Smoking at time of CIS increases the risk of clinically definite multiple sclerosis

Background: Cigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event. Methods: Two hundred and fifty patients, aged 18–50 years, were included in our prospective CIS cohort. At time of the first neurological symptoms, patients completed a questionnaire about smoking habits. Cox regression analyses were performed to calculate univariate and multivariate hazard ratios for CDMS diagnosis in smoking and non-smoking CIS patients. Results: One hundred and fourteen (46%) CIS patients were diagnosed with CDMS during a mean follow-up of 58 months. In total, 79 (32%) patients smoked at time of CIS. Sixty-seven % of the smoking CIS patients were diagnosed with CDMS during follow-up compared to 36% of the non-smoking CIS patients (p < 0.001). Smoking at time of CIS was an independent predictor for CDMS diagnosis (HR 2.3; p = 0.002). Non-smoking CIS patients who had a history of smoking did not have a higher risk for CDMS than those who had never smoked. Conclusions: Smoking at time of CIS was an independent risk factor for a future CDMS diagnosis. This is an additional argument to quit smoking at time of the first attack of suspected MS

Drug adherence and multidisciplinary care in patients with multiple sclerosis: Protocol of a prospective, web-based, patient-centred, nation-wide, Dutch cohort study in glatiramer acetate treated patients (CAIR study)

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definitive treatment is available. Most patients start with a relapsing-remitting course (RRMS). Disease-modifying drugs (DMDs) reduce relapses and disability progression. First line DMDs include glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b, which are all administered via injections. Effectiveness of DMD treatment depends on adequate adherence, meaning year-long continuation of injections with a minimum of missed doses. In real-life practice DMD-treated patients miss 30% of doses. The 6-month discontinuation rate is up to 27% and most patients who discontinue do so in the first 12 months.Treatment adherence is influenced by the socio-economic situation, health care and caregivers, disease, treatment and patient characteristics. Only a few studies have dealt with adherence-related factors in DMD-treated patients. Self-efficacy expectations were found to be related to GA adherence. Patient education and optimal support improve adherence in general. Knowledge of the aspects of care that significantly relate to adherence could lead to adherence-improving measures. Moreover, identification of patients at risk of inadequate adherence could lead to more efficient care.In the near future new drugs will become available for RRMS. Detailed knowledge on factors prognostic of adherence and on care aspects that are associated with adequate adherence will improve the chances of these drugs becoming effective treatments. We investigate in RRMS patients the relationship between drug adherence and multidisciplinary care, as well as factors associated with adherence. Given the differences in the frequency of administration and in the side effects between the DMDs we decided to study patients treated with the same DMD, GA.Methods/design: The Correlative analyses of Adherence In Relapsing remitting MS (CAIR) study is an investigator-initiated, prospective, web-based, patient-centred, nation-wide cohort study in the Netherlands.The primary objective is to investigate whether GA adherence is associated with specific disciplines of care or quantities of specific care. The secondary objective is to investigate whether GA adherence is associated with specific aspects of the socio-economic situation, health care and caregivers, disease, treatment or patient characteristics.All data are acquired on-line via a study website. All RRMS patients in the Netherlands starting GA treatment are eligible. Patients are informed by neurologists, nurses, and websites from national MS patient organisations. All data, except on disability, are obtained by patient self-reports on pre-defined and random time points. The number of missed doses and the number of patients having discontinued GA treatment at 6 and 12 months are measures of adherence. Per care discipline the number of sessions and the total duration of care are measures of received care. The full spectrum of non-experimental care that is available in the Netherlands is assessed. Care includes 'physical' contacts, contacts by telephone or internet, health-promoting activities and community care activities. Care received over the preceding 14 days is assessed by patients at baseline and every other week thereafter up to month 12. Every 3 months neurologists and nurses record care disciplines to which patients have been referred.The Dutch Adherence Questionnaire-90 (DAQ-90) is a 90-item questionnaire based on the World Health Organisation (WHO) 2003 report on adherence and comprehensively assesses five domains of evidence-based determinants of adherence: socio-economic, health care and caregivers, disease, treatment, and patient-related factors. In addition, self-efficacy is assessed by the MS Self-Efficacy Scale (MSSES), and mood and health-related quality of life (HRQoL) by the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Relapses and adverse events probably or definitively related to GA are also reported.Discussion: In this study data is mainly acquired by patients' self-reporting via the internet. On-line data acquisition by patients does not require study visits to the hospital and can easily be integrated into daily life. The web-based nature of the study is believed to prevent missing data and study drop-outs. Moreover, the automated process of filling in questionnaires ensures completeness and consistency, thus improving data quality. The combination of patient-reported outcomes, fully web-based data capture and nation-wide information to all eligible patients are distinguishing features of the study and contribute to its scientific potential.Trial registration: Netherlands Trial Register (NTR): NTR2432

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study

Introduction: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. Methods: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. Results: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28–84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). Conclusion: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies

Epstein–Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the CNS of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n = 9), which is often accompanied by EBV reactivation. The frequencies of nonclass-switched and class-switched memory B cells were reduced at 3–7 months, while only class-switched B cells returned back to baseline at 24–36 months posttransplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+

Guillain-Barre syndrome after SARS-CoV-2 infection in an international prospective cohort study

In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barre syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12-22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not

High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome

__Background:__ A promising biomarker for axonal damage early in the disease course of multiple sclerosis (MS) is neurofilament light chain (NfL). It is unknown whether NfL has the same predictive value for MS diagnosis in children as in adults. __Objective:__ To explore the predictive value of NfL levels in cerebrospinal fluid (CSF) for MS diagnosis in paediatric and adult clinically isolated syndrome (CIS) patients. Methods: A total of 88 adult and 65 paediatric patients with a first attack of demyelination were included and followed (mean follow up-time in adults: 62.8 months (standard deviation (SD) ±38.7 months) and 43.8 months (SD ±27.1 months) in children). Thirty control patients were also included. Lumbar puncture was done within 6 months after onset of symptoms. NfL was determined in CSF using enzyme-linked immunosorbent assay (ELISA). COX regression analyses were used to calculate hazard ratios (HR) for clinically definite multiple sclerosis (CDMS) diagnosis. __Results:__ After adjustments for age, oligoclonal bands (OCB), and asymptomatic T2 lesions on baseline magnetic resonance imaging (MRI), increased NfL levels in both paediatric and adult CIS patients were associated with a sh

Second intravenous immunoglobulin dose in patients with Guillain-Barre syndrome with poor prognosis (SID-GBS):a double-blind, randomised, placebo-controlled trial

Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (>= 12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of >= 6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1.4 (95% CI 0.6-3.3; p=0.45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products. Copyright (C) 2021 Elsevier Ltd. All rights reserved

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies

Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the central nervous system of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n=9), which is often accompanied by EBV reactivation. The frequencies of non-class-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months post-transplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n=15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under germinal center-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS. This article is protected by copyright. All rights reserved