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      Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study

      research-article
      , MPhil a , b , c , d , x , , BMBCh e , f , , MD h , , MBChB c , d , i , , MRes a , b , , MBChB i , , PhD j , , MBChB i , , MSc l , , MBChB l , , MRCPCH m , , MBBCh i , , MBBCh n , , MBChB k , , MBChB p , , MBBS p , q , , Prof, MD r , s , , MBChB r , , Prof, MSc t , , MBChB t , , PhD m , u , , MRCPCH v , , MBChB w , , MRCPCH w , , MBBS w , , Prof, FRCR x , , MBChB e , , MBBS e , , BMBCh y , z , , MSc x , , MBChB x , , Prof, PhD g , , Prof, PhD o , z , , PhD m , u , , PhD h , , DPhil e , f , , Prof, FMedSci a , b , aa , * , , DPhil a , b , x , * , , PhD a , b , aa , * , , MBBS a , x , * , * , CoroNerve study group
      The Lancet. Child & Adolescent Health
      Elsevier Ltd.

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          Abstract

          Background

          The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents.

          Methods

          We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data.

          Findings

          Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9–5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1–17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group).

          Interpretation

          This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes.

          Funding

          UK Research and Innovation, Medical Research Council, Wellcome Trust, National Institute for Health Research.

          Related collections

          Most cited references28

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          Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

          The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations.
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            Neurological associations of COVID-19

            Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.
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              Neuropathology of patients with COVID-19 in Germany: a post-mortem case series

              Background Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS. Methods In this post-mortem case series, we investigated the neuropathological features in the brains of patients who died between March 13 and April 24, 2020, in Hamburg, Germany. Inclusion criteria comprised a positive test for SARS-CoV-2 by quantitative RT-PCR (qRT-PCR) and availability of adequate samples. We did a neuropathological workup including histological staining and immunohistochemical staining for activated astrocytes, activated microglia, and cytotoxic T lymphocytes in the olfactory bulb, basal ganglia, brainstem, and cerebellum. Additionally, we investigated the presence and localisation of SARS-CoV-2 by qRT-PCR and by immunohistochemistry in selected patients and brain regions. Findings 43 patients were included in our study. Patients died in hospitals, nursing homes, or at home, and were aged between 51 years and 94 years (median 76 years [IQR 70–86]). We detected fresh territorial ischaemic lesions in six (14%) patients. 37 (86%) patients had astrogliosis in all assessed regions. Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 34 (79%) patients. SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem. The presence of SARS-CoV-2 in the CNS was not associated with the severity of neuropathological changes. Interpretation In general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included. Funding German Research Foundation, Federal State of Hamburg, EU (eRARE), German Center for Infection Research (DZIF).
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                Author and article information

                Journal
                Lancet Child Adolesc Health
                Lancet Child Adolesc Health
                The Lancet. Child & Adolescent Health
                Elsevier Ltd.
                2352-4642
                2352-4650
                15 July 2021
                15 July 2021
                Affiliations
                [a ]Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool, UK
                [b ]National Institute for Health Research Health Protection Research Unit on Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK
                [c ]Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi
                [d ]Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi
                [e ]Department of Neurology, Great Ormond Street Hospital for Children, London, UK
                [f ]Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
                [g ]Institute for Global Health, University College London, London, UK
                [h ]Evelina Children's Hospital, London, UK
                [i ]Children's Neurosciences, Leeds Teaching Hospitals NHS Trust, Leeds, UK
                [j ]Department of Neurology, Barts and The London NHS Trust, London, UK
                [k ]Paediatric Neurology Department, Oxford Children's Hospital, Oxford, UK
                [l ]Child and Adolescent Mental Health Services, Leeds Community Healthcare Trust, Leeds, UK
                [m ]Translational and Clinical Research Institute, University of Newcastle, Newcastle, UK
                [n ]Department of Neurology, Southampton Children's Hospital, Southampton, UK
                [o ]Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK
                [p ]Department of Paediatric Neurology, Nottingham Children's Hospital, Nottingham, UK
                [q ]School of Medicine, University of Nottingham, Nottingham, UK
                [r ]Paediatric Neurosciences, Royal Hospital for Children, Glasgow, UK
                [s ]Paediatric Neurosciences Research Group, Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK
                [t ]Department of Neurology, Birmingham Children's Hospital, Birmingham, UK
                [u ]Department of Neurology, Royal Victoria Infirmary, Newcastle, UK
                [v ]Department of Paediatrics, Northumbria Healthcare NHS Foundation Trust, Newcastle, UK
                [w ]Department of Neurology, Royal Manchester Children's Hospital, Manchester, UK
                [x ]Alder Hey Children's NHS Foundation Trust, Liverpool, UK
                [y ]NIHR Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
                [z ]Department of Neurology, Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
                [aa ]The Walton Centre NHS Foundation Trust, Liverpool, UK
                Author notes
                [* ]Correspondence to: Dr Rachel Kneen, Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK
                [*]

                Joint last authors

                [†]

                Study group members are listed in the appendix (pp 14–16)

                Article
                S2352-4642(21)00193-0
                10.1016/S2352-4642(21)00193-0
                8279959
                34273304
                d9918821-755e-4649-b47c-79b6beb9130b
                © 2021 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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