Annabelle Y. Lao

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. Conclusion— Higher pretreatment SBP levels are associated with poor recanalization in patients with acute stroke treated with intravenous tPA.

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.

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.

Effect of body positioning during transcranial Doppler detection of right-to-left shunts

We adopted an expanded transcranial Doppler (TCD) protocol to evaluate if additional injections of agitated saline in different positions would improve shunt detection or grading. We report the safety and feasibility of this expanded contrast TCD protocol. Patients with ischemic stroke were evaluated. The standard protocol for RLS detection was followed and expanded after the initial injection in the supine position to the right lateral decubitus, upright sitting, and sitting with right lateral leaning. Changes in blood pressure, heart rate, and any subjective complaints were noted. Changes in body position and additional agitated saline injections were tolerated. Right‐to‐left shunt (RLS) was detected in 35% of patients (n = 55). If the initial supine testing was negative, all subsequent positions/injections were also negative for RLS. However, if the supine injection was positive for RLS, the change in body positions increased the microbubble (μB) count in eight of 19 (42%) RLS‐positive patients. The mean μB count in RLS‐positive patients was 20 (95% CI: 9–32). The use of three additional body positions increased the μB count to 73 (95% CI: 13–132). The highest μB yield was achieved in the upright sitting position. Our findings support the safety and feasibility of the expanded TCD protocol. If the initial supine Valsalva‐aided contrast TCD test is negative, there may be no need to study the patient in additional positions. However, if μB are detected in the supine position, additional testing for RLS in alternative positions may be found to be worthwhile.

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.

Detection of Right-to-Left Shunts: Comparison between the International Consensus and Spencer Logarithmic Scale Criteria

International Consensus Criteria (ICC) consider right‐to‐left shunt (RLS) present when Transcranial Doppler (TCD) detects even one microbubble (μB). Spencer Logarithmic Scale (SLS) offers more grades of RLS with detection of >30 μB corresponding to a large shunt. We compared the yield of ICC and SLS in detection and quantification of a large RLS.

Association of Pretreatment ASPECTS Scores with tPA‐Induced Arterial Recanalization in Acute Middle Cerebral Artery Occlusion

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.

Effects of MLC601 on Early Vascular Events in Patients After Stroke The CHIMES Study

Background and Purpose— Early vascular events are an important cause of morbidity and mortality in the first 3 months after a stroke. We aimed to investigate the effects of MLC601 on the occurrence of early vascular events within 3 months of stroke onset. Methods— Post hoc analysis was performed on data from subjects included in the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study, a randomized, placebo-controlled, double-blinded trial that compared MLC601 with placebo in 1099 subjects with ischemic stroke of intermediate severity in the preceding 72 hours. Early vascular events were defined as a composite of recurrent stroke, acute coronary syndrome, and vascular death occurring within 3 months of stroke onset. Results— The frequency of early vascular events during the 3-month follow-up was significantly less in the MLC601 group than in the placebo group (16 [2.9%] versus 31 events [5.6%]; risk difference=−2.7%; 95% confidence interval, −5.1% to −0.4%; P=0.025) without an increase in nonvascular deaths. Kaplan–Meier survival analysis showed a difference in the risk of vascular outcomes between the 2 groups as early as the first month after stroke (Log-rank P=0.024; hazard ratio, 0.51; 95% confidence interval, 0.28–0.93). Conclusions— Treatment with MLC601 was associated with reduced early vascular events among subjects in the CHIMES study. The mechanisms for this effect require further study. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

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.