Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying ...progression but no randomized trial was conducted so far.
To compare CPM to methylprednisolone (MP) in SPMS.
Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 95% CI: 0·31-1·22(p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely (1·14-4.29; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
Clinicaltrials.gov NCT00241254.
Background:
Cognitive impairment in multiple sclerosis (MS) primarily applies to information processing speed (IPS).
Objective:
To evaluate psychometric properties of a new digit/symbol substitution ...test in healthy subjects and patients with MS, and assess its ability to detect IPS impairment in patients with MS.
Methods:
A sample of MS patients, 60 relapsing–remitting (RRMS) and 41 primary progressive MS (PPMS), and 415 healthy controls (HCs) underwent an IPS battery, including assessment of reaction times of subtests of the Test of Attentional Performance battery and a newly developed in-house digit/symbol substitution task, the Computerised Speed Cognitive Test (CSCT). The CSCT was additionally evaluated in a second cohort of 31 RRMS and 12 progressive MS patients, for comparison with the Symbol Digit Modalities Test (SDMT).
Results:
The CSCT had good reliability in both HCs and patients with MS. It showed a weak practice effect at the 6-month time point. This test had good ecological validity in MS patients. There was a strong correlation between the CSCT with the SDMT and with other IPS tests in patients with MS. The CSCT had the best sensitivity for predicting IPS impairment and was one of the most accurate tests among the IPS battery.
Conclusion:
The CSCT appeared as a good candidate for detecting IPS impairment in MS patients.
To determine MRI predictors for cognitive outcome in patients with early relapsing-remitting multiple sclerosis (MS).
Forty-four patients recently diagnosed with clinically definite MS were followed ...up with clinical and cognitive evaluations at 1, 2, 5, and 7 years and underwent brain MRI including magnetization transfer (MT) imaging at baseline and 2 years. Cognitive evaluation was also performed in 56 matched healthy subjects at baseline. Cognitive testing included the Brief Repeatable Battery. Imaging parameters included lesion load, brain parenchymal fraction (BPF), ventricular fraction (VF), and mean MT ratio (MTR) of lesion and normal-appearing brain tissue (NABT) masks.
At baseline, patients presented deficits of memory, attention, and information processing speed (IPS). Over 2 years, all magnetic resonance parameters deteriorated significantly. Over 7 years, Expanded Disability Status Scale score deteriorated significantly. Fifty percent of patients deteriorated on memory cognitive domain and 22.7%of patients on IPS domain. Seven-year change of memory scores was significantly associated with baseline diffuse brain damage (NABT MTR). IPS z score change over 7 years was correlated with baseline global atrophy (BPF), baseline diffuse brain damage, and central brain atrophy (VF) change over 2 years.
The main predictors of cognitive changes over 7 years are baseline diffuse brain damage and progressive central brain atrophy over the 2 years after MS diagnosis.
Background:
The Brief Computerized Cognitive Assessment in Multiple Sclerosis (BCCAMS) is a short neuropsychological battery for persons with multiple sclerosis (PwMS).
Objectives:
The main objective ...of the study is to validate the BCCAMS.
Methods:
PwMS and healthy subjects (HS) were evaluated using the BCCAMS which include two computerized tests, the Computerized Speed Cognitive Test and the Computerized Episodic Visual Memory Test (CEVMT), a newly developed visuospatial memory test, and the French learning test. The Minimal Assessment of Cognitive Function in MS (MACFIMS), including the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) tests, was also administered. Regression-based norms of the BCCAMS were calculated in 276 HS. BCCAMS was compared with BICAMS and MACFIMS for detection of cognitive impairment (CI).
Results:
Out of 120 PwMS, CI was detected using the BCCAMS, BICAMS (one impaired test), and MACFIMS (two impaired tests) in 59.1%, 50%, and 37.9%, respectively. The BCCAMS produced the same predictive value as that of the BICAMS battery for detecting CI in the MACFIMS.
Conclusion:
This study validated the BCCAMS as a validated computerized short assessment for information processing speed and learning in MS.
Abstract Objective The aim of this work is to study the relationship between information processing speed (IPS) impairment and motor testing that reflects cerebellar function in persons with multiple ...sclerosis (PwMS). Methods 60 persons with relapsing–remitting multiple sclerosis with a mean disease duration of 4.2 ± 4 years were studied cross-sectionally. Motor cerebellar functioning was studied using the Nine-Hole Peg Test (NHPT) and the Kurtzke Functional Status Scales, and several cognitive domains were evaluated (IPS, working memory, episodic memory, attention, executive function). Correlations between the global NHPT score and neuropsychological test scores or impairment in each cognitive domain were studied using univariate and multivariate analyses. Results The NHPT and a test of IPS significantly differentiated PwMS with and without cerebellar impairment. The NHPT total score was correlated with measures of IPS. Multivariate analyses showed a correlation between the NHPT and measures of IPS, but not between the NHPT and other neuropsychological tests that did not have a speed component. Conclusion In this sample of PwMS, motor cerebellar impairment assessed by the NHPT was correlated with IPS impairment.
Hydrocephalus features include ventricular dilatation and periventricular edema due to transependymal resorption of cerebrospinal fluid (CSF). Aquaporin 4 (AQP4), a water channel protein located at ...the blood–brain barrier, might facilitate the removal of this excess of water from the parenchyma into the blood. First, we hypothesized a link between AQP4 expression and the severity of hydrocephalus. We further hypothesized that movements of water through AQP4 could affect apparent diffusion coefficient (ADC) measurements. Communicating inflammatory hydrocephalus was induced in 45 rats, and at various stages, magnetic resonance imaging (MRI) was used to measure CSF volume and periventricular ADC, with immunostaining being used to determine periventricular AQP4. We found an up-regulation of periventricular AQP4 in hydrocephalic rats that was strongly correlated with both CSF volume (Pearson=0.87, p<0.00001) and periventricular ADC (Pearson=0.85, p<0.00001). AQP4 were first located on astrocyte endfeet, but later on the whole membrane of astrocytes that became hypertrophic in the most severe and chronic hydrocephalic rats. These results show that AQP4 expression follows an adaptative profile to the severity of hydrocephalus, which is probably a protective response mechanism. They also suggest that ADC, on top of informing about cell sizes and interstitial bulk water, might also indirectly reflect quantitative water channel expression.
Objectives:We investigated proinflammatory M1 and immunomodulatory M2 activation profiles of circulating monocytes in relapsing experimental autoimmune encephalomyelitis (EAE) model of multiple ...sclerosis, and tested whether altered M1/M2 equilibrium promotes CNS inflammation.
Results:Approaches of MRI macrophage tracking with USPIO nanoparticles and expression patterns of M1/M2 macrophages and microglia in brain and M1/M2 monocytes in blood samples at various disease stages revealed that M1/M2 equilibrium in blood and CNS favors mild EAE, while imbalance towards M1 promotes relapsing EAE. We consequently investigated whether M2 activated monocyte restoration in peripheral blood could cure acute clinical EAE disease. Administration of ex vivo activated M2 monocytes both suppressed ongoing severe EAE and increased immunomodulatory expression pattern in lesions, confirming their role in the induction of recovery.
Conclusion:We conclude that imbalance of monocyte activation profiles and impaired M2 expression, are key factors in development of relapses. Our study opens new perspectives for therapeutic applications in MS.
Cognitive impairment is important to consider in the assessment of multiple sclerosis (MS) patients. A short battery of cognitive assessment, the Brief International Cognitive Assessment for Multiple ...Sclerosis (BICAMS), has been developed to address the need for rapid assessment by combining 3 tests assessing the main cognitive spheres reached in MS.
To establish regression-based norms of the BICAMS in French speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS).
In all, 123 PwMS including 40 with relapsing-remitting MS, 41 patients with secondary progressive MS and 42 with primary progressive MS and 276 HS were evaluated by the BICAMS including 3 tests, the Symbol Digit Modalities Test (SDMT), the French Verbal learning test (FVLT) a French-adapted memory test, (or the California Verbal Learning Test (CVLT) at retesting) and the Brief Visuo-Spatial Memory Test (BVMT-R). The standards for these tests were established in the healthy population using a multiple regression technique. Validity in MS was measured.
Regression-based norms of BICAMS tests have been established in the HS population. 50.4% of PwMS have impairment for at least one BICAMS test (-1.5SD on the Z-score). The most common pathological test was the FVLT altered in 36.6% of patients, followed by the SDMT and the BVMT-R. The re-test reliability was good for the various BICAMS tests, 0.891 for SDMT, 0.781 for FVLT/CVLT and 0.669 for BVMT-R.
This study establishes the validity of the BICAMS as a short and easy to apply battery for a brief assessment of the speed of information processing and episodic memory in MS.
Abstract Background The independent prognostic value of cerebrospinal fluid analysis in multiple sclerosis is not established. Objective To determine the prognostic value of intrathecal synthesis in ...a cohort of patients with relapsing-onset MS taking into consideration demographic and imaging parameters. Methods In this prospective cohort study conducted from 1993 to 2013, we analyzed the time to confirmed disability (persistent above 6 months) and irreversible disability (persistent for the entire disease course) of two disability milestones, Expanded Disability Status Scale score ≥ 4 or 6, and the time to secondary progressive onset in 579 patients with relapsing-onset multiple sclerosis. Demographic parameters (age at onset, gender) and imaging parameters (periventricular lesions) were included in the Cox models. Results 447 patients (77.2%) had intrathecal synthesis (oligoclonal bands and/or increased immunoglobulin G index value). No statistically significant relation was found between intrathecal synthesis and the time to reach each disability milestone or secondary progressive onset. An age older than 40 years and more than 3 periventricular lesions predicted a worse prognosis. Conclusions Cerebrospinal fluid analysis did not predict the time to disability milestones in relapsing-onset multiple sclerosis independently of age and imaging data.
•MACFIMS regression-based norms were established in French speaking healthy subjects•32.7% of persons with MS had cognitive impairment according to MACFIMS.•Learning and processing speed were the ...most affected cognitive functions.
The Minimal Assessment of Cognitive Function in Multiple sclerosis (MACFIMS) is an internationally recognised battery of neuropsychological tests for patients with multiple sclerosis (MS).
To establish regression-based norms for the MACFIMS in French-speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS).
136 PwMS, including 43 with relapsing-remitting MS, 46 with secondary progressive MS and 45 with primary progressive MS, as well as 276 HS were enrolled. Regression-based norms and validity were established for the seven tests of the MACIMS: the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), the French learning test (FLT) a French-adapted memory test (or the California Verbal Learning Test (CVLT) at re-testing), the Judgment of Line Orientation Test (JLO), the ‘épreuve de classement de cartes de Champagne’ (ECCC), a French adaptation of the DKEF-sorting test, the Brief Visuospatial Memory Test (BVMT-R) and the Controlled Oral Word Association Test (COWAT).
Regression-based norms of MACFIMS tests were established in the HS population. The MACFIMS battery was able to identify cognitive impairment (CI) (at least two abnormal tests in different domains) in 32.7% of PwMS. The domains with more frequent impairment were (in descending order): learning followed by IPS, delayed memory, verbal fluency and working memory.
This study established the regression-based norms for French subjects of the French adaptation of the MACFIMS and its validity in PwMS.
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