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Abstract Background Baló’s Concentric Sclerosis (BCS) is a rare heterogeneous demyelinating disease with a variety of phenotypes on Magnetic Resonance Imaging (MRI). Existing literature lacks data especially on the therapeutic approach of the disease which we intended to elucidate by means of suggesting a new possible BCS classification and introducing different therapeutic concepts based on each BCS-subgroup characteristics. Methods We present a retrospective study of eight treated patients with BCS-type lesions, emphasizing on MRI characteristics and differences on therapeutic maneuvers. Results Data analysis showed: at disease onset the BCS-type lesion was tumefactive (size ≥2 cm) in 6 patients, with a mean size of 2.7 cm (± 0.80 SD); a coexistence of MS-like plaques on brain MRI was identified in 7 patients of our cohort. The mean age was 26.3 years (±7.3 SD) at disease onset and the mean follow-up period was 56.8 months (range 9–132 months). According to radiological characteristics and response to therapies, we further categorized them into 3 subgroups: a) Group-1; BCS with or without coexisting nonspecific white matter lesions; poor response to intravenous methylprednisolone (IVMP); treated with high doses of immunosuppressive agents (4 patients), b) Group-2; BCS with typical MS lesions; good response to IVMP; treated with MS-disease modifying therapies (2 patients), c) Group-3; BCS with typical MS lesions; poor response to IVMP; treated with rituximab (2 patients). Conclusions Our study introduces a new insight regarding the categorization of BCS into three subgroups depending on radiological features at onset and during the course of the disease, in combination with the response to different immunotherapies. Immunosuppressive agents such as cyclophosphamide are usually effective in BCS. However, therapeutic alternatives like anti-CD20 monoclonal antibodies or more classical disease-modifying MS therapies can be considered when BCS has also mixed lesions similar to MS. Future studies with a larger sample size are necessary to further establish these findings, thus leading to better treatment algorithms and improved clinical outcomes.

Abstract Background Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to β-interferon. It acts against CD52, leading primarily to lymphopenia. Recent data have shown that mild neutropenia is observed in 16% of treated MS-patients whereas severe neutropenia occurred in 0.6%. Case presentation Herein, we present the case of a 34-year-old woman with relapsing-remitting MS, with a history of treatment with glatiramer acetate and natalizumab, who subsequently received Alemtuzumab (12 mg / 24 h × 5 days). 70-days after the last Alemtuzumab administration, the patient displayed neutropenia (500 neutrophils/μL) with virtual absence of B-cells (0.6% of total lymphocytes), low values of CD4-T-cells (6.6%) and predominance of CD8-T-cells (48%) and NK-cells (47%); while large granular lymphocytes (LGL) predominated in the blood-smear examination. Due to prolonged neutropenia (5-days) the patient was placed on low-dose corticosteroids leading to sustained remission. Conclusion This is the first case of a patient with relapsing-remitting MS with neutropenia two months post-Alemtuzumab, with simultaneous presence of LGL cells in the blood and a robust therapeutic response to prednisolone. We recommend testing with a complete blood count every 15 days in the first 3 months after the 1st Alemtuzumab administration and searching for large granular lymphocytes cell expansion on microscopic examination of the peripheral blood if neutropenia develops.

A 47-year-old female patient with multiple sclerosis (MS) developed symptomatic intermittent 2nd degree atrioventricular block (AVB) of five-hour duration, five hours after the first two doses of fingolimod, that resolved completely. Frequency domain analysis of heart rate variability (HRV) revealed increased parasympathetic activity and decreased sympathetic tone, while modified Ewing tests were suggestive of impaired cardiac sympathetic function. We hypothesize that expression of this particular arrhythmia might be related to autonomic nervous system (ANS) dysfunction due to demyelinating lesions in the upper thoracic spinal cord, possibly augmented by the parasympathetic effect of the drug.

Tumor necrosis factor antagonists (anti-TNFa) are an established therapeutic option for several autoimmune and inflammatory bowel diseases. Despite their clinical effectiveness, neurological adverse events have been reported and literature data suggest a potential role of anti-TNFa in the induction of demyelination of the CNS. We present four patients treated with anti-TNFa who developed symptoms suggestive of CNS demyelination. The first patient, a 17-year-old male who received etanercept for psoriatic arthritis for eight months, presented with dysesthesias up to T4 level. The second patient, a 30-year-old male treated with adalimumab for three years due to ankylosing spondylitis, presented with right unilateral tinnitus. The third case, a 47-year-old female, received etanercept for four years because of psoriatic arthritis and developed persistent headache and left-sided face and head numbness. Finally, the fourth patient, a 57-years-old female treated with etanercept for six years due to ankylosing spondylitis, presented with difficulty in speech, swallowing, and ptosis of the right corner of the mouth. In all cases, brain MRI showed lesions suggestive of demyelination, while positive oligoclonal bands were detected in the CSF. Anti-TNFa treatments were discontinued and patients showed clinical improvement with pulsed intravenous corticosteroid therapy. CNS demyelination following anti-TNFa treatment represents a relatively rare but potential serious complication. Close follow-up and MRI monitoring of these patients is mandatory to elucidate whether the clinical manifestations represent adverse events occurring during anti-TNFa therapy or a first demyelinating episode.

Aquaporins (AQPs; AQP0-AQP12) are water channels expressed in many and diverse cell types, participating in various functions of cells, tissues, and systems, including the central nervous system (CNS). AQP dysfunction and autoimmunity to AQPs are implicated in several diseases. The best-known example of autoimmunity against AQPs concerns the antibodies to AQP4 which are involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathy, causing also CNS demyelination. The present review focuses on the discovery and the potential role of antibodies against AQP1 in the CNS, and their potential involvement in the pathophysiology of NMOSD. We describe (a) the several techniques developed for the detection of the AQP1-antibodies, with emphasis on methods that specifically identify antibodies targeting the extracellular domain of AQP1, i.e., those of potential pathogenic role, and (b) the available evidence supporting the pathogenic relevance of AQP1-antibodies in the NMOSD phenotype.

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vakrakou, Karachaliou, Chroni, Zouvelou, Tzanetakos, Salakou, Papadopoulou, Tzartos, Voumvourakis, Kilidireas, Giannopoulos, Tsivgoulis and Tzartos.)

Proton magnetic resonance spectroscopy ( 1 H-MRS) is an advanced method of examining metabolic profiles. The present study aimed to assess in vivo metabolite levels in areas of normal-appearing grey (thalamus) and white matter (centrum semiovale) using 1 H-MRS in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis and compare them to healthy controls (HCs). Data from 35 patients with CIS (CIS group), of which 23 were untreated (CIS-untreated group) and 12 were treated (CIS-treated group) with disease-modifying-therapies (DMTs) at the time of 1 H-MRS, and from 28 age- and sex-matched HCs were collected using a 3.0 T MRI and single-voxel 1 H-MRS (point resolved spectroscopy sequence; repetition time, 2,000 msec; time to echo, 35 msec). Concentrations and ratios of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline (tCho), myoinositol, glutamate (Glu), glutamine (Gln), Glu + Gln (Glx) and glutathione (Glth) were estimated in the thalamic-voxel (th) and centrum semiovale-voxel (cs). For the CIS group, the median duration from the first clinical attack to 1 H-MRS was 102 days (interquartile range, 89.5.-131.5). Compared with HCs, significantly lower Glx(cs) (P=0.014) and ratios of tCho/tCr(th) (P=0.026), Glu/tCr(cs) (P=0.040), Glx/tCr(cs) (P=0.004), Glx/tNAA(th) (P=0.043) and Glx/tNAA(cs) (P=0.015) were observed in the CIS group. No differences in tNAA levels were observed between the CIS and the HC groups; however, tNAA(cs) was higher in the CIS-treated than in the CIS-untreated group (P=0.028). Compared with those in HC group, decreased Glu(cs) (P=0.019) and Glx(cs) levels (P=0.014) and lower ratios for tCho/tCr(th) (P=0.015), Gln/tCr(th) (P=0.004), Glu/tCr(cs) (P=0.021), Glx/tCr(th) (P=0.041), Glx/tCr(cs) (P=0.003), Glx/tNAA(th) (P=0.030) and Glx/tNAA(cs) (P=0.015) were found in the CIS-untreated group. The present findings showed alterations in the normal-appearing grey and white matter of patients with CIS; moreover, the present results suggested an early indirect treatment effect of DMTs on the brain metabolic profile of these patients., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Tzanetakos et al.)

Current understanding of Multiple Sclerosis (MS) pathophysiology implicates perturbations in adaptive cellular immune responses, predominantly T cells, in Relapsing-Remitting forms (RRMS). Nevertheless, from a clinical perspective MS is a heterogeneous disease reflecting the heterogeneity of involved biological systems. This complexity requires advanced analysis tools at the single-cell level to discover biomarkers for better patient-group stratification. We designed a novel 44-parameter mass cytometry panel to interrogate predominantly the role of effector and regulatory subpopulations of peripheral blood myeloid subsets along with B and T-cells (excluding granulocytes) in MS, assessing three different patient cohorts: RRMS, PPMS (Primary Progressive) and Tumefactive MS patients (TMS) (n=10, 8, 14 respectively). We further subgrouped our cohort into inactive or active disease stages to capture the early underlying events in disease pathophysiology. Peripheral blood analysis showed that TMS cases belonged to the spectrum of RRMS, whereas PPMS cases displayed different features. In particular, TMS patients during a relapse stage were characterized by a specific subset of CD11c+CD14+ CD33+, CD192+, CD172+-myeloid cells with an alternative phenotype of monocyte-derived macrophages (high arginase-1, CD38, HLA-DR-low and endogenous TNF-a production). Moreover, TMS patients in relapse displayed a selective CD4 T-cell lymphopenia of cells with a Th2-like polarised phenotype. PPMS patients did not display substantial differences from healthy controls, apart from a trend toward higher expansion of NK cell subsets. Importantly, we found that myeloid cell populations are reshaped under effective disease-modifying therapy predominantly with glatiramer acetate and to a lesser extent with anti-CD20, suggesting that the identified cell signature represents a specific therapeutic target in TMS. The expanded myeloid signature in TMS patients was also confirmed by flow cytometry. Serum neurofilament light-chain levels confirmed the correlation of this myeloid cell signature with indices of axonal injury. More in-depth analysis of myeloid subsets revealed an increase of a subset of highly cytolytic and terminally differentiated NK cells in PPMS patients with leptomeningeal enhancement (active-PPMS), compared to those without (inactive-PPMS). We have identified previously uncharacterized subsets of circulating myeloid cells and shown them to correlate with distinct disease forms of MS as well as with specific disease states (relapse/remission)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vakrakou, Paschalidis, Pavlos, Giannouli, Karathanasis, Tsipota, Velonakis, Stadelmann-Nessler, Evangelopoulos, Stefanis and Kilidireas.)

Introduction: Multiple sclerosis (MS) is a highly heterogeneous inflammatory disease of the central nervous system. Patient-reported outcomes (PROs) in a real-world clinical setting can provide detailed information about MS from the patient's perspective. PROs were used here to assess quality of life (QoL), treatment satisfaction, clinical efficacy, and safety outcomes in a Greek cohort of relapsing remitting MS (RRMS) patients treated with oral teriflunomide (14 mg/day)., Methods: AURELIO was a 2-year, prospective, observational study whose QoL primary endpoint was assessed with the Multiple Sclerosis Impact Scale (MSIS-29). Secondary endpoints included analyses of Patient Determined Disease Steps (PDDS), Treatment Satisfaction Questionnaire for Medication (TSQM), Expanded Disability Status Scale (EDSS), annualized relapse rate (ARR), adherence, and safety outcomes., Results: AURELIO enrolled 282 patients (62.8% female; mean age 44.8 [SD ± 11] years; EDSS 2.0 [SD ± 1.6]; 44.6% treatment-naïve), with 212 patients (75%) remaining on treatment at study end. MSIS-29 total scores remained stable, while the MSIS-29 psychological scale showed significant improvement (p = 0.0015) at 2 years vs. baseline. TSQM scores at 2 years showed significant improvements in effectiveness (+ 6.6, p = 0.0001), convenience (+ 1.9, p = 0.0256), and global satisfaction (+ 8.1, p = 0.0001) vs. baseline. Disease progression was stable as indicated by non-significant changes in PDDS and EDSS vs. baseline. The ARR was low at 0.065, with a slightly higher ARR in previously treated (0.070) vs. naïve patients (0.058). Adherence was high at > 90%. Overall, 91 patients (32.3%) in the study reported a total of 215 safety events (32 serious, of which 21 were classified as mild-moderate). No new safety signals were observed., Conclusions: These data highlight the importance of PROs to facilitate personalized treatment strategies in MS. In line with other teriflunomide studies, AURELIO showed stable QoL, efficacy and safety outcomes, and good treatment satisfaction both in treatment-naïve and previously treated patients in this Greek cohort of patients with RRMS., (© 2022. The Author(s).)

Objective: While multiple sclerosis (MS) is considered the cornerstone of autoimmune demyelinating CNS disorders, systemic autoimmune diseases (SADs) are important MS mimickers. We sought to explore whether distinct clinical, laboratory, and imaging characteristics along with quantitation of peripheral blood type I interferon (IFN) activity could aid in differentiating between them. Methods: A total of 193 consecutive patients with imaging features suggesting the presence of CNS demyelinating disease with or without relevant clinical manifestations underwent full clinical, laboratory, and imaging evaluation, including testing for specific antibodies against 15 cellular antigens. Expression analysis of type I IFN-inducible genes (MX-1, IFIT-1, and IFI44) was performed by real-time PCR, and a type I IFN score, reflecting type I IFN peripheral activity, was calculated. After joint neurological/rheumatological evaluation and 1 year of follow-up, patients were classified into MS spectrum and CNS autoimmune disorders. Results: While 66.3% (n = 128) of the patients were diagnosed with MS spectrum disorders (predominantly relapsing-remitting MS), 24.9% (n = 48) were included in the CNS autoimmune group, and out of those, one-fourth met the criteria for SAD (6.7% of the cohort, n = 13); the rest (18.1% of the cohort, n = 35), despite showing evidence of systemic autoimmunity, did not fulfill SAD criteria and comprised the "demyelinating disease with autoimmune features" (DAF) subgroup. Compared to the MS spectrum, CNS autoimmune patients were older, more frequently females, with increased rates of hypertension/hyperlipidemia, family history of autoimmunity, cortical dysfunction, anti-nuclear antibody titers ≥1/320, anticardiolipin IgM positivity, and atypical for MS magnetic resonance imaging lesions. Conversely, lower rates of infratentorial and callosal MRI lesions, CSF T2 oligoclonal bands, and IgG-index positivity were observed in CNS autoimmune patients. Patients fulfilling SAD criteria, but not the DAF group, had significantly higher peripheral blood type I IFN scores at baseline compared to MS spectrum [median (IQR)]: 50.18 (152.50) vs. -0.64 (6.75), p -value: 0.0001. Conclusion: Our study suggests that underlying systemic autoimmunity is not uncommon in patients evaluated for possible CNS demyelination. Distinct clinical, imaging and laboratory characteristics can aid in early differentiation between MS and CNS-involving systemic autoimmunity allowing for optimal therapeutic strategies. Activated type I IFN pathway could represent a key mediator among MS-like-presenting SADs and therefore a potential therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Karathanasis, Rapti, Nezos, Skarlis, Kilidireas, Mavragani and Evangelopoulos.)

Tumefactive demyelinating lesions (TDL) represent a diagnostic dilemma for clinicians, and in rare atypical cases a collaboration of a neuroradiologist, a neurologist, and a neuropathologist is warranted for accurate diagnosis. Recent advances in neuropathology have shown that TDL represent an umbrella under which many different diagnostic entities can be responsible. TDL can emerge not only as part of the spectrum of classic multiple sclerosis (MS) but also can represent an idiopathic monophasic disease, a relapsing disease with recurrent TDL, or could be part of the myelin oligodendrocyte glycoprotein (MOG)- and aquaporin-4 (AQP4)-associated disease. TDL can appear during the MS disease course, and increasingly cases arise showing an association with specific drug interventions. Although TDL share common features with classic MS lesions, they display some unique features, such as extensive and widespread demyelination, massive and intense parenchymal infiltration by macrophages along with lymphocytes (mainly T but also B cells), dystrophic changes in astrocytes, and the presence of Creutzfeldt cells. This article reviews the existent literature regarding the neuropathological findings of tumefactive demyelination in various disease processes to better facilitate the identification of disease signatures. Recent developments in immunopathology of central nervous system disease suggest that specific pathological immune features (type of demyelination, infiltrating cell type distribution, specific astrocyte pathology and complement deposition) can differentiate tumefactive lesions arising as part of MS, MOG-associated disease, and AQP4 antibody-positive neuromyelitis optica spectrum disorder. Lessons from immunopathology will help us not only stratify these lesions in disease entities but also to better organize treatment strategies. Improved advances in tissue biomarkers should pave the way for prompt and accurate diagnosis of TDL leading to better outcomes for patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vakrakou, Brinia, Svolaki, Argyrakos, Stefanis and Kilidireas.)

Aims: Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible therapeutic choices in patients with tumefactive demyelinating lesions (TDLs)., Methods: A retrospective analysis of 50 patients with at least one TDL was performed at an academic neurology center (2008-2020)., Results: Our cohort comprised mostly women (33/50) with a mean age of 38 years at TDL onset. The mean follow-up time was 76 months. The mean Expanded Disability Status Scale score at TDL onset and at the latest neurological evaluation was 3.7 and 2.3, respectively. We subcategorized the patients into seven groups based mainly on the clinical/radiological findings and disease course. Group A included patients presenting with a Marburg-like TDL ( n  = 4). Groups B and C comprised patients presenting with monophasic ( n  = 7) and recurrent TDLs ( n  = 12), respectively. Multiple sclerosis (MS) patients who subsequently developed TDL ( n  = 16) during the disease course were categorized as Group D. Group E comprised patients who initially presented with TDL and subsequently developed a classical relapsing-remitting MS without further evidence of TDL ( n  = 5). Groups F ( n  = 2) and G ( n  = 4) involved MS patients who developed TDL during drug initiation (natalizumab, fingolimod) and cessation (interferon, fingolimod), respectively. Regarding long-term treatments applied after corticosteroid administration in the acute phase, B-cell-directed therapies were shown to be highly effective especially in cases with recurrent TDLs. Cyclophosphamide was spared for more aggressive disease indicated by a poor response to corticosteroids and plasma exchange failure., Conclusion: Tumefactive central nervous system demyelination is an heterogenous disease; its stratification into distinct groups according to different phenotypes can establish more efficient treatment strategies, thus improving clinical outcomes in the future., Competing Interests: Conflict of interest statement: AGV, GV, PT, EG, AD, EP, LS has nothing to disclose. DT has received research grants and lecture fees from Sanofi Genzyme, Biogen, Teva, and Novartis. JST has shares in the research and diagnostic laboratory of Tzartos NeuroDiagnostics. He has also received travel grants from Genzyme, Genesis Pharma, Teva, and Novartis and advisory boards from Genesis Pharma, Novartis, and Teva. MA has received research grants from Biogen, Merck-Serono, Novartis, Teva, Bayer, and Genzyme, as well as lecture-fees from Novartis, Teva, Biogen, and Genzyme. EA has received research grants from Biogen, Merck-Serono, Novartis, and Sanofi Aventis, as well as lecture-fees from Teva. GK has received research grants from Genesis Pharma and Teva, consultation fees, advisory board remuneration and honoraria from Genzyme, Genesis Pharma, Teva, and Novartis. MEE has received travel grants and consulting fees from Biogen, Novartis, Teva, Genzyme, and Merk. CK has received grants and honoraria from: Bayer, Biogen, Genesis Pharma, Merck-Serono, Novartis, Sanofi Genzyme, Teva., (© The Author(s), 2021.)

Background: Baló's Concentric Sclerosis (BCS) is a rare heterogeneous demyelinating disease with a variety of phenotypes on Magnetic Resonance Imaging (MRI). Existing literature lacks data especially on the therapeutic approach of the disease which we intended to elucidate by means of suggesting a new possible BCS classification and introducing different therapeutic concepts based on each BCS-subgroup characteristics., Methods: We present a retrospective study of eight treated patients with BCS-type lesions, emphasizing on MRI characteristics and differences on therapeutic maneuvers., Results: Data analysis showed: at disease onset the BCS-type lesion was tumefactive (size ≥2 cm) in 6 patients, with a mean size of 2.7 cm (± 0.80 SD); a coexistence of MS-like plaques on brain MRI was identified in 7 patients of our cohort. The mean age was 26.3 years (±7.3 SD) at disease onset and the mean follow-up period was 56.8 months (range 9-132 months). According to radiological characteristics and response to therapies, we further categorized them into 3 subgroups: a) Group-1; BCS with or without coexisting nonspecific white matter lesions; poor response to intravenous methylprednisolone (IVMP); treated with high doses of immunosuppressive agents (4 patients), b) Group-2; BCS with typical MS lesions; good response to IVMP; treated with MS-disease modifying therapies (2 patients), c) Group-3; BCS with typical MS lesions; poor response to IVMP; treated with rituximab (2 patients)., Conclusions: Our study introduces a new insight regarding the categorization of BCS into three subgroups depending on radiological features at onset and during the course of the disease, in combination with the response to different immunotherapies. Immunosuppressive agents such as cyclophosphamide are usually effective in BCS. However, therapeutic alternatives like anti-CD20 monoclonal antibodies or more classical disease-modifying MS therapies can be considered when BCS has also mixed lesions similar to MS. Future studies with a larger sample size are necessary to further establish these findings, thus leading to better treatment algorithms and improved clinical outcomes.

Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features., (Copyright © 2020 Vakrakou, Tzanetakos, Argyrakos, Koutsis, Evangelopoulos, Andreadou, Anagnostouli, Breza, Tzartos, Gialafos, Dimitrakopoulos, Velonakis, Toulas, Stefanis and Kilidireas.)

Objective: Despite frequent use of fingolimod (FTY) and dimethyl fumarate (DMF), studies comparing clinical efficacy and withdrawal rates of DMF and FTY concerning different pretreatment situations are rare. The aim of our study was to compare relapse occurrence and withdrawal rates of DMF and FTY in different pretreatment situations., Methods: Patients from 4 European centers were retrospectively identified and followed until the 1st relapse after treatment start or if no relapse occurred for a maximum of 2 years. Cox regression analyses adjusted for relapsing-remitting MS (RRMS) disease duration, sex, and region were performed for the following pretreatment situations: treatment naive or injectables or DMF/FTY or natalizumab., Results: Seven hundred thirty-two patients with RRMS (female/male: 2.4:1.0; DMF n = 409, FTY n = 323) were analyzed. Compared with FTY-treated patients, DMF-treated patients discontinued treatment more frequently mainly because of side effects (DMF/FTY: 29.3%/20.7%). Clinical relapses occurred in 24.5% of the patients within 24 months. Survival analysis demonstrated that compared with FTY treatment, DMF treatment was associated with an adjusted hazard ratio (aHR) for occurrence of relapse of 1.9 (95% CI 1.4-2.6, p < 0.001, n = 732). Stratification into pretreatment groups unmasked a higher relapse risk in DMF patients pretreated with natalizumab (aHR [95% CI] 4.5 [1.9-10.8], p = 0.001, n = 122) or to a lesser extend also in treatment-naive patients (aHR [95% CI] 1.9 [1.01-3.6], p = 0.045, n = 230). No differences were observed in patients pretreated with injectables or the respective other oral drug (injectables: p > 0.05, n = 341; other oral: p > 0.05, n = 39)., Conclusions: DMF treatment was associated with higher clinical disease activity compared with FTY treatment. A subgroup analysis suggested beneficial effects of FTY in treatment-naive and patients pretreated with natalizumab., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to β-interferon. It acts against CD52, leading primarily to lymphopenia. Recent data have shown that mild neutropenia is observed in 16% of treated MS-patients whereas severe neutropenia occurred in 0.6%., Case Presentation: Herein, we present the case of a 34-year-old woman with relapsing-remitting MS, with a history of treatment with glatiramer acetate and natalizumab, who subsequently received Alemtuzumab (12 mg / 24 h × 5 days). 70-days after the last Alemtuzumab administration, the patient displayed neutropenia (500 neutrophils/μL) with virtual absence of B-cells (0.6% of total lymphocytes), low values of CD4-T-cells (6.6%) and predominance of CD8-T-cells (48%) and NK-cells (47%); while large granular lymphocytes (LGL) predominated in the blood-smear examination. Due to prolonged neutropenia (5-days) the patient was placed on low-dose corticosteroids leading to sustained remission., Conclusion: This is the first case of a patient with relapsing-remitting MS with neutropenia two months post-Alemtuzumab, with simultaneous presence of LGL cells in the blood and a robust therapeutic response to prednisolone. We recommend testing with a complete blood count every 15 days in the first 3 months after the 1st Alemtuzumab administration and searching for large granular lymphocytes cell expansion on microscopic examination of the peripheral blood if neutropenia develops.

Background: Although Fingolimod (FGD) and Natalizumab (NTZ) appear to be effective in relapsing-remitting multiple sclerosis (RRMS), they have never been directly compared in a randomized clinical trial (RCT)., Methods and Findings: We evaluated the comparative efficacy of FGD vs. NTZ using a meta-analytical approach. Data from placebo-controlled RCTs was used for indirect comparisons and observational data was utilized for head-to-head comparisons. We identified 3 RCTs (2498 patients) and 5 observational studies (2576 patients). NTZ was associated with a greater reduction in the 2-year annualized relapse rate (ARR; SMDindirect = -0.24;95% CI: from -0.44 to -0.04; p = 0.005) and with the probability of no disease activity at 2 years (ORindirect:1.82, 95% CI: from 1.05 to 3.15) compared to FGD, while no differences between the two therapies were found in the proportion of patients who remained relapse-free (ORindirect = 1.20;95% CI: from 0.84 to 1.71) and those with disability progression (ORindirect = 0.76;95% CI: from 0.48 to 1.21) at 2 years. In the analysis of observational data, we found no significant differences between NTZ and FGD in the 2-year ARR (SMD = -0.05; 95% CI: from -0.26 to 0.16), and 2-year disability progression (OR:1.08;95% CI: from 0.77 to 1.52). However, NTZ-treated patients were more likely to remain relapse-free at 2-years compared to FGD (OR: 2.19;95% CI: from 1.15 to 4.18; p = z0.020)., Conclusions: Indirect analyses of RCT data and head-to-head comparisons of observational findings indicate that NTZ may be more effective than FGD in terms of disease activity reduction in patients with RRMS. However, head-to-head RCTs are required to independently confirm this preliminary observation., Competing Interests: Dr. Tsivgoulis has received research support (not related to this project) by Teva Pharmaceutical Hellas, Genesis Pharma, Merck Serono and Novartis Hellas. Dr. Grigoriadis has received research support (not related to this project) by Biogen Idec, Novartis, TEVA, Merck Serono, and Genesis Pharma. Dr. Dardiotis has received research support (not related to this project) from Novartis Hellas SA, Genesis Pharma, Bayer Hellas AG, Genzyme, Teva and Merck-Serono. Dr. Dardiotis has also received research support (not related to this project) by Novartis. Dr. Papathanasopoulos has received research support (not related to this project) by Biogen Idec, Novartis, TEVA, Merck Serono, and Genesis Pharma. Dr. Voumvourakis has received research support (not related to this project) by Teva Pharmaceutical Hellas, Merck Serono, Genzyme, Genesis Pharma and Novartis Hellas. All authors have no other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Capecitabine is a well tolerated and safe 5-fluorouracil agent for adjuvant, neoadjuvant chemotherapy or metastatic cases. Neurological side effects require discontinuation of chemotherapy. We report this unique case of a 50-year-old female, who presented an isolated episode of dysarthria and ataxia under bevacizumab, capecitabine, and oxaliplatin treatment due to reversible multifocal leukoencephalopathy that did not recur after readministration of chemotherapy.

Importance: A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS., Methods: We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates., Results: DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66-0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as "first" and "second" line RRMS therapies [(RR = 0.72, 95% CI = 0.65-0.80) vs. (RR = 0.72, 95% = 0.57-0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64-0.87) vs. RR = 0.74 (95% CI = 0.66-0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5-20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies., Conclusions: Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as "first" or "second" line therapies. Attrition bias needs to be taken into account in the interpretation of these findings.

Objectives: Brain atrophy is associated with cognitive deficits in patients with clinically isolated syndrome (CIS) and can predict conversion to clinical definite multiple sclerosis. The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMDs) on brain atrophy in patients with CIS., Methods: Eligible placebo-control randomized clinical trials of patients with CIS that had reported changes in brain volume during the study period were identified by searching the MEDLINE, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. This meta-analysis adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses., Results: Three eligible studies were identified, comprising 1362 patients. The mean percentage change in brain volume was found to be significantly lower in DMD-treated patients versus placebo-treated subgroups (standardized mean difference [SMD]: = -0.13, 95% confidence interval [CI]: -0.25, 0.01; p = 0.04). In the subgroup analysis of the two studies that provided data on brain-volume changes for the first (0-12 months) and second (13-24 months) year of treatment, DMD attenuated brain-volume loss in comparison with placebo during the second year (SMD = -0.25; 95% CI: -0.43, -0.07; p < 0.001), but not during the first year of treatment (SMD = -0.01; 95% CI: -0.27, 0.24; p = 0.93). No evidence of heterogeneity was found between estimates, while funnel-plot inspection revealed no evidence of publication bias., Conclusions: DMDs appear to attenuate brain atrophy over time in patients with CIS. The effect of DMDs on brain-volume loss is evident after the first year of treatment.

Background: The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMD) on brain atrophy in patients with relapsing-remitting multiple sclerosis (RRMS) using available randomized-controlled trial (RCT) data., Methods: We conducted a systematic review and meta-analysis according to PRISMA guidelines of all available RCTs of patients with RRMS that reported data on brain volume measurements during the study period., Results: We identified 4 eligible studies, including a total of 1819 RRMS patients (71% women, mean age 36.5 years, mean baseline EDSS-score: 2.4). The mean percentage change in brain volume was found to be significantly lower in DMD versus placebo subgroup (standardized mean difference: -0.19; 95%CI: -0.27--0.11; p<0.001). We detected no evidence of heterogeneity between estimates (I2 = 30%, p = 0.19) nor publication bias in the Funnel plots. Sensitivity analyses stratifying studies according to brain atrophy neuroimaging protocol disclosed no evidence of heterogeneity (p = 0.16). In meta-regression analyses, the percentage change in brain volume was found to be inversely related with duration of observation period in both DMD (meta-regression slope = -0.03; 95% CI: -0.04--0.02; p<0.001) and placebo subgroups (meta-regression slope = -0.05; 95% CI: -0.06--0.04; p<0.001). However, the rate of percentage brain volume loss over time was greater in placebo than in DMD subgroup (p = 0.017, ANCOVA)., Conclusions: DMD appear to be effective in attenuating brain atrophy in comparison to placebo and their benefit in delaying the rate of brain volume loss increases linearly with longer treatment duration.

A 47-year-old female patient with multiple sclerosis (MS) developed symptomatic intermittent 2nd degree atrioventricular block (AVB) of five-hour duration, five hours after the first two doses of fingolimod, that resolved completely. Frequency domain analysis of heart rate variability (HRV) revealed increased parasympathetic activity and decreased sympathetic tone, while modified Ewing tests were suggestive of impaired cardiac sympathetic function. We hypothesize that expression of this particular arrhythmia might be related to autonomic nervous system (ANS) dysfunction due to demyelinating lesions in the upper thoracic spinal cord, possibly augmented by the parasympathetic effect of the drug.

Tumor necrosis factor antagonists (anti-TNFa) are an established therapeutic option for several autoimmune and inflammatory bowel diseases. Despite their clinical effectiveness, neurological adverse events have been reported and literature data suggest a potential role of anti-TNFa in the induction of demyelination of the CNS. We present four patients treated with anti-TNFa who developed symptoms suggestive of CNS demyelination. The first patient, a 17-year-old male who received etanercept for psoriatic arthritis for eight months, presented with dysesthesias up to T4 level. The second patient, a 30-year-old male treated with adalimumab for three years due to ankylosing spondylitis, presented with right unilateral tinnitus. The third case, a 47-year-old female, received etanercept for four years because of psoriatic arthritis and developed persistent headache and left-sided face and head numbness. Finally, the fourth patient, a 57-years-old female treated with etanercept for six years due to ankylosing spondylitis, presented with difficulty in speech, swallowing, and ptosis of the right corner of the mouth. In all cases, brain MRI showed lesions suggestive of demyelination, while positive oligoclonal bands were detected in the CSF. Anti-TNFa treatments were discontinued and patients showed clinical improvement with pulsed intravenous corticosteroid therapy. CNS demyelination following anti-TNFa treatment represents a relatively rare but potential serious complication. Close follow-up and MRI monitoring of these patients is mandatory to elucidate whether the clinical manifestations represent adverse events occurring during anti-TNFa therapy or a first demyelinating episode.

Introduction. Central nervous system involvement, either clinical or subclinical, has been reported mainly in X-linked Charcot-Marie-Tooth (CMT-X) patients. Case Presentation. We present the case of a 31-year-old man with a genetically confirmed history of CMT1A who developed CNS involvement mimicking multiple sclerosis (MS). Clinical, imaging, and laboratory findings suggested an autoimmune CNS demyelination. Discussion. Although the simultaneous existence of CMT1A and MS could be coincidental we postulate that overexpression of PMP22, the target protein in CMT1A, might influence the immunological self-tolerance to CNS proteins via molecular mimicry, leading to a CNS autoimmune demyelinating disorder.