Luis Brieva

A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis. Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or ‘transitional’ forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months. The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed. Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months. We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

Expression of chemokine receptors in the different clinical forms of multiple sclerosis

Chemokines and their receptors are important in the trafficking of peripheral leukocytes into the central nervous system, a major event in the pathogenesis of multiple sclerosis (MS). Evidence based on clinical, pathological and magnetic resonance imaging grounds supports some divergence between forms of MS with relapses [relapsing-remitting (RR) and secondary progressive (SP)] and the primary progressive (PP) form. To elucidate whether different pathogenic mechanisms are involved in PPMS, we compared membrane expression of a group of CC and CXC chemokine receptors (CCR1, CCR5, CXCR3, CXCR4) in peripheral blood of 68 MS patients (25 PPMS, 23 SPMS and 20 RRMS) and 26 healthy controls. We found a significant increase in surface expression of CCR5 in CD4+, CD8+, CD19+ and CD14+ cells as well as an increased percentage of CXCR3 and CXCR4 in CD14+ cells in MS patients compared to controls. Increased levels of CXCL10 (IP-10) and CCL5 (RANTES) in cerebrospinal fluid were also observed in a subgroup of MS patients. These results support that chemokines and their receptors are involved in the pathogenesis of MS. However, a pattern of chemokine-chemokine receptor expression characteristic of each clinical form of the disease failed to be observed.

Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone

Background and objective Fatigue is one of the most limiting symptoms in multiple sclerosis (MS) and the mechanisms underlying its origin are poorly understood. Our aim was to test whether fatigue in MS is associated with endocrine markers. Methods We longitudinally studied 73 progressive MS patients. Fatigue was assessed at baseline and at 3, 6, 12 and 24 months using the Fatigue Severity Scale (FSS). Given the longitudinal design of our study, patients were labelled as sustained fatigued when FSS scores were ≤5.0 at all time points, and as non-fatigued when FSS scores were ≤5.0 at all time points. Serum levels of dehydroepiandrosterone (DHEA), its sulphated conjugate (DHEAS) and cortisol were measured at each time point. Results Twenty-nine patients scored >5.0 in the FSS at all time points, and 9 patients (12.3%) scored ≤5.0 at all time points. Mean baseline levels of DHEAS and DHEA were lower in MS patients with sustained fatigue when compared to patients without fatigue (P=0.01 and P=0.03 respectively). Analysis of DHEAS and DHEA over time showed significantly lower hormone levels in patients with fatigue [F(1,31)=6.14, P=0.019 for DHEAS; F(1,32)= 6.63, P=0.015 for DHEA]. Conclusions Fatigue in progressive MS could be related to low serum levels of DHEA and DHEAS. Our results suggest that these hormones should be considered as biological markers of fatigue in MS patients and that hormone replacement may thus be tested as an option to treat fatigue in MS patients.

Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism

Metabolomic and lipidomic analyses have been used for the profiling of neurodegenerative processes, both in targeted and untargeted approaches. In this work we have applied these techniques to the study of CSF samples of multiple sclerosis (MS) patients (n = 9), compared with samples of non‐MS individuals (n = 9) using mass‐spectrometry. We have used western‐blot and analyzed cell culture to confirm pathogenic pathways suggested by mass‐spectrometric measurements. The results of the untargeted approach of metabolomics and lipidomics suggest the existence of several metabolites and lipids discriminating both populations. Applying targeted lipidomic analyses focused to a pathogenic pathway in MS, oxidative stress, reveal that the lipid peroxidation marker 8‐iso‐prostaglandin F2α is increased in CSF from MS patients. Furthermore, as lipid peroxidation exerts its pathogenical effects through protein modification, we studied the incidence of protein lipoxidation, revealing specific increases in carboxymethylated, neuroketal and malondialdehyde‐mediated protein modifications in proteins of CSF from MS patients, despite the absence of their precursors glyoxal and methylglyoxal. Finally, we report that the level of neuroketal‐modified proteins correlated with a hitherto unknown increased amount of autoantibodies against lipid peroxidation‐modified proteins in CSF, without compensation by signaling induced by lipid peroxidation via peroxisome proliferator‐activated receptor γ (PPARγ). The results, despite the limitation of being obtained in a small population, strongly suggest that autoimmunity against in situ produced epitopes derived from lipid peroxidation can be a relevant pathogenic factor in MS.

The California, ABCD, and Unified ABCD2 Risk Scores and the Presence of Acute Ischemic Lesions on Diffusion-Weighted Imaging in TIA Patients

Background and Purpose— Some clinical models, like California ABCD and unified ABCD2 scores, are now available to predict the early risk of stroke after a TIA. Despite the transitivity of symptoms, DWI identified an area of acute brain ischemia in almost half of patients. It would be interesting to know how the presence of DWI abnormalities relates to clinical risk scores to plan other prognostic variables or to recommend the performance of DWI. Methods— We prospectively studied 135 consecutive TIA patients visited by the neurologists in our institution. All patients underwent DWI (3.8±1.7 days after symptoms onset). Clinical risk scores (California, ABCD, and ABCD2) were calculated prospectively for each patient. The identification of acute ischemic lesions (positive DWI) was related to the presence of clinical features and clinical risk scores. Results— DWI were positive in 67 (49.6%) patients. After Bonferroni adjustment, elevated ABCD, ABCD2, and California scores were not associated with a positive DWI. However, some clinical symptoms such as facial palsy and motor weakness were associated with a positive DWI (P<0.001). The logistic regression model identified only facial palsy as an independent predictor of acute ischemic lesions (odds ratio 6.26, 95% CI 2.49 to 15.71, P<0.001). Conclusion— Clinical symptoms such as motor impairment, but not clinical risk scores, were associated with a positive DWI. Performing a DWI may add prognostic information to clinical risk scales as a predictor of stroke recurrence after TIA in future large studies.

Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: what is the optimal cut-off for the three components?

For the Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), components of the Multiple Sclerosis Functional Composite (MSFC), cut-off points of 20% change have previously been defined as meaningful endpoints of functional decline. Recently, however, a 15% change of MSFC components was introduced. The objective of this study was to determine optimal cut-offs for all MSFC components to indicate clinical disease progression in a primary progressive (PP) multiple sclerosis (MS) population. T25FW, 9HPT and the Paced Auditory Serial Addition Test (PASAT) were performed in 161 patients with PPMS with a 2-year interval. Absolute and relative differences in test scores were calculated. For each cut-off point of relative change, proportions of patients who progressed (deterioration beyond cut-off value) and improved (improvement beyond cut-off value) were calculated. Further, we calculated the ratio of ‘improved’ versus ‘progressed’ patients. Line graphs were created indicating: percentage progressed patients, percentage improved patients, and ratio of improved versus progressed patients. The optimal cut-off was determined by searching the cut-off point with the lowest ratio of improved versus progressed patients, while at the same time capturing a substantial amount of progression. For both T25FW and 9HPT, the ratio between patients that improved and worsened clearly decreased between the cut-offs of 15% and 20%. For the PASAT, the ratio between patients improved and worsened was persistently poor. In conclusion, a cut-off of 20% for both T25FW and 9HPT has a better signal-to-noise ratio than lower values (e.g. 15%) and is therefore preferable for the assessment of disease progression. No satisfactory cut-off point for the PASAT could be determined.

Predictive value of ankle brachial index in patients with acute ischaemic stroke.

Background:  The ankle brachial index (ABI) is a known measure of lower‐limb peripheral artery disease (PAD), as well as a marker for other cardiovascular disease events.

The search for responsive clinical endpoints in primary progressive multiple sclerosis.

Objective To determine whether in primary progressive multiple sclerosis (PPMS) combining scores of Expanded Disability Status Scale (EDSS) with data from Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT) would produce a clinical endpoint that has a higher event rate than EDSS alone. Methods In a group of 161 PPMS patients, EDSS, T25FW, and 9HPT were performed at three time points over 2 years. We calculated how many patients showed clinically meaningful deterioration (or improvement) on individual and combined scales. We defined improvements on one scale with deterioration on the other as “opposing changes.” We investigated the possible effect of baseline disability on the definition of our endpoint by dividing the population into two subsets of patients determined by baseline EDSS level. Results On individual scales, event rates were highest on T25FW: 34% and 46% 1 year and 2 years after baseline. On a combination of two scales, at 1 year the event rate was highest on T25FW/9HPT (46%; with a high rate of opposing changes) and at 2 years on T25FW/EDSS (57%; with a lower rate of opposing changes). In both subsets, event rates were highest on T25FW and (at 2 years) on the combination of T25FW/EDSS. Conclusions T25FW has the highest event rate as a single scale, independent of baseline disability level. A term of 2 years turned out to be more meaningful to observe than 1 year. “Worsening on either T25FW or EDSS” is the most appropriate composite endpoint in this patient group.

Patterns of diffusion‐weighted magnetic resonance imaging associated with etiology improve the accuracy of prognosis after transient ischaemic attack

Objective:  Diffusion‐weighted magnetic resonance imaging (DWI) is a sensitive diagnostic tool for detecting acute ischaemic lesions in patients with transient ischaemic attacks (TIAs). The additional predictive value of DWI lesion patterns is not well known.

Decreased MMP-9 production in primary progressive multiple sclerosis patients

Background: An increase in MMP-9 levels has been found in relapsing-remitting (RR) multiple sclerosis (MS) showing correlation with magnetic resonance (MR) parameters mainly during relapses. However, data regarding primary progressive (PP) MS is scarce. Objectives: To determine both the pro and active forms of MMP-9 in PPMS and transitional progressive (TP) MS, RRMS and healthy controls (HC), and to assess the relationship between MMP-9 levels and clinical and radiological variables in PP/TPMS. Methods: 73 patients with PP/TPMS, 50 RRMS and 43 HC were studied. Levels of pro and active forms of MMP-9 in serum were measured with ELISA. EDSS and MSFC scores were recorded and T2- and T1-weighted MR scans were obtained at the time of blood sampling and one and two years later for PP/TP MS cases. Results: MMP-9 levels were 202.27 ng/ml for PP/TPMS, 242.20 ng/ml for RRMS and 274.49 ng/ml for HC. MMP-9 levels were significantly lower in PP/TPMS compared to RRMS(P-0.026) and HC (P- 0.001). No significant correlations were found between MMP-9 levels and clinical scores or radiological parameters. Conclusions: These results point to different regulatory mechanisms of MMP-9 production and/or activity between PP/TPMS and RRMS.