Patrick Vroomen

Cerebral Autoregulation in Stroke A Review of Transcranial Doppler Studies

Background and Purpose— Cerebral autoregulation may become impaired after stroke. To provide a review of the nature and extent of any autoregulation impairment after stroke and its course over time, a technique allowing repeated bedside measurements with good temporal resolution is required. Transcranial Doppler (TCD) in combination with continuous blood pressure measurements allows noninvasive continuous bedside investigation with high temporal resolution of the dynamic and the steady-state components of cerebral autoregulation. Therefore, this review focuses on all TCD studies on cerebral autoregulation in the setting of documented ischemic stroke. Methods— PubMed and EMBASE were searched for studies of stroke, autoregulation, and TCD. Studies were either acute phase (<96 hours after index stroke) or chronic phase (>96 hours after index stroke) autoregulation studies. Quality of studies was studied in a standardized fashion. Results— Twenty-three studies met the inclusion criteria. General agreement existed on cerebral autoregulation being impaired, even after minor stroke. Bilateral impairment of autoregulation was documented, particularly after lacunar stroke. Studies showed progressive deterioration of cerebral autoregulation in the first 5 days after stroke and recovery over the next 3 months. Impaired cerebral autoregulation as assessed by TCD was related to neurological deterioration, the necessity for decompressive surgery, and poor outcome. Synthesis of the data of various studies was, however, limited by studies not meeting key methodological criteria for observational studies. Conclusions— TCD in combination with continuous blood pressure measurement offers a method with a high temporal resolution feasible for bedside evaluation of cerebral autoregulation in the stroke unit. TCD studies have shown impairment of cerebral autoregulation in various subtypes of ischemic stroke. To improve the synthesis of data from various research groups, there is urgent need for standardization of methodology of TCD studies in cerebral autoregulation.

Optimizing Cutoff Scores for the Barthel Index and the Modified Rankin Scale for Defining Outcome in Acute Stroke Trials

Background and Purpose— There is little agreement on how to assess outcome in acute stroke trials. Cutoff scores for the Barthel Index (BI) and modified Rankin Scale (mRS) are frequently arbitrarily chosen to dichotomize favorable and unfavorable outcome. We investigated sensitivity and specificity of BI cutoff scores in relation to the mRS to obtain the optimal corresponding BI and mRS scores. Methods— BI and mRS scores were collected from 1034 ischemic stroke patients. Sensitivity and specificity were calculated for BI cutoff scores from 45 to 100 in mRS score 1, 2, and 3 and were plotted in receiver operator characteristic (ROC) curves. Results— The cutoff scores for the BI with the highest sum of sensitivity and specificity were 95 (sensitivity 85.6%; specificity 91.7%), 90 (sensitivity 90.7%; specificity 88.1%), and 75 (sensitivity 95.7%; specificity, 88.5%) for, respectively, mRS 1, 2, and 3. The area under the ROC curve was 0.933 in mRS 1, 0.960 in mRS 2, and 0.979 in mRS 3. Conclusions— The optimal cutoff scores for the BI were 95 for mRS 1, 90 for mRS 2, and 75 for mRS 3. For future acute stroke trials that assess stroke outcome with the BI and mRS, we recommend the use of these BI cutoff score(s) with the corresponding mRS cutoff score(s), to ensure the use of consistent and uniform end points.

Intravenous Alteplase for Stroke Beyond the Guidelines and in Particular Clinical Situations

Background and Purpose— Because of the risk of hemorrhage, especially in the brain, thrombolytic therapy with intravenous alteplase is restricted by guidelines, and only a small number of selected patients are being treated. Findings from metaanalyses, post hoc analyses of the randomized trials, and postlicensing experience suggest that more subjects, who otherwise have a poor predicted outcome without treatment, might benefit from intravenous alteplase. Summary of Review— There is a strong indication that treatment may still be beneficial beyond 3 hours up until 4.5 hours. The risk of symptomatic intracerebral hemorrhage is not increased in patients aged 80 years or older. Excluding patients with severe stroke or with early ischemic changes in more than one third of the middle cerebral artery territory on baseline CT scan is probably not necessary when treatment is started <3 hours of symptom onset. Patients with minor or improving symptoms can also benefit. Intravenous thrombolysis appears appropriate as first line therapy for posterior circulation stroke. Alteplase can be given to patients with cervical artery dissection, seizure at onset and evidence of acute ischemia on brain imaging, and after carefully weighing risk and benefit in pregnancy and during menstruation. There are anecdotal reports on its use in children, patients with recent myocardial infarction, cardiac embolus, intracranial aneurysm or arteriovenous malformation, prior stroke and recent surgery. There appears to be a substantially increased risk of symptomatic cerebral hemorrhage in hyperglycemic stroke patients. The combined intravenous and intraarterial approach to recanalization appears safe and is currently under investigation in a randomized trial. Conclusions— This document does not intend to change the guidelines but reviews the literature on the use of intravenous alteplase for stroke beyond guidelines and in particular conditions.

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial

IMPORTANCE Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION trialregister.nl Identifier: NTR1804.

Safety of antiplatelet therapy prior to intravenous thrombolysis in acute ischemic stroke

BACKGROUND There is some uncertainty whether prior use of antiplatelet (AP) drugs increases the risk of symptomatic intracerebral hemorrhage (SICH) and influences functional outcome in patients with ischemic stroke treated with intravenous thrombolysis. OBJECTIVE To assess whether prior use of AP drugs is related to outcome following intravenous tissue plasminogen activator therapy in patients with ischemic stroke. DESIGN, SETTING, AND PATIENTS A single-center prospective observational cohort study of the relation between prior AP therapy, occurrence of SICH, and functional outcome of consecutive patients with ischemic stroke undergoing intravenous thrombolysis with tissue plasminogen activator in a university hospital between April 1, 2002, and November 30, 2006. MAIN OUTCOME MEASURES The occurrence of SICH and favorable outcome reflecting independence defined as a modified Rankin Scale score of 2 or lower at 3 months. RESULTS Of the 301 patients who received intravenous tissue plasminogen activator, 89 used AP drugs prior to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 12 patients (13.5%; 95% confidence interval, 7.8%-22.3%) who had received AP drugs and in 6 patients (2.8%; 95% confidence interval, 1.2%-6.2%) without prior AP therapy (P = .001). Multivariate analysis revealed that prior AP therapy was an independent predictor of SICH (odds ratio, 6.0; 95% confidence interval, 2.0-17.1). Nonetheless, prior AP therapy was independently associated with a favorable outcome (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). CONCLUSION Despite a higher incidence of SICH, the net benefit of intravenous tissue plasminogen activator therapy for acute ischemic stroke was greater in patients using AP drugs.

Responsiveness and Minimal Clinically Important Change of the Pain Disability Index in Patients With Chronic Back Pain

Study Design. Prospective cohort study. Objective. The objective of this study was to test the responsiveness and minimal clinically important change (MCIC) of the Pain Disability Index (PDI) in patients with chronic back pain (CBP). Summary of Background Data. Treatment of patients with CBP is primarily focused on reduction of disability. For disability measurement, the PDI is a widely used questionnaire. There are, however, no data available on responsiveness and MCIC. Methods. Two hundred forty-two patients with CBP were included in this study. Patients filled in the PDI at baseline and at discharge. The PDI consists of 2 subscales: 1 measuring voluntary activities and 1 measuring obligatory activities. PDI was anchored at 2 self-reported global perceived effect (GPE) scales for complaints and self-care, respectively. Responsiveness was considered sufficient when Area Under the Receiver Operating Characteristics (ROC) Curve (AUC) was higher than 0.70. To test interpretability, change scores and MCIC were calculated. MCIC was tested by determination of optimal cut-off point of the ROC curve and determination of specificity and sensitivity of the optimal cut-off point. Results. AUCs were 0.76 and 0.77 depending on the external criterion. The subscale obligatory activities did not meet the criteria for responsiveness (AUC: 0.63–0.69). MCIC of the PDI was 9.5 points for GPE “complaints” and 8.5 for GPE “self-care.” Conclusion. The total score of the PDI as well as the subscale of voluntary activities is responsive. Partly because of floor effects, the subscale obligatory activities are not sufficiently responsive in patients with CBP. However, the responsiveness of this subscale in other patient groups should be further tested. In patients with CBP, change can be considered clinically important when PDI score has decreased 8.5 to 9.5 points.

Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients with Proximal Anterior Circulation Stroke

Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. Results— We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0). Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. Clinical Trial Registration— URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

The Incidence of Stroke Mimics Among Stroke Department Admissions in Relation to Age Group

BACKGROUND Acute stroke therapies are effective but may have serious adverse effects. This makes an accurate diagnosis mandatory. Acute stroke is diagnosed on the basis of neurologic findings, laboratory testing, and a computed tomography scan of the brain. This is the first study to investigate the incidence of stroke mimics beyond the triaging stage and just before therapy decisions across age groups. METHODS In all, 669 consecutive patients assessed at the emergency department by a neurologist were admitted to the stroke department with a provisional diagnosis of stroke. Patient registries of possible mimics were cross-referenced. RESULTS In all, 637 patients (95.2%) had a correct diagnosis of stroke. A total of 15 patients turned out to have migraine with prolonged aura, 13 had a conversion disorder, 4 had partial epilepsy, and one was hypoglycemic. Under the age of 50 years, stroke mimics occurred in 21% of 87 patients. Above the age of 50 years, stroke mimics were very rare (3% of 583 patients). CONCLUSIONS In patients being considered for acute stroke interventions, stroke mimics need to be considered particularly when the patient is younger than 50 years. In older patients, features typical of stroke mimics do not rule out a stroke.

Measuring disability in stroke: relationship between the modified Rankin scale and the Barthel index

Background and purposeThe effectiveness of therapeutic interventions in acute stroke trials is traditionally measured with the modified Rankin scale (mRs) and the Barthel index (BI). The mRs is a global disability scale divided into six steps from total independence to total dependence. The BI assesses ten basal activities of daily living, of which eight assess level of dependence (bathing, grooming, using stairs, dressing, feeding, toilet use, transfers and walking). The aim of this study was to investigate the relationship between the mRs and the total scores and item-scores of the BI.MethodsDuring a period of 3 months mRs and BI scores were collected from two multicentre randomised, placebo-controlled trials with lubeluzole (515 and 519 patients). In each patient we compared the mRs grades with the total BI score and the scores on the ten subitems.ResultsFor both trials there was extensive overlap of BI scores between mRs grades and a wide range in BI scores among patients with mRs grades 3 and 4. We also found discrepancies between the BI item-scores and mRs grades. About 40% of patients with mRs grades 1 (able to carry out all usual activities) and 2 (able to look after own affairs without assistance) were not independent on at least one activity of the BI. In both studies, about 30% of the patients needed help or supervision for walking, although they were classified as mRs 3 (requiring some help but able to walk without assistance).ConclusionsInvestigators in stroke trials use the mRs as a subjective global disability scale, and they do not strictly take into account limitations in performing specific basal activities of daily living, as assessed by the BI, to assign mRs grades.

Proportion of Patients Treated With Thrombolysis in a Centralized Versus a Decentralized Acute Stroke Care Setting

Background and Purpose— Today, treatment of acute stroke consists of tissue-type plasminogen activator (tPA), admission to a stroke unit, and aspirin. Although tPA treatment is the most effective, there is substantial undertreatment. Centralized care may affect rate, timing, and outcome of thrombolysis compared to decentralized treatment in community hospitals. The present study aimed to assess the impact of organizational models on the proportion of patients undergoing tPA treatment. Methods— A prospective, multicenter, observational study among 13 hospitals in the North of the Netherlands was conducted. In the centralized model, tPA treatment for 4 hospitals was administered in 1 stroke center. The decentralized model comprised 9 community hospitals. Primary outcome was the proportion of patients treated with tPA. Secondary outcome measures were proportion of patients arriving within 4.5 hours, safety, 90-day functional outcome, and onset-to-door, door-to-needle, and onset-to-needle times. Potential confounders were adjusted using logistic regression analysis. Results— Two hundred eighty-three and 801 ischemic stroke patients were enrolled in the centralized and decentralized settings. Numbers of patients treated with tPA were 62 (21.9%) and 113 (14.1%) (OR, 1.72; 95% CI, 1.22–2.43). Adjusting for potential confounders did not alter results (OR, 2.03; 95% CI, 1.39–2.96). In the centralized setting, significantly more patients arrived at the hospital within the 4.5-hour time window (P<0.01), and shorter door-to-needle times were reached (35 versus 47 minutes). Other secondary outcome measures did not differ across setting. Conclusions— In a centralized setting, the results demonstrate a 50% increased likelihood of treatment. Prehospital factors seem to contribute to this result.