[Psychometric Evaluation of the 'German Neurological Fatigue Index for Multiple Sclerosis (NFI-MS-G)' in a Sample of Rehabilitation Patients with Multiple Sclerosis]. / Psychometrische Prüfung des deutschsprachigen "Neurologischen Fragebogens zur Müdigkeit bei Multipler Sklerose (NFI-MS-G)" bei Rehabilitanden mit Multipler Sklerose.

PURPOSE: The purpose of this study was to provide a patient-reported outcome measure for people with multiple sclerosis (MS) comprehensively reflecting the construct of fatigue and developed upon the assumptions of the Rasch model. The Neurological Fatigue Index - Multiple Sclerosis (NFI-MS) is based on both a medical and patient-described symptom framework of fatigue and has been validated. Therefore, in this study the German version of the NFI-MS (NFI-MS-G) consisting of a physical and cognitive subscale and a summary scale was validated. METHOD: In this bi-centre-study, 309 people with MS undergoing outpatient rehabilitation or being≥2 months before or after their inpatient rehabilitation completed the German NFI-MS-G twice within 14-21 days together with other questionnaires. Correlation with established questionnaires and Rasch analysis were used for its validation. Additionally, psychometric properties of known-groups validity, internal consistency, test-retest reliability, measurement precision and readability were tested. Finally, the English NFI-MS and German NFI-MS-G were compared with each other to equate the language versions. RESULTS: The NFI-MS-G showed good internal construct validity, convergent and known-groups validity and internal consistency (Cronbach's alpha 0.84-0.93). The physical subscale showed minor local dependencies between items 1 and 7, 2 and 3 and 4 to 6, that could be treated by combining the respective items to testlets. Unidimensionality was found for the physical and cognitive subscales but not for the summary scale. Replacing the summary scale, a 2-domains subtest measuring the higher-order construct of fatigue was created. Good test-retest reliability (Lin's concordance correlation coefficient of 0.86-0.90) and low floor and ceiling effects were demonstrated. The NFI-MS-G was found easily readable and invariant across groups of gender, age, disease duration, timepoint and centre. CONCLUSION: The German version of the NFI-MS comprehensively represents the construct of fatigue and has adequate psychometric properties. The German version differs from the English original version with respect to a lack of unidimensionality of the summary scale and minor local dependencies of the physical subscale that could be canceled out using a testlet analysis.

Successful long-term management of spasticity in people with multiple sclerosis using a software application: Results from a randomized, controlled, multicenter study.

BACKGROUND AND PURPOSE: Successful long-term treatment of spasticity in people with multiple sclerosis (pwMS) is challenging. We investigated the effects of multidisciplinary inpatient rehabilitation (MIR) and an individualized self-training program delivered by an app on spasticity in pwMS. METHODS: First, we assessed the efficacy of 4-week MIR in ambulatory pwMS (Expanded Disability Status Scale < 7.0) with moderate to severe lower limb spasticity (defined by ≥4 points on the Numeric Rating Scale for spasticity [NRSs]) in a cohort of 115 pwMS at seven rehabilitation centers in Austria. In the case of a clinically relevant improvement in spasticity of ≥20% on the NRSs following MIR (n = 94), pwMS were randomly allocated in a 1:1 ratio to either the newly designed MS-Spasticity App or to a paper-based self-training program for 12 weeks. The primary outcome was change in NRSs (German Clinical Trials Registry DRKS00023960). RESULTS: MIR led to a significant reduction of 2.0 points on the NRSs (95% confidence interval [CI] = 2.5-2.0, p < 0.000). MIR was further associated with a statistically significant improvement in spasticity on the Modified Ashworth Scale, strength, and all mobility outcomes. Following MIR, self-training with the MS-Spasticity App was associated with a sustained positive effect on the NRSs, whereas paper-based self-training led to a worsening in spasticity (median NRSs difference = 1.0, 95% CI = 1.7-0.3, p = 0.009). The MS-Spasticity App was also associated with a significantly better adherence to self-training (95% vs. 72% completion rate, p < 0.001). CONCLUSIONS: In pwMS, MIR is able to significantly improve lower limb spasticity, strength, and mobility. Following MIR, an individually tailored antispasticity program delivered by an app leads to sustained positive long-term management.

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score.

BACKGROUND AND PURPOSE: There is a lack of evidence guiding discontinuation of disease-modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS. METHODS: We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon-ß or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98). RESULTS: The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%-85%), moderate (36%-38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts. CONCLUSIONS: The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs.

German translation, cultural adaptation and validation of the unidimensional self-efficacy scale for multiple sclerosis.

BACKGROUND: Self-efficacy concerns individuals' beliefs in their capability to exercise control in specific situations and complete tasks successfully. In people with multiple sclerosis (PwMS), self-efficacy has been associated with physical activity levels and quality of life. As a validated German language self-efficacy scale for PwMS is missing the aims of this study were to translate the Unidimensional Self-Efficacy Scale for Multiple Sclerosis (USE-MS) into German, establish face and content validity and cultural adaptation of the German version for PwMS in Austria. A further aim was to validate the German USE-MS (USE-MS-G) in PwMS. METHODS: Permission to translate and validate the USE-MS was received from the scale developers. Following guidelines for translation and validation of questionnaires and applying Bandura's concept of self-efficacy, the USE-MS was forward-backward translated with content and face validity established. Cultural adaptation for Austria was performed using cognitive patient interviews. Reliability was assessed using Cronbach's alpha, Person separation index and Lin's concordance correlation coefficient. Rasch analysis was employed to assess construct validity. Comparison was made to scales for resilience, general self-efficacy, anxiety and depression, multiple sclerosis fatigue and health-related quality of life. Data were also pooled with an historic English dataset to compare the English and German language versions. RESULTS: The translation and cultural adaptation were successfully performed in the adaptation process of the USE-MS-G. Pretesting was conducted in 30 PwMS, the validation of the final USE-MS-G involved 309 PwMS with minimal to severe disability. The USE-MS-G was found to be valid against the Rasch model when fitting scale data using a bifactor solution of two super-items. It was shown to be unidimensional, free from differential item functioning and well targeted to the study population. Excellent convergent and known-groups validity, internal consistency, person separation reliability and test-retest reliability were shown for the USE-MS-G. Pooling of the English and German datasets confirmed invariance of item difficulties between languages. CONCLUSION: The USE-MS-G is a robust, valid and reliable scale to assess self-efficacy in PwMS and can generate interval level data on an equivalent metric to the UK version. TRIAL REGISTRATION: ISRCTN Registry; ISRCTN14843579 ; prospectively registered on 02. 01. 2019.

Month-of-birth-effect in multiple sclerosis in Austria.

BACKGROUND: The month-of-birth-effect (MoBE) describes the finding that multiple sclerosis (MS) patients seem to have been born significantly more frequently in spring, with a rise in May, and significantly less often in autumn and winter with the fewest births in November. OBJECTIVES: To analyse if the MoBE can also be found in the Austrian MS population, and if so, whether the pattern is similar to the reported pattern in Canada, United Kingdom, and some Scandinavian countries. METHODS: The data of 7886 MS patients in Austria were compared to all live births in Austria from 1940 to 2010, that is, 7.256545 data entries of the Austrian birth registry and analysed in detail. RESULTS: Patterns observed in our MS cohort were not different from patterns in the general population, even when stratifying for gender. However, the noticeable and partly significant ups and downs over the examined years did not follow the distinct specific pattern with highest birth rates in spring and lowest birth rates in autumn that has been described previously for countries above the 49th latitude. CONCLUSION: After correcting for month-of-birth patterns in the general Austrian population, there is no evidence for the previously described MoBE in Austrian MS patients.

Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors.

BACKGROUND: Stable disease course may prompt consideration of disease-modifying treatment (DMT) discontinuation in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To investigate the clinical outcome after DMT discontinuation and to identify predictive factors supporting decision-making. METHODS: We included 221 RRMS patients, who discontinued DMT after ⩾12 months and had documented follow-up ⩾2 years after discontinuation. Hazard ratios (HRs) with 95% confidence intervals (CIs) regarding relapse and disability progression after DMT discontinuation were calculated from Cox regression models. RESULTS: Age >45 years at discontinuation (HR = 0.47, CI = 0.23-0.95, p = 0.038), absence of relapses for ⩾4 years on DMT before discontinuation (HR = 0.29, CI = 0.10-0.82, p = 0.020) and absence of contrast enhancing lesions (HR = 0.46, CI = 0.28-0.78, p = 0.004) were independent predictors of absence of relapse after discontinuation. Age >45 years and absence of relapses ⩾4 years on DMT combined had an HR of 0.06 (CI = 0.01-0.44, p < 0.001). Higher Expanded Disability Status Scale (EDSS) at discontinuation, age >45 years and longer disease duration were significantly associated with disability progression after discontinuation. CONCLUSION: While freedom from further disease activity is generally unpredictable, there is a subset of patients (age ⩾45 years, DMT intake ⩾4 years without evidence of clinical or radiological disease activity) having a high likelihood of remaining relapse-free after DMT discontinuation. However, close clinical monitoring for recurrent disease activity is mandatory after discontinuing treatment.

Comparison of patient-reported outcomes of physical activity and accelerometry in people with multiple sclerosis and ambulatory impairment: A cross-sectional study.

BACKGROUND: Accelerometers and patient-reported outcomes (PRO) are used to assess physical activity (PA) in people with multiple sclerosis (pwMS). So far it is unknown, however, whether these assessments represent mobility limitations in pwMS with mild and moderate to severe disability alike. The primary aim of the study was to assess the correlation between accelerometry and International Physical Activity Questionnaire (IPAQ) scores in pwMS with different degrees of ambulatory impairment. Taken its frequent use into account, the Godin Leisure Time Exercise Questionnaire (GLTEQ) was investigated as additional PRO. METHODS: In a prospective cohort of pwMS, correlational analyses were performed between the number of daily steps, time spent in light, moderate to vigorous PA (MVPA) and time spent sitting as assessed using accelerometry (ActiGraph®-GT3X), and the respective IPAQ and GLTEQ scores. Additionally, associations of PA with disease-specific characteristics, aerobic capacity (VO2peak), walking assessments (Timed 25-Foot Walk, T25FW; 2-Minute Walk Test, 2MWT) and walking perception (Multiple Sclerosis Walking Scale-12; MSWS-12) were explored. Patient subgroups with mild (Expanded Disability Status Scale; EDSS score <4.0) and moderate to severe disability (EDSS ≥4.0) were analysed for the impact of ambulatory impairment on PA. Multiple linear regression was used to determine predictors of PA. RESULTS: A total of 56 pwMS completed the study, with a mean (standard deviation, SD) age of 48.4 (10.3) years, disease duration of 14.8 (9.6) years and median (interquartile range) EDSS score of 3.5 (2.0 - 4.4). Moderate to weak correlations were found between daily step count and IPAQ total metabolic equivalent (MET) minutes/week (p < 0.001; r = 0.506), MVPA MET-minutes/week (p < 0.01; r = 0.479) and walking MET-minutes/week (p < 0.05; r = 0.372) in the total cohort. Time spent sitting was inversely correlated with total MET-minutes/week and MVPA MET-minutes/week (p < 0.05; r = -0.358 and r = -0.365). Subgroup analysis revealed, that daily step count was significantly correlated with total MET-minutes/week, MVPA MET-minutes/week and walking MET-minutes/week (p < 0.01, r = 0.569; p < 0.01, r = 0.531 and p < 0.05, r = 0.480, respectively) in the "mild disability" subgroup only, whereas time spent sitting was inversely correlated with total MET-minutes/week (p < 0.05; r = -0.582) in the "moderate to severe disability" subgroup. There was no association between objectively assessed PA and GLTEQ scores in any group. In the total cohort, moderate to weak correlations were found between daily step count and walking assessments (T25FW: p < 0.01, ρ = -0.508; 2MWT: p < 0.01, ρ=0.463) and MSWS-12 (p < 0.001; ρ = -0.609). Moderate to weak correlations were also observed between VO2peak and walking assessments (T25FW: p < 0.01; ρ = -0.516; 2MWT: p < 0.01, ρ=0.480). Multiple linear regression analysis identified disability and VO2peak as predictors of PA (p = 0.045; ß=0.25 and p < 0.001; ß=0.49). CONCLUSION: Significant associations of objective PA measurements using accelerometry with IPAQ were found only in pwMS with "mild disability". In pwMS with "moderate to severe disability", IPAQ did not reflect the objectively assessed amount of PA. In our cohort, GLTEQ showed no association with objectively assessed PA. Thus, an MS-specific self-reported questionnaire for assessing PA is warranted.

Actual and imagined music-cued gait training for people with multiple sclerosis: a multicentre qualitative study.

OBJECTIVES: To explore the experiences and acceptability of music-cued motor imagery (MCMI), music-cued gait training (MCGT), and combined MCMI and MCGT (MCMI-MCGT) in people with multiple sclerosis (pwMS). We also aimed to explore participants' self-rated health status postintervention and gather recommendations for further programme development. DESIGN: Qualitative study alongside the double-blind randomised controlled real and imagined gait training with music-cueing (RIGMUC) multicentre trial of MCMI, MCGT and MCMI-MCGT. SETTING: PwMS recruited for the RIGMUC trial from Departments of Neurology at Medical Universities of Innsbruck and Graz and Clinic for Rehabilitation Muenster, Austria. PARTICIPANTS: All 132 pwMS with mild to moderate disability randomised into the trial were included in the analysis. METHODS: Participants practised home-based MCMI, MCGT or MCMI-MCGT for 30 min, 4×/week, for 4 weeks. Three trained researchers conducted weekly semistructured telephone interviews during the intervention period, supporting adherence, addressing problems, sharing experiences and assessing intervention acceptability. Follow-up interviews at 4-week postintervention aimed to understand participants' self-rated changes in walking, fatigue and overall health compared with their prestudy condition. Investigator triangulation was employed among the researchers to enhance trustworthiness and credibility. RESULTS: Using thematic analysis, we identified five themes: (1) empowerment, (2) remaining in sync, (3) interconnection between imagined and actual walking, (4) sustaining focus and (5) real-world transfer. Participants appreciated and found the imagined and actual MCGT innovative. Problems included concentration issues, early fatigue in advanced disability and difficulty synchronising with music cues. Positive changes in walking, fatigue and overall health postinterventions were reported offering valuable insights for programme development. CONCLUSIONS: A participatory study to codevelop a music-cued exercise programme for pwMS seems appropriate as participants appreciated the innovation and effectiveness of both imagined and actual MCGT. Future studies should also investigate pwMS' potential and limitations in enhancing their MCMI abilities with intensive therapist-supported practice. TRIAL REGISTRATION NUMBER: DRKS00023978.

Actual and Imagined Music-Cued Gait Training in People with Multiple Sclerosis: A Double-Blind Randomized Parallel Multicenter Trial.

BACKGROUND: Actual and imagined cued gait trainings have not been compared in people with multiple sclerosis (MS). OBJECTIVE: To analyze the effects of cued motor imagery (CMI), cued gait training (CGT), and combined CMI and cued gait training (CMI-CGT) on motor, cognitive, and emotional functioning, and health-related quality of life in people with MS. METHODS: In this double-blind randomized parallel-group multicenter trial, people with MS were randomized (1:1:1) to CMI, CMI-CGT, or CGT for 30 minutes, 4×/week for 4 weeks. Patients practiced at home, using recorded instructions, and supported by ≥6 phone calls. Data were collected at weeks 0, 4, and 13. Co-primary outcomes were walking speed and distance, analyzed by intention-to-treat. Secondary outcomes were global cognitive impairment, anxiety, depression, suicidality, fatigue, HRQoL, motor imagery ability, music-induced motivation, pleasure and arousal, self-efficacy, and cognitive function. Adverse events and falls were continuously monitored. RESULTS: Of 1559 screened patients, 132 were randomized: 44 to CMI, 44 to CMI-CGT, and 44 to CGT. None of the interventions demonstrated superiority in influencing walking speed or distance, with negligible effects on walking speed (η2 = 0.019) and distance (η2 = 0.005) observed in the between-group comparison. Improvements in walking speed and walking distance over time corresponded to large effects for CMI, CMI-CGT, and CGT (η2 = 0.348 and η2 = 0.454 respectively). No severe study-related adverse events were reported. CONCLUSIONS: CMI-GT did not lead to improved walking speed and distance compared with CMI and CGT alone in people with MS. Lack of a true control group represents a study limitation. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00023978.

Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients.

We performed a replication study in 883 Austrian multiple sclerosis (MS) patients and 972 control individuals for 25 previously risk-associated loci (39 SNPs). Two loci, rs1109670 (DDEF2/MBOAT2, p < 0.02) and rs16914086 (TBC1D2, p < 0.05), are replicated here for the first time. Furthermore, we tested all 39 SNPs for association with age at disease onset and measures of disease severity. We observed a trend for association of rs3135388 (HLA-DRB1*1501, p < 0.01), rs7090530 (IL2RA, p < 0.026) and rs1841770 (ZIC1, p < 0.017) with a younger age at MS onset and of rs12044852 (CD58, p < 0.035) with shorter time to reach EDSS6.

Persistency of neutralizing antibodies depends on titer and interferon-beta preparation.

BACKGROUND: Neutralizing antibodies (NAbs) affect the efficacy of interferon-beta (IFNß) treatment in multiple sclerosis (MS) patients, particularly if NAbs persist. Persistency depends on NAb titers, which differ between IFNß preparations. OBJECTIVE: This study evaluated IFNß preparation-specific NAb cut-off titers during early treatment for prediction of NAb persistency. METHODS: Patients who had at least one NAb test between 12 and 30 months (baseline) as well as after more than 48 months (follow-up) on IFNß treatment were included in this longitudinal study. RESULTS: At baseline 1064 patients had a NAb test. Of those, 203 had a follow-up test. In the follow-up group 23.2% of patients were NAb positive during baseline. NAb frequency significantly decreased by 40.7% in the IFNß-1a and by 60% in the IFNß-1b group at follow-up after a mean time of 75.4 months on treatment, and median NAb titers decreased significantly in both groups. During baseline, NAb titers of >258 neutralizing units (NU) had a sensitivity of 81.3% and a specificity of 90.9% in the IFNß-1a group, whereas titers of >460 NU had a sensitivity of 100% and a specificity of 91.7% in the IFNß-1b group to predict persistency at follow-up. When these cut-off titers are applied, 10.2% of all treated patients developed persistent NAbs. CONCLUSION: IFNß preparation-specific NAb cut-off titers for prediction of NAb persistency, which may be useful in individual treatment decision making, are provided.

Effects of actual and imagined music-cued gait training on motor functioning and brain activity in people with multiple sclerosis: protocol of a randomised parallel multicentre trial.

INTRODUCTION: Motor imagery (MI) refers to the mental rehearsal of a physical action without muscular activity. Our previous studies showed that MI combined with rhythmic-auditory cues improved walking, fatigue and quality of life (QoL) in people with multiple sclerosis (pwMS). Largest improvements were seen after music and verbally cued MI. It is unclear whether actual cued gait training achieves similar effects on walking as cued MI in pwMS. Furthermore, in pwMS it is unknown whether any of these interventions leads to changes in brain activation. The purpose of this study is therefore to compare the effects of imagined and actual cued gait training and a combination thereof on walking, brain activation patterns, fatigue, cognitive and emotional functioning in pwMS. METHODS AND ANALYSIS: A prospective double-blind randomised parallel multicentre trial will be conducted in 132 pwMS with mild to moderate disability. Randomised into three groups, participants will receive music, metronome and verbal cueing, plus MI of walking (1), MI combined with actual gait training (2) or actual gait training (3) for 30 min, 4× per week for 4 weeks. Supported by weekly phone calls, participants will practise at home, guided by recorded instructions. Primary endpoints will be walking speed (Timed 25-Foot Walk) and distance (2 min Walk Test). Secondary endpoints will be brain activation patterns, fatigue, QoL, MI ability, anxiety, depression, cognitive functioning, music-induced motivation-to-move, pleasure, arousal and self-efficacy. Data will be collected at baseline, postintervention and 3-month follow-up. MRI reference values will be generated using 15 matched healthy controls. ETHICS AND DISSEMINATION: This study follows the Standard Protocol Items: Recommendations for Interventional Trials-PRO Extension. Ethical approval was received from the Ethics Committees of the Medical Universities of Innsbruck (1347/2020) and Graz (33-056 ex 20/21), Austria. Results will be disseminated via national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS00023978.

Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases.

Recent studies demonstrated the presence of autoantibodies to native myelin oligodendrocyte glycoprotein (MOG) in juvenile patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). However, so far no longitudinal studies on anti-MOG antibodies have been performed. Therefore, we determined serum and CSF antibodies against native human MOG in 266 pediatric and adult subjects with ADEM, clinically isolated syndrome (CIS), MS, other neurological diseases (OND) and healthy controls (HC) and longitudinal samples of 25 patients with ADEM, CIS, MS and OND using an immunofluorescence assay. We detected serum high-titer MOG IgG in 15/34 (44%) patients with ADEM, but only rarely in CIS (3/38, 8%), MS (2/89, 2%), OND (1/58, 2%) and HC (0/47). Longitudinal analysis of serum anti-MOG IgG showed different temporal dynamics of serum antibody responses in ADEM, CIS and MS and indicated an association of a favorable clinical outcome in ADEM with a decrease in antibody titers over time.

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders.

BACKGROUND: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. RESULTS: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. CONCLUSIONS: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Estimating Risk of Multiple Sclerosis Disease Reactivation in Pregnancy and Postpartum: The VIPRiMS Score.

BACKGROUND: Evidence guiding personalized decision-making with respect to disease-modifying therapy (DMT) around pregnancy in relapsing multiple sclerosis (RMS) is lacking. OBJECTIVE: To generate and validate a risk score for disease reactivation intrapartum and postpartum in RMS. METHODS: From the Vienna Innsbruck MS database (VIMSD), we included 343 pregnancies in patients with RMS. Primary endpoint was disease reactivation. Patients were randomly assigned 2:1 in a generation and validation dataset. A predictive score was calculated using the Cox regression and validated. RESULTS: In the generation dataset, occurrence of relapse and type of DMT in the year before conception, DMT washout duration, the Expanded Disability Status Scale (EDSS) at conception, and time until DMT restart postpartum were identified as independent predictors of disease reactivation (p < 0.001). The resulting 10-point risk score robustly predicted reactivation (explaining 75% of variance, p < 0.001) identifying patients at high [≥6 points; mean risk 65%; range 50-100%; hazard ratio (HR) 14.5], intermediate (3-5 points; mean risk 24%; range 15-35%; HR 4.3), and low risk (≤2 points; mean risk 6%; range 0-8%) of disease reactivation in pregnancy and up to 6 months postpartum. CONCLUSION: The composite Vienna Innsbruck Pregnancy Risk in Multiple Sclerosis (VIPRiMS) score is a valuable clinical tool to support patients and neurologists in anticipating risk and, thus, individualizing treatment decision-making around pregnancy.

Beneficial effects of multi-disciplinary rehabilitation in postacute COVID-19: an observational cohort study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic increases the demand for postacute care in patients after a severe disease course. Various long-term sequelae are expected and rehabilitation medicine is challenged to support physical and cognitive recovery. AIM: We aimed to explore the dysfunctions and outcome of COVID-19 survivors after early postacute rehabilitation. DESIGN: Observational cohort study. METHODS: This study evaluated the postacute sequelae of patients hospitalized for SARS-CoV-2 infection and analyzed rehabilitative outcomes of a subgroup of patients included in the prospective observational multicenter CovILD study. RESULTS: A total of 23 subjects discharged after severe to critical COVID-19 infection underwent an individualized, multiprofessional rehabilitation. At the start of postacute rehabilitation, impairment of pulmonary function (87%), symptoms related to postintensive care syndrome, and neuropsychological dysfunction (85%) were frequently found, whereas cardiac function appeared to be largely unaffected. Of interest, multi-disciplinary rehabilitation resulted in a significant improvement in lung function, as reflected by an increase of forced vital capacity (P=0.007) and forced expiratory volume in one second (P=0.014), total lung capacity (P=0.003), and diffusion capacity for carbon monoxide (P=0.002). Accordingly, physical performance status significantly improved as reflected by a mean increase of six-minute walking distance by 176 (SD±137) meters. Contrarily, a considerable proportion of patients still had limited diffusion capacity (83%) or neurological symptoms including peripheral neuropathy at the end of rehabilitation. CONCLUSIONS: Individuals discharged after a severe course of COVID-19 frequently present with persisting physical and cognitive dysfunctions after hospital discharge. Those patients significantly benefit from multi-disciplinary inpatient rehabilitation. CLINICAL REHABILITATION IMPACT: Our data demonstrated the highly promising effects of early postacute rehabilitation in survivors of severe or critical COVID-19. This findings urge further prospective evaluations and may impact future treatment and rehabilitation strategies.

Improving our understanding of the most important items of the Multiple Sclerosis Walking Scale-12 indicating mobility dysfunction: Secondary results from a RIMS multicenter study.

BACKGROUND: The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is currently the most widely validated, patient-reported outcome measure assessing patients' perception of the impact of multiple sclerosis (MS) on walking ability. To date, the majority of previous studies investigating the MSWS-12 have focused on the total score despite individual items being potentially informative. Therefore, our objective was to examine the associations between the individual items of the MSWS-12 and mobility and whether these associations depend on disability level. METHODS: Participants completed the MSWS-12, Two-Minute Walk Test (2MWT), Timed 25-Foot Walk (T25FW), Timed Up and Go Test (TUG) and the Four Square Step Test (FSST). Subsequently, they were divided into two groups according to their disability level, classified as either "mildly" or "moderately-severely" disabled. The correlation between individual items of the MSWS-12 and clinical measures of mobility were separately examined by Spearman's correlation coefficients; linear regression analyses were performed for each disability group, with/without adjusting for cognition, age and gender. RESULTS: 242 people with MS (PwMS), 108 mildly and 134 moderately-severely disabled, were included. Stronger correlations between the MSWS-12 items and mobility tests were found in the mildly disabled compared to the moderately-severely disabled group. The linear regression analysis showed that in the mildly disabled, item 9 (use of support outdoors) explained 35.4%, 30.8%, and 23.7% of the variance related to the 2MWT, T25FW and TUG, respectively. As for the moderately-severely disabled, the linear regression analysis presented a model which included item 8 (use of support indoors), explaining 31.6%, 18.0%, 20.2% and 9.5% of the variance related to the 2MWT, T25FWT, TUG and FSST, respectively. CONCLUSIONS: Items 8 and 9 of the MSWS-12 focusing on the patient's use of walking support in and outdoors, provide a robust indicator of mobility capabilities for mildly and moderately-severely disabled PwMS.

Influence of interferon-beta therapy switching on neutralizing antibody titres: results from the Austrian Switch Study.

Neutralizing antibodies against interferon-beta are associated with a reduction of the efficacy of this drug. Continuing treatment leads to a decline or even loss of neutralizing antibodies over years. No strategies are currently available to shorten the period of neutralizing antibody positivity. The objective of this study was to investigate the effect of switching between high and low immunogenic interferon-beta products on neutralising antibody titres. Twenty-four patients treated with the subcutaneously administered interferon-beta 1b or 1a and high titres of neutralizing antibodies were included. At baseline interferon-beta therapy was interrupted for 3 months and two pulses of high dose methylprednisolone were applied. Patients were then randomized to receive either the previous interferon-beta preparation or the low immunogenic intramuscular interferon-beta 1a. The primary end-point was the change of neutralizing antibody titres 12 months after randomization. Twelve patients were switched to interferon-beta 1a intramuscularly and 12 patients remained on previous treatment. Median neutralizing antibody titres were 846 NU at baseline and 196 NU at the end of the study. The median change of neutralizing antibody titres did not differ significantly between therapy switchers and non-switchers. Baseline and final neutralizing antibody titres correlated significantly. In conclusion, neither switching nor continuous therapy with any subcutaneous interferon-beta preparation significantly changed neutralizing antibody titres.

Ecological validity of walking capacity tests following rehabilitation in people with multiple sclerosis.

BACKGROUND: Walking capacity tests are commonly used to evaluate interventions aiming at reducing walking impairment in people with multiple sclerosis (pwMS). However, their ecological validity has recently been questioned. The aim of the present study was to investigate the ecological validity of the 2- and 6-minutes walking tests (2MWT and 6MWT) and the timed 25-foot walk (T25FW) after 28 days of multidisciplinary inpatient rehabilitation (MIR) in pwMS using accelerometry. METHODS: PwMS wore an accelerometer on 7 consecutive days within a 14-day period prior to MIR, performed 2/6MWT and T25FW at the beginning and at the end of MIR, followed by another 7 consecutive days of accelerometry. RESULTS: Significant improvements in 2/6MWT and T25FW after MIR in a cohort of 76 pwMS (mean age = 47.9, SD 8.3 years) were overall correlated to a significant gain in everyday life mobility (total steps/day). However, the correlation was strongly dependent on pre-existing walking disability defined by EDSS and only pwMS with "mild" walking impairment (EDSS 2-3.5) were able to transfer benefits measurable by walking capacity tests into improved everyday life mobility, while pwMS with "moderate to severe" walking disability (EDSS 4-6.5) were not. CONCLUSION: Ecological validity of changes in walking capacity tests following MIR is strongly dependent on pre-existing walking impairment.