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Background: Multiple sclerosis (MS) cognitive tests are resource intensive and limited by practice effects that prevent frequent retesting. Brief, reliable and valid monitoring tools are urgently needed to detect subtle, subclinical cognitive changes in people with MS. Cognitive monitoring over time could contribute to a new definition of disease progression, supplementing routine clinical monitoring. Methods: MSReactor is a web-based battery that measures psychomotor (processing) speed, visual attention and working memory, using simple reaction time tasks. Clinic-based tasks were completed at baseline and 6 monthly with home testing 1–3 monthly. Acceptability, quality of life, depression and anxiety surveys were completed. We studied its correlation with the Symbol Digit Modalities Test, practice effects, test–retest reliability and the discriminative ability of MSReactor. Results: A total of 450 people with MS were recruited over 18 months, with 81% opting to complete home-based testing. Most participants (96%) would be happy (or neutral) to repeat the tasks again and just four reported the tasks made them ‘very anxious’. Persistence of home testing was high and practice effects stabilized within three tests. MSReactor tasks correlated with Symbol Digit Modalities Test scores and participants with MS performed slower than healthy controls. Conclusion: MSReactor is a scalable and reliable cognitive screening tool that can be used in the clinic and remotely. MSReactor task performance correlated with another highly validated cognitive test, was sensitive to MS and baseline predictors of cognitive performance were identified.

Background: Optic nerve sheath fenestration (ONSF) longitudinal outcomes remain unclear and are vital in the assessment of vision failure in patients with raised intracranial pressure (ICP). Furthermore, limited observational data exists regarding its use in other causes of raised ICP. Objective: To determine the efficacy and safety of ONSF for idiopathic intracranial hypertension (IIH), cerebral venous sinus thrombosis (CVST), and other indications. Method: Multicentre study from a tertiary hospital and specialty eye referral hospital in Melbourne, Australia, from July 2000 to December 2020. A total of 116 eyes from 70 patients undergoing ONSF were retrospectively reviewed with patient demographics, surgery indications, visual acuity (VA), visual fields, fundus photos of optic discs, retinal nerve fibre layer (RNFL) thickness, average thickness of optic discs on optical coherence tomography (OCT), and complications recorded. Parametric tests were used to compare the treatment groups pre- and post-operatively. Results: A total of 116 eyes from 70 patients underwent ONSF, which involved 92 eyes with IIH, 9 eyes with CVST, and 15 eyes with other aetiologies (‘Other’). Post ONSF, there was a best corrected visual acuity (BCVA) improvement or stabilisation in 84% of patients in all groups, with 50% achieving a BCVA of 6/6 or better at the final follow-up. RNFL, visual fields, and fundus grades all trended towards improvement, with most improvement noted by day 360. Common complications included transient diplopia (n = 29, 25%) and worsening of visual function requiring further cerebrospinal fluid (CSF) diversion procedures (n = 20, 17%). Complications were most significant in the ‘Other’ group with 1/3 of eyes requiring further CSF diversion procedures. Conclusion: Our data demonstrates effectiveness in the use of ONSF in papilloedema with visual failure due to IIH or CVST and when other CSF diversion procedures or medical therapies have failed.

Background: Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Objectives: Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate). Design: This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD. Methods: This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW). Results: After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070–0.092) for natalizumab patients and 0.191 (0.178–0.205) for BRACETD patients (p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42–0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients. Conclusion: Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.

Background/ObjectivesFailure of natalizumab to control disease activity in multiple sclerosis (MS) is an uncommon event. It is currently unknown whether switching to an alternative high-efficacy disease-modifying therapy offers any benefits over persevering with natalizumab.MethodsPatients from the MSBase cohort suffering failure of natalizumab therapy, defined as breakthrough relapses or ≥3 new or gadolinium-enhancing lesions on MRI, were identified. Multivariable Andersen-Gill cumulative hazard models were used to analyse the associations of several variables with the risk of further relapses following natalizumab failure. Subsequent treatment decision was included as a time-dependent exposure. Secondary analyses evaluated the effect of treatment decisions on the risk of subsequent new MRI activity, expanded disability status scale (EDSS) worsening, and disease-activity free survival.Results1,131 natalizumab-treated patients fulfilled the inclusion criteria. Of these, 85 de-escalated treatment, 39 switched to anti-CD20 therapy, and 28 switched to alemtuzumab. Following natalizumab failure, switch to an anti-CD20 therapy was associated with a significantly lower risk of relapse (HR=0.51, 95%CI=0.29–0.88) compared to continuing natalizumab. Treatment de-escalation, or cessation, were associated with an increased risk of subsequent relapses (HR=1.40, 95%CI=1.10–1.79; HR=1.89, 95%CI=1.09–3.28, respectively). We did not find any evidence of a difference for switching to alemtuzumab, or outcomes studies in the secondary analyses.ConclusionWe have shown that following natalizumab failure, switching to B-cell depleting agents (ocrelizumab and rituximab), but not alemtuzumab, is associated with a clinically meaningful reduction in the risk of relapses in comparison to continuing natalizumab therapy. Clinicians should consider B-cell depletion following natalizumab failure where appropriate.

Background/ObjectivesCladribine reduces the frequency of relapses by 57% and disability worsening by 33% compared to placebo in relapsing-remitting multiple sclerosis (RRMS). No head-to-head comparisons of cladribine to other potent immunotherapies are available.MethodsPatients with RRMS who were treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab from 01/2018 were identified in the global MSBase cohort study and 2 UK centres. Included patients were followed for >=6 months and had a minimum of 3 disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARR), and disability outcomes. All subsequent events were analysed, regardless of changes in treatment status.ResultsThe 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 (ARR 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 (HR1.08, 95%CI 0.47–2.47) or alemtuzumab (0.73, 0.26–2.07), but was lower for patients treated with natalizumab (0.35, 0.13–0.94) and ocrelizumab (0.45, 0.26–0.78).ConclusionCladribine is an effective therapy, associated with low absolute ARR. While cladribine effectiveness on relapses is superior to fingolimod, alemtuzumab is superior to cladribine in reducing relapses. Natalizumab and ocrelizumab are superior to cladribine in reducing both relapses and disability accrual. Cladribine can thus be viewed as a step-up in effectiveness from fingolimod, but less effective than the most potent intravenous MS therapies.

BackgroundOfatumumab is a self-administered disease modifying therapy (DMT) approved in Australia for relapsing multiple sclerosis (RMS). We have previously described a novel, high efficacy therapy (HET) classification system1 which includes ofatumumab and other monoclonal antibody therapies, ocrelizumab, natalizumab and alemtuzumab. Given the reimbursement of ofatumumab in October 2021, and in the context of this proposed classification system, we analysed the utilisation of these HETs for multiple sclerosis (MS) in Australia.MethodsDMT utilisation was analysed using an unbiased 10% sample of the Pharmaceutical Benefits Scheme Claims database as supplied by Services Australia. Patients-on-therapy (PoT) counts were attributed to the most recently prescribed DMT whilst initiations were defined as the first time a patient was prescribed a new DMT (treatment-naïve and switch) during a specified time-period.ResultsFrom September, 2021 (pre-ofatumumab reimbursement) to October, 2023, PoT for any DMT rose by 10.4% (23,070-to-25,460). In the same period, HET PoT rose by 31.3% (9,830-to-12,910), driven by increases in ofatumumab (+2,010), ocrelizumab (+1,050), and natalizumab (+110). By contrast, non-HET PoT fell by 5.2% (13,240-to-12,550), driven by fingolimod (-1,020) and dimethyl fumarate (-530). In the 12 months prior to ofatumumab reimbursement, 46.7% (2,200/4,710) of DMT initiations were HET but this proportion rose to 53.1% (2,920/5,500) in the most recent 12 month period (November-October 2023), driven by ofatumumab (1,200; 21.8%), ocrelizumab (1,090; 19.8%), and natalizumab (730; 11.5%).ConclusionsThe availability of a self-administered, at-home HET option in ofatumumab has correlated with an expansion of HET utilisation in Australia.Reference Butzkueven, et al. P755. ECTRIMS-ACTRIMS 2023.

BackgroundUpper limb dysfunction is a common debilitating feature of relapsing remitting multiple sclerosis (RRMS). We aimed to examine the longitudinal trajectory of the iPad-based Manual Dexterity Test (MDT) and predictors of change over time.MethodsWe prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients with an EDSS score of less than four. Longitudinal data was analysed with mixed effect modelling and latent class mixed models. We examined whether group membership in latent classes were predictive of a confirmed decrease in MDT.ResultsAt a population level, MDT remained stable over time. No practice effect was seen. Baseline disability and T2 lesion volume were the strongest predictors of longitudinal MDT performance.Latent class analysis identified 2 classes of MDT trajectories. In the slower trajectory, greater variability and a weak association with sustained worsening of MDT was present. Group trajectory based on latent class analysis and baseline MDT was different, signifying the importance of latent processes in upper limb function in pwMS.ConclusionIn this cohort of mild to moderate RRMS, MDT scores remained stable over time with no evidence of a practice effect at a population level. Trajectory analysis based on latent class identified a cohort with greater variability and risk of sustained worsening. Our findings show the importance of latent processes in determining upper limb function trajectories in pwMS.

BackgroundCognitive impairment is one of the most common and debilitating symptoms of relapsing remitting multiple sclerosis (RRMS). Digital cognitive biomarkers require less time and resources and are rapidly gaining popularity in clinical settings. We examined the longitudinal trajectory of the iPad-based Processing Speed Test (PST) and predictors of change over time.MethodsWe prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients with an EDSS score of less than four. Longitudinal data was analysed with mixed effect modelling and latent class mixed models.ResultsAt a population level, PST trajectory was stable. A small practice effect was present up to the 4th visit. Age, baseline disability, T2 lesion volume, male gender and depression were associated with less correct PST responses, whilst years of education and full/part-time employment were associated with more correct PST responses.We identified four trajectories of processing speed with latent class analysis. The lowest latent class was typified by the lack of a practice effect and was associated with a greater hazard of time to sustained 5% decrease in PST (HR 2.84, 95%CI 1.16–6.94, p=0.02).ConclusionIn this cohort of mild to moderate RRMS, PST scores remained largely stable over time. Membership in the worst latent class trajectory was associated with a sustained 5% PST decrease. Poor cognitive performance at baseline and the lack of a practice effect is a predictor of future cognitive decline and should prompt early intervention for maximising cognitive function such as treatment escalation.

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing–remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 – UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. Discussion: This highlights the importance of a healthcare system’s approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

ObjectivesTo characterize the use of ofatumumab (OFA), a fully human self-administered anti-CD20 monoclonal antibody, in a real-world setting in Australia by assessing the profile of relapsing multiple sclerosis (RMS) patients initiating OFA through an evaluation of patient demographics, background MS disease characteristics and prior therapy history as recorded in MSBase.MethodsThis is a retrospective secondary use of MSBase Registry data study, describing the baseline characteristics of RMS patients in Australia initiated on OFA treatment, including demographics, disease duration, expanded disability status scale (EDSS), treatment history with disease-modifying therapies (DMTs) prior to commencing OFA and proportion of naïve patients initiating ofatumumab relative to patients having received a prior DMT.ResultsAs of 1st January 2024, MSBase has included 320 eligible patients initiated on OFA, with 22.2% treatment naïve, 30.9% switching from ocrelizumab, 14.7% switching from natalizumab, 3.1% from alemtuzumab and 27.7% from oral DMTs. The reasons for switching DMT to OFA included scheduled stop (13.1%), evidence of disease activity (9.1%), convenience (6.9%), side effects/intolerance (6.2%), JCV antibody positive (2.8%), pregnancy planned/confirmed (2.5%) and not reported (37.2%). The median age of patients initiating OFA was 42.67 [36.65, 51.98] years, with a median disease duration of 9.19 [3.61, 17.11] years and median EDSS of 2 [1.5, 3.5].ConclusionThe real-world data from this secondary use of data MSBase registry analysis provides a valuable snapshot of the Australian experience of relapsing MS patients initiated on OFA, with 22% of patients treated as first line therapy.