Multiple sclerosis (MS) represents a spectrum of demyelination that depends on disease duration and clinical categorization. Most patients present with the relapsing-remitting form of the disease. ...The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). Predicting which CIS patients are at high risk for MS is complicated by the disparity between clinical attacks and the extent of axon pathology. However, recent interferon-beta (IFN-beta) trials have demonstrated a delay in time to the second demyelinating event with early treatment, and early treatment could also slow the progression from RRMS to secondary-progressive MS (SPMS). Clinical findings in combination with brain MRI and CSF analysis can be used in CIS patients to evaluate their risk for clinically definite MS (CDMS). Application of the McDonald criteria also allows an earlier MS diagnosis by using new MRI lesions to define dissemination in time. Early immunomodulatory therapy for selected CIS patients may eventually prevent future axon pathology and progression of disability in this lifelong disease.
Relapses, exacerbations, and attacks are synonymous for new or worsened neurologic symptoms that are the hallmark of relapsing-remitting multiple sclerosis. Management of relapses is not always ...straightforward. The clinician must distinguish between true relapses, symptom fluctuation, and pseudo-relapses. Risks and benefits of treating a relapse must be considered. Once the decision to treat is made, most clinicians would pursue a course of corticosteroids. Consensus may end there, as there is no clear-cut "best" route of administration or dosing schedule. The patient presenting with their first relapse or clinically isolated syndrome may be at risk for the development of multiple sclerosis. Clinical presentation, CSF findings, and MRI may all give clues as to the risk for future demyelinating events.
Background:
Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS).
Objective:
Characterize the safety and efficacy of ADS-5102 (amantadine) ...extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment.
Methods:
This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed.
Results:
A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE—suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test (p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed.
Conclusion:
ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.
•Black and Hispanic patients are historically underrepresented in MS trials.•MS course and immunology differ in black and Hispanic vs white patients.•The CHIMES trial is studying ocrelizumab in black ...and Hispanic patients with RMS.•Baseline differences were observed for patients in CHIMES compared with OPERA.
Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population.
CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18–65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya.
A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non–BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI.
BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS.
NCT04377555
The management paradigm for multiple sclerosis (MS) is moving toward earlier diagnosis (on the basis of clinical, paraclinical, and laboratory findings), differentiation of patients with varying ...prognoses, and earlier implementation of treatment in selected individuals. On the basis of a survey conducted at the American Association of Neuroscience Nurses Annual Conference in 2009, several topics were identified for which nurses indicated a need for new and updated information, including current diagnostic methods for MS, optimal time to initiate treatment of MS, and emerging therapies for MS. This article was designed to address these issues.
Purpose:
To promote understanding of cognitive impairment in multiple sclerosis (MS), recommend optimal screening, monitoring, and treatment strategies, and address barriers to optimal management.
...Methods:
The National MS Society (“Society”) convened experts in cognitive dysfunction (clinicians, researchers, and lay people with MS) to review the published literature, reach consensus on optimal strategies for screening, monitoring, and treating cognitive changes, and propose strategies to address barriers to optimal care.
Recommendations:
Based on current evidence, the Society makes the following recommendations, endorsed by the Consortium of Multiple Sclerosis Centers and the International Multiple Sclerosis Cognition Society:
Increased professional and patient awareness/education about the prevalence, impact, and appropriate management of cognitive symptoms.
For adults and children (8+ years of age) with clinical or magnetic resonance imaging (MRI) evidence of neurologic damage consistent with MS:
As a minimum, early baseline screening with the Symbol Digit Modalities Test (SDMT) or similarly validated test, when the patient is clinically stable;
Annual re-assessment with the same instrument, or more often as needed to (1) detect acute disease activity; (2) assess for treatment effects (e.g. starting/changing a disease-modifying therapy) or for relapse recovery; (3) evaluate progression of cognitive impairment; and/or (4) screen for new-onset cognitive problems.
For adults (18+ years): more comprehensive assessment for anyone who tests positive on initial cognitive screening or demonstrates significant cognitive decline, especially if there are concerns about comorbidities or the individual is applying for disability due to cognitive impairment.
For children (<18 years): neuropsychological evaluation for any unexplained change in school functioning (academic or behavioral).
Remedial interventions/accommodations for adults and children to improve functioning at home, work, or school.
Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. ...Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.
We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.
Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 95% CI 0·86–20·85; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 95% CI 1·05–23·20; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.
We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab.
Biogen.
The experience with spasticity varies among individuals with multiple sclerosis and spasticity (MSS), as they may not recognize it as spasticity or have the language to describe their symptoms. This ...can lead to potential delays in diagnosis and treatment.
Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity was an online survey completed by 1177 individuals with MSS in 2021. It sought to capture symptoms of spasticity, variability of symptoms, specific spasticity triggers, and how conversations with physicians were initiated.
The mean age of the cohort was 56.8 years and it was 78% women. Prior to spasticity onset, 65% of respondents felt minimally prepared or unprepared for possibly developing spasticity and were unaware that spasticity manifests as part of MS. Eighty percent experienced spasticity daily, which was variable in severity and duration. Spasticity was triggered by a range of factors and 90% of those surveyed were unable to predict when it would occur or its severity. Day-to-day variability of spasticity prevented 65% of respondents from doing things they wished to do. Sixty percent were confused by their symptoms, not recognizing them as spasticity. Although 91% reported experiencing muscle spasms, only 69% used "muscle spasms" to describe their symptoms. Other descriptors included "muscle tightness," "stiffness," "cramping," and "pain." After recognizing spasticity, 78% proactively initiated discussions with their physicians, 52% wished they had done so sooner, and 42% delayed the conversation by up to or more than a year.
Results emphasize the variable nature of spasticity and the lack of a common language to describe symptoms, underscoring the importance of education, earlier recognition, and customized treatments tailored to the severity and duration of spasticity symptoms.
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease marked by a heterogeneous clinical presentation and disease course. Although improvements in the recognition and management of MS ...have been made in recent years, challenges remain due to the complex nature of the disease. Clinicians must remain current with their skills as knowledge surrounding MS care continues to advance. Here we report results of a performance improvement (PI) continuing medical education (CME) activity that was designed to promote evidence-based care of patients with MS. Participants demonstrated significant improvements in assessing disease-related complications, treating cognitive dysfunction, assessing adherence, and providing disease-related educational materials. These data support the role of PI CME in improving clinician practices that align with quality MS patient care.
Abstract Background: It is not known whether the currently available treatment regimen of interferon beta-1b (IFN²-1b) 250 µg provides the maximum benefit possible in the treatment of ...relapsing-remitting multiple sclerosis (RRMS), or whether higher doses of IFN²-1b will prove to be more beneficial. Objective: The objective of the present study was to evaluate the tolerability and safety profile of IFN²-1b 500 µg compared with the currently approved 250-µg dose. Methods: A multicenter, randomized, double-blind, parallel-group pilot study was carried out to compare IFN²-1b 250 µg with IFN²-1b 500 µg, both self-administered SC QOD for ≥ 12 weeks in patients with RRMS. Patients in both groups started with 25% (0.25 mL) of their final dose and were scheduled to increase the dose by 0.25 mL every 2 weeks, so that the full dose (1.0 mL, 250 µg or 500 µg) would be reached by week 7. The primary outcome measure was the percentage of patients experiencing each of the following adverse events (AEs): influenza-like symptoms (general term used to code the presence of>1 symptom typical of influenza), fever, myalgia, asthenia, headache, injection-site reactions, injection-site pain, or liver or hematologic abnormalities. All patients underwent a priori magnetic resonance imaging (MRI) with 0.1 mmol/kg gadolinium (Gd)-diethylenetriaminepentaacetic acid as contrast medium at screening and at week 12. MRI evaluation was included as a safety measure to monitor for excessive new disease not visible through clinical symptoms. Results: Seventy-seven patients were assessed for inclusion in the study. Of these, 6 patients were screening failures and the remaining 71 were randomized to treatment (38–250 and 33–500 µg IFN²-1b). The uneven numbers in the groups were a consequence of the randomization process. Two patients in the 250-µg group (withdrawal of consent) and 1 in the 500-µg group (not completing follow-up visit) prematurely discontinued medication. The demographic characteristics were not significantly different between the 250-µg (n = 38; mean SD age, 37.9 8.3 years; weight, 83.5 19.0 kg; height, 168.4 9.3 cm) and 500-µg (n = 33; mean SD age, 37.8 7.7 years; weight, 82.3 19.5 kg; height, 169.9 10.5 cm) treatment groups. The patients in both groups were mostly white (87% and 73%, respectively). Baseline Expanded Disability Status Scale scores also were not significantly different between the 2 groups (mean SD score, 2.8 1.4 vs 2.0 1.4, respectively). In the IFN²-1b 250-µg group, 97% of the patients titrated to the full dose at some point during the course of the study, compared with 91% of the 500-µg group ( P = NS). A dose-response effect was observed in some of the more frequent AEs (no. %) that included influenza-like syndrome (250-µg group, 13 34 vs 500-µg group, 16 48), asthenia (13 34 vs 16 48, respectively), headache (12 32 vs 12 36), myalgia (10 26 vs 13 39), hypesthesia (10 26 vs 11 33), nausea (6 16 vs 8 24), paresthesia (6 16 vs 8 24), myasthenia (4 11 vs 8 24), chills (3 8 vs 6 18), depression (3 8 vs 5 15), back pain (2 5 vs 5 15), increased liver enzymes (4 11 vs 6 18), lymphopenia (4 11 vs 3 9), fever (2 5 vs 4 12), and pain in extremities (1 3 vs 4 12). The between-group incidence of injection-site reactions was not significantly different. No new or unexpected AEs were recorded. Changes in MRI parameters between screening and 12 weeks were not significantly different between dose groups; these included median T2 lesion volume, median Gd-enhancedlesionvolume,medianGd-enhancedlesion number, and mean number of newly active lesions. Conclusions: IFN²-1b 500 µg administered SC QOD was generally well tolerated in these patients with RRMS. Large, randomized controlled studies are needed to determine if there are significant differences in MRI end points between the 250- and 500-µg doses.
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