scholarly journals Cerebrospinal fluid markers in incident pediatric-onset multiple sclerosis: a nationwide study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyla A. McKay ◽  
Ronny Wickström ◽  
Jan Hillert ◽  
Virginija Danylaite Karrenbauer
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Relapse Rate ◽  
Negative Binomial ◽  
Negative Binomial Regression ◽  
Expanded Disability Status Scale ◽  
Binomial Regression ◽  
Disability Status ◽  
Igg Index ◽  
Pediatric Onset

AbstractTo investigate whether cerebrospinal fluid (CSF) markers differ between pediatric-onset multiple sclerosis (PoMS, onset < 18 years) and adult-onset (AoMS), and whether these markers are associated with clinical outcomes among PoMS. Prospective nationwide registry study of incident MS, including persons with a CSF sample < 3 years post-MS onset. We compared CSF oligoclonal band (OCB) status, immunoglobulin G (IgG) index levels, and mononuclear cell count between PoMS and AoMS. Within the PoMS cohort we analyzed the association between CSF markers, relapse rate and Expanded Disability Status Scale (EDSS) score, using negative binomial regression and generalized estimating equations, respectively. The cohort consisted of 130 PoMS and 3228 AoMS cases. The PoMS group had higher odds of OCB-positivity (odds ratio: 2.70; 95% CI 1.21–7.67). None of the CSF markers were associated with relapse rate in the PoMS cohort; however, OCB-positivity was associated with higher EDSS scores. This study suggested that PoMS more commonly display CSF evidence for intrathecal IgG production than AoMS. Further, we found evidence of a relationship between OCB-positivity and subsequent disability, suggesting that they could play a role in the prognostication of MS in children.

scholarly journals Cerebrospinal fluid ATP metabolites in multiple sclerosis

2010 ◽  
Vol 16 (5) ◽  
pp. 549-554 ◽  
Author(s):  
G. Lazzarino ◽  
AM Amorini ◽  
MJ Eikelenboom ◽  
J. Killestein ◽  
A. Belli ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Energy Demand ◽  
High Performance ◽  
Axonal Degeneration ◽  
Conduction Block ◽  
Atp Depletion ◽  
Expanded Disability Status Scale ◽  
Disability Status ◽  
Atp Metabolism

Increased axonal energy demand and mitochondrial failure have been suggested as possible causes for axonal degeneration and disability in multiple sclerosis. Our objective was to test whether ATP depletion precedes clinical, imaging and biomarker evidence for axonal degeneration in multiple sclerosis. The method consisted of a longitudinal study which included 21 patients with multiple sclerosis. High performance liquid chromatography was used to quantify biomarkers of the ATP metabolism (oxypurines and purines) from the cerebrospinal fluid at baseline. The Expanded Disability Status Scale, MRI brain imaging measures for brain atrophy (ventricular and parenchymal fractions), and cerebrospinal fluid biomarkers for axonal damage (phosphorylated and hyperphosphorylated neurofilaments) were quantified at baseline and 3-year follow-up. Central ATP depletion (sum of ATP metabolites >19.7 µmol/litre) was followed by more severe progression of disability if compared to normal ATP metabolites (median 1.5 versus 0, p< 0.05). Baseline ATP metabolite levels correlated with change of Expanded Disability Status Scale in the pooled cohort ( r= 0.66, p= 0.001) and subgroups (relapsing—remitting patients: r= 0.79, p< 0.05 and secondary progressive/primary progressive patients: r= 0.69, p< 0.01). There was no relationship between central ATP metabolites and either biomarker or MRI evidence for axonal degeneration. The data suggests that an increased energy demand in multiple sclerosis may cause a quantifiable degree of central ATP depletion. We speculate that the observed clinical disability may be related to depolarisation associated conduction block.

Switch from sequestering to anti-CD20 depleting treatment: disease activity outcomes during wash-out and in the first 6 months of ocrelizumab therapy

2021 ◽  
pp. 135245852110056
Author(s):  
Elisabetta Signoriello ◽  
Giacomo Lus ◽  
Simona Bonavita ◽  
Roberta Lanzillo ◽  
Francesco Saccà ◽  
...  
Keyword(s):  
Disease Activity ◽  
Negative Binomial ◽  
Previous Treatment ◽  
Negative Binomial Regression ◽  
Binomial Regression ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Magnetic Resonance Imaging Mri ◽  
Anti Cd20 ◽  
The Impact

Objectives: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity. Methods: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models. Results: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse. Discussion and Conclusion: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM

2010 ◽  
Vol 17 (3) ◽  
pp. 303-311 ◽  
Author(s):  
Patrizia Sola ◽  
Jessica Mandrioli ◽  
Anna M Simone ◽  
Diana Ferraro ◽  
Roberta Bedin ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Prognostic Value ◽  
Age At Onset ◽  
Disease Course ◽  
Expanded Disability Status Scale ◽  
Biological Factors ◽  
Primary Progressive ◽  
Disability Status ◽  
The Impact

Background: There is increasing evidence on cerebrospinal fluid (CSF) oligoclonal IgM (OCIgM) predicting a more aggressive disease course in relapsing–remitting Multiple Sclerosis (MS), while there is a scarcity of data for primary progressive MS (PPMS). Objective: Our aim was to investigate the presence and possible prognostic value of CSF OCIgM in a group of PPMS and in a group of relapsing-onset MS patients. The possible prognostic role of other clinical and biological factors was also evaluated. Methods: We calculated the impact of single clinical and biological factors, including CSF OCIgM at onset, on the probability of reaching an Expanded Disability Status Scale of 3 and 4 in 45 PPMS and 104 relapsing-onset MS patients. Results: CSF OCIgM were found in only 13% of PPMS patients and did not influence the time taken to reach an Expanded Disability Status Scale of 3 and 4. Conversely, they were present in 46% of relapsing-onset MS patients and increased the risk of reaching an Expanded Disability Status Scale of 4. Clinical factors with a negative prognostic value in PPMS were age at onset <30 years and onset with pyramidal symptoms, while onset with sensory symptoms in relapsing-onset MS predicted a more favourable course. Conclusion: This study confirms that, in relapsing-onset MS patients, the presence of CSF OCIgM at onset predicts a worse disease course. In the cohort of PPMS patients, however, CSF OCIgM were rare, suggesting that heterogeneous pathogenetic mechanisms may be involved in the different MS forms.

Optimal design and analysis of phase I/II clinical trials in multiple sclerosis with gadolinium-enhanced lesions as the endpoint

2010 ◽  
Vol 16 (7) ◽  
pp. 840-847 ◽  
Author(s):  
Brian C Healy ◽  
David Ikle ◽  
Eric A Macklin ◽  
Gary Cutter
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Phase I ◽  
Treatment Effect ◽  
Repeated Measures ◽  
Regression Models ◽  
Negative Binomial ◽  
Negative Binomial Regression ◽  
Delayed Treatment ◽  
Binomial Regression

Many phase I/II clinical trials in multiple sclerosis use gadolinium-enhanced lesions as the outcome measure. The best scanning interval and analysis for this outcome has not been determined. The objective of this study was to compare timing schemes and analysis techniques in terms of power for phase I/II clinical trials. Data were simulated under four scenarios assuming a negative binomial distribution for the number of new lesions and an exponential distribution for the duration of enhancement. The first scenario assumed an immediate treatment effect on the number of new lesions, while the second scenario assumed a delayed treatment effect. The third scenario assumed a higher proportion of patients had no new lesions, and the final scenario assumed an immediate treatment effect on the duration of enhancement. For each scenario, power for a six-month trial with 100 patients per arm was calculated using 10 analysis strategies. The scanning intervals tested were monthly scans, bimonthly scans and a single end-of-study scan. In addition, cost-effectiveness of each trial design and analysis was compared. Negative binomial regression models for the total number of new lesions were the most powerful analyses under an immediate treatment effect, and repeated measures models with a categorical time effect were the most powerful analyses under a delayed treatment effect. Although monthly scans generally provided most power, this design was also most costly. Designs with fewer scans per patient provide similar power and are more cost-effective. Negative binomial regression models are more powerful than non-parametric approaches.

scholarly journals Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials

2018 ◽  
Vol 4 (2) ◽  
pp. 205521731877861 ◽  
Author(s):  
Jutta Gärtner ◽  
Tanuja Chitnis ◽  
Angelo Ghezzi ◽  
Daniela Pohl ◽  
Wolfgang Brück ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Young Adults ◽  
Disease Activity ◽  
Relapse Rate ◽  
Negative Binomial ◽  
Age Groups ◽  
Young Patients ◽  
Negative Binomial Regression ◽  
Phase 3 ◽  
Double Blind

Background Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population. Objective The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials. Methods Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-treat population at age 20 (youngest) and 30 (young) and compared to the overall population. Models used included a negative binomial regression (ARR/neT2) and a logistic regression (NEDA), with age at baseline as a continuous covariate. Results ARRs were higher in younger patients (all p < 0.05), and significantly reduced with fingolimod versus placebo or interferon beta-1a (IFN β-1a), with the percentage reduction inversely proportional to age. Fingolimod was significantly associated with a lower number of neT2 lesions versus placebo/IFN in all age groups except versus IFN in the youngest patients. Regardless of age, fingolimod-treated patients were more likely to achieve NEDA-3 versus placebo/IFN β-1a, with strongest benefits in the youngest patients (all p < 0.05). Conclusions Young adults show higher levels of MS disease activity, and may particularly benefit from fingolimod treatment compared with the overall study population.

A method for evaluating treatment switching criteria in multiple sclerosis

2010 ◽  
Vol 16 (12) ◽  
pp. 1483-1489 ◽  
Author(s):  
Brian C Healy ◽  
Bonnie I Glanz ◽  
James Stankiewicz ◽  
Guy Buckle ◽  
Howard Weiner ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Relapse Rate ◽  
Negative Binomial ◽  
Cox Regression ◽  
Treatment Change ◽  
Treatment Switching ◽  
Disease Modifying Therapy ◽  
Significant Difference ◽  
Disability Status ◽  
Secondary Analyses

Background and Objective: We investigated a method to evaluate a treatment switching approach, namely treatment change after one multiple sclerosis (MS) relapse. Methods: Patients who experienced a relapse while on a first-line disease-modifying therapy, glatiramer acetate, were identified. Based on their subsequent course, patients were divided into two groups: those who changed treatment and those who did not. Patients were allowed to change to any other treatment. Subsequent annualized relapse rate and time to next relapse were compared in the two groups. Since patients were not randomized to treatment group, negative binomial and Cox regression models were used to control for several potential clinical confounders, including relapse severity, relapse duration, age, disease duration and presence of previous/combination therapy. In addition, an inverse probability of treatment weighting model was used to control for confounding. Several secondary analyses investigated patient subgroups. Results: Statistical modeling showed that there was no significant difference between groups in terms of relapse rate (rate ratio; 95% CI = 0.68; 0.35, 1.31) and time to next relapse (hazard ratio; 95% CI = 0.61; 0.30, 1.25). All secondary analyses confirmed these results. In addition, no significant difference in time to sustained progression on the Expanded Disability Status Scale was observed ( p > 0.05). Our approach allowed investigation of the choice to change treatment after a relapse. Conclusions: Our results showed that a single relapse may not be sufficient to indicate treatment failure. Although clinical confounders were addressed in our modeling, unmeasured confounders, particularly the presence of magnetic resonance imaging activity, may have biased our conclusion.

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