Defining causality in COVID-19 and neurological disorders

Ellul, Mark; Varatharaj, Aravinthan; Nicholson, Timothy R; Pollak, Thomas A; Thomas, Naomi; Easton, Ava; Zandi, Michael S; Manji, Hadi; Solomon, Tom; Carson, Alan; Turner, Martin R.; Kneen, Rachel; Galea, Ian; Pett, Sarah; Thomas, Rhys; Michael, Benedict

doi:10.1136/jnnp-2020-323667

Cited by 74 publications

(86 citation statements)

References 11 publications

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“…Future hypothesis testing studies building on our findings to infer causal relationships between infection and neurological or neuropsychiatric presen tations should adhere to basic principles, such as the criteria for causation outlined by Bradford Hill as they pertain to pandemic respiratory infection and effects on the brain. 19 Many cerebrovascular events were identified in our study, as reported in previous cohorts and case reports of acute COVID19 complications. 1,20,21 The pathophysio logical mechanisms that underlie cerebrovascular events in COVID19 require further study, but there is a potential biological rationale for a vasculopathy, with a report of SARSCoV2 endothelitis in organs outside the cerebral vasculature 22 and cerebrovascular events, 23 in addition to coagulopathy, along with conventional stroke risk during sepsis.…”

Section: Discussionsupporting

confidence: 72%

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

Varatharaj

Thomas

Ellul

et al. 2020

The Lancet Psychiatry

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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.

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Section: Discussionsupporting

confidence: 72%

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

Varatharaj

Thomas

Ellul

et al. 2020

The Lancet Psychiatry

Self Cite

1,142

1,005

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“…Therefore, it is important to learn more about SARS-CoV-2-induced brain affection and its short- as well as its long-term consequences. As such targets for future clinical and brain coronavirus-related research and unmet needs are summarized: Human postmortem brain studies are essential to understand HCoV-induced brain pathologies (Ellul et al 2020 ; Glatzel 2020 ), including neuropathology and regional human postmortem neurotransmitter analyses. Moreover, molecular biological and—genetic studies should give evidence for functional disturbances caused by coronavirus affection.…”

Section: Discussionmentioning

confidence: 99%

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses

Riederer

Meulen

2020

J Neural Transm

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While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood-brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS-dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.

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“…Standardized case reporting and the application of Bradford Hill criteria will be essential in defining causality. 88 Thrombotic and cerebrovascular complications are not uncommon in critically ill patients due to systemic inflammation, prolonged immobility, intermittent AF, sedation, mechanical ventilation, and central catheter placement, but can be effectively prevented by prophylactic anti-coagulants. 89 This is not the case in COVID-19 (and the previous SARS outbreak) and a recent retrospective cohort study has suggested an incidence of stroke 7-8 times higher in patients hospitalized with COVID-19 infection compared with those hospitalized by influenza, 90 supporting the possibility of a SARS-CoV-2-driven hyper-coagulant state.…”

Section: Systemic Implications Of Sars-cov-2 Infectionmentioning

confidence: 99%

Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic

South

McCulloch

McColl

et al. 2020

International Journal of Stroke

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Anecdotal reports and clinical observations have recently emerged suggesting a relationship between COVID-19 disease and stroke; highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. In this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which SARS-CoV-2 may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. Some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. The current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms.

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Defining causality in COVID-19 and neurological disorders

Cited by 74 publications

References 11 publications

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses

Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic

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