CHInese medicine NeuroAiD efficacy on stroke recovery - Extension study (CHIMES-E): A multicenter study of long-term efficacy

© 2015 S. Karger AG, Basel. 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.Link_to_subscribed_fulltex

The accuracy of transcranial Doppler in the diagnosis of middle cerebral artery stenosis

Background and Purpose: It was the aim of this study to systematically review available literature on the accuracy of transcranial Doppler (TCD) compared with angiography for the diagnosis of 6 50% middle cerebral artery stenosis in patients with transient ischemic attack or ischemic stroke. Methods: We performed a systematic review that included original articles published on TCD accuracy from 1982 until the end of December 2005 using angiography as the gold standard. The following measures of diagnostic accuracy were obtained from each primary study: sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Weighted mean averages were then calculated from individual results for different velocity cutoffs. Results: Six papers met our selection criteria. Using laboratory-specific variable mean flow velocity cutoffs, self-reported best accuracy results yield a mean weighted average sensitivity of 92%, specificity of 92%, PPV of 88% and NPV of 98% for 80 cm/s cutoff. For 100 cm/s cutoff, the sensitivities were 100%, specificity 97%, PPV 88% and NPV 100%. Conclusions: Although limited to few reports, this analysis demonstrates fair TCD performance against angiography. Since increasing velocity cutoffs do not yield decreasing sensitivity and increasing specificity, further studies are required to determine optimal velocity values and possibly other criteria such as velocity ratios to develop a screening test with balanced performance parameters. Copyright (c) 2007 S. Karger AG, Basel

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

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 >= 1.2 was considered high. Focal intracranial disease was defined as >= 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

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 (μS) 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 μS traces included large ( > 8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small ( < 5μ) μS from acute patients without shunts receiving thrombolysis and perflutren-lipid μS. Results: In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P < 0.001. Small μS 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 μS can produce continuous flow enhancement for 4 seconds. Small μS velocities on m-mode in obstructed vessels (39.8±11.3 cm/s) were similar to large μS 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 μS passage duration through a small power motion Doppler gate can quantify the dose of delivered μS. Ultrasound can determine a minimum number of μS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of μS smaller than red blood cells may reflect plasma flow velocities around acute occlusions

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 &gt; 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 &lt; 0.05) predictors of 3-month outcome. Conclusion - Higher pretreatment SBP levels are associated with poor recanalization in patients with acute stroke treated with intravenous tPA

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 &amp; 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 &lt;= 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 &lt; .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