Very-long T2-weighted imaging of the non-lesional brain tissue in multiple sclerosis patients.

The purpose of this study is to demonstrate that T2-weighted imaging with very long echo time (TE > 300 ms) can provide relevant information in neurodegenerative/inflammatory disorder. Twenty patients affected by relapsing-remitting multiple sclerosis with stable disease course underwent 1.5 T 3D FLAIR, 3D T1-weighted, and a multi-echo sequence with 32 echoes (TE = 10-320 ms). Focal lesions (FL) were identified on FLAIR. T1-images were processed to segment deep gray matter (dGM), white matter (WM), FL sub-volumes with T1 hypo-intensity (T1FL), and dGM volumes (atrophy). Clinical-radiological parameters included Expanded Disability Status Scale (EDSS), disease duration, patient age, T1FL, and dGM atrophy. Correlation analysis was performed between the mean signal intensity (SI) computed on the non-lesional dGM and WM at different TE versus the clinical-radiological parameters. Multivariable linear regressions were fitted to the data to assess the association between the dependent variable EDSS and the independent variables obtained by T1FL lesion load and the mean SI of dGM and WM at the different TE. A clear trend is observed, with a systematic strengthening of the significance of the correlation at longer TE for all the relationships with the clinical-radiological parameters, becoming significant (p < 0.05) for EDSS, T1FL volumes, and dGM atrophy. Multivariable linear regressions show that at shorter TE, the SI of the T2-weighted sequences is not relevant for describing the EDSS variability while the T1FL volumes are relevant, and vice versa, at very-long TEs (around 300 ms); the SI of the T2-weighted sequences significantly (p < 0.05) describes the EDSS variability. By very long TE, the SI primarily originates from water with a T2 longer than 250 ms and/or free water, which may be arising from the perivascular space (PVS). Very-long T2-weighting might detect dilated PVS and represent an unexplored MR approach in neurofluid imaging of neurodegenerative/inflammatory diseases.

Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis.

BACKGROUND: Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking. OBJECTIVES: To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS. METHODS: Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab were identified in the global MSBase cohort and two additional UK centres. Patients were followed for ⩾6/12 and had ⩾3 in-person disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARRs) and disability outcomes. RESULTS: The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab) or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (0.07 vs. 0.12, p = 0.006) and a higher ARR than natalizumab (0.10 vs. 0.06, p = 0.03), ocrelizumab (0.09 vs. 0.05, p = 0.008) and alemtuzumab (0.17 vs. 0.04, p < 0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.47-2.47) or alemtuzumab (HR 0.73, 95% CI 0.26-2.07), but was lower for patients treated with natalizumab (HR 0.35, 95% CI 0.13-0.94) and ocrelizumab (HR 0.45, 95% CI 0.26-0.78). There was no evidence for a difference in disability improvement. CONCLUSION: Cladribine is an effective therapy that can be viewed as a step up in effectiveness from fingolimod, but is less effective than the most potent intravenous MS therapies.

Long-term use of rituximab increases T cell count in MS patients.

Rituximab has been used to treat MS patients in Iceland for over a decade. However, long-term effect of rituximab on leukocyte populations has not yet been elucidated. By retrospective analysis of flow cytometric data from 349 patients visiting the neurological ward at The National University Hospital of Iceland from 2012 to 2023 for rituximab treatment, the long-term effect of rituximab and whether the effect was dose dependent (1000mg vs 500mg) was evaluated. No difference was detected in efficacy of B cell depletion in patients treated with 500mg as an initial dose of rituximab when compared to 1000mg. Long-term use of rituximab led to an increase in T cell count (p=0,0015) in patients receiving 3-8 doses of rituximab (1.5-8 years of treatment). The increase occurred in both CD4+ (p=0,0028) and CD8+ T cells (p=0,0015) and led to a decrease in the CD4/CD8 ratio (p=0,004). The most notable difference lies in reshaping the balance between näive and effector CD8+ T cells. The clinical implications of long-term treatment with rituximab and its effect on the T cell pool needs to be explored further. Since no difference in B cell depletion was detected between the two patient groups, 1000mg as an initial dose might be excessive, suggesting a personalized dosing regimen might have therapeutic and financial advantages.

The Potential Association Between microRNA 135-5P and p62 and Their Effect on NRF2 Pathway in Multiple Sclerosis.

Background: Multiple Sclerosis (MS) is a prevalent non-traumatic disabling disease affecting young adults, characterized by complexity in its pathogenesis. Nuclear factor erythroid 2-Related Factor 2 (NRF2) serves as a crucial transcriptional regulator of anti-inflammatory and antioxidant enzymes, influenced by the ubiquitous protein p62. It acts as a scaffold directing substrates to autophagosomes. This study aims to explore the potential association between microRNA 135-5p and p62 and their impact on inflammation and oxidative stress through the NRF2 pathway in MS. Methods: The study included 30 healthy controls and 60 MS patients (relapsing-remitting and secondary progressive). Real-time PCR was employed for the detection of Nrf2, p62, miRNA135-5P, and NF-κB in serum, while p53 levels were determined using ELISA. Results: Nrf2 and p62 expression was significantly downregulated in the MS group compared to controls. Conversely, miRNA135-5P, NF-κB expression, and P53 levels were significantly elevated in the MS group. Conclusions: This study reveals a potential association between miRNA 135-5p and p62, indicating their role in the pathogenesis of MS. Results suggest that miRNA 135-5p and p62 may influence inflammation and oxidative stress in MS through the NRF2 pathway, potentially mediated by NF-κB and p53.

Management of patients with neurological diseases considering post-pandemic coronavirus disease 2019 (COVID-19) related risks and dangers - An updated European Academy of Neurology consensus statement.

BACKGROUND AND PURPOSE: In October 2020, the European Academy of Neurology (EAN) consensus statement for management of patients with neurological diseases during the coronavirus disease 2019 (COVID-19) pandemic was published. Due to important changes and developments that have happened since then, the need has arisen to critically reassess the original recommendations and address new challenges. METHODS: In step 1, the original items were critically reviewed by the EAN COVID-19 Task Force. In addition, new recommendations were defined. In step 2, an online survey with the recommendations forged in step 1 was sent to the Managing Groups of all Scientific and Coordinating Panels of EAN. In step 3, the final set of recommendations was made. RESULTS: In step 1, out of the original 36 recommendations, 18 were judged still relevant. They were edited to reflect the advances in knowledge and practice. In addition, 21 new recommendations were formulated to address the new knowledge and challenges. In step 2, out of the 39 recommendations sent for the survey, nine were approved as they were, whilst suggestions for improvement were given for the rest. In step 3, the recommendations were further edited, and some new items were formed to accommodate the participants' suggestions, resulting in a final set of 41 recommendations. CONCLUSION: This revision of the 2020 EAN Statement provides updated comprehensive and structured guidance on good clinical practice in people with neurological disease faced with SARS-CoV-2 infection. It now covers the issues from the more recent domains of COVID-19-related care, vaccine complications and post-COVID-19 conditions.

Niacin produces an inconsistent treatment response in the EAE model of multiple sclerosis.

Niacin was found in the lysolecithin model of multiple sclerosis (MS) to promote the phagocytic clearance of debris and enhance remyelination. Lysolecithin lesions have prominent microglia/macrophages but lack lymphocytes that populate plaques of MS or its experimental autoimmune encephalomyelitis (EAE) model. Thus, the current study assessed the efficacy of niacin in EAE. We found that niacin inconsistently affects EAE clinical score, and largely does not ameliorate neuropathology. In culture, niacin enhances phagocytosis by macrophages, but does not reduce T cell proliferation. We suggest that studies of niacin for potential remyelination in MS should include a therapeutic that targets adaptive immunity.

NMDAR autoimmune encephalitis and fulminant relapse of multiple sclerosis: a rare overlap syndrome.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease that has been rarely associated with AQP4-IgG and MOG-IgG demyelinating diseases, and even more rarely with multiple sclerosis. We present the case of a woman in her 40s with confirmed NMDAR encephalitis and coexistent fulminant relapse of multiple sclerosis treated with alemtuzumab 6 years prior, who had a favourable outcome following treatment with ocrelizumab. We proceed to systematic review of similar reported cases, finding a lower than anticipated prevalence of underlying malignancy compared with isolated NMDAR encephalitis, in this rare overlap syndrome.

Early clinical effect of cladribine in patients with highly active multiple sclerosis in Mexico.

Background: Cladribine shows efficacy in multiple sclerosis (MS), but Latin American (LATAM) real-world data is limited, despite potential sociodemographic variations. Objective: Investigate baseline characteristics and clinical response in highly active MS patients in Mexico, identifying predictors of early treatment response. Method: A multicenter cohort study analyzed retrospective data from individuals with "highly active" MS in the Cladribine Patient Support Program across 11 Mexican clinics. Criteria included one-year prior treatment with another disease-modifying treatment and recent relapse with specific MRI findings. Primary outcomes focused on achieving NEDA-3 status after 12 months. Results: In the follow-up, 67.5% maintained NEDA-3 status. Baseline EDSS scores decreased significantly from 1.50 to 1.00 (p = 0.011), with no confirmed disability worsening. No significant differences were observed between NEDA-3 achievers and non-achievers in demographic and clinical variables. No severe adverse events were reported. Conclusion: Cladribine showed early and effective control of active MS in Mexican patients, demonstrating a secure profile with minimal adverse events. This study provides valuable real-world evidence in the LATAM context.

Distinguishing the role of positivity bias, cognitive impairment and emotional reactivity in the deontological preference in multiple sclerosis during moral dilemmas: a social cognition study protocol.

Background: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by a broad and unpredictable range of symptoms, including cognitive and sociocognitive dysfunction. Among these social-cognitive functions, moral judgment has been explored in persons with MS (PwMS) using moral dilemmas, where participants must decide whether to sacrifice one person to save a greater number. Opting for such a sacrifice reflects utilitarian reasoning (sacrificing one for the benefit of many is deemed acceptable), while refusing reflects deontological reasoning (such sacrifice is considered morally wrong). Compared to controls, PwMS have been shown to make greater deontological moral choices in such dilemmas. Objectives: While PwMS have demonstrated a higher tendency for deontological moral choices in moral dilemmas compared to controls, the underlying determinants of this reasoning pattern remain unclear. In this project, we aim to investigate cognitive, emotional, and motivational factors that may explain deontological decision-making in MS. Methods and analysis: We will recruit a sample of 45 PwMS and 45 controls aged 18-55 years. The type of response, deontological or utilitarian, to a series of 20 vignettes of moral dilemmas will constitute the primary outcomes. Global cognitive performance, positivity bias, alexithymia and empathy levels as well as emotional reactivity measured by electrodermal activity (EDA) during moral dilemmas will be secondary outcomes. Ethics and dissemination: Ethics approval was granted by a national ethical committee (CPP Ouest III, national number 2023-A00447-38). The project is sponsored by the ARSEP Foundation. Findings will be presented at national and international conferences, as well as published in peer-reviewed scientific journals.

No immediate change in systemic cytokines following an eccentric muscle training session in people with multiple sclerosis.

Background: Eccentric muscle contractions elicit distinct physiological responses, including modulation of the cytokine profile. Although relevant for rehabilitation, the effect of eccentric muscle training on the immune system has never been investigated in multiple sclerosis (MS). Objectives: Examine the immediate cytokine response of interleukin-4 (IL-4), IL-6, IL-10, IL-17a, interferon-gamma, and tumor necrosis factor-alpha after a moderate eccentric training session in individuals with MS. Additionally, further investigate the association between systemic cytokine levels at rest and clinical measures of mobility and lower limb functional strength. Design: Observational study. Methods: The first session included blood sampling for baseline cytokine measures. Subsequently, the participant completed a battery of clinical assessments related to mobility and lower limb strength, that is, the Timed-Up-and-Go Test, Five-Repetition-Sit-to-Stand-Test (5STS), Four-Square-Step-Test, and Two-Minute-Walk-Test. The second session included the eccentric exercise training session, followed by a second blood sampling to assess the acute cytokine response to the eccentric training bout. This session comprised 10 exercises concentrating on the strength of the trunk and lower extremities. Results: Twenty-seven people with MS (pwMS), with a mean age of 40.1 years, participated in the study. No difference was demonstrated in the cytokine concentration values between baseline and immediately after the eccentric training session. The 5STS explained 30.3% of the variance associated with interferon-gamma, 14.8% with IL-4, and 13.8% with IL-10. Conclusion: An eccentric training bout does not impact cytokine concentration in the blood and, consequently, does not boost a pro-inflammatory response, thus, it can be performed on pwMS in a rehabilitation setting.

A strength-lengthening exercise session doesn't affect inflammation markers in people with multiple sclerosis The article explores how a specific type of exercise, called eccentric muscle training, affects people with multiple sclerosis (MS). Eccentric muscle training involves exercises where the muscle lengthens under tension, like when you slowly lower a heavy object. This type of exercise is known for causing unique physical responses, including changes in certain proteins in the blood that help control the immune system and inflammation. The main goal of the study was to see if a session of eccentric muscle training would change the levels of these proteins, called cytokines, in the blood of people with MS immediately after exercise. The cytokines studied included IL-4, IL-6, IL-10, IL-17a, INF-γ, and TNF-α. These proteins are important because they help regulate inflammation and immune responses. The researchers also wanted to know if there was any connection between the levels of these proteins at rest and measures of mobility and leg strength. Twenty-seven people with MS took part in the study. Their average age was 40.1 years. In the first session, blood samples were taken to measure the baseline levels of these proteins, and various tests were conducted to assess mobility and leg strength. In the second session, participants completed an eccentric training session, and another blood sample was taken immediately after to see if there were any immediate changes in the protein levels. The results showed no significant differences in the protein levels before and after the exercise session. This suggests that a single session of eccentric muscle training does not cause an immediate inflammatory response in the blood. Therefore, this type of exercise can be safely included in rehabilitation programs for people with MS without the risk of causing harmful inflammation. Overall, the study supports the safety of eccentric muscle training for people with MS and provides valuable insights into its immediate effects on the immune system.

A pilot study of monocytes in relapsing remitting multiple sclerosis: Correlation with disease activity.

Background: Numerous immune cells are involved in developing multiple sclerosis (MS). Monocytes are believed to be the first to enter the brain and initiate inflammation. The role of monocyte subtypes in MS needs to be better understood. Objective: The current study aims to investigate the presence of different subsets of monocytes in relapsing-remitting MS (RRMS) Egyptian patients and their correlation with disease activity. Methods: This study included 44 RRMS patients (22 patients in relapse, 22 patients in remission), diagnosed according to the 2017 MacDonalds criteria, and 44 matched healthy controls. Personal and medical histories were taken from the patients, and the Expanded Disability Status Scale (EDSS) was used to evaluate the degree of impairment. Characterization of peripheral blood monocyte subsets was done by flow cytometry for all participants. Results: The percentage of classical, intermediate, and non-classical monocyte subsets showed a significant increase in RRMS patients than controls with p-values of 0.029, 0.049, and 0.043, respectively. In the RRMS patients, there were no statistically significant correlations (p-values >0.05) between the EDSS scores, the duration of disease, and number of relapses in the past year and the percentages of the various monocyte subsets. Furthermore, there were no significant differences in the percentage of each monocyte subset between RRMS patients in remission and those experiencing a relapse (p-values >0.05). However, patients with evidence of activity in magnetic resonance imaging (MRI) had a significantly high percentage of non-classical monocytes with a p-value of 0.002. Conclusion: In RRMS patients, the three monocyte subsets (classical, non-classical and intermediate) increase significantly regardless of the disease activity. This increase denotes the vital role of monocytes and innate immunity in MS pathology, especially the non-classical monocyte subset. These findings suggest that monocytes might be a promising MS therapeutic target.

Association between peripheral blood immunological status and intrathecal inflammatory markers differentiate multiple sclerosis clinical phenotypes.

BACKGROUND: The difference in the clinical course, response to therapy, and distribution of CNS inflammation in primary-progressive (PPMS) and relapsing-remitting multiple sclerosis (RRMS) suggests differences in the underlying immunological characteristics of the disease. We aimed to investigate differences in immunological profiles in relation to intrathecal inflammation in different MS forms. METHODS: The peripheral blood (PB) proportions of CD4 + and CD8 + T-cells and CD19 + B-cells were retrospectively compared with the markers of intrathecal immunoglobulin G (IgG) synthesis at diagnosis: IgG index, percentage of intrathecal IgG synthesis (IF IgG), the number of oligoclonal bands (OCB), depending on the blood-brain barrier (BBB) function, and antibody specific index to neurotrophic viruses (MRZH reaction). RESULTS: Thirty-six controls, 71 RRMS and 25 PPMS were enrolled. PPMS had higher percentage of CD4 + T-cells compared to RRMS (P = 0.043) and controls (P = 0.003). The percentage of CD8 + T-cells and CD19 + B-cells, and respective absolute cell counts did not differ according to the MS phenotype. In RRMS with the dysfunctional BBB, the IgG index (r = 0.642, P = 0.012) correlated significantly with the CD19 + B-cells while the CD4 + T-cells inversely correlated with IF IgG (r=-0.574, P = 0.039). Interestingly, in PPMS the number of OCB was positively associated with CD4+ (r = 0.603, P = 0.015) and negatively associated with CD8 + T-cells (r=-0.554, P = 0.033), while IF IgG negatively correlated with CD8 + T-cells (r=-0.689, P = 0.003), but only in the preserved BBB function. CONCLUSIONS: The PB CD4 + T-cells and B-cells were associated with the intrathecal inflammation in RRMS with BBB dysfunction while CD8 + T-cells were involved in PPMS with CNS-compartmentalized inflammation.

Study of the impact of multiple sclerosis on the reproductive life of Spanish women: An online survey.

BACKGROUND: Women have a higher risk of developing multiple sclerosis (MS) than men. The natural reproductive period from menarche to menopause corresponds to the period of active inflammatory disease in MS. Mothers and pregnant women with MS need information about how their disease may affect pregnancy and breastfeeding. AIM: The aim was to explore the reproductive factors in an MS-diagnosed population and to identify ways to support patients and their decision-making process. METHODS: We conducted a cross-sectional, Web-based survey of women living with MS in Asturias (Spain) using a community-based participatory approach. FINDINGS: Early menarche may predict the onset of MS. Pregnancy improves the general health of patients and reduces the number of relapses. Breastfeeding is often not practised and may cause concern in women. MS does not affect the age of menopause, but it can worsen symptoms. However, menopause does not increase the number of MS relapses. CONCLUSIONS: MS is increasingly diagnosed at an earlier age, which increases the number of women who become pregnant after being diagnosed with MS. The decrease in MS relapses during pregnancy and the increase during the postpartum period are consistent with previous reports. Women who choose to breastfeed are in the minority due to treatment incompatibility, although some currently used treatments are compatible with breastfeeding. However, there is a lack of information on this which should be investigated.

Subcutaneous administration of natalizumab can lead to lower drug concentrations compared to intravenous administration.

BACKGROUND: Several studies reported lower drug concentrations with subcutaneous natalizumab compared to intravenous natalizumab. With the emergence of extended interval dosing, gaining more insight into lower concentrations after subcutaneous administration is essential. METHODS: We compared serum trough concentrations between subcutaneous and intravenous administration within a matched cohort (n = 50). RESULTS: Subcutaneous administration (n = 25) was associated with lower concentrations compared to intravenous administration (n = 25) (log-B=-0.28, p = 0.01). In an exploratory group of 11 patients receiving extended interval dosing of subcutaneous natalizumab, the median trough concentration was even lower. CONCLUSION: Subcutaneous natalizumab can lead to lower drug concentrations, potentially limiting extended interval dosing.

Machine learning-driven diagnosis of multiple sclerosis from whole blood transcriptomics.

Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.

Practical Recommendations from the Gulf Region on the Therapeutic Use of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis: Impact of the Latest Real-World Evidence on Clinical Practice.

Cladribine tablets (CladT), like alemtuzumab, acts as an immune reconstitution therapy. However, CladT is administered orally (alemtuzumab is given by infusion) and without the potential for serious side effects that limit the therapeutic use of alemtuzumab in multiple sclerosis (MS). Treatment with CladT, given initially as short courses of treatment 1 year apart, provides years of freedom from MS disease activity in responders to treatment. The appearance of mild or moderate MS disease activity after the initial 2 years of treatment may prompt careful follow-up or a further course of CladT, depending on the nature of the activity and individual circumstances. The appearance of severe MS disease activity requires a switch to an alternative high-efficacy disease-modifying treatment (DMT). The accumulating data from CladT-treated people with MS in real-world studies, including those with follow-up durations extending for years beyond the initial treatment, have demonstrated long-term freedom from MS disease activity in a good proportion of patients. This clinical experience has also confirmed that treatment with CladT is generally safe and well tolerated. The best time to prescribe a high-efficacy DMT is the subject of debate, with evidence that earlier versus later use of such agents may provide more effective long-term protection from disability progression. High-efficacy DMTs have traditionally been reserved for use in people with MS and high disease activity on presentation or breakthrough disease on one or more DMTs, as per the current product labels. The latest evidence from real-world studies suggests that CladT is effective and safe in DMT-naïve patients, including those with shorter disease duration.

Longitudinal epidemiology of multiple sclerosis over 60 years in Newcastle, Australia: 1961 to 2021.

INTRODUCTION: Newcastle, Australia, has been serially studied for MS epidemiology since 1961, showing consistently increasing prevalence estimates and incidence rates, including to our 2011 study. OBJECTIVES: To assess the 2011-2021 epidemiology of MS in Newcastle and to compare with previous measures. METHODS: Demographic and clinical data were extracted from medical records of MS cases residing in Newcastle, as identified by public and private clinicians. Prevalence (2011 and 2021) and incidence rates (2011-2021, from onset and from diagnosis) and mortality rate (2011-2021) were estimated and age-standardised to the 2021 Australian population. RESULTS: The 2021 prevalence was 173.1/100,000 (age-standardised = 178.7/100,000, F/M-sex-ratio = 3.3), a 42.2 % increase from 2011 (F/M-sex-ratio = 3.1), 175.0 % from 1996 (F/M-sex-ratio = 2.6), and 831.0 % from 1961 (F/M-sex-ratio = 1.2). The 2011-21 age-standardised onset incidence rate was 3.5/100,000 person-years (F/M-sex-ratio = 2.8), a 68.7 % increase from 1971 to 81 (F/M-sex-ratio = 1.1) and 44.5 % from 1986 to 96 (F/M-sex-ratio = 2.3). The age-standardised diagnosis incidence rate was 6.1/100,000 (F/M-sex-ratio = 2.2), statistically unchanged from that in 2001-2011 (6.8/100,000, F/M-sex-ratio = 3.2). The 2011-21 mortality rate was 2.1/100,000 person-years (2.2 age-standardised, F/M-sex-ratio = 1.4), with a standardised mortality ratio of 1.6. CONCLUSION: The Newcastle region continues to be a high frequency zone for MS. The incidence rate from onset is significantly increased from previous estimates, but incidence rate from diagnosis is stable. Prevalence and incidence sex ratios have stabilised at roughly 3.0, similar to other Australian sites.

Novel model of multiple sclerosis induced by EBV-like virus generates a unique B cell population.

Epstein-Barr virus (EBV) is deemed a necessary, yet insufficient factor in the development of multiple sclerosis (MS). In this study, myelin basic protein-specific transgenic T cell receptor mice were infected with murid gammaherpesvirus 68 virus (MHV68), an EBV-like virus that infects mice, resulting in the onset neurological deficits at a significantly higher frequency than influenza or mock-infected mice. MHV68 infected mice exhibited signs including optic neuritis and ataxia which are frequently observed in MS patients but not in experimental autoimmune encephalomyelitis mice. MHV68-infected mice exhibited increased focal immune cell infiltration in the central nervous system. Single cell RNA sequencing identified the emergence of a population of B cells that express genes associated with antigen presentation and costimulation, indicating that gammaherpesvirus infection drives a distinct, pro-inflammatory transcriptional program in B cells that may promote autoreactive T cell responses in MS.

Person-centred integrated care for people living with Parkinson's, Huntington's and Multiple Sclerosis: A systematic review.

INTRODUCTION: People living with long-term neurological conditions (LTNCs) have complex needs that demand intensive care coordination between sectors. This review aimed to establish if integrated care improves outcomes for people, and what characterises successful interventions. METHODS: A systematic review of the literature was undertaken evaluating multisectoral integrated care interventions in people living with Parkinson's disease (PD), Multiple Sclerosis (MS) and Huntington's disease (HD). Strength of evidence was rated for the different outcomes. RESULTS: A total of 15 articles were included, reporting on 2095 patients and caregivers, finding that integrated care can improve people's access to resources and reduce patients' depression. UK studies indicated improvements in patients' quality of life, although the international literature was inconclusive. Few programmes considered caregivers' outcomes, reporting no difference or even worsening in depression, burden and quality of life. Overall, the evidence showed a mismatch between people's needs and outcomes measured, with significant outcomes (e.g., self-management, continuity of care, care experience) lacking. Successful programmes were characterised by expert knowledge, multisectoral care coordination, care continuity and a person-centred approach. CONCLUSIONS: The impact of integrated care programmes on people living with LTNCs is limited and inconclusive. For a more person-centred approach, future studies need to assess integrated care from a service-user perspective. PATIENT AND PUBLIC CONTRIBUTION: Thirty people living with LTNCs were involved in this review, through defining research questions, validating the importance of the project, and increasing the researchers' understanding on what matters to service users. A patient and public involvement subgroup of representatives with lived experience on PD, MS and HD identified the need for more person-centred integrated care, with specific concerns over care fragmentation, care duplication and care continuity. This was key to data analysis and formulating the characteristics of successful and unsuccessful integrated care programmes from the perspective of service users. The discrepancy between service users' needs and the outcomes assessed in the literature point to user-driven research as the solution to address what matters to patients and caregivers.

Increased intraindividual variability (IIV) in reaction time is the earliest indicator of cognitive change in MS: A two-year observational study.

Background: Cognitive decline in multiple sclerosis (MS) is common, but unpredictable, and increases with disease duration. As such, early detection of cognitive decline may improve the effectiveness of interventions. To that end, the Symbol Digit Modalities Test (SDMT) is effective in detecting slow processing speed as it relates to cognitive impairment, and intraindividual variability (IIV) observed in trials assessing continuous reaction time (RT) may be a useful indicator of early cognitive changes. Here, we will assess cognitive IIV changes in adults with early MS. Methods: Adults with relapsing-remitting MS (RRMS), <11 years since diagnosis, were recruited nationally. Baseline and two-year follow-up assessments included Brief International Cognitive Assessment in MS (BICAMS) and Cogstate computerized tests. Intraindividual variability in RT was calculated from psychomotor tasks and data were age-normalized. Results: A total of 44 of the 66 participants completed follow-up (mean age, 34.0 ± 5.5 years; 66 % female; mean disease duration, 4.1 ± 2.9 years; median Expanded Disability Status Scale (EDSS) score, 1.5 [0 to 6.0]). Participants were grouped by SDMT z-score median split. Groups did not differ in demographics or clinical features. The higher baseline SDMT group was faster (p = 0.05) in RT and less variable (lower IIV, p = 0.001). At the two-year follow-up, the higher SDMT group showed increased variability (p = 0.05) compared to the lower SDMT group, with no significant RT or BICAMS changes. Conclusions: In early MS, higher SDMT performance at baseline is associated with less cognitive variability but may indicate susceptibility to increased variability over time, highlighting the importance of monitoring IIV for early cognitive changes.