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Background: The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete., Methods: A total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up., Findings: A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio [OR] 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis., Interpretation: This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Multiple sclerosis (MS) is an autoimmune disease for which auto-antibodies fully validated as diagnostic and prognostic biomarkers are widely desired. Recently, an immunoreactivity against the inward rectifying potassium channel 4.1 (KIR4.1) has been reported in a large proportion of a group of MS patients, with amino acids 83-120 being the major epitope. Moreover, a strong correlation between anti-KIR4.1 83-120 and anti-full-length-protein auto-antibodies titer was reported. However, this finding received limited confirmation., Objective: Validation of the diagnostic potential of anti-KIR4.1 83-120 antibodies in 78 MS patients, 64 healthy blood donors, and 42 individuals with other neurological diseases., Methods: Analysis of anti-KIR4.1 83-120 antibodies by enzyme-linked immunosorbent assay (ELISA) using a mouse antiserum we produced as a new ELISA reliability control. Additionally, evaluation of reactivity against 293-T cells transiently transfected with full-length KIR4.1 by flow cytometry., Results: We found antibodies to KIR4.1 83-120 only in 13 out of 78 (16.6%) MS patients; among these, only 2 were positive for anti-full-length KIR4.1 antibodies., Conclusion: Employing a new reliability control and a new cytofluorometric assay, we cannot support anti-KIR4.1 83-120 auto-antibodies as a reliable biomarker in MS.

Introduction: Fatigue and sleep disorders are frequently reported in patients affected by Multiple Sclerosis (MS) but the causes and the relationship are not yet fully understood. This study aimed at evaluating their prevalence, at determining the relationships between clinical findings of MS and the occurrence of sleep disorders and at investigating the relations between sleep disorders and fatigue., Methods: One hundred and two MS patients were enrolled in the study. They were analyzed on both their clinical features (type of MS, disease duration, clinical severity, type of treatment, presence of spinal demyelinating lesions) and specific scales scores (Expanded Disability Status Scale, Modified Fatigue Impact Scale - MFIS, Self-Administered Anxiety Scale - SAS, Beck's Depression Inventory - BDI, Pittsburgh Sleep Quality Index - PSQI, Epworth Sleepiness Scale - ESS, and the Berlin's questionnaire for Obstruction Sleep Apnea Syndrome - OSAS)., Results: Patients with poor sleep quality are more frequently fatigued (p=0.001), have higher MFIS global scores (p<0.001), higher prevalence of RLS symptoms (p=0.049), and show higher scores at BDI (p=0.017) and SAS (p≤0.001). Conversely patients with fatigue show older age (p=0.005), higher prevalence of sleepiness (p=0.021), higher prevalence of RLS symptoms (p=0.030), higher prevalence of poor sleep quality (p<0.001) with higher PSQI scores (p<0.001), higher scores on the BDI (p<0.001) and SAS (p≤0.001)., Conclusion: This study shows that MS is associated with a high prevalence of sleep complaints, including subjectively poor sleep quality, excessive daytime sleepiness, RLS and symptoms of OSAS. Further, it demonstrated a strict relation between fatigue and sleep disorders. Finally, it underlines their relationship with anxiety and depression in MS patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Despite the existence of therapeutic guidelines, management of multiple sclerosis relapse remains heterogeneous. Optimisation of relapse outcome demands an improved understanding of the neurologist's therapeutic attitude towards relapse management, which is the aim of this study. Neurologists from 13 multiple sclerosis centres completed a questionnaire every time they assessed multiple sclerosis relapses. The questionnaire requested a guided description of the relapse's clinical characteristics and an indication of the prescribed therapy, supported with up to 3 out of 20 suggested reasons. Over 3 months, 368 questionnaires were collected. Median percentage (%) of 21 relapses resulting in a prescription was 88.9%. Corticosteroids represented the most frequent prescription. A short-course of high-dose intravenous methylprednisolone was the most used corticosteroid (73.7%). Treatment was administrated mainly in day case unit (80.0%) and at home (13.6%). A tapered therapy was prescribed to 28.8% of patients. Neurologists' therapeutic decisions were driven mainly by relapse severity (45.3%) and symptom evolution (24.2%). Our study confirms the therapeutic attitude of multiple sclerosis specialists in treating relapses with high-dose intravenous corticosteroids in a day hospital setting, with a tapering in a proportion of cases. The main reasons for prescription are relapse severity and symptom evolution.

Elevated anti-Epstein-Barr virus (EBV) antibody levels are present in serum of Multiple sclerosis (MS) patients but literature lacks of studies comparing anti-EBV antibody levels between MS and other neurological diseases. We evaluate anti-VCA IgG and IgM, anti-EBNA1 IgG, anti-Cytomegalovirus IgG and IgM titres in serum and cerebrospinal fluid (CSF) of 267 MS, 50 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and 88 Amyotrophic Lateral Sclerosis (ALS) patients. We found increased titres of anti-EBV-IgG in serum and CSF of MS subjects as compared to CIDP and ALS patients thus providing additional evidence for a possible involvement of EBV in MS., (Copyright 2010 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a T-cell autoimmune disease of the central nervous system (CNS). Predominance of women in autoimmune diseases suggests that sex hormones may play a role in disease susceptibility. A possible role for prolactin, a neuroendocrine peptide with powerful immunomodulatory properties, is suggested in MS. We describe the case of a 32-year-old man affected by relapsing-remitting MS who experienced the first MS clinical event during the development of a prolactin-secreting adenoma and the only two MS relapses during adenoma recurrence. Prolactin may have facilitated the inflammatory process and triggered MS clinical attacks, suggesting a role of prolactin in immunomodulation and therefore in autoimmune disease course.

The term Tourettism refers to Tourette Syndrome (TS)-like symptoms which appear secondary to a variety of both acquired and congenital neurological and neuropsychiatric disorders or following an exposure to several drugs. The association between Tourettism and Multiple Sclerosis (MS) is very rare. Only two cases of patients affected by MS who also showed a simple phonic tic and complex vocal tics respectively have been reported. The case here described reports of a 30 year-old woman affected by secondary-progressive MS who developed, 7 years after the onset of the disease, TS-like symptoms which were responsive to quetiapine. At that time her brain MRI, when compared with the previous scan, showed an increased lesion burden and an increased atrophy in the regions around Sylvian fissures. Considering recent findings on TS, the increased atrophy in these strategic brain regions could be responsible for the tics onset in our patient. At the same time, the diffuse involvement of the white matter and the progressive brain atrophy which we observed could have impaired the cortico-striato-thalamo-cortical circuits consistently implicated in the pathogenesis of TS. In conclusion, we can hypothesize that in our case Tourettism and MS could be considered causal related more than coincidentally associated.

Cerebral tumor and multiple sclerosis (MS) relapses can show overlapping clinical and magnetic resonance imaging features. In a previous study we observed in relapsing MS patients increased T-bet, pSTAT1, and pSTAT3 expressions in circulating mononuclear cells. During the data analysis we observed that T-bet, pSTAT1, and pSTAT3 expression was not increased in circulating mononuclear cells from a relapsing-remitting (RR)MS patient with recent onset of new neurological signs due to glioblastoma multiforme. In conclusion, our patient represents an exemplary case which suggests that T-bet, pSTAT1, and pSTAT3 expression in peripheral blood mononuclear cells (PBMCs) might be useful to differentiate MS relapses from other noninflammatory diseases.

Not all patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) develop clinically defined MS (CDMS). At first clinical event we observed increased production of IL17, IFNgamma and IL10 by peripheral blood mononuclear cells from patients with CIS that remained high in remission. In CD4+ T cells pSTAT3 expression was higher in patients who subsequently converted to CDMS than in patients who did not and controls. The persistency of high levels of pSTAT3 in circulating CD4+ T cells from CIS patients after the first clinical event may favor the early conversion to CDMS.

Multiple sclerosis (MS) and celiac disease (CD) are considered to be T-cell-mediated autoimmune diseases. We describe a woman affected by a relapsing-remitting demyelinating disease of the central nervous system and occult CD (MS-CD), who showed during neurologic exacerbations a strong increased expression of T-bet, the key transcription factor for the development of Th1 cells, in circulating T, B cells and monocytes. Conversely, no difference of T-bet expression was observed in B cells from relapsing-remitting MS patients, either in relapse or in remission, and in controls. In the MS-CD patient, the interaction between MS- and CD-related inflammatory processes may result in an amplification of Th1 immune response.

Despite the relatively frequent involvement of the basal ganglia and subthalamic nucleus by multiple sclerosis (MS) plaques, movement disorders (MD), other than tremor secondary to cerebellar or brainstem lesions, are uncommon clinical manifestations of MS. MD were present in 12 of 733 patients with MS (1.6%): three patients had parkinsonism, two blepharospasm, five hemifacial spasm, one hemidystonia, and one tourettism. MD in patients with MS are often secondary to demyelinating disease. Also in cases without response to steroid treatment and demyelinating lesions in critical regions, it is not possible to exclude that MD and MS are causally related.

We evaluated the spontaneous IL17, IFNgamma and IL10 production by peripheral blood mononuclear cells from patients affected by clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) both in acute phase and in remission, relapsing remitting MS (RRMS) both in relapse and in remission, not-relapsing secondary progressive MS (SPMS) and controls. We observed higher IL17 levels in CIS patients both in acute phase and in remission than in SPMS patients and controls. On the contrary no difference in IL17 production was observed among RRMS patients and CIS, SPMS patients and controls. IFNgamma levels were significantly higher in CIS patients in acute phase than in CIS and RRMS patients in remission, SPMS patients and controls. Moreover, we observed higher IFNgamma spontaneous production in relapsing RRMS patients than in remitting RRMS and SPMS patients and controls. IL10 levels were significantly higher in remitting CIS and in relapsing RRMS patients than in SPMS patients and controls. There was no difference in IFNgamma, IL10 and IL17 levels between SPMS patients and controls. Our data suggest that IL17 might play a crucial role mainly in the early phase of MS, while IFNgamma seems to be involved both in the early phase and in the following relapses of the disease.

Study Design: Retrospective examination., Objective: To define the clinical characteristics and response to therapy of spinal multiple sclerosis (MS)., Setting: Italy., Methods: Retrospective review was performed on 563 patients with clinical definite MS. Selection criteria were two or more spinal cord lesions in the presence of normal magnetic resonance imaging of the brain., Results: Spinal MS was diagnosed in 13 patients (2.3%) out of 563 with clinical definite MS. There were seven female and six male patients; nine had a relapsing-remitting (RR) and four, a primary progressive (PP) course. All patients were treated with immunosoppressive or immunomodulatory therapy. Mean disease duration in patients with RR-MS was 13.1+/-10.1 years with a mean age at onset of 29.5+/-14.3 years; the mean Expanded Disability Status Scale (EDSS) at the time of the study was 3.5+/-2.5 with a progression index of 0.28. Mean disease duration in patients with PP course was 7+/-6.2 years with a mean age at onset of 56.7+/-10.4 years; the mean EDSS at the time of the study was 6.2+/-2.0 with a progression index of 1.48., Conclusions: Patients with spinal RR-MS are characterised by an early disease onset with minimal or moderate disability progression; patients with spinal PP-MS show a late disease onset and more rapid disability progression. In our series of spinal MS patients, disability progression seems to be mainly due to the disease course and age at onset rather than to the site of lesion.

Antibodies against myelin oligodendrocyte antigens have been found in the immunoreactive brain lesions of Multiple Sclerosis (MS) patients. Recently it has been proposed that these antibodies can be used as a prognostic marker in the course of disease. However, the serum levels of these autoantibodies during different phases of disease activity or after an immunomodulatory therapy have been poorly investigated. In this study the serum levels of anti-myelin oligodendrocyte glycoprotein (MOG) (directed against the epitopes 1-26 and 15-40) and anti-myelin basic protein (MBP) antibodies were sequentially measured in the same MS patient either in relapse or remission phases. We found that MS patients in the relapse phase had higher serum anti-MOG (peptides 1-26 and 15-40) and anti-MBP antibody levels than controls. In addition, the levels of anti-MOG 1-26 were also elevated during the relapse as compared with the remission phase but no significant changes were found in the levels of anti-MOG 15-40 of anti-MBP antibodies. We also evaluated the effect of interferon-beta (beta) therapy on anti-myelin antibodies. 1-year of interferon-beta treatment did not induce any changes in the levels of anti-MOG and anti-MBP antibodies. In conclusion, these data indicate that the use of peripheral levels of autoantibodies against MOG and MBP as marker of multiple sclerosis might be complicated by the phase of disease activity and by the epitope of the MOG protein used.

The role of leptin was investigated in relapsing-remitting multiple sclerosis (MS). Control and MS patients showed comparable baseline serum leptin levels. During the first year of IFNbeta-1a treatment, leptin significantly decreased since 2 months after starting therapy in 11 patients who had no relapses. A significant decrease in IL12/IL10 ratio was observed in this group of patients only after 1 year of treatment. An increase of leptin was observed before the first clinical exacerbation in 13 relapsing patients. Leptin may play a pathogenic role in MS and can be a useful marker of disease activity and response to therapy.

Abstract: In pregnant women affected by multiple sclerosis (MS) we observed increased percentages of CD4+CD25+Foxp3+ T regulatory cells at the 1st and the 2nd trimester of gestation that was associated with a decreased T-bet expression in CD4+ T cells. In women showing clinical relapse and/or new lesions at MRI after delivery we found, a higher expression of T-bet, pSTAT1 and pSTAT3 in CD4+, CD8+ T cells and CD14+ cells, associated with an increase of IFNγ and IL17 production by PBMC at the 3rd trimester of gestation and after delivery. Our data suggest that the expansion of circulating CD4+CD25+Foxp3+ regulatory T cells and the lower expression of T-bet in CD4+ T cells may account for the decreased MS activity during pregnancy. The expression of T-bet, pSTAT1 and pSTAT3 in peripheral blood CD4+ and CD8+ T cells and monocytes could be useful to identify MS patients who will develop a relapse after delivery. [Copyright &y& Elsevier]

Pathogenic autoimmune cells are demonstrated to be able to produce neurotrophic factors during acute phase of multiple sclerosis (MS). In this study, we determined the production of various neurotrophins [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4)] and some pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)] by unstimulated peripheral blood mononuclear cells (PBMC) in 21 relapsing-remitting MS patients during different phases of disease (stable, relapse and post-relapse). During acute phase of disease, we detected a considerable increase of BDNF, TNF-α and IFN-γ production, while significantly higher levels of GDNF, NGF, NT3 and NT4 were found in post-relapse phase. When neurotrophin production was correlated with clinical outcome (complete or partial recovery from new symptoms), we found a significantly higher BDNF production in relapse phase followed by increased GDNF, NGF, NT3 and NT4 levels during post-relapse phase in subjects with complete remission only. During relapse phase, we detected a significant increase of pro-inflammatory cytokines, that was more evident in patients with partial recovery. The neuroprotective potential of immune cells seems to be inversely correlated with disease duration and with the age of patients. [ABSTRACT FROM AUTHOR]