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Defining causality in COVID-19 and neurological disorders
  1. Mark Ellul1,2,3,
  2. Aravinthan Varatharaj4,5,
  3. Timothy R Nicholson6,
  4. Thomas Arthur Pollak6,
  5. Naomi Thomas7,8,
  6. Ava Easton9,
  7. Michael S Zandi10,
  8. Hadi Manji10,
  9. Tom Solomon1,2,3,
  10. Alan Carson11,
  11. Martin R Turner12,
  12. Rachel Kneen1,3,13,
  13. Ian Galea4,5,
  14. Sarah Pett14,15,
  15. Rhys Huw Thomas7,16,
  16. Benedict Daniel Michael1,2,3
  17. CoroNerve Steering Committee
    1. 1 NIHR Health Protection Research Unit for Emerging and Zoonotic Infection, Liverpool, UK
    2. 2 Neurology, The Walton Centre NHS Foundation Trust, Liverpool, UK
    3. 3 Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
    4. 4 Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
    5. 5 Wessex Neurosciences Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
    6. 6 Institute of Psychiatry Psychology & Neuroscience (IoPPN), King's College London, London, UK
    7. 7 Translational and Clinical Research Institute, Newcastle University, Newcastle, UK
    8. 8 Royal Victoria Infirmary, Newcastle, UK
    9. 9 Encephalitis Society, Malton, UK
    10. 10 Queen Square Institute of Neurology, University College London, London, UK
    11. 11 Department of Psychiatry, University of Edinburgh, Edinburgh, UK
    12. 12 Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK
    13. 13 Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, Merseyside, UK
    14. 14 Institute for Global Health, University College London, London, UK
    15. 15 MRC CTU at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
    16. 16 Department of Neurology, Royal Victoria Infirmary, Newcastle, UK
    1. Correspondence to Dr Benedict Daniel Michael, University of Liverpool Institute of Infection and Global Health, Liverpool L69 3BX, UK; benmic{at}

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    When faced with acute neurological presentations in a patient with COVID-19, how confident can one be that SARS-CoV2 is causal?


    Clinicians are increasingly recognising neurological presentations occur in some patients.1 A case series from Wuhan described associated neurological syndromes (eg, ‘dizziness’ and ‘impaired consciousness’), but with little detail regarding symptomatology, and cerebrospinal fluid (CSF) and neuroimaging findings.2 The extent to which these disorders were caused by the virus per se, rather than being complications of critical illness, unmasking of degenerative disease, or iatrogenic effects of repurposed medications is not clear.

    Numerous case reports have since emerged and, at the time of writing, published cases include encephalopathy,3 encephalitis,4 Guillain-Barré syndrome (GBS)5 and stroke.6 In most of these cases, the virus has been identified in respiratory samples, and in a small number in CSF. So far, the reporting of clinical features has been extremely variable, for example, several cases have claimed to report encephalitis without clear evidence of central nervous system (CNS) inflammation, which would not meet established definitions of the disease.7

    Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is associated with neurological manifestations is of critical importance as this may result in substantial morbidity and mortality.

    Defining causality

    It is crucial that neurologists and neuropsychiatrists apply a systematic strategy to determine whether there is evidence that SARS-CoV2 is causing these manifestations, whether they are a consequence of severe systemic disease alone, or simply coincidence. In 1965, Hill proposed criteria on which to build an argument for disease causation, which …

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