Multiple Sclerosis Journal - Experimental, Translational and Clinical最新文献

Background: Research cohort data suggest diagnostic delay in multiple sclerosis (MS) has diminished in tandem with MS diagnostic criteria revisions, yet other studies have not replicated this finding. Recent data indicate misdiagnosis of initial symptoms of MS is a frequent contributor to diagnostic delay.

Objectives: This survey study assessed diagnostic delay and misdiagnosis in an MS patient registry.

Methods: Participants completed the survey study between November 12, 2021, through December 22, 2021.

Results: There were 428 participants. Diagnostic delay was a median of 2.0 months (mean of 22.8 months, range: 0-32.9 years); 173/428 (40.4%) reported misdiagnosis of symptoms later attributed to MS, and this was associated with longer diagnostic delay (p < 0.001). Diagnostic delay decreased over time proximal to revisions to MS diagnostic criteria. 217/428 (50.7%) reported earlier symptoms retrospectively recognized as referable to MS that were not clinically evaluated, resulting in a diagnostic delay median of 5.4 years (mean 8.9 years, range: 0-47.4 years).

Conclusions: Diagnostic delay was prevalent and associated with frequent misdiagnosis of initial symptoms of MS and earlier unevaluated symptoms later attributed to MS. Studies tracing the diagnostic journey of patients with MS are needed to understand and prevent causes of diagnostic delay.

Background: Blood-based biomarkers have emerged as promising tools to optimize treatment decisions in multiple sclerosis (MS) including initiation, switch, or cessation of disease modifying therapies.

Objectives: The clinically validated MS disease activity (MSDA) test measures 18 proteins to derive a disease activity score. This study tests the clinical utility of MSDA in real-world practice.

Methods: Twenty clinicians from 14 clinics conducted a chart review utilizing a retrospective, longitudinal design, with a pre-post component. Chart reviews captured clinician decision-making before and after receipt of each MSDA result, while separate clinician assessments also captured the perceived impact of MSDA on MS management.

Results: A total of 352 charts were reviewed. The overall rate of clinical decision changes after MSDA testing (19.4%) exceeded predefined benchmarks. The proportion of patient time points where clinicians "strongly agreed" or "agreed" that MSDA results influenced their decision-making was greater when multiple longitudinal MSDA results were available compared to a single result: 69.2% (95%CI: [60.2%, 78.3%) vs. 59.8% (95%CI: [43.7%, 76.0%]), respectively.

Conclusion: When used in addition to standard of care, MSDA demonstrates clinical utility for real-world decision-making in MS management, based on objective changes in treatment plan and clinician-reported impact, which increases with longitudinal use.

Background: Falls in people with multiple sclerosis (pwMS) lead to morbidity and expense.

Objective: Identify clinical metrics associated with falls.

Methods: Eighty-six pwMS completed fall surveys, timed 25-foot walk (T25FW), and motion analysis with Clario Opal devices. Logistic regression models were created.

Results: Median age was 54.5 years (range 21-73), 62% (53) were female. The cohort included 58% with relapsing (50) and 42% with progressive MS (36). Those who reported falling in the last year were older (median age 58 vs 52.5, p = .03) and had a higher Patient Determined Disease Step (PDDS) score (median 3 vs 1, p < .0001). Falls were associated with worse balance metrics including sway area (median 2.3 degrees² vs 1.2, p = .01), jerk (median 3.3 m²/s⁵ vs 1.6, p = .005), and slower T25FW (median 11.5 s vs 8; p < .0001). A multivariable regression model based on gait aid use and T25FW time >10.8 s (c = 0.80) was derived. Having both features portended a probability of falling of 0.97, while having neither, a probability of 0.26.

Conclusions: Falls in pwMS are more frequent in patients who are older, have higher PDDS, slower walking, and worse balance. Gait aid use and T25FW >10.8 s were strongly associated with falls in the past year.

Background: Cognitive dysfunction in individuals with multiple sclerosis (MS) is associated with limitations in daily activities and restricted participation. Existing interventions for cognitive dysfunction often show inconsistent transfer to everyday activities and typically require frequent clinic visits, which can be challenging for patients with MS due to mobility issues. To address this barrier, we developed a telehealth-based cognitive intervention that is based on metacognitive strategy training.

Objective: Examine the feasibility and impact of a telehealth-based cognitive intervention on activity and participation in persons with MS.

Methods: Ten participants with MS were included in a remote six-week, 12 sessions cognitive treatment program. The treatment emphasized self-generation and metacognitive strategies to enhance cognitive function. Participants' cognitive abilities were evaluated at baseline (Time 1), midtreatment (Time 2), and posttreatment (Time 3).

Results: Participants demonstrated improved memory, self-awareness, strategy use, and functional status. Participants reported enhanced confidence and better focus and found the remote program engaging and applicable to daily life, reporting increased preparedness for learning.

Conclusion: Results provide preliminary proof-of-concept data suggesting that telehealth-based cognitive intervention is well accepted by patients and may improve cognitive functions in persons with MS. These data support the need for a larger trial for this intervention.

Background: Evidence on neurochemical mechanisms underlying response to apheresis in steroid-refractory Multiple Sclerosis (MS) attacks is limited.

Objective: To examine the effect of immunoadsorption (IA) versus plasma exchange (PLEX) on serum immunological parameters [IgG, IgA, IgM, kappa- and lambda-immunoglobulin free light chains (κ-FLC, λ-FLC), CXCL13, CXCL12] and the predictive value of these parameters on response to apheresis.

Methods: Pre- and postprocedural serum samples of 38 participants (IA: n = 19, PLEX: n = 19) from the IAPEMS trial (NCT02671682), conducted in our tertiary centre, were examined.

Results: Serum immunoglobulins were strongly reduced after both procedures (IgG: IA median -96.04%; PLEX median -85.98%). κ-FLC levels were reduced after PLEX (median -34.74%), not affected by IA. Both procedures caused a decrease in λ-FLC levels. CXCL13 slightly increased after PLEX (median +24.16%), conversely decreased after IA (median -21.92%). CXCL12 levels were reduced after IA (median -45.69%), but not significantly altered after PLEX. None of the serum parameters evaluated showed predictive value for apheresis response.

Conclusion: IA and PLEX have a differential effect on serum immunological parameters. IA appears to reduce B-cell derived inflammation more effectively. This finding requires further evaluation and comparative analysis with clinical outcomes, especially in the context of the efficacy of B-cell therapies in treating MS.

Background: Innovations are essential to meet the needs of people with MS (PwMS), particularly in addressing delays in diagnosis and treatment, and in supporting patient self-management.

Objectives: To evaluate the real-world use and outcomes of digital technologies and holistic management strategies for MS at a UK Centre.

Methods: Digital tools for PwMS included Patients Know Best (a personal health record) and CONNECTPlus^® (an educational app). Tools for healthcare professionals included Infoflex (a clinical database with MSProDiscuss for assessing disease progression). A Healthy Lifestyle Clinic was introduced to promote brain health. The impact of these interventions on time-to-diagnosis, time-to-disease-modifying therapy (DMT) initiation, non-elective admissions, and hospital costs was evaluated retrospectively from 2018 to 2023, comparing pre-intervention (2018-2019) with post-intervention (2020-2023) periods, while accounting separately for COVID-19 years (2020-2021).

Results: Trends indicated a higher likelihood of disease progression in patients with delayed MS diagnosis (p < 0.001), and a reduction in time from diagnosis to DMT initiation, from an average of 23.5 to 5.8 months (p = 0.024), post-MS Infoflex disease management database implementation. Non-elective admissions and healthcare costs also decreased compared to neighbouring hospitals.

Conclusions: Digital and holistic interventions were associated with positive trends in MS care delivery. Further research is needed to validate these findings.

Background: Multiple sclerosis (MS) involves symptoms that may be impacted by angiogenesis. Vascular endothelial growth factor (VEGF), a potent pro-angiogenic molecule, is elevated in early MS, but its activity in later disease is understudied. [Met⁵]-enkephalin (ENK) has anti-angiogenic activity and is decreased in persons with MS (PwMS).

Objectives: To determine salient symptoms of MS and evaluate relationships between common MS symptoms and angiogenesis-associated biomarkers.

Methods: PwMS and non-MS control participants were identified for this cross-sectional study. Walking times and self-reported fatigue, anxiety, depression, and pain were measured. Serum VEGF and [Met⁵] ENK levels were measured in a subset of PwMS.

Results: PwMS (n = 66) had significantly greater fatigue than controls (n = 35). In PwMS, fatigue, anxiety, depression, and pain were positively intercorrelated; fatigue was positively correlated with slower walking. Serum ENK and VEGF had a trending negative relationship. Serum ENK, but not VEGF, had a trending negative relationship with the length of disease. Serum ENK and VEGF were not correlated to walking time or self-report measures.

Conclusion: Fatigue is a salient MS symptom when compared to non-MS controls. Imbalanced pro- and anti-angiogenic signaling may influence fatigue in established MS, but further studies with larger sample sizes are needed to elucidate this potential relationship.

Background: Assessing and interpreting walking capacity in persons with Multiple sclerosis (PwMS) is essential in clinical practice and research - and thus for PwMS themselves - yet research evaluating cut-points is limited. The present study aims to establish cut-points for 6-min walk test (6MWT), six spot step test (SSST), and timed 25-foot walk test (T25FWT) in PwMS.

Methods: Classification of PwMS having walking impairments and PwMS having limited or no walking impairments was based on distinct benchmarks for each walking test, as derived from the 12-item Multiple Sclerosis Walking Scale (MSWS-12) on a 5-point Likert scale. Cut-points, area under the curve (AUC), sensitivity (Se), and specificity (Sp) were established using receiver operating characteristic curve analyses.

Results: A total of n = 211 ambulatory PwMS were enrolled (68% females, 54 ± 11 years, patient-determined disease step 2.9 ± 1.9 [range; 0-7], 65.1% relapse-remitting Multiple sclerosis). The following cut-points between the two groups were established: 6MWT (446 m; AUC = 0.82, Se = 0.87, Sp = 0.78), SSST (0.121 rounds/s (corresponding to 8.3 s); AUC = 0.80, Se = 0.84, Sp = 0.75), and T25FWT (1.39 m/s (corresponding to 5.5 s); AUC = 0.79, Se = 0.89, Sp = 0.69).

Conclusion: Cut-points discriminating PwMS having walking impairments vs. PwMS having limited or no walking impairments were identified for 6MWT (446 m), SSST (8.3 s), and T25FWT (5.5 s).

Background: Patients with multiple sclerosis (MS) on some disease-modifying therapies (i.e., natalizumab), report a "wearing-off" effect characterized by increased symptoms directly before infusions. Prior research suggests this may reflect natural MS fluctuations rather than true treatment waning; however, this has not been confirmed for anti-CD20 agents (e.g., ocrelizumab). Daily step count (STEPS) can reflect overall function. This study examined temporal associations between anti-CD20 therapy infusions and STEPS.

Methods: Retrospective analysis evaluated data from two Fitbit-monitored cohorts (N = 145 total, 32 anti-CD20-treated participants) across 60 treatment cycles. Monthly STEPS were recorded directly pre- and three-month post-infusion over the six-month treatment intervals. Mixed-effects models evaluated the relationship between infusion timing, STEPS, and participant demographics, controlling for confounding variables.

Results: No significant difference in STEPS was observed pre- versus post-infusion (p = 0.32). An average decrease of 3.3% was noted post-infusion but was not statistically significant. No associations between STEPS and participant characteristics (e.g., age, disability level) were identified. Individual variability existed, but no clear group-level trends emerged.

Conclusions: This study found no evidence of an association between timing of anti-CD20 infusion and changes in STEPS. Findings highlight the need for integrating objective measures with patient-reported outcomes and biomarkers in future research to better understand potential treatment fluctuations.

Background: To recover normal functions, remyelination in multiple sclerosis is crucial. Although endogenous remyelination occurs, it is often insufficient, and finding molecules promoting repair of demyelinated lesions is needed.

Objectives: To compare the remyelination potential of evobrutinib, an inhibitor of Bruton's tyrosine kinase and clemastine, an antagonist of M1 muscarinic acetylcholine receptor.

Methods: Remyelination was investigated in lysolecithin demyelinated organotypic mouse cerebellar slices and a transgenic Xenopus model of inducible-demyelination.

Results: Evobrutinib (100 nM) and clemastine (200 nM) potentiated remyelination of mouse cerebellar slices by a factor of 2.9 and 1.76, respectively. In conditionally demyelinated Xenopus, evobrutinib and clemastine increased remyelination by a factor of 1.61 and 1.92, respectively. Evobrutinib targets Bruton's tyrosine kinase expressed by microglia, and we showed that the increase in number of myeloid cells following demyelination is due to an extravasation from nearby vessels of macrophages migrating toward the optic nerve. In contrast, clemastine is expected to antagonize muscarinic receptor 1 expressing cells of the oligodendroglial lineage. We investigated a possible synergistic effect on remyelination by adding simultaneously both molecules. In both experimental models tested no significative improvement on remyelination of co-treatment with evobrutinib plus clemastine was observed.

Discussion: While evobrutinib increased 1.59 fold the number of microglia/macrophages, in the presence of clemastine the number of innate immune cells was decreased by 0.39 fold, therefore counteracting the beneficial effect of microglia/macrophages on remyelination.