Remission of early persistent cladribine-induced neutropenia after filgrastim therapy in a patient with Relapsing - Remitting Multiple Sclerosis.

BACKGROUND: Cladribine tablets were recently approved for the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS), reducing B cells and T cells, followed by reconstitution of the adaptive immune system, with transient and mild effects on the innate one. Cladribine is also the standard first-line and subsequent treatment for Hairy-Cell Leukemia (HCL), frequently complicated by neutropenic fever. Recombinant human Granulocyte Colony-Stimulating Factor (G-CSF; Filgrastim) has been proved to reduce neutropenia by increasing neutrophil count. CASE REPORT: To the best of our knowledge, we report the first case of early and persistent high grade non febrile neutropenia after oral cladribine therapy in a 49-year-old RR-MS patient, successfully treated with Filgrastim. CONCLUSIONS: This report suggests that in selected cases, cladribine requires early monitoring of blood sample as it may be responsible for early neutropenia, requiring specific treatment.

The HLA-DRB1 risk alleles for multiple sclerosis are differentially expressed in blood cells of patients from Southern Italy.

HLA gene expression has an important role in the autoimmune disease predisposition. We investigated the mRNA expression profile of the risk alleles HLA-DRB1*15 and HLA-DRB1*13 in a cohort of subjects both multiple sclerosis (MS) patients and healthy controls. Moreover, we explored the expression of the allele HLA-DRB1*11 that is very frequent in our cohort from southern Italy. We found that the expression of MS-associated alleles in heterozygous MS patients was always higher than the nonassociated alleles. The differential risk allele expression occurred also in nonaffected subjects, though with a lower increment compared to MS patients.

Pragmatic abilities in multiple sclerosis: The contribution of the temporo-parietal junction.

Recent studies showed that multiple sclerosis (MS) patients might experience communicative deficits, specifically in pragmatics (i.e., the ability to integrate the context-dependent aspects of language). A crucial region for pragmatics is the temporo-parietal junction, in particular the so-called Geschwind's area (GA), which is involved in high-level language processes, including the comprehension of narratives, metaphor, and irony. We evaluated the relationship between pragmatic abilities, measured through the Assessment of Pragmatic Abilities and Cognitive Substrates (APACS) test, and the functional connectivity (FC) of the bilateral GAs, assessed through a seed-based analysis of Resting-State fMRI in patients with MS. A positive correlation was observed between APACS scores and the FC for both the right and the left GA and the paracingulate cortex. Our findings suggest that the brain FC for social communication involves connections extending over both hemispheres, including right and left GAs and right and left paracingulate cortex, possibly impaired in patients with MS. This study offers preliminary evidence for future researches enrolling also a control sample to explore the involvement of GA in pragmatics in neurological disorders as well as in healthy conditions.

Communication in Multiple Sclerosis: Pragmatic Deficit and its Relation with Cognition and Social Cognition.

OBJECTIVE: Cognitive functions have been largely investigated in multiple sclerosis. Less attention has been paid to social communication abilities, despite their presumptive affect on quality of life. We run the first comprehensive assessment of pragmatic skills in multiple sclerosis, evaluating also the relationship between pragmatics and other cognitive domains. METHODS: Forty-two multiple sclerosis patients and 42 controls were tested for pragmatic abilities, neuro-cognition, social cognition, depression, and fatigue. RESULTS: Patients performed poorly in most pragmatic tasks compared to controls. Globally, 55% of patients performed below the 5th percentile in the total pragmatic score. Notably, pragmatic skills did not differ between cognitively impaired and unimpaired patients. However, an association was found between pragmatics and verbal fluency, as measured in the Word List Generation. Finally, we observed an association of pragmatic abilities with social cognition, and a trend with psychosocial functioning. CONCLUSION: Overall, the study shows a diffuse pragmatic impairment in multiple sclerosis, not associated with the patient's global neuropsychological profile. By contrast, our findings suggest a close relation between pragmatics and specific cognitive aspects such as executive functions, and between pragmatics and social cognition. This study underlines the need of looking beyond classical cognitive performance, to consider underestimated communicative disturbances of high clinical relevance.

Immunometabolic profiling of T cells from patients with relapsing-remitting multiple sclerosis reveals an impairment in glycolysis and mitochondrial respiration.

BACKGROUND: Metabolic reprogramming is shaped to support specific cell functions since cellular metabolism controls the final outcome of immune response. Multiple sclerosis (MS) is an autoimmune disease resulting from loss of immune tolerance against central nervous system (CNS) myelin. Metabolic alterations of T cells occurring during MS are not yet well understood and their studies could have relevance in the comprehension of the pathogenetic events leading to loss of immune tolerance to self and to develop novel therapeutic strategies aimed at limiting MS progression. METHODS AND RESULTS: In this report, we observed that extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), indicators of glycolysis and oxidative phosphorylation, respectively, were impaired during T cell activation in naïve-to-treatment relapsing remitting (RR)MS patients when compared with healthy controls. These results were also corroborated at biochemical level by a reduced expression of the glycolitic enzymes aldolase, enolase 1, hexokinase I, and by reduction of Krebs cycle enzymes dihydrolipoamide-S-acetyl transferase (DLAT) and dihydrolipoamide-S-succinyl transferase (DLST). Treatment of RRMS patients with interferon beta-1a (IFN beta-1a) was able to restore T cell glycolysis and mitochondrial respiration as well as the amount of the metabolic enzymes to a level comparable to that of healthy controls. These changes associated with an up-regulation of the glucose transporter-1 (GLUT-1), a key element in intracellular transport of glucose. CONCLUSIONS: Our data suggest that T cells from RRMS patients display a reduced engagement of glycolysis and mitochondrial respiration, reversible upon IFN beta-1a treatment, thus suggesting an involvement of an altered metabolism in the pathogenesis of MS.

The effects of mechanical focal vibration on walking impairment in multiple sclerosis patients: A randomized, double-blinded vs placebo study.

BACKGROUND: Multiple Sclerosis is a heterogeneous disorders involving in early stage gait and balance. Together with immunomodulating therapies, rehabilitation had a crucial role in improving motor tasks and quality of life. Between the emerging techniques, Focal Vibrations (FV) could play a role, but they have been used in MS only to reduce muscle tone and fatigue alone or together with botulinum toxin. OBJECTIVE: To assess whether FV is effective on walking impairment in a cohort of MS patients. METHODS: We performed a single-centre randomized, double-blind, sham-controlled study to investigate efficacy of FV vs sham vibration in 20 RR MS patients. Ten patients received treatment with the active device and ten patients sham treatment. Demographical, clinical and gait instrumental data analysis have been collected for each patient at baseline (T0), after treatment (T1) and after three weeks of wash out (T2). RESULTS: Both groups were clinically and demographically comparable. Treated patients showed significant improvements during the first right step (FRS) (p = 0.007), average stride lenght (ASL) (p = 0.012), double support right (DSRT) (p = 0.016) and left (DSLT) (p = 0.003) time. Non-treated patients didn't show any significance for any dynamic variables. Moreover, on posturographic measurements we registered only a trend towards significance in swing area with eyes open (SAEO) (p = 0.087). We also found in treated group significant improvements in FRT (p = 0.018); BBS (p = 0.037) and FSS scales (p = 0.038) between T1 and T0. Lastly, we found a significant inverse correlation in the treated group between disease duration and percentage of improvement for DSLT (r = - 0.775; p = 0.014) in T1 vs T0 and percentage of improvement of FSS, with an inverse correlation with both disease duration (r = - 0.775; p = 0.014) and AGE (r = - 0.733, p = 0.025) in T1 vs T0CONCLUSION: Our results suggest a beneficial effect of FV on walking impairment in MS patients suffering from spasticity and/or postural instability, which partially lasted until follow up.