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

Background: Progression independent of relapse activity (PIRA) may occur in patients with relapsing multiple sclerosis (MS) and is a major contributor to disability accumulation.

Objectives: We evaluated whether a panel of cerebrospinal fluid (CSF) biomarkers (neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), total-Tau (T-Tau), ubiquitin C-terminal hydrolase 1 (UCHL-1), and the phospho-Tau (P-Tau)181/T-Tau ratio) at diagnosis could discriminate patients who will develop PIRA in early disease phases.

Methods: CSF levels of NfL, GFAP, T-Tau, and UCHL-1 were measured with SIMOA, of P-Tau181, and the ratio P-Tau181/T-Tau with chemiluminescent immunoassay in 80 newly diagnosed MS patients who were followed up for three years with six-month Expanded Disability Status Scale (EDSS) assessments and yearly MRI scans.

Results: Nineteen participants developing PIRA exhibited elevated GFAP and UCHL-1 levels, and reduced P-Tau181/T-Tau ratio. These biomarkers remained significant predictors of the outcome after adjusting for confounders, particularly older age at onset and higher baseline EDSS. Additionally, we identified moderate positive correlations between NfL-GFAP, NfL-UCHL-1, and GFAP-UCHL-1 levels, and moderate negative correlations between P-Tau181/T-Tau ratio and NfL, GFAP, and UCHL-1 levels.

Conclusions: The elevation of GFAP and UCHL-1 likely reflects the role of astrocytic activation, while the reduction of the P-Tau181/T-Tau ratio may indicate disrupted Tau metabolism in individuals at risk of PIRA. Our findings suggest that combining these innovative biomarkers with clinical risk factors could improve early prognostic accuracy.

Background: In relapsing-remitting multiple sclerosis (RRMS), the assessment of clinical disease activity can be challenging.

Objectives: To determine the diagnostic potential of serum neurofilament light (sNfL) and glial fibrillary acidic protein (sGFAP) to distinguish a relapse from other causes of deterioration.

Methods: In this multicenter, prospective study, RRMS patients with new neurological symptoms in the last 14 days were followed for 12 weeks. A diagnosis was established by the treating physician or, when in doubt, a panel of experienced neurologists. Blood samples were taken at baseline and week 12.

Results: A total of 65 patients were included. At baseline, patients with a clear relapse had a significantly higher median sNfL (14.6 pg/mL) than those with a clear other cause (9.5 pg/mL, p = 0.004). Although not significant after correction for multiple testing, median sGFAP was also higher in relapse patients (73.0 vs 64.6 pg/mL, p = 0.036). An sNfL value below 6.0 pg/mL had a high sensitivity (67% at baseline (CI 22.3-95.7%) and 100% at follow-up (CI 54.1-100%)) to rule out a relapse.

Conclusions: Analysis of sNfL level can be useful as an add-on investigation to determine whether disease activity is present in patients with RRMS presenting with new symptoms.

Background: SPRINT-MS was a placebo-controlled phase 2 trial of ibudilast in secondary and primary progressive multiple sclerosis. The trial included multimodal imaging to assess brain tissue integrity. This contribution focuses on improved analysis methods of diffusion tensor imaging to refine its application in clinical trials.

Objective: Reassess diffusion tensor imaging from the SPRINT-MS trial.

Methods: Postprocessing incorporated corrections for bulk motion, eddy current distortion, outlier replacement, and intra-volume movement. The ICBM-DTI-81 white matter parcellation map was coregistered into native space. Six unilateral and 21 bilateral regions of interest were identified. Median radial diffusivity was the primary outcome measure for this analysis. A linear mixed-effects model was used to assess the interaction between time and treatment for the outcome measure with Holm correction for multiple comparisons.

Results: Radial diffusivity in the cingulum and cerebellar peduncles showed a significant difference in rate of change between treatment and placebo groups (2.7-7.4 × 10^-3 mm²/s per 24-week time period, p < 0.04). Radial diffusivity was unchanged (declined) in the treatment (placebo) groups, consistent with preservation (deterioration) of tissue integrity.

Conclusion: Our results suggest that the diffusion tensor imaging of the cingulum and cerebellar peduncles may be useful target outcome metrics in neuroprotective trials in progressive multiple sclerosis.

The deep cervical lymph nodes (dCLNs) are sites of immune presentation and B-cell maturation from the brain, and potentially involved in mechanisms of neuroinflammation. We hypothesized a reduction in dCLN volume following B-cell depletion therapy. In a retrospective cohort, we segmented bilateral dCLN from T2-FLAIR MRI at "prebaseline," "baseline," and "post-B-cell depletion" timepoints. Using a multivariable mixed-effect regression model, we find no changes in dCLN volumes between prebaseline and baseline timepoints (p > 0.05), but a significant decrease of 158 mm³ following ocrelizumab infusion (t = -3.3, p = 0.005). Baseline use of a disease-modifying therapy was also significantly associated with a smaller dCLN volume and attenuated the effects of B-cell depletion. These results are congruent with therapeutic mechanisms, although other alternative explanations for reductions in dCLN volumes cannot be ruled out based on this data. Deep CLN represent potential imaging biomarkers of pharmacological or clinical utility and warrant further investigation.

Background: Fingolimod was approved in 2010 for the treatment of relapsing-remitting multiple sclerosis, generally as second-line therapy. While its efficacy in reducing the relapse rate is well-recognized, the dermatologic complications of fingolimod remain unexplored. Herein, we aimed to report our experience with multiple sclerosis patients treated with fingolimod who underwent periodic dermatologic examinations.

Materials and methods: A prospective cohort of 323 patients with multiple sclerosis treated with fingolimod were assessed for dermatologic manifestations over 60 months. The neurologic and dermatologic examinations were done biannually to identify and categorize skin-related adverse events.

Results: Over a mean follow-up of 60 months, of the 323 patients, 32.19% (104 patients) developed skin abnormalities after a mean interval of 25.77 ± 24.36 months since fingolimod initiation. The majority of patients (91.34%) were female, with a mean age of 36.40 ± 7.45 years and a mean disease duration of 122 ± 58.56 months. The most common findings included melanocytic nevus (65.38%) and infectious lesions (11.53%). The severity of skin lesions varied, with most cases manageable with topical treatments. However, ten patients (9.61%) who developed refractory genital human papillomavirus (n = 2), melanocytic nevus (n = 3), dysplastic nevi (n = 3), fibrous papules (n = 1), and molluscum contagiosum (n = 1) had to discontinue their treatment.

Conclusion: Fingolimod treatment in patients with multiple sclerosis is associated with a range of dermatologic findings, predominantly mild to moderate in severity. This population warrants awareness of these potential adverse events and regular follow-up.

Background: Multiple sclerosis (MS), a chronic neurological disease, is typically managed with disease-modifying therapies (DMTs) to reduce relapse rates and slow disease progression. Some of these DMTs can cause infusion-related reactions (INRRs), which range from mild symptoms to severe allergic reactions. Corticosteroids are commonly used in premedication regimens to mitigate INRRs. However, long-term use of corticosteroids carries health risks. This study aims to compare the effectiveness of a standard corticosteroid regimen with an adjusted, low-dose regimen in reducing INRRs among people living with MS, receiving ocrelizumab (Xacrel), with the goal of optimizing safety while minimizing corticosteroid exposure.

Methods: In a single-blind, randomized, parallel-group clinical trial conducted at Sina Hospital, 200 adult patients with MS who had previously received ocrelizumab were recruited and randomly assigned to either a standard or adjusted premedication regimen groups. The standard regimen group (n = 101) received 100 mg intravenous (IV) methylprednisolone, along with cetirizine and acetaminophen tablets as premedication, while the adjusted regimen group (n = 99) received a reduced dose of 8 mg IV dexamethasone. The incidence of INRRs and their severity was monitored up to 1-hour post-infusion and 24-h post-infusion. Statistical analyses, including Chi-square tests and logistic regression, were used to evaluate the frequency of INRRs, characterize symptom profiles, and identify potential predictive factors for INRRs occurrence.

Results: Overall, the standard premedication demonstrated more efficacy in reducing the occurrence of INRRs, while the adjusted regimen group showed a significantly higher incidence of INRRs compared to the standard regimen group (78.8% vs. 40.6%, p-value <0.01). Specific INRRs symptoms, such as itching (29.3% in the adjusted group vs. 8.3% in the standard group, p-value <0.01) and throat irritation (65.7% vs. 31.7%, p-value <0.01), were notably more frequent in the adjusted regimen group. Most INRRs were mild to moderate in severity in both groups. There was no statistically significant difference in the occurrence of severe reactions between the two groups. Notably, a history of INRRs from previous infusions was identified as a strong predictor of INRRs in the current study, with an odds ratio of 6.27 (95% CI: 3.36-11.70), highlighting the importance of patients' history in managing INRRs risk.

Conclusions: The standard premedication regimen was more effective in reducing INRRs in people living with MS, receiving Xacrel compared to the reduced corticosteroid regimen. However, the findings suggest that a lower corticosteroid regimen may be beneficial for some patients, as there was no significant difference in the incidence of severe INRRs between the two groups.

Background: Early disease-modifying therapy (DMT) improves outcomes in patients with relapsing-remitting multiple sclerosis (pwRRMS), but reasons for delayed or absent initiation are unclear.

Objective: To investigate reasons and trends for delayed or absent DMT initiation among Finnish pwRRMS.

Methods: A nationwide retrospective study using the Finnish MS Registry identified 2363 pwRRMS diagnosed between 2010 and 2019 in the participating centers. Patients never receiving DMT or starting >2 years post-diagnosis were compared to those initiating DMT within a year of diagnosis.

Results: We identified 193 pwRRMS who never started DMT, 88 had delayed initiation over 2 years, and 1944 started within a year. The no/delayed DMT group was older at diagnosis (mean 38.7 vs 35.2 years, p < 0.001). Corticosteroid-treated relapses were more frequent among early initiators. Optic neuritis was more common in patients with delayed or no DMT. Treatment refusal was the primary reason for delayed/no DMT (35.6%), with 68% of refusers never starting. From 2010to 2019, delayed/no DMT initiation (p = 0.007) and treatment refusal (p = 0.004) decreased significantly.

Conclusion: Delayed or absent DMT initiation is linked to older age, optic neuritis, disease inactivity, and treatment refusal, which declined over time, likely due to expanded DMT options.

Background: Epilepsy is two to three times more common in patients with multiple sclerosis (pwMS) compared to the general population. Patients with MS and epilepsy without other identifiable causes (MS + E) show greater cortical damage than those without epilepsy (MS-E). However, it's unclear whether MS + E patients exhibit distinct cognitive and neuropsychological features requiring specific management.

Methods: In a cohort of pwMS from three MS centers, MS + E patients were identified and data on MS clinical features, epilepsy history, and treatments were collected. A matched group of MS-E patients was included. Assessments included cognitive and neuropsychiatric tests. Cognitive impairment (CI) was defined as scoring ≥1.5 standard deviations below normative values in ≥1 cognitive domain.

Results: CI was more prevalent in MS + E (n = 33) patients than in MS-E (n = 33). MS + E patients had lower processing speed (p < 0.01) and visuospatial memory (p = 0.03). MS + E was independently associated with CI (odds ratio 3.6, 95% confidence interval 1.21-12). Somatization, phobia, anxiety, and depression were the most affected neuropsychological domains in MS + E, with global psychological distress negatively correlating with processing speed (rho -0.36, p = 0.048).

Conclusions: MS + E is associated with higher CI, particularly in processing speed and visuospatial memory, alongside psychological distress, highlighting the need for targeted multidisciplinary care to improve outcomes and quality of life.

Background and objectives: Late-onset MS (LOMS, symptom onset after age 50) remains underrepresented in clinical trials, leading to a gap in knowledge about the efficacy of disease-modifying therapies (DMTs). This study aims to evaluate treatment outcomes in relapsing LOMS.

Methods: A retrospective electronic medical record study at Northwestern University analyzed patients with LOMS presenting between 2004 and 2021. Demographic, clinical, DMT, and MRI data were extracted. Statistical analyses evaluated progression based on DMT efficacy.

Results: Overall, 63 patients (63% female, 76% white, median onset 55 years) were followed for a median of 7.6 years. Most patients (73%) were started on low/moderate efficacy DMTs (LET/MET). Increasing baseline EDSS was associated with an increased risk of reaching EDSS 6 (P < .001), but increasing age at diagnosis/treatment was not associated with increasing disability attainment (P = .527). Patients on LET/MET had no difference in progression to EDSS 6.0 compared to no DMT (P = .354) or change in Age-Related Multiple Sclerosis Severity Score (ARMSS) from the start of treatment/diagnosis to last follow-up (P = .477).

Discussion: The effect of LET/MET DMTs is less pronounced in older adults and may not significantly impact long-term disability outcomes.