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Innate immunity activation in the central nervous system (CNS) is known to contribute to the development of depression through NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome assembly. Furthermore, administration of agmatine (AGM), a nitric oxide synthase (NOS) inhibitor, reverses stress-induced NLRP3 inflammasome activation in rats. We examined the effects of chronically-administered nitric oxide (NO) pathway modulating drugs on NLRP1/3-mediated neuroinflammatory responses and depressive-like behaviors in chronic unpredictable mild stress (CUMS) depression model of rats. CUMS model was applied to the adult male Sprague-Dawley rats for 6 weeks and the treatments were daily administered via intraperitoneal route in the last 3 weeks of CUMS procedure. Depressive-like behaviors were assessed by sucrose preference and forced swimming tests. The levels of NLRP inflammasome components (NLRP1, NLRP3, ASC, caspase-1 and IL-1β) were investigated in the prefrontal cortex by real time PCR and western blot methods. CUMS-induced depressive-like behaviors were coupled with the overactivation of NLRP1 and NLRP3 inflammasome sensors and increased levels of IL-1β. Depressive-like behaviors were ameliorated by chronic AGM and NOS inhibitor treatments. AGM and other NOS inhibitor treatments were found to be more effective in suppressing NLRP3 and NLRP1, respectively. All inhibitor reagents downregulated inflammasome components and IL-1β. These results suggest that both neuronal NLRP1 and microglial NLRP3 inflammasomes are involved in chronic stress-induced depressive-like behaviors. The antidepressant effects of AGM, iNOS and nNOS inhibitors are associated with the downregulation of CNS inflammasome expression levels. NO-pathway modulating drugs might provide novel therapeutic strategies for depression.

The syndrome of headache accompanied with transient neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL), is a rare, benign and self limiting syndrome. In the 2nd Edition of the International Classification of Headache Disorders, HaNDL syndrome was defined in secondary headache group as "Headache attributed to non-vascular intracranial disorder". The etiology of HaNDL is still unknown. In recent years, some authors have shown that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis. In this paper, the definition of HaNDL syndrome, clinical picture and epidemiology of HaNDL syndrome, etiopathogenesis, differential diagnosis and treatment will be reviewed with the recent literature.

Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies (GAD-Ab) often presents with treatment-resistant partial seizures, as well as other central nervous system symptoms. In contrast to several other well-characterized autoantibodies, GAD-Ab has very rarely been associated with status epilepticus. We report a 63-year-old woman initially admitted with somnolence and psychiatric findings. The EEG findings, of generalized and rhythmical slow spike-wave activity over the posterior regions of both hemispheres, together with the clinical deterioration in responsiveness, led to the diagnosis of non-convulsive status epilepticus. Investigation of a broad panel of autoantibodies, revealed only increased serum GAD-Ab levels. Following methylprednisolone and intravenous immunoglobulin treatments, the patient's neurological symptoms improved, EEG findings disappeared and GAD-Ab levels significantly decreased. GAD-Ab should be added to the list of anti-neuronal antibodies associated with non-convulsive status epilepticus. Disappearance of clinical findings and seroreversion after immunotherapy suggest that GAD-Ab might be involved in seizure pathogenesis.

The complement system is profoundly involved in the pathogenesis of acetylcholine receptor (AChR) antibody (Ab) related myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG). The most characteristic finding of muscle pathology in both MG and EAMG is the abundance of IgG and complement deposits at the nerve-muscle junction (NMJ), suggesting that AChR-Ab induces muscle weakness by complement pathway activation and consequent membrane attack complex (MAC) formation. This assumption has been supported with EAMG resistance of complement factor C3 knockout (KO), C4 KO and C5 deficient mice and amelioration of EAMG symptoms following treatment with complement inhibitors such as cobra venom factor, soluble complement receptor 1, anti-C1q, anti-C5 and anti-C6 Abs. Moreover, the complement inhibitor decay accelerating factor (DAF) KO mice exhibit increased susceptibility to EAMG. These findings have brought forward improvisation of novel therapy methods based on inhibition of classical and common complement pathways in MG treatment.

Multiple sclerosis (MS) and epilepsy are common disorders, the co-occurrence of which has been of considerable interest. This study aimed to evaluate the prevalence and clinical features of epileptic seizures in patients with definite MS including those with pediatric onset (≤16 years of age). Out of 2,300 patients with definite MS followed in our outpatient clinic, 36 with epileptic seizures were identified. In this cohort, 8 out of 146 pediatric cases had seizures. The clinical and demographic features of the patients were recorded. Multiple logistic regression model with the occurence of seizures as the dependent variable was performed to identify the risk factors for seizure occurrence in MS patients. The prevalence of epileptic seizures was 1.5 % in definite MS patients, 1.3 % in adult-onset (comparable to seizure prevalence in the general population) and 5.5 % in pediatric MS patients (≤16 years old). Twenty-six of 36 (72 %) patients with MS and epilepsy developed recurrent seizures after the first epileptic seizure. Mean annual relapse rate (p ≤ 0.001), mean expanded disability status scale (EDSS) score (p = 0.004) and the ratio of patients with pediatric onset (p = 0.01) were higher in MS patients with seizures. In the multiple logistic regression analysis, age at MS onset and EDSS at the last examination were found to be predictors of seizure occurrence. Occurrence of seizures during the clinical course of MS appears to be associated with early-onset and increased disease severity and might be coincidental in adults.

Autoantibodies to glutamic acid decarboxylase are found in some rare neurological diseases. However, acute peripheral neuropathy associated with antiglutamic acid decarboxylase autoimmunity has not been reported previously. Here we report a case of a patient who presented with acute cranial and peripheral neuropathy in association with the presence of serum antiglutamic acid decarboxylase antibodies. A 13-year-old boy was admitted to our pediatric neurology clinic with diplopia due to sixth cranial nerve palsy and ascending motor weakness in all extremities. The nerve conduction studies showed bilateral motor and sensory demyelinating neuropathy. Full recovery was achieved following intravenous immunoglobulin treatment. Glutamic acid decarboxylase autoimmunity-associated neurological diseases spectrum may also include acute demyelinating peripheral neuropathy.

Activation of complement components is crucial in the progression and severity of myasthenia gravis and experimental autoimmune myasthenia gravis (EAMG). Mice deficient in complement component C4 or treated with monoclonal antibody to C1q are resistant to EAMG. In this study, we show that inhibition of complement cascade activation by suppressing the expression of a critical low-abundant protein, C2, in the classical complement pathway, significantly improved clinical and immunopathological manifestations of EAMG. Two weeks after a second booster immunization with acetylcholine receptor, when mice exhibit muscle weakness, i.p. injection of C2 siRNA significantly suppressed C2 mRNA in the blood cells and liver of EAMG mice. Treatment of EAMG mice with C2 siRNA, once a week for 5 weeks, significantly improved muscle strength, which was further evidenced by functional AChR preservation in muscle, reduction in number of C3 and membrane-attack complexes at neuro-muscular junctions in forelimb muscle sections, and a transient decrease in serum IgG2b levels. Our study shows for the first time that siRNA-mediated suppression of C2, a component of the classical complement system, following established disease, can effectively contribute to the remission of EAMG. Therefore, C2 siRNA mediated therapy can be applied in all complement mediated autoimmune diseases.

Objective: This study was conducted to characterize the prevalence and clinical features of kleptomania, an impulse control disorder, in patients with Behçet's disease involving the central nervous system. Subjects and Methods: Medical records of 350 patients with neuro-Behçet's disease were evaluated, and clinical and neuropsychological features of patients with kleptomania were noted. Results: Of the 350 neuro-Behçet's disease patients 6 (1.7%) had presented with symptoms that fulfilled the criteria of kleptomania according to the revised 4th version of the Diagnostic and Statistical Manual of Mental Disorders. The 6 patients (5 men, 1 woman) had parenchymal lesions and had developed kleptomania during remission. Magnetic resonance imaging done on the 6 patients before the onset of kleptomania mostly revealed brainstem lesions. Psychiatric assessment did not show any comorbid psychiatric disorders and neuropsychological evaluation showed executive dysfunction in all patients. Conclusion: The 6 patients with kleptomania had developed a frontal lobe syndrome.

Epilepsy may present as a symptom of many neurological disorders and often an etiological factor cannot be identified. There is some evidence that immune mechanisms might play a role in the pathogenesis of certain epileptic syndromes. The evidence in support of this idea includes apparent association of seizures with certain autoimmune diseases, numerous reports of the detection of theoretically relevant serum autoantibodies, an acute or subacute onset of the seizures, a rapidly progressive course, and a favorable response to immunotherapy. In this article, we summarize (i) epilepsies where clinical and biologic data strongly support the pathogenic role of autoantibodies. (ii) epilepsies where immune-mediated inflammation occurs, but the full pathogenic cascade is either not clear or only strongly hypothesized and (iii) autoimmune diseases associated with seizures or epilepsy.

Background Adipokines may be involved in multiple sclerosis (MS) as well as other inflammatory diseases. This study aimed to analyze the value of serum adipokine levels as biomarkers in determining the clinical progression of MS. Methods A total of 90 subjects including 40 healthy individuals and 50 MS patients [24 with classical clinical course of MS (C-MS), 26 with benign MS (B-MS)] were recruited for this study. The levels of serum adipokines and inflammatory mediators were measured using immunoassay methods. Results The levels of adiponectin, MCP-1, TNF-α and IL-6 were significantly higher in C-MS patients compared with B-MS patients and healthy controls. Only adiponectin and MCP-1 levels remained significantly high after Bonferroni correction. Adiponectin, MCP-1 and TNF-α levels showed a modest correlation with expanded disability status scale (EDSS) scores, which disappeared after Bonferroni correction. Conclusions Our findings suggest the potential role of adipokines in pathogenesis and clinical progression of MS. Adiponectin and MCP-1 might potentially serve as prognostic biomarkers in MS.

INTRODUCTION Topiramate has a negative modulatory effect on voltage-gated ion channels involved in neuromuscular junction transmission. To investigate the potential impact of topiramate on muscle contraction, phrenic nerve-hemidiaphragm preparations were used as a neuromuscular junction model. METHODS Phrenic nerve-hemidiaphragm preparations were isolated from rats and were mounted in oxygenated Krebs solution. Preparations were stimulated in the presence of topiramate and phenytoin with a rectangular pulse at 0.1 Hertz, 0.3 miliseconds, and 3 miliseconds of duration, forming indirect, direct single, and tetanic muscle contractions, respectively. The expressed tension was isometrically recorded via a force displacement transducer on a polygraph. RESULTS Topiramate and phenytoin directly and indirectly reduced contractions in a time-dependent manner. By contrast, topiramate, but not phenytoin, showed an excitatory effect on contraction in tetanic potentiation. CONCLUSION To our knowledge, our study is the first to show the effects of topiramate on muscle contraction and neuromuscular junction transmission. Topiramate needs to be used with caution in patients with muscle weakness and respiratory problems.

Neuromyelitis optica (NMO) is an inflammatory/demyelinating disorder predominantly affecting the optic nerves and spinal cord. Recent findings showed an underlying humoral abnormality in NMO, characterized by a serum antibody against aquaporin-4 (Aqp-4-Ab). In this study, we evaluated the Aqp-4-Ab status among Turkish patients with NMO to determine the clinical and prognostic relevance. Serum samples from 35 consecutive patients with NMO followed at a single center and diagnosed according to the 2006 revised criteria, were evaluated for Aqp-4-Ab. All samples were obtained during a relapse prior to any immunosuppressive treatment. Aqp-4-Ab was positive in 21/35 (60%) patients. Among these cases, 11 had an EDSS of 6.0 or more, whereas only two patients in the seronegative group had such severe disability (p < 0.05). Overall, seropositive cases had a mean EDSS score of 5.1 ± 2.2 compared with 3.5 ± 1.7 in seronegative cases (p < 0.01). There were trends towards female predominance in seropositive cases and a monophasic course predominance in seronegative cases. Disease duration, age at onset, number of attacks and time to definite NMO did not differ between groups. Our findings in this single-center cohort suggest that the presence of Aqp-4-Ab might have a prognostic significance indicating a more severe disease course.

Background Seronegative NMO is highly prevalent in non-Western countries implying the presence of as yet unknown antibodies (Ab). We investigated potential novel Ab in aquaporin-4 Ab (AQP-4-Ab) positive and negative NMO patients. Methods Sera of 20 NMO patients were examined for AQP-4, myelin oligodendrocyte glycoprotein (MOG) and glycine receptor (GlyR) Ab by cell-based assays. Results AQP-4-Ab was identified in 10 NMO patients, MOG-Ab was detected only in one AQP-4-Ab positive patient and GlyR-Ab was detected in two AQP-4-Ab negative patients. GlyR-Ab positive patients displayed simultaneous optic neuritis and transverse myelitis attacks and relatively low disability, whereas MOG and AQP-4-Ab double positive patient had a significantly increased disability. Conclusion This study showed for the first time the presence of GlyR-Ab in Turkish NMO patients. In contrast with previous reports, MOG Ab does not appear to be a distinctive marker for Turkish AQP-4-Ab negative NMO patients.

Encephalitis associated with leucine-rich glioma inactivated 1 (LGI1) antibodies is often encountered in elderly male patients and may infrequently present with isolated syndromes. A 6-year-old boy was admitted with acute onset severe oral and facial stereotypic and choreiform movements. On his neurologic examination, he had repetitive and rhythmic movements in orolingual muscles including tongue protrusion, limb chorea and minimal facial stereotypic movements. Anti-streptolysin O (ASO) titers were found severely elevated in several measurements. Well-characterized antibodies against ion channels and synapse proteins were negative whereas LGI1 antibody was positive in both serum and CSF. Marked clinical improvement was observed after immunotherapy. Here, we present the first pediatric case with LGI1 antibody associated hyperkinetic movement disorders and emphasize the importance of investigating neuronal autoantibodies in patients with isolated and treatment resistant movement disorders.

OBJECTIVE: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a “reverse” round-robin with 15 centers across Europe/U.S. METHODS: Samples from ALS and control patients (5/5 each center, n = 150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories. RESULTS: CSF pNfH was increased (p 568.5 pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%). CONCLUSION: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up. © 2016 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases

BackgroundAlthough specific role players are currently unknown, contribution of inflammatory mediators has been suggested in the pathophysiology of idiopathic intracranial hypertension (IIH), which is a disease more prevalent in obese female individuals of childbearing age. We aimed to investigate the levels of adipokines and cytokines to demonstrate possible markers for inflammation that participate in IIH pathophysiology and their association with clinical features of IIH.MethodsIIH patients, diagnosed according to the revised criteria, and age-, gender- and body mass index (BMI)-matched healthy controls were enrolled in this study. Serum samples were evaluated for insulin-like growth factor 1, insulin, nesfatin, adiponectin, interleukin (IL)-1β, IL-6, IL-8, leptin, plasminogen activator inhibitor type-1, resistin, tumour necrosis factor-alpha (TNF-α) and monocyte chemotactic protein 1 via enzyme-linked immunosorbent assay or multiplex immunoassays.ResultsIL-1β level was significantly higher ( p = 0.012), and IL-8 and TNF-α levels were significantly lower in the IIH group ( p ConclusionAltered serum levels of IL-1β, IL-8 and TNF-α seem to be associated with IIH pathogenesis, and these cytokines may be used as prognostic markers in IIH to predict relapse.

Background and Objective Autoimmunity is an emerging field of research in the etiology of different neurological disorders including epilepsy. We aimed to investigate the presence of neuronal autoantibodies in focal epilepsy with unknown cause and their clinical correlates in both drug-responsive and resistant patients. Method Between 2009 and 2010 94 patients were prospectively enrolled, had their antibodies tested and clinically followed." An additional 50 age- and gender-matched controls were also tested for antibodies. Age at examination, gender, age at onset, seizure frequency, risk factors, seizure precipitants, and type of seizures were noted. Plasma obtained from patients was frozen at −80 °C and analysed for autoantibodies against VGKC-complex, VGCC, GAD, LGI1, CASPR2, NMDA, AMPA and GABAB receptors with immunocytochemistry and radioimmunoassay as required. Results Thirteen (13.8%) patients, but none of the controls, had antibodies (p = 0.003). Antibodies were directed against the uncharacterized components of VGKC-complex in 5 patients (5.3%), GAD in 4 patients (4.2%), NMDA-R in 1 patient (1%), AMPA-R in 1 patient (1%) and both GAD and VGKC-complex in 2 patients (2.1%). Prognosis of epilepsy, in subsequent follow-up, did not correlate to general presence of anti-neuronal antibodies with slightly more patients with antibodies epilepsy control than without (76.9% vs. 69.1%, not-statistically significant. Three patients with suspected active autoimmunity and epilepsy who were treated, showed a response to treatment with a reduction in the seizure frequency. Although most clinical features were identical between seropositive and seronegative patient groups, seropositive patients were more likely to have inflammatory/autoimmune disorders in their medical history. Discussion In keeping with previous studies, we have shown anti-neuronal antibodies in a proportion of focal epilepsy patients. Although autoimmunity might merely occur as a bystander effect in many chronic neurological disorders, association of anti-neuronal antibodies with good response to immunotherapy and coexisting autoimmune disorders suggests that anti-neuronal autoimmunity might participate in seizure formation at least in a subgroup of focal epilepsy patients. Conclusion Immunity may play a role in some patients with unknown etiology regardless of prognosis and immunmodulatuar treatment may be helpful in seropositive group.

Introduction Antibodies directed against neuronal surface antigens have recently been identified in patients with focal temporal lobe epilepsy (TLE) of unknown cause and mesial TLE with hippocampal sclerosis (MTLE-HS), thereby emphasizing the role of autoimmunity in TLE. Antibodies to contactin-associated protein-like 2 (CASPR2) are prevalent in MTLE-HS patients. We aimed to find out whether anti-neuronal autoimmunity might be involved in CASPR2 antibody-related MTLE-HS. Methods Surgically resected medial temporal lobe specimens of seropositive and seronegative MTLE-HS patients were examined with hematoxylin and eosin and immunohistochemical staining using specific immune cell markers. Results Two of 5 CASPR2 antibody-positive MTLE-HS patients showed polymorphonuclear and mononuclear cells infiltrating the subarachnoidal region. One of these patients also showed mononuclear cell infiltration in the parenchyma of the temporal lobe cortex. Subarachnoidal and parenchymal infiltrates contained CD3+, CD8+, and CD68+ cells. None of the 13 seronegative MTLE-HS patients displayed cellular infiltrates in their brain samples, and all MTLE-HS patients showed marked neuronal cell loss but no immune cell infiltration in their hippocampi. Conclusion Our results show that CASPR2 antibody-associated MTLE-HS can present with central nervous system inflammation; thus, this subtype of MTLE-HS might have an autoimmune origin.

Management of neuro-Behcet’s disease can be divided into two stages: treatment of acute attacks and prevention of relapses. Treatment of acute attacks is accomplished by high-dose intravenous corticosteroids followed by maintenance treatment with oral steroids for 6–12 months depending on the type and severity of the neurological involvement. Relapses can be prevented by using immunosuppressants. Oral immunosuppressants such as azathioprine and mycophenolate are the most widely utilized agents for this purpose. Patients who are refractory or who cannot tolerate these medications can be managed by cyclophosphamide, interferon alpha, or anti-TNF-α monoclonal antibodies such as infliximab, etanercept, and adalimumab. Recent reports showed that newer agents such as tocilizumab, canakinumab, and anakinra, which exert their biological activity through IL-1 and IL-6 pathways, are also promising treatment alternatives for progressive or relapsing patients.

Background Chemokines are known to play a major role in driving inflammation and immune responses in several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and Parkinson's disease. Inflammation has also been implicated in the pathogenesis of schizophrenia. Aim We aimed to investigate a potential link between chemokines and schizophrenia and analyze the role of MCP-1-A2518G, SDF-1-3'A, CCR5-delta32, CCR5-A55029G, CXCR4-C138T and CCR2-V64I gene polymorphisms in the Turkish population. Methods Genotyping was conducted by PCR-RFLP based on 140 patients and 123 unrelated healthy controls to show the relation between chemokine gene variants and schizophrenia risk. Results Frequencies of CCR5-A55029G A genotypes and CCR5-A55029G AG genotypes were found higher in patients than the controls and even also CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes significantly associated according to Bonferroni correction. However, no significant association was found for any of the other polymorphisms with the risk of schizophrenia. Conclusions Our findings suggest that CCR5-A55029G polymorphisms and CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes might have association with schizophrenia pathogenesis.

Sera of myasthenia gravis (MG) patients with muscle-specific receptor kinase-antibody (MuSK-Ab) predominantly display the non-complement fixing IgG4 isotype. Similarly, mouse IgG1, which is the analog of human IgG4, is the predominant isotype in mice with experimental autoimmune myasthenia gravis (EAMG) induced by MuSK immunization. The present study was performed to determine whether IgG1 anti-MuSK antibody is required for immunized mice to develop EAMG. Results demonstrated a significant correlation between clinical severity of EAMG and levels of MuSK-binding IgG1 +, IgG2 + and IgG3 + peripheral blood B cells in MuSK-immunized wild-type (WT) mice. Moreover, MuSK-immunized IgG1 knockout (KO) and WT mice showed similar EAMG severity, serum MuSK-Ab levels, muscle acetylcholine receptor concentrations, neuromuscular junction immunoglobulin and complement deposit ratios. IgG1 and IgG3 were the predominant anti-MuSK isotypes in WT and IgG1 KO mice, respectively. These observations demonstrate that non-IgG1 isotypes can mediate MuSK-EAMG pathogenesis.

Objective Our aim was to investigate the prevalence of neuronal autoantibodies (NAbs) in a large consecutive series with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and to elucidate the clinical and laboratory clues for detection of NAbs in this prototype of frequent, drug-resistant epilepsy syndrome. Methods Consecutive patients diagnosed with MTLE fulfilling the MRI criteria for HS were enrolled. The sera of patients and various control groups (80 subjects) were tested for eight NAbs after ethical approval and signed consents. Brain tissues obtained from surgical specimens were also investigated by immunohistochemical analysis for the presence of inflammatory infiltrates. The features of seropositive versus seronegative groups were compared and binary logistic regression analysis was performed to explore the differentiating variables. Results We found antibodies against antigens, contactin-associated protein-like 2 in 11 patients, uncharacterised voltage-gated potassium channel (VGKC)-complex antigens in four patients, glycine receptor (GLY-R) in 5 patients, N -methyl-d-aspartate receptor in 4 patients and γ-aminobutyric acid receptor A in 1 patient of 111 patients with MTLE-HS and none of the control subjects. The history of status epilepticus, diagnosis of psychosis and positron emission tomography or single-photon emission CT findings in temporal plus extratemporal regions were found significantly more frequently in the seropositive group. Binary logistic regression analysis disclosed that status epilepticus, psychosis and cognitive dysfunction were statistically significant variables to differentiate between the VGKC-complex subgroup versus seronegative group. Conclusions This first systematic screening study of various NAbs showed 22.5% seropositivity belonging mostly to VGKC-complex antibodies in a large consecutive series of patients with MTLE-HS. Our results indicated a VGKC-complex autoimmunity-related subgroup in the syndrome of MTLE-HS.

Background and purpose Neuromyelitis optica (NMO) is a severe demyelinating inflammatory disorder associated with serum antibodies against aquaporin 4 (AQP4-Ab). A significant number of patients with NMO remain seronegative over time. Long-term observational magnetic resonance imaging (MRI) studies of the CNS in patients with NMO are rare or of limited duration. The objective of this study is to determine long-term MRI characteristics of seropositive and seronegative patients, and assess possible overlap with multiple sclerosis (MS). Methods Clinical and radiological characteristics of 28 patients with NMO at onset and of 17 patients after an average follow-up time of 9 years were recorded. Fifty percent of patients were seropositive for AQP4-Ab. Onset and final brain/spinal MRI scans were retrospectively analysed and compared. Results Significantly more patients in the seronegative group had brain lesions at onset. Spinal lesions of seropositive patients were longer and showed increased cord swelling at onset MRI scans. After the follow-up time the differences between both groups disappeared. Patients in the seropositive group tended to develop brain lesions over time. No patient fulfilled Barkhof's or McDonald's radiological criteria for MS at onset or over time. Conclusion Brain MRI features show differences between seropositive and seronegative patients at time of onset in NMO, but differences between groups vanish over time. None of the AQP4-negative patients fulfill radiological MS criteria on a long-term basis, suggesting that seronegative NMO constitutes an independent entity.

Experimental autoimmune myasthenia gravis (EAMG) in mice has been used to unravel the pathogenic mechanisms and to be used as a preclinical model of myasthenia gravis (MG). Induction of predominantly ocular EAMG in HLA-DQ8 transgenic mice immunized with acetylcholine receptor (AChR) subunits demonstrated the importance of nonconformationally expressed AChR subunits in extraocular muscle involvement. Wild-type (WT) and CD4(+) T cell knockout (KO) C57BL/6 mice developed EAMG upon immunization with AChR in incomplete Freund's adjuvant plus lipopolysaccharide. AChR-specific IgG2(+) B cell frequencies, estimated by Alexa-conjugated AChR, and AChR-reactive IgG2b levels significantly correlated with the clinical grades of EAMG in WT mice. CD4(+) T cell-deficient EAMG mice exhibited AChR antibodies mainly of the IgG2b isotype, emphasizing T helper-independent B cell activation pathways in EAMG induction. These novel EAMG models have suggested that diverse immunopathological mechanisms might contribute to EAMG or MG pathogenesis.

Background Patients with the syndrome of headache with neurological deficits and lymphocytosis (HaNDL) typically present with recurrent and temporary attacks of neurological symptoms and cerebrospinal fluid lymphocytosis. Aim and methods To identify potential HaNDL‐associated antibodies directed against neuronal surface and/or synapse antigens, sera of four HaNDL patients and controls were screened with indirect immunohistochemistry, immunofluorescence, cell-based assay, radioimmunoassay, protein macroarray and enzyme-linked immunosorbent assay (ELISA). Results Although HaNDL sera did not yield antibodies to any of the well-characterized neuronal surface or synapse antigens, protein macroarray and ELISA studies showed high-titer antibodies to a subunit of the T-type voltage-gated calcium channel (VGCC), CACNA1H, in sera of two HaNDL patients. Conclusion Our results support the notion that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis and occurrence of neurological symptoms.

Levels of several cytokines were evaluated in the sera of patients with neuromyelitis optica (NMO) and paraneoplastic or nonparaneoplastic autoimmune encephalitis (AE) and healthy controls (HC). AE patients had higher serum interleukin-17 (IL-17), interferon-gamma (IFN-γ), and IL-12 levels than NMO patients and HC. Also, AE patients with antibodies to cell surface antigens (voltage-gated potassium channel, N-methyl-d-aspartate receptor) displayed increased serum Th17 cytokine (IL-17, IL-23) levels as compared with AE patients with antibodies to intracellular antigens (Hu, Yo), NMO patients, and HC. Aquaporin-4 (Aqp-4) antibody positive NMO patients had higher serum IL-9 levels than Aqp-4 antibody negative NMO patients. IL-17, IL-23, IL-12, and antibody levels were significantly correlated in AE patients with antibodies to cell surface antigens. Our results support the notion that different pathogenic mechanisms are involved in central nervous system diseases associated with antibodies to intracellular and cell surface neuronal antigens. T helper 1 (Th1)-/Th17-type immunities and IL-9 might be important therapeutic targets in AE and NMO, respectively.

IntroductionThere is growing evidence about neuroinflammation in the aetiopathogenesis of bipolar disorder. Early diagnosis and intervention strategies are thought to be excessively important lately.ObjectivesTo check neuroinflammation levels in early stage bipolar disorder and explore the associations with clinical variables.AimsWe aimed to evaluate inflammation and neurodegeneration findings in early stage bipolar disorder.MethodsSerum interleukin 1-receptor antagonist (IL-1Ra), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), high sensitive C reactive protein (hs-CRP), S100B and neuron specific enolase (NSE) levels were assessed by enzyme-linked immunosorbent assays in a total of 30 patients with bipolar disorder in the early stage and compared with 30 matched healthy controls. The clinical symptoms were rated using Montgomery Asberg Depression Scale, Young Mania Rating Scale, Positive and Negative Syndrome Scale and Clinical Global Impression Scale.ResultsAmong the patients with bipolar disorder, 14 (% 46.6) were in a manic/hypomanic state and 12 (% 40) were in a euthymic state. Serum IL-6 levels were significantly higher (P = 0.018), TNF-α and S100B levels were significantly lower in the early stage group (P < 0.001 and P = 0.03, respectively). After repeated analysis with only drug-naive patients, the results showed no difference. There was a positive and significant correlation between TNF-α levels and CGI, MADRS scores (all P < 0.05); NSE levels and MADRS scores (P < 0.05).ConclusionsThis study supported the association of early stage bipolar disorder with inflammation and neurodegeneration. IL-6 may be a potential biomarker. Thus, early diagnosis and intervention may be crucial to prevent progressive neuroinflammation and neurodegeneration in early stages of disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

In myasthenia gravis (MG), the neuromuscular transmission is impaired by antibodies (Abs) specific for muscle acetylcholine receptor (AChR). Anti-AChR Abs can be detected in the serum of MG patients, although their levels do not correlate with disease severity. In this study, we developed a flow cytometric assay for the detection of peripheral blood AChR-specific B cells to characterize B cell phenotypes associated with experimental autoimmune myasthenia gravis (EAMG). Alexa-conjugated AChR was used as a probe for AChR-specific B cells (B220+Ig+). Mice with EAMG had significantly elevated frequencies of AChR-specific IgG2+ and IgM+ B cells. While the frequencies of IgG2+ B cells and plasma anti-AChR IgG2 levels significantly correlated with the clinical grades of EAMG, the frequencies of IgM+ B cells and plasma anti-AChR IgM levels did not. These results indicate that the frequency of AChR-specific and IgG1+ (mouse IgG2 equivalent) peripheral blood B cells and anti-AChR IgG1 levels could be potential biomarkers for MG disease severity.

To identify an antibody biomarker for prediction of conversion from radiologically isolated syndrome (RIS) to relapsing remitting multiple sclerosis (RRMS).Sera of 13 RIS patients were screened by a protein macroarray derived from human fetal brain cDNA library.Sequencing of a clone with the highest signal intensity revealed sorcin as a potential target autoantigen in RIS patients. ELISA studies showed high-titer sorcin-antibodies in 3 of 4 RIS patients who converted to RRMS in a 5-year follow-up period and 13 of 23 control RRMS patients.The value of sorcin antibody as a predictor of conversion from RIS to RRMS requires to be tested in larger prospective studies.

Uveitis is occasionally encountered in multiple sclerosis (MS) patients. The objective of this report is to investigate whether uveitis has a prognostic impact on the clinical course of MS. Several clinical and demographic features were compared between 41 MS patients with uveitis and 100 randomly selected MS patients without uveitis. While there were no significant differences by means of gender, age of MS onset, oligoclonal band positivity and disease duration, EDSS and progression index (PI) scores of MS patients with uveitis were significantly lower than those without uveitis ( p = 0.004 and

Background: GQ1b antibody (GQ1b-Ab) is detected in approximately two-thirds of sera of patients with Bickerstaff’s encephalitis (BE). Whilst some of the remaining patients have antibodies to other gangliosides, many patients with BE are reported to be seronegative. Methods and Results: Voltage-gated potassium channel antibody (VGKC-Ab) at high titer was detected during the diagnostic work-up of one patient with BE. Sera of an additional patient with BE and nine patients with Miller Fisher syndrome (MF) (all GQ1b-Ab positive) were investigated for VGKC-Ab and other anti-neuronal antibodies by radioimmunoprecipitation using 125I-dendrotoxin-VGKC and immunohistochemistry, respectively. Two patients with MF exhibited moderate titer VGKC-Abs. Regardless of positivity for VGKC or GQ1b antibodies, serum IgG of all patients with BE and MF reacted with the molecular layer and Purkinje cells of the cerebellum in a distinctive pattern. Conclusion: Voltage-gated potassium channel antibodies might be involved in some cases of BE or MF. The common staining pattern despite different antibody results suggests that there might be other, as yet unidentified, antibodies associated with BE and MF.

We report a 44-year-old man presenting with left hemiparesis following influenza vaccination. The neuroimaging studies showed a large, contrast-enhancing brainstem lesion and multiple punctate lesions suggesting microhaemorrhages in both cerebral hemispheres. The patient showed a remarkable response to high dose steroid treatment. Detailed diagnostic studies failed to yield any results supporting inflammatory/demyelinating diseases, suggesting that influenza vaccination might have been associated with the clinical findings. Our case implies that vaccination might be related with a wide range of clinical syndromes, including brainstem encephalitis.

Classical complement pathway factor, C4 is required for experimental autoimmune myasthenia gravis (EAMG) pathogenesis. C4 is also a central component of the mannose binding lectin (MBL) pathway suggesting that this pathway might also be involved in MG pathogenesis. However, MBL gene deficient mice displayed intact anti-acetylcholine receptor (AChR)-immune response and neuromuscular junction (NMJ) IgG and complement accumulation following AChR-immunization. Moreover, no significant difference was observed between the serum MBL levels of 77 anti-AChR antibody positive generalized MG patients and 105 healthy controls. Therefore, MBL pathway does not play a role in EAMG/MG pathogenesis.

Mice deficient for complement factors C3, C4, or C5 are resistant to experimental autoimmune myasthenia gravis (EAMG). Acetylcholine receptor (AChR) immune lymph node cells (LNC) of C3 deficient mice produce less interleukin 6 (IL-6), and EAMG-resistant IL-6 deficient mice have less serum C3. Increased serum C1q-circulating immune complex (CIC) levels correlated with EAMG disease severity in RIIIS/J mice. The CIC promotes EAMG severity by stimulating the production of LNC IL-6, serum C1q, and C3 via FCgammaR interaction. Therefore, EAMG/MG could be treated by blocking the activation of classical complement pathway (CCP) and/or IL-6. Anti-C1q antibody administration before and following AChR immunization suppressed EAMG by reducing LNC IL-6 production and neuromuscular junction deposits of IgG, C3, and C5b-C9 complexes. Treatment with low dose (10 microg) of anti-C1q antibody twice a week for 4 weeks in mice with ongoing clinical EAMG reduced the clinical severity of disease and LNC IL-6 production. Therefore, inhibitors of CCP factors C1q, C2, or C4 could treat MG and would preserve the alternate complement pathway activation. Our goal is to tailor MG therapy using anti-C2/C4 reagents in combination, with or without anti-cytokine (e.g., anti-IL-6) reagents.

Deficiency of the inhibitory FcgammaRIIB renders mice susceptible to autoimmune disorders characterized with cellular infiltration of target tissue. To analyze the role of FcgammaRIIB in an antibody-mediated autoimmune disease, experimental autoimmune myasthenia gravis (EAMG), FcgammaRIIB knockout (KO) and wild-type mice were immunized with acetylcholine receptor (AChR). In contrast with previous reports, FcgammaRIIB KO mice were mildly resistant to EAMG despite preserved anti-AChR antibody production and neuromuscular junction complement deposition capacity. EAMG resistance was associated with reduced lymph node cell IL-6 and IL-10 production and increased CD4(+)CD25(+) cell ratios in lymph nodes. Our data suggest that FcgammaRIIB promotes antibody-mediated autoimmunity.

We report two men with limbic encephalitis (LE) refractory to corticosteroids, IVIg and plasma exchange. Both patients had serum/CSF antibodies that reacted with the cytoplasm of neurons. Probing of a hippocampal cDNA library resulted in the isolation of adenylate kinase 5 (AK5). Patients' antibodies, but not those of 111 controls, recognized AK5-expressing phage plaques. Human AK5-affinity purified antibodies reproduced the neuronal immunolabeling of patients' antibodies, and co-localized with a rabbit AK5 antibody, confirming that the brain autoantigen was AK5. Detection of antibodies to AK5 in LE patients carries a poor prognosis, and suggests the prompt use of aggressive immunosuppression.

To test the feasibility of classical complement pathway manipulation in experimental autoimmune myasthenia gravis (EAMG) treatment, C57BL/6 (B6) and RIIIS/J mice with EAMG were treated with 10 microg or 100 microg of anti-C1q Ab or isotype Ab. Treatment with 10 microg anti-C1q Ab significantly reduced the clinical severity, decreased lymph node cell IL-6 production and T cell populations. Conversely, administration of 100 microg anti-C1q Ab caused harmful side effects such as increased serum anti-acetylcholine receptor antibody, immune complex, C3 and lymph node B cell levels and kidney C3 and IgG deposits, which reduced the treatment efficacy.

To investigate the significance of humoral immunological factors in juvenile myasthenia gravis (JMG) patients, 11 children with JMG (age of onset between 2 and 13 years) and 8 healthy controls were enrolled. Plasma IL-2, IL-10, IFN-gamma, TNF-alpha, complement factor C3, C4, and C1q levels were measured by ELISA. IL-2, IL-10, TNF-alpha, C3, and C4 levels were significantly elevated in the patient group. Moreover, plasma IL-10 levels were associated with the presence of anti-AChR antibody and response to treatment suggesting a critical role for IL-10 in JMG pathogenesis.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of the dopaminergic neurons in substantia nigra, presumably due to increased apoptosis and oxidative stress. To investigate whether PD-induced survival/apoptosis gene expression changes can serve as prognostic biomarkers of PD, we measured expression levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway factors and additional apoptotic and anti-apoptotic factors in peripheral blood mononuclear cells (PBMC) of PD patients (n=50) and healthy controls (n=50) by real time PCR. Expression levels of apoptotic factors phosphatase and tensin homolog (PTEN) and mitochondrial apoptosis-inducing factor 1 (AIFM1) were significantly decreased, anti-apoptotic factors DJ-1 and Akt-1 were significantly increased and anti-apoptotic Bcl-2 was significantly decreased in PD patients. Expression levels of AIFM1 were significantly correlated with Hoehn-Yahr scores. Moreover, PD patients with postural instability showed significantly reduced expression levels of anti-apoptotic DJ-1, Akt-1 and mTOR than PD patients without postural instability. Expression profiles of brain samples of mice with rotenone-induced PD model and PBMC samples of PD patients showed remarkable resemblance. Our results indicate that the anti-apoptotic PI3K/Akt pathway is over activated in PD, presumably as an effort to compensate for increased neuronal apoptosis and oxidative stress. By contrast, patients with postural instability show reduced anti-apoptotic factor expression suggesting that this compensating mechanism fails in patients with this particular motor symptom. PBMC expression levels of AIFM1 might serve as a biomarker of disability and disease progression in PD.

Background Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction (NMJ), mostly associated with acetylcholine receptor (AChR) antibodies. Around 5–10 % of MG patients show antibodies to muscle-specific tyrosine kinase (MuSK). Mesenchymal stem cell (MSC) administration has been shown to ameliorate muscle weakness in the experimental autoimmune myasthenia gravis (EAMG) model induced by AChR immunization. Methods To investigate the efficacy of stem cell treatment in MuSK-related EAMG, clinical and immunological features of MuSK-immunized mice with or without dental follicle MSC (DFMSC) treatment were compared. Results MuSK-immunized mice intravenously treated with DFMSC after second and third immunizations showed significantly lower EAMG incidence and severity and reduced serum anti-MuSK antibody, NMJ IgG, and C3 deposit levels and CD11b+ lymph node cell ratios. Moreover, lymph node cells of DFMSC-administered mice showed reduced proliferation and IL-6 and IL-12 production responses to MuSK stimulation. By contrast, proportions of B and T cell populations and production of a wide variety of cytokines were not affected from DFMSC treatment. Conclusions Our results suggest that DFMSC treatment shows its beneficial effects mostly through suppression of innate immune system, whereas other immune functions appear to be preserved. Stem cell treatment might thus constitute a specific and effective treatment method in MuSK-associated MG. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0451-0) contains supplementary material, which is available to authorized users.