Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether ...cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.
This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Metabolic derangements following traumatic brain injury are poorly characterized. In this single-centre observational cohort study we combined 18F-FDG and multi-tracer oxygen-15 PET to ...comprehensively characterize the extent and spatial pattern of metabolic derangements. Twenty-six patients requiring sedation and ventilation with intracranial pressure monitoring following head injury within a Neurosciences Critical Care Unit, and 47 healthy volunteers were recruited. Eighteen volunteers were excluded for age over 60 years (n = 11), movement-related artefact (n = 3) or physiological instability during imaging (n = 4). We measured cerebral blood flow, blood volume, oxygen extraction fraction, and 18F-FDG transport into the brain (K1) and its phosphorylation (k3). We calculated oxygen metabolism, 18F-FDG influx rate constant (Ki), glucose metabolism and the oxygen/glucose metabolic ratio. Lesion core, penumbra and peri-penumbra, and normal-appearing brain, ischaemic brain volume and k3 hotspot regions were compared with plasma and microdialysis glucose in patients. Twenty-six head injury patients, median age 40 years (22 male, four female) underwent 34 combined 18F-FDG and oxygen-15 PET at early, intermediate, and late time points (within 24 h, Days 2-5, and Days 6-12 post-injury; n = 12, 8, and 14, respectively), and were compared with 20 volunteers, median age 43 years (15 male, five female) who underwent oxygen-15, and nine volunteers, median age 56 years (three male, six female) who underwent 18F-FDG PET. Higher plasma glucose was associated with higher microdialysate glucose. Blood flow and K1 were decreased in the vicinity of lesions, and closely related when blood flow was <25 ml/100 ml/min. Within normal-appearing brain, K1 was maintained despite lower blood flow than volunteers. Glucose utilization was globally reduced in comparison with volunteers (P < 0.001). k3 was variable; highest within lesions with some patients showing increases with blood flow <25 ml/100 ml/min, but falling steeply with blood flow lower than 12 ml/100 ml/min. k3 hotspots were found distant from lesions, with k3 increases associated with lower plasma glucose (Rho -0.33, P < 0.001) and microdialysis glucose (Rho -0.73, P = 0.02). k3 hotspots showed similar K1 and glucose metabolism to volunteers despite lower blood flow and oxygen metabolism (P < 0.001, both comparisons); oxygen extraction fraction increases consistent with ischaemia were uncommon. We show that glucose delivery was dependent on plasma glucose and cerebral blood flow. Overall glucose utilization was low, but regional increases were associated with reductions in glucose availability, blood flow and oxygen metabolism in the absence of ischaemia. Clinical management should optimize blood flow and glucose delivery and could explore the use of alternative energy substrates.
•The frequency of degenerative findings in 155 patients with cervical cord compression was analysed.•This was done with network analysis, hierarchical clustering and comparison to ...literature.Ligamentous pathology and congenital stenosis were associated with symptomatic cord compression.•Hierarchical Cluster Analysis indicated four sub-groups.•These sub-groups may benefit from closer monitoring.
Degenerative cervical myelopathy (DCM) arises from spinal degenerative changes injuring the cervical spinal cord. Most cord compression is incidental, referred to as asymptomatic spinal cord compression (ASCC). How and why ASCC differs from DCM is poorly understood. In this paper, we study a local cohort to identify specific types and groups of degenerative pathology more likely associated with DCM than ASCC.
This study was a retrospective cohort analysis (IRB Approval ID: PRN10455). The frequency of degenerative findings between those with ASCC and DCM patients were compared using network analysis, hierarchical clustering, and comparison to existing literature to identify potential subgroups in a local cohort (N = 155) with MRI-defined cervical spinal cord compression. Quantitative measures of spinal cord compression (MSCC and MCC) were used to confirm their relevance.
ELF (8.7 %, 95 % CI 3.8–13.6 % vs 35.7 %, 95 % CI 27.4–44.0 %) Congenital Stenosis (3.9 %, 95 % CI 0.6–7.3 % vs 25.0 %, 95 % CI 17.5–32.5 %), and OPLL (0.0 %, 95 % CI 0.0–0.0 % vs 3.6 %, 95 % CI 0.3–6.8 %) were more likely in patients with DCM. Comparative network analysis indicated loss of lordosis was associated with ASCC, whilst ELF with DCM. Hierarchical Cluster Analysis indicated four sub-groups: multi-level disc disease with ELF, single-level disc disease without loss of lordosis and OPLL with DCM, and single-level disc disease with loss of lordosis with ASCC. Quantitative measures of cord compression were higher in groups associated with DCM, but similar in patients with single-level disc disease and loss of lordosis.
This study identified four subgroups based on degenerative pathology requiring further investigation.
Objective. Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient ...trajectories over the entire disease narrative, from ictus to late outcome. Methods. Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. Results. Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. Conclusions. These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point.
A longitudinal analysis of patients with traumatic brain injury in the US (TRACK-TBI cohort study) found that 62 (78%) of 79 participants who were in a functionally vegetative state 2 weeks after ...injury had regained consciousness by 12 months, and 14 (25%) of 56 participants with available data regained orientation according to the Disability Rating Scale by 12 months.2 A propensity score analysis by TRACK-TBI comparing patients who had withdrawal of life-sustaining therapies to those who did not found that 25 (45%) of 56 patients in the matched cohort recovered to at least partial independence (Glasgow Outcome Score Extended ≥4).3 This finding indicates that a proportion of patients who underwent withdrawal of life sustaining therapies potentially could have recovered at least to this level. Survivors of an acute brain injury who have poor functional outcomes consistently report their quality of life to be at or above normative levels.5 This discordance between injury severity and perceived quality of life raises questions about clinicians’ understanding of what is a good versus a poor outcome, and highlights the difficulties faced when discussing with families and surrogate decision makers what would be an acceptable outcome. ...a retrospective study of more than 34 000 people who did not survive a cardiac arrest found that only 3245 (9·4%) of 34 585 patients underwent at least one neurodiagnostic test, including CT.9 A clearer understanding of the natural history of coma recovery for different causes would help to weigh up the merits of advanced imaging techniques versus waiting and assessing clinically, if MRI or EEG become challenging.
Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this ...difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
Background:
Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown ...predictive values for the presence of intracranial lesions.
Aim:
To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors.
Methods:
Blood samples from patients with acute TBI (all severities) were collected <24 h post trauma. The outcome was measured >6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities.
Results:
When sensitivity was set at 95–100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities.
Conclusion:
Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI.
The prolonged mechanical ventilation that is often required by patients with severe COVID-19 is expected to result in significant intensive care unit-acquired weakness (ICUAW) in many of the ...survivors. However, in our post-COVID-19 follow-up clinic we have found that, as well as the anticipated global weakness related to loss of muscle mass, a significant proportion of these patients also have disabling focal neurological deficits relating to multiple axonal mononeuropathies. Amongst the 69 patients with severe COVID-19 that have been discharged from the intensive care units in our hospital, we have seen 11 individuals (16%) with such a mononeuritis multiplex. In many instances, the multi-focal nature of the weakness in these patients was initially unrecognised as symptoms were wrongly assumed to relate simply to “critical illness neuromyopathy”. While mononeuropathy is well recognised as an occasional complication of intensive care, our experience suggests that such deficits are surprisingly frequent and often disabling in patients recovering from severe COVID-19.
...multiple large-scale studies were launched in the spring of 2020 to study COVID-19 neurological disorders, including the CoroNerve Study Group 4, the Italian Society of Neurology’s NEUROCOVID ...study 14, the James S. McDonnell Foundation’s COVID-19 Recovery of Consciousness Consortium 15, the European Academy of Neurology’s EANCore project 10, 16, the Latin American Brain Injury Consortium (LABIC) 17, the Prospective Observational Study of Subarachnoid hemorrhage and IntracereBral hemorrhage patients in Latin America (POSSIBLE) network’s COVID-19 study 17, and the Global Consortium Study of Neurological Dysfunction in COVID-19 (GCS-NeuroCOVID) 17, 18. Tier 2 represents the workhorse of data collection for global studies and provides a level of detail that would be available from institutions in most developed countries and many developing countries. Tier 3 represents even more specialized data collection by centers and investigators with expertise in a given area and would likely require custom-built data collection designed by the study group addressing a specific research question. ...we chose a feature-based approach to avoid making assumptions without firm evidence about the mechanisms by which COVID-19 affects the nervous system.
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