Objective
This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently ...approved, DS‐specific therapies and emerging disease‐modifying treatments.
Methods
A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease‐modifying therapies) and nominated the 31‐member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS.
Results
There was strong consensus that infants 2–15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first‐ to third‐line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease‐modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians.
Significance
This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease‐modifying therapies.
Background and purpose
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is therefore a need for a reference tool compiling current data to aid ...professionals in treatment decisions. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.
Methods
This guideline has been developed using the GRADE methodology and following the updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. Literature searches up to December 2016 were performed and the evidence is presented narratively and, when possible, combined in a meta‐analysis. The quality of evidence was rated into four categories – very high, high, low and very low − according to the risk of bias. The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results
A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease‐modifying drugs approved by the European Medicine Agency at the time of publication. A total of 21 recommendations were agreed by the guideline working group members after three rounds of consensus.
Conclusion
The present guideline, which includes descriptions of the evidence together with recommendations, will enable homogeneity of treatment decisions across Europe.
Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The ...first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.
Background
This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the ...European Reference Network for Neuromuscular Diseases (ERN EURO‐NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS).
Methods
Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available.
Results
A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence NICE guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease‐modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end‐of‐life management.
Conclusions
This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.
Introduction
A 2017 study had analyzed the preparedness of the U.S. health care system to deliver a disease‐modifying Alzheimer's treatment and predicted substantial wait times. We update the ...prediction with an improved model and newer data.
Methods
The model tracks patients from initial evaluation, cognitive testing by a dementia specialist, confirmatory biomarker testing, and infusion delivery. All steps after initial evaluation are assumed to be capacity constrained. Model parameters and assumptions about care‐seeking behavior were derived from the published literature and expert input.
Results
If patients were referred based on a brief cognitive test, wait times for specialist visits would reach around 50 months. If referral also required a positive blood‐based biomarker test, wait times would be around 12 months. In both scenarios, wait times for confirmatory biomarker testing and infusion treatment would be limited.
Discussion
Better diagnostic tools at initial evaluation may reduce unnecessary delays in access to treatment.
The aim of study was to collect and analyze data on relapsing-remitting multiple sclerosis (RRMS) patients receiving disease modifying therapies (DMTs) in Poland.
The observational, multi-center with ...prospective data collection study included all RRMS patients receiving DMTs reimbursed by the National Health Fund (NFZ) in Poland, monitored by the Therapeutic Program Monitoring System (SMPT). The demographic profile, disability status and treatment modalities were analyzed.
Data from 12,341 patients were collected, including 70.1% women and 29.9% men, therein 11,653 patients in the first-line and 1026 in second-line therapeutic DMTs programme. Proportion female to male was 2.36 in the first-line and 1.9 in the second-line. The mean age was 36.4 years (±SD 10.6) in the first-line and 35.1 years (±SD 9.7) in the second line. The mean time of observation in the first line was 3.7 years (±SD 2.4) and in the second line was 2.8 years (±SD 1.3). The mean time from the first symptoms to MS diagnosis was 24.54 months (median 7.23), and from MS diagnosis to treatment: 39.35 months (median 10.12). There was a positive correlation between time to start treatment and higher the initial EDSS score (R 0.29, p < 0.001). The choice of the first-line medication depends on the region of the country.
In Poland, only about one third of all MS patients is treated with DMTs. There is a need to improve the quality of MS patients healthcare and their access to DMTs.
Mixed models for repeated measures (MMRMs) are ubiquitous when analyzing outcomes of clinical trials. However, the linearity of the fixed‐effect structure in these models largely restrict their use ...to estimating treatment effects that are defined as linear combinations of effects on the outcome scale. In some situations, alternative quantifications of treatment effects may be more appropriate. In progressive diseases, for example, one may want to estimate if a drug has cumulative effects resulting in increasing efficacy over time or whether it slows the time progression of disease. This article introduces a class of nonlinear mixed‐effects models called progression models for repeated measures (PMRMs) that, based on a continuous‐time extension of the categorical‐time parametrization of MMRMs, enables estimation of novel types of treatment effects, including measures of slowing or delay of the time progression of disease. Compared to conventional estimates of treatment effects where the unit matches that of the outcome scale (eg, 2 points benefit on a cognitive scale), the time‐based treatment effects can offer better interpretability and clinical meaningfulness (eg, 6 months delay in progression of cognitive decline). The PMRM class includes conventionally used MMRMs and related models for longitudinal data analysis, as well as variants of previously proposed disease progression models as special cases. The potential of the PMRM framework is illustrated using both simulated and historical data from clinical trials in Alzheimer's disease with different types of artificially simulated treatment effects. Compared to conventional models it is shown that PMRMs can offer substantially increased power to detect disease‐modifying treatment effects where the benefit is increasing with treatment duration.
Background
While the majority of patients with Alzheimer's disease resides in low and middle‐income countries, little is known of their preparedness for emerging disease‐modifying treatments. We ...analyze the preparedness of Brazil, one of the most populous middle‐income countries, from a capacity and institutional preparedness perspective.
Methods
Desk research and 12 interviews for background and capacity data. Markov model to estimate wait times for access to treatment.
Findings
Brazil has no national dementia strategy or established pathway for evaluation of cognitive concerns, and dementia is typically diagnosed late if at all. While members of private health plans have ready access to elective specialty care, wait times in the public sector are long. Assuming potentially treatment‐eligible patients are referred from primary to specialty care based on a brief cognitive exam and a blood test for the Alzheimer's pathology, available capacity will not be sufficient to match the projected demand. The biggest obstacle is availability of dementia specialist visits, and the effect of population growth and ageing means that the wait list for specialist appointment will continue to grow from around 400,000 in 2022 to over 2.2 million in 2040. We do not project substantial wait times for confirmatory biomarker testing and treatment delivery but note that this is a consequence of patients waiting for their specialist appointments. These queues will result in estimated persistent wait times for treatment of around two years on average with substantial differences between the public and private sectors, as capacity growth is insufficient to keep up with increasing demand.
Discussion
Our findings suggest that Brazil is ill‐prepared to provide timely access to an Alzheimer's treatment with predicted wait times of about two years, largely because of a limited number of dementia specialists.
Background and purpose
COVID‐19 continues to challenge neurologists in counseling persons with multiple sclerosis (pwMS) regarding disease‐modifying treatment (DMT) and vaccination. The objective ...here was to characterize predictors of COVID‐19 outcome in pwMS.
Methods
We included pwMS with polymerase chain reaction‐confirmed COVID‐19 diagnosis from a nationwide population‐based registry. COVID‐19 outcome was classified as either mild or severe. Impact of DMT, specifically anti‐CD20 monoclonal antibodies (anti‐CD20), and vaccination on COVID‐19 outcome was determined by multivariate models adjusted for a priori risk (determined by a cumulative risk score comprising age, disability, and comorbidities).
Results
Of 317 pwMS with COVID‐19 (mean age = 41.8 years SD = 12.4, 72.9% female, median Expanded Disability Status Scale = 1.5 range = 0–8.5, 77% on DMT 16% on anti‐CD20), 92.7% had a mild course and 7.3% a severe course, with 2.2% dying from COVID‐19. Ninety‐seven pwMS (30.6%) were fully vaccinated. After a median 5 months from vaccination to SARS‐CoV‐2 infection (range = 1–9), severe COVID‐19 occurred in 2.1% of fully vaccinated pwMS compared to 9.5% in unvaccinated pwMS (p = 0.018).
A priori risk robustly predicted COVID‐19 severity (R2 = 0.605, p < 0.001). Adjusting for a priori risk, anti‐CD20 treatment was associated with increased COVID‐19 severity (odds ratio OR = 3.3, R2 = 0.113, p = 0.003), but exposure to any other DMT was not. Fully vaccinated pwMS showed a significantly decreased risk for severe COVID‐19 (OR = 0.21, R2 = 0.144, p < 0.001).
Conclusions
In a population‐based MS cohort, COVID‐19 course is primarily predicted by a priori risk (depending on age, disability, and comorbidities) explaining about 60% of variance. Anti‐CD20 treatment is associated with a moderately increased risk, whereas reassuringly vaccination provides protection from severe COVID‐19.
Predictors of COVID‐19 outcome were investigated in 317 patients with multiple sclerosis (pwMS) from a nationwide population‐based registry. A priori risk (determined by a cumulative risk score comprising age, disability, and comorbidities) robustly predicted COVID‐19 severity, explaining about 60% of variance; anti‐CD20 treatment was associated with increased COVID‐19 severity (odds ratio OR = 3.3), but exposure to any other disease‐modifying treatment was not. Fully vaccinated pwMS showed a significantly decreased risk for severe COVID‐19 (OR = 0.21).
Background and purpose
Coronavirus disease 2019 (COVID‐19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were ...concurrently on disease‐modifying treatment (DMT) with B‐cell depleting agents or sphingosine‐1‐phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID‐19 vaccination.
Methods
Since March 2020, demographics and clinical data of patients with MS who developed COVID‐19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be ‘protected by vaccination’ if they were (i) fully vaccinated and (ii) tested positive for COVID‐19 in the period ranging from 14 days to 6 months after the last administered vaccine.
Results
On 19 December 2022, 418 COVID‐19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being ‘unprotected by vaccination’ was significantly associated with a worse COVID‐19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio OR 3.96), in patients on ongoing DMT other than anti‐CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti‐CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis.
Conclusions
Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B‐cell depleting agents.
Coronavirus disease 2019 vaccination has been associated with dampened immune responses in patients with multiple sclerosis who are concurrently on B‐cell depleting agents or sphingosine‐1‐phosphate receptor modulators. The results are presented of a Belgian retrospective cohort study comparing COVID‐19 outcome between patients with multiple sclerosis that were protected by vaccination and those that were not, across different disease‐modifying treatment regimens. Overall, COVID‐19 vaccination protected against severe infection but it was not possible to confirm this effect in patients on B‐cell depleting agents.
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