Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. RESULTS: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. CONCLUSION: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

The World Federation of Neurology and the challenges in Environment Neurology.

Since its establishment the World Federation of Neurology (WFN) has manifested a keen interest in the environment and its relation to neurological diseases. Thus, in 2007 the WFN renamed the "Neurotoxicological Research Group" to "Environmental Neurology Research Group". In this short article, we review some recent events which illustrate the WFN involvement in Environmental Neurology as well its concerns about global health matters involving environmental issues.

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients.

Circulating immune cells in multiple sclerosis.

Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS-associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.

A guide to facilitate the early treatment of patients with idiopathic demyelinating disease (multiple sclerosis and neuromyelitis optica).

Definite diagnosis of inflammatory demyelinating disease (multiple sclerosis (MS) and neuromyelitis optica (NMO)) may require time, but early treatment offers the opportunity to maximize patient outcomes. The purpose of this report is to provide guidance to facilitate early treatment decisions for patients with inflammatory demyelinating disease, before definitive diagnosis. Neurology experts reviewed the existing literature and clinical evidence. A treatment decision pathway was developed, defining patients for whom first-line MS disease-modifying therapies (a) are unlikely to be effective, (b) may be effective but require careful monitoring and (c) are likely to provide benefit. This algorithm seeks to ensure that patients, particularly those in Asia, receive appropriate treatment early in inflammatory demyelinating disease.

Longitudinally extensive myelopathy in Caucasians: a West Australian study of 26 cases from the Perth Demyelinating Diseases Database.

OBJECTIVES: To characterise West Australian cases of longitudinally extensive myelopathy (LEM). METHODS: Twenty six patients with LEM were identified from a cohort of 983 patients with demyelinating disease. Clinical and MRI data and AQP4-IgG results were reviewed. RESULTS: LEM cases were classified as conventional MS (CMS) 13, neuromyelitis optica (NMO) 7, and isolated LEM 6. LEM was the initial presentation in 13/26 cases. In CMS cases lesions were mainly in the lower cervical cord (C4-C7) whereas in NMO and isolated LEM they were more often thoracic and were longer. The severity of disability was highly variable but was greater in the NMO than the CMS group. Only one of 20 patients tested was seropositive for AQP4-IgG. CONCLUSION: LEM occurred as part of CMS or NMO or in isolation. Patients with LEM had highly heterogeneous clinical characteristics and a low rate of AQP4-IgG seropositivity.

Clinical trials of multiple sclerosis therapies: improvements to demonstrate long-term patient benefit.

BACKGROUND: The therapeutic goal for multiple sclerosis (MS) is to achieve a better long-term outcome. However, since available data come from short-term studies, it is important to review the evidence that current therapies provide long-term benefit. METHOD AND RESULTS: Long-term data from both registry studies and long-term follow-up studies, and efficacy treatment data were reviewed. Registry data show that the course of MS is predictable after a certain level of disability is reached, indicating that short-term efficacy data from randomized, controlled trials provide evidence of long-term benefit. Long-term studies of patients originally enrolled in pivotal randomized, controlled trials consistently show that delayed or discontinued treatment provides less benefit than continuous therapy. The 16-Year Long-Term Follow-Up Study of interferon beta-1b (IFNbeta-1b; Betaferon/Betaseron) therapy had the highest ascertainment of long-term follow-up efforts of the pivotal trials, which led to the currently approved therapies. Disability scores at the start of treatment were predictive of their current disability scores. In addition, this 16-year study showed an excellent safety profile with no unexpected side effects to IFNbeta-1b and a lower mortality rate after 16 years compared with those receiving placebo treatment during the pivotal study (6 deaths vs 20 deaths). CONCLUSION: This article reviews the key data and provides recommendations for optimizing clinical studies in MS to demonstrate long-term patient benefit.

The effects of vinblastine on endothelial cells.

The development of drug-eluting stents to combat the problem of in-stent restenosis has revolutionized interventional cardiology. However, concerns have emerged about the risk of late angiographic stent thromboses associated with drug-eluting stents. It has been shown that noncytotoxic concentrations of paclitaxel exert an antiangiogenic effect, suggesting that paclitaxel and similar agents may inhibit key cellular functions in a threshold-independent manner. In this study, the effect of vinblastine, an antimitotic drug, on endothelial cells is analyzed. It is investigated whether noncytotoxic concentrations of the drug could exert an antirestenotic effect. The change in levels of cell proliferation, activity, and viability in human umbilical vein endothelial cells was measured at a range of concentrations and over a number of time points. Also, the level of apoptotic activity in response to vinblastine was analyzed. This study shows that the concentration of vinblastine most appropriate in restenosis treatment would be between 0.1 and 1 nM. At this concentration, vinblastine exerts a distinct biological effect without causing an increase in apoptotic activity. These results emphasize the importance of finding an appropriate concentration window in order to minimize the risk of delayed endothelialization and thrombosis.

Characterisation of the spectrum of demyelinating disease in Western Australia.

BACKGROUND: The diversity of multiple sclerosis (MS) and the nosology of the conventional form of MS (CMS), optic-spinal MS (OSMS) and neuromyelitis optica (NMO) have been subject to controversy. AIMS: The purpose of this study was to investigate whether the current Asian optic-spinal multiple sclerosis (OSMS) criteria could also apply in Western countries, and whether or not cerebrospinal fluid (CSF) and imaging features in the Western Australian patient population of demyelinating disease was similar to that found in Asia. METHODS: This study retrospectively reviewed 915 individual case notes with central nervous system demyelinating disease seen by two neurologists in Western Australia (WA). 842 cases had sufficient data to be included in the analysis. The patient population was predominantly Caucasian, representing approximately two-thirds of MS cases in WA. The mean duration of follow-up for the whole studied cohort was 12.5 years, with 136 patients (16.2%) being followed-up for more than 20 years. RESULTS: The study confirmed the relatively low frequency of OSMS as a proportion of total demyelinating disease occurring in western countries, with 31 OSMS (3.7%) cases in contrast to 703 CMS cases (83.5%). It is likely, however, that our retrospective classification significantly underestimated the proportion of OSMS cases when compared with prospectively classified Asian cohorts. There were 11 OSMS cases that could also be classified as NMO according to published diagnostic criteria. The remainder of the spectrum comprised clinically isolated syndromes such as 50 acute myelitis (AM, 5.9%), 42 optic neuritis (ON, 5%) and 16 "atypical" cases such as tumefactive MS and acute disseminated encephalomyelitis (1.9%). The clinical characteristics of OSMS in our study were compatible with so-called Asian MS in many respects: oligoclonal bands (OCBs) were less frequent in OSMS (29.4%) than in CMS (66.4%, p = 0.003); visual evoked potentials and spinal MRI abnormalities were more prevalent in OSMS (85% and 92.6%) than in CMS (71.4% and 85%); as were long spinal cord lesions in OSMS (22.2%) versus CMS (3.4%, p,0.001). Brain abnormalities were seen in 48.4% of OSMS patients and 96.2% of CMS patients (p = 0.001). OCBs were identified in 7% of acute myelitis, 14.3% of optic neuritis and 73.4% of primary progressive MS patients. CONCLUSIONS: This cross-sectional study presents the full spectrum of demyelinating disease in WA, which has a stable population representing 10% of the total Australian population and suggests that the current classifications of MS, OSMS or NMO, ON and AM share many clinical and laboratory features, such as female predominance, age at onset, duration of disease and CSF investigations (including OCBs and MRI). Moreover, characteristics of the WA population were similar to those reported in Asian patients.

Analysis of the effects of surface treatments on nickel release from nitinol wires and their impact on candidate gene expression in endothelial cells.

Nitinol has many applications in the medical device industry, however the large amount of nickel, a known allergen and carcinogen remains a serious concern. Studies have already shown that nickel ions induce the differential expression of a range of genes, including cell adhesion molecules. This study sought to determine the level of nickel ions released from nitinol wires that had been surface treated by etching and mechanically polishing or etching and pickling compared to untreated wires and determine the biological impact of the wires on human umbilical vein endothelial cells (HUVECs) at the transcriptional level by real-time PCR. The four different wire types were incubated in media and the amount of nickel eluted after 24, 48 and 72 h was determined. HUVECs were then cultured and incubated with the four different wire types for 24 h. Cells were harvested, RNA isolated and real-time PCR was carried out to measure the expression levels of ICAM-1, VCAM-1 and E-selectin, three known inflammatory mediators, compared to control cells. E-selectin, a marker of endothelial cell injury and activation was found to be significantly up-regulated in cells incubated with wires that released the highest amount of nickel ions. Nickel ions are released from nitinol wires with certain surface characteristics and these ions have a biological effect on HUVECs in vitro.

An investigation into the effect of surface roughness of stainless steel on human umbilical vein endothelial cell gene expression.

The surface properties of vascular devices dictate the initial postimplantation reactions that occur and thus the efficacy of the implantation procedure. Over the last number of years, a number of different stent designs have emerged and stents are generally polished to a mirror finish during the manufacturing procedure. This study sought to investigate the effect of stainless steel surface roughness on endothelial cell gene expression using an appropriate cell culture in vitro assay system. Stainless steel discs were roughened by shot blasting or polished by mechanical polishing. The surface roughness of the treated and untreated discs was determined by atomic force microscopy (AFM). Cells were seeded on collagen type 1 gels and left to attach for 24 h. Stainless steel discs of varying roughness were then placed in contact with the cells and incubated for 24 h. RNA extractions and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was then performed to determine the expression levels of candidate genes in the treated cells compared to suitable control cells. E-selectin and vascular cellular adhesion molecule (VCAM-1) were found to be significantly up-regulated in cells incubated with polished and roughened samples, indicating endothelial cell activation and inflammation. This study indicates that the surface roughness of stainless steel is an important surface property in the development of vascular stents.

Global gene expression analysis of the effects of vinblastine on endothelial cells, when eluted from a thermo-responsive polymer.

In-stent restenosis remains a significant problem associated with bare metal stents. This drawback has prompted research into improving stent design and the development of novel coatings, including drug-eluting stents. A number of drug-eluting stents are currently on the market; however, the success rate of these stents in complex situations has been found to be quite low. Thus, there remains potential for the development of more suitable drug-eluting stents. The aims of this study were to use a thermoresponsive polymer to develop a system to locally deliver vinblastine, an antimitotic agent currently used as an anticancer drug, and in addition, assess the effects of this drug at the gene expression level in vitro. An N-isopropylacrylamide/N-tert-butylacrylamide (NiPAAm/NtBAAm) copolymer solution in the ratio 65:35 was prepared and appropriate volumes of vinblastine were added to generate two final drug concentrations of 22 nanomoles/film or 0.022 nanomoles/film. Stainless steel discs (316) were coated with the copolymer solution or this solution containing drug. Human endothelial cells were cultured on collagen type 1 gels and then incubated with the coated discs for 24 h. Gene expression studies using oligonucleotide microarray analysis and quantitative RT-PCR were then performed. Microarray analysis revealed that vinblastine causes the differential expression of a range of genes involved in a variety of different functions, including cell cycle and apoptosis. The changes in expression of some of these genes culminate in cell cycle arrest and apoptotic pathways.

Cytocompatibility of novel tin oxide thin films.

The capacity of tin oxide films to support cell growth was investigated. Three substrates were used for the test: glass coverslips, glass coverslips spin coated with tin oxide and commercially available 316 stainless steel. The wettabilities and surface roughness of the three surfaces were measured before seeding 3T3 fibroblasts onto the samples. The behaviour of the cells grown on the tin oxide was compared to the uncoated glass and the steel and results showed that the cell growth on tin oxide compared favourably with the other substrates. The surface wettability appeared to have the strongest effect on cell adhesion to tin oxide.

Corrosion behavior of nitinol wires in body fluid environments.

In this study, breakdown potentials were measured for unpolished and mechanically polished nitinol wires in simulated body fluids. These wires are similar to those used in the manufacture of stents. Considerable scatter was observed in the results indicating a variable surface state. After appropriate heat treatments, the measured breakdown values were lower but more reproducible for the mechanically polished samples. Significantly higher breakdown potentials were observed for cross-section wire samples. Some wires were tested in human blood and the breakdown values were higher than in Ringer and 0.9% NaCl solutions. Energy dispersive X-ray analysis of the surface layers indicated that oxide thickening occurred after heat treatments. Dynamic secondary ion mass spectroscopy also revealed thickened surface oxides on the wires. The oxide was predominantly made up of TiO(2) with a very thin layer of NiO at the outer surface. Galvanic corrosion tests were performed on nitinol wires coupled with gold, elgiloy/phynox, and stainless steel. Nitinol was found to be anodic in all cases yet the currents measured were small. In tests in which nitinol-gold couples were immersed in 0.9% NaCl for periods up to 12 months, only very small amounts of nickel (in the part per billion range) were released into solution and scanning electron microscopy examination revealed no corrosion.

Passivation of nitinol wire for vascular implants--a demonstration of the benefits.

This study investigated a passivation process for polished nitinol wires and vascular stent components, after being given a typical shape setting heat treatment. Heat treated samples were passivated in a nitric acid solution and a series of corrosion tests, surface analysis and chemical analysis was performed. Potentiodynamic polarization tests demonstrated a significant increase in breakdown potential for passivated samples, compared to heat treated surfaces. Surface analysis indicated that the passivation reduces Ni and NiO content in the oxide and increases TiO2 content. Chemical analysis of passivation solutions suggests that the improvement in corrosion resistance is proportional to the quantity of nickel removed. Long term immersion tests demonstrate that nickel release from the surface of the material decreases with time and the quantity of nickel released is lower for passivated samples. The improved corrosion resistance is maintained after extended periods of immersion in saline solution.

Focal accumulation of intra-axonal mitochondria in demyelination of the cat optic nerve.

Mitochondrial accumulation has been reported at sites of degenerating nerve fibres. The reason for focal accumulation of mitochondria within axons has not previously been investigated. The aim of this study was to quantitate changes in mitochondrial concentration within demyelinated axons and determine if these changes were due to obstruction of the free passage of organelles within the fibre. The average number of mitochondria per unit area of axon within axons of normal cat optic nerve and optic nerve in which demyelination had been induced with anti-galactocerebroside (GC) was determined using transmission electron microscopy. Increased numbers of mitochondria were demonstrated at the site of demyelination, peaking at approximately two and a half times the value for normal non-lesioned nerves at 6-7 days after anti-GC administration [0.66+/-0.06 (SD) mitochondria per microm2 of axon compared to 0.28+/-0.04 in controls; P < 0.05]. The mitochondrial concentration gradually decreased over the next 20 days towards normal values. The concentration of mitochondria within non-myelinated axons of cat retina (0.55+/-0.18) was also determined and shown to be comparable to the values for the demyelinated optic axons (0.66+/-0.06). It is proposed that the accumulation of mitochondria within demyelinated axons reflects the adaptive process of the axon during the early restoration of impulse conduction rather than the obstruction of the free passage of organelles within the fibre.