Non-invasive brain stimulation to assess neurophysiologic underpinnings of lower limb motor impairment in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disease resulting in axonal demyelination and an amalgamation of symptoms which commonly result in decreased quality of life due to mobility dysfunction and limited participation in meaningful activities. NEW METHOD: The use of non-invasive brain stimulation (NIBS) techniques, specifically transcranial magnetic and transcranial direct current stimulation, have been essential in understanding the pathophysiological decrements related to disease progression, particularly with regard to motor impairments. Although the research in this area has primarily focused on the upper extremities, new interest has arisen in understanding the neurophysiological underpinnings of lower limb impairment. Therefore, the purpose of this review is to: first, provide an overview of common NIBS techniques used to explore sensorimotor neurophysiology; second, summarize lower limb neuromuscular and mobility impairments typically observed in PwMS; third, review the current knowledge regarding interactions between TMS-assessed neurophysiology and lower limb impairments in PwMS; and fourth, provide recommendations for future NIBS studies based on current gaps in the literature. RESULTS: PwMS exhibit reduced excitability and increased inhibitory neurophysiologic function which has been related to disease severity and lower limb motor impairments. Comparison with existing methods: Moreover, promising results indicate that the use of repetitive stimulation and transcranial direct current stimulation may prime neural adaptability and prove useful as a therapeutic tool in ameliorating lower limb impairments. CONCLUSIONS: While these studies are both informative and promising, additional studies are necessary to be conclusive. As such, studies assessing objective measures of lower limb impairments associated with neurophysiological adaptations need further evaluation.

CLICK-MS and MASTER-2 Phase IV trial design: cladribine tablets in suboptimally controlled relapsing multiple sclerosis.

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023. Trial registration number • CLICK-MS: NCT03933215 (ClinicalTrials.gov) Full title; CLadribine tablets: observational evaluation of effectIveness and patient-reported outcomes in suboptimally Controlled patients previously taKing injectable disease-modifying drugs for relapsing forms of Multiple Sclerosis • MASTER-2: NCT03933202 (ClinicalTrials.gov) Full title; Cladribine tablets: observational evaluation of effectiveness and patient-reported outcomes in suboptiMAlly controlled patientS previously Taking oral or infusion disEase-modifying dRugs for relapsing forms of multiple sclerosis.

Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis.

BACKGROUND: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity. OBJECTIVE: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data. METHODS: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing-remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients' clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse. RESULTS: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1-24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9-80% of patients and peaked at 4-7 months, whereas radiological disease activity was observed in 7-87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation (p ⩽ 0.05). CONCLUSIONS: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.

Remyelination Therapy in Multiple Sclerosis.

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons and eventual neurodegeneration. Current treatments approved for the treatment of relapsing forms of MS target the aberrant immune response and successfully reduce the severity of attacks and frequency of relapses. Therapies are still needed that can repair damage particularly for the treatment of progressive forms of MS for which current therapies are relatively ineffective. Remyelination can restore neuronal function and prevent further neuronal loss and clinical disability. Recent advancements in our understanding of the molecular and cellular mechanisms regulating myelination, as well as the development of high-throughput screens to identify agents that enhance myelination, have lead to the identification of many potential remyelination therapies currently in preclinical and early clinical development. One problem that has plagued the development of treatments to promote remyelination is the difficulty in assessing remyelination in patients with current imaging techniques. Powerful new imaging technologies are making it easier to discern remyelination in patients, which is critical for the assessment of these new therapeutic strategies during clinical trials. This review will summarize what is currently known about remyelination failure in MS, strategies to overcome this failure, new therapeutic treatments in the pipeline for promoting remyelination in MS patients, and new imaging technologies for measuring remyelination in patients.

Neurologic complications of vaccinations.

This chapter reviews the most common neurologic disorders associated with common vaccines, evaluates the data linking the disorder with the vaccine, and discusses the potential mechanism of disease. A literature search was conducted in PubMed using a combination of the following terms: vaccines, vaccination, immunization, and neurologic complications. Data were also gathered from publications of the American Academy of Pediatrics Committee on Infectious Diseases, the World Health Organization, the US Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System. Neurologic complications of vaccination are rare. Many associations have been asserted without objective data to support a causal relationship. Rarely, patients with a neurologic complication will have a poor outcome. However, most patients recover fully from the neurologic complication. Vaccinations have altered the landscape of infectious disease. However, perception of risk associated with vaccinations has limited the success of disease eradication measures. Neurologic complications can be severe, and can provoke fear in potential vaccines. Evaluating whether there is causal link between neurologic disorders and vaccinations, not just temporal association, is critical to addressing public misperception of risk of vaccination. Among the vaccines available today, the cost-benefit analysis of vaccinations and complications strongly argues in favor of vaccination.

Guidelines and best practices for appropriate use of dalfampridine in managed care populations.

Multiple sclerosis (MS) is a complex chronic, progressing disease that contributes to poor quality of life (QOL) for patients and high costs for managed care organizations. Currently, disease-modifying treatments (DMTs) constitute the platform pharmacotherapy for MS patients. Despite their efficacy, for many patients taking DMTs there is little evidence of their effect on QOL in general or symptom management. Impaired mobility contributes to direct and indirect costs. Annual direct medical costs for MS with gait impairment average nearly $21,000 per patient. Decreased mobility is also associated with higher absenteeism rates, thus raising indirect costs. Dalfampridine has been shown to improve walking in patients with MS. The effects of dalfampridine can complement those of DMTs by improving walking ability as a key component of overall mobility and a primary concern among many MS patients. Improved walking could potentially help contain some of the direct and indirect costs associated with MS care.

Emerging therapies for treatment of multiple sclerosis.

In the last decade, a new armamentarium of immune-based therapies have been developed and tested in patients with multiple sclerosis. Some of these therapies are showing a high level of efficacy, with an acceptable adverse effect profile. Because present therapies have significant limitations in slowing disease progression, require injections, are sometimes associated with significant side effects of immunosuppression, and do little to reverse disability, identifying more effective treatments is an important goal for clinical research in multiple sclerosis. However, in order to improve our current approach to disease-modifying therapies, it is imperative to promote the development of individualized therapy strategies.

Recent advances in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating, neurodegenerative disorder of the central nervous system. Despite the lack of an etiologic factor, it has been consistently demonstrated that the immune system plays a crucial role in the pathogenesis of MS. The traditional description of immunopathogenesis of MS suggests a preferential CD4+ TH1 cell activity causing tissue damage by the release of pro-inflammatory cytokines and subsequent demyelination and axonal loss. Recent evidence, however, suggests that other immune cells including TH17 cells, CD8+ effector T cells, CD4+ CD25+ regulatory T cells, and B cells may play a prominent role in MS immunopathology. A better understanding of the molecular and cellular components of the immunopathogenesis of MS is allowing the development of novel therapies.