Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (preprint)

Neurological complications occur in a significant proportion of COVID-19 cases. In order to identify key biomarkers, we measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants admitted to hospital for management of COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided convalescent sera (up to76 weeks post admission). Compared to 60 controls, brain injury biomarkers (total-Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in participants with altered consciousness. Total-Tau (tTau) and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness and correlated with brain injury biomarker levels. Inflammatory mediators were lower in convalescent sera than acute sera. Levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with tTau levels even at later time points. When compared to acute COVID-19 patients with a normal Glasgow Coma Scale score (GCS), network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase of COVID-19 and we found brain injury markers persist during convalescence and may be driven by a para-infectious process involving a dysregulated host response.

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (preprint)

We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission). Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2R, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point. When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFN{gamma}, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

Sociodemographic, mental health, and physical health factors associated with participation within re-contactable mental health cohorts: an investigation of the GLAD Study (preprint)

Background: The Genetic Links to Anxiety and Depression (GLAD) Study is a large cohort of individuals with lifetime anxiety and/or depression, designed to facilitate re-contact of participants for mental health research. At the start of the pandemic, participants from three cohorts, including the GLAD Study, were invited to join the COVID-19 Psychiatry and Neurological Genetics (COPING) study to monitor mental and neurological health. However, previous research suggests that participation in longitudinal studies follows a systematic, rather than random, process, which can ultimately bias results. Therefore, this study assessed participation biases following the re-contact of GLAD Study participants. Methods: In April 2020, all current GLAD Study participants (N = 36,770) were invited to the COPING study. Using logistic regression, we investigated whether sociodemographic, mental, and physical health characteristics were associated with participation in the COPING baseline survey. Subsequently, we used a zero-inflated negative binomial regression examined whether these factors were related to participation in the COPING follow-up surveys. Results: For aim one, older age, female gender identity, non-binary or prefer to self-define gender identity, having one or more physical health disorders, and providing a saliva kit for the GLAD Study were associated with an increased odds of completing the COPING baseline survey. In contrast, lower educational attainment, Asian or Asian British ethnic identity, Black or Black British ethnic identity, higher alcohol consumption at the GLAD sign-up survey and current or ex-smoking were associated with a reduced odds. For aim 2, older age, female gender, and saliva kit provision were associated with greater COPING follow-up survey completion. On the other hand, lower educational attainment, ex-smoking, higher alcohol consumption at the GLAD Study sign-up, and self-reported attention deficit hyperactivity disorder had negative relationships. Conclusions: Participation biases surrounding sociodemographic and physical health characteristics were particularly evident when re-contacting the GLAD Study volunteers. Future researchers re-contacting participants from existing cohorts/BioResources should be mindful of participation bias and how it may affect results obtained from analyses.

The Eating Disorders Genetics Initiative (EDGI) United Kingdom (preprint)

Objective The Eating Disorders Genetics Initiative United Kingdom (EDGI UK), part of the National Institute for Health and Care Research (NIHR) Mental Health BioResource, aims to deepen our understanding of the environmental and genetic aetiology of eating disorders. EDGI UK launched in February 2020 and is partnered with the UK eating disorders charity, Beat. There are multiple EDGI branches worldwide. Method EDGI UK recruits via media and clinical services. Anyone living in England, at least 16 years old, with a lifetime probable or clinical eating disorder is eligible to sign up online: edgiuk.org . Participants complete online questionnaires, donate a saliva sample for genetic analysis, and consent to medical record linkage and recontact for future studies. Results As of September 2022, EDGI UK has recruited 8,397 survey participants: 98% female, 93% white, 97.7% cisgender, 67% heterosexual, and 52% have a university degree. Half (51.7%) of participants have returned their saliva kit. The most common diagnoses are anorexia nervosa (42.7%), atypical anorexia nervosa (31.4%), bulimia nervosa (33.2%), binge-eating disorder (14.6%), and purging disorder (33.5%). Conclusion EDGI UK is the largest UK eating disorders study but needs to increase its diversity, and efforts are underway to do so. It also offers a unique opportunity to accelerate eating disorder research, and collaboration between researchers and participants with lived experience, with unparalleled sample size.

Risk and protective factors for new onset binge eating, low weight, and self-harm symptoms in over 25,000 individuals in the UK during the COVID-19 pandemic (preprint)

Objective: The disruption caused by the COVID-19 pandemic has been associated with poor mental health, including increases in eating disorder and self-harm symptoms. We investigated risk and protective factors for new onset of these symptoms during the pandemic. Method: Data were from the COVID-19 Psychiatry and Neurological Genetics study and the Repeated Assessment of Mental health in Pandemics Study (n = 45,058). Exposures were socio-demographic characteristics, lifetime psychiatric disorder, and COVID-related variables, including SARS-CoV-2 infection/illness with COVID-19. We identified four sub-samples of participants without pre-pandemic experience of our outcomes: binge eating (n = 18,172), low weight (n = 19,148), suicidal and/or self-harm ideation (n = 12,650), and self-harm (n = 20,266). Participants reported on our outcomes at frequent intervals (fortnightly to monthly). We fitted four logistic regression models to identify factors associated with new onset of our outcomes. Results: Within each subsample, new onset was reported by: 16.9% for binge eating, 8.9% for low weight, 26.6% for suicidal and/or self-harm ideation, and 3.3.% for self-harm. Shared risk factors included having a lifetime psychiatric disorder, not being in paid employment, and higher pandemic worry scores. Conversely, infection with SARS-CoV-2/illness with COVID-19 was linked to lower odds of all outcomes. Other factors were associated with one outcome, such as pandemic-related loneliness with suicidal and/or self-harm ideation. Discussion: Overall, we detected shared risk factors that may drive the comorbidity between eating disorders and self-harm. Subgroups of individuals with these risk factors may require more frequent monitoring during future pandemics.

Cohort Profile: Longitudinal population-based study of COVID-19 in UK adults (COVIDENCE UK) (preprint)

Background: Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is estimated to have caused more than 18 million deaths worldwide as of end-May 2022. Methods: COVIDENCE UK is a longitudinal population-based study that investigates risk factors for, and impacts of, COVID-19 in UK residents aged [≥]16 years. A unique feature is the capacity to support trial-within-cohort studies to evaluate interventions for prevention of COVID-19 and other acute respiratory illnesses. Participants complete a detailed online baseline questionnaire capturing self-reported information relating to their socio-demographic characteristics, occupation, lifestyle, quality of life, weight, height, longstanding medical conditions, medication use, vaccination status, diet and supplemental micronutrient intake. Follow-up on-line questionnaires capturing incident symptoms of COVID-19 and other acute respiratory infections, incident swab test-confirmed COVID-19, doses of SARS-CoV-2 vaccine received, and quality of life are completed at monthly intervals. Results: The study was launched on 1st May 2020 and closed to recruitment on 6th October 2021. A total of 19,981 participants enrolled and consented to 5-year follow-up with medical record linkage. Their mean age was 59.1 years (range 16.0 to 94.4 years), 70.2% were female, and 93.7% identified their ethnic origin as White. Analyses conducted to date have provided key insights into risk factors for SARS-CoV-2 infection and COVID-19 disease, determinants of SARS-CoV-2 vaccine immunogenicity and efficacy, and impacts of COVID-19 on health economic outcomes. The cohort has also supported conduct of a Phase 3 randomised trial-within-cohort study (CORONAVIT) evaluating implementation of a test-and-treat approach to correcting sub-optimal vitamin D status on incidence and severity of acute respiratory infections, including COVID-19. Conclusions: The COVIDENCE UK dataset represents a valuable resource containing granular information on factors influencing susceptibility to, and impacts of, COVID-19 in UK adults. Researchers wishing to access anonymised participant-level data should contacting the corresponding author for further information.

Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity (preprint)

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly. We sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray. During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens. Furthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.

Reliability of multi-modal MRI-derived brain phenotypes for multi-site assessment of neuropsychiatric complications of SARS-CoV-2 infection (preprint)

Background Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Methods A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI) and arterial spin labelling (ASL) was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N=8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King’s College London). Over 2,000 Imaging Derived Phenotypes (IDPs) measuring both data quality and regional image properties of interest were automatically estimated by customised UKB image processing pipelines. Components of variance and intra-class correlations were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Results Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. First considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, but there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data. Conclusion These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonization of data collected from sites using scanners supplied by different manufacturers. These protocols have already been adopted for MRI assessments of post-COVID patients in the UK as part of the COVID-CNS consortium.

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK (preprint)

Background: The COVID-19 pandemic is a novel population-level stressor. As such, it is important to examine pandemic-related changes in mental health and to identify which individuals are at greatest risk of worsening symptoms. Methods: Online questionnaires were administered to 34,465 individuals in the UK, recruited from existing cohorts or via social media. Around one third (n = 12,718) with prior diagnoses of depression or anxiety completed pre-pandemic mental health assessments, allowing prospective investigation of symptom change. We examined changes in depression, anxiety and PTSD symptoms using prospective, retrospective and global ratings of change assessments. We also examined the effect of key risk factors on changes in symptoms.Outcomes: Prospective analyses showed small decreases in depression (PHQ-9: - .43 points) and anxiety symptoms (GAD-7: -.33 points), and increases in PTSD symptoms (PCL-6: .22 points). Conversely, retrospective analyses demonstrated large significant increases in depression (2.40 points) and anxiety symptoms (1.97 points) and 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Using both prospective and retrospective symptom measures, regression analyses demonstrated that worsening depression, anxiety and PTSD symptoms were associated with i) prior mental health diagnoses, ii) female gender; iii) young age, and iv) unemployed or student status.Interpretation: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously-reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias underestimating prior symptom severity.

Pre-pandemic mental health and disruptions to healthcare, economic, and housing outcomes during COVID –19: evidence from 12 UK longitudinal studies (preprint)

Background The COVID-19 pandemic and associated virus suppression measures have disrupted lives and livelihoods and people already experiencing mental ill-health may have been especially vulnerable. Aim To quantify mental health inequalities in disruptions to healthcare, economic activity and housing. Method 59,482 participants in 12 UK longitudinal adult population studies with data collected prior to and during the COVID-19 pandemic. Within each study we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to three domains: healthcare (medication access, procedures, or appointments); economic activity (employment, income, or working hours); and housing (change of address or household composition). Meta-analyses were used to pool estimates across studies. Results Across the analysed datasets, one to two-thirds of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. One standard deviation higher pre-pandemic psychological distress was associated with: (i) increased odds of any healthcare disruptions (OR=1.30; [95% CI:1.20–1.40]) with fully adjusted ORs ranging from 1.24 [1.09–1.41] for disruption to procedures and 1.33 [1.20– 1.49] for disruptions to prescriptions or medication access; (ii) loss of employment (OR=1.13 [1.06–1.21]) and income (OR=1.12 [1.06 –1.19]) and reductions in working hours/furlough (OR=1.05 [1.00–1.09]); (iii) no associations with housing disruptions (OR=1.00 [0.97–1.03]); and (iv) increased likelihood of experiencing a disruption in at least two domains (OR=1.25 [1.18–1.32]) or in one domain (OR=1.11 [1.07–1.16]) relative to no disruption. Conclusion People experiencing psychological distress pre-pandemic have been more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening the existing inequalities in mental health.

Risk Factors for Developing COVID-19: A Population-Based Longitudinal Study (COVIDENCE UK) (preprint)

Background: Risk factors for severe COVID-19 include older age, male sex, obesity, Black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. Methods: We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 st May 2020 to 5 th February 2021 . Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted odds ratios (aORs) for associations between potential risk factors and risk of COVID-19. Findings: We recorded 446 incident cases of COVID-19 in 15,227 participants (2.9%). Increased risk of developing COVID-19 was independently associated with Asian/Asian British vs . White ethnicity (aOR 2.31, 95% CI 1.35-3.95), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11-1.43) , any vs . no visits to/from other households in previous week (aOR 1.33, 1.07-1.64), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.01-1.09), frontline occupation excluding health/social care vs. no frontline occupation (aOR 1.49, 1.12-1.98), and raised body mass index (BMI) (aOR 1.51 [1.20-1.90] for BMI 25.0-30.0 kg/m 2 and 1.38 [1.05-1.82] for BMI >30.0 kg/m 2 vs. BMI <25.0 kg/m 2 ). Atopic disease was independently associated with decreased risk (aOR 0.76, 0.59-0.98). No independent associations were seen for age, sex, other medical conditions, diet, or micronutrient supplement use. Interpretation: After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased risk of developing COVID-19, while atopic disease was associated with decreased risk. Trial Registration: It is registered with ClinicalTrials.gov (NCT04330599). Funding: Barts Charity, Health Data Research UK Declaration of Interest: None to declare. Ethical Approval: The study was sponsored by Queen Mary University of London and approved by<br>Leicester South Research Ethics Committee (ref 20/EM/0117).

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK) (preprint)

Summary Background Risk factors for severe COVID-19 include older age, male sex, obesity, Black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. Methods We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 st May 2020 to 5 th February 2021. Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted odds ratios (aORs) for associations between potential risk factors and risk of COVID-19. Findings We recorded 446 incident cases of COVID-19 in 15,227 participants (2.9%). Increased risk of developing COVID-19 was independently associated with Asian/Asian British vs . White ethnicity (aOR 2.31, 95% CI 1.35-3.95), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11-1.43), any vs . no visits to/from other households in previous week (aOR 1.33, 1.07-1.64), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.01-1.09), frontline occupation excluding health/social care vs . no frontline occupation (aOR 1.49, 1.12-1.98), and raised body mass index (BMI) (aOR 1.51 [1.20-1.90] for BMI 25.0-30.0 kg/m 2 and 1.38 [1.05-1.82] for BMI >30.0 kg/m 2 vs . BMI <25.0 kg/m 2 ). Atopic disease was independently associated with decreased risk (aOR 0.76, 0.59-0.98). No independent associations were seen for age, sex, other medical conditions, diet, or micronutrient supplement use. Interpretation After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased risk of developing COVID-19, while atopic disease was associated with decreased risk. Funding Barts Charity, Health Data Research UK

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19 (preprint)

The COVID-19 pandemic death toll now surpasses two million individuals and there is a need for early identification of individuals at increased risk of mortality. Host genetic variation partially drives the immune and biochemical responses to COVID-19 that lead to risk of mortality. We identify and prioritise blood proteins and biomarkers that may indicate increased risk for severe COVID-19, via a proteome Mendelian randomization approach by collecting genome-wide association study (GWAS) summary statistics for >4,000 blood proteins. After multiple testing correction, troponin I3, cardiac type (TNNI3) had the strongest effect (odds ratio (O.R.) of 6.86 per standard deviation increase in protein level), with proteinase 3 (PRTN3) (O.R.=2.48), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2) (O.R.=2.29), the C4A-C4B heterodimer (O.R.=1.76) and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) (O.R.=1.73) also being associated with higher odds of severe COVID-19. Conversely, major histocompatibility complex class I polypeptide-related sequence A (MHC1A) (O.R.=0.6) and natural cytotoxicity triggering receptor 3 (NCR3) (O.R.=0.46) were associated with lower odds. These proteins are involved in heart muscle contraction, natural killer and antigen presenting cells, and the major histocompatibility complex. Based on these findings, it may be possible to better predict which patients may develop severe COVID-19 and to design better treatments targeting the implicated mechanisms.

Spectrum, Risk Factors, and Outcomes of Neurological and Psychiatric Complications of COVID-19: A UK-Wide Cross-Sectional Surveillance Study (preprint)

Background: SARS-CoV2 is associated with neurological and psychiatric complications including cerebrovascular events, encephalopathy and peripheral nerve disease. Detailed clinical data, including factors associated with recovery, is lacking, hampering prediction modelling and targeted therapeutic interventions. We studied COVID-associated neurological and psychiatric complications, to investigate the key clinical features, including those associated with outcome.Methods: This UK-wide cross-sectional surveillance study of neurological and psychiatric complications of COVID-19 in adult hospitalised patients captured detailed data on demographics/risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions, based on criteria adopted by the World Health Organisation, were used, with cross-specialty independent adjudication for discrepant cases. Patients meeting multiple clinical case definitions were identified. Cases of stroke were compared to normative data during the equivalent time-period prior to the pandemic. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome.Findings: 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy not meeting delirium criteria; and peripheral nerve-disorders (41, 15%). 27% of cerebrovascular events occurred in patients <60 years. Relative to those >60 years old, the younger patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and more frequently had systemic thrombotic events. Nevertheless, in both younger and older stroke cases there was an association with conventional, modifiable, cerebrovascular risk factors. The timing of neurological presentation varied between disease groups. In 34 cases (13%), clinical case definitions overlapped, and these cases were more likely to require intensive care and ventilation. Regardless of clinical case definition, older age, a higher pre-COVID-19 frailty score, and a high admission white cell count independently associated with a poor outcome. Limited recovery was most common for those with cerebrovascular events. Interpretation: COVID-19 is associated with a broad spectrum of presentations throughout the nervous system, at varied time points relative to respiratory disease. Outcomes vary between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of age and frailty. A severe encephalopathy occurs after COVID-19 and is associated with requiring intensive care and ventilation. COVID-19 is associated with large and multi-vessel stroke in young people, often with non-CNS thrombotic disease and requires further study. Nevertheless, conventional, modifiable risk factors were associated with stroke, even in younger people, suggesting the potential for public health intervention for this and future pandemics. These clinical data should be combined with blood and neuroimaging biomarkers so that patients can be stratified to targeted existing or novel therapeutics.

UK-Wide Surveillance of Neurological and Neuropsychiatric Complications of COVID-19: The First 153 Patients (preprint)

Background: Increasingly neurological complications of COVID-19 are identified, mostly in small series. Larger studies have been limited by both geography and specialty.Consequently, the breadth of complications is not represented. Comprehensive characterization of clinical syndromes is critical to rationally select and evaluate potential therapies.Methods: During the exponential pandemic phase, we developed coordinated online portals for rapid notification across the spectrum of major UK neuroscience bodies, representing neurology, stroke, psychiatry, and intensive care. Evidence of infection and clinical case definitions were applied prospectively. Cases were compared to overall Government Public Health COVID-19 reporting.Findings: Within three weeks, 153 cases were notified, both geographically and temporally representative of overall COVID-19 Public Health reports. Median (range) age was 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes, nine (12%) intracerebral hemorrhages, and one CNS vasculitis.The second most common group were 39 (31%) who had altered mental status, including 16 (41%) with encephalopathy of whom seven (44%) had encephalitis. The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses; including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4 (17%) an affective disorder. Cerebrovascular events predominated in older patients. Conversely, altered mental status, whilst present in all ages, had disproportionate representation in the young.Interpretation: This is the first nationwide, cross-specialty surveillance study of acute complications of COVID-19 in the nervous system. Alteration in mental status was common, reflecting encephalopathy/encephalitis and primary psychiatric diagnoses, often in young patients.These data provide valuable and timely information urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy throughout the areas of neurology and neuropsychiatry.