or absent recanalization (n=257, 160+/-22 mm Hg, P=0.010). Pretreatment SBP levels were inversely associated with complete recanalization (OR per 10-mm Hg increase: 0.85; 95% CI: 0.74 to 0.98, P=0.022) after adjustment for demographics, risk factors, stroke severity, pretreatment Thrombolysis in Brain Ischemia grades, and continuous versus intermittent exposure to transcranial Doppler. Although patients with poor functional 3-month outcomes (modified Rankin Scale >2) had higher pretreatment SBP values (160+/-25 mm Hg) than functionally independent patients (154+/-20 mm Hg, P=0.027), pretreatment SBP levels were not independently associated with functional outcome on multivariable analysis. Age, complete recanalization, baseline National Institutes of Health Stroke Scale score, and time from symptom onset to tPA bolus were independent (P<0.05) predictors of 3-month outcome. CONCLUSIONS: Higher pretreatment SBP levels are associated with poor recanalization in patients with acute stroke treated with intravenous tPA.

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.

Acute painless paraparesis due to bilateral femoral artery occlusion.

Acute peripheral arterial occlusion is a medical emergency manifesting with pain, pallor, absence of pulse, paralysis, and paresthesia. Neurological deficits have occasionally been described as the presenting symptoms of acute arterial ischemia. We report a patient with acute bilateral occlusion of the femoral arteries and an underlying severe atherosclerotic aorto-iliac disease who presented with acute painless paraplegia and anesthesia in the lower extremities. The patient underwent arterial thrombectomy of the right and left femoral artery, followed by angioplasty and stent insertion of the right and left common iliac artery within 5 h from the onset of his symptoms. Subsequent physical therapy resulted in rapid improvement in the strength of his lower extremities and the patient was able to walk unaided after two weeks.

Durability of the beneficial effect of MLC601 (NeuroAiD™) on functional recovery among stroke patients from the Philippines in the CHIMES and CHIMES-E studies.

Background and Aim A pre-specified country analysis of subjects from the Philippines in the CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) Study showed significantly improved functional and neurological outcomes on MLC601 at month (M) 3. We aimed to assess these effects on long-term functional recovery in the Filipino cohort. Methods The CHIMES-E (extension) Study evaluated subjects who completed three months of randomized placebo-controlled treatment in CHIMES up to two years. Blinding of treatment allocation was maintained and all subjects received standard stroke care and rehabilitation. Modified Rankin Score (mRS) and Barthel Index (BI) were assessed in-person at M3 and by telephone at M6, M12, M18, M24. Odds ratios (OR) with corresponding 95% confidence intervals (CI) for functional recovery using ordinal analysis of mRS and for achieving functional independence (mRS 0-1 or BI ≥ 95) at each time point were calculated, adjusting for age, sex, baseline National Institute of Health Stroke Scale (NIHSS), onset-to-treatment time (OTT) and pre-stroke mRS. Results The 378 subjects (MLC601 192, placebo 186) included in CHIMES-E from the Philippines (mean age 60.2 ± 11.1) had more women ( p < 0.001), worse baseline NIHSS ( p < 0.001) and longer onset to treatment time ( p = 0.002) compared to other countries. Baseline characteristics were similar between treatment groups. The treatment effect of MLC601 seen at M3 peaked at M6 with OR for mRS shift of 1.53 (95% CI 1.05-2.22), mRS dichotomy 0-1 of 1.77 (95% CI 1.10-2.83), and BI ≥ 95 of 1.87 (95% CI 1.16-3.02). The beneficial effect persisted up to M24. Conclusion The beneficial effect of MLC601 seen at M3 in the Filipino cohort is durable up to two years after stroke.

Baseline characteristics and treatment response of patients from the Philippines in the CHIMES study.

BACKGROUND: The CHIMES Study compared MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 h. Sites from the Philippines randomized 504 of 1099 (46%) patients in the study. We aimed to define the patient characteristics and treatment responses in this subgroup to better plan future trials. METHODS: The CHIMES dataset was used to compare the baseline characteristics, time from stroke onset to study treatment initiation, and treatment responses to MLC601 between patients recruited from Philippines and the rest of the cohort. Treatment effect was analyzed using end-points at month 3 as described in the primary publication, that is, modified Rankin Score, National Institutes of Health Stroke Scale, and Barthel Index. RESULTS: The Philippine cohort was younger, had more women, worse baseline National Institutes of Health Stroke Scale, and longer time delay from stroke onset to study treatment compared with the rest of the cohort. Age (P = 0·003), baseline National Institutes of Health Stroke Scale (P < 0·001), and stroke onset to study treatment initiation (P = 0·016) were predictors of modified Rankin Score at three-months. Primary analysis of modified Rankin Score shift was in favor of MLC601 (adjusted odds ratio 1·41, 95% confidence interval 1·01-1·96). Secondary analyses were likewise in favor of MLC601 for modified Rankin Score dichotomy 0-1, improvement in National Institutes of Health Stroke Scale (total and motor scores), and Barthel Index. CONCLUSIONS: The treatment effects in the Philippine cohort were in favor of MLC601. This may be due to inclusion of more patients with predictors of poorer outcome.

Safety and dose-escalation study design of Transcranial Ultrasound in Clinical SONolysis for acute ischemic stroke: the TUCSON Trial.

Rationale Transcranial Doppler (TCD) monitoring during intravenous tissue plasminogen activator (i.v.-tPA) infusion increases recanalization rates in acute ischemic stroke. Addition of perflutren-lipid microspheres MRX-801 (microS) may further enhance the process of recanalization. This article describes the design of the Transcranial Ultrasound in Clinical SONolysis (TUCSON) trial. Aims and Design TUCSON is a phase I-II, randomized, placebo-controlled, open-label, safety, dose-escalation clinical trial of microS+TCD ultrasound (sonolysis). Patients with acute ischemic stroke and arterial intracranial occlusions are enrolled within 3 h of symptom onset. All patients receive standard i.v.-tPA and will be randomized to 90 min of continuous 2-MHz TCD+microS or 90 min of saline+brief TCD vessel assessments. The safety profile of four escalating dose tiers will be assessed. Arterial occlusions and recanalization are defined with the Thrombolysis in Brain Ischemia flow grades. Study Outcomes Safety is determined by the rates of symptomatic intracerebral hemorrhage within 36 h. Neurological deficits and outcomes are measured with the National Institute of Health Stroke Scale and modified Rankin Scale (mRS). The signal-of-efficacy is determined by rates of recanalization, dramatic or early clinical recovery within 2 h, clinical recovery at 24-36 h and independent outcome (mRS 0-2) at 90 days.

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.