Summary Background Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, ...sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. Methods We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov , number NCT00127530. Findings The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0·0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25·2% (95% CI 21·5% to 28·8%) and 4·7% (1·0% to 8·4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (−6·84, 95% CI −9·65 to −4·02) than timed walk non-responders (0·05, −1·48 to 1·57; p=0·0002). Safety data were consistent with previous studies. Interpretation Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit. Funding Acorda Therapeutics Inc.
Introduction: Multiple sclerosis (MS) causes focal lesions of immune-mediated demyelinating events followed by slow progressive accumulation of disability. Over the past 2 decades, multiple ...medications have been studied and approved for use in MS. Most of these agents work by modulating or suppressing the peripheral immune system. Siponimod is a newer-generation sphingosine 1 phosphate (S1P) receptor modulator that internalizes S1P1 receptors, thereby inhibiting efflux of lymphocytes from lymph nodes and thymus. There are promising data suggesting that it may also have a direct neuroprotective property independent of peripheral lymphocytopenia.
Areas covered: We reviewed the pharmacology and the clinical and radiological effects of siponimod.
Expert opinion: The selective effect of siponimod on the S1P1 and S1P5 receptors offers a favorable side-effect profile and transient bradycardia can be avoided by dose titration. A phase-II study showed that siponomod has dose-dependent beneficial effects in patients with relapsing remitting disease. The results of a phase-III study suggest that siponimod may be beneficial in secondary progressive MS, at least in patients with disease activity.
Introduction: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive axonal loss. Clinically, this is ...manifest as relapsing and remitting neurological symptoms and progressive accumulation of disability. Ibudilast is a nonselective phosphodiesterase inhibitor which works by blocking the cleavage of cyclic adenosine monophosphate (cAMP). It has been found to have anti-inflammatory and neuroprotective properties in animal studies and in-vitro studies; it is currently being studied in progressive MS.
Areas covered: This article reviews various studies looking at ibudilast as a potential therapy for MS. It summarizes prior and current clinical trials of ibudilast in MS as well as its pharmacology.
Expert opinion: Although ibudilast has not been found to decrease the focal inflammatory activity in relapsing MS, it was shown to have an effect on preserving brain volume and disability progression. Ibudilast may have a role in the treatment of progressive MS phenotypes.
Histologically assessed hepatocyte ballooning is a key feature discriminating non-alcoholic steatohepatitis (NASH) from steatosis (NAFL). Reliable identification underpins patient inclusion in ...clinical trials and serves as a key regulatory-approved surrogate endpoint for drug efficacy. High inter/intra-observer variation in ballooning measured using the NASH CRN semi-quantitative score has been reported yet no actionable solutions have been proposed.
A focused evaluation of hepatocyte ballooning recognition was conducted. Digitized slides were evaluated by 9 internationally recognized expert liver pathologists on 2 separate occasions: each pathologist independently marked every ballooned hepatocyte and later provided an overall non-NASH NAFL/NASH assessment. Interobserver variation was assessed and a ‘concordance atlas’ of ballooned hepatocytes generated to train second harmonic generation/two-photon excitation fluorescence imaging-based artificial intelligence (AI).
The Fleiss kappa statistic for overall interobserver agreement for presence/absence of ballooning was 0.197 (95% CI 0.094–0.300), rising to 0.362 (0.258–0.465) with a ≥5-cell threshold. However, the intraclass correlation coefficient for consistency was higher (0.718 0.511–0.900), indicating ‘moderate’ agreement on ballooning burden. 133 ballooned cells were identified using a ≥5/9 majority to train AI ballooning detection (AI-pathologist pairwise concordance 19–42%, comparable to inter-pathologist pairwise concordance of between 8–75%). AI quantified change in ballooned cell burden in response to therapy in a separate slide set.
The substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, too subjective for its presence or complete absence to be unequivocally determined as a trial endpoint. A concordance atlas may be used to train AI assistive technologies to reproducibly quantify ballooned hepatocytes that standardize assessment of therapeutic efficacy. This atlas serves as a reference standard for ongoing work to refine how ballooning is classified by both pathologists and AI.
For the first time, we show that, even amongst expert hepatopathologists, there is poor agreement regarding the number of ballooned hepatocytes seen on the same digitized histology images. This has important implications as the presence of ballooning is needed to establish the diagnosis of non-alcoholic steatohepatitis (NASH), and its unequivocal absence is one of the key requirements to show ‘NASH resolution’ to support drug efficacy in clinical trials. Artificial intelligence-based approaches may provide a more reliable way to assess the range of injury recorded as “hepatocyte ballooning”.
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•Hepatocyte ballooning identification underpins regulatory-approved drug efficacy endpoints in clinical trials.•We report substantial variation in ballooned cell identification by expert hepatopathologists.•Our data suggest that ballooning is too subjective for its presence or complete absence to be used as a trial endpoint.•A ‘concordance atlas’ of cells identified as ballooned by multiple pathologists can be used to train AI-based image analysis.•AI-based approaches may provide a more reliable way to assess the range of injury recorded as hepatocyte ballooning.
Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment ...decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.
Purpose of Review
This systematic review evaluated the impact of the COVID-19 pandemic on obsessive–compulsive symptoms.
Recent Findings
Most studies showed that obsessive–compulsive symptoms ...worsened during the early stages of the pandemic, particularly for individuals with contamination-related obsessive–compulsive disorder (OCD), though other symptoms dimensions were found to worsen as well. Many patients and individuals in the general population experienced new obsessive–compulsive-like symptoms centered on COVID-19. Self-reported rates of symptom exacerbation and COVID-19-focused symptoms were consistently lower in studies that recruited patients from specialty clinics (compared to online samples). Most studies were conducted in Spring/Summer, 2020.
Summary
The COVID-19 pandemic has been an enormous stressor for individuals with OCD, especially for those with contamination symptoms. Regardless, there is strong reason to believe gold standard treatment approaches for OCD have maintained strong efficacy. Disseminating and effectively delivering evidence-based treatments for OCD is an urgent public health priority.
•Virtual house calls were found to be feasible for MS patient follow-up visits.•Virtual house calls for MS patients had high participant satisfaction.•Participants appreciated the cost/time savings ...provided by virtual house calls.•Remote neurologic exams provided similar information compared with in-person exams.
Telemedicine, the remote delivery of health care services, increases access to care for patients with mobility or geographic limitations. Virtual house calls (VHCs) are one type of telemedicine in which clinical visits are conducted remotely using an audio-visual connection with the patient at home. Use of VHCs is more established in other neurologic disorders but is only recently being formally evaluated in multiple sclerosis (MS). This randomized crossover study systematically assessed VHCs compared with in-clinic visits in persons with MS.
Recruitment occurred in a university based MS clinic. Each subject completed one VHC and one in-clinic follow-up visit. A 1:1 randomization determined whether the VHC or in-clinic follow-up visit occurred first. Baseline surveys included demographics and MS history; post-visit surveys elicited subject responses regarding each visit type to assess feasibility, satisfaction, and cost differences. Outcomes were compared using t-tests for continuous variables and Fisher's exact test for proportions.
Thirty-six participants completed both study visits and both post-visit surveys. VHC feasibility was demonstrated by a lack of statistically significant difference in the number of completed VHCs as compared with in-clinic visits. VHCs provided both cost and time savings to participants. The majority of participants reported that they would recommend telemedicine visits to others (97.1%) and rated it easy to connect via telemedicine (94.3%). In qualitative comments, participants expressed appreciation for VHCs due to convenience and similarity to in-clinic visits.
VHCs were found to be feasible, cost-effective, and appealing to persons with MS and physicians, supporting their utility as a care delivery method for MS.
Abstract
A growing interest in aptamer research, as evidenced by the increase in aptamer publications over the years, has led to calls for a go-to site for aptamer information. A comprehensive, ...publicly available aptamer dataset, which may be a repository for aptamer data, standardize aptamer reporting, and generate opportunities to expand current research in the field, could meet such a demand. There have been several attempts to create aptamer databases; however, most have been abandoned or removed entirely from public view. Inspired by previous efforts, we have published the UTexas Aptamer Database, https://sites.utexas.edu/aptamerdatabase, which includes a publicly available aptamer dataset and a searchable database containing a subset of all aptamer data collected to date (1990–2022). The dataset contains aptamer sequences, binding and selection information. The information is regularly reviewed internally to ensure accuracy and consistency across all entries. To support the continued curation and review of aptamer sequence information, we have implemented sustaining mechanisms, including researcher training protocols, an aptamer submission form, data stored separately from the database platform, and a growing team of researchers committed to updating the database. Currently, the UTexas Aptamer Database is the largest in terms of the number of aptamer sequences with 1,443 internally reviewed aptamer records.
Graphical Abstract
Graphical Abstract
Objective
A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended‐release dalfampridine (4‐aminopyridine) 10mg twice ...daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics.
Methods
This was a 39‐center, double‐blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25‐Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on‐treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect.
Results
One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine‐treated TWRs during the 8‐week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0–28.4%); the mean improvement at the last on‐treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings.
Interpretation
This interventional study provides class 1 evidence that dalfampridine extended‐release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses. Ann Neurol 2010;68:494–502
Background
The impact of disease-modifying treatments (DMTs) on multiple sclerosis (MS) long-term outcomes is continuously evolving. Retrospective analyses of large and long-term registries could ...provide information regarding general disease trajectories and risk factors that are commonly not investigated in shorter clinical trial settings.
Methods
Retrospective observational study of people with MS (pwMS) registered in New York State MS Consortium (NYSMSC) since 1996. Disability outcomes of reaching sustained Expanded Disability Status Scale (EDSS) scores of 4.0, 6.0 and transition to secondary-progressive MS (SPMS) were confirmed at follow-up. Four DMT categories were determined (1) continuous DMT use, (2) discontinued DMT, (3) (re)started DMT and (4) never treated with DMT. Patient-reported outcomes (PRO) were acquired using LIFEware system. Kaplan–Meier survival curves and adjusted analysis of covariance (ANCOVA) were used to determine the rate and factors related to disability progression.
Results
Total of 1893 pwMS were included with baseline average age of 43.2 years (SD = 10.4), 9.6 years of disease duration (SD = 8.8), median EDSS of 3.0 (IQR 2.0–3.5) and average follow-up time of 6.9 years (SD = 4.9). In addition to being male, older, more disabled and reporting worse PROs at baseline, pwMS who discontinued DMT had more than 5.5 times greater risk of reaching sustained EDSS of 4.0 (OR = 5.56, 95% CI 2.78–11.0,
p
< 0.001). Similarly, pwMS who discontinued DMT during the NYSMSC follow-up had 3.8- and 4.7-times greater risk to reach sustained EDSS 6.0 (OR = 3.86, 95% CI 2.12–7.02,
p
< 0.001), and to transition to SPMS (OR = 4.77, 95% CI 2.9–7.87,
p
< 0.001). Propensity matching analysis confirmed the worse clinical outcomes.
Conclusions
In addition to known predictors of long-term clinical outcomes, pwMS who discontinue DMT have worse long-term disability trajectory when compared to both early and late DMT starters. PRO-based indicators may suggest worse clinical outcomes.
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