Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01525290.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Treatment-Relevant Findings in Transesophageal Echocardiography After Stroke: A Prospective Multicenter Cohort Study.

BACKGROUND AND PURPOSE: Cardiac ultrasound to identify sources of cardioembolism is part of the diagnostic workup of acute ischemic stroke. Recommendations on whether transesophageal echocardiography (TEE) should be performed in addition to transthoracic echocardiography (TTE) are controversial. We aimed to determine the incremental diagnostic yield of TEE in addition to TTE in patients with acute ischemic stroke with undetermined cause. METHODS: In a prospective, observational, pragmatic multicenter cohort study, patients with acute ischemic stroke or transient ischemic attack with undetermined cause before cardiac ultrasound were studied by TTE and TEE. The primary outcome was the rate of treatment-relevant findings in TTE and TEE as defined by a panel of experts based on current evidence. Further outcomes included the rate of changes in the assessment of stroke cause after TEE. RESULTS: Between July 1, 2017, and June 30, 2019, we enrolled 494 patients, of whom 492 (99.6%) received TTE and 454 (91.9%) received TEE. Mean age was 64.7 years, and 204 (41.3%) were women. TEE showed a higher rate of treatment-relevant findings than TTE (86 [18.9%] versus 64 [14.1%], P<0.001). TEE in addition to TTE resulted in 29 (6.4%) additional patients with treatment-relevant findings. Among 191 patients ≤60 years additional treatment-relevant findings by TEE were observed in 27 (14.1%) patients. Classification of stroke cause changed after TEE in 52 of 453 patients (11.5%), resulting in a significant difference in the distribution of stroke cause before and after TEE (P<0.001). CONCLUSIONS: In patients with undetermined cause of stroke, TEE yielded a higher number of treatment-relevant findings than TTE. TEE appears especially useful in younger patients with stroke, with treatment-relevant findings in one out of seven patients ≤60 years. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03411642.

Dopamine boosts intention and action awareness in Parkinson's disease.

Dopaminergic deficiency in Parkinson's disease (PD) has been associated with underactivation of the supplementary motor area and a reduction of voluntary actions. In these patients, awareness of intention to act has been shown to be delayed. However, delayed awareness of intention to act has also been shown in patients with hyperdopaminergic states and an excess of unwilled movements, as in Tourette's, and in patients with functional movement disorders. Hence, the role of dopamine in the awareness of intention and action remains unclear. 36 PD patients were tested ON and OFF dopaminergic medication and compared with 35 healthy age-matched controls. In addition, 17 PD patients with subthalamic deep brain stimulation (DBS) were tested ON medication and ON and OFF stimulation. Participants judged either the moment a self-generated action was performed, or the moment the urge to perform the action was felt, using the "Libet method". Temporal judgments of intention and action awareness were comparable between unmedicated PD patients and controls. Dopaminergic medication boosted anticipatory awareness of both intentions and actions in PD patients, relative to an unmedicated condition. The difference between ON/OFF DBS was not statistically reliable. Functional improvement of motor ability in PD through dopaminergic supplementation leads to earlier awareness of both intention, and of voluntary action.

[Acute treatment of ischemic stroke : Current standards]. / Akutbehandlung des ischämischen Schlaganfalls : Aktuelle Standards.

Important milestones of acute ischemic stroke (AIS) treatment were achieved in recent years. The results of two randomized controlled trials revealed that intravenous thrombolysis is efficacious for treatment of AIS patients with a symptom onset <9 h or an unknown time of symptom onset in the presence of beneficial patterns in advanced stroke imaging. These patterns comprise the evidence of salvageable tissue at risk of infarction in perfusion of computed tomography (so-called penumbral imaging) or a mismatch between the diffusion-weighted imaging (DWI) und fluid-attenuated inversion recovery (FLAIR) sequences in magnetic resonance imaging (so-called DWI-FLAIR mismatch). Another two randomized controlled trials resulted in evidence of a high effectiveness of mechanical thrombectomy using advanced imaging of selected AIS patients with a symptom onset <24 h or an unknown time window. This article provides an overview of the current study results and recommendations for the selection of imaging for evidence-based effective acute treatment of stroke patients.

Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements.

Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the motor network.

Effect of Comorbidity Burden and Polypharmacy on Poor Functional Outcome in Acute Ischemic Stroke.

PURPOSE: Comorbidities and polypharmacy are risk factors for worse outcome in stroke. However, comorbidities and polypharmacy are mostly studied separately with various approaches to assess them. We aimed to analyze the impact of comorbidity burden and polypharmacy on functional outcome in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT). METHODS: Acute ischemic stroke patients with large vessel occlusion (LVO) treated with MT from a prospective observational study were analyzed. Relevant comorbidity burden was defined as a Charlson Comorbidity Index (CCI) score ≥ 2, polypharmacy as the intake of ≥ 5 medications at time of stroke onset. Favorable outcome was a score of 0-2 on the modified Rankin scale at 90 days after stroke. The effect of comorbidity burden and polypharmacy on favorable outcome was studied via multivariable regression analysis. RESULTS: Of 903 patients enrolled, 703 AIS patients (mean age 73.4 years, 54.9% female) with anterior circulation LVO were included. A CCI ≥ 2 was present in 226 (32.1%) patients, polypharmacy in 315 (44.8%) patients. Favorable outcome was less frequently achieved in patients with a CCI ≥ 2 (47, 20.8% vs. 172, 36.1%, p < 0.001), and in patients with polypharmacy (69, 21.9% vs. 150, 38.7%, p < 0.001). In multivariable regression analysis including clinical covariates, a CCI ≥ 2 was associated with lower odds of favorable outcome (odds ratio, OR 0.52, 95% confidence interval, 95% CI 0.33-0.82, p = 0.005), while polypharmacy was not (OR 0.81, 95% CI 0.52-1.27, p = 0.362). CONCLUSION: Relevant comorbidity burden and polypharmacy are common in AIS patients with LVO, with comorbidity burden being a risk factor for poor outcome.

Haemorrhage after thrombectomy with adjuvant thrombolysis in unknown onset stroke depends on high early lesion water uptake.

BACKGROUND AND PURPOSE: In wake-up stroke, CT-based quantitative net water uptake (NWU) might serve as an alternative tool to MRI to guide intravenous thrombolysis with alteplase (IVT). An important complication after IVT is symptomatic intracerebral haemorrhage (sICH). As NWU directly implies ischaemic lesion progression, reflecting blood-brain barrier injury, we hypothesised that NWU predicts sICH in patients who had a ischaemic stroke undergoing thrombectomy with unknown onset. METHODS: Consecutive analysis of all patients who had unknown onset anterior circulation ischaemic stroke who underwent CT at baseline and endovascular treatment between December 2016 and October 2020. Quantitative NWU was assessed on baseline CT. The primary endpoint was sICH. The association of NWU and other baseline parameters to sICH was investigated using inverse-probability weighting (IPW) analysis. RESULTS: A total of 88 patients were included, of which 46 patients (52.3%) received IVT. The median NWU was 10.7% (IQR: 5.1-17.7). The proportion of patients with any haemorrhage and sICH were 35.2% and 13.6%. NWU at baseline was significantly higher in patients with sICH (19.1% vs 9.6%, p<0.0001) and the median Alberta Stroke Program Early CT Score (ASPECTS) was lower (5 vs 8, p<0.0001). Following IPW, there was no association between IVT and sICH in unadjusted analysis. However, after adjusting for ASPECTS and NWU, there was a significant association between IVT administration and sICH (14.6%, 95% CI: 3.3% to 25.6%, p<0.01). CONCLUSION: In patients with ischaemic stroke with unknown onset, the combination of high NWU with IVT is directly linked to higher rates of sICH. Besides ASPECTS for evaluating the extent of the early infarct lesion, quantitative NWU could be used as an imaging biomarker to assess the degree of blood-brain barrier damage in order to predict the risk of sICH in patients with wake up stroke.

Patient-Reported Quality of Life After Intravenous Alteplase for Stroke in the WAKE-UP Trial.

BACKGROUND AND OBJECTIVES: Intravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL). METHODS: WAKE-UP was a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EuroQol five-dimensional questionnaire (EQ-5D) at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome. RESULTS: Among 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02-0.12, p = 0.005). In addition, mean EQ VAS was higher with alteplase than with placebo (72.6 vs 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9-11.8, p < 0.001). Eighty-five percent of the total treatment effect of alteplase on the EQ-5D index was mediated using the mRS score while there was no significant direct effect. By contrast, the treatment effect on the EQ VAS was mainly through the direct pathway (60%), whereas 40% was mediated by the mRS. DISCUSSION: Assessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number, NCT01525290; EudraCT number, 2011-005906-32.

Association Between Net Water Uptake and Functional Outcome in Patients With Low ASPECTS Brain Lesions: Results From the I-LAST Study.

BACKGROUND AND OBJECTIVES: The effect of mechanical thrombectomy (MT) on functional outcome in patients with ischemic stroke with low ASPECTS is still uncertain. ASPECTS rating is based on the presence of ischemic hypoattenuation relative to normal; however, the degree of hypoattenuation, which directly reflects net uptake of water, is currently not considered an imaging biomarker in stroke triage. We hypothesized that the effect of thrombectomy on functional outcome in low ASPECTS patients depends on early lesion water uptake. METHODS: For this multicenter observational study, patients with anterior circulation stroke with ASPECTS ≤5 were consecutively analyzed. Net water uptake (NWU) was assessed as a quantitative imaging biomarker in admission CT. The primary end point was the rate of favorable functional outcome defined as modified Rankin Scale score 0-3 at day 90. The effect of recanalization on functional outcome was analyzed according to the degree of NWU within the early infarct lesion. RESULTS: A total of 254 patients were included, of which 148 (58%) underwent MT. The median ASPECTS was 4 (interquartile range [IQR] 3-5), and the median NWU was 11.4% (IQR 8.9%-15.1%). The rate of favorable outcome was 27.6% in patients with low NWU (<11.4%) vs 6.3% in patients with high NWU (≥11.4%; p < 0.0001). In multivariable logistic regression analysis, NWU was an independent predictor of outcome, whereas vessel recanalization (modified thrombolysis in cerebral infarction ≥2b) was only significantly associated with better outcomes if NWU was lower than 12.6%. In inverse-probability weighting analysis, recanalization was associated with 20.7% (p = 0.01) increase in favorable outcome in patients with low NWU compared with 9.1% (p = 0.06) in patients with high NWU. DISCUSSION: Early NWU was independently associated with clinical outcome and might serve as an indicator of futile MT in low ASPECTS patients. NWU could be tested as a tool to select low ASPECTS patients for MT. TRIAL REGISTRATION INFORMATION: The study is registered within the ClinicalTrials.gov Protocol Registration and Results System (NCT04862507).

Higher comorbidity burden is associated with lower self-reported quality of life after stroke.

Introduction: This study assesses the association of comorbidity burden and polypharmacy with self-reported quality of life after stroke. Patients and methods: We performed a post-hoc analysis of a prospective, single-center, observational study of outcome evaluation by patient-reported outcome measures in stroke clinical practice. Consecutive patients with acute ischemic stroke (AIS) were enrolled and self-reported health-related quality of life (HrQoL) was assessed 90 days after acute stroke using the Patient-reported Outcomes Measurement Information System 10-Question Short-Form (PROMIS-10). Comorbidities at baseline were assessed by the Charlson Comorbidity Index (CCI). Polypharmacy was defined as medication intake of ≥5 at baseline. We used linear regression analysis to study the association of CCI, polypharmacy and other clinical covariates with HrQoL after stroke. Results: Of 781 patients (median age 76 years, 48.4% female) enrolled, 30.2% had a CCI Score ≥2, and 31.5% presented with polypharmacy. At follow up, 71 (9.1%) had died. In 409 (52.4%) reached for outcome evaluation, Global Physical Health T-Score was 43.8 ± 10 and Global Mental Health T-Score was 43.5 ± 8.76, indicating lower HrQoL than the average population. A CCI Score ≥2, higher NIHSS Score, female sex, dependency on others for dressing, toileting and mobility before index stroke, atrial fibrillation and hypertension were independent predictors of worse physical and mental health outcomes, while polypharmacy was not. Conclusion: In patients with AIS, high comorbidity burden and polypharmacy are frequent. Comorbidity burden at admission is independently associated with worse self-reported physical and mental health three months after stroke.

Effect of Intravenous Alteplase on Functional Outcome and Secondary Injury Volumes in Stroke Patients with Complete Endovascular Recanalization.

Intravenous thrombolytic therapy with alteplase (IVT) is a standard of care in ischemic stroke, while recent trials investigating direct endovascular thrombectomy (EVT) approaches showed conflicting results. Yet, the effect of IVT on secondary injury volumes in patients with complete recanalization has not been analyzed. We hypothesized that IVT is associated with worse functional outcome and aggravated secondary injury volumes when administered to patients who subsequently attained complete reperfusion after EVT. Anterior circulation ischemic stroke patients with complete reperfusion after thrombectomy defined as thrombolysis in cerebral infarctions (TICI) scale 3 after thrombectomy admitted between January 2013-January 2021 were analyzed. Primary endpoints were the proportion of patients with functional independence defined as modified Rankin Scale (mRS) score 0-2 at day 90, and secondary injury volumes: Edema volume in follow-up imaging measured using quantitative net water uptake (NWU), and the rate of symptomatic intracerebral hemorrhage (sICH). A total of 219 patients were included and 128 (58%) patients received bridging IVT before thrombectomy. The proportion of patients with functional independence was 28% for patients with bridging IVT, and 34% for patients with direct thrombectomy (p = 0.35). The rate of sICH was significantly higher after bridging IVT (20% versus 7.7%, p = 0.01). Multivariable logistic and linear regression analysis confirmed the independent association of bridging IVT with sICH (aOR: 2.78, 95% CI: 1.02-7.56, p = 0.046), and edema volume (aOR: 8.70, 95% CI: 2.57-14.85, p = 0.006). Bridging IVT was associated with increased edema volume and risk for sICH as secondary injury volumes. The results of this study encourage direct EVT approaches, particularly in patients with higher likelihood of successful EVT.

Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke.

Introduction: Higher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase. Methods: WAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22-36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group. Results: Of 503 randomized patients, WBC count and baseline parameters were available in 437 patients (µ = 64.7 years, 35.2% women) on admission and 355 patients (µ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1-9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7-9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78-0.94 and aOR 0.88, 95% CI 0.79-0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05-1.24 and aOR 1.13, 95% CI 1.00-1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08-6.07). Conclusion: Higher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested. Trial Registration: ClinicalTrials.gov Identifier: NCT01525290.

Reversible Ischemic Lesion Hypodensity in Acute Stroke CT Following Endovascular Reperfusion.

BACKGROUND AND OBJECTIVES: In acute stroke, early ischemic lesion hypodensity on CT is considered the imaging hallmark of brain infarction, representing a state of irreversible tissue damage with a continual increase of net water uptake. This dogma, however, is challenged by rare cases of apparently reversed early lesion hypodensity after complete reperfusion. The purpose of this study was to investigate the occurrence of reversible ischemic edema after endovascular treatment. METHODS: One hundred eighty-four patients with acute ischemic anterior circulation stroke were included after consecutive screening. Ischemic brain edema was determined with quantitative lesion net water uptake (NWU) in admission CT and follow-up CT based on CT densitometry, and ΔNWU was calculated as the difference. The association of edema progression to imaging and clinical parameters was investigated. Clinical outcome was assessed with the modified Rankin Scale (mRS) scores at day 90. RESULTS: Of 184 patients, 27 (14.7%) showed edema arrest and 3 (1.6%) exhibited significant edema reversibility. Higher degree of recanalization (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.46-6.01, p < 0.01) and shorter time from imaging to recanalization (OR per hour 0.32, 95% CI 0.18-0.54, p < 0.0001) were significantly associated with edema arrest or reversibility. Clinical outcome was significantly better in patients without edema progression (median mRS score 2 vs 5, p = 0.004). DISCUSSION: Although rare, lesion hypodensity considered to be representative of early infarct in acute stroke CT may be reversible after complete recanalization. Arrest of edema progression of acute brain infarct lesions may occur after successful rapid vessel recanalization, resulting in improved functional outcome. Future research is needed to investigate conditions in which early revascularization may halt or even reverse vasogenic edema of ischemic tissue.

24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke.

INTRODUCTION: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke. PATIENTS AND METHODS: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke. RESULTS: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile. CONCLUSIONS: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290.

Learning volition: A longitudinal study of developing intentional awareness in Tourette syndrome.

Tourette syndrome (TS) is characterized by the presence of involuntary movements (tics) which are, at least partly, generated within 'voluntary' motor pathways. Here we reassess 16 TS patients (age 19 ± 2.3 years) who participated in a mental chronometry study of volition 5.5 years previously (Ganos C et al. Cortex. 2015 Mar.; 64:47-54), and 16 age-matched controls. Participants estimated the time of their own voluntary movements (Libet's M judgement), or of conscious intention to make voluntary movements (Libet's W judgement), in separate blocks. We considered M judgement as a control condition. Therefore, the experience of an intention to move occurring prior to actual movement onset, as measured by the W-M gap, was taken as the cardinal feature of volition. Time estimates of the TS group did not differ significantly from controls, for either M or W judgement. Further, M and W time estimates in the TS group had not changed significantly between the two assessments. However, exploratory analyses revealed a strong relation between disease duration and the development of M- and W-judgements: the longer was the disease duration, the less was the developmental increase in the W-M gap (linear regression, p = .003). In conclusion, our results suggest compromised development of experience of volition in developing TS patients. The developmental difficulty in processing internal premotor signals for voluntary actions could reflect the chronic persistence of tics from adolescence to adulthood.

Symptoms and probabilistic anatomical mapping of lacunar infarcts.

BACKGROUND: The anatomical distribution of acute lacunar infarcts has mainly been studied for supratentorial lesions. In addition, little is known about the association with distinct stroke symptoms, not summarized as classical lacunar syndromes. We aimed to describe the spatial lesion distribution of acute supra- and infratentorial lacunar infarcts and their association with stroke symptoms in patients eligible for thrombolysis. METHODS: All patients enrolled in the WAKE-UP trial (efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in wake-up stroke) were screened for lacunar infarcts on diffusion-weighted imaging (DWI). The relationship between the anatomical distribution of supra- and infratentorial lacunar infarcts, their demographic characteristics and acute stroke symptoms, defined by the National Institutes of Health Stroke Scale (NIHSS) score, were correlated and compared. RESULTS: Maps of lesion distribution from 224 lacunar infarct patients (76 [33.9%] females, mean age [standard deviation] of 63.4 [11.5] years) were generated using computational image mapping methods. Median infarct volume was 0.73 ml (interquartile range [IQR] 0.37-1.15 ml). Median NIHSS sum score on hospital arrival was 4 (IQR 3-6). 165 (73.7%) patients had lacunar infarcts in the supratentorial deep white or grey matter, while 59 (26.3%) patients had infratentorial lacunar infarcts. Patients with supratentorial lacunar infarcts presented with a significantly lower occurrence of deficits in the NIHSS items gaze (p < 0.001) and dysarthria (p = 0.008), but had more often a paresis of the left arm (p = 0.009) and left leg (p = 0.068) compared to patients with infratentorial infarcts. CONCLUSIONS: The anatomical lesion distribution of lacunar infarcts reveals a distinct pattern and supports an association of localization with different stroke symptoms. TRIAL REGISTRATION: NCT01525290.

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions.

PURPOSE: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI). METHODS: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions. RESULTS: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011). CONCLUSION: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial.

Importance: The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment. Objective: To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts. Design, Setting, and Participants: This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information. Main Outcomes and Measures: The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms. Results: Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93). Conclusions and Relevance: While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.

Oculogyric crises: Etiology, pathophysiology and therapeutic approaches.

Oculogyric crisis (OGC) describes the clinical phenomenon of sustained dystonic, conjugate and typically upward deviation of the eyes lasting from seconds to hours. It was initially observed in patients with postencephalitic parkinsonism, but since then a number of conditions have been associated with OGC. These include drug-induced reactions, hereditary and sporadic movement disorders, and focal brain lesions. Here, we systematically review the literature and discuss the spectrum of disorders associated with OGC in order to aid clinicians place this rare but distinctive clinical sign into the appropriate diagnostic context. We also provide a brief synthesis of putative pathophysiological mechanisms, as well as therapeutic recommendations based on the literature and our own experience.