Bruce V. Taylor

Purpose: Informal carers (‘proxies’) are often asked to report on the health of individuals who cannot self-report, either from their own (‘proxy-proxy’) or the patient’s (‘proxy-person’) perspectives. It remains unclear which perspective proxies find most useful. Understanding this is important for designing measures that proxies can complete. We conducted an exploratory study on which perspective proxies find most useful and why, when reporting pain and physical function in dementia and symptoms in multiple sclerosis (MS). Methods: This study used data from two cross-sectional online surveys: one for proxies of people with MS and another for people with dementia. Proxies were asked to indicate which perspective they found most useful and why for communicating symptoms in MS, and pain or physical function in dementia, to healthcare professionals (HCPs). Quantitative responses were summarised using percentages; qualitative responses were analysed using content analysis. Results: 55 proxies reported on MS symptoms, 29 on pain in dementia, and 33 on physical function in dementia. The most selected perspectives were: 35% (19/55) proxy-proxy for MS symptoms, 38% (11/29) proxy-person for pain and 39% (13/33) either of the perspectives for physical function. Proxy-person was valued for empathy and person-centredness, especially in reporting pain and MS symptoms. Proxy-proxy was appreciated for objectivity and reducing conflict, particularly in physical function. Using either perspective was considered most useful for balancing views and reducing misinterpretation in both conditions. Conclusion: Proxies’ most useful perspectives vary slightly by domain and condition. Incorporating an understanding of how proxies approach the challenge of reporting may improve measure design.

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only routinely recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI: 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI: 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI: 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI: 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI: 10.7%-12.2%) without (aHR 1.38 [95% CI: 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI: 12.4%-23.4%]) versus continuation (38.9% [95% CI: 35.8%-42.1%]), aHR 0.34 (95% CI: 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI: 10.8%-22.2%]) versus continuation (17.7% [95% CI: 15.3%-20.1%]), aHR 0.89 (95% CI: 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

Brain magnetic resonance imaging (MRI) abnormalities are an important finding in the evaluation of patients with suspected autoimmune encephalitis (AE). There have been few studies evaluating the frequency and prognostic significance of MRI abnormalities, especially hippocampal swelling, in anti-N-methyl-D-aspartate receptor (NMDAR) and anti-leucine-rich glioma-inactivated 1 (LGI1) Ab-mediated encephalitides. We conducted a multi-centre, retrospective study involving adult patients with confirmed antibody-mediated encephalitis and at least one MRI scan from 10 Australian hospitals (n = 139). MRI scans were evaluated by a neuroradiologist blinded to the specific autoimmune encephalitis diagnosis. We evaluated associations between acute MRI abnormalities (e.g. hippocampal swelling) with 12-month function (modified Rankin scale, mRS ≥2 = worse outcome) and radiological findings. In patients with anti-LGI1 Ab-mediated encephalitis, we identified hippocampal swelling on initial MRI to be associated with worse function at 12 months (OR 0.03; 95% CI 0.003, 0.34; P = 0.005). We found initial AE-associated T2/fluid attenuated inversion recovery (FLAIR) hyperintensities were not associated with 12-month mRS in either the anti-NMDAR (OR 0.39; 95% CI 0.04, 3.97; P = 0.42) or anti-LGI1 Ab-mediated encephalitis groups (OR 0.34; 95% CI 0.07, 1.57; P = 0.17). In anti-LGI1 Ab-mediated encephalitis, both hippocampal swelling (OR 5.76; 95% CI 1.14, 29.02; P = 0.03) and T2/FLAIR hyperintensity (OR 6.81; 95% CI 1.28, 36.22; P = 0.03) were related to the development of mesial temporal atrophy and hippocampal sclerosis. Acute hippocampal swelling is associated with worse outcomes in anti-LGI1 Ab-mediated encephalitis and, alongside initial T2/FLAIR hyperintensity, is associated with the development of both mesial temporal atrophy and hippocampal sclerosis.

Multiple sclerosis (MS) is strongly linked to Epstein-Barr Virus (EBV) infection, yet how antiviral immunity contributes to disease pathogenesis remains unclear. Here we delineate EBV-specific CD8+ T cell responses at antigen and single cell resolution in treatment-naïve people with MS. This analysis reveals selective expansion of CD8+ T cells directed to EBV-encoded latent antigens, including EBNA3A and EBNA1. These antigen-specific T cells display enhanced cytotoxicity, a distinct T cell receptor repertoire, and upon engagement with autologous EBV-transformed B cells, adopt a type I interferon-dominated transcriptional state. Most importantly, these MS-specific transcriptional signatures exhibit shared genetic architecture with MS susceptibility genes, supported by enrichment in MS GWAS signals and brain-derived eQTL datasets. Our findings reframe EBV-specific immunity in MS as a state of antigen-specific dysregulation, implicating aberrant surveillance of latently infected B cells as a central pathogenic mechanism and propose latent EBV-specific CD8⁺ T cells as targets for therapeutic intervention.

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI 10.7%-12.2%) without (aHR 1.38 [95% CI 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI 12.4%-23.4%]) versus continuation (38.9% [95% CI 35.8%-42.1%]), aHR 0.34 (95% CI 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI 10.8%-22.2%]) versus continuation (17.7% [95% CI 15.3%-20.1%]), aHR 0.89 (95% CI 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

In Ausimmune, an Australian multicenter incident case–control study, Epstein–Barr virus (EBV)-related measures, including anti-EBNA antibodies and infectious mononucleosis, show multiple sclerosis (MS) associations mediated by DNA methylation (DNAm). Human herpesvirus-6 (HHV-6) DNA has also been linked to increased MS onset risk, though its mechanisms remain unknown. Therefore, we examined an expanded set of human herpesvirus indices including HHV-6 indices. We first tested associations with MS-associated DNAm modules, then assessed whether HHV-6 DNA contributes to MS onset through DNAm pathways. Serological (serum) and viral load (whole blood) measures of EBV (DNA, viral capsid antigen, early antigen diffuse and restricted), HHV-6 (DNA, IgM, IgG), cytomegalovirus (CMV) (IgG), and varicella zoster virus (DNA, IgG) were collected. DNAm was measured from whole blood (Illumina Infinium Human Methylation EPIC v1). DNAm-module (A1–A5) scores were derived using an epigenome-wide association study for MS onset risk and dimension-reduction methods. A total of 206 cases and 348 matched controls were analyzed. Multivariable linear regression demonstrated associations between HHV-6 DNA positivity and the A2-module, and between higher CMV IgG and the A4 module. Counterfactual mediation analysis indicated that 45% of the positive association of HHV-6 DNA positivity with MS onset risk was mediated through the A2 module (Pindirect = .008). The A2 module showed enrichment for lymphatic and immune pathways. These results provide evidence for a distinct DNAm module as a plausible mechanism underlying the associations of HHV-6 with MS onset. Importantly, these epigenetic pathways appear to mediate associations with human herpesviruses beyond EBV. These findings provide further insights into how environmental factors relate to MS onset through epigenetic programming.

Background: Individuals with multiple sclerosis (MS) often use multiple medications, but evidence comparing their effectiveness is scarce. This study aims to (a) describe pain medication use and perceived effectiveness, (b) identify factors associated with the total number of pain medications, (c) explore the reasons for stopping and (d) use qualitative data to explore the lived experience of PwMS in relation to pain medication effectiveness and reasons for stopping. Methods: Participants from the Australian MS Longitudinal Study completed a pain survey in 2021 ( n = 1691); 26 participants self‐nominated to participate in focus groups. Participants with regular pain were asked which pain medications they used, to what extent the medications reduced pain, which medications they stopped using and the reasons for stopping. Quantitative data were analysed using descriptive statistics; negative binomial regression was used to determine factors associated with the total number of medications. Qualitative data were analysed using thematic analysis. Results: Among 899 participants with regular pain, 87.3% were using pain medication. In terms of perceived effectiveness, 62.3% of all reported medications resulted in ‘much improvement’, ‘very much improvement’ or ‘complete pain relief’. The medications commonly reported to be effective were opioid‐containing medications, cannabinoids, antimigraine medications, a combination of paracetamol and nonsteroidal anti‐inflammatory drug (NSAID) products and sedatives. Having more pain types, greater pain severity, being female and greater disability (all p < 0.05) were associated with taking a higher number of medications. Common reasons for stopping a medication were side effects and ineffectiveness. Qualitative data supported the quantitative findings. Conclusions: Most people with pain used medications, and the effectiveness was acceptable for the majority of people. Despite that, stopping medications until the right ones were found was common, often due to side effects and ineffectiveness. This suggests that, with adjustments to treatment plans, effective pain control is achievable for most PwMS with pain.

Background: Multiple sclerosis (MS) diagnosis relies on identifying disease episodes disseminated in space and time, and excluding other disease explanations. MS is a genetically complex autoimmune and neurodegenerative disorder that shares features with some monogenic progressive neurological conditions. The extent to which people diagnosed with MS have an alternate diagnosis (MS mimic), or genetic multimorbidity is unknown. Additionally, the burden of rare variation associated with MS risk and severity in monogenic neurological disease genes has not been evaluated. We investigated the prevalence of disease-causing variants in progressive neurological disease genes, and their contribution to MS risk and severity, in 4,340 MS cases diagnosed in sub-speciality clinics in Australia and New Zealand, and in 2,861 local controls. Methods: Exome sequencing and array-based genotyping data were analysed for 1,680 genes with pathogenic or likely pathogenic variants reported in ClinVar. Clinical history reviews of MS cases with putative disease-causing variants were conducted. We specifically examined the contribution of rare, likely deleterious variants in a subset of 30 hereditary spastic paraplegia (HSP) genes in 421 individuals with progressive onset MS (POMS). Gene-based association tests with MS risk and severity were performed for all genes in the cohort. Results: We identified 166 MS cases (3.82%) with variants prompting clinical history reviews, and of 75 cases reviewed, four (0.13% of all cases) had either genetic multimorbidity in addition to MS or a potential misdiagnosis. In contrast to previous findings we observed no enrichment of likely deleterious variants in HSP genes in POMS, nor did we find significant associations between neurological disease genes and MS risk or severity. Conclusions: Our findings suggest that rare deleterious genetic variation in progressive neurological disease genes does not play a substantive role in MS risk or severity, and that misdiagnosis is exceedingly rare in this cohort. Consequently, among individuals diagnosed with MS by a specialist, a very small proportion may benefit from clinical genomic testing to inform MS diagnosis or an alternate diagnosis, which could have implications for healthcare management.