To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value = 3.55 × 10–9), IL12A (P = 3.08 × 10–8) and MPHOSPH9/CDK2AP1 (P = 3.96 × 10–8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P = 1.18 × 10–5) and in peripheral blood mononuclear cells from subjects with MS (P = 0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

recently it has become clear that hyponatraemia in the cerebral salt wasting syndrome is accompanied by hypovolaemia.' 2 We report a patient with cerebral salt wasting after aneurysmal subarachnoid haemorrhage who showed remarkable changes in urine production during surgery. A 46 year old woman was admitted with severe headache and vomiting. Physical examination was unremarkable. Brain CT showed a subarachnoid haemorrhage with blood in the suprasellar cisterns and the left Sylvian fissure. Two days later she developed mild hyponatraemia and polyuria; salt and fluid loss were fully compensated by 0 9% NaCl infusion. On day 9 she was found unconscious with respiratory failure and bradycardia and CT disclosed a recurrent subarachnoid haemorrhage in the left Sylvian fissure. The patient regained consciousness and she gradually recovered from a mild aphasia and right facial weakness. However, from day 12 onwards she again developed a progressive polyuria of up to 21 200 ml per day (on day 22) and a 24 hour renal sodium loss of 2630 mmol. The plasma sodium range was between 128 and 142 mmol/l, and the colloid osmotic pressure was between 18-7 and 24-0 mm Hg. Serum ADH concentrations were normal.Treatment with fludrocortisone had no effect on renal sodium loss. Despite the extreme polyuria plasma atrial natriuretic protein concentrations were within the normal range (up to 11-1 pmol/l, normal 3-23 pmol/l); atrial natriuretic protein in CSF was not assessed. Daily transcranial Doppler sonography was indicative of cerebral vasospasm and therefore angiography was postponed until day 22. An aneurysm of the left middle cerebral artery was disclosed, which was successfully clipped on day 24. Whereas the diuresis 24 hours before and after the neurosurgical procedure was 600-700 ml/hour, the mean intraoperative (from incision to the last suture) production of urine was 150 ml/hour. The largest reduction in diuresis was seen while the dura was open. Soon after suturing the dura, urine production rose to preoperative values. Two days after surgery diuresis decreased remarkably and was back to normal on the fourth day after operation. Repeated measurements of plasma sodium were also normal. The patient had fully recovered two months after the operation.Our patient had a very pronounced urinary sodium loss of up to 60 g per day.Opening of the dura resulted in a decrease in diuresis of 75%. Both a reactive increase of CSF production and a decrease in the intracranial pressure may have been important. Because an increase of atrial natriuretic protein in CSF (and maybe other humoral factors) results in a decrease in CSF production and an increase in natriuresis, an increase in CSF production after loss of CSF through the open dura may have induced a decrease of atrial natriuretic protein, resulting in a decrease in natriuresis.In patients with subarachnoid haemorrhage D6czi and Bodosi found a linear correlation between the intracranial pressure and atrial natriuretic protein concentrations in CSF. So lowering the intracranial pressur...

Background: People with multiple sclerosis face significant employment-related challenges, with little known of the drivers of these outcomes. Objective: We examined prospective trajectories of employment-related outcomes up to 11 years following a first episode of central nervous system (CNS) demyelination (FCD). Methods: Participants were aged 18–59 years, at FCD, with at least two observations and were employed at study entry or anytime during follow-up ( n = 207). Outcomes were employment status (full-time, part-time and unemployed), average workhours per week and disability support pension (DSP; receiving/not receiving). We used group-based trajectory modelling to identify groups with common trajectories. Factors associated with trajectory membership were explored using log-multinomial regression. Results: Distinct trajectories were identified for employment (4), workhours (4) and DSP (2). Compared with stable full-time, female sex was strongly associated with being in the stable part-time trajectory (risk ratio (RR): 5.35; 95% confidence interval (CI) = 2.56–11.20; p < 0.001). A greater level of disability at 5-year review (RR: 1.35; 95% CI = 1.19–1.53) and having more than two comorbidities at baseline (RR: 2.77; 95% CI = 1.37–5.64) were associated with being in early and late deteriorated employment trajectories, respectively. Compared with the increased part-time trajectory, every additional relapse during the 5 years post-FCD was associated with a 10% increased risk of being in the reduced part-time trajectory (RR = 1.10; 95%CI = 1.00–1.22). For every additional EDSS point at 5-year review, the risk of being in the DSP trajectory increased (RR = 1.21; 95% CI = 1.05–1.41). Conclusion: These trajectories indicate substantial heterogeneity and the complex impact of MS on employment from its earliest timepoints. Understanding these trends could enable better targeting of interventions to facilitate workforce retention, particularly for females, those with a higher number of comorbidities, more frequent relapses and greater rate of disability accrual.

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Background: The strong association of multiple sclerosis (MS) and Epstein-Barr virus (EBV) infection raises the question whether there might be EBV seronegative patients with MS at all. Objective: To determine the rate of EBV seronegativity in a large and well-characterized cohort of patients with a clinically isolated syndrome (CIS) or early relapsing-remitting (RR)MS. Methods: Epstein-Barr nuclear antigen-1 (EBNA-1) antibodies were measured by a chemiluminescent assay (CLIA) in serum samples of 901 patients (median [interquartile range] age 33 [27-41] years, 69.9% females) with a CIS (n = 380) or early RRMS (n = 521) from the German National MS cohort. In EBNA-1 antibody seronegative patients, antibodies to the EBV viral capsid antigen (VCA) were measured by CLIA. EBNA-1 and VCA antibody double seronegative patients were analysed by an EBV immunoblot. Results: Antibodies to EBNA-1 were detected in 839 of 901 patients with CIS/RRMS. Of the 62 EBNA-1 antibody seronegative patients, 45 had antibodies to VCA. Of the 17 remaining patients, all had antibodies to EBV as detected by EBV immunoblot. Thus, all 901 (100%) patients with CIS/RRMS investigated in this study were EBV seropositive. Conclusions: The absence of EBV seronegativity in this large cohort of patients with early MS provides further evidence for a crucial role of EBV in MS and suggests that a negative EBV serology in a patient with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS. Disclosure SA reports no disclosures. BE reports no disclosures. BA received travel grants from Novartis, not related to this work. NH reports no disclosures. GA reports no disclosures. IRK reports no disclosures. M-MH received travel expenses from Bayer Health Care and honoraria for an advisory board from Merck Serono GmbH. LA reports no disclosures. FL serves as an advisory board member for Roche Pharma and has received travel grants from Teva Pharma. SG reports no disclosures. LK received compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Roche, Novartis Pharma); research support (Biogen, Novartis Pharma). SGM received honoraria for lecturing, travel expenses for attending meetings, and/or financial research support from Almirall,

compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pain may be present in both LGI-Ab + and CASPR2-Ab+patients, and is immunotherapy responsive. Serum IgG from CASPR2-Ab+patients more frequently bound sensory neurons and dorsal root ganglia, suggesting pathophysiological differences which may underlie the more severe pain in these patients.

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