Assessment of T2 lesion-based disease activity volume outcomes in predicting disease progression in multiple sclerosis over 10 years.

BACKGROUND: New/enlarging T2 lesion count and T2-lesion volume (LV) are used as conventional secondary endpoints in clinical trials of patients with multiple sclerosis (PwMS). However, those outcomes may have several limitations, such as inability to account for heterogeneity of lesion formation/enlargement frequency and their dynamic volumetric behavior. Measurement of volume rather than count of new/enlarging lesions may be more representative outcome of dynamic changes over time. OBJECTIVES: To investigate whether new/enlarging T2-LV is more predictive of confirmed disability progression (CDP), compared to total T2-LV or new/enlarging T2 lesion count over long-term follow-up. METHODS: We studied 176 early relapsing-remitting PwMS who were followed with annual MRI examinations over 10 years. T2-LV, new/enlarging T2-LV, and new/enlarging lesion count were determined. Cumulative count/volumes were obtained. 10-year CDP was confirmed after 48-weeks. ANCOVA analysis detected MRI outcome differences in stable (n = 76) and CDP (n = 100) groups at different time points, after correction for multiple comparisons. RESULTS: PwMS with CDP had greater cumulative new/enlarging T2-LV at 4 years (p = 0.049), and enlarging T2-LV at 4- (p = 0.039) and 6-year follow-up (p = 0.032), compared to stable patients. PwMS with CDP did not differ from stable ones in new/enlarging T2 lesion count or total T2-LV at any of the study timepoints. PwMS with Expanded Disability Status Scale change >2.0 had significantly greater enlarging T2 lesion count (p = 0.01) and enlarging T2-LV (p = 0.038) over the 10-year follow-up. CONCLUSION: Enlargement of T2 lesions is more strongly associated with long-term disability progression compared to other conventional T2 lesion-based outcomes.

Comparative Effectiveness and Cost-Effectiveness of Natalizumab and Fingolimod in Patients with Inadequate Response to Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

BACKGROUND: Patients with highly active relapsing-remitting multiple sclerosis inadequately responding to first-line therapies (interferon-based therapies, glatiramer acetate, dimethyl fumarate, and teriflunomide, known collectively as "BRACETD") often switch to natalizumab or fingolimod. OBJECTIVE: The aim was to estimate the comparative effectiveness of switching to natalizumab or fingolimod or within BRACETD using real-world data and to evaluate the cost-effectiveness of switching to natalizumab versus fingolimod using a United Kingdom (UK) third-party payer perspective. METHODS: Real-world data were obtained from MSBase for patients relapsing on BRACETD in the year before switching to natalizumab or fingolimod or within BRACETD. Three-way-multinomial-propensity-score-matched cohorts were identified, and comparisons between treatment groups were conducted for annualised relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M). Results were applied in a cost-effectiveness model over a lifetime horizon using a published Markov structure with health states based on the Expanded Disability Status Scale. Other model parameters were obtained from the UK MS Survey 2015, published literature, and publicly available UK sources. RESULTS: The MSBase analysis found a significant reduction in ARR (rate ratio [RR] = 0.64; 95% confidence interval [CI] 0.57-0.72; p < 0.001) and an increase in CDI6M (hazard ratio [HR] = 1.67; 95% CI 1.30-2.15; p < 0.001) for switching to natalizumab compared with BRACETD. For switching to fingolimod, the reduction in ARR (RR = 0.91; 95% CI 0.81-1.03; p = 0.133) and increase in CDI6M (HR = 1.30; 95% CI 0.99-1.72; p = 0.058) compared with BRACETD were not significant. Switching to natalizumab was associated with a significant reduction in ARR (RR = 0.70; 95% CI 0.62-0.79; p < 0.001) and an increase in CDI6M (HR = 1.28; 95% CI 1.01-1.62; p = 0.040) compared to switching to fingolimod. No evidence of difference in CDW6M was found between treatment groups. Natalizumab dominated (higher quality-adjusted life-years [QALYs] and lower costs) fingolimod in the base-case cost-effectiveness analysis (0.453 higher QALYs and £20,843 lower costs per patient). Results were consistent across sensitivity analyses. CONCLUSIONS: This novel real-world analysis suggests a clinical benefit for therapy escalation to natalizumab versus fingolimod based on comparative effectiveness results, translating to higher QALYs and lower costs for UK patients inadequately responding to BRACETD.

Approaches and challenges in the diagnosis and management of secondary progressive multiple sclerosis: A Central Eastern European perspective from healthcare professionals.

Secondary progressive multiple sclerosis (SPMS) is a debilitating condition characterized by gradual worsening after an initial relapsing disease course. Despite the recent advances in our understanding of the disease, the diagnosis and treatment of SPMS continue to be challenging in routine clinical practice. The aim of this review article is to present the views of leading MS experts on the challenges in the diagnosis and management of SPMS and clinicians' perspectives in Central and Eastern Europe. This article also provides recommendations of MS experts to improve the situation with diagnosis and management of SPMS. Many countries within Central and Eastern Europe have high prevalence of MS (>100 per 100,000 population). Consistent with the global trend, in the absence of reliable tests or biomarkers, SPMS at early stage remains undiagnosed. Due to diagnostic uncertainty and lack of a universally accepted disease definition, clinicians rely more on retrospective analysis of the clinical symptoms to confirm the diagnosis. With the lack of awareness and poor understanding of the timing of the onset of SPMS, clinicians may tend to direct attention to relapses than the symptoms of progression, which leads to underestimation of SPMS. Although several predictors of progression to SPMS have been identified, their predictive value is highly variable. Therefore, defining the transitioning period as a separate stage of MS is essential. According to experts' opinion, frequent follow-up of patients and periodic assessment of progression are recommended for the timely identification of patients transitioning from RRMS to SPMS. MSProDiscuss Tool is an example of a quick assessment tool for identifying patients progressing from RRMS to SPMS. MS progression is usually assessed by changes in Expanded Disability Status Scale (EDSS) scores. As EDSS scores tend to fluctuate when measured in the short term (3-6 months), a longer period (≥12 months) may be needed to confirm the progression. Assessment of cognitive function is also important for evaluating secondary progression. Compartmentalization of inflammation within the central nervous system is an important reason behind the limited success of disease-modifying therapies (DMTs) for treating SPMS. Most of the DMTs fail to cross the blood-brain barrier; only 38% of the tested DMTs achieved their primary endpoint in SPMS. In Europe, siponimod is the first oral treatment for adults with active SPMS. Particularly, in Central and Eastern Europe, patients with SPMS are still being prescribed less efficacious DMTs and interferons. The absence of alternative treatments in SPMS supports the use of new products (siponimod and others); however the decision to initiate siponimod therapy in more severe patients (EDSS score of 7 or higher) should be individualized in consultation with the payers. The focus should be on early treatment initiation to delay disease progression.

Comments and Corrections Corrections to "Automated Assessment of Oral Diadochokinesis in Multiple Sclerosis Using a Neural Network Approach: Effect of Different Syllable Repetition Paradigms".

In the above article [1], the name of the first author was misspelled. The correct name is Kriss Rozenstoks.

Automated Assessment of Oral Diadochokinesis in Multiple Sclerosis Using a Neural Network Approach: Effect of Different Syllable Repetition Paradigms.

Slow and irregular oral diadochokinesis represents an important manifestation of spastic and ataxic dysarthria in multiple sclerosis (MS). We aimed to develop a robust algorithm based on convolutional neural networks for the accurate detection of syllables from different types of alternating motion rate (AMR) and sequential motion rate (SMR) paradigms. Subsequently, we explored the sensitivity of AMR and SMR paradigms based on voiceless and voiced consonants in the detection of speech impairment. The four types of syllable repetition paradigms including /ta/, /da/, /pa/-/ta/-/ka/, and /ba/-/da/-/ga/ were collected from 120 MS patients and 60 matched healthy control speakers. Our neural network algorithm was able to correctly identify the position of individual syllables with a very high average accuracy of 97.8%, with the correct temporal detection of syllable position of 87.8% for 10 ms and 95.5% for 20 ms tolerance value. We found significantly altered diadochokinetic rate and regularity in MS compared to controls across all types of investigated tasks ( ). MS patients showed slower speech for SMR compared to AMR tasks, whereas voiced paradigms were more irregular. Objective evaluation of oral diadochokinesis using different AMR and SMR paradigms may provide important information regarding speech severity and pathophysiology of the underlying disease.

Clinical relevance of brain atrophy assessment in multiple sclerosis. Implications for its use in a clinical routine.

INTRODUCTION: Brain atrophy measurement in multiple sclerosis (MS) has become an important outcome for determining patients at risk for developing physical and cognitive disability. AREAS COVERED: In this article, we discuss the methodological issues related to using this MRI metric routinely, in a clinical setting. Understanding trajectories of annualized whole brain, gray and white matter, thalamic volume loss, and enlargement of ventricular space in specific MS phenotypes is becoming increasingly important. Evidence is mounting that disease-modifying treatments exert a positive effect on slowing brain atrophy progression in MS. Expert Commentary: While there is a need to translate measurement of brain atrophy to clinical routine at the individual patient level, there are still a number of challenges to be met before this can actually happen, including how to account for biological confounding factors and pseudoatrophy, standardize acquisition and analyses parameters, which can influence the accuracy of the assessments.

Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome.

Cognitive impairment (CI) may occur in clinically isolated syndrome (CIS) patients. While the relationship between CI and magnetic resonance imaging (MRI) has been investigated extensively in multiple sclerosis (MS), MRI correlates of CI in CIS patients are unknown. To investigate the evolution of CI and to determine brain MRI structural correlates associated with CI in CIS patients. This prospective 24-month observational study examined 81 CIS patients treated with 30 µg of intramuscular interferon beta 1a once a week. MRI acquisition and neuropsychological (NP) assessment were performed at baseline, 6, 12 and 24 months. Participants were tested with Czech-validated version of Minimal Assessment of Cognitive Function in MS battery and MRI measures of lesion activity and burden, and global, tissue-specific and regional brain atrophy were performed. Over 24 months, 36 CIS patients developed clinically definite MS (CDMS). CI was observed in 10 (12.3 %) CIS patients at baseline and at the 24 months follow-up. Eight CIS patients changed their CI status over the follow-up (four improved and four worsened). No significant difference in development of CI was detected between stable CIS patients and those who developed CDMS. In multivariate regression and mixed-effect model analyses, no significant relationship was found between NP and MRI parameters. The lack of significant relationship between MRI metrics and cognition in this group of CIS patients could be attributed to several factors including the cognitive reserve, effect of disease-modifying therapy and relatively short follow-up period.