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Pediatric-onset multiple sclerosis (MS, POMS) accounts for 3–5% of all MS cases and is characterized by a highly inflammatory profile, often warranting treatment with high-efficacy agents. Our aim is to present real-world data of a series of 18 Hellenic POMS patients treated with natalizumab (NTZ) either as adolescents or as adults, after high disease activity has efficiently subsided. Clinical and imaging/laboratory data from 18 POMS patients who have received at least one NTZ infusion were selected in this single-center retrospective observational study. Human leukocyte antigen (HLA) genotyping was performed with standard low-resolution sequence-specific oligonucleotide techniques. Eighteen patients with a mean age of disease onset of 15.3 ± 2.4 years were treated with NTZ with a mean of 51.7 ± 46.4 infusions, 6 as adolescents and 12 as adults. 22.2% were treatment naïve. At the end of the observational period, patients of both groups remained relapse-free, with no radiological activity and significantly reduced disability accumulation. No evidence of disease activity (NEDA)-3 status was achieved in 66.7% of all patients, 58.3% in the adult-treated, and 83.3% in the adolescent-treated POMS patients. NTZ was generally well tolerated. Only 5 adverse events were observed, in 3 patients who were carriers of the HLA-DRB1*15 (HLA-DRB1*15/HLA-DRB1*11 and HLA-DRB1*15/HLA-DRB1*13 genotypes), 1 homozygous for the HLA-DRB1*03 allele and 1 heterozygous for HLA-DRB1*04 and HLA-DRB1*16 alleles. NTZ is highly efficacious and mostly safe for POMS patients with high disease activity in all age groups. The role of immunogenetics in personalized patient evaluation and treatment needs to be further investigated. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Background/Purpose: Primary Sjögren’s Syndrome (SS) is characterized by B lymphocyte hyperactivity with B cell activating factor (BAFF) acting as an important regulator. Single Nucleotide Polymorphisms (SNPs) of the BAFF gene have been implicated in the pathogenesis of several autoimmune diseases characterized by heightened fatigue levels, including primary SS. We aimed to explore potential associations between BAFF SNPs and fatigue status of primary SS patients. Methods: Fatigue status was assessed in 199 consecutive primary SS patients (Greek cohort) using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Clinical, histological, laboratory, psychometric and personality data were also collected. DNA extracted from peripheral blood of all patients underwent evaluation for the presence of five BAFF SNPs (rs9514827, rs1041569, rs9514828, rs1224141, rs12583006) by PCR. To confirm our findings, an independent replicative cohort of 62 primary SS patients (Dutch cohort) was implemented. Finally, 52 multiple sclerosis (MS) patients were served as disease controls (MS cohort). Analysis of BAFF SNPs in association with fatigue levels was performed by the online platforms SNPStats and SHEsis and the SPSS 26 and Graph Pad Prism 8.00 software. Results: TT genotype of the rs9514828 BAFF polymorphism was significantly less frequent in the fatigued primary SS patients of the Greek cohort compared to the non-fatigued (14.1% vs 33.3%). The corresponding ORs [95%CI] in the dominant and overdominant models were 0.33 [0.15-0.72], p=0.003 and 0.42 [0.23-0.78], p=0.005 respectively. The association remained significant after adjustment for the variables contributing to fatigue in the univariate analysis (OR [95% CI]: 0.3 [0.1-0.9], p=0.026). Accordingly, in the Dutch cohort, there was a trend of lower mental fatigue among patients carrying the TT rs9514828 BAFF genotype compared to their CC counterparts (4.1 ± 2.4 vs 6.0 ± 2.2 respectively, p=0.06). The rs9514828 BAFF SNP was not significantly associated with fatigue in the MS cohort. Conclusions: We report a novel association between genetic makeup and primary SS-associated fatigue with the rs9514828 TT genotype decreasing the likelihood of fatigue development among these patients. These findings need validation in multi-center studies. Copyright © 2022 Flessa, Zampeli, Evangelopoulos, Natsis, Bodewes, Huijser, Versnel, Moutsopoulos and Mavragani.

The exact immunopathogenesis, genetic mechanisms and triggering factors underlying myasthenia gravis (MG) and neuromyelitis optica (NMO) remain unknown and the coexistence may underline an aetiopathogenetic link be- tween these two diseases. We report the cases of two thymectomized patients with acetylcholine receptor (AChR) antibody (Ab)-positive MG who eventually developed AQP4-NMO. Next-Generation Sequencing (NGS) analysis showed that patient-1 had two HLA alleles previously associated with MG, mainly HLA-A*01:01:01 and HLA-DRB1*03:01, present in a haplotype in Caucasian MG patients (HLA-A1-B8-DR3-DQ2). Patient-2, expressed HLA-C*07:01:01, a well characterized MG risk factor and HLA-DQB1*05:02:01, previously described both in MG and NMO patients. Finally, we observed two common alleles in patient 1 and 2, HLA-DQA1*05:01:01 and HLA-DPB1*04:02:01. We believe that this study provides clinical evidence of the role of specific HLA alleles in rare forms of combined human peripheral and CNS autoimmunity, a fact that enhances the aim towards tailor-made therapeutic decision making. © 2022

We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab. © 2021 Elsevier B.V.

Introduction: Accumulating data highlights that the dysregulation of type I interferon (IFN) pathways plays a central role in the pathogenesis of several systemic and organ-specific autoimmune diseases. Advances in understanding the role of type I IFNs in these disorders can lead to targeted drug development as well as establishing potential disease biomarkers. Areas covered: Here, we summarize current knowledge regarding the role of type I IFNs in the major systemic, as well as organ-specific, autoimmune disorders, including prominent inflammatory CNS disorders like multiple sclerosis. Expert opinion: Type I IFN involvement and its clinical associations in a wide spectrum of autoimmune diseases represents a promising area for research aiming to unveil common pathogenetic pathways in systemic and organ-specific autoimmunity. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

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. © The Author(s), 2021.

Objective: Colloid cysts of the third ventricle are benign intracranial tumors. They are most commonly presented with signs of intracranial hypertension due to obstructive hydrocephalus, including headache, nausea/vomiting and vision disturbances, whereas extrapyramidal symptoms such as tremor are very rare. Sudden death, due to abruptly developed hydrocephalus, can be also observed. Although paroxysmal symptomatology attributed to the intermittent obstruction of the foramen of Monro is considered the “classical” clinical presentation, it is rather the exception in clinical practice. Case Report: A 42-year-old woman with no medical history was admitted to the neurology department as suffering from a potential demyelinating disease due to episodes of paroxysmal tremor of her right lower limb and persistent mild gait instability, which presented 15 days prior to her arrival. She also complained of episodes of partially position-dependent bilateral headache over the last 10 years, as well as episodes of vertigo over the last 4 years. On arrival, her gait was shuffling and mildly wide-based and an intermittent tremor of her right lower limb was observed in supine and sitting positions, but not in a prone position. Brain magnetic resonance imaging (MRI) demonstrated a round cystic lesion of the third ventricle, accompanied by hydrocephalus with enlargement of lateral ventricles. MRI findings were highly indicative of a colloid cyst. The patient underwent resection of the mass and the tremor resolved after surgery. Conclusion: Given the greatly heterogeneous clinical presentation of colloid cysts, our case highlights the significance of the prompt diagnosis of this rare but potentially fatal cause of paroxysmal limb tremor. © 2020 Angelopoulou et al.

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.

IgG4-related disease (IgG4-RD) is a disorder with various clinical manifestations. Central nervous system (CNS) involvement is well recognized, with hypertrophic pachymeningitis and hypophysitis being the most common manifestations. Spinal cord involvement is an extremely rare manifestation. We present the first case of an IgG4-RD patient with spinal cord parenchymal disease and concurrent hypophysitis. We review also the current literature about CNS parenchymal involvement in the context of IgG4-RD. A young female presented with clinical symptoms of myelitis. Cervical spinal cord magnetic resonance imaging (MRI) displayed features of longitudinally extensive transverse myelitis (LETM). Brain MRI showed a small number of high-intensity lesions in the deep white matter and enlargement of hypophysis with homogeneous gadolinium enhancement (asymptomatic hypophysitis). Diagnostic workup revealed elevated IgG4 serum levels (146 mg/dL). Our patient fulfilled the organ-specific diagnostic criteria of IgG4-hypophysitis. Treatment with intravenous glucocorticoids led to rapid clinical response, and to the substantial resolution of imaging findings. Azathioprine was used as a maintenance treatment. One relapse occurred 2 years after the initial diagnosis and patient was re-treated with glucocorticoids. Three years after relapse, patient is in remission with azathioprine. We present the first case of myelitis with radiological features of LETM associated with increased IgG4 serum levels and the simultaneous presence of asymptomatic IgG4-related hypophysitis. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Background: Numerous cross-sectional studies report cognitive impairment in multiple sclerosis (MS), but longitudinal studies with sufficiently long-term follow-up are scarce. Objective: We aimed to investigate the cognitive 10-year course of a cohort of MS patients. Methods: 59 patients with clinically isolated syndrome (CIS) or relapsing–remitting (RR) MS were evaluated with Rao’s Brief Repeatable Battery of Neuropsychological Tests at baseline and follow-up (at least 10 years later). They constituted 47.2% of 124 consecutive CIS and RRMS patients originally evaluated at baseline. Patients assessed at follow-up were well matched for baseline clinical characteristics with dropouts. Results: The proportion of MS patients with overall cognitive impairment was increased by 10% within the 10-year period. When grouped on the basis of impairment in specific cognitive domains at baseline, patients originally impaired showed improvement at follow-up, while the opposite trend was observed for patients non-impaired at first assessment. A detailed case-by-case investigation revealed mixed evolution patterns, several patients fail in fewer domains at follow-up compared to baseline or failing at different domains at follow-up compared to baseline. Conclusions: This study suggests a more fluid picture for the evolution of cognitive function in a subgroup of MS patients and contradicts the concept of an inevitable, progressively evolving “dementia”. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Comorbidities including subclinical atherosclerosis, neuropsychological aberrations and lymphoproliferation represent a major burden among patients with systemic autoimmune diseases; they occur either as a result of intrinsic disease related characteristics including therapeutic interventions or traditional risk factors similar to those observed in general population. Soluble molecules recently shown to contribute to subclinical atherosclerosis in the context of systemic lupus erythematosus (SLE) include among others B-cell activating factor (BAFF), hyperhomocysteinemia, parathormone (PTH) levels and autoantibodies against oxidized lipids. Variations of the 5, 10- methylenetetrahydrofolate reductase (MTHFR) gene -the main genetic determinant of hyperhomocystenemia in humans-as well the interferon regulatory factor-8 (IRF8), FcγRIIA and BAFF genes have been all linked to subclinical atherosclerosis in SLE. BAFF variants have been also found to confer increased risk for subclinical atherosclerosis and lymphoma development in Sjogren's syndrome (SS) patients. Other genes shown to be implicated in SS lymphoproliferation include genes involved a. in inflammatory responses such as the NFκB regulator Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and the Leukocyte immunoglobulin-like receptor A3 (LILRA3) immunoreceptor, b. B cell activation and signaling (BAFF/BAFF-receptor), c. type I IFN pathway such as three-prime repair exonuclease 1 (TREX1), d. epigenetic processes including DNA methylation (MTHFR rs1801133, 677T allele) and e. genomic instability (MTHFR rs1801131, 1298C allele). Emerging soluble biomarkers for SS related lymphoma include mediators of B cell growth and germinal center formation such as BAFF, FMS-like tyrosine kinase 3 ligand (Flt‐3L) and CXCL13 as well as inflammatory contributors such as inteleukin (IL)-17, IL-18, ASC, LILRA3 and the extracellular lipoprotein-associated phospholipase A2 (Lp-PLA2). In regard to fatigue and neuropsychologic features in the setting of SS, contributing factors such as BAFF variants, antibodies against neuropeptides, proteins involved in nervous system function as well as inflammatory cytokines have been reported. © 2019 Elsevier Ltd

Objective X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS. Methods Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity. Results We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS. Conclusions We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor. © Author(s) (or their employer(s)) 2019.

Anti-NMDA receptor (NMDA-r) encephalitis is a relatively rare cause of autoimmune encephalitis with divergent clinical presentations. We report a case of an adult patient with anti-NMDA-r encephalitis presenting with isolated, abrupt-onset aphasia. Her condition remained unaltered over a period of 6 months. The patients’ electroencephalogram findings were typical for NMDA-r encephalitis; however, her magnetic resonance imaging and cerebrospinal fluid analysis were normal. She responded well to immunotherapy, and aphasia eventually resolved. The natural course of the present case contradicts the rapidly progressive nature of typical NMDA-r encephalitis. Furthermore, it broadens the clinical spectrum of anti-NMDA-r encephalitis, to incorporate isolated, nonprogressive aphasia. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Background Spastic paretic hemifacial contracture (SPHC) is characterized by sustained unilateral contraction of the facial muscles associated with mild ipsilateral facial paresis. Rarely described in the context of multiple sclerosis (MS), it has never been reported as presenting symptom of MS. Case reports Two patients developed SPHC within the context of a clinically isolated syndrome suggestive of MS. EMG revealed continuous resting activity of irregularly firing motor unit potentials, associated with impaired recruitment upon voluntary contraction. SPHC remitted fully in both patients. Conclusions SPHC, a rare but distinct clinical and EMG entity, can occasionally be the presenting feature of MS. © 2017 Elsevier B.V.

Objective To integrate neurophysiological findings with clinical and imaging data in a consecutive series of multiple sclerosis (MS) patients developing facial numbness during the course of an MS attack. Methods Nine consecutive patients with MS and recent-onset facial numbness were studied clinically, imaged with routine MRI, and assessed neurophysiologically with trigeminal somatosensory evoked potential (TSEP), blink reflex (BR), masseter reflex (MR), facial nerve conduction, facial muscle and masseter EMG studies. Results All patients had unilateral facial hypoesthesia on examination and lesions in the ipsilateral pontine tegmentum on MRI. All patients had abnormal TSEPs upon stimulation of the affected side, excepting one that was tested following remission of numbness. BR was the second most sensitive neurophysiological method with 6/9 examinations exhibiting an abnormal R1 component. The MR was abnormal in 3/6 patients, always on the affected side. Facial conduction and EMG studies were normal in all patients but one. Conclusions Facial numbness was always related to abnormal TSEPs. A concomitant R1 abnormality on BR allowed localization of the responsible pontine lesion, which closely corresponded with MRI findings. We conclude that neurophysiological assessment of MS patients with facial numbness is a sensitive tool, which complements MRI, and can improve lesion localization. © 2016 Elsevier B.V.

Various specific human glucocorticoid receptor (NR3C1) gene polymorphisms have been described in multiple sclerosis (MS) patients and correlated with disease progression, susceptibility and aggressiveness. Herein, we investigated the presence of gene alterations in the entire coding region of the NR3C1 in MS patients of variable clinical status (CIS, RRMS and SPMS) and the association(s) of these alterations with severity of disease (EDSS), response to glucocorticoid (GC) treatment and clinical improvement. Sixty Caucasian Greek MS patients were included. Sequencing the coding sequences and intron-exon boundaries of the NR3C1 did not reveal the presence of mutation(s) in any of the MS patients. Three previously described polymorphisms were detected: P.N363S (rs6195), p.N766N (rs6196) and c.1469-16G > T (rs6188). None of the identified alleles/genotypes were found to be associated with the severity of disease, response to glucocorticoids and disease subtypes. Known polymorphism, such as ER22/23EK that has been previously detected in MS patients, was not detected. There is a considerable ethnicity-related variation in the frequency of the NR3C1 polymorphisms. Although a genetic basis of the glucocorticoid sensitivity exists in healthy population, in the presence of chronic inflammation and abundance of cytokines-such in MS patients-other factors appear to play a more important role in GC sensitivity. © 2016 Elsevier B.V. All rights reserved.