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Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4 +, CD8 +, CD19 + and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8 + cells (85% of mutations). In follow-up after a median time of 2.3 years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKEF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPM and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies. (C) 2016 The Authors. Published by Elsevier Inc.

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).

Background Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale. Methods INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH ( Results were presented as overall cumulative odds ratios (ORs) and 95% CI. Results Low ambient temperature ( Conclusions Exposure to low ambient temperature within several hours increases the risk of ICH.

Background-Few studies have discussed the emergency call and prehospital care as a continuous process to decrease the prehospital and in-hospital delays for acute stroke. To identify features associated with early hospital arrival ( Methods and Results-This was a 2-year prospective observational study. All stroke patients who were transported to the hospital by emergency medical services and received recanalization therapy were recruited for the study. For a sample of 308 patients, the stroke code was activated in 206 (67%) and high priority was used in 258 (84%) of the emergency calls. Emergency medical services transported 285 (93%) of the patients using the stroke code and 269 (87%) using high priority. In the univariate analysis, the most dominant predictors of early hospital arrival were transport using stroke code (P= 0.001) and high priority (P= 0.002) and onset-to-call (P<0.0001) and on-scene times (P= 0.052). In the regression analysis, the influences of high-priority transport (P<0.01) and onset-to-call time (P<0.001) prevailed as significant in both dichotomies of early arrival and treatment. The on-scene time was found to be surprisingly long (> 23.5 minutes) for both early and late-arriving patients. Conclusions-Fast emergency medical services activation and ambulance transport promoted early hospital arrival and treatment. Although patient-dependent delays still dominate the prehospital process, it should be ensured that the minutes on the scene are well spent.

Background: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. Summary: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. Key Message: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions. (C) 2016 S. Karger AG, Basel

Cerebral venous thrombosis (CVT) affects mainly working-aged individuals. Functional recovery after CVT is generally considered good with about 3/4 of patients achieving short-term independence. However, vascular events, long-term functional outcome, and employment after CVT remain poorly investigated. We identified consecutive adult CVT patients treated at the Helsinki University Hospital (1987-2013) and invited them to a follow-up visit. Each clinical examination was combined with interview. We also recorded recurrent venous thromboembolism (VTE) and hemorrhagic events during follow-up and antithrombotic medication use. A modified Rankin Scale (mRS) served to assess functional outcome. Logistic regression served to identify independent factors associated with unemployment and functional recovery. Of the 195 patients identified, 21 died, 9 declined to participate, and 4 were excluded from the study. Thus, 161 patients (106 women) underwent an examination after a median of 39 months (interquartile range 14-95). VTE (one of which was CVT) occurred in 9 (6 %) patients, and severe hemorrhagic events in 10 (6 %). Functional outcome was good, with 84 % scoring 0-1 on the mRS; 42 % reported residual symptoms. Altogether, 91 (57 %) patients were employed. After adjusting for age and sex, a National Institutes of Health Stroke Scale score > 2 at admission and low education level, associated with both unfavorable functional outcome and unemployment. Long-term functional outcome after CVT may appear good if measured with mRS, but patients often have residual symptoms and are frequently unable to return to their previous work.

Introduction: We studied associations of the stress hormones copeptin and cortisol with outcome and organ dysfunction after out-of-hospital cardiac arrest (OHCA). Methods: Plasma was obtained after consent from next of kin in the FINNRESUSCI study conducted in 21 Finnish intensive care units (ICUs) between 2010 and 2011. We measured plasma copeptin (pmol/L) and free cortisol (nmol/L) on ICU admission (245 patients) and at 48 hours (additional 33 patients). Organ dysfunction was categorised with 24-hour Sequential Organ Failure Assessment (SOFA) scores. Twelve-month neurological outcome (available in 276 patients) was classified with cerebral performance categories (CPC) and dichotomised into good (CPC 1 or 2) or poor (CPC 3 to 5). Data are presented as medians and interquartile ranges (IQRs). A Mann-Whitney U test, multiple linear and logistic regression tests with odds ratios (ORs) 95% confidence intervals (CIs) and beta (B) values, repeated measure analysis of variance, and receiver operating characteristic curves with area under the curve (AUC) were performed. Results: Patients with a poor 12-month outcome had higher levels of admission copeptin (89, IQR 41 to 193 versus 51, IQR 29 to 111 pmol/L, P = 0.0014) and cortisol (728, IQR 522 to 1,017 versus 576, IQR 355 to 850 nmol/L, P = 0.0013). Copeptin levels fell between admission and 48 hours (P Conclusions: Admission copeptin and free cortisol were not of prognostic value regarding 12-month neurological outcome after OHCA. Higher admission copeptin and cortisol were associated with ICU death, and copeptin predicted subsequent organ dysfunction.

Background: Integration of afferent somatosensory input with motor-cortex output is essential for accurate movements. Prior studies have shown that tactile input modulates motor-cortex excitability, which is reflected in the reactivity of the similar to 20-Hz motor-cortex rhythm. similar to 20-Hz rebound is connected to inhibition or deactivation of motor cortex whereas suppression has been associated with increased motor cortex activity. Although tactile sense carries important information for controlling voluntary actions, proprioception likely provides the most essential feedback for motor control. Methods: To clarify how passive movement modulates motor-cortex excitability, we studied with magnetoencephalography (MEG) the amplitudes and peak latencies of suppression and rebound of the similar to 20-Hz rhythm elicited by tactile stimulation and passive movement of right and left index fingers in 22 healthy volunteers. Results: Passive movement elicited a stronger and more robust similar to 20-Hz rebound than tactile stimulation. In contrast, the suppression amplitudes did not differ between the two stimulus types. Conclusion: Our findings suggest that suppression and rebound represent activity of two functionally distinct neuronal populations. The similar to 20-Hz rebound to passive movement could be a suitable tool to study the functional state of the motor cortex both in healthy subjects and in patients with motor disorders.

BackgroundCervical artery dissection (CeAD) patients with or without stroke are frequently treated with either antiplatelet agents or vitamin K antagonists (VKAs), but few data are reported on the use of nonvitamin K oral anticoagulants (NOACs). MethodsBetween November 2011 and January 2014, we recorded data from patients with a stroke due to vertebral (VAD) or internal carotid artery dissection (ICAD). Patients using oral anticoagulants were included in the study and were divided into two treatment groups: patients using NOACs and those using VKAs. Excellent outcome was defined on modified Rankin Scale (mRS) 1 at 6months. ResultsOf 68 stroke patients (67% male; median age 45 [39-53]), six (8.8%; two with VAD and four with ICAD) were treated with NOACs: three with direct thrombin inhibitor dabigatran and three with direct factor Xa inhibitor rivaroxaban. National Institutes of Health Stroke Scale score at baseline was 4 (3-7) in the NOAC versus 2 (1-7) in the VKA groups. Complete recanalization at 6months was seen in most patients in the NOAC (n=5; 83%) and VKA (n=34; 55%) groups. All the patients using NOACs had mRS 1 at 6months and none had an intracerebral hemorrhage (ICH). In the VKA group most patients (n=48; 77%) had mRS 1, one patient (1.7%) had an ICH and one died. ConclusionsIn this small, consecutive single-center patient sample treating ischemic stroke patients with CeAD with NOACs did not bring up safety concerns and resulted in similar, good outcomes compared to patients using VKAs.

Temporal and frontal activations have been implicated in learning of novel word forms, but their specific roles remain poorly understood. The present magnetoencephalography (MEG) study examines the roles of these areas in processing newly-established word form representations. The cortical effects related to acquiring new phonological word forms during incidental learning were localized. Participants listened to and repeated back new word form stimuli that adhered to native phonology (Finnish pseudowords) or were foreign (Korean words), with a subset of the stimuli recurring four times. Subsequently, a modified 1-back task and a recognition task addressed whether the activations modulated by learning were related to planning for overt articulation, while parametrically added noise probed reliance on developing memory representations during effortful perception. Learning resulted in decreased left superior temporal and increased bilateral frontal premotor activation for familiar compared to new items. The left temporal learning effect persisted in all tasks and was strongest when stimuli were embedded in intermediate noise. In the noisy conditions, native phonotactics evoked overall enhanced left temporal activation. In contrast, the frontal learning effects were present only in conditions requiring overt repetition and were more pronounced for the foreign language. The results indicate a functional dissociation between temporal and frontal activations in learning new phonological word forms: the left superior temporal responses reflect activation of newlyestablished word-form representations, also during degraded sensory input, whereas the frontal premotor effects are related to planning for articulation and are not preserved in noise.

Acquired amusia is a common disorder after damage to the middle cerebral artery (MCA) territory. However, its neurocognitive mechanisms, especially the relative contribution of perceptual and cognitive factors, are still unclear. We studied cognitive and auditory processing in the amusic brain by performing neuropsychological testing as well as magnetoencephalography (MEG) measurements of frequency and duration discrimination using magnetic mismatch negativity (MMNm) recordings. Fifty-three patients with a left (n = 24) or right (n = 29) hemisphere MCA stroke (MRI verified) were investigated 1 week, 3 months, and 6 months after the stroke. Amusia was evaluated using the Montreal Battery of Evaluation of Amusia (MBEA). We found that amusia caused by right hemisphere damage (RHD), especially to temporal and frontal areas, was more severe than amusia caused by left hemisphere damage (LHD). Furthermore, the severity of amusia was found to correlate with weaker frequency MMNm responses only in amusic RHD patients. Additionally, within the RHD subgroup, the amusic patients who had damage to the auditory cortex (AC) showed worse recovery on the MBEA as well as weaker MMNm responses throughout the 6-month follow-up than the non-amusic patients or the amusic patients without AC damage. Furthermore, the amusic patients both with and without AC damage performed worse than the non-amusic patients on tests of working memory, attention, and cognitive flexibility. These findings suggest domain-general cognitive deficits to be the primary mechanism underlying amusia without AC damage whereas amusia with AC damage is associated with both auditory and cognitive deficits.