RSS 1.0Neurology
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P579/1741 Accumulation of iron-rim lesions correlates with change in cognition in early multiple sclerosisIntroduction: Iron rim lesions (IRLs) detected on susceptibility weighted imaging (SWI) are associated with higher disability scores in established MS and represent indicators of clinical worsening and progression of MS over the long term. It is not clear if the presence of IRL at diagnosis and detection of IRL early accumulation are clinically meaningful in early MS. Objectives/Aims: To assess whether the presence and number of IRLs detected in the first two years in newly diagnosed patients with relapsing remitting MS (RRMS) are associated with short term cognitive change. Method(s): 90 newly diagnosed RRMS patients (first symptoms =4 IRLs. IRL prevalence was higher greater in males (p=0.01). 36% pf people with MS with IRL at diagnosis developed at least an additional IRL over a mean follow up of 21 months. Of the 69% of patients who had no IRLs at diagnosis, 16 (28%) developed at least one IRL over a median follow up of 17.25 months. No significant correlation was found between IRL count at diagnosis and baseline SDMT scores, or between the IRL count at baseline and the change in SDMT scores at follow-up. In contrast, the accumulation of additional IRLs correlated with SDMT change at both the 1 year (p 0.006) and 2-year follow-up (p 0.004). Type of DMT did not influence this. . Conclusion(s): The accumulation of IRLs in early MS in the first two years after diagnosis already correlates with changes in cognitive measures. IRL accumulation may hold prognostic value for long-term cognitive impairment in MS.
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P421/1709: The neutrophil-to-lymphocyte ratio is a marker of acute inflammation but does not predict relapses or disease severity in a UK cohort of people with MOGAD and NMOSDIntroduction: Neutrophil-to-lymphocyte ratio (NLR) is a blood marker of systemic inflammation. Two studies from China have recently proposed NLR as biomarker of disease severity in people with oligodendrocyte glycoprotein associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), with higher NLR in NMOSD compared to MOGAD. Objectives/Aims: To assess if NLR predicts relapse risk and worse disability in a group of patients with MOGAD and NMOSD from the East Midlands of England. Method(s): We extracted demographic, clinical and biology data of people with MOGAD and NMOSD aquaporin4 IgG positive, attending the NMOSD/MOGAD specialist clinic at the Queen's Medical Centre in Nottingham, UK. We compared NLR in relapse and remission, and how NLR correlates with relapse rate, risk of early relapses (<6 months, considered marker of risk of recurrence in MOGAD), disease course (monophasic vs relapsing), and disability accumulation (EDSS). Two-tailed student t-test, Mann- Whitney U test, Chi-Square or Fisher's exact tests were used for detecting the differences. Receiver operator curve (ROC) analysis was used to assess the ability of NLR to distinguish between MOGAD and NMOSD aquaporin4 IgG positive. Binary logistic regression analysis was used to evaluate potential risk factors for disease recurrence. Estimates of the probability of relapse were obtained using a univariate Cox Proportional Hazards model. Result(s): We collected data of 28 patients with MOGAD (16 women; average age 33.4y; 13 relapsing MOGAD) and 37 patients with NMOSD AQP4IgG+(33 women; average age 45y) with a mean duration of follow-up of 8.6y (median 7.5y) and 9.8y (median 6.8y) respectively. NLR was higher in relapse than in remission in both MOGAD and NMOSD, but did not differentiate between the two conditions. NLR at disease onset had no predictive value in discerning the event of relapse < 6 months from onset. NLR at diagnosis (at first attack) or in remission had no association with the event of first relapse after diagnosis, number of relapses and disability accumulation for any of the two conditions, and could not differentiate between monophasic and relapsing forms of MOGAD. Conclusion(s): NLR is merely a marker of acute inflammation in MOGAD and NMOSD and cannot serve as predictor for risk of relapse or disability accumulation.
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Beta interferons as immunotherapy in multiple sclerosis: A new outlook on a classic drug during the COVID-19 pandemicBeta interferons (IFN-beta) are pleiotropic cytokines with antiviral properties. They play important roles in the pathogenesis of multiple sclerosis (MS), an incurable immune-mediated disorder of the central nervous system. The clinical expression of MS is heterogeneous, with relapses of neuroinflammation and with disability accrual in considerable part unrelated to the attacks. The injectable recombinant IFN-beta preparations are the first approved disease-modifying treatments for MS. They have moderate efficacy in reducing the frequency of relapses, but good long-term cost-efficacy and safety profiles, so are still widely used. They have some tolerability and adherence issues, partly mitigated in recent years by the introduction of a PEGylated formulation and use of 'smart' autoinjector devices. Their general impact on long-term disability is modest but could be further improved by developing accurate tools for identifying the patient profile of best responders to IFN-beta. Here, we present the IFN-beta-based immunomodulatory therapeutic approaches in MS, highlighting their place in the current coronavirus disease (COVID-19) pandemic. The potential role of IFN-beta in the treatment of COVID-19 is also briefly discussed.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Limited value of radiomics compared to quantitative MRI measures for predicting 10-year disability in newly diagnosed multiple sclerosis: A real-world data exploratory study (P11-6.018)Objective: To compare the predictive value of radiomic features versus quantitative MRI for long-term disability in newly-diagnosed people with Multiple Sclerosis (MS). Background(s): MRI measures (lesions, linear-atrophy) correlate with MS severity, however their predictive value for long-term prognosis is limited. Machine learning (ML) classifiers perform well for cross-sectional disability prediction, but their value for longterm EDSS-prediction is unclear. Design/Methods: 158 MRI (sagittal T2-FLAIR and T1-weighted spin-echo sequences) and clinical data-sets of eighty-one patients with MS from the Nottingham MS Clinic 52 women;35.4(+/-10.3)y; diagnosis, five- and ten-years data] were used. We measured the T2-FLAIR-lesion( 3mm)number/volumes, and linear-atrophy (third-ventricular width, medullary width, corpus callosum index and inter-caudate diameter) using 3DSlicer4.13.0. 107 radiomics features were extracted from the T2-FLAIR images using Pyradiomics package. A Multilayer-Perceptron (MLP) model was trained on clinical data, with/without the radiomic features, to forecast the likelihood of EDSS score 6 at 10y. Due to the limited amount of data, a feature-ranking strategy was executed using Random Forest. With a fine-tuning on a small validation set, the number of features was reduced to <10 to reduce noise and prevent overfitting. esults: The MLP classifiers were tested on the whole dataset using 5-fold cross-validation approach. The accuracy for predicting 10y EDSS 6 before/after feature selection was 0.56/0.77 for the set of features including clinical/demographic and quantitative MRI data. Baseline(diagnosis) clinical/demographic features alone had a comparable accuracy (0.74). Adding radiomic features obtained from the clinical scans at diagnosis did not significantly improve accuracy (0.56/0.79). Adding 5y-followup data slightly improved accuracy (0.62/0.85). Conclusion(s): Within the limitation of the small sample-size, the use of radiomic features from first (diagnostic) MS clinical scan does not significantly improve the prediction of long-term disability accumulation compared to quantitative MRI. Mechanisms underlying disability progression in MS are complex, and predictive models should account for the relative weight of various factors beyond routine brain imaging.
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Guillain–Barré syndrome variant occurring after SARS-CoV-2 vaccinationAlthough SARS-CoV-2 vaccines are very safe, we report 4 cases of the bifacial weakness with paresthesias variant of Guillain-Barre syndrome (GBS) occurring within 3 weeks of vaccination with the Oxford-AstraZeneca SARS-CoV-2 vaccine. This rare neurological syndrome has previously been reported in association with SARS-CoV-2 infection itself. Our cases were given either intravenous immunoglobulin, oral steroids, or no treatment. We suggest vigilance for cases of bifacial weakness with paresthesias variant GBS following vaccination for SARS-CoV-2 and that postvaccination surveillance programs ensure robust data capture of this outcome, to assess for causality. ANN NEUROL 2021;90:315-318.Copyright © 2021 American Neurological Association.
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Hookworm treatment for relapsing multiple sclerosis: A randomized double-blinded placebo-controlled trialImportance: Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS. Objective(s): To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS. Design, Setting, and Participant(s): This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-To-Treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-Three patients were screened; of these, 71 were recruited (2 ineligible/declined). Intervention(s): Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment. Main Outcomes and Measures: The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood. Result(s): Patients (mean SD] age, 45 9.5] years; 50 women 71%]) were randomized to receive hookworm (35 49.3%]) or placebo (36 50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 51.4%] vs 10/36 27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 4.4%]; placebo, 34 3.9%]; P =.01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo. Conclusions and Relevance: Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity. Trial Registration: ClinicalTrials.gov Identifier: NCT01470521.Copyright © 2020 American Medical Association. All rights reserved.
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Human endogenous retroviruses and multiple sclerosis: Causation, association, or after-effect?From the early days of MS discovery, infections have been proposed as a possible cause of the disease. In the last three decades, an association between human endogenous retrovirus expression and MS has been further investigated and confirmed. Nevertheless, the role of such retroviruses in the disease needs clarification. In this review, we introduce MSRV/HERV-W and describe its association with MS. We then summarize the evidence for the involvement of MSRV/HERV-W in the aetiology and progression of MS and its possible role as biomarker and drug target. Biological mechanisms for HERV effects in MS may involve the activation of innate immune pathways by the envelope protein of MSRV (MSRVEnv). In addition to in vitro and experimental studies, further insight on how HERVs may influence immune-mediated pathology in MS may also come from the use of antiretroviral treatments in patients.Copyright © The Author(s), 2017.
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Decreased interferon-beta induced STAT-4 activation in immune cells and clinical outcome in multiple sclerosisObjectives: Interferon-beta (IFN-beta) is used in the treatment of multiple sclerosis (MS). IFN-beta activation of signal transduction and activation of transcription (STAT)-4 is linked to its immunomodulatory effects. Previous studies suggest a type I IFN deficit in immune cells of patients MS, but data on interferon-alpha/beta receptor (IFNAR) expression and the relationship with treatment response are conflicting. Here, we compare IFN-beta-mediated STAT4 activation in immune cells of untreated patients with MS and controls. Material(s) and Method(s): Peripheral blood mononuclear cells from 27 untreated patients with relapsing MS, obtained before the initiation of IFN-beta treatment, and 12 matched controls were treated in vitro with IFN-beta. Total and phosphorylated STAT4 (pSTAT4) and IFNAR were measured by flow cytometry and quantitative PCR. The patients were followed up for 5 years. Result(s): pSTAT4 induction by IFN-beta was lower in patients with MS than in controls, as was expression of IFNAR. pSTAT4 expression did not correlate with the clinical outcome at 5 years, measured by EDSS change. There was a negative correlation between the baseline IFNAR1 mRNA levels and relapse rate. Conclusion(s): The results suggest decreased IFN-beta responsiveness in patients with MS, associated with reduced STAT4 activation and reduced IFNAR expression. This reduced responsiveness does not appear to affect the long-term clinical outcome of IFN-beta treatment.Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Accelerated intermittent theta burst transcranial magnetic stimulation of the dorsolateral prefrontal cortex for chronic knee osteoarthritis painOBJECTIVE: This study assessed feasibility, safety, and tolerability of accelerated intermittent theta burst stimulation (aiTBS) with effective connectivity-guidance targeting the left dorsolateral prefrontal cortex (lDLPFC) from the right anterior insular (rAI) in chronic knee osteoarthritis pain., METHODS: The BoostCPM clinical trial (ISRCTN15404076) was a randomized, sham-controlled, single-blind, parallel-group pilot study in patients with mild-moderate chronic pain. Participants were assigned 2:1 (active: sham) aiTBS for 4 consecutive days (totaling 36,000 pulses) at a daily dose of 9000 pulses (5 sessions of 1800 pulses). Primary outcomes included safety, tolerability, pain-related and affective outcomes, and quantitative sensory testing., RESULTS: 45 participants received active (n = 33) or sham (n = 12) aiTBS. No serious adverse events were recorded, and protocol adherence (tolerability) was 80.6 % and 100 % for active and sham. Follow-up response rate was 78.1 % and overall acceptance/satisfaction was 89 %. Pain relief was observed immediately after treatment and lasted 16 weeks with clinically meaningful reduction of pain burden, but no differences between groups., CONCLUSIONS: aiTBS with rAI-connected lDLPFC targeting is a safe, well tolerated, feasible, and acceptable intervention in chronic pain patients. However, we found no additional improvements compared to sham., SIGNIFICANCE: Further studies of aiTBS and lDLPFC targeting for pain relief are warranted. Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.
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Acute inflammatory diseases of the central nervous system after SARS-CoV-2 vaccinationBackground and objectives: Acute inflammatory CNS diseases include neuromyelitis optica spectrum disorders (NMOSDs) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Both MOGAD and acute disseminated encephalomyelitis (ADEM) have been reported after vaccination. Consequently, the mass SARS-CoV-2 vaccination program could result in increased rates of these conditions. We described the features of patients presenting with new acute CNS demyelination resembling NMOSDs or MOGAD within 8 weeks of SARS-CoV-2 vaccination. Methods: The study included a prospective case series of patients referred to highly specialized NMOSD services in the UK from the introduction of SARS-CoV-2 vaccination program up to May 2022. Twenty-five patients presented with new optic neuritis (ON) and/or transverse myelitis (TM) ± other CNS inflammation within 8 weeks of vaccination with either AstraZeneca (ChAdOx1S) or Pfizer (BNT162b2) vaccines. Their clinical records and paraclinical investigations including MRI scans were reviewed. Serologic testing for antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin 4 (AQP4) was performed using live cell-based assays. Patients' outcomes were graded good, moderate, or poor based on the last clinical assessment. Results: Of 25 patients identified (median age 38 years, 14 female), 12 (48%) had MOG antibodies (MOGIgG+), 2 (8%) had aquaporin 4 antibodies (AQP4IgG+), and 11 (44%) had neither. Twelve of 14 (86%) antibody-positive patients received the ChAdOx1S vaccine. MOGIgG+ patients presented most commonly with TM (10/12, 83%), frequently in combination with ADEM-like brain/brainstem lesions (6/12, 50%). Transverse myelitis was longitudinally extensive in 7 of the 10 patients. A peak in new MOGAD cases in Spring 2021 was attributable to postvaccine cases. Both AQP4IgG+ patients presented with brain lesions and TM. Four of 6 (67%) seronegative ChAdOx1S recipients experienced longitudinally extensive TM (LETM) compared with 1 of 5 (20%) of the BNT162b2 group, and facial nerve inflammation was reported only in ChAdOx1S recipients (2/5, 40%). Guillain-Barre syndrome was confirmed in 1 seronegative ChAdOx1S recipient and suspected in another. Discussion: ChAdOx1S was associated with 12/14 antibody-positive cases, the majority MOGAD. MOGAD patients presented atypically, only 2 with isolated ON (1 after BNT162b2 vaccine) but with frequent ADEM-like brain lesions and LETM. Within the seronegative group, phenotypic differences were observed between ChAdOx1S and BNT162b2 recipients. These observations might support a causative role of the ChAdOx1S vaccine in inflammatory CNS disease and particularly MOGAD. Further study of this cohort could provide insights into vaccine-associated immunopathology.
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An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosisIntroduction: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. Areas covered: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. Expert opinion: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.Copyright © 2023 Informa UK Limited, trading as Taylor & Francis Group.
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Brain connectivity-guided, optimised theta burst transcranial magnetic stimulation to improve central pain modulation in knee osteoarthritis pain (BoostCPM): Protocol of a pilot randomised clinical trial in a secondary care setting in the UKIntroduction Chronic pain is a common health problem that is not efficiently managed by standard analgesic treatments. There is evidence that treatment resistance may result from maladaptive brain changes in areas that are fundamental to the perception of pain. Knee osteoarthritis is one of the most prevalent causes of chronic pain and commonly associated with negative affect. Chronic knee osteoarthritis pain is also associated with altered right anterior insula functional connectivity. We posit that reversal of these brain circuit alterations may be critical to alleviate chronic pain and associated negative affect, and that this can be achieved through non-invasive neuromodulation techniques. Despite growing interest in non-invasive neuromodulation for pain relief and proven efficacy in depression, results in chronic pain are mixed with limited high-quality evidence for clinical and mechanistic efficacy. Limitations include patient heterogeneity, imprecision of target selection, uncertain blinding and protocols that may deliver pulses at subclinical efficacy. Methods and analysis We hence developed an optimised treatment protocol of connectivity-guided intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex with accelerated delivery on four consecutive days (allowing 4 days within the same week as protocol variation) with five daily treatment sessions that will be piloted in a sham-controlled design in 45 participants with chronic knee pain. This pilot study protocol will assess feasibility, tolerability and explore mechanistic efficacy through serial functional/structural magnetic resonance imaging (MRI) and quantitative sensory testing. Ethics and dissemination This pilot trial has been approved by the Ethics Committee Cornwall and Plymouth. Results of the pilot trial will be submitted to peer-reviewed journals, presented at research conferences and may be shared with participants and PPI/E advisors. Trial registration number ISRCTN15404076.Copyright © 2023 BMJ Publishing Group. All rights reserved.
