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Background: The Greater Hobart region (42.5°S) of Tasmania has consistently had the highest recorded prevalence and incidence rates of multiple sclerosis (MS) in Australia. We reassessed MS epidemiology in 2009-2019 and assessed longitudinal changes over 68 years.Methods: Cases recruited from clinic-based datasets and multiple other data sources. 2019 prevalence and 2009-2019 annual incidence and mortality rates estimated, and differences assessed using Poisson regression.Results: 436 MS cases resident on prevalence day were identified, and 130 had symptom onset within 2009-2019. Prevalence 197.1/100 000 (95% CI 179.4 to 216.5; 147.2/100 000 age standardised, 95% CI 126.5 to 171.3), a 36% increase since 2001 and 3.1-fold increase since 1961. 2009-2019 incidence rate=5.9/100 000 person-years, 95% CI 5.0 to 7.0 (6.1/1000 000 age standardised, 95% CI 4.7 to 7.9), a 2.8-fold increase since 1951-1961 and 65% since 2001-2009. 2009-2019 mortality rate=1.5/100 000 person-years, 95% CI 1.1 to 2.2 (0.9/100 000 age standardised, 95% CI 0.4 to 1.7), comparable to 2001-2009 (1.0/100 000) but reduced by 61% from 1951 to 1959 (2.1/100 000). 2001-2009 standardised mortality ratio=1.0 in 2009-2019, decreased from 2.0 in 1971-1979. Female:male prevalence sex ratio was 2.8, comparable to the 2009 value (2.6); incidence sex ratio (2.9) increased from 2001 to 9 (2.1). Comparisons with Newcastle, Australia (latitude=32.5°S) demonstrate a near complete abrogation of the latitudinal gradients for prevalence (ratio=1.0) and incidence (ratio=1.1), largely attributable to changing Hobart demography.Conclusions: Prevalence and incidence of MS continue to increase significantly in Hobart, alongside marked reductions in mortality and increased case longevity. The marked increase in incidence is of particular note and may reflect longstanding changes in MS risk behaviours including changing sun exposure, obesity rates, and smoking behaviours, particularly in females. Falling mortality contributes to increase longevity and prevalence, likely reflecting improved overall MS healthcare and implementation of disease-modifying therapy. [ABSTRACT FROM AUTHOR]

Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether lipid-related or body mass index (BMI)-related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS).Methods: The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, ΔEDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting ΔEDSS. All analyses were conducted using linear regression.Results: Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with ΔEDSS. The constructed lipid CGRS showed a significant, dose-dependent association with ΔEDSS (ptrend=1.4×10-6), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in ΔEDSS. We also found significant interactions between the CGRS and lipid levels in modulating ΔEDSS, including high-density lipoprotein (HDL; pinteraction=0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; pinteraction=0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL.Interpretation: In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression. [ABSTRACT FROM AUTHOR]

Background: The direct comparative evidence on treatment effects of available multiple sclerosis (MS) disease-modifying therapies (DMTs) is limited, and few studies have examined the benefits of DMTs on employment outcomes. We compared the effects of DMTs used in the previous 5 years on improving the work attendance, amount of work and work productivity of people with MS.Methods: The Australian MS Longitudinal Study collected data from participants on DMTs usage from 2010 to 2015 and whether DMTs contributed to changes in employment outcomes. We classified 11 DMTs into three categories based on their clinical efficacy (β-interferons and glatiramer acetate as category 1; teriflunomide and dimethyl fumarate as category 2; fingolimod, natalizumab, alemtuzumab and mitoxantrone as category 3). Each DMT used by a participant was treated as one observation and analysed by log-multinomial regression.Results: Of the 874 participants included, 1384 observations were generated. Those who used category 3 (higher efficacy) DMTs were 2-3 times more likely to report improvements in amount of work, work attendance and work productivity compared with those who used category 1 (classical injectable) DMTs. Natalizumab was associated with superior beneficial effects on patient-reported employment outcomes than fingolimod (RR=1.76, 95% CI 1.02 to 3.03 for increased work attendance and RR=1.46, 95% CI 1.02 to 2.10 for increased work productivity).Conclusions: Those using the higher efficacy (category 3) DMTs, particularly fingolimod and natalizumab, reported significant increases in amount of work, work attendance and work productivity, suggesting they have important beneficial effects on work life in people with MS. [ABSTRACT FROM AUTHOR]

People with multiple sclerosis (PwMS) commonly use complementary and alternative medicines (CAM), but an understanding of their efficacy is lacking. Here, we quantitatively review the class I and class II studies of treatment efficacy for multiple sclerosis from January 2001 to January 2017, in order to assess the modern evidence for CAM use. The 38 studies included in this review are divided across five CAM types (cannabis, diet, exercise, psychological approaches and other). We found little evidence to support CAM efficacy. The studies contained little replication in intervention, primary outcomes or study design. Six of 16 CAMs included in this review were only researched in a single study. Future work in this area should build consensus around study methodologies and primary outcomes. [ABSTRACT FROM AUTHOR]

Background: Due to the lack of prospective studies with longitudinal data on relapse, past genetic studies have not attempted to identify genetic factors that predict relapse risk (the primary endpoint of many pivotal clinical trials testing the efficacy of multiple sclerosis (MS) disease-modifying drugs) at a genome-wide scale.Methods: We conducted a genome-wide association analysis (GWAS) to identify genetic variants that predict MS relapse risk, using a three-stage approach. First, GWAS was conducted using the southern Tasmania MS Longitudinal Study with 141 cases followed prospectively for a mean of 2.3 years. Second, GWAS was conducted using the Ausimmune Longitudinal Study with 127 cases having a classic first demyelinating event followed for 5 years from onset. Third, the top hits with p<5.0×10-6 from the first two stages were combined with a longitudinal US paediatric MS cohort with 181 cases followed for 5 years after onset. Predictors of time to relapse were evaluated by a mixed effects Cox model. An inverse variance fixed effects model was then used to undertake a meta-analysis.Results: In the pooled results, using these three unique longitudinal MS cohorts, we discovered one novel locus (LRP2; most significant single nucleotide polymorphism rs12988804) that reached genome-wide significance in predicting relapse risk (HR=2.18, p=3.30×10-8). LRP2 is expressed on the surface of many central nervous system cells including neurons and oligodendrocytes and is a critical receptor in axonal guidance.Conclusions: The finding of a genetic locus that has extensive effects on neuronal development and repair is of interest as a potential modulator of MS disease course. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prospective associations between adiposity and lipid-related variables and conversion to multiple sclerosis (MS), time to subsequent relapse and progression in disability.Methods: A cohort of 279 participants with a first clinical diagnosis of central nervous system demyelination was prospectively followed to 5-year review. Height, weight, waist and hip circumference were measured, and serum samples taken for measurement of lipids and apolipoproteins. Survival analysis was used for conversion to MS and time to relapse, and linear regression for annualised change in disability (Expanded Disability Status Scale).Results: Higher body mass index (BMI; adjusted HR (aHR): 1.22 (1.04 to 1.44) per 5 kg/m2 increase), hip circumference (aHR: 1.32 (1.12 to 1.56) per 10 cm increase) and triglyceride levels (aHR: 1.20 (1.03 to 1.40) per unit increase) were associated with increased risk of subsequent relapse, while adiposity and lipid-related measures were not associated with conversion to MS. In addition, higher BMI (β: 0.04 (0.01 to 0.07) per 5 kg/m2 increase), hip circumference (β: 0.04 (0.02 to 0.08) per 10 cm increase), waist circumference (β: 0.04 (0.02 to 0.07) per 10 cm increase), total cholesterol to high-density lipoprotein ratio (TC/HDL ratio; β: 0.05 (0.001 to 0.10) and non-HDL; β: 0.04 (0.001 to 0.08) at study entry) were associated with a higher subsequent annual change in disability.Conclusions: Higher levels of adiposity, non-HDL and TC/HDL ratio were prospectively associated with a higher rate of disability progression, and higher adiposity and triglycerides were associated with relapse but not with conversion to MS. Improving the lipid profile and losing weight into the healthy range could reduce the accumulation of disability. [ABSTRACT FROM AUTHOR]

Background: The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies.Methods: Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (ΔEDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS).Results: We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted ΔEDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: those having ≥5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with ≤2. The CGRS for ΔEDSS was also significant: those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with ≤2, and the CGRS model explained 32% of the variance in disability in this study cohort.Conclusions: These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP. [ABSTRACT FROM AUTHOR]

Background Altered reactivity of peripheral blood mononuclear cells (PBMC) and their production of cytokines may affect multiple sclerosis (MS) clinical course. We assessed the relationship of stimulated PBMC-produced IFN-γ, TNF-α, IL-4 and IL-10 in modulating relapse risk using a prospective cohort with established relapsing-remitting MS. Methods Cytokine production from PBMCs taken in summer and winter was measured by ELISA. Predictors of cytokines assessed by multilevel mixed-effects linear regression. Predictors of relapse assessed by survival analysis. Results Increasing IFN-y was associated with increasing relapse risk, while increasing TNF-α reduced relapse risk after adjusting for IFN-γ. IL-10 and IL4 were not consistently associated with relapse risk. IFN-γ's effects on relapse were greatly attenuated by immunomodulatory therapies, by summer season and by higher serum vitamin D, whereas TNF-α's inverse association with relapse was only present in these circumstances. The TNF-α inverse association with relapse was only present among persons carrying the wild-type of the functional SNP rs1800693 in TNFRSF1A that has been previously associated with MS risk. Conclusions We found strong effects of IFN-γ and TNF-α on relapse risk, these differing by immunomodulatory therapy, season, and serum vitamin D, as well as by genotype. These results indicate altered reactivity of immune cells modulate MS disease. [ABSTRACT FROM AUTHOR]

Background: The interplay between genes and environmental factors on multiple sclerosis (MS) clinical course has been little studied. Methods: We conducted a prospective cohort study of 141 participants with relapsing-remitting MS (RRMS) and genotype data followed from 2002 to 2005 and examined genes in the vitamin D metabolism and vitamin D receptor (VDR)/retinoid X receptor (RXR) transcription factor formation pathway. Gene-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis. Genetic predictors of 25-hydroxyvitamin D (25(OH)D) were evaluated by multilevel mixed-effects linear regression. Significance threshold was adjusted by Bonferroni correction for the number of genes evaluated. Results: The relationship between 25(OH)D and hazard of relapse was significantly different for different alleles of two intronic single nucleotide polymorphisms (SNPs) (rs908742 in PRKCZ and rs3783785 in PRKCH) in the protein kinase C (PKC) family genes (pinteraction=0.001, padj=0.021, respectively). Two other intronic SNPs (rs1993116 in CYP2R1and rs7404928 in PRKCB) were significantly associated with lower levels of 25(OH)D (pinteraction=0.001, padj=0.021, respectively). A cumulative effect of multiple 'risk' genotypes on 25(OH) D levels and hazard of relapse was observed for the significant SNPs (ptrend=7.12×10-6 for 25(OH)D levels, ptrend=8.86×10-6 for hazard of relapse). Conclusions: Our data support the hypothesis that gene-vitamin D interactions may influence MS clinical course and that the PKC family genes may play a role in the pathogenesis of MS relapse through modulating the association between 25(OH)D and relapse. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Improved prevention and treatment will depend on a greater understanding of the causes and mechanisms involved in its onset and progression. MS is clearly driven by both environmental and genetic factors. Established contributory environmental factors include lower ultraviolet radiation exposure and lower vitamin D levels, Epstein-Barr virus and smoking. Our current understanding of MS genetics is undergoing a major upgrade as new genetic technologies are applied to large MS studies. In this article, we review the current literature describing a genetic contribution to MS susceptibility and review the methods to detect genetic variants that may underlie the genetic contribution to MS. We also consider how reporting of genetic discoveries in MS in the lay press has caused some confusion among patients and their families, who, not surprisingly, think that these discoveries can be translated into an available genetic test to diagnose MS or recognise family members at risk of developing MS. We review the current limited clinical use of genetics in the diagnosis and management of MS. [ABSTRACT FROM AUTHOR]

Background: There is a striking latitudinal gradient in multiple sclerosis (MS) prevalence, but exceptions in Mediterranean Europe and northern Scandinavia, and some systematic reviews, have suggested that the gradient may be an artefact. The authors sought to evaluate the association between MS prevalence and latitude by meta-regression. Methods and findings: Studies were sourced from online databases, reference mining and author referral. Prevalence estimates were age-standardized to the 2009 European population. Analyses were carried out by means of random-effects meta-regression, weighted with the inverse of within-study variance. The authors included 650 prevalence estimates from 321 peer reviewed studies; 239 were age-standardized, and 159 provided sex-specific data. The authors found a significant positive association (change in prevalence per degree-latitude) between age-standardized prevalence (1.04, p<0.001) and latitude that diminished at high latitudes. Adjustment for prevalence year strengthened the association with latitude (2.60, p<0.001). An inverse gradient in the Italian region reversed on adjustment for MS-associated HLA- DRB1 allele distributions. Adjustment for HLA-DRB1 allele frequencies did not appreciably alter the gradient in Europe. Adjustment for some potential sources of bias did not affect the observed associations. Conclusion: This, the most comprehensive review of MS prevalence to date, has confirmed a statistically significant positive association between MS prevalence and latitude globally. Exceptions to the gradient in the Italian region and northern Scandinavia are likely a result of genetic and behaviourale cultural variations. The persistence of a positive gradient in Europe after adjustment for HLA-DRB1 allele frequencies strongly supports a role for environmental factors which vary with latitude, the most prominent candidates being ultraviolet radiation (UVR)/ vitamin D. [ABSTRACT FROM AUTHOR]

Background: Hobart, Tasmania, has been the site of two major studies of multiple sclerosis (MS) frequency, in 1951-1961 and 1971-1981. Since then, there have been no studies of MS frequency in Hobart.Methods: Using a prevalent cohort of 226 cases in 2001 and 265 in 2009, the authors undertook a two-stage survey of MS frequency in Hobart. Combined with the published data from the two preceding studies, the authors conducted a time-trend analysis of MS epidemiology over 1951-2009.Results: The age-standardised prevalence in 2001 was 96.6/100 000, and 99.6/100 000 in 2009, a significant increase from the 1961 prevalence of 32.5/100 000 (p<0.001). Female prevalence increased over each time point; male prevalence increased between 1961 and 2001 but was unchanged thereafter. Incidence over 2001-2009 was 3.7/100 000, significantly increased from the 1951-1961 incidence of 2.2/100 000 (p=0.004), though the majority of this was between 1951-1961 and 1971-1981. Mortality fell by half from 2.4/100 000 in 1951-1959 to 1.0/100 000 in 2001-2009-this decreased mortality and an older cohort contribute to the increase in prevalence. Neither prevalence (p=0.48) nor incidence (p=0.18) sex ratios changed significantly between 1951 and 2009.Conclusions: Between 1951 and 2009, the age-standardised prevalence of MS in Hobart increased threefold, and the incidence nearly doubled. Part of the increase in prevalence was due to an increased longevity, decreased mortality and increased incidence. Differences in patterns by birthplace may be explained by the Australian assisted-migration programme of 1945-1981. These data do not demonstrate the strong and significant changes in sex ratio observed elsewhere. [ABSTRACT FROM AUTHOR]

Presents information on a study which examined the consequences of suboptimal care before admission to intensive care units. Methodology used in the study; Number of patients that received suboptimal care; Percentage of intensive care mortalities that were recorded; Suggestion on how to improve quality of care before admission to intensive. INSETS: Suggestions to improve quality of care before admission to...;Key messages.

In this article, the author focuses on a research by researcher A. Scalfari and colleagues related to the onset of progression in multiple sclerosis (MS) cases. He informs that researchers have found that early relapses within the first 2 years of MS influence the timing of onset of progression and patients reach secondary progression multiple sclerosis (SPMS) in 4.8 years earlier than those with early relapse in 2 years. He also reflects on the time of secondary progression (SP) onset.

The author reflects on the impact of sunshine on the inflammatory disease multiple sclerosis (MS). He cites a study conducted by physician Donald Acheson in 1960 which suggests that sunshine is related to the global distribution of MS. He also discusses Vitamin D as a plausible mediator of sunshine's protective effect on immune system of MS patients. He also comments on the harmful effects of sunshine as in ultra violet radiation (UVR)-induced skin cancers.

The author discusses various aspect of multiple sclerosis severity score (MSSS), a method to quantify multiple sclerosis (MS). It discusses the difficulty in predicting the rate of progression for an individual with multiple sclerosis (MS). It says that MSSS can be used to assist an MS patient but only after four years of disease growth. It also mentions that the basic reason for difficulty in disease prediction is intrapersonal and interpersonal variability for the disease.

A response by Wei Shen Lim and colleagues to a letter to the editor about their study of H1N1 pneumonia cohort.

Background Early identification of patients with H1N1 influenza-related pneumonia is desirable for the early instigation of antiviral agents. A study was undertaken to investigate whether adults admitted to hospital with H1N1 influenza-related pneumonia could be distinguished clinically from patients with non-H1N1 community-acquired pneumonia (CAP). Methods Between May 2009 and January 2010, clinical and epidemiological data of patients with confirmed H1N1 influenza infection admitted to 75 hospitals in the UK were collected by the Influenza Clinical Information Network (FLU-CIN). Adults with H1N1 influenza-related pneumonia were identified and compared with a prospective study cohort of adults with CAP hospitalised between September 2008 and June 2010, excluding those admitted during the period of the pandemic. Results Of 1046 adults with confirmed H1N1 influenza infection in the FLU-CIN cohort, 254 (25%) had H1N1 influenza-related pneumonia on admission to hospital. In-hospital mortality of these patients was 11.4% compared with 14.0% in patients with inter-pandemic CAP (n=648). A multivariate logistic regression model was generated by assigning one point for each of five clinical criteria: age ≤65⇔…years, mental orientation, temperature ≥38°C, leucocyte count ≤12⇔-109/l and bilateral radiographic consolidation. A score of 4 or 5 predicted H1N1 influenza-related pneumonia with a positive likelihood ratio of 9.0. A score of 0 or 1 had a positive likelihood ratio of 75.7 for excluding it. Conclusion There are substantial clinical differences between H1N1 influenza-related pneumonia and inter-pandemic CAP. A model based on five simple clinical criteria enables the early identification of adults admitted with H1N1 influenza-related pneumonia. [ABSTRACT FROM AUTHOR]

Reports on the use of mixed appointment system in an urban general practice. Benefits of the system on patients; Applicability of the system in consultations; Consideration on the differences in the social class of patients.

Background: Previous natural history studies highlighted a consistent heterogeneity of disability trajectories among individuals with primary or secondary progressive multiple sclerosis (MS). However, evidence on disability progression in relapsing onset MS is scarce.The aim of this study was to investigate heterogeneity in disability accumulation over 10 years following a first clinical diagnosis of central nervous system demyelination (FCD) and identify genetic, demographic, environmental and clinical factors associated with these trajectories., Methods: We used group-based trajectory models to measure heterogeneity in disability trajectories based on the Expanded Disability Status Scale (EDSS) in a prospectively assessed cohort of 263 participants. To capture sustained neurological impairments and avoid issues related to significant changes in EDSS associated with relapse, we did not consider EDSS points recorded within 3 months of a relapse., Results: We identified three distinct and clinically meaningful disability trajectories: No/minimal, moderate and severe. Those in the no/minimal disability trajectory showed no appreciable progression of disability (median EDSS∼1 at 10-year review) while those in the moderate and severe disability trajectories experienced disability worsening (median time to reach EDSS 4 was 9 and 7 years, respectively). Compared with the no/minimal disability trajectory, those with older age, a higher number of relapses within the first 5 years post-FCD, and a higher number of comorbidities at baseline were more likely to be in the worse disability trajectory. Surprisingly, baseline MRI and anatomical site of initial symptoms did not influence long-term outcomes., Conclusions: Those at higher risk of faster MS disability progression can be identified based on their early clinical characteristics with potential therapeutic implications for early intervention and treatment escalation., Competing Interests: Competing interests: BVT has received compensation for consulting, talks and advisory/steering board activities for Merck, Novartis, Biogen and Roche. He receives research funding support from MS Research Australia, Medical Research Future Fund Australia and the National Health and Medical Research Council Australia., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There are currently no specific biomarkers for multiple sclerosis (MS). Identifying robust biomarkers for MS is crucial to improve disease diagnosis and management., Methods: This study first used six Mendelian randomisation methods to assess causal relationship of 174 metabolites with MS, incorporating data from European-ancestry metabolomics (n=8569-86 507) and MS (n=14 802 MS cases, 26 703 controls) genomewide association studies. Genetic scores for identified causal metabolite(s) were then computed to predict MS disability progression in an independent longitudinal cohort (AusLong study) of 203 MS cases with up to 15-year follow-up., Results: We found a novel genetic causal effect of serine on MS onset (OR=1.67, 95% CI 1.51 to 1.84, p=1.73×10 -20 ), such that individuals whose serine level is 1 SD above the population mean will have 1.67 times the risk of developing MS. This is robust across all sensitivity methods (OR ranges from 1.49 to 1.67). In an independent longitudinal MS cohort, we then constructed time-dynamic and time-fixed genetic scores based on serine genetic instrument single-nucleotide polymorphisms, where higher scores for raised serum serine level were associated with increased risk of disability worsening, especially in the time-dynamic model (RR=1.25, 95% CI 1.10 to 1.42, p=7.52×10 -4 )., Conclusions: These findings support investigating serine as an important candidate biomarker for MS onset and disability progression., Competing Interests: Competing interests: BVT has received compensation for consulting, talks, and advisory/steering board activities for Merck, Novartis, Biogen, and Roche. He receives research funding support from MS Research Australia, Medical Research Future Fund Australia and the National Health & Medical Research Council Australia., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Little is known about the comparative effectiveness of multiple sclerosis (MS) disease-modifying therapies (DMTs) on patient-reported outcomes in MS. We compared the effects of natalizumab to other DMTs in relation to MS symptom severity, quality of life, disability, disease progression and employment outcomes using real-world data., Methods: We included 2817 observations in 2015, 2016 and 2017 from 1382 participants in the Australian MS Longitudinal Study. Information on treatment, health and employment outcomes was prospectively collected by questionnaires. Marginal structural models with interaction terms for DMT×time were used to compare natalizumab and other comparator treatment groups., Results: Natalizumab was associated with improvements over time, or general trends of improvement, in the severity of many symptoms and work productivity loss. Compared with any other DMTs, natalizumab was associated with superior effects over time for 8 of 23 patient-reported outcomes, with similar directions of effect observed for another 6, demonstrating consistency. There were no differences in effect for spasticity, fatigue, pain, feelings of depression, disability, European quality of life five dimension index, presenteeism and work status. Natalizumab did not perform significantly worse over time compared with any other DMTs for any of the outcomes., Conclusions: Natalizumab was associated with superior outcomes over time for many patient-reported health and employment outcomes when compared with other DMTs in this large prospective cohort study. These findings may influence treatment selection in clinical practice and future treatment cost-effectiveness analyses., Competing Interests: Competing interests: TK has served on scientific advisory boards for Roche, Sanofi-Genzyme, Novartis, Merck and Biogen; served on a steering committee for Brain Atrophy Initiative by Sanofi-Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research support from Biogen. Dr. Taylor Bruce is a JNNP Associate Editor/Editorial Board Member., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate whether lipid-related or body mass index (BMI)-related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS)., Methods: The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, ΔEDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting ΔEDSS. All analyses were conducted using linear regression., Results: Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with ΔEDSS. The constructed lipid CGRS showed a significant, dose-dependent association with ΔEDSS (p trend =1.4×10 -6 ), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in ΔEDSS. We also found significant interactions between the CGRS and lipid levels in modulating ΔEDSS, including high-density lipoprotein (HDL; p interaction =0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; p interaction =0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL., Interpretation: In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression., Competing Interests: Competing interests: A-LP received personal fees from Biogen Pty Ltd and the fees were used for travel and conference presentation. BVT has received travel grants and honoraria for presentations and Advisory Board membership from Biogen Pty Ltd, Merck Serona Ltd, Roche Pty Ltd Novartis Pty Ltd and Sanofi Pty Ltd., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Due to the lack of prospective studies with longitudinal data on relapse, past genetic studies have not attempted to identify genetic factors that predict relapse risk (the primary endpoint of many pivotal clinical trials testing the efficacy of multiple sclerosis (MS) disease-modifying drugs) at a genome-wide scale., Methods: We conducted a genome-wide association analysis (GWAS) to identify genetic variants that predict MS relapse risk, using a three-stage approach. First, GWAS was conducted using the southern Tasmania MS Longitudinal Study with 141 cases followed prospectively for a mean of 2.3 years. Second, GWAS was conducted using the Ausimmune Longitudinal Study with 127 cases having a classic first demyelinating event followed for 5 years from onset. Third, the top hits with p<5.0×10 -6 from the first two stages were combined with a longitudinal US paediatric MS cohort with 181 cases followed for 5 years after onset. Predictors of time to relapse were evaluated by a mixed effects Cox model. An inverse variance fixed effects model was then used to undertake a meta-analysis., Results: In the pooled results, using these three unique longitudinal MS cohorts, we discovered one novel locus ( LRP2 ; most significant single nucleotide polymorphism rs12988804) that reached genome-wide significance in predicting relapse risk (HR=2.18, p=3.30×10 -8 ). LRP2 is expressed on the surface of many central nervous system cells including neurons and oligodendrocytes and is a critical receptor in axonal guidance., Conclusions: The finding of a genetic locus that has extensive effects on neuronal development and repair is of interest as a potential modulator of MS disease course., Competing Interests: Competing interests: Dr Graves reports grants from Biogen, Genentech, S3 group, outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry., Background: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established., Methods: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases., Results: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD., Conclusions: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry., Competing Interests: Competing interests: MHB has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. MBo has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, BiogenIdec and Roche. BJB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, AbbVie and Biogen Idec, has received travel sponsorship from Abbott and ViiV Healthcare and has received research support funding from EIi Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, BiogenIdec, Merck Serono, Novartis and Sanofi-Genzyme, has received speaker honoraria from Biogen Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme and was the recipient of an unencumbered research grant from Biogen Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WMC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, BiogenIdec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck Serono. RCD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney and the Petre Foundation and has received honoraria from Biogen Idec and Bristol-Myers Squibb as an invited speaker. MjF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, BiogenIdec, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. TJK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and BiogenIdec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer Schering Pharma and Merck Serono and has received scientific consulting fees from GlaxoSmithKline China, Biogen Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer,Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi-Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RALM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, Biogen Idec, CSL, Merck Serono, Novartis and Sanofi-Genzyme. MPMa has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis and Sanofi-Aventis Genzyme. DFM has received honoraria for attendance at advisory boards from Biogen Idec and Novartis, and travel sponsorship from Bayer Schering Pharma, Biogen Idec and Sanofi-Genzyme. PAMcC has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JAP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi-Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme and Teva. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi-Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer Schering Pharma. IS has received remuneration for Advisory Board activities from Biogen, CSL and Bayer Schering Pharma and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering Pharma. MS has received research support from Novartis, Biogen Idec and BioCSL. JSp has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. BVT has received travel sponsorship from Novartis and Bayer Schering Pharma. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received speaker honoraria from Biogen Idec and Euroimmun AG and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen Idec and Novartis, travel sponsorship from Biogen Idec, Bayer Schering Pharma and Teva and is an investigator in clinical trials funded by Biogen Idec and Teva. DA, SBh, SBl, KB, MBr, WBr, WBu, CSB, CCM, LC, AC, CD, KD, DF, DG, SHa, APDH, SHe, SHo, SJ-S, AJK, M-WL, CL, CO’G, MPM, CS, RS, JSt, AV, SV, MWa, RJW, RCW, MWo and EMY report no disclosures., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process., Methods: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression., Results: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10 -23 ). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10 -17 ). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10 -265 )., Conclusions: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: The interplay between genes and environmental factors on multiple sclerosis (MS) clinical course has been little studied., Methods: We conducted a prospective cohort study of 141 participants with relapsing-remitting MS (RRMS) and genotype data followed from 2002 to 2005 and examined genes in the vitamin D metabolism and vitamin D receptor (VDR)/retinoid X receptor (RXR) transcription factor formation pathway. Gene-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis. Genetic predictors of 25-hydroxyvitamin D (25(OH)D) were evaluated by multilevel mixed-effects linear regression. Significance threshold was adjusted by Bonferroni correction for the number of genes evaluated., Results: The relationship between 25(OH)D and hazard of relapse was significantly different for different alleles of two intronic single nucleotide polymorphisms (SNPs) (rs908742 in PRKCZ and rs3783785 in PRKCH) in the protein kinase C (PKC) family genes (p(interaction)=0.001, p(adj)=0.021, respectively). Two other intronic SNPs (rs1993116 in CYP2R1and rs7404928 in PRKCB) were significantly associated with lower levels of 25(OH)D (p(interaction)=0.001, p(adj)=0.021, respectively). A cumulative effect of multiple 'risk' genotypes on 25(OH)D levels and hazard of relapse was observed for the significant SNPs (p(trend)=7.12×10(-6) for 25(OH)D levels, p(trend)=8.86×10(-6) for hazard of relapse)., Conclusions: Our data support the hypothesis that gene-vitamin D interactions may influence MS clinical course and that the PKC family genes may play a role in the pathogenesis of MS relapse through modulating the association between 25(OH)D and relapse.