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in category neurology

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1: Six-month Neurological and Psychiatric Outcomes in 236,379 Survivors of COVID-19
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Posted 24 Jan 2021

Six-month Neurological and Psychiatric Outcomes in 236,379 Survivors of COVID-19
23,232 downloads medRxiv neurology

Maxime Taquet, John R Geddes, Masud Husain, Sierra Luciano, Paul J Harrison

Background. Neurological and psychiatric sequelae of COVID-19 have been reported, but there are limited data on incidence rates and relative risks. Methods. Using retrospective cohort studies and time-to-event analysis, we estimated the incidence of ICD-10 diagnoses in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; Parkinsonism; Guillain-Barre syndrome; nerve/nerve root/plexus disorders; myoneural/muscle disease; encephalitis; dementia; mood, anxiety, and psychotic disorders; substance misuse; and insomnia. Data were obtained from the TriNetX electronic health records network (over 81 million patients). We compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory infections using a Cox model. We investigated the effect on incidence estimates of COVID-19 severity, as proxied by hospitalization and encephalopathy (including delirium and related disorders). Findings. 236,379 patients survived a confirmed diagnosis of COVID-19. Among them, the estimated incidence of neurological or psychiatric sequelae at 6 months was 33.6%, with 12.8% receiving their first such diagnosis. Most diagnostic categories were commoner after COVID-19 than after influenza or other respiratory infections (hazard ratios from 1.21 to 5.28), including stroke, intracranial haemorrhage, dementia, and psychotic disorders. Findings were equivocal for Parkinsonism and Guillain-Barre syndrome. Amongst COVID-19 cases, incidences and hazard ratios for most disorders were higher in patients who had been hospitalized, and markedly so in those who had experienced encephalopathy. Results were robust to sensitivity analyses, including comparisons against an additional four index health events. Interpretation. The study provides evidence for substantial neurological and psychiatric morbidity following COVID-19 infection. Risks were greatest in, but not limited to, those who had severe COVID-19. The information can help in service planning and identification of research priorities.

2: SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability
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Posted 13 Oct 2020

SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability
8,589 downloads medRxiv neurology

Fernanda Crunfli, Victor Corasolla Carregari, Flavio Protasio Veras, Pedro Henrique Vendramini, Aline Gazzola Fragnani Valenca, Andre Saraiva Leao Marcelo Antunes, Carolina Brandao-Teles, Giuliana da Silva Zuccoli, Guilherme Reis-de-Oliveira, Licia C. Silva-Costa, Verônica Monteiro Saia-Cereda, Ana Campos Codo, Pierina Lorencini Parise, Daniel A. Toledo-Teixeira, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Icaro Maia Santos de Castro, Bruno Marcel Silva Melo, Glaucia M. Almeida, Egidi Mayara Silva Firmino, Isadora Marques Paiva, Bruna Manuella Souza Silva, Rafaela Mano Guimaraes, Raíssa Guimarães Ludwig, Gabriel Palermo Ruiz, Thiago Leite Knittel, Gustavo Gastão Davanzo, Jaqueline Aline Gerhardt, Patrícia Brito Rodrigues, Julia Forato, Mariene Ribeiro Amorim, Natalia Silva Brunetti, Matheus Cavalheiro Martini, Maíra Nilson Benatti, Sabrina Batah, Li Siyuan, Rafael Batista João, Lucas Scardua Silva, Mateus Henrique Nogueira, Italo Karmann Aventurato, Mariana Rabelo de Brito, Marina Koutsodontis Machado Alvim, José Roberto da Silva Junior, Lívia Liviane Damião, Maria Ercilia de Paula Castilho Stefano, Iêda Maria Pereira de Sousa, Elessandra Dias da Rocha, Solange Maria Gonçalves, Luiz Henrique Lopes da Silva, Vanessa Bettini, Brunno Machado de Campos, Guilherme Vieira Nunes Ludwig, Rosa Maria Mendes Viana, Ronaldo Martins, Andre Schwambach Vieira, José Carlos Alves-Filho, Eurico de Arruda Neto, Adriano Sebollela, Fernando Cendes, Paulo Louzada-Junior, Rene Donizeti Oliveira, Fernando Q. Cunha, André Damásio, Marco Aurélio Ramirez Vinolo, Carolina Demarchi Munhoz, Steven Kastrup Rehen, Helder I Nakaya, Thais Mauad, Amaro Nunes Duarte-Neto, Luiz Fernando Ferraz da Silva, Marisa Dolhnikoff, Paulo Saldiva, Alexandre Todorovic Fabro, Alessandro Farias, Pedro Manoel M. Moraes-Vieira, José Luiz Proença Módena, Clarissa Lin Yasuda, Marcelo A. Mori, Thiago Mattar Cunha, Daniel Martins-de-Souza

COVID-19 patients may exhibit neuropsychiatric and neurological symptoms. Here we found that anxiety and cognitive impairment are manifested by 28-56% of COVID-19 convalescent individuals with mild respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 25% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. We also found that neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons and in the biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and consequently leads to neuronal death or dysfunction. These processes are likely to contribute to the structural and functional alterations in the brain of COVID-19 patients.

3: Acute myelitis after SARS-CoV-2 infection: a case report.
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Posted 18 Mar 2020

Acute myelitis after SARS-CoV-2 infection: a case report.
7,798 downloads medRxiv neurology

Kang Zhao, Jucun Huang, Dan Dai, Yuwei Feng, Liming Liu, Shuke Nie

We report a case of acute myelitis in a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A 66-year-old man with coronavirus disease 2019 was admitted with acute flaccid paralysis of the bilateral lower limbs and urinary and bowel incontinence. All serum microbiological test results were negative, except for SARS-CoV-2 nucleic acid testing. Clinical findings indicated post-infectious acute myelitis. He received treatment containing ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, human immunoglobulin, and mecobalamin. With a diagnosis of post-infectious acute myelitis and comprehensive treatment, paralysis of the bilateral lower extremities ameliorated. After two negative novel coronavirus RNA nasopharyngeal swab tests, he was discharged and transferred to a designated hospital for isolation and rehabilitation therapy.

4: Autoantibodies against the prion protein in individuals with PRNP mutations
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Posted 08 Oct 2019

Autoantibodies against the prion protein in individuals with PRNP mutations
5,975 downloads medRxiv neurology

Karl Frontzek, Manfredi Carta, Marco Losa, Mirka Epskamp, Georg Meisl, Alice Anane, Jean-Philippe Brandel, Ulrike Camenisch, Joaquín Castilla, Stéphane Haïk, Tuomas P. J. Knowles, Ewald Lindner, Andreas Lutterotti, Eric Vallabh Minikel, Ignazio Roiter, Jiri G Safar, Raquel Sanchez-Valle, Dana Žáková, Simone Hornemann, Adriano Aguzzi

Structured abstractO_ST_ABSObjectiveC_ST_ABSTo determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease. MethodsIn this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human IgG1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between a) PRNP mutation carriers versus controls and b) asymptomatic versus symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts. ResultsWe found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status nor clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunological disorders, as well as PRNP codon 129 polymorphism. ConclusionsPathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC IgG autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well tolerated. Clinicaltrials.gov identifier NCT02837705.

5: COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report
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Posted 21 Apr 2020

COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report
4,063 downloads medRxiv neurology

Tianshu Zhang, Michael B. Rodricks, Ellen Hirsh

We present the first described case of Acute disseminated encephalomyelitis (ADEM) in a COVID-19 patient. The clinical features with head CT and brain MRI changes were described. Our described case is an atypical presentation of the novel coronavirus in a young patient and is illustrative of the possible approaches to explore the treatable differential etiologies.

6: The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis
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Posted 13 Jan 2020

The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis
3,788 downloads medRxiv neurology

David Baker, Gareth Pryce, Louisa K James, Monica Marta, Klaus Schmierer

ObjectiveOcrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval. MethodsInternet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600mg treatment cycles (week 0-72), followed by an 18 month treatment-free period. ResultsCD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events. ConclusionsOcrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression. Further studies are now clearly required to determine whether this data is robust, as few people seemed to complete the study.

7: The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study
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Posted 20 Jun 2020

The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study
3,716 downloads medRxiv neurology

Andrea Pilotto, Stefano Masciocchi, Irene Volonghi, Elisabetta del Zotto, Eugenio Magni, Valeria De Giuli, Francesca Caprioli, Nicola Rifino, Maria Sessa, Michele Gennuso, Maria Sofia Cotelli, Marinella Turla, Ubaldo Balducci, Sara Mariotto, Sergio Ferrari, Alfonso Ciccone, Fabrizio Fiacco, Alberto Imarisio, Barbara Risi, Alberto Benussi, Emanuele Foca', Francesca Caccuri, Matilde Leonardi, Roberto Gasparotti, Francesco Castelli, Gianluigi Zanusso, Alessandro Pezzini, Alessandro Padovani

Background: Several preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet. Objective: to describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment. Design: The ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. Results: Out of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions and relevance: We found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations.

8: High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms
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Posted 06 Jul 2020

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms
3,553 downloads medRxiv neurology

Christiana Franke, Caroline Ferse, Jakob Kreye, S Momsen Reincke, Elisa Sanchez-Sendin, Andrea Rocco, Mirja Steinbrenner, Stefan Angermair, Sascha Treskatsch, Daniel Zickler, Kai-Uwe Eckardt, Rick Dersch, Jonas Hosp, Heinrich J. Audebert, Matthias Endres, Christoph J. Ploner, Harald Prüss

COVID-19 intensive care patients occasionally develop neurological symptoms. The absence of SARS-CoV-2 in most cerebrospinal fluid (CSF) samples suggests the involvement of further mechanisms including autoimmunity. We therefore determined whether anti-neuronal or anti-glial autoantibodies are present in eleven consecutive severely ill COVID-19 patients presenting with unexplained neurological symptoms. These included myoclonus, cranial nerve involvement, oculomotor disturbance, delirium, dystonia and epileptic seizures. Most patients showed signs of CSF inflammation and increased levels of neurofilament light chain. All patients had anti-neuronal autoantibodies in serum or CSF when assessing a large panel of autoantibodies against intracellular and surface antigens relevant for central nervous system diseases using cell-based assays and indirect immunofluorescence on murine brain sections. Antigens included proteins well-established in clinical routine, such as Yo or NMDA receptor, but also a variety of specific undetermined epitopes on brain sections. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). While several underlying autoantigens still await identification in future studies, presence of autoantibodies may explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

9: New insights on the genetic etiology of Alzheimer and related dementia
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Posted 04 Oct 2020

New insights on the genetic etiology of Alzheimer and related dementia
3,399 downloads medRxiv neurology

Celine Bellenguez, Fahri Kucukali, Iris Jansen, Victor Andrade, Sonia Morenau-Grau, Najaf Amin, Adam Naj, Benjamin Grenier-Boley, Rafael Campos Martin, Peter Holsman, Anne Boland, Luca Kleideman, Vincent Damotte, Sven Vander Lee, Pablo Garcia, Yang Qiong, Joshua C. Bis, Marcos Costa, Julien Chapuis, Vilmentas Giedraitis, Maria J Bullido, Adolfo Lopez de Munain, Jordi Perez-Tur, Pascual Sanchez-Juan, Raquel Sanchez-Valle, Victoria Alvarez, Pau Pastor, Miguel Medina, Jasper Van Dongen, Christine Van Broeckhoven, Rik Vandenberghe, Sebastiaan Engelborghs, Gael Nicolas, Florence Pasquier, Olivier Hanon, Carole Dufouil, Claudine Berr, Stephanie Debette, Jean-Francois Dartigues, Gianfranco Spalletta, Benedetta Nacmias, Vincenzo Solfrezzi, Barbara Berroni, Lucio Tremolizzo, Davide Seripa, Paolo Caffara, Antonio Daniele, Daniela Galimberti, Innocenzo Rainero, Luisa Benussi, Alesio Squassina, Patricia Mecoci, Lucilla Parnetti, Carlo Masullo, Beatrice Arosio, John Hardy, Simon Mead, Kevin Morgan, Clive Holmes, Patrick Kehoe, Bob Woods, EADB consortium, Charge Consortium, ADGC Consortium, Jin Sha, Yi Zhao, Chien-Yueh Lee, Pavel p Kuksa, Kara L Hamilton-Nelson, Brian Kunkle, William S Bush, Eden R. Martin, Li-San Wang, Richard Mayeux, Lindsay A. Farrer, Jonathan L. Haines, Ruiqi Wang, Claudia Satizabal, Bruce Psaty, Oscar Lopez, Florentino Sanchez-Garcia, Borge G Nordestgaard, Anne Tybjaeg-hansen, Jesper Qvist Thomassen, Caroline Graff, Goran Papenberg, Hilkka Soininen, Miia Kivipelto, Annakaisa Haapasalo, Tiia Ngandu, Anne Koivisto, Teemu Kuulasmaa, Laura Molina Porcel, Johannes Kornhuber, Oliver Peters, Anja Schneider, Nikolaos Scarmeas, Martin Dichgans, Lutz Froelich, Dan Rujescu, Janine Diehl-Schmid, Timo Grimmer, Matthias Schmid, Markus M Mothen, Edna Grunblatt, Julius Popp, Norbert Scherbaum, Shima Mehrabian, Deckert Jurgen, dag Aareland, Geir Selbaeck, Ingvild Saltvedt, Srdjan Djurovic, Henne Holstege, Yolande A.L. Pijnenburg, John Van Swieten, Inez Ramakers, Aad Van der Lugt, Jurgen A.H.R. Claassen, Geert Jan Biessels, Philip Scheltens, Carmen Antunez, Pablo Mir, Luis Miguel Real, Jose Maria Garcia-Alberca, Gerard Pinol-Ripoll, Guillermo Garcia-Ribas, Manuel Serrano-Rios, Franck Jessen, Alexandre de Mendoca, Jakub Hort, Margaret A. Pericak-Vance, Magda Tsolaki, Philippe Amouyel, Julie Williams, Ruth Frikke-Schmidt, Jordi Clarimon, Jean-Francois Deleuze, Giacomina Rossi, Sudha Seshadri, Ole Andreassen, Martin Ingelsson, Mikko Hiltunen, Kristel Sleegers, Gerald SChellenberg, Cornelia Van Duijn, Rebecca Sims, Wiesje Van der Flier, Agustin Ruiz, Alfredo Ramirez, Jean-Charles Lambert

Alzheimer disease (AD) is a severe and incurable neurodegenerative disease, and the failure to find effective treatments suggests that the underlying pathology remains poorly understood. Due to its strong heritability, deciphering the genetic landscape of AD and related dementia (ADD) is a unique opportunity to advance our knowledge. We completed a meta-analysis of genome-wide association studies (39,106 clinically AD-diagnosed cases, 46,828 proxy-ADD cases and 401,577 controls) with the most promising signals followed-up in 25,392 independent AD cases and 276,086 controls. We report 75 risk loci for ADD, including 42 novel ones. Pathway-enrichment analyses confirm the involvement of amyloid/Tau pathways, highlight the role of microglia and its potential interaction with APP metabolism. Numerous genes exhibited differential expression or splicing in AD-related conditions and gene prioritization implies EGFR signaling and TNFapha pathway through LUBAC complex. We also generated a novel polygenic risk score strongly associated with the risk of future dementia or progression from mild cognitive impairment to dementia. In conclusion, by more than doubling the number of loci associated with ADD risk, our study offers new insights into the pathophysiological processes underlying AD and offers additional therapeutic entry-points and tools for translational genomics

10: Havana Syndrome Among Canadian Diplomats: Brain Imaging Reveals Acquired Neurotoxicity
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Posted 29 Sep 2019

Havana Syndrome Among Canadian Diplomats: Brain Imaging Reveals Acquired Neurotoxicity
2,759 downloads medRxiv neurology

Alon Friedman, Cynthia Calkin, Amanda Adams, Guillermo Aristi Suarez, Tim Bardouille, Noa Hacohen, A. Laine Green, R. Rishi Gupta, Javeria Hashmi, Lyna Kamintsky, Jong Sung Kim, Robert Laroche, Diane MacKenzie, Dan Milikovsky, Darren Oystreck, Jillian Newton, Greg Noel, Jonathan Ofer, Maher Quraan, Claire Reardon, Margaux Ross, Derek Rutherford, Matthias Schmidt, Yonatan Serlin, Crystal Sweeney, Janine Verge, Leah Walsh, Chris Bowen

BACKGROUNDIn late 2016, US diplomats stationed in Havana began presenting with a variety of neurological manifestations that proved difficult to diagnose. Though previous studies suggested a likely association with brain injury, the mechanism of injury, brain regions involved, and etiology remained unknown. METHODSWe conducted a multimodal study examining 26 Canadian diplomats and their family members, the majority of whom presented with symptoms similar to their American counterparts while residing in Havana. Assessments included a medical history, self-reported symptom questionnaires, cognitive assessments, blood tests, and brain imaging assessments (magnetic resonance imaging (MRI) and magnetoencephalography (MEG)). Individuals showing signs of brain injury underwent further neurological, visual, and audio-vestibular assessments. Eight participants were tested both before and after living in Havana. RESULTSOur assessment documents multiple functional and structural impairments, including significant spatial memory impairment, abnormal brain-stem evoked potentials, degradation of fibre tracts in the fornix and posterior corpus callosum, blood-brain barrier injury to the right basal forebrain and anterior insula, and abnormal paroxysmal slowing events of cortical activity. Subsequent mass-spectrometry and blood analyses documented reduced serum cholinesterase activity and the presence of organophosphates (Temephos) and pyrethroid metabolites (3-phenoxybenzoic acid or 3-BPA). CONCLUSIONSOur findings confirm brain injury, specify the regions involved, and raise the hypothesis of overexposure to cholinesterase inhibitors as a plausible etiology. If correct, our hypothesis bears public health ramifications (see Discussion) and suggests a course of action for reducing exposure in the future. FUNDINGGlobal Affairs Canada.

11: Similarities between the neurological symptoms of COVID-19 and Functional Neurological Disorder: A systematic overview of systematic reviews and implications for future neurological healthcare services
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Posted 25 Jul 2020

Similarities between the neurological symptoms of COVID-19 and Functional Neurological Disorder: A systematic overview of systematic reviews and implications for future neurological healthcare services
2,758 downloads medRxiv neurology

Tamar Wildwing, Nicole Holt

Objective: In response to the rapid spread of COVID-19, this paper provides health professionals with better accessibility to available evidence, summarising findings from a systematic overview of systematic reviews of the neurological symptoms seen in patients with COVID-19. Implications of so-called Long Covid on neurological services and primary care and similarities with other neurological disorders are discussed. Methods: Firstly, a systematic overview of current reviews of neurological symptoms of COVID-19 was conducted. Secondly the implications of these findings are discussed in relation to the potential effect on neurological services and the similarities in the experience of patients with COVID-19 and those with other neurological disorders. Results: Twenty-nine systematic reviews were identified within seven databases, published between 11th April 2020 and 27th August 2020. The results indicated (so far), that COVID-19 exhibits two types of neurological symptoms; life threatening symptoms such as Guillain Barre Syndrome and encephalitis, and less devastating symptoms such as fatigue and myalgia. These so-called lesser symptoms appear to be emerging as longer-term for some sufferers and have been recently labelled Long Covid. When compared, these Long Covid symptoms are very similar to other neurological conditions such as Chronic Fatigue Syndrome (CFS) and Functional Neurological Disorder (FND). Conclusions: Implications for neurological healthcare services in the UK may include longer waiting times and a need for more resources (including more qualified health professionals). There is also a possible change-effect on perceptions of other neurological conditions such as CFS and FND, particularly for health professionals. Future research is recommended to explore changes in perceptions of neurological symptoms because of COVID-19, particularly for health professionals.

12: Steroid-responsive severe encephalopathy in SARS-CoV-2 infection
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Posted 17 Apr 2020

Steroid-responsive severe encephalopathy in SARS-CoV-2 infection
2,208 downloads medRxiv neurology

Andrea Pilotto, SIlvia Odolini, Stefano Masciocchi, Agnese Comelli, Irene Volonghi, Stefano Gazzina, Sara Nocivelli, Alessandro Pezzini, Emanuele Focà, Arnaldo Caruso, Matilde Leonardi, Maria Pia Pasolini, Roberto Gasparotti, Francesco Castelli, Nicholas J Ashton, Kaj Blennow, Henrik Zetterberg, Alessandro Padovani

SARS-CoV-2 infection has the potential for targeting central nervous system and several neurological symptoms have been described in patients with severe respiratory distress. Here we described the case of an otherwise healthy 60-year old subject with SARS-CoV-2 infection but only mild respiratory abnormalities who developed severe progressive encephalopathy associated with mild pleocytosis and hyperproteinorrachia. MRI was negative whereas EEG showed theta waves on the anterior brain regions. Serum and CSF analyses excluded other known infectious or autoimmune disorders. The patient dramatically improved after high-doses steroid treatment suggesting an inflammatory-mediated brain involvement related to SARS-CoV-2 infection

13: Etiologic Subtypes of Ischemic Stroke in SARS-COV-2 Virus patients
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Posted 08 May 2020

Etiologic Subtypes of Ischemic Stroke in SARS-COV-2 Virus patients
2,034 downloads medRxiv neurology

Ketevan Berekashvili, Adam A Dmytriw, Volodomyr Vulkanov, Shashank Agarwal, Amit Khaneja, David Turkel-Parella, Jeremy Liff, Jeffrey Farkas, Thambirajah Nandakumar, Ting Zhou, Jennnifer Frontera, David E Kahn, Sun Kim, Kelly A Humbert, Matthew D Sanger, Shadi Yaghi, Aaron Lord, Karthikeyan Arcot, Ambooj Tiwari

Objective: To describe the ischemic stroke etiopathogenesis related to COVID-19 in a cohort of NYC hospitals. Background: Extra-pulmonary involvement of COVID-19 has been reported in the hepatic, renal and hematological systems. Most neurological manifestations are non-focal but few have reported the characteristics of ischemic strokes or investigated its pathophysiology. Methods: Over the last 6 weeks, data from four centers in New York City were collected to review the possible ischemic stroke types seen in COVID-19 positive patients. Their presentation, demographics, other related vascular risk factors, associated laboratory and coagulation markers, as well as imaging and outcomes were collected. Results: In our study, age range of patients was 25-75 with no significant male preponderance. 70% presented for acute hospitalization due the stroke. About a fifth did not have common risk factors for ischemic stroke like diabetes and hypertension. None had history of atrial fibrillation or smoking. 50% had poor outcome with four ending in mortality and one in a critical condition due ARDS. All had high Neutrophil/Lymphocyte ratio except one who demonstrated some neurological recovery. In 70% of our cases, D-dimer levels were collected, and all showed mild to severe elevation. None of the emergent large vessel occlusion (LVO) cases had known cardiac risk factors but two out of five were found to have cardiac abnormalities during the course of their hospitalization. All LVOs had hypercoagulable lab markers especially elevated D-dimer and/or Fibrinogen. The LVO patients were younger and sicker with a median age of 46 and mean NIHSS of 24 as opposed to non-LVOs with a median age of 62 and mean NIHSS of 6 respectively. Conclusion: COVID-19 related ischemic events can be small vessel, branch emboli or large vessel occlusions. The latter is often associated with either a hypercoagulable state or cardio-embolism. Patient outcomes were worse when multi-organ or pulmonary system failure prevailed. Keywords: COVID-19, Acute Ischemic strokes, Emergent Large Vessel Occlusion, Mechanical Thrombectomy

14: Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza
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Posted 21 May 2020

Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza
1,644 downloads medRxiv neurology

Alexander E. Merkler, Neal S. Parikh, Saad Mir, Ajay Gupta, Hooman Kamel, Eaton Lin, Joshua Lantos, Edward J. Schenck, Parag Goyal, Samuel S. Bruce, Joshua Kahan, Kelsey N. Lansdale, Natalie M. LeMoss, Santosh B. Murthy, Philip E. Stieg, Matthew E. Fink, Costantino Iadecola, Alan Z. Segal, Thomas R. Campion, Ivan Diaz, Cenai Zhang, Babak B. Navi

Importance: Case series without control groups suggest that Covid-19 may cause ischemic stroke, but whether Covid-19 is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection is uncertain. Objective: To compare the rate of ischemic stroke between patients with Covid-19 and patients with influenza, a respiratory viral illness previously linked to stroke. Design: A retrospective cohort study. Setting: Two academic hospitals in New York City. Participants: We included adult patients with emergency department visits or hospitalizations with Covid-19 from March 4, 2020 through May 2, 2020. Our comparison cohort included adult patients with emergency department visits or hospitalizations with influenza A or B from January 1, 2016 through May 31, 2018 (calendar years spanning moderate and severe influenza seasons). Exposures: Covid-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the nasopharynx by polymerase chain reaction, and laboratory-confirmed influenza A or B. Main Outcomes and Measures: A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, etiological mechanisms, and outcomes. We used logistic regression to compare the proportion of Covid-19 patients with ischemic stroke versus the proportion among patients with influenza. Results: Among 2,132 patients with emergency department visits or hospitalizations with Covid-19, 31 patients (1.5%; 95% confidence interval [CI], 1.0%-2.1%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78) and 58% were men. Stroke was the reason for hospital presentation in 8 (26%) cases. For our comparison cohort, we identified 1,516 patients with influenza, of whom 0.2% (95% CI, 0.0-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was significantly higher with Covid-19 than with influenza infection (odds ratio, 7.5; 95% CI, 2.3-24.9). Conclusions and Relevance: Approximately 1.5% of patients with emergency department visits or hospitalizations with Covid-19 experienced ischemic stroke, a rate 7.5-fold higher than in patients with influenza. Future studies should investigate the thrombotic mechanisms in Covid-19 in order to determine optimal strategies to prevent disabling complications like ischemic stroke.

15: Early postmortem brain MRI findings in COVID-19 non-survivors
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Posted 08 May 2020

Early postmortem brain MRI findings in COVID-19 non-survivors
1,597 downloads medRxiv neurology

Tim Coolen, Valentina Lolli, Niloufar Sadeghi, Antonin Rovai, Nicola Trotta, Fabio S Taccone, Jacques Creteur, Sophie Henrard, Jean-Christophe Goffard, Olivier Dewitte, Gilles Naeije, Serge Goldman, Xavier De Tiege

Importance: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered to have potential neuro-invasiveness that might lead to acute brain disorders or contribute to respiratory distress in patients with coronavirus disease 2019 (COVID-19). Brain magnetic resonance imaging (MRI) data in COVID-19 patients are scarce due to difficulties to obtain such examination in infected unstable patients during the COVID-19 outbreak. Objective: To investigate the occurrence of structural brain abnormalities in non-survivors of COVID-19 in a virtopsy framework. Design: Prospective, case series study with postmortem brain MRI obtained early (<24h) after death. Setting: Monocentric study. Participants: From 31/03/2020 to 24/04/2020, consecutive decedents who fulfilled the following inclusion criteria were included: death <24 hours, SARS-CoV-2 detection on nasopharyngeal swab specimen, chest computerized tomographic (CT) scan suggestive of COVID-19, absence of known focal brain lesion, and MRI compatibility. Main Outcome(s) and Measure(s): Signs of acute brain injury and MRI signal abnormalities along the olfactory tract and brainstem were searched independently by 3 neuroradiologists, then reviewed with neurologists and clinicians. Results: Among the 62 patients who died from COVID-19 during the inclusion period, 19 decedents fulfilled inclusion criteria. Subcortical micro- and macro-bleeds (2 decedents), cortico-subcortical edematous changes evocative of posterior reversible encephalopathy syndrome (PRES, one decedent), and nonspecific deep white matter changes (one decedent) were observed. Asymmetric olfactory bulbs were found in 4 other decedents without downstream olfactory tract abnormalities. No brainstem MRI signal abnormality. Conclusions and Relevance: Postmortem brain MRI demonstrates hemorrhagic and PRES-related brain lesions in non-survivors of COVID-19 that might be triggered by the virus-induced endothelial disturbances. SARS-CoV-2-related olfactory impairment seems to be limited to olfactory bulbs. The absence of brainstem MRI abnormalities does not support a brain-related contribution to respiratory distress in COVID-19.

16: Ataxia as a presenting manifestation of COVID -19: Report of a single case
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Posted 26 May 2020

Ataxia as a presenting manifestation of COVID -19: Report of a single case
1,569 downloads medRxiv neurology

Debaleena Mukherjee, Peyalee Sarkar, Souvik Dubey, Biman Kanti Ray, Alak Pandit, Durjoy Lahiri

Even though various neurological presentations of COVID-19 have surfaced up, ataxia as a presenting feature has rarely been reported so far. We hereby describe a confirmed case of SARS-CoV-2 infection which not only presented with ataxia but also had delayed onset of typical respiratory features. This case represents an atypical manifestation of COVID-19.

17: Three-month outcomes in hospitalized COVID-19 patients
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Posted 18 Oct 2020

Three-month outcomes in hospitalized COVID-19 patients
1,526 downloads medRxiv neurology

Jude PJ Savarraj, Angela B Burkett, Sarah N Hinds, Atzhiry S Paz, Andres Assing, Shivanki Juneja, Gabriela Delevati Colpo, Luis F Torres, Aaron Gusdon, Louise McCullough, H Alex Choi

COVID-19 is an ongoing pandemic with a devastating impact on public health. Acute neurological symptoms have been reported after a COVID-19 diagnosis, however there is no data available on the long-term neurological symptoms. Using a prospective registry of hospitalized COVID-19 patients, we assessed the neurological assessments (including functional, cognitive and psychiatric assessments) of several hospitalized patients at 3 months. Our main finding is that 71% of the patients still experienced neurological symptoms at 3 months and the most common symptoms being fatigue (42%) and PTSD (29%). 64% of the patients report pain symptoms we well. Cognitive symptoms were found in 12%. Our preliminary findings suggests the importance of investigating long-term and rationalizes the need for further studies investigating the neurologic outcomes after COVID-19.

18: Cerebral Microvascular Injury in Severe COVID-19
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Posted 24 Jul 2020

Cerebral Microvascular Injury in Severe COVID-19
1,493 downloads medRxiv neurology

John Conklin, Matthew P Frosch, Shibani Mukerji, Otto Rapalino, Mary Maher, Pamela W. Schaefer, Michael H. Lev, Ramon G. Gonzalez, Sudeshna Das, Samantha N. Champion, Colin Magdamo, Pritha Sen, George Kyle Harrold, Haitham Alabsi, Erica Normandin, Bennett Shaw, Jacob E. Lemieux, Pardis C Sabeti, John A. Branda, Emery N. Brown, M Brandon Westover, Susie Y Huang, Brian L Edlow

IMPORTANCE: Microvascular lesions are common in patients with severe COVID-19. Radiologic-pathologic correlation in one case suggests a combination of microvascular hemorrhagic and ischemic lesions that may reflect an underlying hypoxic mechanism of injury, which requires validation in larger studies. OBJECTIVE: To determine the incidence, distribution, and clinical and histopathologic correlates of microvascular lesions in patients with severe COVID-19. DESIGN: Observational, retrospective cohort study: March to May 2020. SETTING: Single academic medical center. PARTICIPANTS: Consecutive patients (16) admitted to the intensive care unit with severe COVID-19, undergoing brain MRI for evaluation of coma or focal neurologic deficits. EXPOSURES: Not applicable. MAIN OUTCOME AND MEASURES: Hypointense microvascular lesions identified by a prototype ultrafast high-resolution susceptibility-weighted imaging (SWI) MRI sequence, counted by two neuroradiologists and categorized by neuroanatomic location. Clinical and laboratory data (most recent measurements before brain MRI). Brain autopsy and cerebrospinal fluid PCR for SARS-CoV 2 in one patient who died from severe COVID-19. RESULTS: Eleven of 16 patients (69%) had punctate and linear SWI lesions in the subcortical and deep white matter, and eight patients (50%) had >10 SWI lesions. In 4/16 patients (25%), lesions involved the corpus callosum. Brain autopsy in one patient revealed that SWI lesions corresponded to widespread microvascular injury, characterized by perivascular and parenchymal petechial hemorrhages and microscopic ischemic lesions. CONCLUSIONS AND RELEVANCE: SWI lesions are common in patients with neurological manifestations of severe COVID-19 (coma and focal neurologic deficits). The distribution of lesions is similar to that seen in patients with hypoxic respiratory failure, sepsis, and disseminated intravascular coagulation. Collectively, these radiologic and histopathologic findings suggest that patients with severe COVID-19 are at risk for multifocal microvascular hemorrhagic and ischemic lesions in the subcortical and deep white matter.

19: High-contrast in-vivo imaging of tau pathologies in Alzheimer's and non-Alzheimer's disease tauopathies
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Posted 11 Mar 2020

High-contrast in-vivo imaging of tau pathologies in Alzheimer's and non-Alzheimer's disease tauopathies
1,469 downloads medRxiv neurology

Kenji Tagai, Maiko Ono, Manabu Kubota, Soichiro Kitamura, Keisuke Takahata, Chie Seki, Yuhei Takado, Hitoshi Shinotoh, Yasunori Sano, Kiwamu Matsuoka, Hiroyuki Takuwa, Masafumi Shimojo, Manami Takahashi, Kazunori Kawamura, Tatsuya Kikuchi, Maki Okada, Haruhiko Akiyama, Hisaomi Suzuki, Mitsumoto Onaya, Takahiro Takeda, Kimihito Arai, Nobutaka Arai, Nobuyuki Araki, Yuko Saito, Yasuyuki Kimura, Masanori Ichise, Yutaka Tomita, Ming-Rong Zhang, Tetsuya Suhara, Masahiro Shigeta, Naruhiko Sahara, Makoto Higuchi, Hitoshi Shimada

Depositions of fibrillary tau protein aggregates are implicated in diverse tauopathies, including Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD). A panel of radiochemicals has enabled in-vivo positron emission tomography (PET) of AD tau pathologies composed of all six tau isoforms, while sensitive detection of FTLD tau inclusions, mostly consisting of tau isoforms with three or four repeat domains only, has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing tau deposits with all isoform composites. In-vitro assays demonstrated the reactivity of this compound with tau pathologies in AD, four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and three-repeat tauopathies represented by Picks disease (PiD). We could also utilize PM-PBB3 for bimodal, multiscale optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of radiolabeled 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant PSP tau topologies. Notably, the in-vivo reactivity of 18F-PM-PBB3 with three- and four-repeat tau lesions was strongly supported by neuropathological examinations of autopsied and biopsied brains derived from PiD, PSP and CBD patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of the neuropathological basis, composed of PSP, CBD and PiD, underlying the diverse clinical phenotypes of FTLD. Taking these findings together, we propose the new tau probe as a powerful tool for etiological, diagnostic and therapeutic PET assessments of the tau pathogenesis in AD and FTLD spectra at nonclinical and clinical levels. One Sentence SummaryWe developed a positron emission tomography probe for tau fibrils in an animal model and patients with Alzheimers disease and non-Alzheimers disease tauopathies with high contrast, enabling translational assessments of the tau pathogenesis and diagnostic evaluations of disease-specific and stage-dependent tau topologies on an individual basis.

20: Redefining multiple sclerosis phenotypes using MRI
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Posted 04 Dec 2019

Redefining multiple sclerosis phenotypes using MRI
1,453 downloads medRxiv neurology

Arman Eshaghi, Alexandra Young, Peter Wijertane, Ferran Prados, Douglas Arnold, Sridar Narayanan, Charles R.G Guttmann, Frederik Barkhof, Daniel C Alexander, Alan J. Thompson, Declan Chard, Olga Cicarelli

BackgroundThere are 4 courses of multiple sclerosis (MS): clinically-isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary-progressive MS (PPMS) and secondary-progressive MS (SPMS). We aimed to achieve a further sophistication in the definition of MS phenotypes by identifying patient subgroups who accumulate magnetic resonance imaging (MRI) abnormalities with similar patterns. We assessed whether data-driven subtyping predicted clinical outcome and response to experimental treatments. MethodsIn this retrospective study, we included longitudinal data from 8,545 people with MS who had 31,451 visits from 14 double-blind randomised controlled trials and three observational cohorts. We included cross-sectional data from 14,928 healthy volunteers. For each visit, we processed brain MRI scans. We obtained 18 MRI variables, includ that included the volume of the cortex of each lobe and deep grey matter, cerebellar grey matter and wite matter, total lesion volume, cerebral white matter, brainstem, and T1/T2 ratio in regions of the normal appearing white matter (or NAWM). We trained a machine learning algorithm, called SuStaIn, on 14 datasets to identify data-driven subtypes. We then tested it in three external, independent datasets.we assessed the external validity of our model by testing if we could predict 24-week confirmed Expanded Disability Status Scale (EDSS) progression, disease activity, and the reduction in EDSS worsening in each subtype on treatment vs placebo. To investigate whether there was a difference in the treatment response between the SuStaIn subtypes we used linear mixed effect modles FindingsWe identified three data-driven subtypes with a distinct neuroanatomical spread of abnormality and termed subtypes according to areas they affected early in disease course: cortex-first (44% of patients), NAWM-first (30%), and the lesion-first (26%). Data-driven subtyping and staging, but not clinical classifications or EDSS at baseline, was associated with time to EDSS progression ({beta}Subtype=0.04 and {beta}stage=-0.06, p<0.01 for all). In external datasets, compared to the cortex-first, the lesion-first subtype had a shorter time to EDSS progression (hazard ratios range=1.75 to 1.82 across trials, p<0.01) and higher disease activity (p<0.05 for relapse rate and gad-enhancing lesions). In three progressive MS trials the lesion-first subtype showed the greatest treatment response (64% more than the cortex-first, p<0.001). InterpretationData-driven MS subtypes and stages, when compared with clinical classification or baseline EDSS better predicts the subsequent clinical course and treatment response. Data-driven subtyping has the potential to prospectively enrich clinical trials with patients who are more likely to respond to treatments. FundingInternational Progressive MS Alliance. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the Medline database for entries with "multiple sclerosis" and "clinical classification" keywords in their title or abstract published before February 2019. We found two consensus-based recommendations defining MS disease courses. First, in 1996, Lublin and colleagues who devised clinical classification for multiple sclerosis (MS) based on clinical evolution into relapse-onset or progressive onset course. This definition was revised in 2013 with specific terms for relapsing-remitting, secondary progressive and primary progressive terms while considering underlying processes from clinical or brain imaging assessments (progression and disease activity). However, the clinical classification of MS is retrospective and the boundary between MS phenotypes remains subjective mainly based on clinical evolution. Added value of this studyHere we applied machine learning methods to brain magnetic-resonance imaging to identify data-driven subgroups of patients who share similar patterns in accumulation of abnormalities in large cohorts from recent double-blind randomised controlled trials of MS. We found three subtypes with a distinct neuroanatomical spread of abnormality. These data-driven subtypes could predict disability progression, disease activity, and treatment response in relapse-onset and progressive MS and even within patients with a single clinical subtype. Implications of the all available evidenceData-driven MS subtyping has the potential to enrich trial cohorts with those who have the most potential to demonstrate treatment effects.

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