Domain-specific cognitive impairment in multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: Methods of cognitive measurements in multiple sclerosis (MS) are not standardized. We aimed to identify the prevalence of cognitive domain-specific impairment (DSI) in MS by using subtests of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) with analyzing different cutoff values. METHODS: The systematic review and meta-analysis were registered on PROSPERO (ID: CRD42021287004). The systematic literature search was performed via PubMed, Embase, and CENTRAL on 24 October 2021. Inclusion criteria were adults of different MS subtypes (CIS, RRMS, PPMS, and SPMS) with the condition of distinct DSI measured by BRB-N. Pediatric MS, computerized versions of BRB-N, and patients receiving steroids were excluded. Primary outcome was pooled prevalence rates of impaired patients within each cutoff and MS subtype, with 95% confidence interval, I-squared statistics for heterogeneity, and chi-squared test for subgroup differences. Risk of bias was assessed using the "JBI Quality Assessment Tool for Prevalence Studies." RESULTS: In 48 eligible observational studies (n = 3431 patients), the three most prevalent thresholds were the 2.0 SD and 1.5 SD below the mean of normative values, and the score below the fifth percentile of the normative values. A progressively increasing worsening of the overall DSI was observed from CIS, moving toward RRMS, PPMS, and SPMS. INTERPRETATION: Cognitive impairment is observed in all MS phenotypes, with varying degrees. Due to several potential influencing factors, our comprehensive literature review has not revealed consistent findings, and we, therefore, recommend considering a more sophisticated, "individual referencing" approach, acknowledging the diverse clinical and sociodemographic characteristics among populations and disparities in cognitive testing.

Treatment of relapsing multiple sclerosis in Hungary - consensus recommendation from the Hungarian neuroimmunology society.

Multiple sclerosis (MS) may impact quality of life, careers and family plans of the affected individuals. The current treatments with disease modifying therapies aim to prevent people with MS (pwMS) from disability accumulation and progression. Different countries have different reimbursement policies resulting in inequalities in patient care among geographical regions. Access to anti-CD20 therapies for relapsing MS is restricted in Hungary because therapy of individual cases only is reimbursed. In the light of the latest research and national guidelines, 17 Hungarian MS experts agreed on 8 recommendations regarding relapsing pwMS using the Delphi round method. Strong agreement (> 80%) was achieved in all except one recommendation after three rounds, which generated a fourth Delphi round. The experts agreed on treatment initiation, switch, follow-up and discontinuation, as well as on special issues such as pregnancy, lactation, elderly population, and vaccination. Well-defined national consensus protocols may facilitate dialogue between policymakers and healthcare professionals and thus contribute to better patient care in the long run.

Real-world outcomes for a complete nationwide cohort of more than 3200 teriflunomide-treated multiple sclerosis patients in The Danish Multiple Sclerosis Registry.

OBJECTIVE: Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013-2019. METHODS: This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits. RESULTS: A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up. CONCLUSIONS: Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity.

Clinical Characteristics and Outcome of Neuronal Surface Antibody-Mediated Autoimmune Encephalitis Patients in a National Cohort.

Background: In our previous single-center study of autoimmune encephalitis (AE) related autoantibody test results we found positivity in 60 patients out of 1,034 with suspected AE from 2012 through 2018 as part of a Hungarian nationwide program. In our current multicenter retrospective study, we analyzed the clinical characteristics and outcome of AE patients with positive neuronal cell surface autoantibody test results. Methods: A standard online questionnaire was used to collect demographic and clinical characteristics, laboratory and imaging data, therapy and prognosis of 30 definitive AE patients in four major clinical centers of the region. Results: In our study, 19 patients were positive for anti-NMDAR (63%), 6 patients (20%) for anti-LGI1, 3 patients for anti-GABABR (10%) and 3 patients for anti-Caspr2 (10%) autoantibodies. Most common prodromal symptoms were fever or flu-like symptoms (10/30, 33%). Main clinical features included psychiatric symptoms (83%), epileptic seizures (73%) and memory loss (50%). 19 patients (63%) presented with signs of central nervous system (CNS) inflammation, which occurred more frequently in elder individuals (p = 0.024), although no significant differences were observed in sex, tumor association, time to diagnosis, prognosis and immunotherapy compared to AE patients without CNS inflammatory markers. Anti-NMDAR encephalitis patients were in more severe condition at the disease onset (p = 0.028), although no significant correlation between mRS score, age, sex and immunotherapy was found. 27% of patients (n = 8) with associated tumors had worse outcome (p = 0.045) than patients without tumor. In most cases, immunotherapy led to clinical improvement of AE patients (80%) who achieved a good outcome (mRS ≤ 2; median follow-up 33 months). Conclusion: Our study confirms previous publications describing characteristics of AE patients, however, differences were observed in anti-NMDAR encephalitis that showed no association with ovarian teratoma and occurred more frequently among young males. One-third of AE patients lacked signs of inflammation in both CSF and brain MRI, which emphasizes the importance of clinical symptoms and autoantibody testing in diagnostic workflow for early introduction of immunotherapy, which can lead to favorable outcome in AE patients.

Comparative effectiveness of teriflunomide and dimethyl fumarate: A nationwide cohort study.

OBJECTIVE: To compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple sclerosis (RRMS) in a real-world setting. METHODS: We identified all patients starting TFL or DMF from the Danish Multiple Sclerosis Registry and compared on-treatment efficacy outcomes between DMF using TFL, adjusted for clinical baseline variables and propensity score-based methods. RESULTS: We included 2,236 patients in the study: 1,469 patients on TFL and 767 on DMF. Annualized relapse rates (ARRs) in TFL and DMF were 0.16 (95% confidence interval [CI] 0.13-0.20) and 0.09 (95% CI 0.07-0.12), respectively. Relapse rate ratio for DMF/TFL was 0.58 (95% CI 0.46-0.73, p < 0.001). DMF had a higher relapse-free survival proportion at 48 months of follow-up (p < 0.05). We observed no difference in Expanded Disability Status Scale score worsening. Discontinuations due to disease breakthrough were 10.2% (95% CI 7.6%-12.8%) and 22.1% (95% CI 19.2%-25.0%) for DMF and TFL, respectively. A subgroup analysis of ARRs in 708 patients with available baseline MRI T2 lesion amount reported similar results after adjustment. CONCLUSION: We found lower ARR, higher relapse-free survival, and lower incidence of discontinuation due to disease breakthrough on treatment with DMF compared with TFL. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, DMF is more effective in preventing relapses and has lower discontinuation due to disease breakthrough compared with TFL.

Nationwide prevalence and incidence study of neuromyelitis optica spectrum disorder in Denmark.

OBJECTIVES: To estimate the nationwide population-based incidence, prevalence, and geographical distribution of neuromyelitis optica (NMO) spectrum disorder (NMOSD) in Denmark based on the 2015 International Panel for NMO Diagnosis (IPND) criteria. METHODS: We conducted a multicentre, historically prospective study. Data were sourced from the Danish National Patient Registry, the Danish Multiple Sclerosis Registry, departments of neurology, and laboratories providing aquaporin-4 antibody test. Cases were selected based on the 2006 Wingerchuk and the 2015 IPND criteria and were individually validated by an expert panel. RESULTS: We confirmed NMO in 30 cases (2006 criteria) and NMOSD in 56 cases (2015 IPND criteria) between 2007 and 2014. Defined by the 2006 criteria, the incidence of NMO was 0.029 per 100,000 person-years (95% confidence interval [CI] 0.014-0.051), and the prevalence (aged 16 years and older) was 0.566 per 100,000 (95% CI 0.370-0.830). Based on the 2015 IPND criteria, the incidence of NMOSD was 0.070 per 100,000 person-years (95% CI 0.046-0.102), and the prevalence (aged 16 years and older) was 1.09 per 100,000 (95% CI 0.808-1.440), without regional differences. CONCLUSIONS: Our estimates of incidence and prevalence are similar to other Caucasian population-based studies using the 2015 IPND criteria. We found no geographical clustering in Denmark.

Cerebrovascular hemodynamic changes in multiple sclerosis patients during head-up tilt table test: effect of high-dose intravenous steroid treatment.

Demyelination in multiple sclerosis (MS) may cause damage to the vegetative nervous system. Our objective was to examine cerebral autoregulation assessed via blood pressure and cerebral blood flow velocity fluctuations during head-up tilt table testing. We also investigated the effects of high-dose intravenous corticosteroid treatment. Transcranial Doppler registration of middle cerebral artery blood flow velocity and continuous blood pressure and heart rate monitoring were performed at rest and during tilt table testing in 30 MS patients. Ten age-matched healthy subjects were also examined as controls. Correlations between mean arterial blood pressure (MBP) and cerebral blood flow velocity (CBF) fluctuations were averaged, yielding the correlation coefficient index Mx. For a subgroup of 11 patients with acute exacerbations, results were also evaluated before and after methylprednisolone treatment (1 g/day intravenously for 5 days). No significant differences in the autoregulatory indices were seen between patients and controls, or between pre- and post-steroid results. Modeling CBF velocity changes associated with a 1-mmHg increase in MBP, significant differences (p < 0.05) were detected in patients vs. controls, and also after vs. before steroid administration. We conclude that cerebrovascular autoregulation impairments are detectable in early phase MS. Corticosteroid treatment has a significant effect on hemodynamic changes in acute exacerbations.

Can a physician predict the clinical response to first-line immunomodulatory treatment in relapsing-remitting multiple sclerosis?

BACKGROUND: Decreased relapse rate and slower disease progression have been reported with long-term use of immunomodulatory treatments (IMTs, interferon beta or glatiramer acetate) in relapsing-remitting multiple sclerosis. There are, however, patients who do not respond to such treatments, and they can be potential candidates for alternative therapeutic approaches. OBJECTIVE: To identify clinical factors as possible predictors of poor long-term response. METHODS: A 9-year prospective, continuous follow-up at a single center in Hungary to assess clinical efficacy of IMT. RESULTS: In a patient group of 81 subjects with mean IMT duration of 54 ± 33 months, treatment efficacy expressed as annual relapse rate and change in clinical severity from baseline did not depend on the specific IMT (any of the interferon betas or glatiramer acetate), and on mono- or multifocal features of the initial appearance of the disease. Responders had shorter disease duration and milder clinical signs at the initiation of treatment. Relapse-rate reduction in the initial 2 years of treatment predicted clinical efficacy in subsequent years. CONCLUSION: Based on these observations, we suggest that a 2-year trial period is sufficient to decide on the efficacy of a specific IMT. For those with insufficient relapse reduction in the first 2 years of treatment, a different IMT or other therapeutic approaches should be recommended.

[Long-term application of the multiple sclerosis functional composite test in Debrecen, Hungary]. / A sclerosis multiplex funkcionális összetevo teszt alkalmazásanak vizsgálata hosszú távon debrecenben.

INTRODUCTION: The multiple sclerosis functional composite (MSFC) has been recommended by the National Multiple Sclerosis Society as a new clinical outcome measure. It is based on measurements in three clinical dimensions: leg function/ambulation (timed 25-foot walk), arm function (9 hole peg test) and cognitive function (paced auditory serial addition test). Scores on component measures are converted to standard scores (Z-scores), that reflect patient performance. This method has not yet been introduced into routine clinical practice. PATIENTS AND METHODS: Since March 2000 over the five years period the MSFC calculation was applied to 17 patients with relapsing-remitting multiple sclerosis (age mean: 37.4 +/- 10.8 years, duration of the disease: 5.5 +/- 4.9 years, EDSS: 2.7 +/- 1.4) seen at the neuroimmunological outpatient clinic to evaluate its usefulness and its correlation with the traditionally applied expanded disability status scale (EDSS). Thirteen patients received immunomodulatory treatment (interferon beta and glatiramer acetate), one patient received immunosuppressant therapy (azathioprine), and there was one patient, who developed secondary-progressive phase and we changed the interferon treatment to mitoxantrone. MSFC and EDSS were measured at 3., 6., 9, 12., 18 and 60 months of follow-up. RESULTS: The prospective study confirmed a strong correlation between EDSS and MSFC in multiple sclerosis. The MSFC was more sensitive to clinical changes than EDSS. Our results after 18 months of follow up are already published. After five years arm/hand function and leg function/ambulation were the most sensitive measures for disease progression. In contrast with the literature we did not experience correlation with cognitive changes. CONSEQUENCES: We demonstrated strong correlation between MSFC and EDSS after a longer period. MSFC is a simple method, suitable for follow-up of multiple sclerosis patients in everyday clinical practice.

[Application of the Multiple Sclerosis Functional Composite in Debrecen]. / A sclerosis multiplex összetett funkcionális index alkalmazhatóságának vizsgálata Debrecenben.

INTRODUCTION: The Multiple Sclerosis Functional Composite (MSFC) has been recommended by the National Multiple Sclerosis Society as a new clinical outcome measure. It is based on measurements in three clinical dimensions: leg function/ambulation (timed 25-foot walk), arm function (9-hole peg test), and cognitive function (paced auditory serial addition test). Scores on component measures are converted to standard scores (Z-scores) that reflect patient performance. This method has not yet been introduced into routine clinical practice. PATIENTS AND METHOD: MSFC calculation was applied to 17 patients with relapsing-remitting multiple sclerosis (age mean: 37.4+/-10.8 years; duration of the disease: 5.5+/-4.9 years, EDSS: 2.7+/-1.4) seen at the neuroimmunological outpatient clinic to evaluate its usefulness and its correlation with the traditionally applied Expanded Disability Status Scale (EDSS) and with patient-reported quality of life. Fifteen patients received immunomodulatory treatment (interferon beta and glatiramer acetate). MSFC and EDSS were measured at 0, 3, 6, 9, 12, 18 months, and questionnaires on quality of life were filled in by the patients at 0, 6, 12, 18 months of follow-up. RESULTS: The prospective study confirmed a strong correlation between EDSS and MSFC (Spearman correlation test, p=0.03, 0.004, 0.002, 0.004, 0.0008, 0.002; R=-0.54, -0.66, 0.68, -0.65, -0.73, -0.69) in multiple sclerosis. The MSFC was more sensitive to clinical changes than EDSS. The extent of changes on the two scales correlated only after 18 months (p<0.005, R=-0.65). The arm/hand function was the most sensitive measure for disease progression. There was no correlation between the quality of life and either of the two other clinical parameters. CONCLUSION: MSFC is a simple method, suitable for follow-up of multiple sclerosis patients in everyday clinical practice.