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1. Serum neurofilament light levels in normal aging and their association with morphologic brain changes

Author: Michael Khalil, Lukas Pirpamer, Edith Hofer, Margarete M. Voortman, Christian Barro, David Leppert, Pascal Benkert, Stefan Ropele, Christian Enzinger, Franz Fazekas, Reinhold Schmidt, and Jens Kuhle
Subjects: Science
Abstract: Neurofilament (NfL) levels in CSF and blood have been established as a biomarker of neuronal damage in neurodegenerative diseases, and there is an age-dependent increase in NfL levels in CSF. Here the authors demonstrate that serum NfL levels increase in healthy aging people and predict and correlate with brain volume loss.
Published: 2020
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2. Incidence of Developmental Venous Anomalies in Patients With Multiple Sclerosis: A 3 Tesla MRI Study

Author: Marton Magyar, Thomas Gattringer, Christian Enzinger, Eva Hassler, Richard Partl, Michael Khalil, Gernot Reishofer, Hannes Deutschmann, and Franz Fazekas
Subjects: multiple sclerosis, developmental venous anomaly (DVA), central nervous system, magnetic resonance imaging, clinically isolated syndrome (CIS), Neurology. Diseases of the nervous system, RC346-429
Abstract: ObjectivesThere is evidence of involvement of the venous system in multiple sclerosis (MS). If this bears also an association with the frequency and extent of developmental venous anomalies (DVA) still has to be determined. We therefore investigated this in patients with different phenotypes of MS and in comparison, to a control population.MethodsWe analyzed the contrast-enhanced T1-weighted MR scans of 431 patients (clinically isolated syndrome—CIS, n = 108; MS, n = 323) and of 162 control individuals for the presence of a DVA. We also measured the size of the DVA and draining vein and compared the DVA frequency between MS phenotypes.ResultsA DVA was found in 38 (8.8 %) of patients with CIS or MS and in 11 (6.8%) controls (p = 0.4). DVA frequency was highest in CIS (14.8%) and lowest in progressive MS (4.0%). The mean cranio-caudal and axial extension of the DVA was significantly lower in MS patients than controls (p < 0.05).ConclusionsThe frequency of DVA in MS patients is comparable to that in controls. Whether DVA size and appearance may change over time will have to be investigated in a longitudinal manner and with larger sample size.
Published: 2022
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3. Factors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease

Author: Thomas Berger, Monika Adamczyk-Sowa, Tünde Csépány, Franz Fazekas, Tanja Hojs Fabjan, Dana Horáková, Alenka Horvat Ledinek, Zsolt Illes, Gisela Kobelt, Saša Šega Jazbec, Eleonóra Klímová, Fritz Leutmezer, Konrad Rejdak, Csilla Rozsa, Johann Sellner, Krzysztof Selmaj, Pavel Štouracˇ, Jarmila Szilasiová, Peter Turcˇáni, Marta Vachová, Manuela Vanecková, László Vécsei, and Eva Kubala Havrdová
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: At two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.
Published: 2020
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4. The influence of iron oxidation state on quantitative MRI parameters in post mortem human brain

Author: Christoph Birkl, Anna Maria Birkl-Toeglhofer, Christian Kames, Walter Goessler, Johannes Haybaeck, Franz Fazekas, Stefan Ropele, and Alexander Rauscher
Subjects: Brain iron, Iron oxidation state, Ferric iron, Ferrous iron, Quantitative MRI, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: A variety of Magnetic Resonance Imaging (MRI) techniques are known to be sensitive to brain iron content. In principle, iron sensitive MRI techniques are based on local magnetic field variations caused by iron particles in tissue. The purpose of this study was to investigate the sensitivity of MR relaxation and magnetization transfer parameters to changes in iron oxidation state compared to changes in iron concentration. Therefore, quantitative MRI parameters including R1, R2, R2∗, quantitative susceptibility maps (QSM) and magnetization transfer ratio (MTR) of post mortem human brain tissue were acquired prior and after chemical iron reduction to change the iron oxidation state and chemical iron extraction to decrease the total iron concentration. All assessed parameters were shown to be sensitive to changes in iron concentration whereas only R2, R2∗ and QSM were also sensitive to changes in iron oxidation state. Mass spectrometry confirmed that iron accumulated in the extraction solution but not in the reduction solution. R2∗ and QSM are often used as markers for iron content. Changes in these parameters do not necessarily reflect variations in iron content but may also be a result of changes in the iron’s oxygenation state from ferric towards more ferrous iron or vice versa.
Published: 2020
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5. Minor Structural Differences in the Cervical Spine Between Patients With Cervical Dystonia and Age-Matched Healthy Controls

Author: Petra Katschnig-Winter, Christian Enzinger, Dennis Bohlsen, Marton Magyar, Stephan Seiler, Edith Hofer, Sebastian Franthal, Nina Homayoon, Mariella Kögl, Karoline Wenzel, Hannes Deutschmann, Franz Fazekas, Reinhold Schmidt, and Petra Schwingenschuh
Subjects: cervical dystonia, cervical spine, MRI, structural, inter-rater reliability, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Cervical dystonia is the most common form of focal dystonia. The frequency and pattern of degenerative changes of the cervical spine in patients with cervical dystonia and their relation to clinical symptoms remain unclear as no direct comparison to healthy controls has been performed yet. Here, we used magnetic resonance imaging (MRI) to investigate (1) whether structural abnormalities of the cervical spine are more common in patients with cervical dystonia compared to age-matched healthy controls, (2) if there are clinical predictors for abnormalities on MRI, and (3) to calculate the inter-rater reliability of the respective radiological scales.Methods: Twenty-five consecutive patients with cervical dystonia and 20 age-matched healthy controls were included in the study. MRI scans of the cervical spine were analyzed separately by three experienced raters blinded to clinical information, applying different MRI rating scales. Structural abnormalities were compared between groups for upper, middle, and lower cervical spine segments. The associations between scores differentiating both groups and clinical parameters were assessed in dystonia patients. Additionally, inter-rater reliability of the MRI scales was calculated.Results: Comparing structural abnormalities, we found minor differences in the middle cervical spine, indicated by a higher MRI total score in patients but no significant correlation between clinical parameters and MRI changes. Inter-rater reliability was satisfying for most of the MRI rating scales.Conclusion: Our results do not provide evidence for a role of MRI of the cervical spine in the routine work-up of patients with cervical dystonia in the absence of specific clinical signs or symptoms.
Published: 2020
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6. Global Outcome Assessment Life-long after stroke in young adults initiative—the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis

Author: Vincent Thijs, Didier Leys, Takanari Kitazono, David Tanne, Nilufer Yesilot, João Pedro Marto, Miguel Viana-Baptista, Karoliina Aarnio, Antonio Arauz, Manuel Bolognese, Raf Brouns, Batnairamdal Chuluun, Enkhzaya Chuluunbaatar, Byambasuren Dagvajantsan, Stephanie Debette, Adi Don, Chris Enzinger, Esme Ekizoglu, Simon Fandler-Höfler, Franz Fazekas, Anette Fromm, Thomas Gattringer, Giosue Gulli, Michael Hoffmann, Christina Jern, Katarina Jood, Masahiro Kamouchi, Young Seo Kim, Janika Korv, Tsong-Hai Lee, Nicolas Martinez-Majander, Victoria Mifsud, Aleksandra Pikula, Jose Luis Ruiz-Sandoval, Bettina Sarnowski, KS Tan, T Tatlisumak, Riina Vibo, Ulrike Waje-Andreassen, Alessandro Pezzini, Jukka Putaala, Frank‐Erik de Leeuw, Anil M Tuladhar, Merel S Ekker, Mina A Jacob, Myrna ME van Dongen, Arunkar K Annamalai, Miguel A Barboza, Thiago F Hora, Steven J Kittner, Timothy J Kleinig, Catharina JM Klijn, Noortje AM Maaijwee, Man M Mehndiratta, Vinicius V Montanaro, Mayowa O Owolabi, Vinod B Patel, Matthew C Phillips, Floris HBM Schreuder, Rick H Swartz, Teddy Y Wu, and Bartlomiej Piechowski-Jozwiak
Subjects: Medicine
Abstract: Introduction Worldwide, 2 million patients aged 18–50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients.Methods and analysis The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18–50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.Ethics and dissemination Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.
Published: 2019
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7. Are morphologic features of recent small subcortical infarcts related to specific etiologic aspects?

Author: Sebastian Eppinger, Thomas Gattringer, Lena Nachbaur, Simon Fandler, Lukas Pirpamer, Stefan Ropele, Joanna Wardlaw, Christian Enzinger, and Franz Fazekas
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Recent small subcortical infarcts (RSSIs) mostly result from the occlusion of a single, small, brain artery due to intrinsic cerebral small-vessel disease (CSVD). Some RSSIs may be attributable to other causes such as cardiac embolism or large-artery disease, and their association with coexisting CSVD and vascular risk factors may vary with morphological magnetic resonance imaging (MRI) features. Methods: We retrospectively identified all inpatients with a single symptomatic MRI-confirmed RSSI between 2008 and 2013. RSSIs were rated for size, shape, location (i.e. anterior: basal ganglia and centrum semiovale posterior cerebral circulation: thalamus and pons) and MRI signs of concomitant CSVD. In a further step, clinical data, including detailed diagnostic workup and vascular risk factors, were analyzed with regard to RSSI features. Results: Among 335 RSSI patients (mean age 71.1 ± 12.1 years), 131 (39%) RSSIs were >15 mm in axial diameter and 66 (20%) were tubular shaped. Atrial fibrillation (AF) was present in 44 (13.1%) and an ipsilateral vessel stenosis > 50% in 30 (9%) patients. Arterial hypertension and CSVD MRI markers were more frequent in patients with anterior-circulation RSSIs, whereas diabetes was more prevalent in posterior-circulation RSSIs. Larger RSSIs occurred more frequently in the basal ganglia and pons, and the latter were associated with signs of large-artery atherosclerosis. Patients with concomitant AF had no specific MRI profile. Conclusion: Our findings suggest the contribution of different pathophysiological mechanisms to the occurrence of RSSIs in the anterior and posterior cerebral circulation. While there appears to be some general association of larger infarcts in the pons with large-artery disease, we found no pattern suggestive of AF in RSSIs.
Published: 2019
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8. Clinical Characteristics of Patients with Tick-Borne Encephalitis (TBE): A European Multicentre Study from 2010 to 2017

Author: Benno Kohlmaier, Nina A. Schweintzger, Manfred G. Sagmeister, Vendula Švendová, Daniela S. Kohlfürst, Astrid Sonnleitner, Manuel Leitner, Andrea Berghold, Erich Schmiedberger, Franz Fazekas, Alexander Pichler, Jana Rejc-Marko, Daniel Růžek, Lucie Dufková, Darina Čejková, Petr Husa, Martina Pýchová, Lenka Krbková, Václav Chmelík, Věra Štruncová, Dace Zavadska, Guntis Karelis, Aukse Mickiene, Joanna Zajkowska, Petra Bogovič, Franc Strle, Werner Zenz, and the EU-TICK-BO STUDY GROUP
Subjects: tick-borne encephalitis, vaccine-preventable disease, meningomyelitis, central paresis, peripheral paresis, Biology (General), QH301-705.5
Abstract: Tick-borne encephalitis (TBE) virus is a major cause of central nervous system infections in endemic countries. Here, we present clinical and laboratory characteristics of a large international cohort of patients with confirmed TBE using a uniform clinical protocol. Patients were recruited in eight centers from six European countries between 2010 and 2017. A detailed description of clinical signs and symptoms was recorded. The obtained information enabled a reliable classification in 553 of 555 patients: 207 (37.3%) had meningitis, 273 (49.2%) meningoencephalitis, 15 (2.7%) meningomyelitis, and 58 (10.5%) meningoencephalomyelitis; 41 (7.4%) patients had a peripheral paresis of extremities, 13 (2.3%) a central paresis of extremities, and 25 (4.5%) had single or multiple cranial nerve palsies. Five (0.9%) patients died during acute illness. Outcome at discharge was recorded in 298 patients. Of 176 (59.1%) patients with incomplete recovery, 80 (27%) displayed persisting symptoms or signs without recovery expectation. This study provides further evidence that TBE is a severe disease with a large proportion of patients with incomplete recovery. We suggest monitoring TBE in endemic European countries using a uniform protocol to record the full clinical spectrum of the disease.
Published: 2021
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9. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

Author: A. Dessa Sadovnick, Anthony L. Traboulsee, Cecily Q. Bernales, Jay P. Ross, Amanda L. Forwell, Irene M. Yee, Lena Guillot-Noel, Bertrand Fontaine, Isabelle Cournu-Rebeix, Antonio Alcina, Maria Fedetz, Guillermo Izquierdo, Fuencisla Matesanz, Kelly Hilven, Bénédicte Dubois, An Goris, Ianire Astobiza, Iraide Alloza, Alfredo Antigüedad, Koen Vandenbroeck, Denis A. Akkad, Orhan Aktas, Paul Blaschke, Mathias Buttmann, Andrew Chan, Joerg T. Epplen, Lisa-Ann Gerdes, Antje Kroner, Christian Kubisch, Tania Kümpfel, Peter Lohse, Peter Rieckmann, Uwe K. Zettl, Frauke Zipp, Lars Bertram, Christina M Lill, Oscar Fernandez, Patricia Urbaneja, Laura Leyva, Jose Carlos Alvarez-Cermeño, Rafael Arroyo, Aroa M. Garagorri, Angel García-Martínez, Luisa M. Villar, Elena Urcelay, Sunny Malhotra, Xavier Montalban, Manuel Comabella, Thomas Berger, Franz Fazekas, Markus Reindl, Mascha C. Schmied, Alexander Zimprich, and Carles Vilariño-Güell
Subjects: multiple sclerosis, genetics, linkage, association, plasminogen, Genetics, QH426-470
Abstract: Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
Published: 2016
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10. Ischemic Stroke 3 Months After Wrapping of an Incidental Aneurysm

Author: Birgit Poltrum, Markus Beitzke, Franz Fazekas, and Thomas Gattringer
Subjects: Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Published: 2023
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11. Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis

Author: Christina Hermetter, Franz Fazekas, and Sonja Hochmeister
Subjects: autoimmune encephalitis, antibodies, surface antigens, clinical relevance, treatment, Neurology. Diseases of the nervous system, RC346-429
Abstract: In recent years, new antibodies have been discovered which mediate autoimmune encephalitis. This immunological response can be triggered by an infection or a tumor. Classical onconeuronal antibodies are directed against intracellular neuronal agents but recently, a novel group of antibodies to neuronal cell-surface and synaptic antigens associated with different CNS-syndromes, has been discovered. Interestingly, the syndromes in this group can be successfully treated with immunotherapy and frequently do not have underlying tumors. The aim of this review is to describe the current state of knowledge about autoimmune encephalitis, in order to provide clinicians with a concise, up-to-date overview. Thus, a comprehensive literature search was performed in medical databases. The literature was carefully studied and new findings focusing on the symptoms, diagnosis and treatment were summarized and interpreted. Even though it might be challenging in some cases, the awareness of certain symptom constellations and demographic information, in combination with laboratory- and MRI-results, allows clinicians to make the diagnosis of probable autoimmune encephalitis at an early stage. Treatment can therefore be initiated faster, which significantly improves the outcome. Further investigations could define the underlying pathogenic mechanisms. Randomized controlled trials, paired with increasing clinical experience, will be necessary to improve the identification of affected patients, treatment strategies, and outcomes in the years to come.
Published: 2018
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12. Repeated Endovascular Treatment of Early Recurrent Proximal Middle Cerebral Artery Occlusion: Case Report and Brief Review of the Literature

Author: Simon Fandler, Hannes Deutschmann, Franz Fazekas, and Thomas Gattringer
Subjects: thrombectomy, endovascular treatment, stroke, ischemic stroke, recurrent stroke, large vessel occlusion, Neurology. Diseases of the nervous system, RC346-429
Abstract: Mechanical thrombectomy (MT) is the gold standard treatment for large vessel occlusion (LVO) stroke of the anterior circulation. Whether MT can also be effectively and safely performed in early recurrent LVO is largely unclear. We present the case of a middle-aged patient who was successfully treated by MT for right proximal middle cerebral artery (MCA) occlusion with excellent outcome. One day after discharge (9 days after the first MT), the patient was readmitted with wake-up stroke. MRI again revealed right proximal MCA occlusion with severe diffusion–perfusion mismatch. Repeat MT was performed and once more led to almost full recovery. The recurrent strokes were attributed to ulcerated non-stenosing plaques in the ipsilateral internal carotid artery, which prompted thromboendarterectomy. In an 18-months follow-up period, no further vascular events occurred. In conclusion, repeated MT for early recurrent LVO appears feasible in carefully selected patients. The collection of similar cases via registries would be desirable.
Published: 2018
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13. Management of multiple sclerosis patients in central European countries: current needs and potential solutions

Author: Thomas Berger, Monika Adamczyk-Sowa, Tünde Csépány, Franz Fazekas, Tanja Hojs Fabjan, Dana Horáková, Zsolt Illes, Eleonóra Klimová, Fritz Leutmezer, Konrad Rejdak, Csilla Rozsa, Saša Šega Jazbec, Jarmila Szilasiová, Peter Turčáni, Marta Vachová, László Vécsei, and Eva Havrdová
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: Multiple sclerosis (MS) experts in Europe are facing rapidly rising demands of excellence due to the increasing complexity of MS therapy and management. A central European expert board of MS experts met to identify needs and obstacles with respect to raising quality of MS care in central and Eastern European countries. There are substantial variations across countries regarding delivery of care and its cost structure, as well as access to treatment. To date, Eastern European countries are often less able to afford reimbursement of immunomodulatory agents than Western countries. Overall, approximately 40% of working-age patients are not working due to MS. Costs rise steeply with increasing disability; indirect costs constitute the bulk of the financial burden in patients with severe MS. Magnetic resonance imaging (MRI) assessment is meanwhile obligatory as the diagnostic interface in the management of MS patients. Recommended measures directed at improving quality of care include the collection of patient data in registries, enhanced education of healthcare professionals, implementation of national strategies aiming at reducing regional variation, optimization of approval processes, and removal of administrative barriers. Local partnerships with authorities such as those that represent the interests of employees can contribute to leverage the importance of epidemiological data. The need for education extends to (neuro)radiologists who are responsible for reporting MRI findings in expert quality. Dissemination of the Magnetic Resonance Imaging in MS (MAGNIMS) protocol would be an important step in this context. Also, clinical freedom of choice is rated as essential. Physicians should have access to a range of treatment options due to the complexity of disease. Guidelines such as the upcoming EAN-ECTRIMS clinical practice guideline also aim at providing a basis for argumentation in negotiations with national health authorities.
Published: 2018
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14. Predictive value of different conventional and non-conventional MRI-parameters for specific domains of cognitive function in multiple sclerosis

Author: Daniela Pinter, Michael Khalil, Alexander Pichler, Christian Langkammer, Stefan Ropele, Peter B. Marschik, Siegrid Fuchs, Franz Fazekas, and Christian Enzinger
Subjects: Cognition, Cognitive efficiency, Memory, Normalized cortical volume, Lesion load, Quantitative MRI, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Objective: While many studies correlated cognitive function with changes in brain morphology in multiple sclerosis (MS), few of them used a multi-parametric approach in a single dataset so far. We thus here assessed the predictive value of different conventional and quantitative MRI-parameters both for overall and domain-specific cognitive performance in MS patients from a single center. Methods: 69 patients (17 clinically isolated syndrome, 47 relapsing–remitting MS, 5 secondary-progressive MS) underwent the “Brief Repeatable Battery of Neuropsychological Tests” assessing overall cognition, cognitive efficiency and memory function as well as MRI at 3 Tesla to obtain T2-lesion load (T2-LL), normalized brain volume (global brain volume loss), normalized cortical volume (NCV), normalized thalamic volume (NTV), normalized hippocampal volume (NHV), normalized caudate nuclei volume (NCNV), basal ganglia R2* values (iron deposition) and magnetization transfer ratios (MTRs) for cortex and normal appearing brain tissue (NABT). Results: Regression models including clinical, demographic variables and MRI-parameters explained 22–27% of variance of overall cognition, 17–26% of cognitive efficiency and 22–23% of memory. NCV, T2-LL and MTR of NABT were the strongest predictors of overall cognitive function. Cognitive efficiency was best predicted by NCV, T2-LL and iron deposition in the basal ganglia. NTV was the strongest predictor for memory function and NHV was particularly related to memory function. Conclusions: The predictive value of distinct MRI-parameters differs for specific domains of cognitive function, with a greater impact of cortical volume, focal and diffuse white matter abnormalities on overall cognitive function, an additional role of basal ganglia iron deposition on cognitive efficiency, and thalamic and hippocampal volume on memory function. This suggests the usefulness of using multiparametric MRI to assess (micro)structural correlates of different cognitive constructs.
Published: 2015
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15. 2021 MAGNIMS–CMSC–NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis

Author: Mike P Wattjes, Olga Ciccarelli, Daniel S Reich, Brenda Banwell, Nicola de Stefano, Christian Enzinger, Franz Fazekas, Massimo Filippi, Jette Frederiksen, Claudio Gasperini, Yael Hacohen, Ludwig Kappos, David K B Li, Kshitij Mankad, Xavier Montalban, Scott D Newsome, Jiwon Oh, Jacqueline Palace, Maria A Rocca, Jaume Sastre-Garriga, Mar Tintoré, Anthony Traboulsee, Hugo Vrenken, Tarek Yousry, Frederik Barkhof, Àlex Rovira, María A Rocca, Mar Tintore, Alex Rovira, Wattjes, Mike P, Ciccarelli, Olga, Reich, Daniel S, Banwell, Brenda, de Stefano, Nicola, Enzinger, Christian, Fazekas, Franz, Filippi, Massimo, Frederiksen, Jette, Gasperini, Claudio, Hacohen, Yael, Kappos, Ludwig, Li, David K B, Mankad, Kshitij, Montalban, Xavier, Newsome, Scott D, Oh, Jiwon, Palace, Jacqueline, Rocca, Maria A, Sastre-Garriga, Jaume, Tintoré, Mar, Traboulsee, Anthony, Vrenken, Hugo, Yousry, Tarek, Barkhof, Frederik, Rovira, Àlex, Rocca, María A, Tintore, Mar, and Rovira, Alex
Subjects: Adult, Male, medicine.medical_specialty, Consensus, Multiple Sclerosis, Adolescent, MEDLINE, Contrast Media, Gadolinium, Inversion recovery, Appropriate use, Pediatrics, 030218 nuclear medicine & medical imaging, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Humans, Medical physics, In patient, Child, Aged, Monitoring, Physiologic, medicine.diagnostic_test, business.industry, Multiple sclerosis, Reproducibility of Results, Magnetic resonance imaging, Middle Aged, Prognosis, medicine.disease, Research findings, Magnetic Resonance Imaging, Clinical Practice, Treatment Outcome, Disease Progression, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
Published: 2021
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16. Multimodal assessment of white matter tracts in amyotrophic lateral sclerosis.

Author: Florian Borsodi, Valeriu Culea, Christian Langkammer, Michael Khalil, Lukas Pirpamer, Stefan Quasthoff, Christian Enzinger, Reinhold Schmidt, Franz Fazekas, and Stefan Ropele
Subjects: Medicine, Science
Abstract: Several quantitative magnetic resonance imaging (MRI) techniques have been proposed to investigate microstructural tissue changes in amyotrophic lateral sclerosis (ALS) including diffusion tensor imaging (DTI), magnetization transfer imaging, and R2* mapping. Here, in this study, we compared these techniques with regard to their capability for detecting ALS related white matter (WM) changes in the brain and their association with clinical findings. We examined 27 ALS patients and 35 age-matched healthy controls. MRI was performed at 3T, after which we analyzed the diffusion properties, the magnetization transfer ratio (MTR), and the effective transversal relaxation rate R2* in 18 WM tracts that were obtained by a fully automated segmentation technique. ALS patients, especially with a bulbar onset, showed a bilateral increase in radial and mean diffusivity, as well as a reduction in fractional anisotropy of the corticospinal tract (CST), and diffusion changes in the parietal and temporal superior longitudinal fasciculus. A reduction of the MTR was found in both CSTs and an R2* reduction was seen only in the left CST. Tract-specific diffusion properties were not related to clinical status in a cross-sectional manner but demonstrated some association with disease progression over three subsequent months. DTI reveals more widespread WM tissue changes than MTR and R2*. These changes are not restricted to the CST, but affect also other WM tracts (especially in patients with bulbar onset), and are associated with the short term course of the disease.
Published: 2017
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17. FMRI to probe sex-related differences in brain function with multitasking.

Author: Melanie Tschernegg, Christa Neuper, Reinhold Schmidt, Guilherme Wood, Martin Kronbichler, Franz Fazekas, Christian Enzinger, and Marisa Koini
Subjects: Medicine, Science
Abstract: Although established as a general notion in society, there is no solid scientific foundation for the existence of sex-differences in multitasking. Reaction time and accuracy in dual task conditions have an inverse relationship relative to single task, independently from sex. While a more disseminated network, parallel to decreasing accuracy and reaction time has been demonstrated in dual task fMRI studies, little is known so far whether there exist respective sex-related differences in activation.We subjected 20 women (mean age = 25.45; SD = 5.23) and 20 men (mean age = 27.55; SD = 4.00) to a combined verbal and spatial fMRI paradigm at 3.0T to assess sex-related skills, based on the assumption that generally women better perform in verbal tasks while men do better in spatial tasks. We also obtained behavioral tests for verbal and spatial intelligence, attention, executive functions, and working memory.No differences between women and men were observed in behavioral measures of dual-tasking or cognitive performance. Generally, brain activation increased with higher task load, mainly in the bilateral inferior and prefrontal gyri, the anterior cingulum, thalamus, putamen and occipital areas. Comparing sexes, women showed increased activation in the inferior frontal gyrus in the verbal dual-task while men demonstrated increased activation in the precuneus and adjacent visual areas in the spatial task.Against the background of equal cognitive and behavioral dual-task performance in both sexes, we provide first evidence for sex-related activation differences in functional networks for verbal and spatial dual-tasking.
Published: 2017
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18. Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Author: Henry Ma, Eleni Sakka, Hugues Chabriat, Duncan Wilson, Appu Suman, Peter J. Kelly, SL Ho, Charlotte Zerna, Eric Jouvent, Lawrence K.S. Wong, Anthea Parry, Frances Harrington, Jan Stam, Christopher Patterson, Rustam Al-Shahi Salman, Shigeru Inamura, Krishna A Dani, Henry Houlden, Sebastian Thilemann, Kotaro Iida, Chao Xu, Eunbin Ko, Daniel Guisado-Alonso, Urs Fischer, Caroline E. Lovelock, Man Yu Tse, Wing Chi Fong, Azlisham Mohd Nor, Clare Shakeshaft, Philippe Maeder, Henrik Gensicke, Stefan T. Engelter, James Okwera, Christopher Chen, Dulka Manawadu, John F. Corrigan, Efrat Kliper, Shelagh B. Coutts, Alexander P. Leff, Kam Tat Leung, Chathuri Yatawara, Leopold Hertzberger, M. Eline Kooi, Kazuhisa Yoshifuji, Hing Lung Ip, Keon-Joo Lee, Sanjeevikumar Meenakishundaram, Hiroyuki Irie, Marc Randall, Hatice Ozkan, Hideo Hara, Jill Abrigo, Raquel Delgado-Mederos, Shaloo Singhal, Enrico Flossmann, Beatriz Gómez-Ansón, Paul O'Mahony, Carmen Barbato, Ahamad Hassan, Francesca M Chappell, Harald Proschel, Vincent Mok, Masashi Nishihara, Lakshmanan Sekaran, Derya Selcuk Demirelli, Chu Peng Hoi, Hakan Ay, Joan Martí-Fàbregas, Rebeca Marín, Anne Cristine Guevarra, Martin Cooper, Einor Ben Assayag, Anne-Marie Mendyk, Christine Roffe, Myung Suk Jang, Maarten van Gemert, Hannah Cohen, Jae-Sung Lim, YK Wong, Bonnie Y.K. Lam, Janet Putterill, Wouter Schoonewille, Nick S. Ward, Nikola Sprigg, Kui Kai Lau, Bernard Esisi, Peter M. Rothwell, Henk Verbiest, Kirsty Harkness, Elisa Merino, Gareth Ambler, Arumug Nallasivam, Nigel Smyth, Paul A. Armitage, Heinrich Mattle, Pol Camps-Renom, Martin M. Brown, David Cohen, Min Lou, Pankaj Sharma, Sarah Gunkel, Elles Douven, Andreas Charidimou, Djamil Vahidassr, Cathy Soufan, Alexandros A Polymeris, Michael G. Hennerici, Chris Moran, Rachel Marsh, Mahmud Sajid, Kyohei Fujita, David J. Werring, Joanna M. Wardlaw, Derek Hayden, Joseph Kwan, Timothy J. England, Jaap van der Sande, Luis Prats-Sánchez, Paul Guyler, Ryan Hoi Kit Cheung, Koon-Ho Chan, Frank-Erik de Leeuw, Simone Browning, Jon Scott, Adrian Barry, Alejandro Martínez-Domeño, Luc Bracoub, Dinesh Chadha, Ijaz Anwar, Deborah Kelly, Moon-Ku Han, Anil M. Tuladhar, Thomas Gattringer, Fiona Carty, Abduelbaset Elmarim, Syed Mansoor, Enrico Flossman, Dilek Necioglu Orken, Jane Sword, Velandai Srikanth, Ping Wing Ng, Thomas W. Leung, Richard Shek-kwan Chang, Hans Rolf Jäger, Marwan El-Koussy, Jeroen Hendrikse, Khaled Darawil, Kazunori Toyoda, Mathuri Prabhakaran, Karim Mahawish, Ethem Murat Arsava, Jihoon Kang, Kwok Kui Wong, Michael Power, Felix Fluri, Enas Lawrence, Maam Mamun, Sissi Ispoglou, Mathew Burn, Siu Hung Li, Henry K.F. Mak, Kaori Miwa, Els De Schryver, Franz Fazekas, Jonathan G. Best, Louise Shaw, Hen Hallevi, Keith W. Muir, Ilse Burger, Adrian Wong, Nils Peters, Susana Muñoz-Maniega, Yusuke Yakushiji, David Calvet, Mark White, Michael McCormick, Vinodh Krishnamurthy, David Hargroves, Jan C. Purrucker, Tae Jin Song, Masayuki Shiozawa, Noortje A.M. Maaijwee, Prasanna Aghoram, Nicolas Christ, Lino Ramos, Yannie Soo, Thanh G. Phan, Parashkev Nachev, David J. Seiffge, Kim Wiegertjes, Leo H. Bonati, Chahin Pachai, Oi Ling Chan, Yvo B.W.E.M. Roos, Santiago Medrano-Martorell, Natan M. Bornstein, Elizabeth A. Warburton, Richard Li, Prabel Datta, Pascal P. Gratz, Edmund Ka Ming Wong, Hedley C. A. Emsley, Marie-Yvonne Douste-Blazy, Gunaratam Gunathilagan, Nagaendran Kandiah, Masatoshi Koga, Roland Veltkamp, Lee-Anne Slater, Suk Fung Tsang, Beom Joon Kim, Simon Jung, Zeynep Tanriverdi, Sarah Caine, Peter J. Koudstaal, Laurence Legrand, Kari Saastamoinen, Ale Algra, Jean-Louis Mas, Christine Delmaire, Fidel Nuñez, Robert J. van Oostenbrugge, Sebastian Eppinger, Lillian Choy, Robert Luder, Vincent I.H. Kwa, Aad van der Lugt, Marie Dominique Fratacci, Stephen Makin, Layan Akijian, Régis Bordet, Mi Hwa Yang, Ying Zhou, Elio Giallombardo, Adrian R Parry-Jones, John S. Thornton, Amos D. Korczyn, Narayanaswamy Venketasubramanian, David J. Williams, Aravindakshan Manoj, Julie Staals, Solveig Horstmann, Dianne H.K. van Dam-Nolen, Claire Cullen, Benjamin Wagner, Jun Tanaka, Martin Dennis, Stef Bakker, Gregory Y.H. Lip, L. Jaap Kappelle, Robin Lemmens, Achim Gass, David Mangion, Matthew Smith, Toshio Imaizumi, Wenyan Liu, Jeremy Molad, Christopher Price, Paul J. Nederkoorn, P. J. A. M. Brouwers, Vincent Thijs, Sze Ho Ma, Mark Schembri, Peter Wilkinson, Janice E. O’Connell, Karen Ma, John Ly, Leonidas Panos, Chung Yan Chan, Toshihiro Ide, Christopher Traenka, Joost Jöbsis, Gargi Banerjee, Paul Berntsen, Michael J. Thrippleton, Raymond T.F. Cheung, Christopher Karayiannis, Werner H. Mess, Robert Simister, Jayesh Modi Medanta, Syuhei Ikeda, John Mitchell, Linxin Li, Mauro S.B. Silva, Eric Vicaut, John Coyle, Shoichiro Sato, Michelle Davis, Jonathan Birns, Richard J. Perry, Sean M. Murphy, KC Teo, Maria del C. Valdés Hernández, Bibek Gyanwali, Tarek A. Yousry, Kath Pasco, Sebastian Köhler, Joachim Fladt, Edward S. Hui, Philippe Lyrer, Young Dae Kim, Anna K. Heye, Eric E. Smith, Saima Hilal, Ender Uysal, Ji Hoe Heo, Ysoline Beigneux, Cisca Linn, Hee-Joon Bae, Simon Leach, Winnie C.W. Chu, Ronil V. Chandra, Neurology, ACS - Atherosclerosis & ischemic syndromes, ANS - Neurovascular Disorders, MUMC+: HZC Med Staf Spec Klinische Neurofys (9), RS: Carim - B06 Imaging, MUMC+: HZC Klinische Neurofysiologie (5), Klinische Neurowetenschappen, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Neurologie (3), RS: Carim - B05 Cerebral small vessel disease, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Med Staf Spec Neurologie (9), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Beeldvorming, and MUMC+: DA BV Klinisch Fysicus (9)
Subjects: Adult, Male, Risk, EXTERNAL VALIDATION, medicine.medical_specialty, Neurology, MODELS, Clinical Neurology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Recurrence, Internal medicine, Antithrombotic, Humans, Medicine, Prospective cohort study, 610 Medicine & health, Stroke, METAANALYSIS, Aged, Ischemic Stroke, Science & Technology, medicine.diagnostic_test, business.industry, Proportional hazards model, Magnetic resonance imaging, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Magnetic Resonance Imaging, Ischemic Attack, Transient, ATRIAL-FIBRILLATION, Cardiology, Female, Neurology (clinical), Neurosciences & Neurology, business, Intracranial Hemorrhages, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Fibrinolytic agent, Cohort study
Abstract: Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.
Published: 2021
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19. Quantitative Susceptibility Mapping in Parkinson's Disease.

Author: Christian Langkammer, Lukas Pirpamer, Stephan Seiler, Andreas Deistung, Ferdinand Schweser, Sebastian Franthal, Nina Homayoon, Petra Katschnig-Winter, Mariella Koegl-Wallner, Tamara Pendl, Eva Maria Stoegerer, Karoline Wenzel, Franz Fazekas, Stefan Ropele, Jürgen Rainer Reichenbach, Reinhold Schmidt, and Petra Schwingenschuh
Subjects: Medicine, Science
Abstract: BACKGROUND:Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely. METHODS:The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables. RESULTS:Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra. CONCLUSION:The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.
Published: 2016
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20. Reproducibility of Resting State Connectivity in Patients with Stable Multiple Sclerosis.

Author: Daniela Pinter, Christian Beckmann, Marisa Koini, Eva Pirker, Nicola Filippini, Alexander Pichler, Siegrid Fuchs, Franz Fazekas, and Christian Enzinger
Subjects: Medicine, Science
Abstract: Given increasing efforts to use resting-state fMRI (rfMRI) as a biomarker of disease progression in multiple sclerosis (MS) we here explored the reproducibility of longitudinal rfMRI over three months in patients with clinically and radiologically stable MS. To pursue this aim, two approaches were applied in nine rfMRI networks: First, the intraclass correlation coefficient (ICC 3,1) was assessed for the mean functional connectivity maps across the entire network and a region of interest (ROI). Second, the ratio of overlap between Z-thresholded connectivity maps for each network was assessed. We quantified between-session functional reproducibility of rfMRI for 20 patients with stable MS and 14 healthy controls (HC). Nine rfMRI networks (RSNs) were examined at baseline and after 3 months of follow-up: three visual RSNs, the default-mode network, sensorimotor-, auditory-, executive control, and the left and right fronto-parietal RSN. ROI analyses were constrained to thresholded overlap masks for each individual (Z>0) at baseline and follow-up.In both stable MS and HC mean functional connectivity across the entire network did not reach acceptable ICCs for several networks (ICC
Published: 2016
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21. Lipocalin-2 as an Infection-Related Biomarker to Predict Clinical Outcome in Ischemic Stroke.

Author: Sonja Hochmeister, Odilo Engel, Milena Z Adzemovic, Thomas Pekar, Paul Kendlbacher, Manuel Zeitelhofer, Michaela Haindl, Andreas Meisel, Franz Fazekas, and Thomas Seifert-Held
Subjects: Medicine, Science
Abstract: OBJECTIVES:From previous data in animal models of cerebral ischemia, lipocalin-2 (LCN2), a protein related to neutrophil function and cellular iron homeostasis, is supposed to have a value as a biomarker in ischemic stroke patients. Therefore, we examined LCN2 expression in the ischemic brain in an animal model and measured plasma levels of LCN2 in ischemic stroke patients. METHODS:In the mouse model of transient middle cerebral artery occlusion (tMCAO), LCN2 expression in the brain was analyzed by immunohistochemistry and correlated to cellular nonheme iron deposition up to 42 days after tMCAO. In human stroke patients, plasma levels of LCN2 were determined one week after ischemic stroke. In addition to established predictive parameters such as age, National Institutes of Health Stroke Scale and thrombolytic therapy, LCN2 was included into linear logistic regression modeling to predict clinical outcome at 90 days after stroke. RESULTS:Immunohistochemistry revealed expression of LCN2 in the mouse brain already at one day following tMCAO, and the amount of LCN2 subsequently increased with a maximum at 2 weeks after tMCAO. Accumulation of cellular nonheme iron was detectable one week post tMCAO and continued to increase. In ischemic stroke patients, higher plasma levels of LCN2 were associated with a worse clinical outcome at 90 days and with the occurrence of post-stroke infections. CONCLUSIONS:LCN2 is expressed in the ischemic brain after temporary experimental ischemia and paralleled by the accumulation of cellular nonheme iron. Plasma levels of LCN2 measured in patients one week after ischemic stroke contribute to the prediction of clinical outcome at 90 days and reflect the systemic response to post-stroke infections.
Published: 2016
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22. Relationship between stroke etiology and collateral status in anterior circulation large vessel occlusion

Author: Christian Enzinger, Thomas Gattringer, Eva Hassler, Kurt Niederkorn, Hannes Deutschmann, Nicole Hinteregger, Melanie Haidegger, Marton Magyar, Sebastian Eppinger, Ulrike Wießpeiner, Franz Fazekas, Simon Fandler-Höfler, and Markus Kneihsl
Subjects: medicine.medical_specialty, Neurology, Collateral circulation, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Occlusion, Medicine, Humans, Carotid Stenosis, Adverse effect, Stroke, Neuroradiology, Thrombectomy, Outcome, Retrospective Studies, Original Communication, business.industry, Odds ratio, medicine.disease, Stenosis, Treatment Outcome, Carotid artery diseases, Cerebrovascular Circulation, Cardiology, Neurology (clinical), business, human activities, 030217 neurology & neurosurgery
Abstract: Background and purpose Clinical outcome after mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke is influenced by the intracerebral collateral status. We tested the hypothesis that patients with preexisting ipsilateral extracranial carotid artery stenosis (CAS) would have a better collateral status compared to non-CAS patients. Additionally, we evaluated MT-related adverse events and outcome for both groups. Methods Over a 7-year period, we identified all consecutive anterior circulation MT patients (excluding extracranial carotid artery occlusion and dissection). Patients were grouped into those with CAS ≥ 50% according to the NASCET criteria and those without significant carotid stenosis (non-CAS). Collateral status was rated on pre-treatment CT- or MR-angiography according to the Tan Score. Furthermore, we assessed postinterventional infarct size, adverse events and functional outcome at 90 days. Results We studied 281 LVO stroke patients, comprising 46 (16.4%) with underlying CAS ≥ 50%. Compared to non-CAS stroke patients (n = 235), patients with CAS-related stroke more often had favorable collaterals (76.1% vs. 46.0%). Recanalization rates were comparable between both groups. LVO stroke patients with underlying CAS more frequently had adverse events after MT (19.6% vs. 6.4%). Preexisting CAS was an independent predictor for favorable collateral status in multivariable models (Odds ratio: 3.3, p = 0.002), but post-interventional infarct size and functional 90-day outcome were not different between CAS and non-CAS patients. Conclusions Preexisting CAS ≥ 50% was associated with better collateral status in LVO stroke patients. However, functional 90-day outcome was independent from CAS, which could be related to a higher rate of adverse events.
Published: 2020

23. Ventilation time and prognosis after stroke thrombectomy: the shorter, the better!

Author: Simon Fandler-Höfler, Andrea Berghold, Markus Kneihsl, Thomas Gattringer, Alexander Pichler, Franz Fazekas, Stefan Heschl, Kurt Niederkorn, Placido Argüelles-Delgado, Christian Enzinger, and Hannes Deutschmann
Subjects: Male, Artificial ventilation, medicine.medical_treatment, mechanical ventilation, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Intensive care, medicine, pneumonia, Humans, General anaesthesia, 030212 general & internal medicine, Stroke, intensive care, Aged, Aged, 80 and over, Mechanical ventilation, business.industry, Endovascular Procedures, Neurointensive care, Original Articles, Middle Aged, Prognosis, medicine.disease, stroke, Treatment Outcome, neurocritical care, Neurology, thrombectomy, Anesthesia, Breathing, Original Article, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Background and purpose The aim was to investigate the clinical impact of the duration of artificial ventilation in stroke patients receiving mechanical thrombectomy (MT) under general anaesthesia. Methods All consecutive ischaemic stroke patients who had been treated at our centre with MT for anterior circulation large vessel occlusion under general anaesthesia were identified over an 8‐year period. Ventilation time was analysed as a continuous variable and patients were grouped into extubation within 6 h (‘early’), 6–24 h (‘delayed’) and >24 h (‘late’). Favourable outcome was defined as modified Rankin Scale scores of 0–2 at 3 months post‐stroke. Pneumonia rate and reasons for prolonged ventilation were also assessed. Results Amongst 447 MT patients (mean age 69.1 ± 13.3 years, 50.1% female), the median ventilation time was 3 h. 188 (42.6%) patients had a favourable 3‐month outcome, which correlated with shorter ventilation time (Spearman’s rho 0.39, P 24 h), delayed extubation (6–24 h) was associated with admission outside of core working hours (P
Published: 2020
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24. Mean Platelet Volume Does Not Predict Restenosis After Carotid Artery Stenting in Whites

Author: Gerit Wünsch, Simon Fandler-Höfler, Melanie Haidegger, Markus Kneihsl, Susanna Horner, Christian Enzinger, Hannes Deutschmann, Franz Fazekas, Thomas Gattringer, Kurt Niederkorn, and M. Augustin
Subjects: Male, medicine.medical_specialty, Carotid arteries, Population, 030204 cardiovascular system & hematology, White People, 03 medical and health sciences, 0302 clinical medicine, Restenosis, Internal medicine, medicine, Humans, Platelet activation, Mean platelet volume, education, Aged, Retrospective Studies, Advanced and Specialized Nursing, education.field_of_study, business.industry, Graft Occlusion, Vascular, Atherosclerotic disease, Middle Aged, medicine.disease, Carotid Arteries, Cardiology, Female, Stents, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Mean Platelet Volume, 030217 neurology & neurosurgery
Abstract: Background and Purpose— Mean platelet volume (MPV) indicates platelet activity possibly affecting patient’s risk for progressive atherosclerotic disease. A recent study identified elevated MPV as a predictor of in-stent restenosis (ISR) after carotid artery stenting (CAS) in a Chinese population. However, the role of MPV on the development of ISR following CAS in whites is yet unknown. Methods— We retrospectively identified all consecutive patients who underwent CAS for atherosclerotic disease at our center from 2005 to 2017. All patients were followed clinically and by duplex sonography at 1, 3, and 6 months and annually after CAS. ISR was defined as ≥50% stenosis (NASCET [North American Symptomatic Carotid Endarterectomy Trial] criteria) in the treated vessel. MPV was assessed before CAS, at last follow-up and at the time of ISR detection. Results— Of 392 patients with CAS (mean age 68.5±9.5 years, 26.8% women, 42.3% symptomatic stenosis), 54 had ISR after a mean follow-up time of 32 months. Baseline MPV was not different in ISR compared with non-ISR patients (10.7 versus 10.6 fL, P =0.316). MPV levels did also not change from baseline to ISR detection ( P =0.310) and were not associated with recurrent stroke or vascular events ( P >0.5). Multivariable analysis identified active smoking as the sole risk factor for carotid ISR (odds ratio, 2.53 [95% CI, 1.21–5.29]). Conclusions— We did not identify MPV as a risk factor for ISR after CAS in whites. Smoking cessation is an important target to avoid this complication.
Published: 2020
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25. Brain atrophy in cerebral small vessel diseases: Extent, consequences, technical limitations and perspectives: The HARNESS initiative

Author: Steven M. Greenberg, François De Guio, Leonardo Pantoni, Marco Duering, Joanna M. Wardlaw, Agnès Aghetti, Franz Fazekas, Eric Jouvent, Frank-Erik de Leeuw, and Eric E. Smith
Subjects: Male, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine, Humans, Cognitive Dysfunction, Review Articles, 030304 developmental biology, 0303 health sciences, business.industry, Brain, Cognition, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Magnetic Resonance Imaging, Hyperintensity, Cerebral Small Vessel Diseases, Neurology, Brain size, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Brain atrophy is increasingly evaluated in cerebral small vessel diseases. We aim at systematically reviewing the available data regarding its extent, correlates and cognitive consequences. Given that in this context, brain atrophy measures might be biased, the first part of the review focuses on technical aspects. Thereafter, data from the literature are analyzed in light of these potential limitations, to better understand the relationships between brain atrophy and other MRI markers of cerebral small vessel diseases. In the last part, we review the links between brain atrophy and cognitive alterations in patients with cerebral small vessel diseases.
Published: 2020
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26. Single mean arterial blood pressure drops during stroke thrombectomy under general anaesthesia are associated with poor outcome

Author: A. Kainz, Marton Magyar, Kurt Niederkorn, Thomas Gattringer, Simon Fandler-Höfler, Andrea Berghold, Markus Kneihsl, Eva Hassler, Hannes Deutschmann, Franz Fazekas, Placido Argüelles-Delgado, and Stefan Heschl
Subjects: medicine.medical_specialty, Diastole, 030204 cardiovascular system & hematology, Anaesthesia, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Internal medicine, medicine, Neurocritical care, General anaesthesia, Stroke, Neuroradiology, Thrombectomy, Original Communication, business.industry, Neurointensive care, medicine.disease, Blood pressure, Neurology, Cardiology, Neurology (clinical), business, Large vessel occlusion, 030217 neurology & neurosurgery, Cohort study
Abstract: Background We examined the influence of periprocedural blood pressure (BP), especially critical BP drops, on 3-month functional outcome in stroke patients undergoing mechanical thrombectomy (MT) under general anaesthesia (GA). Methods We screened all patients with anterior circulation large vessel occlusion receiving MT under GA at our centre from January 2011 to June 2016 and selected those who had continuous invasive periinterventional BP monitoring. Clinical and radiological data were prospectively collected as part of an ongoing cohort study, monitoring data were extracted from electronic anaesthesia records. We used uni- and multivariable regression to investigate the association of BP values with unfavourable outcome, defined as modified Rankin Scale scores 3–6 3 months post-stroke. Results 115 patients were included in this study (mean age 65.3 ± 13.0 years, 55.7% male). Periinterventional systolic, diastolic, and mean arterial BP (MAP) values averaged across MT had no effect on outcome. However, single BP drops were related to unfavourable outcome, with absolute MAP drops showing the highest association compared to both systolic and relative BP drops (with reference to pre-interventional values). The BP value with the strongest association with unfavourable outcome was identified as an MAP ever p = 0.01) with a pronounced effect in patients with poor collaterals. An MAP p Conclusions For patients undergoing MT under GA, single MAP drops
Published: 2020

27. Incidence of Developmental Venous Anomalies in Patients With Multiple Sclerosis: A 3 Tesla MRI Study

Author: Marton Magyar, Thomas Gattringer, Christian Enzinger, Eva Hassler, Richard Partl, Michael Khalil, Gernot Reishofer, Hannes Deutschmann, and Franz Fazekas
Subjects: Neurology, Neurology (clinical)
Abstract: ObjectivesThere is evidence of involvement of the venous system in multiple sclerosis (MS). If this bears also an association with the frequency and extent of developmental venous anomalies (DVA) still has to be determined. We therefore investigated this in patients with different phenotypes of MS and in comparison, to a control population.MethodsWe analyzed the contrast-enhanced T1-weighted MR scans of 431 patients (clinically isolated syndrome—CIS, n = 108; MS, n = 323) and of 162 control individuals for the presence of a DVA. We also measured the size of the DVA and draining vein and compared the DVA frequency between MS phenotypes.ResultsA DVA was found in 38 (8.8 %) of patients with CIS or MS and in 11 (6.8%) controls (p = 0.4). DVA frequency was highest in CIS (14.8%) and lowest in progressive MS (4.0%). The mean cranio-caudal and axial extension of the DVA was significantly lower in MS patients than controls (p < 0.05).ConclusionsThe frequency of DVA in MS patients is comparable to that in controls. Whether DVA size and appearance may change over time will have to be investigated in a longitudinal manner and with larger sample size.
Published: 2021

28. Levodopa-responsive Holmes' Tremor Caused by a Single Inflammatory Demyelinating Lesion

Author: Petra Katschnig-Winter, Mariella Koegl-Wallner, Tamara Pendl, Franz Fazekas, and Petra Schwingenschuh
Subjects: Diseases of the musculoskeletal system, RC925-935, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Holmes’ tremor is characterized by a combination of rest, postural, and kinetic tremor that is presumably caused by interruption of cerebello-thalamo-cortical and nigrostriatal pathways. Medical treatment remains unsatisfactory. Case Report: A 16-year-old girl presented with Holmes’ tremor caused by a transient midbrain abnormality on magnetic resonance imaging (MRI). To explore the discrepancy between persistent tremor and resolved MRI changes, we performed dopamine transporter single-photon emission computed tomography (DaT-SPECT) with a 123I-ioflupane that revealed nearly absent DaT binding in the right striatum. Levodopa dramatically improved the tremor. Discussion: This is only the second report of a transient midbrain MRI abnormality disrupting nigrostriatal pathways. The case highlights the sometimes limited sensitivity of morphologic imaging for identifying the functional consequences of tissue damage and confirms that DaT imaging may serve as a predictor for levodopa responsiveness in Holmes’ tremor.
Published: 2015
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29. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Author: Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ischemic Stroke/*diagnostic imaging/*drug therapy, Tomography, X-Ray Computed/methods, Fibrinolytic Agents/adverse effects/*therapeutic use, 030204 cardiovascular system & hematology, Ischemic Stroke/diagnostic imaging, surgery, 0302 clinical medicine, Modified Rankin Scale, 030212 general & internal medicine, 10. No inequality, Infusions, Intravenous, Stroke, Tomography, Time-to-Treatment, General Medicine, Thrombolysis, X-Ray Computed/methods, Tissue Plasminogen Activator/adverse effects, 3. Good health, [SDV] Life Sciences [q-bio], Diffusion Magnetic Resonance Imaging/methods, Treatment Outcome, Meta-analysis, Tissue Plasminogen Activator, Intravenous, medicine.medical_specialty, Infusions, Intravenous thrombolysis, Neuroimaging, Neuroscience(all), Placebo, Tissue Plasminogen Activator/adverse effects/*therapeutic use, 03 medical and health sciences, Fibrinolytic Agents, Internal medicine, medicine, Humans, ddc:610, Ischemic Stroke, business.industry, neurology, Fibrinolytic Agents/adverse effects, Odds ratio, Recovery of Function, medicine.disease, Clinical research, Diffusion Magnetic Resonance Imaging, Human medicine, business, Tomography, X-Ray Computed, Fibrinolytic agent
Abstract: 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.
Published: 2020
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30. Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines

Author: Ute Schaefer, Sonja Hochmeister, Milena Z. Adzemovic, Manuel Zeitelhofer, Muammer Üçal, Franz Fazekas, and Michaela Tanja Haindl
Subjects: Cerebellum, Pathology, medicine.medical_specialty, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, General Chemical Engineering, Encephalomyelitis, Central nervous system, Grey matter, General Biochemistry, Genetics and Molecular Biology, Myelin oligodendrocyte glycoprotein, Animals, Medicine, Cerebral Cortex, General Immunology and Microbiology, biology, business.industry, General Neuroscience, Multiple sclerosis, medicine.disease, Spinal cord, Hyperintensity, Rats, medicine.anatomical_structure, biology.protein, Cytokines, Myelin-Oligodendrocyte Glycoprotein, business
Abstract: Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) and progressively leads to physical disability and death, caused by white matter lesions in the spinal cord and cerebellum, as well as by demyelination in grey matter. Whilst conventional models of experimental allergic encephalomyelitis are suitable for the investigation of the cell-mediated inflammation in the spinal and cerebellar white matter, they fail to address grey matter pathologies. Here, we present the experimental protocol for a novel rat model of cortical demyelination allowing the investigation of the pathological and molecular mechanisms leading to cortical lesions. The demyelination is induced by an immunization with low-dose myelin oligodendrocyte glycoprotein (MOG) in an incomplete Freund's adjuvant followed by a catheter-mediated intracerebral delivery of pro-inflammatory cytokines. The catheter, moreover, enables multiple rounds of demyelination without causing injection-induced trauma, as well as the intracerebral delivery of potential therapeutic drugs undergoing a preclinical investigation. The method is also ethically favorable as animal pain and distress or disability are controlled and relatively minimal. The expected timeframe for the implementation of the entire protocol is around 8 - 10 weeks.
Published: 2021
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31. Predicting atrial fibrillation after cryptogenic stroke via a clinical risk score-a prospective observational study

Author: Egbert Bisping, Harald Mangge, Simon Fandler-Höfler, Edith Hofer, Markus Kneihsl, Sebastian Eppinger, Thomas Gattringer, Isabella Colonna, Daniel Scherr, Melanie Haidegger, Franz Fazekas, and Christian Enzinger
Subjects: medicine.medical_specialty, Atrial enlargement, medicine.drug_class, Ventricular Function, Left, Risk Factors, Internal medicine, Atrial Fibrillation, medicine, Natriuretic peptide, Humans, Stroke, Ischemic Stroke, Framingham Risk Score, Ejection fraction, business.industry, Atrial fibrillation, Stroke Volume, medicine.disease, Neurology, Cardiology, Biomarker (medicine), Observational study, Neurology (clinical), medicine.symptom, business
Abstract: BACKGROUND AND PURPOSE Atrial fibrillation (AF) often remains undiagnosed in cryptogenic stroke (CS), mostly because of limited availability of cardiac long-term rhythm monitoring. There is an unmet need for a pre-selection of CS patients benefitting from such work-up. A clinical risk score was therefore developed for the prediction of AF after CS and its performance was evaluated over 1 year of follow-up. METHODS Our proposed risk score ranges from 0 to 16 points and comprises variables known to be associated with occult AF in CS patients including age, N-terminal pro-brain natriuretic peptide, electrocardiographic and echocardiographic features (supraventricular premature beats, atrial runs, atrial enlargement, left ventricular ejection fraction) and brain imaging markers (multi-territory/prior cortical infarction). All CS patients admitted to our Stroke Unit between March 2018 and August 2019 were prospectively followed for AF detection over 1 year after discharge. RESULTS During the 1-year follow-up, 24 (16%) out of 150 CS patients with AF (detected via electrocardiogram controls, n = 18; loop recorder monitoring, n = 6) were diagnosed. Our predefined AF Risk Score (cutoff ≥4 points; highest Youden's index) had a sensitivity of 92% and a specificity of 67% for 1-year prediction of AF. Notably, only two CS patients with
Published: 2021

32. Planning of stroke care and urgent prehospital care across Europe: Results of the ESO/ESMINT/EAN/SAFE Survey

Author: Esmint, Sònia Abilleira, Valeria Caso, Thomas Gattringer, Ean, Adam Kobayashi, Diana Aguiar de Sousa, Valery L. Feigin, Miquel Gallofré, István Szikora, Franz Fazekas, and Urs Fischer
Subjects: business.industry, Stroke care, medicine.disease, Mechanical thrombectomy, Original Research Articles, Health care, Medicine, cardiovascular diseases, Neurology (clinical), Medical emergency, Quality of care, Cardiology and Cardiovascular Medicine, business, Stroke
Abstract: INTRODUCTION: Adequate planning and implementation of stroke systems of care is key to guarantee a rapid healthcare response and delivery of specific reperfusion therapies among candidates. We assessed the availability of stroke care plans in Europe, and evaluated their impact on rates of reperfusion therapies for stroke. PATIENTS: Based on the European Stroke Organisation (ESO), the European Society of Minimally Invasive Neurological Therapy (ESMINT), the European Academy of Neurology (EAN), and the Stroke Alliance for Europe (SAFE) survey, we analysed specific prespecified items in the questionnaire regarding availability and adequacy of stroke care plans, organised prehospital care and their potential impact on rates of delivery of reperfusion therapies for stroke at the country level. RESULTS: Of 44 participating European countries, 37 have stroke care plans that operate at national and/or regional levels. Most stroke care plans take responsibility for the organisation/implementation of stroke systems of care (86%), quality of care assessment (77%), and act as a liaison between emergency medical systems and stroke physicians (79%). As for stroke systems of care, the focus is mainly on prehospital and in-hospital acute stroke care (Code Stroke systems available in 37/44 countries). Preferred urgent transport is via non-medicalised ambulances (70%). Presence of stroke care plans, stroke registry data, transport of urgent stroke patients via non-medicalised ambulances, and drip-and-ship routing of acute patients showed higher reperfusion treatment rates. DISCUSSION: Availability of stroke care plans, still absent in some European countries, as well as some features of the stroke systems of care are associated with higher reperfusion treatment rates. CONCLUSION: Stroke is not yet a priority everywhere in Europe, which is a barrier to the spread of reperfusion therapies for stroke.
Published: 2019
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33. Predicting Early Mortality of Acute Ischemic Stroke

Author: Julia Ferrari, Wilfried Lang, Kurt Niederkorn, Thomas Gattringer, Alexandra Posekany, Michael Knoflach, Christian Enzinger, Stefan Kiechl, Sebastian Mutzenbach, Birgit Poltrum, Hans-Peter Haring, Johann Willeit, and Franz Fazekas
Subjects: Advanced and Specialized Nursing, medicine.medical_specialty, business.industry, Stroke mortality, medicine.disease, Brain ischemia, Internal medicine, Ischemic stroke, medicine, Cardiology, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Acute ischemic stroke, Stroke
Abstract: Background and Purpose— Several risk factors are known to increase mid- and long-term mortality of ischemic stroke patients. Information on predictors of early stroke mortality is scarce but often requested in clinical practice. We therefore aimed to develop a rapidly applicable tool for predicting early mortality at the stroke unit. Methods— We used data from the nationwide Austrian Stroke Unit Registry and multivariate regularized logistic regression analysis to identify demographic and clinical variables associated with early (≤7 days poststroke) mortality of patients admitted with ischemic stroke. These variables were then used to develop the Predicting Early Mortality of Ischemic Stroke score that was validated both by bootstrapping and temporal validation. Results— In total, 77 653 ischemic stroke patients were included in the analysis (median age: 74 years, 47% women). The mortality rate at the stroke unit was 2% and median stay of deceased patients was 3 days. Age, stroke severity measured by the National Institutes of Health Stroke Scale, prestroke functional disability (modified Rankin Scale >0), preexisting heart disease, diabetes mellitus, posterior circulation stroke syndrome, and nonlacunar stroke cause were associated with mortality and served to build the Predicting Early Mortality of Ischemic Stroke score ranging from 0 to 12 points. The area under the curve of the score was 0.879 (95% CI, 0.871–0.886) in the derivation cohort and 0.884 (95% CI, 0.863–0.905) in the validation sample. Patients with a score ≥10 had a 35% (95% CI, 28%–43%) risk to die within the first days at the stroke unit. Conclusions— We developed a simple score to estimate early mortality of ischemic stroke patients treated at a stroke unit. This score could help clinicians in short-term prognostication for management decisions and counseling.
Published: 2019
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34. Prevalence and short‐term changes of cognitive dysfunction in young ischaemic stroke patients

Author: Daniela Pinter, Gerhard Bachmaier, Simon Fandler, Susanna Horner, Christian Enzinger, Markus Kneihsl, Sebastian Eppinger, K. Krenn, Kurt Niederkorn, Franz Fazekas, and Thomas Gattringer
Subjects: cognition, Adult, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, changes, Neuropsychological Tests, Brain Ischemia, Executive Function, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Ischaemic stroke, Prevalence, medicine, processing speed, Humans, Speech, Attention, Cognitive Dysfunction, Prospective Studies, 030212 general & internal medicine, Effects of sleep deprivation on cognitive performance, Stroke, Rehabilitation, young, business.industry, Age Factors, Neuropsychology, acute, Flexibility (personality), Cognition, Original Articles, Middle Aged, medicine.disease, stroke, Neurology, Disease Progression, Original Article, Female, Neurology (clinical), Cognitive Assessment System, business, 030217 neurology & neurosurgery
Abstract: Background and purpose Information on the prevalence and course of post‐stroke cognitive impairment in young stroke patients is limited. The aim was to assess a consecutive sample of acute young ischaemic stroke patients (18–55 years) for the presence and development of neuropsychological deficits. Methods Patients prospectively underwent a comprehensive clinical and cognitive assessment, examining general cognitive function, processing speed, attention, flexibility/executive function and word fluency within the first 3 weeks after hospital admission (median assessment at day 6) and at a 3 months’ follow‐up (FU). Cognitive dysfunction was defined in comparison to age‐standardized published norms. Results At baseline (N = 114), deficits were highly prevalent in processing speed (56.0%), flexibility/executive function (49.5%), attention (46.4%) and general cognitive function (42.1%). These frequencies were comparable for those with FU assessment (N = 87). In most domains, cognitive performance improved within 3 months, except for word fluency. However, in about one‐third of patients, cognitive deficits (as defined by 1.5 standard deviations below the standardized mean) were still present 3 months after stroke. At FU, 44.0% were impaired in the domain flexibility/executive function, 35.0% in processing speed and 30.0% in attention. Conclusions The high prevalence of cognitive deficits in acute young patients with ischaemic stroke highlights the importance of early post‐stroke cognitive assessment to capture a patient's dysfunction in a comprehensive manner and to offer adequate rehabilitation. The role of factors which promote neuropsychological deficits needs further exploration.
Published: 2019
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35. Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat.

Author: Sonja Hochmeister, Thomas Pekar, Maren Lindner, Maja Kitic, Michaela Haindl, Maria Storch, Franz Fazekas, and Christopher Linington
Subjects: Medicine, Science
Abstract: UnlabelledNeurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum.ResultsImmunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody.ConclusionsWe show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children.
Published: 2014
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36. Tracking of magnetite labeled nanoparticles in the rat brain using MRI.

Author: Naira P Martínez Vera, Reinhold Schmidt, Klaus Langer, Iavor Zlatev, Robert Wronski, Ewald Auer, Daniel Havas, Manfred Windisch, Hagen von Briesen, Sylvia Wagner, Julia Stab, Motti Deutsch, Claus Pietrzik, Franz Fazekas, and Stefan Ropele
Subjects: Medicine, Science
Abstract: This study was performed to explore the feasibility of tracing nanoparticles for drug transport in the healthy rat brain with a clinical MRI scanner. Phantom studies were performed to assess the R1 ( = 1/T1) relaxivity of different magnetically labeled nanoparticle (MLNP) formulations that were based on biodegradable human serum albumin and that were labeled with magnetite of different size. In vivo MRI measurements in 26 rats were done at 3T to study the effect and dynamics of MLNP uptake in the rat brain and body. In the brain, MLNPs induced T1 changes were quantitatively assessed by T1 relaxation time mapping in vivo and compared to post-mortem results from fluorescence imaging. Following intravenous injection of MLNPs, a visible MLNP uptake was seen in the liver and spleen while no visual effect was seen in the brain. However a histogram analysis of T1 changes in the brain demonstrated global and diffuse presence of MLNPs. The magnitude of these T1 changes scaled with post-mortem fluorescence intensity. This study demonstrates the feasibility of tracking even small amounts of magnetite labeled NPs with a sensitive histogram technique in the brain of a living rodent.
Published: 2014
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37. Repetitive long-term hyperbaric oxygen treatment (HBOT) administered after experimental traumatic brain injury in rats induces significant remyelination and a recovery of sensorimotor function.

Author: Klaus Kraitsy, Muammer Uecal, Stefan Grossauer, Lukas Bruckmann, Florentina Pfleger, Stefan Ropele, Franz Fazekas, Gerda Gruenbacher, Silke Patz, Markus Absenger, Christian Porubsky, Freyja Smolle-Juettner, Irem Tezer, Marek Molcanyi, Ulrike Fasching, and Ute Schaefer
Subjects: Medicine, Science
Abstract: Cells in the central nervous system rely almost exclusively on aerobic metabolism. Oxygen deprivation, such as injury-associated ischemia, results in detrimental apoptotic and necrotic cell loss. There is evidence that repetitive hyperbaric oxygen therapy (HBOT) improves outcomes in traumatic brain-injured patients. However, there are no experimental studies investigating the mechanism of repetitive long-term HBOT treatment-associated protective effects. We have therefore analysed the effect of long-term repetitive HBOT treatment on brain trauma-associated cerebral modulations using the lateral fluid percussion model for rats. Trauma-associated neurological impairment regressed significantly in the group of HBO-treated animals within three weeks post trauma. Evaluation of somatosensory-evoked potentials indicated a possible remyelination of neurons in the injured hemisphere following HBOT. This presumption was confirmed by a pronounced increase in myelin basic protein isoforms, PLP expression as well as an increase in myelin following three weeks of repetitive HBO treatment. Our results indicate that protective long-term HBOT effects following brain injury is mediated by a pronounced remyelination in the ipsilateral injured cortex as substantiated by the associated recovery of sensorimotor function.
Published: 2014
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38. Higher education moderates the effect of T2 lesion load and third ventricle width on cognition in multiple sclerosis.

Author: Daniela Pinter, James Sumowski, John DeLuca, Franz Fazekas, Alexander Pichler, Michael Khalil, Christian Langkammer, Siegrid Fuchs, and Christian Enzinger
Subjects: Medicine, Science
Abstract: BACKGROUND:Previous work suggested greater intellectual enrichment might moderate the negative impact of brain atrophy on cognition. This awaits confirmation in independent cohorts including investigation of the role of T2-lesion load (T2-LL), which is another important determinant of cognition in MS. We here thus aimed to test this cognitive reserve hypothesis by investigating whether educational attainment (EA) moderates the negative effects of both brain atrophy and T2-LL on cognitive function in a large sample of MS patients. METHODS:137 patients participated in the study. Cognition was assessed by the "Brief Repeatable Battery of Neuropsychological Tests." T2-LL, normalized brain volume (global volume loss) and third ventricle width (regional volume loss) served as MRI markers. RESULTS:Both T2-LL and atrophy predicted worse cognition, with a stronger effect of T2-LL. Higher EA (as assessed by years of education) also predicted better cognition. Interactions showed that the negative effects of T2-LL and regional brain atrophy were moderated by EA. CONCLUSIONS:In a cohort with different stages of MS, higher EA attenuated the negative effects of white matter lesion burden and third ventricle width (suggestive of thalamic atrophy) on cognitive performance. Actively enhancing cognitive reserve might thus be a means to reduce or prevent cognitive problems in MS in parallel to disease modifying drugs.
Published: 2014
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39. Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study.

Author: Marisa Loitfelder, Franz Fazekas, Karl Koschutnig, Siegrid Fuchs, Katja Petrovic, Stefan Ropele, Alexander Pichler, Margit Jehna, Christian Langkammer, Reinhold Schmidt, Christa Neuper, and Christian Enzinger
Subjects: Medicine, Science
Abstract: BACKGROUND: Extrapolations from previous cross-sectional fMRI studies suggest cerebral functional changes with progression of Multiple Sclerosis (MS), but longitudinal studies are scarce. We assessed brain activation changes over time in MS patients using a cognitive fMRI paradigm and examined correlations with clinical and cognitive status and brain morphology. METHODS: 13 MS patients and 15 healthy controls (HC) underwent MRI including fMRI (go/no-go task), neurological and neuropsychological exams at baseline (BL) and follow-up (FU; minimum 12, median 20 months). We assessed estimates of and changes in fMRI activation, total brain and subcortical grey matter volumes, cortical thickness, and T2-lesion load. Bland-Altman (BA) plots served to assess fMRI signal variability. RESULTS: Cognitive and disability levels remained largely stable in the patients. With the fMRI task, both at BL and FU, patients compared to HC showed increased activation in the insular cortex, precuneus, cerebellum, posterior cingulate cortex, and occipital cortex. At BL, patients vs. HC also had lower caudate nucleus, thalamus and putamen volumes. Over time, patients (but not HC) demonstrated fMRI activity increments in the left inferior parietal lobule. These correlated with worse single-digit-modality test (SDMT) performance. BA-plots attested to reproducibility of the fMRI task. In the patients, the right caudate nucleus decreased in volume which again correlated with worsening SDMT performance. CONCLUSIONS: Given preserved cognitive performance, the increased activation at BL in the patients may be viewed as largely adaptive. In contrast, the negative correlation with SDMT performance suggests increasing parietal activation over time to be maladaptive. Several areas with purported relevance for cognition showed decreased volumes at BL and right caudate nucleus volume decline correlated with decreasing SDMT performance. This highlights the dynamics of functional changes and the strategic importance of specific brain areas for cognitive processes in MS.
Published: 2014
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40. Access to and delivery of acute ischaemic stroke treatments: A survey of national scientific societies and stroke experts in 44 European countries

Author: István Szikora, Diana Aguiar de Sousa, Sònia Abilleira, Urs Fischer, Adam Kobayashi, Valeria Caso, Thomas Gattringer, Rascha von Martial, Valery L. Feigin, Franz Fazekas, Miquel Gallofré, [Aguiar-de-Sousa D] Department of Neurology, University of Lisbon, Hospital de Santa Maria, Lisbon, Portugal. [Von-Martial R, Fischer U] Department of Neurology, University of Bern, Inselspital, Bern, Switzerland. [Abilleira-Castells S] Pla Director de la Malaltia Vascular Cerebral, Agència de Qualitat i Avaluació Sanitàries de Catalunya (AQuAS), Departament de Salut, Generalitat de Catalunya, Barcelona, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. [Gattringer T, Fazekas F] Department of Neurology, Medical University of Graz, Graz, Austria. [Kobayashi A] Interventional Stroke and Cerebrovascular Disease Treatment Centre, Department of Neuroradiology, Institute of Psychiatry and Neurology, Warsaw, Poland. [Gallofré M] Pla Director de la Malaltia Vascular Cerebral, Agència de Qualitat i Avaluació Sanitàries de Catalunya (AQuAS), Departament de Salut, Generalitat de Catalunya, Barcelona, Spain. [Szikora I] National Institute of Clinical Neurosciences, Budapest, Hungary. [Feigin V] National Institute for Stroke & Applied Neurosciences, Auckland, New Zealand. [Caso V] Stroke Unit, University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy., and Departament de Salut
Subjects: medicine.medical_specialty, medicine.medical_treatment, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::trastornos cerebrovasculares::accidente cerebrovascular [ENFERMEDADES], 030204 cardiovascular system & hematology, Geographic Locations::Europe [GEOGRAPHICALS], 03 medical and health sciences, Other subheadings::/statistics & numerical data [Other subheadings], 0302 clinical medicine, Malalties cerebrovasculars - Tractament - Enquestes, Ischaemic stroke, medicine, cardiovascular diseases, Otros calificadores::/estadística & datos numéricos [Otros calificadores], Endovascular treatment, 610 Medicine & health, Stroke, Therapeutics::Drug Therapy::Thrombolytic Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], business.industry, Thrombolysis, Stroke unit care, medicine.disease, Terapéutica::Tratamiento Farmacológico::Terapia Trombolítica [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], terapéutica::farmacoterapia::tratamiento trombolítico [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Europa - Registres mèdics, Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebrovascular Disorders::Stroke [DISEASES], Emergency medicine, Neurology (clinical), Teràpia trombolítica, localizaciones geográficas::Europa (continente) [DENOMINACIONES GEOGRÁFICAS], Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Introduction Acute stroke unit care, intravenous thrombolysis and endovascular treatment significantly improve the outcome for patients with ischaemic stroke, but data on access and delivery throughout Europe are lacking. We assessed best available data on access and delivery of acute stroke unit care, intravenous thrombolysis and endovascular treatment throughout Europe. Methods A survey, drafted by stroke professionals (ESO, ESMINT, EAN) and a patient organisation (SAFE), was sent to national stroke societies and experts in 51 European countries (World Health Organization definition) requesting experts to provide national data on stroke unit, intravenous thrombolysis and endovascular treatment rates. We compared both pooled and individual national data per one million inhabitants and per 1000 annual incident ischaemic strokes with highest country rates. Population estimates were based on United Nations data, stroke incidences on the Global Burden of Disease Report. Results We obtained data from 44 European countries. The estimated mean number of stroke units was 2.9 per million inhabitants (95% CI 2.3–3.6) and 1.5 per 1000 annual incident strokes (95% CI 1.1–1.9), highest country rates were 9.2 and 5.8. Intravenous thrombolysis was provided in 42/44 countries. The estimated mean annual number of intravenous thrombolysis was 142.0 per million inhabitants (95% CI 107.4–176.7) and 72.7 per 1000 annual incident strokes (95% CI 54.2–91.2), highest country rates were 412.2 and 205.5. Endovascular treatment was provided in 40/44 countries. The estimated mean annual number of endovascular treatments was 37.1 per million inhabitants (95% CI 26.7–47.5) and 19.3 per 1000 annual incident strokes (95% CI 13.5–25.1), highest country rates were 111.5 and 55.9. Overall, 7.3% of incident ischaemic stroke patients received intravenous thrombolysis (95% CI 5.4–9.1) and 1.9% received endovascular treatment (95% CI 1.3–2.5), highest country rates were 20.6% and 5.6%. Conclusion We observed major inequalities in acute stroke treatment between and within 44 European countries. Our data will assist decision makers implementing tailored stroke care programmes for reducing stroke-related morbidity and mortality in Europe.
Published: 2021

41. Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults—A Worldwide Meta-analysis

Author: Mina A. Jacob, Merel S. Ekker, Youssra Allach, Mengfei Cai, Karoliina Aarnio, Antonio Arauz, Marcel Arnold, Hee-Joon Bae, Lucrecia Bandeo, Miguel A. Barboza, Manuel Bolognese, Pablo Bonardo, Raf Brouns, Batnairamdal Chuluun, Enkhzaya Chuluunbatar, Charlotte Cordonnier, Byambasuren Dagvajantsan, Stephanie Debette, Adi Don, Chris Enzinger, Esme Ekizoglu, Simon Fandler-Höfler, Franz Fazekas, Annette Fromm, Thomas Gattringer, Thiago F. Hora, Christina Jern, Katarina Jood, Young Seo Kim, Steven Kittner, Timothy Kleinig, Catharina J.M. Klijn, Janika Kõrv, Vinod Kumar, Keon-Joo Lee, Tsong-Hai Lee, Noortje A.M. Maaijwee, Nicolas Martinez-Majander, João Pedro Marto, Man M. Mehndiratta, Victoria Mifsud, Vinícius Montanaro, Gisele Pacio, Vinod B. Patel, Matthew C. Phillips, Bartlomiej Piechowski-Jozwiak, Aleksandra Pikula, Jose Ruiz-Sandoval, Bettina von Sarnowski, Richard H. Swartz, Kay-Sin Tan, David Tanne, Turgut Tatlisumak, Vincent Thijs, Miguel Viana-Baptista, Riina Vibo, Teddy Y. Wu, Nilüfer Yesilot, Ulrike Waje-Andreassen, Alessandro Pezzini, Jukka Putaala, Anil M. Tuladhar, Frank-Erik de Leeuw, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Adolescent, Incidence, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 610 Medicine & health, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Stroke, Young Adult, Risk Factors, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Research Article, Ischemic Stroke
Abstract: Background and ObjectivesThere is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide.MethodsWe performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18–50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression.ResultsWe included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas “other determined stroke” and “undetermined stroke” were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42–4.36).DiscussionEthnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.
Published: 2022
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42. Plasma midregional pro-adrenomedullin improves prediction of functional outcome in ischemic stroke.

Author: Thomas Seifert-Held, Thomas Pekar, Thomas Gattringer, Nicole E Simmet, Hubert Scharnagl, Christoph Bocksrucker, Christian Lampl, Maria K Storch, Tatjana Stojakovic, and Franz Fazekas
Subjects: Medicine, Science
Abstract: BackgroundTo evaluate if plasma levels of midregional pro-adrenomedullin (MR-proADM) improve prediction of functional outcome in ischemic stroke.MethodsIn 168 consecutive ischemic stroke patients, plasma levels of MR-proADM were measured within 24 hours from symptom onset. Functional outcome was assessed by the modified Rankin Scale (mRS) at 90 days following stroke. Logistic regression, receiver operating characteristics (ROC) curve analysis, net reclassification improvement (NRI), and Kaplan-Meier survival analysis were applied.ResultsPlasma MR-proADM levels were found significantly higher in patients with unfavourable (mRS 3-6) compared to favourable (mRS 0-2) outcomes. MR-proADM levels were entered into a predictive model including the patients' age, National Institutes of Health Stroke Scale (NIHSS), and the use of recanalization therapy. The area under the ROC curve did not increase significantly. However, category-free NRI of 0.577 (pConclusionsPlasma MR-proADM levels improve prediction of functional outcome in ischemic stroke when added to the patients' age, NIHSS on admission, and the use of recanalization therapy. Levels of MR-proADM in peripheral blood improve reclassification of patients when the SPAN-100 is used to predict the patients' functional outcome.
Published: 2013
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43. Factors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease

Author: Tünde Csépány, Eleonóra Klímová, Peter Turcˇáni, Tanja Hojs Fabjan, Johann Sellner, Zsolt Illes, Pavel Štouracˇ, Fritz Leutmezer, Saša Šega Jazbec, Krzysztof Selmaj, Monika Adamczyk-Sowa, Marta Vachová, Franz Fazekas, Dana Horakova, Manuela Vaneckova, Alenka Horvat Ledinek, Csilla Rozsa, Thomas Berger, Gisela Kobelt, Konrad Rejdak, Eva Havrdova, Jarmila Szilasiova, and László Vécsei
Subjects: medicine.medical_specialty, Neurology, Review, Disease, burden of disease, neurofilament, multiple sclerosis, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, Documentation, cognitive dysfunction, medicine, magnetic resonance imaging, 030212 general & internal medicine, Intensive care medicine, Disease burden, lcsh:Neurology. Diseases of the nervous system, Pharmacology, Therapeutic Perspectives in Neurology, business.industry, Multiple sclerosis, biomarkers, Cognition, medicine.disease, 3. Good health, Clinical trial, Biomarker (medicine), Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: At two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.
Published: 2020
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44. Features of intracranial hemorrhage in cerebral venous thrombosis

Author: Robin Lemmens, Jonathan M. Coutinho, Antonio Arauz, Alessandro Pezzini, Miguel A Barboza, Nicole Hinteregger, Christian Weimar, Susanna M. Zuurbier, Sini Hiltunen, Vincent Thijs, Pieter-Jan Buyck, Joan Montaner, Carlos Garcia Esperon, Turgut Tatlisumak, Patricia Luiza Nunes Costa, J. Jiménez Conde, Jukka Putaala, K. Afifi, Irene Escudero, G Bellanger, Dimitri Renard, Eva Giralt-Steinhauer, Marc Schlamann, Thomas Gattringer, Franz Fazekas, Philippe Demaerel, ANS - Neurovascular Disorders, ACS - Atherosclerosis & ischemic syndromes, and Neurology
Subjects: Adult, Male, Cerebral veins, medicine.medical_specialty, Subarachnoid hemorrhage, Bleeding, Medizin, Hemorrhage, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Mexico, Stroke, Aged, Retrospective Studies, Venous Thrombosis, business.industry, Subdural hemorrhage, medicine.disease, Cerebral Veins, Thrombosis, Europe, Venous thrombosis, Intracranial Thrombosis, Neurology, Cerebral venous thrombosis, Female, Neurology (clinical), Radiology, business, Intracranial Hemorrhages, 030217 neurology & neurosurgery, Superior sagittal sinus
Abstract: [Background] Cerebral venous thrombosis (CVT) is associated with intracranial hemorrhage., [Aim] To identify clinical and imaging features of CVT-associated intracranial hemorrhage. We hypothesized that higher clot burden would be associated with a higher risk of intracranial hemorrhage., [Methods] We performed a retrospective analysis of an international, multicenter cohort of patients with confirmed cerebral venous thrombosis who underwent computed tomography within 2 weeks of symptom onset. Clinical and imaging features were compared between patients with and without intracranial hemorrhage. Clot burden was assessed by counting the number of thrombosed venous sinuses and veins on confirmatory imaging., [Results] We enrolled 260 patients from 10 institutions in Europe and Mexico. The mean age was 42 years and 74% were female. Intracranial hemorrhage was found in 102 (39%). Among them parenchymal hemorrhage occurred in 64 (63%), in addition, small juxta-cortical hemorrhage was found in 30 (29%), subarachnoid hemorrhage in 24 (24%) and subdural hemorrhage in 11 (11%). Multiple concomitant types of hemorrhage occurred in 23 (23%). Older age and superior sagittal thrombosis involvement were associated with presence of hemorrhage. The number of thrombosed venous sinuses was not associated with intracranial hemorrhage (median number IQRInterquartile ratio] of sinuses/veins involved with hemorrhage 2 (1–3) vs. 2 (1–3) without hemorrhage, p = 0.4)., [Conclusion] The high rate of intracranial hemorrhage in cerebral venous thrombosis is not explained by widespread involvement of the venous sinuses. Superior sagittal sinus involvement is associated with higher bleeding risk.
Published: 2020

45. The European Academy of Neurology is 6 years old: challenges, opportunities and strategic priorities for the future

Author: Claudio L. Bassetti and Franz Fazekas
Subjects: medicine.medical_specialty, Medical education, Neurology, business.industry, Medicine, 610 Medicine & health, Neurology (clinical), business
Published: 2020
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46. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2) : a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Jennifer Graves, Adrian Pace, Maria Pia Sormani, Devon S. Conway, Bianca Weinstock-Guttman, Frederick E. Munschauer, Corey C. Ford, Vernon Rowe, Jana Lizrova Preiningerova, Shiv Saidha, Radek Ampapa, Jens Kuhle, Harold L. Moses, Claire S Riley, Tobias Derfuss, Lilyana Amezcua, Joshua Barton, Kottil Rammohan, Pierre Duquette, Thomas Leist, Alexander Rae-Grant, Evanthia Bernitsas, Myla D. Goldman, R. Talab, Jerry S. Wolinsky, Nina De Klippel, Guillermo Izquierdo Ayuso, Bridget Bagert, Virginia Devonshire, Mariko Kita, Hayrettin Tumani, Bhatia Perminder, Scott D. Newsome, Paul S. Giacomini, Frédéric Sedel, Jan Lycke, M. S. Freedman, Stewart Webb, Sanjay Yathiraj, Agata Klosek, Stephen Krieger, Edward Fox, Malgorzata Zajda, Eva Meluzinova, Valerie J Block, Lluís Ramió-Torrentà, John R. Corboy, Aaron E. Miller, Xavier Montalban, Mark A. Agius, Michelle L Apperson, Patricia K. Coyle, Giancarlo Comi, Jose Enrique Martinez Rodriguez, Daniela Rau, Derrick Robertson, Elias Hamp Birte, Douglas L. Arnold, Fred D. Lublin, Galina Vorobeychik, Benjamin Greenberg, Mathias Buttmann, Daniel Bandari, Ludivine Witkowski, Sharon G. Lynch, Victoria Fernandez Sanchez, Jonathan Calkwood, Maria Satori, Tania Kuempfel, Rana K. Zabad, J. Marc Girard, Bruce A.C. Cree, Ahmed T. Toosy, Don J. Mahad, Bruce A. Cohen, Jozef Koscielniak, Jonathan Carter, Daniel Selchen, Paul Friedemann, Sharon Stoll, Fryze Waldemar, Gerd Reifschneider, Mark S. Freedman, Gary Cutter, Franz Fazekas, Robert T. Naismith, Marta Vachova, Richard MacDonell, Mary Ann Picone, Gavin Giovannoni, Randall Trudell, Barbara Willekens, Orhan Aktas, Mark Marriott, Roger McKelvey, Bruce C.A. Cree, Christopher Severson, Rafael Arroyo Gonzalez, Kyle Smoot, Murat Terzi, Joanna Cooper, Lou Brundin, Hans-Peter Hartung, Piotr Sokolowski, Joe Guadagno, Stephen C. Reingold, Klaus Schmierer, Guy Laureys, Robert P. Lisak, Lawrence Samkoff, Carlo Pozzilli, Celia Oreja Guevara, Mitchel Freedman, Anthony T. Reder, and SPI2 investigative teams
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Biotin, Placebo, Severity of Illness Index, law.invention, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Outcome Assessment, Health Care, Severity of illness, Aged, Disease Progression, Female, Humans, Middle Aged, Multiple Sclerosis, Chronic Progressive, Vitamin B Complex, Walking Speed, Clinical endpoint, Medicine, Expanded Disability Status Scale, business.industry, Multiple sclerosis, medicine.disease, Clinical trial, 030104 developmental biology, Cohort, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract: Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (
Published: 2020

47. The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017

Author: Eveline Sipido, Ettore Beghi, Kalliopi A Christoforidi, Theo Vos, Günther Deuschl, Valery L. Feigin, Franz Fazekas, Claudio L. Bassetti, and Timea Varga
Subjects: Adult, Male, medicine.medical_specialty, Neurology, Population, Context (language use), 610 Medicine & health, Disease, 01 natural sciences, Global Burden of Disease, 03 medical and health sciences, Age Distribution, 0302 clinical medicine, Cost of Illness, Environmental health, Prevalence, medicine, Humans, Disabled Persons, 030212 general & internal medicine, 0101 mathematics, education, Stroke, Aged, Aged, 80 and over, education.field_of_study, business.industry, Incidence, Incidence (epidemiology), 010102 general mathematics, Public Health, Environmental and Occupational Health, Middle Aged, medicine.disease, Quality-adjusted life year, Europe, Years of potential life lost, Female, Quality-Adjusted Life Years, Nervous System Diseases, business
Abstract: Summary Background Neurological disorders account for a large and increasing health burden worldwide, as shown in the Global Burden of Diseases (GBD) Study 2016. Unpacking how this burden varies regionally and nationally is important to inform public health policy and prevention strategies. The population in the EU is older than that of the WHO European region (western, central, and eastern Europe) and even older than the global population, suggesting that it might be particularly vulnerable to an increasing burden of age-related neurological disorders. We aimed to compare the burden of neurological disorders in the EU between 1990 and 2017 with those of the WHO European region and worldwide. Methods The burden of neurological disorders was calculated for the year 2017 as incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability for the countries in the EU and the WHO European region, totally and, separately. Diseases analysed were Alzheimer's disease and other dementias, epilepsy, headache (migraine and tension-type headache), multiple sclerosis, Parkinson's disease, brain cancer, motor neuron diseases, neuroinfectious diseases, and stroke. Data are presented as totals and by sex, age, year, location and socio-demographic context, and shown as counts and rates. Findings In 2017, the total number of DALYs attributable to neurological disorders was 21·0 million (95% uncertainty interval 18·5–23·9) in the EU and 41·1 million (36·7–45·9) in the WHO European region, and the total number of deaths was 1·1 million (1·09–1·14) in the EU and 1·97 million (1·95–2·01) in the WHO European region. In the EU, neurological disorders ranked third after cardiovascular diseases and cancers representing 13·3% (10·3–17·1) of total DALYs and 19·5% (18·0–21·3) of total deaths. Stroke, dementias, and headache were the three commonest causes of DALYs in the EU. Stroke was also the leading cause of DALYs in the WHO European region. During the study period we found a substantial increase in the all-age burden of neurodegenerative diseases, despite a substantial decrease in the rates of stroke and infections. The burden of neurological disorders in Europe was higher in men than in women, peaked in individuals aged 80–84 years, and varied substantially with WHO European region and country. All-age DALYs, deaths, and prevalence of neurological disorders increased in all-age measures, but decreased when using age-standardised measures in all but three countries (Azerbaijan, Turkmenistan, and Uzbekistan). The decrease was mostly attributed to the reduction of premature mortality despite an overall increase in the number of DALYs. Interpretation Neurological disorders are the third most common cause of disability and premature death in the EU and their prevalence and burden will likely increase with the progressive ageing of the European population. Greater attention to neurological diseases must be paid by health authorities for prevention and care. The data presented here suggest different priorities for health service development and resource allocation in different countries. Funding European Academy of Neurology.
Published: 2020
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48. Predictors of Lesion Cavitation After Recent Small Subcortical Stroke

Author: Fergus N. Doubal, Maria del C. Valdés Hernández, Joanna M. Wardlaw, Daniela Pinter, Anna K. Heye, Francesca M Chappell, Stephen Makin, Christian Enzinger, Paul A. Armitage, Franz Fazekas, and Thomas Gattringer
Subjects: Male, medicine.medical_specialty, Fluid-attenuated inversion recovery, Lacunar stroke, 030218 nuclear medicine & medical imaging, Lesion, White matter, 03 medical and health sciences, 0302 clinical medicine, Recent small subcortical infarction, Internal medicine, Fractional anisotropy, medicine, Humans, Endothelial dysfunction, Aged, Subcortical stroke, business.industry, General Neuroscience, Brain, Middle Aged, medicine.disease, Stroke, medicine.anatomical_structure, Diffusion tensor imaging, Blood-Brain Barrier, Cavitation, Stroke, Lacunar, Cardiology, Female, Original Article, Neurology (clinical), medicine.symptom, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, Diffusion MRI, MRI
Abstract: Morphologic evolution of recent small subcortical infarcts (RSSI) ranges from lesion disappearance to lacune formation and the reasons for this variability are still poorly understood. We hypothesized that diffusion tensor imaging (DTI) and blood-brain-barrier (BBB) abnormalities early on can predict tissue damage 1 year after an RSSI. We studied prospectively recruited patients with a symptomatic MRI-defined RSSI who underwent baseline and two pre-specified MRI examinations at 1–3-month and 1-year post-stroke. We defined the extent of long-term tissue destruction, termed cavitation index, as the ratio of the 1-year T1-weighted cavity volume to the baseline RSSI volume on FLAIR. We calculated fractional anisotropy and mean diffusivity (MD) of the RSSI and normal-appearing white matter, and BBB leakage in different tissues on dynamic contrast-enhanced MRI. Amongst 60 patients, at 1-year post-stroke, 44 patients showed some degree of RSSI cavitation on FLAIR, increasing to 50 on T2- and 56 on T1-weighted high-resolution scans, with a median cavitation index of 7% (range, 1–36%). Demographic, clinical, and cerebral small vessel disease features were not associated with the cavitation index. While lower baseline MD of the RSSI (rs = − 0.371; p = 0.004) and more contrast leakage into CSF (rs = 0.347; p = 0.007) were associated with the cavitation index in univariable analysis, only BBB leakage in CSF remained independently associated with cavitation (beta = 0.315, p = 0.046). Increased BBB leakage into CSF may indicate worse endothelial dysfunction and increased risk of tissue destruction post RSSI. Although cavitation was common, it only affected a small proportion of the original RSSI.
Published: 2020
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49. Correction to: Features of intracranial hemorrhage in cerebral venous thrombosis

Author: Vincent Thijs, Sini Hiltunen, Eva Giralt-Steinhauer, Alessandro Pezzini, K. Afifi, Antonio Arauz, Susanna M. Zuurbier, Thomas Gattringer, Jonathan M. Coutinho, Carlos Garcia-Esperon, G Bellanger, Joan Montaner, Jordi Jimenez-Conde, Marc Schlamann, Irene Escudero, Christian Weimar, Philippe Demaerel, Nicole Hinteregger, Franz Fazekas, Robin Lemmens, Turgut Tatlisumak, Pieter-Jan Buyck, Paolo Costa, Jukka Putaala, Miguel A Barboza, and Dimitri Renard
Subjects: Venous thrombosis, medicine.medical_specialty, Neurology, business.industry, medicine, MEDLINE, Medizin, Neurology (clinical), Radiology, medicine.disease, business, Neuroradiology
Abstract: The original version of this article unfortunately contained mistakes. The correct information is given below.
Published: 2020

50. Abnormalities of resting state functional connectivity are related to sustained attention deficits in MS.

Author: Marisa Loitfelder, Massimo Filippi, Mara Rocca, Paola Valsasina, Stefan Ropele, Margit Jehna, Siegrid Fuchs, Reinhold Schmidt, Christa Neuper, Franz Fazekas, and Christian Enzinger
Subjects: Medicine, Science
Abstract: ObjectivesResting state (RS) functional MRI recently identified default network abnormalities related to cognitive impairment in MS. fMRI can also be used to map functional connectivity (FC) while the brain is at rest and not adhered to a specific task. Given the importance of the anterior cingulate cortex (ACC) for higher executive functioning in MS, we here used the ACC as seed-point to test for differences and similarities in RS-FC related to sustained attention between MS patients and controls.DesignBlock-design rest phases of 3 Tesla fMRI data were analyzed to assess RS-FC in 31 patients (10 clinically isolated syndromes, 16 relapsing-remitting, 5 secondary progressive MS) and 31 age- and gender matched healthy controls (HC). Participants underwent extensive cognitive testing.ObservationsIn both groups, signal changes in several brain areas demonstrated significant correlation with RS-activity in the ACC. These comprised the posterior cingulate cortex (PCC), insular cortices, the right caudate, right middle temporal gyrus, angular gyri, the right hippocampus, and the cerebellum. Compared to HC, patients showed increased FC between the ACC and the left angular gyrus, left PCC, and right postcentral gyrus. Better cognitive performance in the patients was associated with increased FC to the cerebellum, middle temporal gyrus, occipital pole, and the angular gyrus.ConclusionWe provide evidence for adaptive changes in RS-FC in MS patients compared to HC in a sustained attention network. These results extend and partly mirror findings of task-related fMRI, suggesting FC may increase our understanding of cognitive dysfunction in MS.
Published: 2012
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