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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.

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.

Background Clinical trials have shown the therapeutic effect of fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RR-MS), but its influence on nervous conduction assessed by evoked potentials (EPs) has not been previously investigated. Methods EP data of 20 patients examined 12months prior to initiation of fingolimod ( t =−1), at treatment initiation ( t =0) and 1year later ( t =+1) were compared. Each EP (VEP, MEP, SEP) and EP sum score, a global evoked potential score as the sum score of the each EP score was evaluated and correlated with Expanded Disability Status Scale (EDSS). Results During pre-treatment period (1year) EDSS worsened while one year after fingolimod treatment EDSS remained stable. From t −1 to t 0 VEP, SEP, MEP and EP sum score worsened while from t 0 to t +1 VEP, SEP and EP sum score improved, and MEP score remain stable. VEP and SEP were related to EDSS at baseline ( t =−1), while MEP and total EP sum score were related to EDSS at all time points. Conclusion Fingolimod is able to improve visual and somatosensory evoked potential in RR-MS patients even if clinical disability scale remains stable. VEP and SEP could give eloquent information on pathway underweighted in EDSS. EPs are useful to evaluate fingolimod effects in clinical practice.

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.

Alemtuzumab is a monoclonal antibody targeting the CD52 antigen used in the treatment of relapsing-remitting multiple sclerosis (RRMS). CD52 is expressed by lymphocytes and monocytes but less by neutrophils and not by platelets. We present a case of a 38-year-old woman with RRMS who developed early neutropenia with thrombocytopenia after alemtuzumab infusion. She had no fever or symptoms of infection or purpura. After two weeks her haematological disorders spontaneously resolved. We reported the first case of neutropenia and thrombocytopenia as a possible event occurring after alemtuzumab infusion in MS patients, even if in a mild grade. So, we recommend to not underestimate these two conditions.

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 naive-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.

Background Spasticity in multiple sclerosis (MS) results from an imbalance of inputs from descending pathways to the spinal motor circuits, as well as from a damage of the corticospinal tract (CST). Objectives To assess CST impairment in MS patients with and without spasticity and to evaluate its evolution under Sativex® treatment. Methods Ten MS patients with spasticity ("cases") underwent clinical (EDSS, 9-hole Peg, Ashworth scale, Timed 25-Foot Walk, and NRS for spasticity), MRI (CST fractional anisotropy [FA]), and electrophysiological (central motor conduction time [CMCT] and H/M ratio) evaluations at baseline and after 12 months. We selected 20 MS patients without spasticity as control group at baseline. Results At baseline, cases showed a lower CST FA (0.492±0.045 vs 0.543±0.047; P=.01) and a higher CMCT (P=.001) compared to the control group. No correlations were found between clinical, electrophysiological, and MRI features. After 12 months, cases showed a decrease in non-prevalent degree of impairment (PDI) side FA (0.502±0.023 vs 0.516±0.033; P=.01) without differences for electrophysiological features compared to baseline. Treatment with Sativex® resulted in a reduction of NRS for spasticity (P=.01). Conclusions We confirm the presence of CST impairment in MS patients with spasticity. We did not identify structural/electrophysiological correlates that could explain Sativex® clinical effect.

Previous studies have reported an involvement of neuroactive steroids as neuroprotective and anti-inflammatory agents in neurological disorders such as multiple sclerosis (MS); an analysis of their profile during a specific clinical phase of MS is largely unknown. The pregnenolone (PREG), dehydroepiandrosterone (DHEA), and allopregnanolone (ALLO) profile was evaluated in cerebrospinal fluid (CSF) in relapsing-remitting multiple sclerosis (RR-MS) patients as well as those in patients affected by non-inflammatory neurological (control group I) and without neurological disorders (control group II). An increase of PREG and DHEA values was shown in CSF of male and female RR-MS patients compared to those observed in both control groups. The ALLO values were significantly lower in female RR-MS patients than those found in male RR-MS patients and in female without neurological disorder. During the clinical relapse, we observed female RR-MS patients showing significantly increased PREG values compared to female RR-MS patients in stable phase, while their ALLO values showed a significant decrease compared to male RR-MS patients of the same group. Male RR-MS patients with gadolinium-enhanced lesions showed PREG and DHEA values higher than those found in female RR-MS patients with gadolinium-enhanced lesions. Similary, male RR-MS patients with gadolinium-enhanced lesions showed PREG and DHEA values higher than male without gadolinium-enhanced lesions. Female RR-MS patients with gadolinium-enhanced lesions showed DHEA values higher than those found in female RR-MS patients with gadolinium-enhanced lesions. Male and female RR-MS patients with gadolinium-enhanced lesions showed ALLO values higher than those found in respective gender groups without gadolinium-enhanced lesions. ALLO values were lower in male than in female RR-MS patients without gadolinium-enhanced lesions. Considering the pharmacological properties of neuroactive steroids and the observation that neurological disorders influence their concentrations, these endogenous compounds may have an important role as prognostic factors of the disease and used as markers of MS activity such as relapses.

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 life quality. 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. Language: en

• Intracranial Mycobacterium avium complex (MAC) infection in immune-competent hosts is exceptional.

Dear Editor, Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system, and interferon beta-1a (IFN-β1a) is a valuable medication in the treatment of the relapsing-remitting form of MS (RR MS). Porphyria cutanea tarda (PCT), which is the most frequent type of porphyria, is the result of a catalytic deficiency of uroporphyrinogen decarboxylase. In sporadic PCT (sPCT), which represents 75% of cases, the deficiency is limited to the liver.1 Accumulated uroporphyrin and other highly carboxylated porphyrins, which are soluble, diffuse from the plasma into the upper dermis. The clinical picture reflects the phototoxic reaction that subsequently occurs in the upper dermis, in that lesions occur almost exclusively in light-exposed areas.2 The cutaneous findings include increased photosensitivity, skin fragility, blistering, erosions, and crusts.1 In this letter we describe new onset of sPCT in a patient with RR MS who was treated with IFN-β1a. In brief, a 33-year-old man without a family history of PCT was admitted to our department complaining of dizziness and diplopia of 3 weeks duration. Neuroimaging revealed several demyelinating lesions in the subcortical white matter and the periventricular regions. Within 4 months he presented with paresthesia and hyposthenia of the left arm, and repeat MRI revealed additional demyelinating lesions (Fig. 1A). The patient was diagnosed with MS according to McDonald criteria3 and was started on treatment with IFN-β1a, which was administered subcutaneously three times weekly. Fig. 1 A: MRI showing several demyelinating lesions. B: Skin lesions on the back of the patient's hands. In the course of his treatment, the patient exhibited no relevant neurological alterations; however, after 5 years he observed the development of skin lesions that were localized to the back of his hands, appearing as bullae up to 1 cm wide, and sometimes larger. There were also crusts, atrophic scars, and areas of hypopigmentation (Fig. 1B). He was diagnosed with dermatitis bullosa, for which he was prescribed prednisone at 25 mg/day, which had no effect. His levels of transaminases were elevated as follows: glutamic-oxaloacetic transaminase, 47 U/L [normal value (NV)