Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Penumbra detection in acute stroke with perfusion magnetic resonance imaging: Validation with 15 O-positron emission tomography.

OBJECTIVE: Accurate identification of the ischemic penumbra, the therapeutic target in acute clinical stroke, is of critical importance to identify patients who might benefit from reperfusion therapies beyond the established time windows. Therefore, we aimed to validate magnetic resonance imaging (MRI) mismatch-based penumbra detection against full quantitative positron emission tomography (15 O-PET), the gold standard for penumbra detection in acute ischemic stroke. METHODS: Ten patients (group A) with acute and subacute ischemic stroke underwent perfusion-weighted (PW)/diffusion-weighted MRI and consecutive full quantitative 15 O-PET within 48 hours of stroke onset. Penumbra as defined by 15 O-PET cerebral blood flow (CBF), oxygen extraction fraction, and oxygen metabolism was used to validate a wide range of established PW measures (eg, time-to-maximum [Tmax]) to optimize penumbral tissue detection. Validation was carried out using a voxel-based receiver-operating-characteristic curve analysis. The same validation based on penumbra as defined by quantitative 15 O-PET CBF was performed for comparative reasons in 23 patients measured within 48 hours of stroke onset (group B). RESULTS: The PW map Tmax (area-under-the-curve = 0.88) performed best in detecting penumbral tissue up to 48 hours after stroke onset. The optimal threshold to discriminate penumbra from oligemia was Tmax >5.6 seconds with a sensitivity and specificity of >80%. INTERPRETATION: The performance of the best PW measure Tmax to detect the upper penumbral flow threshold in ischemic stroke is excellent. Tmax >5.6 seconds-based penumbra detection is reliable to guide treatment decisions up to 48 hours after stroke onset and might help to expand reperfusion treatment beyond the current time windows. ANN NEUROL 2019;85:875-886.

Is Perfusion MRI without Deconvolution Reliable for Mismatch Detection in Acute Stroke? Validation with 15O-Positron Emission Tomography.

BACKGROUND: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions. METHODS: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the -upper PF threshold as defined by PET cerebral blood flow <20 mL/100 g/min. RESULTS: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85-0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84-0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87-0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET. CONCLUSIONS: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke.

Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials.

This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post-stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30-50 ml Cerebrolysin once daily for 10-21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta-analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta-analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke.

Multiparametric Model for Penumbral Flow Prediction in Acute Stroke.

BACKGROUND AND PURPOSE: Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. METHODS: In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models' fits were compared using the likelihood ratio test. RESULTS: The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps (P<1×e-5) and demonstrated higher performance, with an area under the curve of 0.91. However, the absolute difference between the performance of GLM and the best-performing single perfusion parameter (time-to-maximum) was relatively low (area under the curve difference =0.04). CONCLUSIONS: Our results support a dynamic susceptibility contrast magnetic resonance imaging-based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.

Post-stroke dementia - a comprehensive review.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

Contribution of Neuro-Imaging for Prediction of Functional Recovery after Ischemic Stroke.

Prediction measures of recovery and outcome after stroke perform with only modest levels of accuracy if based only on clinical data. Prediction scores can be improved by including morphologic imaging data, where size, location, and development of the ischemic lesion is best documented by magnetic resonance imaging. In addition to the primary lesion, the involvement of fiber tracts contributes to prognosis, and consequently the use of diffusion tensor imaging (DTI) to assess primary and secondary pathways improves the prediction of outcome and of therapeutic effects. The recovery of ischemic tissue and the progression of damage are dependent on the quality of blood supply. Therefore, the status of the supplying arteries and of the collateral flow is not only crucial for determining eligibility for acute interventions, but also has an impact on the potential to integrate areas surrounding the lesion that are not typically part of a functional network into the recovery process. The changes in these functional networks after a localized lesion are assessed by functional imaging methods, which additionally show altered pathways and activated secondary centers related to residual functions and demonstrate changes in activation patterns within these networks with improved performance. These strategies in some instances record activation in secondary centers of a network, for example, also in homolog contralateral areas, which might be inhibitory to the recovery of primary centers. Such findings might have therapeutic consequences, for example, image-guided inhibitory stimulation of these areas. In the future, a combination of morphological imaging including DTI of fiber tracts and activation studies during specific tasks might yield the best information on residual function, reserve capacity, and prospects for recovery after ischemic stroke.

Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials.

This meta-analysis combines the results of two identical stroke studies (CARS-1 and CARS-2) assessing efficacy of Cerebrolysin on motor recovery during early rehabilitation. Cerebrolysin is a parenterally administered neuropeptide preparation approved for the treatment of stroke. Both studies had a prospective, randomized, double-blind, placebo-controlled design. Treatment with 30 ml Cerebrolysin once daily for 3 weeks was started 24-72 h after stroke onset. In addition, patients participated in a standardized rehabilitation program for 21 days that was initiated within 72 h after stroke onset. For both studies, the original analysis data were used for meta-analysis (individual patient data analysis). The combination of these two studies by meta-analytic procedures was pre-planned, and the methods were pre-defined under blinded conditions. The nonparametric Mann-Whitney (MW) effect size of the two studies on the ARAT score on day 90 indicated superiority of Cerebrolysin compared with placebo (MW 0.62, P < 0.0001, Wei-Lachin pooling procedure, day 90, last observation carried forward; N = 442). Also, analysis of early benefit at day 14 and day 21 by means of the National Institutes of Health Stroke Scale, which is regarded as most sensitive to early improvements, showed statistical significance (MW 0.59, P < 0.002). The corresponding number-needed-to-treat (NNT) for clinically relevant changes in early NIHSS was 7.1 (95% CI: 4 to 22). Cerebrolysin had a beneficial effect on motor function and neurological status in early rehabilitation patients after acute ischemic stroke. Safety aspects were comparable to placebo, showing a favourable benefit/risk ratio.

Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND AND PURPOSE: The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo. METHODS: This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90. RESULTS: The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann-Whitney estimator, 0.71; 95% confidence interval, 0.63-0.79; P<0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann-Whitney estimator, 0.62; 95% confidence interval, 0.58-0.65; P<0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated. CONCLUSIONS: Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrialsregister.eu. Unique identifier: 2007-000870-21.

Neuroimaging in vascular cognitive impairment: a state-of-the-art review.

Imaging is critical in the diagnosis and treatment of dementia, particularly in vascular cognitive impairment, due to the visualization of ischemic and hemorrhagic injury of gray and white matter. Magnetic resonance imaging (MRI) and positron emission tomography (PET) provide structural and functional information. Clinical MRI is both generally available and versatile - T2-weighted images show infarcts, FLAIR shows white matter changes and lacunar infarcts, and susceptibility-weighted images reveal microbleeds. Diffusion MRI adds another dimension by showing graded damage to white matter, making it more sensitive to white matter injury than FLAIR. Regions of neuroinflammatory disruption of the blood-brain barrier with increased permeability can be quantified and visualized with dynamic contrast-enhanced MRI. PET shows metabolism of glucose and accumulation of amyloid and tau, which is useful in showing abnormal metabolism in Alzheimer's disease. Combining MRI and PET allows identification of patients with mixed dementia, with MRI showing white matter injury and PET demonstrating regional impairment of glucose metabolism and deposition of amyloid. Excellent anatomical detail can be observed with 7.0-Tesla MRI. Imaging is the optimal method to follow the effect of treatments since changes in MRI scans are seen prior to those in cognition. This review describes the role of various imaging modalities in the diagnosis and treatment of vascular cognitive impairment.

Malignant MCA Infarction: Pathophysiology and Imaging for Early Diagnosis and Management Decisions.

BACKGROUND: Malignant middle cerebral artery infarction is a devastating condition, with up to 80% mortality in conservatively treated patients. The pathophysiology of this stroke is characterized by a large core of severe ischemia and only a relatively small rim of penumbra. Due to the fast development of irreversible morphological damage, cytotoxic edema occurs immediately in a large portion of the ischemic territory. The subsequent damage of the tight junctions leads to the breakdown of the blood brain barrier and vasogenic brain edema, resulting in space-occupying brain swelling. The progressive vasogenic edema reaches its maximum after 1 to several days and exerts a mechanical force on surrounding tissue structures leading to midline shift and transtentorial herniation and finally brain stem compression and death. SUMMARY: Early severe neurological symptoms--hemiparesis, gaze deviation, higher cortical signs--followed by headache, vomiting, papillo edema and reduced consciousness may predict the deleterious course. Imaging supports the suspected diagnosis with hypodense changes on CT extending beyond 50% of the MCA territory. The size of the probably infarcted tissue and a midline shift on CT as well as the size of the lesion on diffusion-weighted MRI are predictive of a malignant course. Reduction of cerebral blood flow below a critical value and volume of irreversible tissue damage detected by positron emission tomography in the early hours after the stroke are indicative of progression to malignant infarction with increased intracranial pressure (ICP) and decreased tissue oxygen tension observed by multimodal neuromonitoring in the later course. Treatment options of malignant infarction include general measures to limit the extent of space-occupying edema, but these therapies have not been efficacious. Only surgical intervention with decompressive hemicraniectomy (DHC) was successful in relieving the effects of increased ICP and of the deleterious shifts of brain tissue. Several controlled clinical trials have proven the efficacy of DHC with a significant decrease in mortality and improved functional outcome. However, DHC must be performed early and with a large diameter, regardless of the age of patients, but in patients beyond 60 years, the higher likelihood of resulting severe disability should be taken into consideration. KEY MESSAGES: Malignant MCA infarction can be predicted early with a high sensitivity by neuroimaging. The early diagnosis is mandatory for DHC, which was shown to reduce mortality and improve functional outcome in several controlled clinical trials.

Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1.

BACKGROUND: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. METHODS: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. RESULTS: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. CONCLUSION: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.

Clinical-Radiological Parameters Improve the Prediction of the Thrombolysis Time Window by Both MRI Signal Intensities and DWI-FLAIR Mismatch.

BACKGROUND: With regard to acute stroke, patients with unknown time from stroke onset are not eligible for thrombolysis. Quantitative diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) MRI relative signal intensity (rSI) biomarkers have been introduced to predict eligibility for thrombolysis, but have shown heterogeneous results in the past. In the present work, we investigated whether the inclusion of easily obtainable clinical-radiological parameters would improve the prediction of the thrombolysis time window by rSIs and compared their performance to the visual DWI-FLAIR mismatch. METHODS: In a retrospective study, patients from 2 centers with proven stroke with onset <12 h were included. The DWI lesion was segmented and overlaid on ADC and FLAIR images. rSI mean and SD, were calculated as follows: (mean ROI value/mean value of the unaffected hemisphere). Additionally, the visual DWI-FLAIR mismatch was evaluated. Prediction of the thrombolysis time window was evaluated by the area-under-the-curve (AUC) derived from receiver operating characteristic (ROC) curve analysis. Factors such as the association of age, National Institutes of Health Stroke Scale, MRI field strength, lesion size, vessel occlusion and Wahlund-Score with rSI were investigated and the models were adjusted and stratified accordingly. RESULTS: In 82 patients, the unadjusted rSI measures DWI-mean and -SD showed the highest AUCs (AUC 0.86-0.87). Adjustment for clinical-radiological covariates significantly improved the performance of FLAIR-mean (0.91) and DWI-SD (0.91). The best prediction results based on the AUC were found for the final stratified and adjusted models of DWI-SD (0.94) and FLAIR-mean (0.96) and a multivariable DWI-FLAIR model (0.95). The adjusted visual DWI-FLAIR mismatch did not perform in a significantly worse manner (0.89). ADC-rSIs showed fair performance in all models. CONCLUSIONS: Quantitative DWI and FLAIR MRI biomarkers as well as the visual DWI-FLAIR mismatch provide excellent prediction of eligibility for thrombolysis in acute stroke, when easily obtainable clinical-radiological parameters are included in the prediction models.

Comparison of the 2 Most Popular Deconvolution Techniques for the Detection of Penumbral Flow in Acute Stroke.

BACKGROUND AND PURPOSE: Dynamic susceptibility-weighted contrast-enhanced (DSC) magnetic resonance imaging (MRI) is used to identify the tissue-at-risk in acute stroke, but the choice of optimal DSC postprocessing in the clinical setting remains a matter of debate. Using 15O-water positron emission tomography (PET), we validated the performance of 2 common deconvolution methods for DSC-MRI. METHODS: In (sub)acute stroke patients with consecutive MRI and PET imaging, DSC maps were calculated applying 2 deconvolution methods, standard and block-circulant single value decomposition. We used 2 standardized analysis methods, a region of interest-based and a voxel-based analysis, where PET cerebral blood flow masks of <20 mL/100 g per minute (penumbral flow) and gray matter masks were overlaid on DSC parameter maps. For both methods, receiver operating characteristic curve analysis was performed to identify the accuracy of each DSC-MR map for the detection of PET penumbral flow. RESULTS: In 18 data sets (median time after stroke onset: 18 hours; median time PET to MRI: 101 minutes), block-circulant single value decomposition showed significantly better performance to detect PET penumbral flow only for mean transit time maps. Time-to-maximum (Tmax) had the highest performance independent of the deconvolution method. CONCLUSIONS: Block-circulant single value decomposition seems only significantly beneficial for mean transit time maps in (sub)acute stroke. Tmax is likely the most stable deconvolved parameter for the detection of tissue-at-risk using DSC-MRI.

Add-on Effects of Repetitive Transcranial Magnetic Stimulation on Subacute Aphasia Therapy: Enhanced Improvement of Functional Communication and Basic Linguistic Skills. A Randomized Controlled Study.

OBJECTIVE: To determine to what extent repetitive transcranial magnetic stimulation (rTMS) combined with speech and language therapy improves functional communication and basic linguistic skills of individuals with subacute aphasia. DESIGN: Randomized, blinded, and sham-controlled study. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Participants (N=30) with subacute aphasia after stroke. INTERVENTIONS: During a 2-week treatment period, half of the participants received 10 sessions of 20-minute inhibitory 1-Hz rTMS over the right inferior frontal gyrus (Brodmann area 45), and the other half received sham stimulation. Directly thereafter, all the participants underwent 45 minutes of speech and language therapy. MAIN OUTCOME MEASURES: Aachen Aphasia Test, Amsterdam-Nijmegen Everyday Language Test (ANELT), a naming screening, and subscales of the FIM, all assessed the day before and the day after treatment period. RESULTS: The participants who received real rTMS significantly improved with respect to all 10 measures of basic linguistic skills and functional communication, whereas sham-treated participants significantly improved in only 6 of 10 measures (paired t tests, P<.05). There was a significant difference in the gains made by the 2 groups on 5 of 10 measures including functional communication (ANELT) (repeated-measures analysis of variance, P≤.05). CONCLUSIONS: For the first time, this study has demonstrated that basic linguistic skills as well as functional communication are bolstered by combining rTMS and behavioral language therapy in patients with subacute aphasia.

Non-invasive repeated therapeutic stimulation for aphasia recovery: a multilingual, multicenter aphasia trial.

Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30 days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45 minutes speech and language therapy session for 10 days. Efficacy is evaluated at 1 and 30 days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add an effective new strategy for early stage poststroke aphasia rehabilitation.

Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques.

BACKGROUND AND PURPOSE: Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear. METHODS: This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2-3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta>4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization. RESULTS: The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P=0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36-1.61; P=0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P=0.013). Time in therapeutic range (67% of the time for international normalized ratio 2-3) analysis by tertiles showed no significant differences across groups. CONCLUSIONS: Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00235248.

Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia.

BACKGROUND AND PURPOSE: Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. METHODS: Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15-water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. RESULTS: The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group (t test, P=0.003). Increases were largest for subtest naming (P=0.002) and tended to be higher for comprehension, token test, and writing (P<0.1). Patients in the rTMS group activated proportionally more voxels in the left hemisphere after treatment than before (difference in activation volume index) compared with sham-treated patients (t test, P=0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change (r2=0.25; P=0.015). CONCLUSIONS: Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks.

Noninvasive brain stimulation for treatment of right- and left-handed poststroke aphasics.

BACKGROUND: Accumulating evidence from single case studies, small case series and randomized controlled trials seems to suggest that inhibitory noninvasive brain stimulation (NIBS) over the contralesional inferior frontal gyrus (IFG) of right-handers in conjunction with speech and language therapy (SLT) improves recovery from poststroke aphasia. Application of inhibitory NIBS to improve recovery in left-handed patients has not yet been reported. METHODS: A total of 29 right-handed subacute poststroke aphasics were randomized to receive either 10 sessions of SLT following 20 min of inhibitory repetitive transcranial magnetic stimulation (rTMS) over the contralesional IFG or 10 sessions of SLT following sham stimulation; 2 left-handers were treated according to the same protocol with real rTMS. Language activation patterns were assessed with positron emission tomography prior to and after the treatment; 95% confidence intervals for changes in language performance scores and the activated brain volumes in both hemispheres were derived from TMS- and sham-treated right-handed patients and compared to the same parameters in left-handers. RESULTS: Right-handed patients treated with rTMS showed better recovery of language function in global aphasia test scores (t test, p < 0.002) as well as in picture-naming performance (ANOVA, p = 0.03) than sham-treated right-handers. In treated right-handers, a shift of activation to the ipsilesional hemisphere was observed, while sham-treated patients consolidated network activity in the contralesional hemisphere (repeated-measures ANOVA, p = 0.009). Both left-handed patients also improved, with 1 patient within the confidence limits of TMS-treated right-handers (23 points, 15.9-28.9) and the other patient within the limits of sham-treated subjects (8 points, 2.8-14.5). Both patients exhibited only a very small interhemispheric shift, much less than expected in TMS-treated right-handers, and more or less consolidated initially active networks in both hemispheres. CONCLUSION: Inhibitory rTMS over the nondominant IFG appears to be a safe and effective treatment for right-handed poststroke aphasics. In the 2 cases of left-handed aphasics no deterioration of language performance was observed with this protocol. However, therapeutic efficiency is less obvious and seems to be more related to the dominance pattern prior to the stroke than to the TMS intervention.