Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom.

BACKGROUND: Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ~ 95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future. METHODS: We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. RESULTS: 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking. CONCLUSIONS: We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

Psychiatric disorders in children with demyelinating diseases of the central nervous system.

INTRODUCTION: The profile of psychiatric disorders associated with multiple sclerosis (MS) may differ in children. We aimed to assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa. PATIENTS AND METHODS: We analyzed linked English Hospital Episode Statistics, and mortality data, 1999-2011. Cohorts were constructed of children admitted with MS and other central nervous system (CNS) demyelinating diseases. We searched for any subsequent episode of care with psychiatric disorders in these cohorts and compared to a reference cohort. RESULTS: Children with CNS demyelinating diseases had an increased rate of psychotic disorders (rate ratio (RR) = 5.77 (95% confidence interval (CI) = 2.48-11.41)); anxiety, stress-related, and somatoform disorders (RR = 2.38 (1.39-3.81)); intellectual disability (RR = 6.56 (3.66-10.84)); and other behavioral disorders (RR = 8.99 (5.13-14.62)). In analysis of the pediatric MS cohort as the exposure, there were elevated rates of psychotic disorders (RR = 10.76 (2.93-27.63)), mood disorders (RR = 2.57 (1.03-5.31)), and intellectual disability (RR = 6.08 (1.25-17.80)). In reverse analyses, there were elevated rates of a recorded hospital episode with CNS demyelinating disease after a previous recorded episode with anxiety, stress-related, and somatoform disorders; attention-deficit hyperactivity disorder (ADHD); autism; intellectual disability; and other behavioral disorders. CONCLUSION: This analysis of a national diagnostic database provides strong evidence for an association between pediatric CNS demyelinating diseases and psychiatric disorders, and highlights a need for early involvement of mental health professionals.

Dietary factors and pediatric multiple sclerosis: A case-control study.

BACKGROUND: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. OBJECTIVE: To determine the association between dietary factors and MS in children. METHODS: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. RESULTS: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). CONCLUSION: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

DNase hypersensitive sites and association with multiple sclerosis.

Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.

Gender identity disorders and multiple sclerosis risk: A national record-linkage study.

BACKGROUND: An altered balance of gonadal hormones in males with gender identity disorders (GIDs) may increase multiple sclerosis (MS) risk both inherently and secondary to treatment in undergoing male-to-female conversion. OBJECTIVE: We investigated any association between GIDs and MS through analysis of record-linked hospital statistics. METHOD: Analysis of English Hospital Episode Statistics, 1999-2012. RESULTS: The adjusted rate ratio (RR) of MS following GIDs in males was 6.63 (95% confidence interval (95% CI) = 1.81-17.01, p = 0.0002). The RR of MS following GIDs in females was 1.44 (95% CI = 0.47-3.37, p = 0.58). CONCLUSION: We report a strong association between GIDs and MS in male-to-females, supporting a potential role for low testosterone and/or feminising hormones on MS risk in males.

Testicular hypofunction and multiple sclerosis risk: a record-linkage study.

The influence of gonadal hormones on multiple sclerosis (MS) is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and MS risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent MS (rate ratio = 4.62, 95% confidence interval = 2.3-8.24, p < 0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females.

Clinical associations between gout and multiple sclerosis, Parkinson's disease and motor neuron disease: record-linkage studies.

BACKGROUND: Uric acid has antioxidant effects on neurons. Abnormally high levels of uric acid are, however, associated with gout. Previous studies have suggested that high levels of uric acid (and the presence of gout) may exert a protective effect against the risk of developing some neurological diseases. We aimed to investigate this hypothesis in a large database of hospital admissions in England. METHODS: We analysed a database of linked statistical records of hospital admissions and death registrations in England (1999-2012). A cohort of people with gout was constructed and followed for development of multiple sclerosis (MS), Parkinson's disease (PD) or motor neuron disease (MND). Then, conversely, cohorts of all people in the database with MS, PD or MND were constructed and followed for subsequent gout. Rate ratios (RRs) were determined, comparing these cohorts with people in a reference cohort. RESULTS: In the gout cohort, we observed a modest elevation of the overall risk of subsequent MS, PD and MND (respectively, RR = 1.27 (95% confidence interval 1.03-1.55), 1.11 (1.05-1.17) and 1.28 (1.11-1.48) which was largely attributable to an increased risk observed in the early years after hospitalisation for gout. The increased risk of neurological disease did not remain after 5 years. In the cohorts of people with MS or PD, there was a significantly reduced risk of subsequent gout admission (RR = 0.79 (0.69-0.89) and 0.83 (0.79-0.87), respectively). This inverse association was sustained over time. There was also a reduced risk of MND following gout which only emerged more than five years following initial gout admission (RR at 5+ years 0.35 (0.15-0.68)). CONCLUSIONS: This study investigated the epidemiological evidence for a protective role of high serum concentration of uric acid, for which we used gout as a proxy, in the aetiology of MS, PD or MND. Our observations do not support this hypothesis. However, when the order was reversed, and we retrospectively followed up patients with MS, PD and MND for a number of years, we found a statistically significant deficit of gout. This suggests that there is relationship between some aspects of these neurodegenerative diseases and metabolism of uric acid.

National survey of UK medical students on the perception of neurology.

BACKGROUND: Medical students perceive neurology to be a difficult subject, a phenomenon described as "neurophobia". Studies investigating student attitudes towards neurology have so far been limited by small sample sizes as a consequence of being conducted within a single medical school or region. We aimed to conduct the first national survey of the perception of neurology among UK medical students. METHODS: A 24 question online survey was designed and distributed in the form of a web-link to all UK medical schools. Responses were collected for 10 weeks with reminders sent at 3 and 6 weeks. A prize-draw of £300 was offered upon completion of the survey. RESULTS: 2877 medical students from 25 of 31 medical schools responded. Students found neurology to be significantly more difficult than other specialties and were least comfortable drawing up a neurological differential diagnosis compared to other specialties (p < 0.0001 for neurology vs. each of the other specialties). Neuroanatomy was regarded as the most important factor contributing to neurology being perceived as difficult. CONCLUSIONS: The findings of the first national survey addressing this issue are consistent with previous research. The perception of neurology remains unchanged, in contrast to the rapidly changing demands of neurological care in an ageing population. Neurological examination and formulating a differential diagnosis are important skills in any medical specialty, and combatting "neurophobia" in medical students is therefore essential.

FIT negative clinic as a safety net for low-risk patients with colorectal cancer: impact on endoscopy and radiology utilisation-a retrospective cohort study.

Background: Faecal immunochemical testing (FIT) is recommended by the National Institute for Health and Care Excellence to triage symptomatic primary care patients who have unexplained symptoms but do not meet the criteria for a suspected lower gastrointestinal cancer pathway. During the COVID-19 pandemic, FIT was used to triage patients referred with urgent 2-week wait (2ww) cancer referrals instead of a direct-to-test strategy. FIT-negative patients were assessed and safety netted in a FIT negative clinic. Methods: We reviewed case notes for 622 patients referred on a 2ww pathway and seen in a FIT negative clinic between June 2020 and April 2021 in a tertiary care hospital. We collected information on demographics, indication for referral, dates for referral, clinic visit, investigations and long-term outcomes. Results: The average age of the patients was 71.5 years with 54% female, and a median follow-up of 2.5 years. Indications for referrals included: anaemia (11%), iron deficiency (24%), weight loss (9%), bleeding per rectum (5%) and change in bowel habits (61%). Of the cases, 28% (95% CI 24% to 31%) had endoscopic (15%, 95% CI 12% to 18%) and/or radiological (20%, 95% CI 17% to 23%) investigations requested after clinic review, and among those investigated, malignancy rate was 1.7%, with rectosigmoid neuroendocrine tumour, oesophageal cancer and lung adenocarcinoma. Conclusion: A FIT negative clinic provides a safety net for patients with unexplained symptoms but low risk of colorectal cancer. These real-world data demonstrate significantly reduced demand on endoscopy and radiology services for FIT-negative patients referred via the 2ww pathway.

The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis.

BACKGROUND: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals. METHODS: PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed. RESULTS: The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13-0.26)) and for paediatric MS was 0.18 (95% CI 0.11-0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03-0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22-0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0-0.43). CONCLUSION: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

Epstein-Barr virus, latitude and multiple sclerosis.

Several lines of evidence support a role for Epstein-Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02-1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased risk of SAH. METHODS: We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999-2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts. RESULTS: There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn's disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison's disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura (RR = 2.42, 1.86-3.11), primary biliary cirrhosis (RR = 2.21, 1.43-3.16) and SLE (RR = 3.76, 3.08-4.55). CONCLUSIONS: Our findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted.

Why Studying Urgency Is Urgent.

Bowel urgency, the sudden and immediate need to have a bowel movement, is one of the most widely reported and debilitating symptoms of ulcerative colitis. Urgency has a profound impact on patient well-being, often resulting in patient disengagement from education, employment, and social activities. Although its prevalence correlates with disease activity, it is present in states of both disease flare and remission. Postulated pathophysiologic mechanisms are complex, but urgency is likely a consequence of both acute inflammation and structural sequelae of chronic inflammation. Bowel urgency is not widely incorporated into clinical assessment indices or clinical trial endpoints, despite being a pivotal symptom influencing patient health-related quality of life. Addressing urgency can be challenging owing to the associated embarrassment for patients in volunteering this symptom, and its management can be nuanced in the context of a paucity of specific evidence to target it, independently of disease activity. Explicitly inquiring about urgency and integrating it into a multidisciplinary team combining gastroenterologists, psychological support, and continence services is essential to achieving shared satisfaction from treatment. This article outlines the prevalence of urgency and its impact on the quality of life of patients, describes postulated driving mechanisms, and makes recommendations for its inclusion in clinical care and research.

Estimated and projected burden of multiple sclerosis attributable to smoking and childhood and adolescent high body-mass index: a comparative risk assessment.

BACKGROUND: Smoking and childhood and adolescent high body-mass index (BMI) are leading lifestyle-related risk factors of global premature morbidity and mortality, and have been associated with an increased risk of developing multiple sclerosis (MS). This study aims to estimate and project the proportion of MS incidence that could be prevented with elimination of these risk factors. METHODS: Prevalence estimates of high BMI during childhood/adolescence and smoking in early adulthood, and relative risks of MS, were obtained from published literature. A time-lag of 10 years was assumed between smoking in early adulthood and MS incidence, and a time-lag of 20 years was assumed between childhood/adolescent high BMI and MS incidence. The MS population attributable fractions (PAFs) of smoking and high BMI were estimated as individual and combined risk factors, by age, country and sex in 2015, 2025 and 2035 where feasible. RESULTS: The combined estimated PAFs for smoking and high BMI in 2015 were 14, 11, 12 and 12% for the UK, USA, Russia and Australia in a conservative estimate, and 21, 20, 19 and 16% in an independent estimate, respectively. Estimates for smoking are declining over time, whereas estimates for high early life BMI are rising. The PAF for high early life BMI is highest in the USA and is estimated to increase to 14% by 2035. CONCLUSIONS: Assuming causality, there is the potential to substantially reduce MS incidence with the elimination of lifestyle-related modifiable risk factors, which are the target of global public health prevention strategies.

Update on the management of multiple sclerosis during the COVID-19 pandemic and post pandemic: An international consensus statement.

In this consensus statement, we provide updated recommendations on multiple sclerosis (MS) management during the COVID-19 crisis and the post-pandemic period applicable to neurology services around the world. Statements/recommendations were generated based on available literature and the experience of 13 MS expert panelists using a modified Delphi approach online. The statements/recommendations give advice regarding implementation of telemedicine; use of disease-modifying therapies and management of MS relapses; management of people with MS at highest risk from COVID-19; management of radiological monitoring; use of remote pharmacovigilance; impact on MS research; implications for lowest income settings, and other key issues.

Effect of different financial competing interest statements on readers' perceptions of clinical educational articles: a randomised controlled trial.

OBJECTIVES: To investigate how different competing interest (COI) statements affect clinical readers' perceptions of education articles. DESIGN: Randomised controlled trial. SETTING AND PARTICIPANTS: Random sample of UK doctors. INTERVENTIONS: We created four permutations of each of two clinical reviews (on gout or dyspepsia), which varied only in terms of the COI statement. Volunteers were blinded and randomised to receive one review and asked to complete a questionnaire after reading it. Blinded factorial analyses of variance and analyses of covariance were carried out to assess the influence of each review and type of COI on outcomes. PRIMARY AND SECONDARY OUTCOMES: Confidence in the article's conclusions (primary outcome), its importance, their level of interest in the article and their likelihood to change practice after reading it. RESULTS: Of 10 889 doctors invited to participate, 1065 (10%) volunteered. Of these, 749 (70%) completed the survey. Analysis of covariance (adjusting for age, sex, job type, years since qualification) showed no significant difference between the groups in participants' confidence in the article (gout: p=0.32, dyspepsia: p=0.78) or their rating of its importance (gout: p=0.09, dyspepsia: p=0.79). For the gout review, participants rated articles with advisory board and consultancies COI as significantly less interesting than those with no COI (p=0.028 with Bonferroni correction). Among participants indicating that they treat the condition and that the article's recommendations differed from their own practice, there was no significant difference in likelihood to change practice between groups (gout: p=0.59, n=59; dyspepsia: p=0.56, n=80). CONCLUSIONS: Doctors' confidence in educational articles was not influenced by the COI statements. Further work is required to determine if doctors do not perceive these COIs as important in educational articles or if they do not pay attention to these statements. More meaningful COI disclosure practices may be needed, which highlight context-specific potential sources of bias to readers. TRIAL REGISTRATION NUMBER: NCT02548312; Results.