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AIM To investigate the association between circulating anti-dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs). METHOD One hundred and thirty-seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4-16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti-D2R antibodies were evaluated using a cell-based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti-D2R antibodies was measured with McNemar's test and repeated-measure logistic regression models, adjusting for potential demographic and clinical confounders. RESULTS At exacerbation, 11 (8%) participants became anti-D2R-positive ('early peri-exacerbation seroconverters'), and nine (6.6%) became anti-D2R-positive at post-exacerbation ('late peri-exacerbation seroconverters'). The anti-D2R antibodies were significantly associated with exacerbations when compared to baseline (McNemar's odds ratio=11, p=0.003) and conditional logistic regression confirmed this association (Z=3.49, p

There is major evidence for the involvement of immunological processes in the pathophysiology of schizophrenia. Especially alterations of T-cell function and activation of the inflammatory response system appear to be linked to schizophrenia. A mild chronic inflammation process has been proposed and repeated findings of altered serum cytokine levels led to the hypothesis of a TH2 shift or cytokine imbalance in schizophrenia. We investigated serum levels of TH1 and TH2 related cytokines and immune markers in 25 patients suffering an acute schizophrenic episode (all unmedicated, 22 neuroleptica-naive) at different stages of disorder (18 first episode, FEP; 7 recurrent episode, REP) compared to 25 age and sex matched healthy controls. In patients, we found an increase of the TH2 system cytokine IL-13 (p = 0.039) and a decrease of the TH1 system markers sICAM-1 (p = 0.011) and sIL-2R (p = 0.063, n. s.). Elevation of the pro-inflammatory cytokine IL-6 was not significant (p = 0.052). The effect of sIL-2R decrease was greater in the FEP subgroup (p = 0.01) of patients. We found no group differences in the other investigated immune markers: IL-4, IL-8, TNF-alpha, and Interferon-gamma, in which most readings were below the lower detection limit of the respective assay. Our findings support the notion of a TH1/TH2 imbalance particularly in the acute manifestation phase of schizophrenia. In the long run, this may lead to the identification of cytokine patterns that are applicable as trait or state markers, may be helpful in making or ensuring diagnosis or in monitoring therapy.

OBJECTIVE Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p

Background Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. Objectives To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. Methods This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. Results All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. Conclusions Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.

Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.

Several lines of evidence support a role for Epstein–Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02–1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals.PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed.The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13-0.26)) and for paediatric MS was 0.18 (95% CI 0.11-0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03-0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22-0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0-0.43).The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

Interest in the role of B-cells in multiple sclerosis (MS) pathogenesis has increased, and a number of B-cell targeted therapies are currently in clinical trials. B-cells are key mediators of the humoral immune response, with roles including antibody production and acting as antigen presenting cells. Whilst previously, the presence of B-cells within MS plaques has been thought to be secondary to T-cell dysregulation, it is now becoming clear that B-cells play an independent role in disease. In this review we will discuss the potential role of B-cells in MS, how this influences our understanding of the disease, and potential therapeutic implications.

Multiple sclerosis (MS) is a complex immune-mediated disorder of the CNS, which results from a combination of genetic and environmental factors and their interactions [1]. Although genome-wide asso...

Background: The N-methyl-D-aspartate receptor (NMDAR) is a type of ionotropic receptor belonging to the glutamate receptor superfamily found abundantly in the cortex, basal ganglia, and sensory pathways of the nervous system. The receptor is highly permeable to calcium ions and plays a key role in the plasticity of synapses, which is believed to underlie memory and learning. The NMDAR has been associated with a range of neurological disorders including ischemic brain damage and epilepsy, andmore speculatively with neurodegenerative disorders such as Alzheimer's and Huntington's chorea. Anti-NMDA receptor encephalitis has been recently identified as treatment responsive encephalitis associatedwith anti-NMDA receptor antibodies (Iizuka and Sakai, 2008). These antibodies bind to the NR1/NR2 heteromers of the NMDAR and antibody levels are known to correlate with the clinical severity of the disease. Clinical features seen in neuropsychiatric disorders such as Tourette's syndrome (TS) overlap with NMDAR receptor encephalitis, which might make it a part of the spectrum of anti-NMDAR disorders. Aims: Pathogenic antibodies against the NMDAR have been implicated in a range of disorders, however, the full clinical spectrum and treatment responses are still unclear. Therefore, in the present study we analysed serum samples from children diagnosed with TS for the presence of anti-NMDAR antibodies. Materials and methods: Sera from 21 TS patients with a mean age of 11 years were analysed for the presence of antibodies against the NMDAR using HEK293 cells transfected with NR1:NR2B subunits and co-transfected with enhanced green fluorescent protein (EGFP). According to the number of cells stained and intensity of staining the samples were scored between 0 and 4 (0= negative, 4= strongly positive). Results: Out of the 21 samples tested in the assay 4 were found positive for antibodies against the NMDAR. All 4 serum samples came frommale patients diagnosed with TS with an age range of 8 to 14 years. Conclusions: In the present study the presence of anti-NMDAR antibodies in the sera of 4 TS patients has been demonstrated. TS is co-morbid with multiple conditions like obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) so an understanding into its pathogenic mechanism would have major implications in the field of neuropsychiatry.

OBJECTIVE: To determine whether multiple sclerosis (MS) and infectious mononucleosis (IM) share common HLA associations. DESIGN: A prospective cohort study was conducted from October 1, 1999, through September 30, 2003. SETTING: University of Edinburgh Richard Verney Health Centre, Edinburgh, Scotland. PATIENTS: Participants included 179 individuals who underwent asymptomatic Epstein-Barr virus seroconversion and 175 patients who developed IM. INTERVENTION: Genotyping for 5 classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1). MAIN OUTCOME MEASURE: Diagnosis of IM and allele frequency. RESULTS: Allelic analysis showed that HLA-DRB1*01:01 was significantly associated with the development of IM (odds ratio, 3.2; P < .001). Patients with IM and HLA-DRB1*01:01 had a lower Epstein-Barr virus viral load compared with those without the allele (median, 783 vs 7366 copies/10(6) peripheral blood mononuclear cells; P = .03). CONCLUSION: HLA-DRB1*01:01 is protective against developing MS; thus, a common genetic basis between IM and MS is not supported.