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The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Supplemental Digital Content is available in the text., Background and Purpose— Computed tomography (CT) perfusion (CTP) provides potentially valuable information to guide treatment decisions in acute stroke. Assessment of interobserver reliability of CTP has, however, been limited to small, mostly single center studies. We performed a large, internet-based study to assess observer reliability of CTP interpretation in acute stroke. Methods— We selected 24 cases from the IST-3 (Third International Stroke Trial), ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke), and POSH (Post Stroke Hyperglycaemia) studies to illustrate various perfusion abnormalities. For each case, observers were presented with noncontrast CT, maps of cerebral blood volume, cerebral blood flow, mean transit time, delay time, and thresholded penumbra maps (dichotomized into penumbra and core), together with a short clinical vignette. Observers used a structured questionnaire to record presence of perfusion deficit, its extent compared with ischemic changes on noncontrast CT, and an Alberta Stroke Program Early CT Score for noncontrast CT and CTP. All images were viewed, and responses were collected online. We assessed observer agreement with Krippendorff-α. Intraobserver agreement was assessed by inviting observers who reviewed all scans for a repeat review of 6 scans. Results— Fifty seven observers contributed to the study, with 27 observers reviewing all 24 scans and 17 observers contributing repeat readings. Interobserver agreement was good to excellent for all CTP. Agreement was higher for perfusion maps compared with noncontrast CT and was higher for mean transit time, delay time, and penumbra map (Krippendorff-α =0.77, 0.79, and 0.81, respectively) compared with cerebral blood volume and cerebral blood flow (Krippendorff-α =0.69 and 0.62, respectively). Intraobserver agreement was fair to substantial in the majority of readers (Krippendorff-α ranged from 0.29 to 0.80). Conclusions— There are high levels of interobserver and intraobserver agreement for the interpretation of CTP in acute stroke, particularly of mean transit time, delay time, and penumbra maps.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Background A growing number of neuroimaging studies suggest distinct neural changes in inflammatory bowel diseases (IBDs). Whether such changes may show similar spatial patterns across distinct neural features within and between specific IBD is unclear. To address this question, we used multivariate multimodal data fusion analysis to investigate structure/function modulation in remitted patients with Crohn's disease (CD) and ulcerative colitis (UC). Methods Patients with IBD (n = 46; n = 31 with CD, n = 15 with UC) in stable remission and 17 healthy controls (HC) underwent structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) as well as cognitive testing. Anxiety, depression, and fatigue were assessed using self-rating questionnaires. sMRI data were analyzed via voxel-based morphometry (VBM) and rs-fMRI data via amplitude of low-frequency fluctuations (ALFFs) and regional homogeneity (ReHo). Detection of cross-information between VBM, ALFF, and ReHo was conducted by means of a joint independent component analysis (jICA), followed by group-inference statistics. Key results Joint independent component analysis detected structural alterations in middle frontal and temporal regions (VBM), and functional changes in the superior frontal gyrus (ReHo) and the medial as well as inferior frontal, inferior temporal, rectal, and subcallosal gyrus (ALFF). One joint component of extracted features of the three modalities differed significantly between IBD patients and controls (p = 0.03), and most distinctly between HC and patients with UC. Conclusions and inferences Using a multivariate data fusion technique, this study provides further evidence to brain alterations in IBD. The data suggest distinct neural differences between CD and UC, particularly in frontotemporal regions.

ObjectiveTo analyze how the evidence of hippocampal diffusion-weighted imaging (DWI) lesions may support the clinical diagnosis of transient global amnesia (TGA).MethodsIn this retrospective observational study, 390 consecutive patients with isolated TGA were analyzed, who were evaluated at our institution between July 1999 and August 2018. The size, location, and number of lesions and time-dependent lesion detectability were examined. The incidence of DWI lesions was reviewed with regard to different levels of clinical diagnostic certainty upon presentation to the emergency department.ResultsHippocampal DWI lesions were detected in 272 (70.6%) patients with TGA, with a mean of 1.05 ± 0.98 (range 0–6) and a mean lesion size of 4.01 ± 1.22 mm (range 1.7–8.6 mm). In the subgroups of lower diagnostic certainty (amnesia witnessed by layperson or self-reported amnestic gap), DWI was helpful in supporting the diagnosis of TGA in 76 (69.1%) patients. In 187 patients with information about the exact onset, DWI lesions were analyzed in relation to latency between onset and MRI. Lesions could be detected at all time points and up to 6 days after symptom onset in individual patients; the highest rate of DWI-positive MRI (93%) was in the 12–24 hours time window.ConclusionMRI findings can support the diagnosis of TGA and may be particularly valuable in situations of low clinical certainty. DWI—ideally performed with a minimum delay of 20 hours after onset—should therefore be considered a useful adjunct to the diagnosis of TGA.

Background and purpose The aim was to study whether ultra-high field 7 T magnetic resonance imaging (MRI) can demonstrate chronic focal defects in the hippocampus corresponding to the former acute diffusion-weighted imaging (DWI) lesions and to assess chronic T2-hyperintense hippocampal lesion load in transient global amnesia (TGA) patients. Methods Follow-up of 7 T MRI of the hippocampus was performed in 13 patients with documented hippocampal DWI lesions (detected via 3 T MRI) after acute TGA. The location of the DWI lesions was transformed to 7 T T2 images after data co-registration. Additionally, the T2-hyperintense lesion load was estimated in each patient and compared with that of 13 healthy controls. Results Magnetic resonance imaging (7 T) was performed after a median of 4 months. No structural abnormality at the site of the previous TGA lesion was observed in any case. None of the controls showed DWI lesions. There was no significant difference between patients and controls concerning the number (P = 0.67) or volume (P = 0.45) of T2-hyperintense hippocampal lesions. Conclusions Diffusion-weighted imaging lesions in patients with TGA do not provoke any visible sequelae and do not result in hippocampal cavities. The occurrence of incidental hippocampal T2 lesions after TGA is not more frequent than in controls.

Objective In multiple sclerosis (MS) lesions blood-brain-barrier (BBB) breakdown is a common phenomenon delineating the phase of focal inflammation in developing MS lesions. In other pathologies like cerebral amyloid angiopathy or arteriosclerotic cerebral small vessel disease permanent cerebral microbleeds (CMB) have been shown to be sensitive markers indicating BBB dysfunction. We were interested in the potential role of T2*-weighted MRI and CMBs as BBB integrity markers in MS. Methods A large cohort of 189 MS patients (179 relapsing remitting MS and 10 secondary progressive MS) was investigated on a 3 T MRI system with conventional and T2*-weighted gradient echo MRI (T2*w) sequences. T2*w images were analysed for CMBs by experienced raters. Results None of the MS patients showed a CMB. Conclusion On T2*w MRI the prevalence of CMBs is not higher in MS patients than what is to be expected in young healthy people. In contrast to pathologies with structural vascular changes like small vessel disease or cerebral amyloid angiopathy, CMBs are not seen in MS where the immune reaction is causing a functional change in the BBB.

While the pathophysiology of transient global amnesia (TGA) is not understood, due to the specific nature of the clinical deficits, transient dysfunction in the medial temporal lobe, especially in the hippocampus, is assumed; however, concomitant disturbances in other brain regions and in executive function have been postulated. In this study, a cohort of 16 patients was prospectively recruited from the emergency department for resting-state functional MRI (fMRI) during the acute stage of TGA, as confirmed by a standardized neuropsychological assessment. Twenty age- and sex-matched controls, as well as twenty patients with a history of TGA, were recruited for comparison. Functional data were processed using independent component analysis (ICA), allowing the complete automatic (data-driven) identification of spontaneous network dynamics. We documented a severe disturbance in anterograde episodic long-term memory in all patients. Group-based ICA of resting-state data in acute TGA patients versus that of controls and patients with a past TGA episode demonstrated reduced FC mainly of structures belonging to the executive network (EN), but also the hippocampus, confirming its pathophysiological involvement in the disorder, as well as areas belonging to the salience network and other subcortical regions. No significant differences were found when comparing connectivity in patients with a history of TGA and controls. Our findings strengthen previous empirical and theoretical accounts of hippocampal and executive dysfunction in TGA. The disruption of frontal, parietal and insular control regions, together with disruption in the hippocampus, provides a new interpretation for the pathophysiology and neuropsychological profile of this neurological disorder on a large-scale network level Keywords: Executive network, Hippocampus, Memory, Transient global amnesia, Resting-state functional connectivity

Background Fatigue is common in patients with inflammatory bowel diseases (IBD). It occurs in up to 80% of patients with active disease, but also a considerable proportion of patients in remission, and significantly affects quality of life. The underlying mechanisms are still poorly understood, and it is still unclear which patients will suffer from fatigue even in luminally quiescent disease. Task-based brain functional studies have examined neural correlates of fatigueability and found changes in the orbitofrontal cortex (OFC), among other regions. To the best our knowledge, the relationship between brain function and fatigue in IBD has not been investigated. This study aimed to examine the association between fatigue and resting-state brain function in remitted IBD patients. Methods We obtained resting-state-functional MRI (rs-fMRI) data from 45 IBD patients in stable remission without current steroid or biological therapy and 17 healthy controls (HCs). Fatigue was assessed with Würzburger Erschöpfungsinventar Multiple Sklerose (WEIMuS). Preprocessing of rs-fMRI-data and calculation of amplitude of low frequency fluctuations (ALFF) was performed using the Data Processing Assistant for rs-fMRI. The resulting individual maps were analysed via second-level SPM multiple regression models in patients and HC to test for correlations between ALFF data and WEIMuS scores. Age, gender and mean framewise displacement were included as covariates of no interest and results were displayed at p < 0.001 (peak level) with a threshold of spatial extent (k) according to the expected voxels per cluster estimated by SPM. Results Fatigue scores did not differ significantly between patients and controls (mean WEIMuS-scores 17.9 (SD 13.9) vs. 12.3 (SD 16.5), p = .17). Proportions of participants with fatigue scores above the cutoff (>32P.) were nearly identical in patients and HC (8/45 vs. 3/17). In patients, fatigue scores correlated positively with ALFF in the right central operculum and negatively with ALFF in the left OFC and left cerebellum (all p < .001, Figure 1). Fatigue and ALFF in the left cerebellum were also found to correlate in HC. Conclusion This study shows fatigue-associated changes in brain activity in several brain regions. The negative association between fatigue and ALFF in the left OFC of IBD patients was not seen in HC, indicating that reduced ALFF in the OFC may represent a neural correlate of IBD-related fatigue. The OFC is thought to be involved in decision-making, which is described to be impaired in many fatigued IBD patients. If the association between fatigue and brain function detected in our study is confirmed in longitudinal IBD studies, these regions could serve as biomarkers when targeting fatigue in IBD.

Background Disturbed brain-gut interactions and a bidirectional relationship between inflammation and psychiatric symptoms such as anxiety and depression are being discussed in patients with inflammatory bowel diseases (IBD). Alterations of brain structure and function in IBD have been reported with heterogeneous results. Whether these changes reflect independent localized deficits or rather a systematic disruption in the anatomical organization of large-scale brain networks remains unclear. The present study investigated the gray matter structural connectome in patients with Crohn's disease (CD). Methods Sixty participants (30 with quiescent CD and 30 matched healthy controls [HC]) underwent high-resolution brain MRI at 3 Tesla. Well-established graph theoretical metrics were analyzed at the global and regional network level and compared between groups. Key results The networks in both groups followed a small-world organization, that is, an architecture that is simultaneously highly segregated and integrated. However, transitivity, a measure of global network segregation, was significantly reduced in patients (P = 0.003). Regionally, patients showed a reduction of nodal betweenness centrality in the right insula and cuneus and the left superior frontal cortex and reduced nodal degree within the left-hemispheric cingulate and the left lateral and right medial orbitofrontal cortex. Conclusion and inferences These findings lend support to the hypothesis that CD is accompanied by alterations in both global network organization and regional connectivity. A deeper understanding of neural central networks in IBD may facilitate the development of complementary strategies in the treatment of "extraintestinal" comorbid conditions such as depression or anxiety.

Introduction Stress-related transient inhibition of memory formation in the hippocampus has been hypothesized as one of the underlying pathomechanisms of transient global amnesia (TGA). TGA episodes, during which patients cannot encode and recall new information (anterograde amnesia affecting episodic long-term memory), are frequently preceded by a psychologically or physically stressful event. Methods We measured salivary cortisol during acute TGA in 14 patients, as well as cortisol day-profiles and the effect of experimental exposure to stress (using the socially evaluated cold pressor test) on cortisol levels during the subacute phase. We assessed psychiatric comorbidity as well as depression, trait anxiety and chronic stress. These findings were compared with data of 20 healthy controls. Findings Nine patients reported a precipitating stressor and all 14 developed typical hippocampal lesions on follow-up MRI. During TGA, salivary cortisol levels were more than 3-fold higher compared to time-matched day levels. While there was no difference in mean cortisol levels of the diurnal rhythm, we found a significant interaction between groups during experimental stress exposure (p = 0.049) with the TGA group revealing a higher cortisol increase. The TGA group reported higher levels of depressive symptomatology (CES-D) and higher scores of chronic stress (TICS) compared with the control group and there was a significant correlation between cortisol increase during TGA and the results of self-rating according to the CES-D (r = 0.615; p = 0.004), as well as to the STAI (r = 0.702; p = 0.001). Conclusion Our findings of enhanced secretion of cortisol in acute TGA patients correlating with symptoms of depression and anxiety and a persisting hyperreactivity to experimental stress in the subacute phase support the hypothesis that stress might be significant for the pathogenesis of TGA.

Background: Acute stroke syndromes with negative diffusion-weighted imaging (DWI) but extensive perfusion deficits are rare and constitute a diagnostic challenge due to different operational definitions of penumbral hypoperfusion in acute stroke patients based on MRI criteria. Methods: MR profiles of 19 patients presenting with acute stroke syndromes with negative DWI in the presence of an extensive area of hypoperfusion on time-to-peak (TTP) maps of dynamic susceptibility contrast perfusion-weighted imaging (PWI) were analysed. DWI and PWI lesions were quantified and interpreted with regard to the clinical course. Results: Despite the large area of abnormal perfusion on TTP maps, the clinical course was benign (median National Institute of Health Stroke Scale 2 at admission, 0 at discharge). The volume of hypoperfused tissue was significantly smaller on postprocessed TTP maps with a TTP delay of >4 s than on unprocessed TTP maps with manual contrast adjustment. Semiquantitatively assessed TTP lesion volume was associated with the presence of DWI lesions on follow-up. Conclusion: TTP maps are highly sensitive to demonstrate even small-scale perfusion abnormalities. The additional information from TTP delay thresholds indicates critically reduced perfusion and appears to be a good prognostic indicator in combination with MR angiography and symptomatology.

Background and Purpose— There are few in vivo data on the pathophysiology of reperfusion during systemic thrombolysis. We monitored the time course of cerebral perfusion changes in patients during thrombolysis with repeated arterial spin labeling perfusion magnetic resonance imaging. Methods— Ten patients with proximal arterial occlusion within 4.5 hours after symptom onset were prospectively enrolled. All patients received intravenous thrombolysis during the magnetic resonance imaging examination. Repeated arterial spin labeling perfusion images were acquired during the 60-minute therapy and at follow-up after 24 to 72 hours. Clinical data, magnetic resonance imaging features, and cerebral perfusion changes were analyzed. Results— Before thrombolysis, arterial spin labeling hypoperfusion and fluid-attenuation inversion recovery vascular hyperintensity in the territory of the occluded arteries were observed in all patients. In 5 patients, extensive arterial transit artifacts (ATA) developed in the hypoperfused area. The ATA corresponded with fluid-attenuation inversion recovery vascular hyperintensities. All 5 patients who developed extensive ATA in the hypoperfused area had complete reperfusion after thrombolysis, whereas the 5 without extensive ATA showed no or only partial reperfusion ( P Conclusions— The development of ATA during thrombolysis is associated with early reperfusion after thrombolysis. arterial spin labeling assessment during intravenous thrombolysis has the potential to guide subsequent therapeutic strategies in patients with acute stroke.

Background: Average serum matrix metalloproteinase (MMP) concentrations in patients with acute stroke have shown to be varying across studies. Possibly, next to true effects, other factors may influence MMP levels. The aim of this study was to investigate the dynamics of these enzymes in repeated measurements in the acute post-stroke period, in respect to different stroke etiologies, and highlight potential sources for variability. Methods: Serum in 233 patients with acute ischemic or hemorrhagic stroke (stroke cohort; SC) was ascertained within 24 h after onset and then 1, 3 and 7 days thereafter. One hundred five controls (control cohort; Co) were recruited. Multi-variable adjustment was carried out using salient extraneous covariates including stroke etiology, clinical severity and lesion size next to a set of routine laboratory parameters. Results: Unadjusted SC MMP-2 concentrations are significantly lower (SC 165.4, 95% CI 158.5-172.4; Co 203.7 ng/ml, 95% CI 190.7-216.5; p < 0.001) and MMP-9 concentrations significantly higher than in controls (SC 608.5 ng/ml, 95% CI 555.3-661.8; Co 475.6 ng/ml, 95% CI 413.6-537.6; p < 0.001). Adjustment mitigates associations between MMP concentrations and stroke etiology, clinical severity, lesion size or differences in temporal profile shown present without adjustment. Salient covariates absorb much of the effect: age, leukocyte count and albumin concentrations are associated significantly with MMP-2 concentrations; only leukocyte count is significantly associated with MMP-9. Conclusions: Concentrations of MMP-2 and MMP-9 in serum in humans measured after acute stroke are potentially influenced by extraneous covariates rather than being directly associated with characteristics of the underlying stroke.

Background Changes in cerebral perfusion during migraine with aura (MA) have been assessed mainly using dynamic susceptibility contrast (DSC) magnetic resonance perfusion imaging. A contrast agent-free method to assess these changes would be desirable. We assessed changes in cerebral perfusion during MA using arterial spin labeling (ASL) perfusion magnetic resonance imaging. Methods We investigated 4 patients with a standardized protocol including ASL perfusion imaging during MA (n = 2) or early headache phase (n = 2) and asymptomatic follow-up. Semiquantitative evaluation was done using a region of interest (ROI) within hypoperfused or hyperperfused areas and corresponding ROIs in the contralateral hemisphere. Relative ratios of mean perfusion in the corresponding ROIs were calculated. DSC imaging was done at initial time points and compared visually with ASL findings. Results In all patients, regional perfusion changes were detected in the acute phase. These abnormalities did not respect the boundaries of major cerebral vascular territories but overlapped onto adjoining regions. During MA, adjacent hypoperfused and hyperperfused areas were found, whereas during headache, regional hyperperfusion only was observed. Perfusion abnormalities normalized on follow-up. Conclusions ASL perfusion imaging is a contrast agent-free method suitable for assessment of reversible perfusion changes during or immediately after MA.

Transient global amnesia (TGA) is a neurological disorder characterized by an acute onset of severe anterograde amnesia. While retrograde amnesia may be present-although to a lesser extent-patients have no further cognitive disturbances or neurological signs. These symptoms resolve fully within several hours leaving a permanent memory gap for the duration of the episode and do not lead to long-term neurological deficits. In addition to well-defined clinical diagnostic criteria, in up to 80 % of patients, small, point-shaped lesions in the hippocampus are detected 24-48 h after symptom onset on diffusion-weighted magnetic resonance images. Despite several etiological hypotheses, to date, there is no scientific proof for the etiology of TGA or the small hippocampal lesions. Interestingly, in a large number of cases, an emotionally or physically straining event precipitates the onset of TGA, suggesting a stress-related mechanism. We report two cases of TGA occurring in legally relevant settings: affecting the victim of brutal burglary and the key witness in a murder trial. In the context of forensic medicine, the knowledge of this disorder and recognition of its typical features are essential.

In multiple sclerosis (MS) occasionally acute lesions show a reduced apparent diffusion coefficient (ADC) on magnetic resonance imaging (MRI); however, the underlying mechanism of this phenomenon is not known. We compared cerebrospinal fluid (CSF) findings with diffusion MRI signal characteristics of acute lesions in 25 patients with MS or a clinically isolated syndrome (CIS) later confirmed as MS. In nine of 25 patients investigated between days 1 and 4 after symptom onset, a reduced intralesional ADC value (–15% to −51%) was accompanied by a marked CSF pleocytosis (11–46 leukocytes/µl). Our results suggest that ADC reduction in acute MS lesions is a phenomenon that is possibly related to an aggressive inflammatory milieu as indirectly indicated by CSF pleocytosis. Furthermore, the ADC reduction and CSF pleocytosis were observed only early after symptom onset, which suggests that both are typically early and transient phenomena.

BACKGROUND AND PURPOSE Arterial spin labeling (ASL) MRI provides information on tissue perfusion by consecutive readout of labeled blood captured in arteries or the microvasculature without using contrast agents. METHODS We used a single-shot 3D acquisition and readout technique for ASL with multiple inflow times (TI) to evaluate hemodynamic compromise and dynamics of arterial blood inflow expressed by the bolus arrival time (BAT). Thirty-six patients with ischemic stroke were examined with a standard multimodal MRI protocol including dynamic susceptibility contrast (DSC) and multi-TI ASL perfusion imaging. Time-to-peak maps were used to classify hemodynamic impairment as either hypo- or hyperperfusion. RESULTS Overall there was a good agreement of ASL perfusion maps with DSC perfusion imaging on visual analysis. Correlations were found between ASL-BAT/(DSC-)Mean transit time (MTT) (r = .416; P < .01) and ASL-CBF/MTT (r = –.489; P < .01). Using ASL, BAT in ischemic territory was delayed by 55% (P = .001) in patients with hypoperfusion (n = 28); CBF was reduced by 39% (P

BACKGROUND AND PURPOSE To describe a patient with relapsing remitting MS who was treated with natalizumab for 36 months. First symptoms of presumptive progressive multifocal leukoencephalopathy (PML) appeared 14 weeks after her last natalizumab infusion. METHODS Neurological examination, MRI and CSF analysis were performed. RESULTS The lack of anti-inflammatory treatment response, clinical course, and serial MRI examinations showed lesion development typical for PML on diffusion-weighted and FLAIR MRI. CSF analysis for JC virus was tested negative twice. CONCLUSIONS This case represents a presumptive PML after discontinuation of natalizumab treatment—similar to the definition established for PML in HIV patients.

Background: Early recanalization and increase in collateral blood supply are powerful predictors of favourable outcome in acute ischaemic stroke. The factors contributing to the heterogeneous response to intravenous thrombolysis therapy in individual patients, however, are not fully understood. The on-going single-centre ‘MR perfusion imaging during thrombolysis' study uses repetitive arterial spin labelling (ASL) measurements to characterize the haemodynamic processes in acute stroke during therapy. The first milestone was to develop an appropriate infrastructure for thrombolysis in the magnetic resonance imaging (MRI) scanner without time delay and ensuring optimal patient safety and care. Methods: Between February and December 2011, 16 patients with acute neurological symptoms suggestive of hemispheric stroke within 4.5 h after symptom onset were included. In addition to clinical data, we documented the time from onset to arrival at the hospital, start and duration of MRI examination, start of thrombolytic therapy, and complications. The decision to thrombolyse was made after a routine stroke MRI protocol. During the 60-min systemic thrombolysis, repetitive ASL perfusion imaging was acquired, providing non-invasive information on cerebral perfusion. Continuous ECG monitoring, pulse oximetry, blood pressure measurements every 5 min, and short neurological assessments every 15 min were performed in every patient. Results: The median initial NIHSS score of the patients presenting with a mean of 84 min after onset was 4 (range 2-18). MRI examination was initiated within a mean of 45 min after arrival at the hospital. Five patients identified as stroke mimics were not treated with recombinant tissue plasminogen activator (rt-PA), and in 1 case with basilar artery occlusion bridging therapy was performed outside the scanner. In the remaining 10 patients, rt-PA therapy was started in the scanner directly after decision making on the basis of clinical information and baseline MRI. The mean door-to-needle time was 60 min (range 44-115) including approximately 10 min needed for acquiring informed consent. While 4 patients required antihypertensive treatment, no relevant complications were encountered. Conclusions: Fast and safe medical care in patients during systemic thrombolysis in the MRI scanner is feasible. Despite the process of obtaining informed consent, with a dedicated and experienced stroke team the door-to-needle time can be kept in a range recommended by current guidelines. Continuous real-time information about the dynamics of cerebral perfusion from ASL perfusion in acute stroke patients undergoing thrombolysis may provide additional information for the understanding of the events following acute arterial obstruction and its course.

Transient global amnesia (TGA) is a disorder with reversible anterograde disturbance of explicit memory, frequently preceded by an emotionally or physically stressful event. By using magnetic resonance imaging (MRI) following an episode of TGA, small hippocampal lesions have been observed. Hence it has been postulated that the disorder is caused by the stress-related transient inhibition of memory formation in the hippocampus. In experimental studies, stress has been shown to affect both explicit and implicit learning – the latter defined as learning and memory processes that lack conscious awareness of the information acquired. To test the hypothesis that impairment of implicit learning in TGA is present and related to stress, we determined the effect of experimental exposure to stress on hippocampal activation patterns during an implicit learning paradigm in patients who suffered a recent TGA and healthy matched control subjects. We used a hippocampus-dependent aversive learning procedure (context conditioning with the phases habituation, acquisition, and extinction) during functional MRI following experimental stress exposure (socially evaluated cold pressor test). After a control procedure, controls showed successful learning during the acquisition phase, indicated by increased valence, arousal and contingency ratings to the paired (CON+) versus the non-paired (CON-) conditioned stimulus, and successful extinction of the conditioned responses. Following stress, acquisition was still successful, however extinction was impaired with persistently increased contingency ratings. In contrast, TGA patients showed impairment of conditioned responses and insufficient extinction after the control procedure, indicated by a lack of significant differences between CON+ and CON- for valence and arousal ratings after the acquisition phase and by significantly increased contingency ratings after the extinction. After stress, aversive learning was not successful with non-significant ratings of all parameters. Concerning brain activation patterns after the control procedure, controls showed increased hippocampal response during acquisition after the control procedure. This was not seen after stress exposure. In TGA patients, we observed an increased response in the right ventral striatum in the acquisition phase following stress. These findings suggest that alterations in implicit learning processes, including impaired hippocampal and increased striatal responses, might play a role in TGA pathophysiology, partly related to acute stress.

A 22-year-old woman was diagnosed with CSF antibody-confirmed NMDA receptor encephalitis after repeated generalized seizures. Initial MRI and EEG were unremarkable (figure). She developed acoustic hallucinations and nonconvulsive status epilepticus (NCSE). MRI at this time showed hyperperfusion on arterial spin labeling maps and reduced apparent diffusion coefficient accompanied by reduced visibility of cortical veins on susceptibility-weighted MRI. The striking correlation between EEG and MRI findings suggests focal metabolic exhaustion (low apparent diffusion coefficient) and increased demand (hyperperfusion) caused by NCSE and reduced paramagnetic effect due to increased levels of oxygenated hemoglobin resulting in reduced venous signal.1,2 All findings normalized under treatment.

Acute ischemic lesions of the posterior optic nerve and optic tract can produce a variety of visual field defects. A 71-year-old woman presented with acute hemianopia, which led to rt-PA thrombolysis for suspected posterior cerebral artery ischemia. 3-Tesla cMRI, however, revealed the cause to be an acute posterior ischemic optic neuropathy. Cases like this may be more common than thought and quite regularly overlooked in clinical practice, especially when there is no high-resolution MRI available. This case strengthens the importance of repeat MR imaging in patients with persistent visual field defects.

Die systemische Thrombolyse ist derzeit die einzige nachgewiesen effektive und zugelassene Akutbehandlung des Schlaganfalls in einem Zeitfenster bis 4,5 Stunden nach Symptombeginn. Zunehmend wird die Kernspintomografie zur Therapieentscheidung beim akuten Schlaganfall, vor allem bei einem Zeitfenster > 4,5 Stunden und somit auserhalb der Zulassungskriterien fur die Thrombolyse eingesetzt, wobei der Nachweis eines therapeutischen Effekts in groseren Studien noch aussteht. Die erste randomisierte kontrollierte Studie, die eine intravenose Thrombolyse mit einer kombinierten intravenosen und intraarteriellen Therapie („Bridging-Konzept“) verglich, wurde kurzlich vorzeitig abgebrochen, weil man keinen statistisch signifikanten Unterschied zwischen beiden Behandlungsarmen erwartete. Beim akuten symptomatischen Verschluss der A. basilaris ermutigen Ergebnisse einer multizentrischen Datenbankanalyse dazu, zunachst stets eine intravenose Therapie durchzufuhren und in Einzelfallen eine interventionelle Anschlussbehandlung zu ermoglichen. Neuere Erkenntnisse deuten darauf hin, dass der Nutzen einer systemischen Thrombolysetherapie nicht nur in der alleinigen Rekanalisation einer verschlossenen groseren Hirnarterie besteht, sondern auch in der Verbesserung des Kollateralflusses und der arteriolaren Mikrozirkulation in der Penumbra liegt.

To perform functional magnetic resonance imaging (fMRI) studies with olfactory stimulation, the stimulation device requires special properties including those of being non-conductive and non-magnetic. It should also be easily portable and should be small enough to be stored easily when not in use. However, presently only a limited number of devices fulfill these criteria; additionally, they are typically associated with high costs. The aim of the study was to investigate whether a newly developed and relatively simple and inexpensive stimulation device would be suitable for fMRI measurements. Our stimulation device was made of standard industrial and laboratory components, has open-source software and consists of 3 core compartments namely: ‘the air inlet, control and distribution section’, ‘the odorant-section’, and ‘the delivery-section’. The device was tested in an fMRI study using 21 healthy normosmic subjects who were stimulated with two odors, d -limonene and terpinen-4-ol. Results from this trial suggest that the stimulation device is capable of creating adequate stimulation suitable for fMRI sequences. In general we describe how all sections of the olfactometer are optimized for the needs of fMRI studies.

BACKGROUND AND PURPOSE: MRI studies have focused on newly developing MS lesions to characterize the early pathology of the disease. DWI is highly sensitive to acute and chronic tissue changes in MS. We characterized the development of acute MS lesions by using DWI in a multiparametric MRI protocol. MATERIALS AND METHODS: Seventy-two consecutive patients presenting with a new symptom with definite MS or a CIS suggestive of central nervous system demyelination were screened with MRI. Patients who showed an acute MRI lesion with a reduction of ADC were studied with serial MRI for up to 4 months after presentation. RESULTS: Ten of 72 screened patients who showed a lesion with a reduced ADC were each examined 4–7 times, resulting in 52 examinations in total. We identified a characteristic sequence of signal-intensity changes: 1) days 0–7: slight T2 hyperintensity and prominent ADC reduction (maximum, −66%), faint or no enhancement on postcontrast T1-weighted images; 2) days 7–10: prominent T2 hyperintensity and contrast enhancement, ADC normalization/pseudonormalization; 3) up to 4 weeks: elevated ADC values, prominent enhancement on postcontrast images; 4) after 4 weeks: partial reversibility of T2 hyperintensity, ADC elevation, and resolution of contrast enhancement. CONCLUSIONS: In a subgroup of patients with MS presenting soon after new symptom onset, a transient reduction of the ADC delineated a short and very early phase of MS lesion evolution. Subsequent pseudonormalization of the ADC occurred along with signs of the development of vasogenic edema.

Since decision-making for thrombolysis in acute stroke settings is restricted to a limited time window and based on clinical assessment and CT findings only, thrombolysis is sometimes applied to patients with a final diagnosis other than a stroke. From a prospectively collected stroke/MRI data bank (2004–2010) with 648 suspected ischemic stroke patients treated with rtPA, we identified patients without evidence of acute infarction on follow-up MRI and a final diagnosis other than a stroke or acute cerebrovascular event. We compared demographics, symptoms, complications, and outcome of patients with stroke mimics (SM) to those with acute infarction. In 42 patients, an SM was diagnosed: seizures in 20, conversion disorder in seven, dementia in six, migraine in three, brain tumor in two, and others in four patients. Patients with SM less often had typical stroke symptoms like dysarthria (p

Fibromuscular dysplasia, predominantly found in adult women, is a rare disease of small and middle-sized arteries of the kidney and brain. We present a case of a 12-year-old girl with acute ischemic stroke, due to fibromuscular dysplasia of the distal internal carotid artery and the proximal middle cerebral artery, which was successfully treated with t-PA.

Age-related white matter changes (ARWMC) appear to correspond to a continuum from normal functioning to clinically overt neurological syndromes. Disturbance of the structural integrity of cerebral fibre tracts-the so-called cerebral network-by ARWMC might be one explanation for this development. From 3 T magnetic resonance imaging (MRI) data of 34 healthy elderly subjects (60-82 years) we calculated the lesion volume of ARWMC and the area of the corpus callosum (CC). Gait, balance and cognition were assessed. We compared these findings in those with mild (n = 22) and advanced (n = 12) ARWMC and performed tract-based spatial statistics (TBSS) to analyze white matter structural integrity. In subjects with advanced ARWMC, TBSS showed a significant decrease of fractional anisotropy (FA) in several large tracts of the white matter including the CC; total CC, CC2 and CC5 areas were significantly smaller. Despite these morphological changes, tests of gait, balance and cognition as measured by the Mini-Mental State Examination (MMSE) were in the normal range for both groups; only the Montreal Cognitive Assessment (MoCA) detected executive and language dysfunction in those with advanced ARWMC. Loss of tissue integrity and atrophy of the CC secondary to spatially remote lesions in the peri- and paraventricular white matter in ARWMC appear to be already detectable in healthy elderly individuals.

For some time, posterior circulation stroke has been neglected in diagnostic and therapeutic studies for various reasons, such as minor incidence compared to anterior circulation stroke or anatomical and vascular characteristics. This changed at least partly when the New England Medical Center (NEMC) Posterior Circulation Registry was initiated, and now the number of publications concerning posterior circulation stroke is continuously increasing. Whether the differences outweigh the similarities between posterior and anterior circulation stroke remains open to debate, but both are the subject of intensive investigations. In this article, we review the most recent literature on different MRI techniques, such as diffusion-weighted and diffusion tensor imaging (DWI and DTI), perfusion-weighted imaging (PWI), vascular imaging, and susceptibility weighted imaging (SWI), in posterior circulation stroke and discuss their diagnostic and prognostic impact as well as general implications for acute treatment.

Background: Patients with posterior circulation stroke (PCS) were underrepresented in or even excluded from the large clinical trials investigating acute therapy with thrombolysis. Therefore, the knowledge about potential benefits and risks of thrombolysis in PCS is sparse. Methods: From July 2004 until June 2007, 237 stroke patients were treated with thrombolysis within 3 h after onset of symptoms in our stroke unit. Baseline characteristics, etiology, CT/MRI stroke patterns, clinical outcome, and complications of patients with PCS were compared to those with anterior circulation stroke (ACS). Results: There were 30 patients in the PCS group; 198 had ACS. In the PCS group, less patients had a history of prior stroke (0/30 vs. 31/198 (15.7%), p = 0.02) and less were treated with platelet inhibitors (6/30 (20.0%) vs. 83/198 (41.9%), p = 0.02). Onset to treatment time was higher in the PCS group (156.2 ± 23.2 vs. 141.1 ± 30.7, p = 0.01). Small vessel disease occurred more often in PCS patients (10/30 (33.3%) vs. 12/198 (6.1%), p < 0.001), whereas stroke of undetermined cause was less frequent (5/30 (16.7%) vs. 75/198 (37.9%), p = 0.02). Correspondingly, PCS patients had more lacunar (13/30 (43.3%) vs. 15/198 (7.3%), p < 0.001) strokes on CT/MRI. Patients with PCS had significantly lower median NIHSS scores after 2 and 24 h, whereas the median NIHSS and mRS scores at discharge as well as the mRS score at the 3-month follow-up, although still lower, did not differ significantly between both groups. Outcome was similar with regard to complications and mortality. Conclusions: Patients with PCS have a higher rate of small vessel disease and lacunar stroke. In terms of potential benefits and risks of thrombolysis, we could demonstrate no significant differences between PCS and ACS. Acute PCS patients should be diagnosed and treated with the same elaborateness as ACS patients.

Background and Purpose— The safety and efficacy of thrombolysis in cervical artery dissection (CAD) are controversial. The aim of this meta-analysis was to pool all individual patient data and provide a valid estimate of safety and outcome of thrombolysis in CAD. Methods— We performed a systematic literature search on intravenous and intra-arterial thrombolysis in CAD. We calculated the rates of pooled symptomatic intracranial hemorrhage and mortality and indirectly compared them with matched controls from the Safe Implementation of Thrombolysis in Stroke–International Stroke Thrombolysis Register. We applied multivariate regression models to identify predictors of excellent (modified Rankin Scale=0 to 1) and favorable (modified Rankin Scale=0 to 2) outcome. Results— We obtained individual patient data of 180 patients from 14 retrospective series and 22 case reports. Patients were predominantly female (68%), with a mean±SD age of 46±11 years. Most patients presented with severe stroke (median National Institutes of Health Stroke Scale score=16). Treatment was intravenous thrombolysis in 67% and intra-arterial thrombolysis in 33%. Median follow-up was 3 months. The pooled symptomatic intracranial hemorrhage rate was 3.1% (95% CI, 1.3 to 7.2). Overall mortality was 8.1% (95% CI, 4.9 to 13.2), and 41.0% (95% CI, 31.4 to 51.4) had an excellent outcome. Stroke severity was a strong predictor of outcome. Overlapping confidence intervals of end points indicated no relevant differences with matched controls from the Safe Implementation of Thrombolysis in Stroke–International Stroke Thrombolysis Register. Conclusions— Safety and outcome of thrombolysis in patients with CAD-related stroke appear similar to those for stroke from all causes. Based on our findings, thrombolysis should not be withheld in patients with CAD.

Transient global amnesia (TGA) is characterized by the abrupt onset of severe amnesia without concomitant focal neurological symptoms. Recent studies revealed that small and punctate MR-signal diffusion-weighted imaging (DWI) lesions can be found within the hippocampus of TGA patients during the post-acute phase. On the basis of dual-process models of recognition memory, the present study examined the hypothesis that hippocampal dysfunction as suggested by these DWI lesions disrupts hippocampus-mediated recollection in patients with TGA, whereas familiarity-based recognition memory that is assumed to be supported by extra-hippocampal brain regions should be unaffected. We administered a recognition memory task for faces and words to eleven TGA patients during the post-acute phase and to eleven matched controls. Receiver operating characteristics (ROCs) were obtained in order to derive estimates of familiarity and recollection by applying a formal dual-process model of recognition memory. Analyses of ROC curves revealed a disruption of recollection in TGA patients' memory for words [t(20)=2.70, p.05], but no difference in familiarity-based recognition memory between patients and controls [t(20)=-1.10, p=.284]. Post hoc analyses indicated that the deficit in recollection is more pronounced in TGA patients who show visible hippocampal lesions on diffusion-weighted MR imaging compared to those without detectable hippocampal lesions. In conclusion, consistent with recent neuroanatomical dual-process models of recognition memory, hippocampal dysfunction in patients with TGA is associated with a selective effect on specific recognition memory subprocesses.

Stem cell therapy seems promising in reducing deficits after focal cerebral ischemia. As stroke may result from intracerebral hemorrhage (ICH) in up to 20% we investigated whether human processed lipoaspirate mesenchymal stem cells (PLA-MSC) influence the functional outcome, migration behavior and the activation of endogenous progenitor cells. Experimental ICH was induced by stereotactic administration of collagenase in rats randomly assigned to the control or treatment group. The latter received 3 x 10(6) PLA-MSC by intravenous (i.v.) injection 24h after ICH induction. The outcome was continuously monitored using the RotaRod test over a period of 4 weeks. Morphometric analysis of ICH was performed consecutively by magnetic resonance imaging (MRI) studies and immunohistochemical analysis. The RotaRod test revealed a significant 1.5-fold improvement (p

Combined 2-MHz ultrasound (US) and second-generation, sulfur hexafluoride microbubbles (MB) treatment (US+MB) was performed in a permanent middle cerebral artery (MCA) occlusion model in rats to evaluate possible effects on the ischemic cascade. We used 16 Wistar rats and the MCA occlusion model for stroke induction. Glutamate, pyruvate, lactate and glycerol levels were measured by intracerebral microdialysis before and after stroke induction and after US+MB application (n = 8) for 20 h. After 24 h, brain infarct volume, apoptosis and IL-6 and TNF-alpha levels were evaluated. The infarct volume was significantly reduced (p < 0.05) in the US+MB-treated group compared with control animals. In additional, glutamate levels were significantly lower in US+MB-treated animals, and these animals showed a higher rate of apoptotic cell death in the infarcted area. The levels of IL-6 and TNF-alpha concentrations were not different in both groups, and there was no apoptotic cell death outside the infarction in animals treated with US+MB. The results demonstrate that US+MB with second generation microbubbles does not have a harmful effect on ischemic stroke in an MCA occlusion model of the rat.

Background and Purpose— To evaluate the potential of a new dynamic MRA sequence (DynAngio) based on arterial spin labeling for the assessment of intracranial collateral flow. Methods— Twelve patients with unilateral internal carotid artery obstruction were investigated. Different patterns of collateral flow were compared between DynAngio, transcranial color-coded duplex ultrasound, and time-of-flight MRA. Results— There was a good agreement between the methods, with sensitivities between 80% and 90%. Small collateral vessels were detected more frequently with DynAngio compared to time-of-flight MRA. Conclusion— DynAngio provides anatomic and similar to transcranial color-coded duplex ultrasound functional information on collateral flow for the assessment of intracranial hemodynamics.

Summary Background Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH. Methods We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915. Findings Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7–197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism). Interpretation In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA. Funding Octapharma.