To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat ...expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
Multimodal
repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.
Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy MSA-C), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years mean 3.1 years) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.
RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.
This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of ...individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
Objective
In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no ...studies have directly compared the outcomes of switching to either of these agents.
Methods
Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing–remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi‐randomization with propensity score–based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise‐censored analyses.
Results
Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on‐study follow‐up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability–time curve) differed between natalizumab and fingolimod (−0.12 vs 0.04 per year, respectively, p < 0.001).
Interpretation
This study suggests that in active multiple sclerosis during treatment with injectable disease‐modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short‐term disability burden. Ann Neurol 2015;77:425–435
Multiple sclerosis (MS) is one of the most common chronic neurological diseases affecting the central nervous system in young adults.
To investigate demographic and clinical factors that are ...effective in the development of irreversible disability from the onset of MS, and to identify factors that affect the transformation from the relapse-remitting MS (RRMS) phase to the progressive MS (PMS) phase.
Retrospective study on 741 patients who were diagnosed with RRMS and PMS according to the McDonald criteria, and were enrolled into the Turkish MS database of the Department of Neurology MS Polyclinic, at the Faculty of Medicine, Karadeniz Technical University, in Trabzon, Turkey. Kaplan-Meier analysis was used to evaluate the time taken to reach EDSS 4 and EDSS 6 from the onset of disease, and the time taken between EDSS 4 and EDSS 6.
Age of onset >40 years; having polysymptomatic-type onset, pyramidal or bladder-intestinal system-related first episode; ≥7 episodes in the first 5 years; and <2 years between the first two episodes were found to be effective for MS patients to reach EDSS 4 and EDSS 6. The demographic and clinical parameters that were effective for progression from EDSS 4 to EDSS 6 were: pyramidal or bladder-intestinal system-related first episode; 4‒6 episodes in the first 5 years; >2 years until start of first treatment; and smoking.
Our findings reveal important characteristics of MS patients in our region. However, the associations between these parameters and MS pathophysiology remain to be elucidated.
Background:
Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely ...intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS.
Objectives:
We sought to develop internationally applicable quality standards for timely, brain health–focused MS care.
Methods:
A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders.
Results:
Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms.
Conclusion:
These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.
Background:
Women with multiple sclerosis (MS) experience an increased risk of relapse in the postpartum period. High-dose methylprednisolone is the first-line treatment for acute relapses.
...Objectives:
To determine the transfer of methylprednisolone into human milk in breastfeeding MS patients.
Methods:
Methylprednisolone therapy was given for postpartum relapse to nine patients for three consecutive days, and seven patients received a daily infusion once a month. Breast milk samples were obtained before infusion and 1, 2, 4, 8, and 12 hours after completion of infusion.
Results:
Methylprednisolone concentrations in milk were below detection limits immediately before infusion. Cmax was measured at 1, 2, 4, 8, and 12 hours after infusion and levels of 2.100, 1.659, 0.680, 0.174, and 0.102 µg/mL were determined, respectively. The absolute infant dose was 98.98 µg/kg/day, and the relative infant dose (RID) was 0.71% of the weight-adjusted maternal dose.
Conclusion:
The level of methylprednisolone transfer into breast milk is very low. The RID for methylprednisolone was lower than the generally accepted value. As methylprednisolone therapy is of short duration, infant exposure would be very low should a mother choose to breastfeed 1 hour after infusion. Waiting 2–4 hours after infusion will limit infant exposure still further.
Background:
Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab.
Objective:
To determine ...predictors of relapse and disability progression when switching from another DMT to ocrelizumab.
Methods:
Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1–2 months or 2–6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP).
Results:
After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57–11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2–6 m compared to <1 m: HR = 9.57, 95% CI = 1.92–47.64, p = 0.006).
Conclusion:
The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
Background:
Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS).
Objective:
We aimed to validate a previously published predictive model of individual ...treatment response using a non-overlapping cohort from the Middle East.
Methods:
We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously.
Results:
The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%–96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%–91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%.
Conclusion:
The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.
OBJECTIVE:To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).
METHODS:Using MSBase, an international cohort ...study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.
RESULTS:Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2–3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio HR 0.9, 95% confidence interval CI 0.7–1.1, p = 0.27). We also did not find differences in any of the secondary endpointsrisk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4–1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8–1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = −0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results.
CONCLUSIONS:Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.
PDF
