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The concept of "autoimmune epilepsy" (AE) has been emphasized more frequently through the recent increase in recognition of various autoantibodies specific to neuronal proteins.To evaluate the attitudes of neurologists in regard to AE, to review the differential diagnosis, treatment options, and to reveal the effect of COVID-19 on this matter.A detailed questionnaire prepared for AE was sent to neurologists via social media and WhatsApp after the approval of the Ethics Committee. The responses of 245 respondents working in different settings were analyzed, and the group with 15 years or less experience in neurology was statistically compared to the group with more than 15 years of experience.Awareness and knowledge levels on AE seemed high in all groups, while 11% had never thought about AE during the differential diagnosis in real life. Before starting treatment, 20% thought that the autoantibody result should definitely support it, and 77.6% reported that they did not recognize AE well. Participants stated that satisfactory guidelines for diagnosis and treatment (88.2%) and widespread laboratory support (83.7%) were lacking. Neurologists with less experience and those working outside of training hospitals get more often consultation from an experienced clinician while diagnosing and conduct more detailed investigations at the diagnosis stage (p = 0.0025, p = 0.0001).This first survey study conducted in a large group of neurologists on the attitudes for the concept of AE suggested that postgraduate education, and diagnostic and treatment guidelines should be organized and antibody screening tests need to be better disseminated.

Sepsis-associated encephalopathy (SAE) is frequently encountered in sepsis and is often accompanied by neuroimaging findings indicating ischemia, hemorrhage, and edema. Posterior reversible encephalopathy syndrome (PRES) has been vastly underrecognized in previously reported cohorts of patients with sepsis and SAE. Our aim was to determine the prevalence and distinguishing clinical, neuroimaging, and electroencephalography features of PRES in SAE.In this prospective observational study, patients with radiologically identified PRES were selected from a consecutively enrolled cohort of 156 patients with SAE and assessed for neurological outcome using the extended Glasgow Outcome Scale for 12 months. Patients with SAE and PRES and other types of brain lesions were compared in terms of clinical and diagnostic workup features.Fourteen of 156 patients (8.9%) were determined to be radiologically compatible with PRES, whereas 48 patients displayed other types of acute brain lesions. Patients with PRES often showed lesions in atypical regions, including frontal lobes, the corpus callosum, and the basal ganglia. Source of infection was mostly gram-negative bacteria originating from pneumonia or intraabdominal infections. Patients with PRES were not different from other patients with SAE with brain lesions in terms of features of sepsis and neurological outcome. However, patients with PRES showed increased prevalence of seizures and intraabdominal source of infection.PRES is highly prevalent in SAE, often encompasses unusual brain regions, and usually presents with generalized seizures. Patients with SAE and PRES do not appear to have distinguishing clinical and diagnostic workup features. However, generalized seizures may serve as warning signs for presence of PRES in patients with SAE.

Objective:Narcolepsy is a chronic sleep disorder long hypothesised to be an autoimmune disease. Complement-mediated immune mechanisms have not been investigated in detail in narcolepsy. Our aim was to establish the significance of classical pathway activation in narcolepsy.Methods:Sera of 42 narcolepsy patients and 26 healthy controls were screened with ELISA to determine the levels of C1q, C3a, C4d and complement component 4 binding protein (C4BP). A home-made ELISA method was developed to detect antibodies to C4BP-alpha (anti-C4BPA). The correlation between complement levels and clinical findings was examined.Results:C1q levels were significantly higher in narcolepsy patients while C4d and C4BP levels were significantly lower compared to healthy controls. C3a levels were comparable among patients and controls. Eleven narcolepsy patients showed serum anti-C4BPA levels. Total rapid eye movements (REM) time, sleep onset latency, REM sleep latency, sleep activity, percentage of wakefulness after sleep onset and Epworth sleepiness scale scores were correlated with levels of different complement factors.Conclusion:Complement-mediated immune mechanisms might partake in narcolepsy pathogenesis. The precise role of autoantibodies on complement level alterations needs to be investigated. Levels of complement factors and degradation products may potentially be utilised as biomarkers to predict the clinical severity of narcolepsy.

Prevalence of acute ische-mic stroke (AIS) is increased in patients with coronavirus disease 2019 (COVID-19). A proposed hypothesis is increased virus-induced propensity to hypercoagulation resulting in arterial thrombosis. Our aim was to provide evidence regarding the involvement of neutrophil extracellular trap (NET) formation (NETosis) in COVID-19 related AIS.Twenty-six consecutively enrolled COVID-19+ pneumonia patients with AIS, 32 COVID-19+ pneumonia patients without AIS and 24 AIS patients without COVID-19 infection were included to the study. Clinical characteristics of recruited patients were collected. Serum levels of citrullinated histone H3 (H3Cit; a factor of NETosis), IL-8 and C5a (mediators associated with NETosis) were measured by ELISA (enzyme-linked immunosorbent assay).H3Cit levels were significantly higher in COVID-19+ AIS patients, whereas all study groups showed comparable IL-8 and C5a levels. There were no significant differences among etiological subgroups of AIS patients with or without COVID-19. AIS patients with COVID-19 showed relatively increased white blood cell, lymphocyte, neutrophil, D-dimer, C-reactive protein and procalcitonin levels than control groups. H3Cit levels did not correlate with clinical/prognostic features and inflammation parameters. H3Cit and IL-8 levels were correlated in COVID-19 patients without stroke but not in COVID-19 positive or negative AIS patients.Increased levels of inflammation parameters and H3Cit in COVID-19 related AIS suggest that NETosis may cause susceptibility to arterial thrombosis. However, H3Cit levels do not correlate with clinical severity measures and inflammation parameters diminishing the prognostic biomarker value of NETosis factors. Moreover, the link between IL-8 and NETosis appears to be abolished in AIS.A Covid-19-betegek körében megnő az akut ischaemiás stroke (AIS) prevalenciája. Egy hipotetikus mechanizmus szerint a vírus megnöveli a hiperkoagulációs hajlamot, ami arteriális thrombosist eredményez. Vizsgálatunk célja az volt, hogy bizonyítsuk: a neutrophil extracelluláris csapdaképződés (NETosis) közreműködik a Covid-19-cel összefüggő AIS kialakulásában.A vizsgálatba n = 26, AIS-ban szenvedő Covid-19-pneumoniás beteget, n = 32 AIS nélküli Covid-19-pneumoniás beteget és n = 24 AIS-ban igen, de Covid-19-ben nem szenvedő beteget vontunk be. Összegyűjtöttük a betegek klinikai adatait. ELISA-val mértük a citrullinált hiszton H3 (H3Cit; a NETosis egy faktora), az IL-8 és a C5a (NETosis-asszociált faktorok) szérumszintjét.A Covid-19 + AIS betegekben szignifi­kánsan magasabb volt a H3Cit-szint, míg az IL-8- és C5a-szintek hasonlóak voltak valamennyi csoportban. A covidos és nem covidos AIS-betegek etiológiaalapú alcsoportjaiban nem találtunk szignifikáns különbségeket. A kont­rollcsoportokkal összehasonlítva, a Covid-19 + AIS betegekben megemelkedett a fehérvérsejt-, a lymphocyta-, és a neutrophilszám, továbbá megnőttek a D-dimer-, C-reaktív protein- és prokalcitoninszintek. A H3Cit-szintek nem függtek össze sem a klinikai/prognosztikus jellem­zőkkel, sem a gyulladásos paraméterekkel. A H3Cit- és az IL-8-szintek összefüggésben álltak egymással az AIS nélküli Covid-19-betegek esetében, azonban nem korreláltak a Covid-pozitív vagy -negatív AIS-betegek esetén.A Covid-19-cel szövődött AIS esetében a gyulladásos paraméterek és a H3Cit megnövekedett szintje azt sugallja, hogy a NETosis arteriális thrombosis iránti fogékonyságot eredményezhet. Mindazonáltal az az eredmény, miszerint a H3Cit-szintek nem korrelálnak a klinikai súlyossággal és a gyulladásos paraméterekkel, lehetetlenné teszi a NETosis-faktorok prognosztikus biomarkerként való használatát. Ráadásul úgy tűnik, hogy az IL-8 és a NETosis közötti kapcsolat megszűnik AIS esetén.

Immunity against cancer cells is at the forefront of fight against highly malignant tumors like glioblastomas (GBM). Autoantibodies and their autoantigen cooperators are one of the promising biomarkers linked to the immune responses and have been reported as having an initiative or prognostic role for certain types of paraneoplastic disorders. Nevertheless, immunoreactivity against antigens expressed in GBM are poorly studied. To date, autoantibodies were identified by pursuing targeted approaches. By contrast, in this study, we collected human GBM tissue and sera samples and by applying proteomics analysis, we determined autoantigen candidates for GBM. Subsequent immunohistochemistry and immunoprecipitation experiments revealed that a solute carrier; SLC3A2 is widely overexpressed in GBMs and therefore, immunoreactivity against SLC3A2 is present in high grade GBM, and SLC3A2 expression is altered in GBMs. No antibody interaction was detected in SLC3A2 expressors of low grade gliomas. Furthermore, autoantibody presence was correlated with prolonged survival of GBM patients. Taken together, for the first time, we reported that the SLC3A2 immunoreaction exists in high grade gliomas with a distinct GBM profile. In conclusion, our findings may open up new avenues for our understanding of glioma prognosis in the context of autoimmunity. This may eventually lead to diagnostic and therapeutic inventions that can be utilized for prevention of the disease progression.

Background/aim Ganglioside antibodies are identified not only in patients with inflammatory neuropathies but also several central nervous system disorders and paraneoplastic neuropathies. Our aim was to investigate whether ganglioside antibodies are found in autoimmune encephalitis patients and may function as a diagnostic and prognostic biomarker. Materials and methods Sera and cerebrospinal fluid (CSF) samples of 33 patients fulfilling the criteria for probable autoimmune encephalitis were collected within the first week of clinical manifestation. None of the patients had evident symptoms and findings of peripheral polyneuropathy. Well-characterized anti-neuronal and paraneoplastic antibodies were investigated in sera and CSF and anti-ganglioside (anti-GM1, GM2, GM3, GD1a, GD1b, GT1b and GQ1b) IgG and IgM antibodies were measured in sera using commercial immunoblots. Results Twenty-eight of 33 autoimmune encephalitis patients displayed antibodies against neuronal surface or onco-neural antigens with N-methyl-D-aspartate receptor (NMDAR), glutamic acid decarboxylase (GAD) and Hu antibodies being the most prevalent. While no anti-ganglioside IgG antibodies were found, 4 patients (2 anti-NMDAR+, 1 anti-GAD+ and 1 antibody negative) with autoimmune limbic encephalitis displayed anti-GM1, anti-GM2, anti-GM3 or anti-GQ1b IgM antibodies. There was no apparent association between anti-ganglioside positivity and clinical and demographic features. Conclusion Serum ganglioside IgM antibodies may infrequently emerge during the clinical course of autoimmune limbic encephalitis without evident polyneuropathy. Absence of the IgG response suggests that these antibodies might have developed as a hyperacute immune response to neuro-axonal destruction. Nevertheless, potential impact of ganglioside antibodies on axonal degeneration and neuronal loss in limbic encephalitis pends to be further investigated.

Epstein-Barr virus (EBV) has been associated with a plethora of neurological manifestations including polyneuropathy and polyradiculopathy. A 27-year-old man with a recent upper respiratory system infection presented with difficulty in walking. His neurological examination revealed reduced muscle strength in both proximal and distal lower limb muscles without sensory and autonomic signs. Needle electromyography showed abnormal spontaneous activity and reduced recruitment of motor units in muscles innervated by multiple lumbo-sacral roots. Cerebrospinal examination showed increased protein levels with normal cell counts. While spinal MRI was normal, whole-body CT and PET examination showed disseminated lymph node enlargement. Anti-EBV viral capsid antigen and anti-nuclear antigen IgG but not IgM was positive, whereas EBV PCR was negative in blood. Analysis of inguinal lymph node biopsy showed reactive lymphoid hyperplasia and EBV DNA. Leucine-rich glioma-inactivated protein 1 (LGI1) antibody was found in serum but not in CSF. All clinical, imaging, and electrophysiological findings improved following steroid and intravenous immunoglobulin treatment. These findings suggested the acute involvement of lumbo-sacral spinal roots and/or motor neurons. Purely motor polyradiculopathy has been reported in both EBV-positive and LGI1 antibody-positive patients, and EBV infection is known to precede different autoimmune manifestations. Whether EBV infection may trigger LGI1 autoimmunity and cause involvement of spinal motor roots and/or motor neurons needs to be further studied.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that may lead to progressive disability. Here, we explored the behavioral pattern and the role of vasculature especially PDGFRB+ pericytes/ perivascular cells, in MS pathogenesis.We have evaluated vascular changes in two different experimental allergic encephalomyelitis (EAE) mice models (MOG and PLP-induced). PDGFRB+ cells demonstrated distinct and different behavioral patterns. In both models, fibrosis formation was detected via collagen, fibronectin, and extracellular matrix accumulation.The PLP-induced animal model revealed that fibrosis predominantly occurs in perivascular locations and that PDGFRB+ cells are accumulated around vessels. Also, the expression of fibrotic genes and genes coding extracellular matrix (ECM) proteins are upregulated. Moreover, the perivascular thick wall structures in affected vessels of this model presented primarily increased PDGFRB+ cells but not NG2+ cells in the transgenic NG2-DsRed transgenic animal model. On the other hand, in MOG induced model, PDGFRB+ perivascular cells were accumulated at the lesion sites. PDGFRB+ cells colocalized with ECM proteins (collagen, fibronectin, and lysyl oxidase L3). Nevertheless, both MOG and PLP-immunized mice showed increasing EAE severity, and disability parallel with enhanced perivascular cell accumulation as the disease progressed from earlier (day 15) to later (day 40).As a result, we have concluded that PDGFRB+ perivascular cells may be participating in lesion progression and as well as demonstrating different responses in different EAE models.

This work was supported by the Scientific Research Projects Coordination Unit of Istanbul University under Grant [35165]. Purpose: Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis that may lead to cognitive decline. Our aim was to investigate whether the neurofilament light chain (NFL) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) could be utilized as prognostic biomarkers in SAE. Materials and methods: In this prospective observational study, baseline serum levels of sTREM2 and cerebrospinal fluid (CSF) levels of sTREM2 and NFL were measured by ELISA in 11 SAE patients and controls. Patients underwent daily neurological examination. Brain magnetic resonance imaging (MRI) and standard electroencephalography (EEG) were performed. Cognitive dysfunction was longitudinally assessed after discharge in 4 SAE patients using the Mini-Mental State Examination (MMSE) and Addenbrooke’s Cognitive Examination-Revised (ACE-R) tests. Results: SAE patients showed higher CSF sTREM2 and NFL levels than controls. sTREM2 and NFL levels were not correlated with the severity measures of sepsis. Three months after discharge, 2 SAE patients displayed ACE-R scores congruent with mild cognitive impairment (MCI), persisting in one patient 12 months after discharge. SAE patients with MCI showed higher CSF NFL levels, bacteremia, and abnormal brain MRI. Patients with increased serum/CSF sTREM2 levels showed trends towards displaying poorer attention/orientation and visuo-spatial skills. Conclusions: sTREM2 and NFL levels may serve as a prognostic biomarker for cognitive decline in SAE. These results lend further support for the involvement of glial activation and neuroaxonal degeneration in the physiopathology of SAE. Publisher's Version Q4 WOS:000647333900001 PubMed ID: 33851572

Objective: We have previously shown altered blood B cells in the first attack blood samples of clinically isolated syndrome (CIS) pa-tients, who converted to multiple sclerosis (MS). Our aim was to investigate levels of B cell receptor (BCR)-associated genes expres-sion in converting CIS (CIS-c) and non-converting CIS patients (CIS-nc) with a 5-year follow-up. Methods: Seven CIS-c patients, 12 CIS-nc patients and 10 age-sex matched healthy donors were enrolled in this study. RNA was extracted from frozen peripheral blood cells of subjects that were obtained in the first attack using a RNA isolation kit. Expression levels of B-cell adaptor protein with ankyrin repeats 1 (BANK1), B lymphocyte kinase (BLK) and Fc receptor-like protein 2 (FCRL2) genes were evaluated samples by real-time polymerase chain re-action (RT-PCR). Results: CIS-nc patients showed elevated BANK1, BLK and FCRL2 gene expression levels as compared to CIS-c patients and healthy controls. Conclusions: Expression levels of the genes that inhibit BCR signal-ing are increased in CIS-nc, suggesting that inhibiting exaggerated B cell response by optimization of B cell proliferation may prevent the progression of clinically isolated syndrome to MS., Amaç: Daha önceki çalışmalarımızda, multipl skleroza (MS) dö-nüşen klinik izole sendrom (KİS) olgularının ilk atakta alınan kan örneklerinde periferik kan B hücre düzeylerinin değiştiğini göste-rilmiştir. Bu çalışmada beş yıllık takipte MS’e dönüşen ve dönüşme-yen KİS olgularında B hücre reseptör (BHR) ilişkili genlerin ekspres-yon düzeylerinin araştırılması amaçlanmıştır. Yöntem: Yedi MS’e dönüşen, 12 MS’e dönüşmeyen KİS olgusu ile yaş ve cinsiyet açısından eşleştirilmiş 10 sağlıklı donör çalışmaya dahil edildi. İlk atak döneminde elde edilen donmuş periferik kan mononükleer hücrelerinden (PKMH) RNA izolasyon kiti kullanılarak total RNAlar izole edildi. Örneklerden gerçek zamanlı polimeraz zincir reaksiyonu (RT-PCR) yöntemi ile ankrin tekrarlı B-hücre adap-tör proteini (BANK1), B lenfosit kinaz (BLK), Fc reseptör benzeri pro-tein 2 (FCRL2) genlerinin ekspresyonları değerlendirildi. Bulgular: MS’e dönüşmeyen KİS olgularında BANK1, BLK ve FCRL2 gen ekspresyon düzeyleri MS’e dönüşen KİS olguları ve sağlıklı kontrollere kıyasla artmış olarak saptandı. Sonuç: BHR sinyalizasyonunu inhibe eden gen ekspresyonlarının MS’e dönüşmeyen olgularda artması, abartılı B hücre yanıtının B hücre proliferasyonunun optimize edilmesi yoluyla baskılanması-nın KİS’ten MS’e ilerleyişi engelleyebileceğini düşündürmüştür.

The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders. ispartof: Schizophrenia Research vol:228 pages:462-471 ispartof: location:Netherlands status: Published online

Glioma is the most prevalent and lethal type of primary tumor of central nervous system. The regulatory role of calcitriol, the active form of vitamin D3, has been determined in various cellular processes including cell survival and apoptosis. To study the impact of AKT-pathway inhibition with or without calcitriol combination on glioma cell viability, the effects of AT7867 (AKT-pathway inhibitor) and calcitriol on cell viability and apoptosis were investigated in glioma C6 cell-line. Optimal doses of calcitriol and AT7867 were determined by MTT- and xCELLigence-assays. Both agents (alone/in combination) effectively suppressed the proliferation of C6 cells. While AT7867 inhibited glioma cell viability more effectively than calcitriol, this inhibitory action of AT7867 was not significantly increased by calcitriol combination. The expression levels of vitamin D receptor(VDR)-triggered molecules, AKT-pathway components and apoptosis factors were compared between calcitriol-, AT7867- and calcitriol + AT7867-treated and non-treated cells. CYP24A1 gene was upregulated and DBP, CYP1A1, CYP27B1, EGFRvIII, AKT-pathway (AKT1, MTOR, CREB, PTEN), apoptosis (BAD, CYC-C, CASP3, APAF-1, BCL2) and MMP3 genes were downregulated by calcitriol treatment.AT7867 treatment induced CYP27B1 upregulation, reduced VDR and AKT-pathway (PI3K, MTOR, CREB, PTEN) gene expression levels but showed a relatively less pronounced effect on apoptosis-related gene levels. The combination of calcitriol and AT7867 treatment generated an effect that was similar to that induced by calcitriol alone. Our results demonstrate that calcitriol and AT7867 have differing actions on AKT- and apoptotic-pathways of C6 glioma cell-line. Calcitriol has a lesser viability reducing impact than AT7867 putatively due to its apoptosis inhibiting action. Supplemental data for this article is available online at https://doi.org/10.1080/13102818.2021.1912641 .

The involvement of inflammation in the pathophysiology of cluster headache (CH) has been suggested, with a role implied for interleukin (IL)-1β. We aimed to measure peripheral blood expression levels of IL-1β-inducing systems, the inflammasome complex, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and investigate their values as putative biomarkers in CH.In this cross-sectional study conducted in the Headache Unit of Istanbul University, Turkey, blood mononuclear cells (PBMCs) and sera were collected from 30 patients with episodic migraine, 4 with chronic CH, and 47 healthy individuals. Levels of inflammasome complex components (NLRP1, NLRP3, caspase 1, and ASC), end products of inflammasome complex activity (IL-1β, IL-18, and nitric oxide synthase isoforms), neuron-specific enolase, other inflammatory factors (NF-κB, HMGB1, and s100b), and anti-inflammatory IL-4 were measured by real-time quantitative polymerase chain reaction and/or enzyme-linked immunosorbent assay.NLRP3 expression levels were significantly reduced in PBMC samples of patients with CH, obtained during CH attacks (n = 24) or headache-free (out of cycle) episodes (n = 10). CH-attack patients showed greater expression levels of IL-1β (2Our results support the involvement of the IL-1β system in attacks of CH. However, the components of the inflammasome complex are suppressed in the peripheral blood and do not appear to play a role in the pathophysiology of CH. These findings argue against a potential biomarker value of the inflammasome complex in CH.

Multiple sclerosis is an autoimmune disorder induced by the infiltration of autoreactive immune cells into the central nervous system. Akt/PKB signaling pathway is crucially involved in T cell development and survival. We aimed to determine whether Akt1 expression levels of regulatory T (Treg) cells are altered in MS and are associated with disease activity. Relapsing–remitting multiple sclerosis (RR-MS, n = 17) patients and healthy individuals (n = 20) were enrolled. Peripheral blood mononuclear cells were isolated and anti-CD3, -CD4, -CD8, -CD25, -CD127 monoclonal antibodies were used to identify the T cell subsets. After stimulation with phorbol myristate acetate/ionomycin, the Akt1 and phosphorylated-Akt1 (p-Akt1) levels of T cell subsets were detected with intracellular staining using flow cytometry. Total Akt1 and p-Akt1 expression levels were found to be suppressed in CD4+ T cell and Treg populations of RR-MS patients. Progression indices were positively correlated with Akt1 expression levels of Tregs indicating that the Akt pathway might partake in the progression of multiple sclerosis. Flow cytometry may effectively be used for the evaluation of the Akt pathway activity. Our findings suggest that the magnitude of suppression of the Akt pathway might serve as a biomarker for the prognosis of multiple sclerosis.

Diagnosis of the syndrome of headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is based on clinical features, and no diagnostic biomarkers are available. We present a case presenting with characteristic features of HaNDL and an MRI lesion in the splenium of corpus callosum. CSF neurofilament light chain (NFL) levels were assessed in this patient together with 7 additional HaNDL patients, 18 multiple sclerosis (MS) patients, and 15 primary headache patients. Both HaNDL and primary headache patients showed significantly lower NFL levels than MS patients. Our results suggest that increased CSF levels of NFL and neuroaxonal loss are not characteristic features of HaNDL. Neurological disorders mimicking HaNDL often present with increased levels of NFL, and thus CSF measurement of NFL might be useful in differential diagnosis of HaNDL.

Antigen-specific immune responses are crucially involved in both multiple sclerosis (MS) and myasthenia gravis (MG). Teriflunomide is an immunomodulatory agent approved for treatment of MS through inhibition of lymphocyte proliferation. MG associated with muscle-specific tyrosine kinase (MuSK) antibodies often manifests with a severe disease course, prompting development of effective treatment methods. To evaluate whether teriflunomide treatment may ameliorate MuSK-autoimmunity, experimental autoimmune MG (EAMG) was induced by immunizing C57BL/6 (B6) mice three times with MuSK in complete Freund's adjuvant (CFA) (n = 17). MuSK-immunized mice were treated daily with teriflunomide (n = 8) or PBS (n = 9) starting from the third immunization (week 8) to termination (week 14). Clinical severity of EAMG was monitored. Immunological alterations were evaluated by measurement of anti-MuSK IgG, neuromuscular junction deposits, and flow cytometric analysis of lymph node cells. In MS patients under teriflunomide treatment, the peripheral blood B cell subset profile was analyzed. B6 mice treated with teriflunomide displayed relatively preserved body weight, lower EAMG prevalence, reduced average clinical grades, higher inverted screen scores, diminished anti-MuSK antibody and NMJ deposit levels. Amelioration of EAMG findings was associated with reduced memory B cell ratios in the lymph nodes. Similarly, MS patients under teriflunomide treatment showed reduced memory B cell, plasma cell, and plasmablast ratios. Teriflunomide treatment has effectively ameliorated MuSK-autoimmunity and thus may putatively be used in long-term management of MuSK-MG as an auxiliary treatment method. Teriflunomide appears to exert beneficial effects through inhibition of effector B cells.

Objective: Although Aquaporin-4 (Aqp-4) gene polymorphisms have been extensively studied in neuromyelitis optica spectrum disorder (NMOSD), there is little evidence on the involvement of Aqp-4 in the pathogenesis of relapsing optic neuritis (RON). Materials and Methods: In our study, we recruited patients who were followed by Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Multiple Sclerosis and Myelin Disorders Unit between 1979 and 2015. Blood samples of the patients were genotyped for potential variants in the exons and the nearby regions of Aqp-4 gene. Results: The Aqp-4 gene was sequenced in 15 patients with RON who were seronegative, 33 patients with NMOSD, and 30 healthy controls. None of the patients showed previously described single nucleotide polymorphisms (SNPs). Three new SNPs were identified in non-exonic regions of the gene. One intronic SNP located in close proximity to the fifth exon had a higher prevalence in patients with RON than patients with NMOSD and healthy controls. Conclusion: Aqp-4 SNPs show a considerable heterogeneous geographic distribution and might be involved in RON pathogenesis.

Objective: Behcet's disease (BD) is a chronic, recurrent and inflammatory disorder characterized by oral and genital aphthous ulcerations, uveitis, skin lesions and skin pathergy reaction. There are many genetic studies focused on determining BD etiology. In this study, we aimed to investigate IL-10 gene expression and rs1554286 single nucleotide polymorphism (SNP) which is located in IL-10 gene. Material and Method: In this study, the blood specimens of BD patients (n=45) and healthy controls (HC) (n=28) were collected for RNA and DNA extraction. We genotyped rs1554286 from the DNA samples (45 BD, 28 HC) using real time PCR. We identified the IL-10 gene expression levels from cDNA samples of patients with sufficient sample amounts (29 patients with BD and 23 HCs). Results: We compared the expression levels of IL-10 gene and also genotyping analysis, and no significant difference was observed between BD patients and HC. Conclusion: In our study, which compared IL-10 gene expression and SNP genotyping between Behcet patients and healthy controls, no difference was found between the two groups. Since this may have occurred due to the low number of samples in our study, studies with higher sample numbers are needed.

Objectives: The ubiquitin/proteasome system is one of the main axes of the pathogenesis of Parkinson's disease (PD). Small ubiquitin-related modifier (SUMO) proteins are involved in many biochemical events including regulation of transcriptional activity, modulation of signal transduction pathways, and response to cellular stress indicating a role for SUMO in the ubiquitin/proteasome system.Methods: In this study, our aim was to examine the prevalence of SUMO gene variants and their clinical associations in PD. Fifty-four consecutively recruited PD patients (34 male, 20 female) and 74 age-gender matched healthy controls (37 male, 37 female) were included. SUMO1, 2, 3 and 4 genes were screened by a next generation sequencing method using blood samples of participants. Single nucleotide polymorphisms (SNPs) with a significantly altered prevalence were determined by Bonferroni correction.Results: Two SNPs in the SUMO4 gene (rs237025 and rs237024) and two SNPs in the SUMO3 gene (rs180313 and rs235293) were found to have altered prevalence in PD. Although there was no association among these SNPs and clinical features of the patients, an increased family history of cancer was found in patients with SUMO3 gene variants.Discussion: Several SUMO SNPs were identified for the first time in PD patients suggesting that SUMO is involved in the pathophysiology of the disease. rs237025 has also been associated with diabetes mellitus indicating a pathogenic mechanism for SUMO that is shared with other degenerative disorders.

Objective: Despite the clues that myasthenia gravis (MG) disease may be associated with inflammasomes, there are no studies in the literature on MG disease and inflammasome complexes. Hence, to address this question, we investigated the possible participation of inflammasomes in experimental autoimmune myasthenia gravis mouse model (EAMG). Material and Method: EAMG was induced in mouse using acetylcholine receptor (AChR) protein, and Anti-AChR IgG antibody levels detected by ELISA in the experimental group confirmed our model. Levels of CASP1, IL-1β, NLRP3, P2X7R, and AKT1 of the experimental and control (complete Freund’s adjuvant -CFA immunized) groups were measured by qRT-PCR. Results: After immunization, the AChR IgG antibody levels were significantly higher in the AChR-immunized group than in the control group (p=0.042). IL-1β levels in the experimental group were significantly higher, compared to the control group (p=0.01). CASP1, NLRP3, and P2X7R levels were also higher compared to the control group. However, these differences did not attain statistical significance (p>0.05). AKT1 levels were lower compared to the control group. There was no correlation between serum antibody concentration and gene expression levels. Conclusion: Our results suggest that there might be inflammasome involvement in the pathology of MG disease. Increase in IL-1β levels indicates the importance of the inflammatory response; however, further studies are necessary to confirm this.

Objective: Multiple Sclerosis (MS) is a progresive and an immune mediated inflammatory central nervous disease. The focus of this study was to determine the possible relationship between B cell immunophenotypes and related gene expressions in the benign MS (BMS) group with disease and cognitive processes. Material and Method: Twenty BMS patients, 16 non-BMS and 28 healthy volunteers were included in the study. Gene expression was performed by real-time PCR (RT-PCR). Immunophenotyping of peripheral B cells was also evaluated by flow cytometry. The relationship between cognitive functions and gene expression levels and B cell subtypes was investigated. Results: It was observed that naive (CD19+ IgD+CD27- ) cells were higher in the BMS group compared to the healthy group (HC), and memory B cells showed opposite changes. Un-switched memory B cells(CD19+IgD+CD27+) were found to be higher in the benign group than in the HC. The expression of BANK and BLNK was found to be lower in both MS groups than in the HC. As a result of neuropsychological examinations and cognitive tests; it was observed that motor processes in BMS were better protected than Non-BMS. Conclusion: These findings support that B cell functions may have molecular and cellular effects, and may lead to regression in inflammation and clinical progression. Molecules showing significant changes in our study may play a role as prognostic biomarkers in MS.

Objective: Anti-neuronal antibodies are found in sera of neuro-Behçet's disease (NBD) patients. In this study, our aim was to analyze the potential mechanisms by which NBD immunoglobulin (Ig) Gs affect neuronal dysfunction. Materials and Methods: Purified IgGs obtained from pooled sera of six each NBD patients and healthy controls (HCs) were administered to Sprague Dawley rats through intraventricular injection. Control rats received phosphate-buffered saline (PBS) only. Locomotor activity was assessed by open field test on days 0, 10, and 25. Cerebral expression levels of intracellular pathway factors associated with cell survival and viability were measured by real-time polymerase chain reaction. Results: Rats treated with NBD IgG exhibited reduced motor activity. On day 25, the mean number of crossings was 44 ± 7, 90 ± 12, and 93 ± 5 and the mean number of rearings was 18 ± 7, 34 ± 5, and 35 ± 6 for NBD IgG, HC IgG, and PBS groups, respectively (P < 0.001). Relative expression levels of Akt-1 (0.4 ± 0.2, 1.0 ± 0.3, and 0.9 ± 0.6; P = 0.004), DJ-1 (0.6 ± 0.2, 1.0 ± 0.6, and 0.9 ± 0.5; P = 0.047), mouse double mininute-2 (0.5 ± 0.3, 0.9 ± 0.2, and 1.0 ± 0.2; P = 0.002), and mechanistic target of rapamycin (0.4 ± 0.2, 0.8 ± 0.4, and 0.9 ± 0.6; P = 0.006) were significantly lower in NBD-IgG group than HC IgG and PBS groups. By contrast, the expression levels of factors associated with apoptosis (caspase 3, mitochondrial carrier homolog 1, and B-cell lymphoma-2) were comparable among different treatment arms. Conclusion: Our results suggest that at least a fraction of NBD IgG interacts with neuronal surface antigens and subsequently decreases neuronal viability through Akt pathway inhibition. By contrast, NBD IgG does not appear to activate neuronal apoptosis. Further identification of the binding sites of serum IgG ıs required.