The COVID-19 Clinical Neuroscience Study (COVID-CNS)

Lead Research Organisation: University of Liverpool
Department Name: Institute of Infection and Global Health

Abstract

COVID-19 patients frequently suffer brain problems during the infection and can be left with symptoms of brain injury. Similar problems have been seen in previous pandemics, including Spanish influenza over 100 years ago, but how and why this occurs is poorly understood.

We have already been notified of 800 UK patients with these complications due to COVID-19. We have a unique opportunity to understand how these problems occur and develop strategies to prevent and treat them. The questions we will ask include in whom does COVID-19 cause injury? Does it do this by invading the brain? Or by triggering excessive immune responses or interfering with the blood supply to nervous tissue?

We will answer these questions through in depth clinical, laboratory, and imaging studies of these 800 patients in comparison to 500 control patients (hospitalised during the pandemic with COVID-19 [400] or without COVID-19 [100]).

Without this understanding, we cannot determine whether anti-viral medication, or treatments that modulate the immune system or that improve blood supply will help, and if so in which patients.

We will apply this understanding through our World Health Organisation-commissioned Task Force (co-Chair Michael) to develop clinical care guidelines, identify patients for targeted clinical trials, and ultimately improve patient outcomes.

We will consent all participants to the NIHR BioResource, establishing COVID-CNS as a trial ready cohort and ensuring data and sample access for other researchers.

N.B. COVID-CNS is jointly led by co-PIs Benedict Michael and Gerome Breen

Technical Summary

Acute neurological complications of COVID-19 affect 20-30% of hospitalised patients, including encephalopathy/delirium, encephalitis, stroke, and Parkinsonism. These are often otherwise unexplained (i.e. excluding risk factors/hypoxia/iatrogenic causes) and often occur in younger patients. Survivors frequently report cognitive impairment, fatigue, and depression. The limited regenerative capacity of the brain means these complications may cause lifelong disability.
There is an urgent, unmet need to understand the biological causes of acute neurological complications of COVID-19 and their sequelae.

In collaboration with CoroNerve and ISARIC-4C's, we have already identified 800 patients who have been hospitalised with these complications. We will:
(1) invite these patients to join the COVID-CNS NIHR BioResource, using existing HRA approvals and protocols;
(2) conduct a case control study to determine the phenotypes and genotypes of these patients relative to 500 previously hospitalised controls including those from ISARIC-4C's and PHOSP-COVID (400 with COVID-19; 100 non-COVID);
(3) collect data from clinical case notes and electronic records, then assess neurological/cognitive/psychiatric sequelae at 3-6 months post-discharge;
(4) analyse brain injury, virologic, and immunological mechanisms in serum and cerebrospinal fluid, and analyse acute MRI's and, at follow up, functional MRI to study the pathophysiology of these complications.

By understanding these mechanisms, we will be able to stratify patients into clinical care pathways and into trials using existing and novel therapies. We will apply this knowledge through our WHO-commissioned Task Force (co-Chair Michael) to have immediate impact on patient care and through our PPI programme. The NIHR BioResource will provide sustainability and, through linkage to the community cohort (n=35,000), will allow us to determine if similar, but milder, symptoms are being experienced more widely.

Publications

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publication icon
Ariño H (2022) Neuroimmune disorders in COVID-19. in Journal of neurology

 
Description Acute neurological complications of COVID-19 range from stroke, to brain inflammation, to MS-like diseases, to generalised brain dysfunction. Often altered mental function occured in younger people, even with mild COVID symptoms or before these developed. This led to WHO screening criteria.

Those with COVID strokes often had preventable risk factors like high blood pressure, highlighting the importance of controlling this.

Once the antiviral (remdesivir) and the anti-inflammatory (dexamethasone) started being used for lung symptoms, brain complication rates decreased significantly.

However, those who had brain dysfunction during COVID showed cognitive impairment even 1 year after COVID with raised brain injury markers in the blood still present, even though the inflammation markers in blood had decreased.

We are now studying what this means for the longer term: Who recovers? Who doesn't? How can we help recovery?
Exploitation Route We now help advise the government on identifying at risk groups, with the WHO on the implications for low and middle income countries, and the Academy of Medical Sciences on future research priorities in light of these findings.
Sectors Healthcare

Government

Democracy and Justice

URL https://www.liverpool.ac.uk/covid-clinical-neuroscience-study/outputs/
 
Description WHO, AMS, NICE, DHSC policy documents, advisory panels, and international guidelines as included
First Year Of Impact 2020
Sector Healthcare
 
Description Academy of Medical Sciences
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
URL https://acmedsci.ac.uk/file-download/4747802
 
Description Advising Department of Health and Social Care on Vulnerable Groups in COVID-19
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description WHO Brain Health Unit
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
URL https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci-Brief-Neurology-2021.1
 
Guideline Title WHO COVID-19 Living Guideline
Description WHO COVID-19 Living Guideline
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL https://reliefweb.int/report/world/clinical-management-covid-19-living-guideline-15-september-2022?p...
 
Description Understanding cerebral inflammation in viral encephalitis - how does neuron-glial signalling drive blood-brain barrier permeability?
Amount £1,028,451 (GBP)
Funding ID MR/V007181/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2021 
End 01/2026
 
Description BLOOD BRAIN BARRIER MODELLING 
Organisation Manchester University
Country United States 
Sector Academic/University 
PI Contribution DIRECTION, FUNDING AND SUPERVISION
Collaborator Contribution ADVANCED TECHNIQUES FOR FLOW-MODELLING MULTI-CELLULAR BLOOD-BRAIN BARRIER MODELS. KEEPS COMMITMENT TO THE THREE R'S AND ADVANCES OUR UNDERSTANDING OF TARGETS TO MITIGATE LEUKOCYTE MIGRATION IN RESPONSE TO BRAIN INFECTION
Impact NOT YET, IN PROGRESS
Start Year 2022
 
Description Liverpool-KCL-Cambridge Infection Neuroscience Consortium 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Establishment of an interdisciplinary clinical-academic UK-wide consortium of researchers across the neurosciences, initially catalysed by the need to study the effects of COVID-19 on the brain and now expanding.
Collaborator Contribution KCL- Genetics of Neuropsychiatry for at risk groups and mental health sequelae Cambridge- Neuroscience of brain injury biomarkers and adaptive immune responses
Impact All COVID papers listed
Start Year 2020
 
Description Liverpool-KCL-Cambridge Infection Neuroscience Consortium 
Organisation University of Cambridge
Department Cambridge Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Establishment of an interdisciplinary clinical-academic UK-wide consortium of researchers across the neurosciences, initially catalysed by the need to study the effects of COVID-19 on the brain and now expanding.
Collaborator Contribution KCL- Genetics of Neuropsychiatry for at risk groups and mental health sequelae Cambridge- Neuroscience of brain injury biomarkers and adaptive immune responses
Impact All COVID papers listed
Start Year 2020
 
Description MURINE MODELLING 
Organisation Harvard University
Country United States 
Sector Academic/University 
PI Contribution DIRECTION, FUNDING AND MENTORSHIP
Collaborator Contribution INTRAVITAL MICROSCOPY AND OTHER ADVANCE IMAGING TECHNIQUES FOR LEUKOCYTE MIGRATION IN TO THE CENTRAL NERVOUS SYSTEM
Impact MICHAEL BD, ET AL. CELL REP 2020: https://pubmed.ncbi.nlm.nih.gov/32937134/
Start Year 2016
 
Title HARMONISATION PROTOCOL FOR BRAIN MRI ACROSS COMPANIES 
Description HARMONISATION PROTOCOL FOR BRAIN MAGNETIC RESONANCE IMAGING ACROSS COMPANIES (GE AND SEIMANS) ALLOWING DIRECTLY COMPARABLE NEUROPATHOLOGICAL IMAGING CORRELATES FOR CLINICAL FEATURES OF COVID-19'S IMPACT ONT HE BRAIN, INCLUDING T1, T2, FLAIR, DIFFUSION AND ARTERIAL LABELLING 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2021 
Open Source License? Yes  
Impact FIRST OPEN ACCESS TOOL FOR GLOBAL BRAIN MRI HARMONISATION 
URL https://www.medrxiv.org/content/10.1101/2021.10.13.21264967v1
 
Description Booklet about the COVID-CNS research study 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact COVID-19 patients frequently suffer brain problems during the infection and can be left with symptoms of brain injury. This was an observational study looking to understand how these problems occur and develop strategies to prevent and treat them. There are some reports of brain-related complications due to having some of the COVID-19 vaccines. We have also studied these complications to see if they are due to the same or different mechanisms to those seen in COVID-19 patients. The booklet was to read about how we recruited patients and what we have learnt so far.
Year(s) Of Engagement Activity 2020,2021,2022
URL https://www.liverpool.ac.uk/media/livacuk/covid-cns/Covid-cns.pdf
 
Description COVID-CNS Webinar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This webinar, hosted by the Encephalitis Society, showcases the COVID-CNS study one year on from completing recruitment. The COVID-CNS scientists and clinicians talk about brain complications related to COVID-19 and audience members ask them questions. Listen to the findings so far and what they plan to do next.
Year(s) Of Engagement Activity 2023
URL https://www.youtube.com/watch?v=L8k6YelXo6w
 
Description Encephalitis Podcast - The COVID-19 Clinical Neuroscience Study 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Benedict Michael talks to host Dr Ava Easton about the COVID-19 Clinical Neuroscience Study - a £2.3 million research study looking in the acute neurological and neuropsychiatric complications of COVID-19. He also shares his thoughts on being a front-line medic during the pandemic and the NHS in general.
Year(s) Of Engagement Activity 2022
URL https://www.youtube.com/watch?v=ibGtj30OSPs
 
Description Encephalitis Society PodCast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Inform general public about COVID-19's effects on the brain
Year(s) Of Engagement Activity 2020
 
Description INTERVEIWS .NATURE NEWS- COVID-19 affecting the brain .BBC NEWS World Service Lancet Psych Paper .BBC NEWS London COVID-19 Neurology in Hospitals and the Community .ROYAL COLLEGE OF PHYSICIANS and ASSOCIATION OF BRITISH NEUROLOGISTS: COVID-19 for Neurologists .ROYAL COLLEGE OF PSYCHIATRISTS: COVID-19 and the Brain .ENCEPHALITIS SOCIETY: COVID-19 Interview .BRITISH ASSOCIATION OF STROKE PHYSICIANS: Stroke in the era of COVID-19 Password: 5K@8M12U .CoroNerve.com MEDIA HIGHLIGHTS .THE G 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact INTERVEIWS

.NATURE NEWS- COVID-19 affecting the brain

.BBC NEWS World Service Lancet Psych Paper

.BBC NEWS London COVID-19 Neurology in Hospitals and the Community

.ROYAL COLLEGE OF PHYSICIANS and ASSOCIATION OF BRITISH NEUROLOGISTS: COVID-19 for Neurologists

.ROYAL COLLEGE OF PSYCHIATRISTS: COVID-19 and the Brain

.ENCEPHALITIS SOCIETY: COVID-19 Interview

.BRITISH ASSOCIATION OF STROKE PHYSICIANS: Stroke in the era of COVID-19 Password: 5K@8M12U

.CoroNerve.com



MEDIA HIGHLIGHTS
.THE GUARDIAN
.CNN
.ITV News
.RADIO CANADA
.THE EXPRESS
.SUNDAY TIMES: COVID-19 and Neuroscience
.DER SPIEGEL: Chronic impacts of COVID-19 on the brain
.THE TELEGRAPH
.THE LANCET NEUROLOGY: Neurological Education in Africa; Breaking the cycle
.THE LANCET INFECTIOUS DISEASES: Surveillance of Neurological Infection
.DAILY MAIL: COVID-19's effects on the brain
Year(s) Of Engagement Activity 2020,2021
URL https://www.bbc.co.uk/sounds/play/p08j2zpr
 
Description Participant Testimonials 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Participants sharing their testimonies about taking part in the COVID-CNS research study.
Year(s) Of Engagement Activity 2020,2021,2022
URL https://www.youtube.com/watch?v=LosbbW3P60s