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      Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases

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          Abstract

          Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12974-021-02293-x.

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          A clinical approach to diagnosis of autoimmune encephalitis.

          Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
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            Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

            Summary Background Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterisation of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain. Methods During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies. Findings The ABN portal was launched on April 2, 2020, the BASP portal on April 3, 2020, and the RCPsych portal on April 21, 2020. Data lock for this report was on April 26, 2020. During this period, the platforms received notification of 153 unique cases that met the clinical case definitions by clinicians in the UK, with an exponential growth in reported cases that was similar to overall COVID-19 data from UK Government public health bodies. Median patient age was 71 years (range 23–94; IQR 58–79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years. Interpretation To our knowledge, this is the first nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients. This study provides valuable and timely data that are urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy. Funding None.
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              Neurofilaments as biomarkers in neurological disorders

              Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.
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                Author and article information

                Contributors
                johann.steiner@med.ovgu.de
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                28 October 2021
                28 October 2021
                2021
                : 18
                : 245
                Affiliations
                [1 ]GRID grid.5807.a, ISNI 0000 0001 1018 4307, Laboratory of Translational Psychiatry, Department of Psychiatry and Psychotherapy, , Otto-Von-Guericke-University Magdeburg, ; Leipziger Str. 44, 39120 Magdeburg, Germany
                [2 ]GRID grid.411087.b, ISNI 0000 0001 0723 2494, Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, , University of Campinas (UNICAMP), ; Campinas, Brazil
                [3 ]GRID grid.411339.d, ISNI 0000 0000 8517 9062, Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Clinic for Cognitive Neurology, , University Hospital Leipzig, ; Leipzig, Germany
                [4 ]GRID grid.275559.9, ISNI 0000 0000 8517 6224, Section Translational Neuroimmunology, Department of Neurology, , Jena University Hospital, ; Jena, Germany
                [5 ]German Center for Mental Health (DZP), Center for Intervention and Research On Adaptive and Maladaptive Brain Circuits Underlying, Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
                [6 ]GRID grid.452320.2, ISNI 0000 0004 0404 7236, Center for Behavioral Brain Sciences, ; Magdeburg, Germany
                Author information
                http://orcid.org/0000-0002-2611-2268
                Article
                2293
                10.1186/s12974-021-02293-x
                8551937
                34711233
                00e1e63a-5547-400f-8fe4-265a79ae8960
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 14 July 2021
                : 8 October 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003107, bundesministerium für gesundheit;
                Award ID: ERA-NET grant no. 01EW2012
                Award Recipient :
                Funded by: Universitätsklinikum Magdeburg (8973)
                Categories
                Review
                Custom metadata
                © The Author(s) 2021

                Neurosciences
                sars-cov-2,covid-19,inflammation,autoimmune encephalitis,nmda receptor,corticosteroid,immunomodulatory agent

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