P. Alan Barber

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Students t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxons test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study.

Controversy exists whether acute hyperglycemia is causally associated with worse stroke outcome or simply reflects a more severe stroke. In reversible ischemia models, hyperglycemia is associated with lactic acidosis and conversion of penumbral tissue to infarction. However, the relationship between hyperglycemia, lactic acidosis, and stroke outcome has not been explored in humans. Sixty‐three acute stroke patients were prospectively evaluated with serial diffusion‐weighted and perfusion‐weighted magnetic resonance imaging and acute blood glucose measurements. Patients with hypoperfused at‐risk tissue were identified by acute perfusion‐diffusion lesion mismatch. As a substudy, acute and subacute magnetic resonance spectroscopy was performed in the 33 most recent patients to assess the relationship between acute blood glucose and lactate production in the ischemic region. In 40 of 63 patients with acute perfusion‐diffusion mismatch, acute hyperglycemia was correlated with reduced salvage of mismatch tissue from infarction, greater final infarct size, and worse functional outcome. These correlations were independent of baseline stroke severity, lesion size, and diabetic status. Furthermore, higher acute blood glucose in patients with perfusion‐diffusion mismatch was associated with greater acute‐subacute lactate production, which, in turn, was independently associated with reduced salvage of mismatch tissue. In contrast, acute blood glucose levels in nonmismatch patients did not independently correlate with outcome measures, nor was there any acute‐subacute increase in lactate in this group. Acute hyperglycemia increases brain lactate production and facilitates conversion of hypoperfused at‐risk tissue into infarction, which may adversely affect stroke outcome. These findings support the need for randomized controlled trials of aggressive glycemic control in acute stroke.

Diffusion- and perfusion-weighted MRI response to thrombolysis in Stroke

Diffusion‐ and perfusion‐weighted magnetic resonance imaging provides important pathophysiological information in acute brain ischemia. We performed a prospective study in 19 sub‐6‐hour stroke patients using serial diffusion‐ and perfusion‐weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub‐6‐hour ischemic stroke patients studied serially with diffusion‐ and perfusion‐weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion‐weighted imaging–diffusion‐weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion‐weighted imaging–diffusion‐weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs −25% in controls). Despite similar baseline diffusion‐weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm3 vs 56cm3 in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of ≥7 points. The natural evolution of acute perfusion‐weighted imaging–diffusion‐weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion‐ and perfusion‐weighted imaging in selecting and monitoring patients for thrombolytic therapy.

The PREP algorithm predicts potential for upper limb recovery after stroke.

Stroke is a leading cause of adult disability and the recovery of motor function is important for independence in activities of daily living. Predicting motor recovery after stroke in individual patients is difficult. Accurate prognosis would enable realistic rehabilitation goal-setting and more efficient allocation of resources. The aim of this study was to test and refine an algorithm for predicting the potential for recovery of upper limb function after stroke. Forty participants were prospectively enrolled within 3 days of ischaemic stroke. First, shoulder abduction and finger extension strength were graded 72 h after stroke onset to compute a shoulder abduction and finger extension score. Secondly, transcranial magnetic stimulation was used to assess the functional integrity of descending motor pathways to the affected upper limb. Third, diffusion-weighted magnetic resonance imaging was used to assess the structural integrity of the posterior limbs of the internal capsules. Finally, these measures were combined in the PREP algorithm for predicting an individuals potential for upper limb recovery at 12 weeks, measured with the Action Research Arm Test. A cluster analysis was used to independently group patients according to Action Research Arm Test score at 12 weeks, for comparison with predictions from the PREP algorithm. There was excellent correspondence between the cluster analysis of Action Research Arm Test score at 12 weeks and predictions made with the PREP algorithm. The algorithm had positive predictive power of 88%, negative predictive power of 83%, specificity of 88% and sensitivity of 73%. This study provides preliminary data in support of the PREP algorithm for the prognosis of upper limb recovery in individual patients. PREP may enable tailored planning of rehabilitation and more accurate stratification of patients in clinical trials.

A three-item scale for the early prediction of stroke recovery

BACKGROUND Accurate assessment of prognosis in the first hours of stroke is desirable for best patient management. We aimed to assess whether the extent of ischaemic brain injury on magnetic reasonance diffusion-weighted imaging (MR DWI) could provide additional prognostic information to clinical factors. METHODS In a three-phase study we studied 66 patients from a North American teaching hospital who had: MR DWI within 36 h of stroke onset; the National Institutes of Health Stroke Scale (NIHSS) score measured at the time of scanning; and the Barthel Index measured no later than 3 months after stroke. We used logistic regression to derive a predictive model for good recovery. This logistic regression model was applied to an independent series of 63 patients from an Australian teaching hospital, and we then developed a three-item scale for the early prediction of stroke recovery. FINDINGS Combined measurements of the NIHSS score (p=0.01), time in hours from stroke onset to MR DWI (p=0.02), and the volume of ischaemic brain tissue on MR DWI (p=0.04) gave the best prediction of stroke recovery. The model was externally validated on the Australian sample with 0.77 sensitivity and 0.88 specificity. Three likelihood levels for stroke recovery-low (0-2), medium (3-4), and high (5-7)-were identified on the three-item scale. INTERPRETATION The combination of clinical and MR DWI factors provided better prediction of stroke recovery than any factor alone, shortly after admission to hospital. This information was incorporated into a three-item scale for clinical use.

Serial Study of Apparent Diffusion Coefficient and Anisotropy in Patients With Acute Stroke

BACKGROUND AND PURPOSE We sought to characterize the evolution of apparent diffusion coefficient (ADC) and apparent diffusion anisotropy (ADA) in acute stroke and to evaluate their roles in predicting stroke evolution and outcome. METHODS We studied 26 stroke patients acutely (<24 hours), subacutely (3 to 5 days), and at outcome (3 months). Ratios of the ADC and ADA within a region of infarction and the normal contralateral region were evaluated and compared with the Canadian Neurological Scale, Barthel Index, and Rankin Scale. RESULTS Heterogeneity in ADC and ADA evolution was observed not only between patients but also within individual lesions. Three patterns of ADA evolution were observed: (1) elevated ADA acutely and subacutely; (2) elevated ADA acutely and reduced ADA subacutely; and (3) reduced ADA acutely and subacutely. At outcome, reduced ADA with elevated ADC was observed generally. We identified 3 phases of diffusion abnormalities: (1) reduced ADC and elevated ADA; (2) reduced ADC and reduced ADA; and (3) elevated ADC and reduced ADA. The ADA ratios within 12 hours correlated with the acute Canadian Neurological Scale (r=0.46, P=0.06), subacute Canadian Neurological Scale (r=0.55, P=0.02), outcome Barthel Index (r=0.62, P=0.01), and Rankin Scale (r=-0.77, P<0.0005) scores. CONCLUSIONS Combined ADC and ADA provide differential patterns of stroke evolution. Early ADA changes reflect cellular alterations in acute ischemia and may provide a potential marker to predict stroke outcome.

Perfusion Magnetic Resonance Imaging Maps in Hyperacute Stroke Relative Cerebral Blood Flow Most Accurately Identifies Tissue Destined to Infarct

Background and Purpose— In ischemic stroke, perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) provide important pathophysiological information. A PWI>DWI mismatch pattern suggests the presence of salvageable tissue. However, improved methods for distinguishing PWI>DWI mismatch tissue that is critically hypoperfused from benign oligemia are required. Methods— We investigated the usefulness of maps of relative cerebral blood flow (rCBF), volume (rCBV), and mean transit time (rMTT) to predict transition to infarction in hyperacute (<6 hours) stroke patients with PWI>DWI mismatch patterns. Semiquantitative color-thresholded analysis was used to measure hypoperfusion volumes, including increasing color signal intensity thresholds of rMTT delay, which were compared with infarct expansion, outcome infarct size, and clinical status. Results— Acute rCBF lesion volume had the strongest correlation with final infarct size (r =0.91, P <0.001) and clinical outcome (r =0.67, P <0.01). There was a trend for acute rCBF>DWI mismatch volume to overestimate infarct expansion between the acute and outcome study (P =0.06). Infarct expansion was underestimated by acute rCBV>DWI mismatch (P <0.001). When rMTT lesions included tissue with moderately prolonged transit times (mean delay 4.3 seconds, signal intensity values 50% to 70%), infarct expansion was overestimated. In contrast, when rMTT lesions were restricted to more severely prolonged transit times (mean delay 6.1 seconds, signal intensity >70%), these regions progressed to infarction in all except 1 patient, but infarct expansion was underestimated (P <0.001). Conclusions— The acute rCBF lesion most accurately identified tissue in the PWI>DWI mismatch region at risk of infarction. Color-thresholded PWI maps show potential for use in an acute clinical setting to prospectively predict tissue outcome.

Priming the motor system enhances the effects of upper limb therapy in chronic stroke.

After stroke, the function of primary motor cortex (M1) between the hemispheres may become unbalanced. Techniques that promote a re-balancing of M1 excitability may prime the brain to be more responsive to rehabilitation therapies and lead to improved functional outcomes. The present study examined the effects of Active-Passive Bilateral Therapy (APBT), a putative movement-based priming strategy designed to reduce intracortical inhibition and increase excitability within the ipsilesional M1. Thirty-two patients with upper limb weakness at least 6 months after stroke were randomized to a 1-month intervention of self-directed motor practice with their affected upper limb (control group) or to APBT for 10-15 min prior to the same motor practice (APBT group). A blinded clinical rater assessed upper limb function at baseline, and immediately and 1 month after the intervention. Transcranial magnetic stimulation was used to assess M1 excitability. Immediately after the intervention, motor function of the affected upper limb improved in both groups (P < 0.005). One month after the intervention, the APBT group had better upper limb motor function than control patients (P < 0.05). The APBT group had increased ipsilesional M1 excitability (P < 0.025), increased transcallosal inhibition from ipsilesional to contralesional M1 (P < 0.01) and increased intracortical inhibition within contralesional M1 (P < 0.005). None of these changes were found in the control group. APBT produced sustained improvements in upper limb motor function in chronic stroke patients and induced specific and sustained changes in motor cortex inhibitory function. We speculate that APBT may have facilitated plastic reorganization in the brain in response to motor therapy. The utility of APBT as an adjuvant to physical therapy warrants further consideration.

Pretreatment diffusion- and perfusion-MR lesion volumes have a crucial influence on clinical response to stroke thrombolysis

We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions <18 mL (77% versus 18% placebo, OR=15.0, P<0.001). Benefit from tPA was also seen with DWI lesions up to 25 mL (69% versus 29% placebo, OR=5.5, P=0.03), but not for DWI lesions >25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.

The influence of diabetes mellitus and hyperglycaemia on stroke incidence and outcome.

Diabetes mellitus is a complex metabolic syndrome with significant effects on the systemic and cerebral vasculature. The incidence and severity of ischaemic stroke are increased by the presence of diabetes, and outcome from stroke is poorer. More than one third of patients admitted with acute stroke are hyperglycaemic at presentation. Reasons for the altered prognosis in diabetes associated stroke are multifactorial. A direct influence of hyperglycaemia at the time of ischaemia is likely to be important. The use of novel methods to delineate stroke topography and pathophysiology such as MR spectroscopy, diffusion and perfusion weighted MRI appear helpful in delineating the effects of hyperglycaemia on stroke pathophysiology. Randomised clinical trials to determine optimal management for patients with hyperglycaemia following stroke are ongoing. Such trials will determine if aggressive control of acute hyperglycaemia following stroke has similar benefits to that observed following acute myocardial infarction. Clinicians responsible for stroke patients should be aware of the importance of adequate glycaemic control in both primary and secondary prevention of stroke.