Tom Solomon

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national longitudinal study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers and reduced anterior cingulate cortex volume one year after admission. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Treatment with corticosteroids during the acute phase appeared protective against cognitive deficits. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies.

The original version of this article omitted three members of the COVID-CNS Consortium. Alex Berry and Obioma Orazulume, who are from the ‘University College London, London, UK’, and Ian Galea, who is from the ‘University of Southampton, Southampton, UK’were added to the list of COVID-CNS Consortium members. This has been corrected in both the PDF and HTML versions of the article.

BackgroundMultiplex polymerase chain reaction assays have the potential to reduce antibiotic use and shorten length of inpatient stay in children with suspected central nervous system infection by obtaining an early microbiological diagnosis. The clinical impact of the implementation of the BioFire FilmArray Meningitis/Encephalitis Panel on the management of childhood meningitis was evaluated at the John Radcliffe Hospital in Oxford and Children’s Health Ireland at Temple Street in Dublin.MethodsChildren who had lumbar punctures performed as part of a septic screen were identified retrospectively through clinical discharge coding and microbiology databases from April 2017 to December 2018. Anonymized clinical and laboratory data were collected. Comparison of antibiotic use, length of stay and outcome at discharge was made with a historical cohort in Oxford (2012–2016), presenting before …

Background:There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking.Objective:To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness.Design:Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children.Setting:Twenty-one NHS Hospitals in the UK.Participants:Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis.Intervention:Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment.Main outcome measure:Participants were followed up …

The proteasome is an evolutionary conserved protease that recognizes and degrades damaged and misfolded proteins via proteolysis. 1 The 26S proteasome consists of the 19S regulatory subunit and the core proteolytic enzyme, 20S proteasome. 2 The proteasome-dependent degradation of tagged, polyubiquitinated proteins is an essential cellular pathway that regulates a wide range of cellular processes, including cell cycle, apoptosis, oxidative stress, cell proliferation and activation of transcription factors such as NF-κB. 3 In contrast to the ubiquitously expressed constitutive proteasome, which is the crucial cellular protease containing the three catalytic subunits, β1, β2 and β5, the immunoproteasome is induced via de novo assembly upon stimulation of cells by Type I and Type II interferons. The incorporation of newly synthetized catalytic subunits, β1i/LMP2, β2i/MECL-1 and β5i/LMP7, is an essential cellular strategy to eliminate intracellular bacteria and viruses. 4 The immunoproteasome exhibits an altered proteolytic function that is required for optimal generation of epitopes for presentation on major histocompatibility complex Class I (MHC-I) molecules in infected cells. It was shown that immunoproteasomes transiently replace constitutive proteasomes during an anti-bacterial (Listeria monocytogenes) and anti-viral (lymphocytic choriomeningitis virus) immune response in the liver. 5 Apart from their function in the generation of a broad pool of MHC-I ligands and in triggering effective activation of cytotoxic T lymphocytes, immunoproteasomes appear to act as a pro-inflammatory factor that is involved in tissue inflammation and damage, as …

BackgroundCOVID-19 has had an unprecedented impact worldwide. Evidence for management interventions emerged rapidly but was difficult for clinicians and others to assess and decide how to use. Our team in India set up a national and international collaboration preparing guidance in real time to help guide clinical practice in the country during a pandemic setting. We describe our methods and the product in this paper.MethodsSpecialized groups comprising core, steering, methodology, evidence synthesis, dissemination and intervention expert working groups were formed. A Cochrane Rapid Review approach was used for prioritised questions in areas of clinical equipoise in management of COVID-19. GRADE methodology was incorporated into this process and expert working groups tailored guidelines for India using the WHO Evidence to Decision framework. This was then disseminated on a widely …

ObjectiveThanks to the introduction of recent national guidelines for treating herpes simplex virus (HSV) encephalitis health outcomes have improved. This paper evaluates the costs and the health-related quality of life implications of these guidelines.Design and settingA sub-analysis of data from a prospective, multi-centre, observational cohort ENCEPH-UK study conducted across 29 hospitals in the UK from 2012 to 2015.Study participantsData for patients aged ≥16 years with a confirmed HSV encephalitis diagnosis admitted for treatment with aciclovir were collected at discharge, 3 and 12 months.Primary and secondary outcome measuresPatient health outcomes were measured by the Glasgow outcome score (GOS), modified ranking score (mRS), and the EuroQoL; health care costs were estimated per patient at discharge from hospital and at 12 months follow-up. In addition, Quality Adjusted Life years (QALYs) were calculated from the EQ-5D utility scores. Cost-utility analysis was performed using the NHS and Social Scare perspective.ResultsA total of 49 patients were included, 35 treated within 48 hours “early” (median [IQR] 8.25 [3.7-20.5]) and 14 treated after 48 hours (median [IQR] 93.9 [66.7 - 100.1]). At discharge, 30 (86%) in the early treatment group had a good mRS outcome score (0–) compared to 4 (29%) in the delayed group. EQ-5D-3L utility value at discharge was significantly higher for early treatment (0.609 vs 0.221, p<0.000). After adjusting for age and symptom duration at admission, early treatment incurred a lower average cost at discharge, £23,086 (95% CI: £15,186 to £30,987) vs £42,405 (95% CI: £25,457 to £59,354) [p …

Background: Implementation of bacterial conjugate vaccines have resulted in dramatic reductions in bacterial meningitis globally. The aetiology of childhood meningitis in the conjugate vaccine era is not well-defined, and differentiating bacterial meningitis from other similar childhood illnesses is a major challenge. The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.Methods: Children aged< 16 years hospitalised with suspected meningitis/encephalitis were included. Meningitis was defined as identification of bacteria/viruses from CSF and/or a CSF WBC> 5/μL. Aetiology and clinical and laboratory features were analysed. Two new clinical decision rules were developed to distinguish bacterial meningitis from aseptic or suspected meningitis.Findings: 3,002 children (median age 2· 4 months, IQR: 1· 0-12· 7) were prospectively recruited at 31 UK hospitals. Overall 1,101/3,002 (36· 7%) had meningitis, including 203 with a bacterial aetiology, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged< six months and 10-16 years, with N. meningitidis and/or S. pneumoniae commonest at age six months–nine years. The Bacterial Meningitis Score had a negative predictive value of 95· 3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after LP (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis.Interpretation: Bacterial meningitis comprised only 6% of children …

Although it is known that COVID-19 can present with a range of neurological manifestations and in-hospital complications, sparse data exist if these initial neurological symptoms of COVID-19 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (PANSC) and if female versus male sex impacts the symptom resolution. In this international, multicentre, prospective observational study across 407 sites from 15 countries (January/30th/2020-April/30th/2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time. PANSC included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia, and muscle aches/joint pain, which were collected at the index hospitalization and during the follow-up assessments. The analysis considered time to resolution of individual and all neurological symptoms. Resulting times were modeled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. Model results were summarized as cumulative probability functions and age- and sex-adjusted median times to resolution. We included 6,862 hospitalized adults with COVID-19, who had follow-up assessments. The median age of participants was 57 years (39.2% females). Males and females had similar baseline characteristics except that more males (vs. females) were admitted to Intensive Care Unit (30.5% vs. 20.3%) and received mechanical ventilation (17.2% vs. 11.8%). Approximately 70% of patients had multiple neurological symptoms at the first follow …

BackgroundBrain infections are a major cause of morbidity and mortality globally. India lacks systematically evidence-informed guidelines for brain infections.MethodsWe had set up a group of experts in brain infections, evidence synthesis and guideline development to produce guidelines for hospital clinicians diagnosing and treating patients with suspected and confirmed brain infections in India. Questions are being drafted and prioritised, and a plan for GRADE-informed evidence synthesis and guideline development is in place, using methods to increase efficiency of the process where possible.Dissemination and outputsThe guidelines will be disseminated through publication as well as on a dedicated website. Training of clinicians in evidence synthesis and guideline development, and setting up a network of institutions and professional societies, will provide lasting impact in terms of national capacity …

BackgroundCOVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs).ObjectivesThe main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality.MethodsAdult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort …

Objectives Encephalitis, brain inflammation and swelling, most often caused by an infection or the body’s immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical predictors of different types of encephalitis to help clinicians consider earlier treatment. Methods We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes. Results 341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had HSV, 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1st dose of aciclovir for those with HSV was 14 hours (IQR 5–50); time to 1st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45–250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x106/L, but they were less likely to have a febrile illness. Conclusions Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy.

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized …

BackgroundPre-existing neurological diseases have been identified as risk factors for severe COVID-19 infection and death. There is a lack of comprehensive literature review assessing the relationship between pre-existing neurological conditions and COVID-19 outcomes. Identification of high risk groups is critical for optimal treatment and care.MethodsA literature review was conducted for systematic reviews, meta-analyses, and scoping reviews published between January 1, 2020 and January 1, 2023. Literature assessing individuals with pre-existing neurological diseases and COVID-19 infection was included. Information regarding infection severity was extracted, and potential limitations were identified.ResultsThirty-nine articles met inclusion criteria, with data assessing >3 million patients from 51 countries. 26/51 (50.9%) of countries analyzed were classified as high income, while the remaining represented …

Novel Infectious diseases have been emerging for thousands of years and will continue to do so in the future as a result of climate change, rapid urbanization, changing land-use patterns, and increasing interaction between humans, animals, and their environment (One Health)

Neurocysticercosis (NCC)—a parasitic CNS infection endemic to developing nations—has been called the leading global cause of acquired epilepsy yet remains understudied. It is currently unknown why a large proportion of patients develop recurrent seizures, often following the presentation of acute seizures. Furthermore, the presentation of NCC is heterogenous and the features that predispose to the development of an epileptogenic state remain uncertain. Perilesional factors (such as oedema and gliosis) have been implicated in NCC-related ictogenesis, but the effects of cystic factors, including lesion load and location, seem not to play a role in the development of habitual epilepsy. In addition, the cytotoxic consequences of the cyst's degenerative stages are varied and the majority of research, relying on retrospective data, lacks the necessary specificity to distinguish between acute symptomatic and …

IntroductionUniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting.MethodsWe invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as “poor” (κ ≤ 0.4), “moderate” or “good” (κ > 0.6).Results1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion …

AA Tamborska a, b, c, GK Wood b, d, E. Westenberg e, D. Garcia-Azorin f, G. Webb b, c, N. Schiess g, M. Netravathi h, B. Baykan i, j, R. Dervaj k, R. Helbok l, S. Lant b, A. Özge m, A. Padovani n, D. Saylor o, E. Schmutzhard l, A. Easton b, p, JB Lilleker q, r, T. Jackson s, t, E. Beghi u, MA Ellul a, b, c, JA Frontera v, T. Pollak w, TR Nicholson x, N. Wood y, KT Thakur z, T. Solomon a, c, aa, RJ Stark ab, ac, AS Winkler e, ad, BD Michael a, b, c,*, Global NeuroResearc h Coalition a National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK b Clinical Infection, Microbiology & Immunology, Institute of Infection, Veterinary and Ecological sciences, University of Liverpool, Liverpool, UK c Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK d Liverpool …

Methods:Record review of medical records of all patients attending neurology emergency and outpatient services at NIMHANS Hospital, diagnosed with AES in 2019, was conducted. Data were collected using standardized data collection forms for all cases in the study. Descriptive analyses (mean and standard deviation for continuous variables and proportions for categorical variables) were conducted. The Chi-square test/Fisher’s exact test was used for the comparison of independent groups for categorical variables, and t-test for comparing means for continuous variables.Results:About 42.6% of AES patients had viral etiology, while in 57.4%, etiology was not ascertained. Common presenting symptoms were fever (96%), altered sensorium (64.4%), seizures (70.3%), headache (42.6%), and vomiting (27.7%). Herpes simplex was the most common (21.8%) identified viral encephalitis, followed by chikungunya (5 …

ImportanceResearch diversity and representativeness are paramount in building trust, generating valid biomedical knowledge, and possibly in implementing clinical guidelines.ObjectivesTo compare variations over time and across World Health Organization (WHO) geographic regions of corticosteroid use for treatment of severe COVID-19; secondary objectives were to evaluate the association between the timing of publication of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial (June 2020) and the WHO guidelines for corticosteroids (September 2020) and the temporal trends observed in corticosteroid use by region and to describe the geographic distribution of the recruitment in clinical trials that informed the WHO recommendation.Design, Setting, and ParticipantsThis prospective cohort study of 434 851 patients was conducted between January 31, 2020, and September 2, 2022, in 63 …