Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55 years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55 years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55-59, 60-65, 66-69, etc. Optimally, such studies should be 3 years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.

• Klíčová slova
• De-escalation, Disease-modifying therapies, Immunosenescence, Multiple sclerosis,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), slowly expanding lesions were shown to be associated with worse disability and prognosis. Their timely detection from cross-sectional data at early disease stages could be clinically relevant to inform treatment planning. Here, we propose to use multiparametric, quantitative MRI to allow a better cross-sectional characterization of lesions with different longitudinal phenotypes. METHODS: We analysed T1 and T2 relaxometry maps from a longitudinal cohort of MS patients. Lesions were classified as enlarging, shrinking, new or stable based on their longitudinal volumetric change using a newly developed automated technique. Voxelwise deviations were computed as z-scores by comparing individual patient data to T1, T2 and T2/T1 normative values from healthy subjects. We studied the distribution of microstructural properties inside lesions and within perilesional tissue. RESULTS AND CONCLUSIONS: Stable lesions exhibited the highest T1 and T2 z-scores in lesion tissue, while the lowest values were observed for new lesions. Shrinking lesions presented the highest T1 z-scores in the first perilesional ring while enlarging lesions showed the highest T2 z-scores in the same region. Finally, a classification model was trained to predict the longitudinal lesion type based on microstructural metrics and feature importance was assessed. Z-scores estimated in lesion and perilesional tissue from T1, T2 and T2/T1 quantitative maps carry discriminative and complementary information to classify longitudinal lesion phenotypes, hence suggesting that multiparametric MRI approaches are essential for a better understanding of the pathophysiological mechanisms underlying disease activity in MS lesions.

• Klíčová slova
• Enlarging lesions, Lesion subtyping, Multiple sclerosis, Quantitative MRI, Relaxometry,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an inflammatory disease affecting the peripheral nerves and the most frequent autoimmune polyneuropathy. Given the lack of established biomarkers or risk factors for the development of CIDP and patients' treatment response, this research effort seeks to identify potential clinical factors that may influence disease progression and overall treatment efficacy. METHODS: In this multicenter, retrospective analysis, we have screened 197 CIDP patients who presented to the University Hospitals in Düsseldorf, Berlin, Cologne, Essen, Magdeburg and Munich between 2018 and 2022. We utilized the respective hospital information system and examined baseline data with clinical examination, medical letters, laboratory results, antibody status, nerve conduction studies, imaging and biopsy findings. Aside from clinical baseline data, we analyzed treatment outcomes using the Standard of Care (SOC) definition, as well as a comparison of an early (within the first 12 months after manifestation) versus late (more than 12 months after manifestation) onset of therapy. RESULTS: In terms of treatment, most patients received intravenous immunoglobulin (56%) or prednisolone (39%) as their first therapy. Patients who started their initial treatment later experienced a worsening disease course, as reflected by a significant deterioration in their Inflammatory Neuropathy Cause and Treatment (INCAT) leg disability score. SOC-refractory patients had worse clinical outcomes than SOC-responders. Associated factors for SOC-refractory status included the presence of fatigue as a symptom and alcohol dependence. CONCLUSION: Timely diagnosis, prompt initiation of treatment and careful monitoring of treatment response are essential for the prevention of long-term disability in CIDP and suggest a "hit hard and early" treatment paradigm.

• Klíčová slova
• Autoimmune, CIDP, Neuroimmunology, Therapy,
• Publikační typ
• časopisecké články MeSH

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.

• Klíčová slova
• Clinically isolated syndrome, Immunotherapy, Interferon beta-1b, Multiple sclerosis,
• MeSH
• demyelinizační nemoci farmakoterapie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• interferon beta 1b * terapeutické užití   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• následné studie MeSH
• progrese nemoci MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• interferon beta 1b * MeSH

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

• Klíčová slova
• ENSEMBLE PLUS, Infusion-related reaction, Ocrelizumab, Phase 3, Relapsing–remitting multiple sclerosis, Shorter infusion,
• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   MeSH
• imunologické faktory * aplikace a dávkování   škodlivé účinky   MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• humanizované monoklonální protilátky * MeSH
• imunologické faktory * MeSH
• ocrelizumab MeSH Prohlížeč

• MeSH
• dospělí MeSH
• dystonie * genetika   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondriální nemoci * genetika   diagnóza   MeSH
• mladiství MeSH
• mutace MeSH
• pohybové poruchy genetika   diagnóza   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH

BACKGROUND: Leg stereotypy syndrome (LSS) is a very common, yet underrecognized condition. The pathophysiology of the condition is not well understood. OBJECTIVE: To evaluate and describe the visual kinematic characteristics of the repetitive leg movements in individuals with LSS. METHODS: In this study, we identified and videotaped individuals diagnosed with LSS at the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas between 2000 and 2023. Only patients with LSS and without any co-morbidities were included in the study. Their medical records were carefully reviewed, and the demographic and clinical data were entered into a database. Video recordings of the repetitive leg movements were then analyzed using TremAn software. RESULTS: We identified 14 individuals with LSS who were videotaped at our center. The videos of the 5 cases were too brief and therefore not suitable for TremAn quantitative analysis. The remaining 9 individuals exhibited regular rhythmic oscillations of the legs. Among these, two individuals displayed rhythmic movements only in video segments where their legs were in crossed positions. The other 7 individuals had regular rhythmic oscillations, always with the toes resting on the floor with the heels raised. Frequency analysis showed values between 4.5 and 6.5 Hz, fairly consistent with a variance below 0.5 Hz in individual cases. The oscillation frequency changed from 5.7 Hz to 2.7 Hz while standing. CONCLUSION: In this study, 6 of 9 individuals with LSS showed 4.5-6.5 Hz regular rhythmic leg movements. Studies involving a larger LSS population with additional electrophysiological evaluations are needed to obtain further insights into this common movement disorder.

• Klíčová slova
• Fidgeting, Leg stereotypy syndrome, Movement disorders, Semi-voluntary, Stereotypy,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The Big Multiple Sclerosis Data (BMSD) network ( https://bigmsdata.org ) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challenges for data sharing and so far, published three scientific papers on pooled datasets as proof of concept for its collaborative design. DATA COLLECTION: Although BMSD registries operate independently on different platforms, similarities in variables, definitions and data structure allow joint analysis of data. Certain coordinated modifications in how the registries collect adverse event data have been implemented after BMSD consensus decisions, showing the ability to develop together. DATA MANAGEMENT: Scientific projects can be proposed by external sponsors via the coordinating centre and each registry decides independently on participation, respecting its governance structure. Research datasets are established in a project-to-project fashion and a project-specific data model is developed, based on a unifying core data model. To overcome challenges in data sharing, BMSD has developed procedures for federated data analysis. FUTURE PERSPECTIVES: Presently, BMSD is seeking a qualification opinion from the European Medicines Agency (EMA) to conduct post-authorization safety studies (PASS) and aims to pursue a qualification opinion also for post-authorization effectiveness studies (PAES). BMSD aspires to promote the advancement of real-world evidence research in the MS field.

• Klíčová slova
• Multiple sclerosis, Patient data network, Patient registries, Real-world evidence,
• MeSH
• big data MeSH
• lidé MeSH
• mezinárodní spolupráce MeSH
• registrace * MeSH
• roztroušená skleróza * epidemiologie   terapie   MeSH
• šíření informací MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

This study presents an in-depth analysis of mitochondrial enzyme activities in Friedreich's ataxia (FA) patients, focusing on the Electron Transport Chain complexes I, II, and IV, the Krebs Cycle enzyme Citrate Synthase, and Coenzyme Q10 levels. It examines a cohort of 34 FA patients, comparing their mitochondrial enzyme activities and clinical parameters, including disease duration and cardiac markers, with those of 17 healthy controls. The findings reveal marked reductions in complexes II and, specifically, IV, highlighting mitochondrial impairment in FA. Additionally, elevated Neurofilament Light Chain levels and cardiomarkers were observed in FA patients. This research enhances our understanding of FA pathophysiology and suggests potential biomarkers for monitoring disease progression. The study underscores the need for further clinical trials to validate these findings, emphasizing the critical role of mitochondrial dysfunction in FA assessment and treatment.

• Klíčová slova
• Biomarkers, Complex I (NQR), Complex II (SQR), Complex IV (COX), Disease monitoring, Friedreich's ataxia, Mitochondrial dysfunction, Neurofilament light chain (NFL), Therapeutic monitoring, Ubiquinone (Coenzyme Q10),
• MeSH
• biologické markery * metabolismus   MeSH
• citrátsynthasa metabolismus   MeSH
• dospělí MeSH
• Friedreichova ataxie * diagnóza   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• ubichinon * analogy a deriváty   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery * MeSH
• citrátsynthasa MeSH
• coenzyme Q10 MeSH Prohlížeč
• ubichinon * MeSH

BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

• Klíčová slova
• CHD8, CHD8-NDD, Autism, Dystonia, Exome sequencing, Movement disorders,
• MeSH
• dítě MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• dystonické poruchy genetika   diagnóza   patofyziologie   komplikace   MeSH
• dystonie genetika   etiologie   patofyziologie   diagnóza   MeSH
• fenotyp * MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neurovývojové poruchy genetika   diagnóza   MeSH
• posunová mutace MeSH
• předškolní dítě MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• CHD8 protein, human MeSH Prohlížeč
• DNA vazebné proteiny * MeSH
• transkripční faktory MeSH