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Neurofilaments (Nf) are major structural proteins that occur exclusively in neurons. In spinal cord injury (SCI), the severity of disease is quantified by clinical measures that have limited sensitivity and reliability, and no blood-based biomarker has been established to further stratify the degree of injury. We aimed to examine a serum-based NfL immunoassay as predictor of the clinical outcome in SCI.Longitudinal measurement of serum NfL was performed in patients with central cord syndrome (CCS, n=4), motor-incomplete SCI (iSCI, n=10), motor-complete SCI (cSCI, n=13) and healthy controls (HC, n=67), and correlated with clinical severity, neurological outcome, and neuroprotective effect of the drug minocycline.Baseline NfL levels were higher in iSCI (21 pg/mL) and cSCI (70 pg/mL) than in HC (5 pg/mL, p=0.006 and p0.001) and CCS (6 pg/mL, p=0.025 and p=0.010). Levels increased over time (p0.001) and remained higher in cSCI versus iSCI (p=0.011) and than in CCS (p0.001). NfL levels correlated with American Spinal Injury Association (ASIA) motor score at baseline (r=-0.53, p=0.004) and after 24 h (r=-0.69, p0.001) and 3-12-month motor outcome (baseline NfL: r=-0.43, p=0.026 and 24 h NfL: r=-0.72, p0.001). Minocycline treatment showed decreased NfL levels in the subgroup of cSCI patients.Serum NfL concentrations in SCI patients show a close correlation with acute severity and neurological outcome. Our data provide evidence that serum NfL is of prognostic value in SCI patients for the first time. Further, blood NfL levels may qualify as drug response markers in SCI.

Background. Mitoxantrone (MTX) and Rituximab (RTX) are successfully used for treatment of multiple sclerosis (MS) and can be combined to increase efficacy. Objective. We used MTX, RTX, and methylprednisolone in a single combined regiment and observed patients prospectively. Methods. We present results of observational pilot study of combined therapy of RTX and MTX in 28 patients with active MS. Therapeutic protocol consisted of two infusions within 14 days. First infusion was 1000 mg methylprednisolone (MP) IV, 1000 mg RTX IV, and 20 mg MTX IV. On day 14, 1000 mg MP IV and 1000 mg RTX IV were given. Patients were followed prospectively from 12 to 48 months. Results and Conclusion. There were no relapses among all 28 patients during the observation period. B-cell depletion of CD19+ and CD19+/CD27+ memory B-cell subpopulation in both compartments was confirmed in all patients at 6 months. We found a more rapid reconstitution of B cells in the CSF than in the peripheral blood and longstanding depression of CD19+CD27+ memory B-cell. Conclusion. Effectiveness of combined regimen of RTX and MTX could be related to longstanding depletion of CD19+CD27+ memory B-cell subset.

The importance of bone health is increasingly recognised, and there is mounting evidence that neurological conditions are associated with a significantly increased risk of osteoporosis and fractures. This increase in risk is likely to be multifactorial. Multiple sclerosis and Parkinson's disease were identified in the Global Longitudinal Study of Osteoporosis in Women study as significantly associated with osteoporosis. Here, we discuss the literature on bone health, falls and fractures in MS and akinetic-rigid syndromes, and suggest strategies to investigate and manage bone health in the neurology clinic.

Background Oligoclonal bands (OCBs) unique to the cerebrospinal fluid are used in the diagnosis of multiple sclerosis (MS). The precise prevalence of OCBs in MS and clinically isolated syndrome (CIS) is unknown. The influence of OCBs on clinical outcomes has not been quantified. OCB prevalence has been associated with latitude in a single study, if confirmed this would provide avenues for further study. Methods Using a systematic review and meta-analysis approach, the proportion of OCB-positive MS and CIS and the influence of OCBs on clinical outcomes were calculated. The relationship between latitude and OCB prevalence was calculated using linear regression. Results Seventy-one articles were included. Overall, 87.7% of 12 253 MS and 68.6% of 2685 CIS patients were OCB positive. OCB-positive MS patients had an OR of 1.96 of reaching disability outcomes, although a number of negative studies did not provide data. OCB-positive CIS patients had an OR of 9.88 of conversion to MS. Latitude predicted OCB status in MS patients (p=0.009) but not in CIS patients. Conclusions This is the largest study of OCB prevalence in MS and CIS. OCB positivity strongly predicts conversion from CIS to MS. The relationship between latitude and OCBs is confirmed, and this finding warrants further investigation.

Background: Patient-Reported Expanded Disability Status Scale (PREDSS) tools are an attractive alternative to the Expanded Disability Status Scale (EDSS) during long term or geographically challenging studies, or in pressured clinical service environments. Objectives: Because the studies reporting these tools have used different metrics to compare the PREDSS and EDSS, we undertook an individual patient data level analysis of all available tools. Methods: Spearman’s rho and the Bland–Altman method were used to assess correlation and agreement respectively. Results: A systematic search for validated PREDSS tools covering the full EDSS range identified eight such tools. Individual patient data were available for five PREDSS tools. Excellent correlation was observed between EDSS and PREDSS with all tools. A higher level of agreement was observed with increasing levels of disability. In all tools, the 95% limits of agreement were greater than the minimum EDSS difference considered to be clinically significant. However, the intra-class coefficient was greater than that reported for EDSS raters of mixed seniority. The visual functional system was identified as the most significant predictor of the PREDSS–EDSS difference. Conclusion: This analysis will (1) enable researchers and service providers to make an informed choice of PREDSS tool, depending on their individual requirements, and (2) facilitate improvement of current PREDSS tools.

Metabolic bone disease is a major public health concern, especially when it manifests as hip fracture which carries significant morbidity and mortality. Individuals with neurological disease are at higher risk of osteopenia, osteoporosis and fragility fracture compared to age-matched controls, yet this is under-appreciated by these patients. Clinician attention to this topic is therefore of importance and should address the bone health of men as well as women, a group in whom it may be an under-recognised problem. Evidence for optimal management of bone health in neurological disease remains to be defined, but a growing literature provides some useful guidance. This review focuses on two conditions, multiple sclerosis and Parkinson’s disease, where research has been active over recent years. In neuroinflammation, shared immunological pathways between bone and brain are a current domain of interest and it will be intriguing to interrogate the action of emerging immunotherapies on these dual compartments.

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.

OBJECTIVE: Multiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible. Siblings of people with MS have an increased risk of both MS and demonstrating asymptomatic changes in keeping with MS. We set out to develop an MS risk score integrating both genetic and environmental risk factors. We used this score to identify siblings at extremes of MS risk and attempted to validate the score using brain MRI. METHODS: 78 probands with MS, 121 of their unaffected siblings and 103 healthy controls were studied. Personal history was taken, and serological and genetic analysis using the illumina immunochip was performed. Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. Scores were initially calculated using log odds ratio from the HLA-DRB1*1501 allele only, secondly using data from all MS-associated SNPs identified in the 2011 GWAS. Subjects with extreme risk scores underwent validation studies. MRI was performed on selected individuals. RESULTS: There was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p

A 22-year-old woman presented with progressive sensory ataxia and optic neuropathy. Previous investigation by her general practitioner had found a low serum vitamin B12, which had been corrected with oral supplementation. Neurological investigations showed raised plasma homocysteine and methylmalonic acid towards the upper limit of normal with a low serum vitamin B12 MRI showed an extensive cord lesion in keeping with subacute combined degeneration of the spinal cord. We treated her with high dose parenteral vitamin B12 and she has made a partial recovery. We discuss the management of patients who present with neurological manifestations of vitamin B12 deficiency; highlighting the fact that parenteral replacement is needed in such cases, even if the serum vitamin B12 level appears to be normal. We also discuss ancillary investigations that should be performed in patients with suspected vitamin B12 deficiency.

This case describes a young woman initially presenting with symptoms suggestive of optic neuritis. She later develops transverse myelitis, and a diagnosis of neuromyelitis optica (NMO; Devic’s disease) is made following investigation. The clinical features and investigative findings associated with NMO are discussed, and are related to the underlying pathology. Differential diagnoses for both optic neuropathy and transverse myelitis are given in the accompanying tables. Treatment options for both acute relapses and long-term immunosuppression are given.

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.

Fampridine (Fampyra) is a selective potassium channel blocker licensed for the improvement of walking in multiple sclerosis. In our New products review, Steve Chaplin presents the clinical data relating to its efficacy and adverse effects and Dr Ruth Dobson discusses its potential role in the treatment of walking disability in multiple sclerosis. Copyright © 2012 Wiley Interface Ltd

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.

Melanoma associated retinopathy is a rare paraneoplastic complication of metastatic cutaneous malignant melanoma. It may present years after the original diagnosis of melanoma. Here we describe a patient with this condition who presented with persistent photopsias and visual loss. We will discuss the electroretinographic findings and their utility.

Multiple sclerosis (MS) is the most common inflammatory demyelinating and degenerative disease of the CNS. The cause of MS is unknown but environmental risk factors are implicated in MS. Several viruses have been proposed as a trigger for MS, and lately Epstein-Barr virus (EBV) has become the leading candidate. An infectious aetiology fits with a number of epidemiological observations in addition to the immunopathological features of the disease. In this review we will summarize the emerging evidence, which demonstrates a strong association between EBV infection and MS. The conundrum remains as to whether EBV is directly involved in the pathophysiology of MS, or alternatively if the immunopathology of MS somehow affects the regulation of EBV infection.

Sativex is an oromucosal cannabinoid spray licensed as add-on therapy for moderate to-severe spasticity in multiple sclerosis. In our New products review Steve Chaplin presents the clinical data relating to its efficacy and side-effects, and Dr Ruth Dobson discusses its place in the treatment of spasticity.

A 51-year-old teacher presented with diplopia and vertiginous symptoms 6 months after cochlear implant insertion, which had been complicated by infection around the implant site. This evolved into a partially steroid-responsive relapsing disorder with sequential ataxia, CN-VI palsy, optic neuritis and a predominantly sensory spinal cord syndrome. Initial investigations were unremarkable (including negative CSF oligoclonal bands) apart from an abnormal VEP confirming previous optic neuritis. MRI was precluded by the cochlear implant. With no clear alternative diagnosis, she was started on MS disease modifying therapy, but continued to deteriorate. On re-investigation, a diagnostic test was performed. The patient was found to be MOG-antibody positive. This case highlights the difficulties encountered when investigating neuroinflammatory conditions without MRI. There remains a question as to whether the implant infection triggered the onset of her neuroinflammatory disorder. It is conceivable that infection-associated immunological changes or blood-brain barrier disruption could promote CNS auto-antigen generation. Despite not having bilateral optic neuritis or a significant motor spinal cord relapse during the disease course, she illustrates many features recently described as part of the expanding phenotype of neuromyelitis optica spectrum disorder. Given the aggressive disease course, early recognition is vital to ensure early treatment to prevent disability accumulation.

Background Natalizumab is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, prolonged treatment is associated with increasing risk of progressive multifocal leukoencephalopathy (PML), with treatment-associated risk up to 1:125 in some patients. Methods We audited the use of natalizumab at St George’s Hospital against NICE and NHS England criteria, examining documented reasons for initiation, ongoing monitoring and termination of treatment between 2014–2016. Results 19 patients (15F) initiated treatment, 5 of whom later stopped/switched treatment (PML risk (1), continued relapses (1), pregnancy (2), progressive disease (1)). 2/3 patients were re-consented at JCV seroconversion. Only 1/19 patient was informed of stopping criteria prior to treatment initiation. 15/19 patients had treatment duration >3 months, of whom 9/15 had regular Consultant reviews. 12/15 had the presence/absence of relapses and 5/15 had EDSS explicitly documented. Conclusions Although natalizumab is being initiated appropriately, there is inadequate discussion of stopping criteria. Improved documentation is required around disability including EDSS. Potential solutions include clear stopping criteria in patient information leaflets and patient self-monitoring of EDSS. The importance of a full multiple sclerosis team with specialist therapies nurses is highlighted.

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Multiple sclerosis (MS) is one of the most common neurodegenerative conditions affecting young adults in the developed world. The precise cause of MS remains unknown; the disease is thought to result from a complex interplay between environ­ mental and genetic risk factors. While MS causes a range of neurological disabilities, which differ between individuals, it is also associated with a significantly increased risk of osteoporosis and fracture. The association between MS, osteo­ porosis and fracture risk was highlighted in the global longitudinal study of osteoporosis in women (the GLOW study) [1]. This large, multinational, observational cohort study of over 60,000 women demonstrated that MS was associated with an age­adjusted hazard ratio (HR) for fracture of 2.0 (95% CI: 1.5–2.8). The only other progressive neuro­ logical disease associated with a significantly increased risk of fracture was Parkinson’s disease (age­adjusted HR: 2.2; 95% CI: 1.6–3.1). The finding of an increased fracture risk in MS has been replicated in other, albeit smaller, databases, which have demonstrated remarkably similar risks [2–4]. The increased fracture risk associated with MS appears to be due, at least in part, to reduced bone mineral density. People with MS have been shown to have reduced bone mineral density at both the femoral neck and lumbar spine [5]. This translates into a significant difference overall in the T­score (used to define osteopenia and osteoporosis) at the femoral neck in people with MS [5]. There has been a widespread assumption that osteoporosis in MS is due to disability and a reduction in weight­bearing exercise. There is certainly evidence of a relation­ ship between disability and bone mineral density in the context of MS – where it has been studied, an inverse correlation exists between the two [5]. However, recent evi­ dence appears to indicate that the situation is more complex than this: a case–control study of 99 newly diagnosed patients with early MS showed that 51% of MS patients exhibited either osteopenia or osteoporosis in at least one skeletal site compared with 37% of controls. This difference was sup­ ported by significantly lower T­scores at both the left femoral hip and lumbar spine in patients with MS in the same cohort [6]. It seems probable that shared etiological factors between low bone mineral density and MS may be at least partly responsible

Over the last few years, vitamin D deficiency has emerged as a risk factor for many diseases. Public awareness of the importance of the 'sunshine vitamin' is increasing, however deficiency remains an ongoing problem. Is an aware- ness of the importance of vitamin D enough to promote healthy people to take supplements or is a different approach required? In this article the importance of vitamin D is dis- cussed and data showing that knowledge of this is not suffi- cient to encourage people to take supplements are presented.

Objective: Interferon-β (IFN-β) has been shown to reduce relapse rates in multiple sclerosis; however, the clinical response appears to vary among individuals. Can early MRI be used to identify those patients who have a poor response to treatment? Methods: A systematic review of studies examining differential treatment response and clinical endpoints in groups defined as responders or nonresponders to IFN-β was performed. Meta-analytic techniques were used to combine study results where appropriate. Results: Patients with MRI evidence of poor response to IFN-β treatment as defined by either ≥2 new hyperintense T2 lesions or new gadolinium-enhancing lesions had significantly increased risk of both future relapses and progression as defined by the Expanded Disability Status Scale. There appeared to be an increased risk of poor outcomes 16 years after treatment initiation in those with an initial poor response to treatment. Previous evidence has shown this not to be the case in placebo arms of clinical trials. Conclusions: For those patients starting IFN-β, early MRI, within 6 to 24 months after starting treatment, has the potential to provide important information when counseling patients about the likelihood of future treatment failure. This can inform treatment decisions before clinical relapses or disease progression.

Background and purpose Lumbar puncture (LP) is a key diagnostic procedure in medicine. Post lumbar puncture headache (PLPHA) is a well recognized complication of LP. Evidence suggests that using atraumatic needles for diagnostic LP (ATNLP) reduces risk of PLPHA. However, clinicians in Europe and the USA routinely use traumatic needles for diagnostic LP (TNLP). The occurrence of PLPHA following ATNLP and TNLP was compared in a clinical setting. Further, a survey was performed exploring use of ATNLP amongst UK neurologists. Methods Service development study. Patients were followed up 2 and 7 days after LP using blinded telephone assessment. A questionnaire was developed to assess use of ATNLP amongst UK neurologists. Frequency, onset, duration and severity of PLPHA were recorded as were use of analgesia, general practitioner consultations, hospital readmissions, days off work due to PLPHA and cost. Neurologists were asked about their familiarity with, and use of, ATNLP. Results One hundred and nine participants attending the Royal London Hospital were included, and 74 attendees of the Association of British Neurologists 2012 conference completed an on-site questionnaire. ATNLP reduced the rate of PLPHA (27.1% vs. 60.4%; P

The Expanded Disability Status Scale (EDSS) is the current 'gold standard' for monitoring disease severity in multiple sclerosis (MS). The EDSS is a physician-based assessment. A patient-related surrogate for the EDSS may be useful in remotely capturing information. Eighty-one patients (EDSS range 0-8) having EDSS as part of clinical trials were recruited. All patients carried out the web-based survey with minimal assistance. Full EDSS scores were available for 78 patients. The EDSS scores were compared to those generated by the online survey using analysis of variance, matched pair test, Pearson's coefficient, weighted kappa coefficient, and the intra-class correlation coefficient. The internet-based EDSS scores showed good correlation with the physician-measured assessment (Pearson's coefficient = 0.85). Weighted kappa for full agreement was 0.647. Full agreement was observed in 20 patients who had EDSS scores ranging from 0 to 6; many of those with 100 % agreement had scores of 5.5-6 (n = 8).The intra-class coefficient was 0.844 overall for all cases. Internet-based FS and EDSS show good agreement with physician-measured scores. Agreement was better in patients with higher scores. Overall patient satisfaction with the web-based assessment was high. An internet-based assessment tool is likely to prove an invaluable tool in the long-term monitoring in MS.

Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among people with multiple sclerosis (MS). This has raised interest in potential clinical benefits of vitamin D supplementation in the management of MS. The objectives were to examine the effect of vitamin D based interventions on the relative risk of relapse in MS. Any randomised controlled trial assessing the effect on the relative risk of relapse of any formulation or dose of vitamin D, in participants with MS, was eligible. The inverse variance with random effects model in Review Manager 5.1 was used to calculate the odds ratio of relapses in high dose vitamin D treated patients vs. controls. Five studies were published as of September 2012, yielding a total of 129 high-dose vitamin D-treated patients and 125 controls. We found no significant association between high-dose vitamin D treatment and risk of MS relapse (OR 0.98, 95% CI 0.45–2.16). In conclusion, although no significant association between high-dose vitamin D treatment and risk of MS relapses was found, the studies were limited by several methodological limitations. Further larger, more prolonged studies are merited.

Background Anti-Epstein–Barr virus (EBV) nuclear antigen-1 (anti-EBNA-1) IgG antibody titres have been found to correlate with MRI and clinical measures of disease activity in MS. Despite being a putative biomarker of disease activity, the effect of disease modifying drugs on anti-EBNA-1 IgG titre has not yet been determined. Methods In this study, we investigated the effect of interferon-beta and natalizumab therapy on prospective sera anti-EBNA-1 IgG titres, using a quantitative ELISA, in patients with relapsing-remitting MS. Results For both the interferon-beta and natalizumab group, there was no significant difference between pre-therapy and post-therapy anti-EBNA-1 IgG titre. There was also no significant difference between the groups with regard to mean percentage change in anti-EBNA-1 IgG titre over 12 months of treatment. Conclusions This study suggests that anti-EBNA-1 IgG titre is unlikely to be a good surrogate marker for disease activity in patients on disease modifying drugs.

Background Month of birth has previously been described as a risk factor for multiple sclerosis (MS). This has been hypothesised to be related to maternal vitamin D levels during pregnancy, although conclusive evidence to support this is lacking. To date, no large studies of latitudinal variation in the month of birth effect have been performed to advance this hypothesis. Methods Previously published data on month of birth from 151 978 MS patients were compared to expected birth rates. A linear regression model was used to assess the relationship between latitude and observed:expected birth ratio of MS patients for each month. Results Analysis of all reported data demonstrated a significant excess of MS risk in those born in April (observed:expected 1.05, p=0.05) and reduction in risk in those born in October (0.95, p=0.04) and November (0.92 p=0.01). A conservative analysis of 78 488 patients revealed an excess MS risk in those born in April (1.07, p=0.002) and May (1.11, p=0.0006), and a reduced risk in those born in October (ratio 0.94, p=0.004) and November (0.88, p=0.0002). A significant relationship between latitude and observed:expected ratio was demonstrated in December, and borderline significant relationships in May and August. Conclusions Month of birth has a significant effect on subsequent MS risk. This is likely to be due to ultraviolet light exposure and maternal vitamin D levels, as demonstrated by the relationship between risk and latitude.

Objectives Biomarkers with the potential for longitudinal measurements are needed in multiple sclerosis (MS). Urine is easy to collect, and repeated sampling is possible. Methods 39 paired CSF and urine samples were taken. Oligoclonal bands (OCBs) were measured in CSF. Kappa and lambda free light chain (FLC), neopterin and ubiquitin C-terminal hydrolase-L1 (UCHL1) were measured in CSF and urine. Results 16/39 samples had OCBs unique to the CSF. CSF FLC levels (P

It has come to the attention of the authors that the value we included for the number of controls participating in the paper by Kister et al 2012 (2011 as epub) in our study “Meta-analysis of the Relationship between Multple Sclerosis and Migraine” is inaccurate. Corrected values for Kister 2012 for Table 1: Total controls: 115888 Controls with migraine: 24337 Controls without migraine: 91551 Fig. 1: Fig. 2

Objective: Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. Methods: We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. Results: Patients with Alzheimer’s disease (AD) (30.8 pg/ml, n=20), Guillain-Barre-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p

Sustained-release fampridine, a slow release formulation of 4-aminopryridine, is a voltage-dependent potassium channel blocker licensed for the treatment of walking difficulties in multiple sclerosis (MS). Studies have demonstrated that approximately one-third of MS patients respond with a clear benefit to their walking speed. Sustained-release Fampridine is not currently available on the National Health Service (NHS), although it has been approved by the Food and Drug Administration (FDA) in the USA and European Medicine Agency (EMA). It appears to have an acceptable adverse event profile, with data from open-label extension studies now becoming available. Concerns have been raised that the use of fampridine may increase the risk of seizures, which were seen at higher rates in patients treated with high doses of sustained-release fampridine. The rate of seizures in those patients on lower doses has not been found to be significantly increased. There are significant barriers at present to the widespread use of fampridine in the UK, which have limited its use in clinical practice to date. Patients with MS are in need of interventions to improve walking and many clinicians feel that this drug may have a role in the symptomatic management of MS.

Additional autoimmune diseases in people with multiple sclerosis (MS) and their relatives have been studied many times. Studies have employed different designs, and yielded conflicting results. We performed a systematic review, and calculated overall risk of additional autoimmune diseases in people with MS and their first-degree relatives. PubMed and Web of Science were searched. Thyroid disease, diabetes, inflammatory bowel disease, psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were studied. A generic inverse variance model was used, and subgroup analysis was used to explore heterogeneity. The OR of thyroid disease was increased in both people with MS (OR 1.66; p < 0.00001) and their relatives (OR 2.38; p < 0.00001). A similar association was seen between MS and inflammatory bowel disease (OR 1.56; p < 0.0001) and psoriasis (OR 1.31; p < 0.0001), although not in relatives. There was no increase in the rate of either SLE or RA. Studies examining diabetes showed significant heterogeneity and evidence of publication bias. There is an increase in the rate of certain autoimmune diseases in people with MS and their first-degree relatives. However, this does not extend to all conditions studied. Given the nonspecific clinical presentation of thyroid disease, it should be considered in all people with MS presenting with nonspecific symptoms.

People with multiple sclerosis (MS) have many reasons to have low bone mineral density and an increased fracture risk. Osteoporosis is a major cause of morbidity and mortality, and is more common in people with MS than the general population. A number of studies have examined the relationship between multiple sclerosis and reduced bone mineral density. In this topical review we seek to address the risk of low bone mineral density, osteoporosis and fractures associated with MS, and make practical suggestions as to how this pertinent issue may be approached in clinical practice.

Background Studies investigating a proposed association between multiple sclerosis (MS) and migraine have produced conflicting results and a great range in the prevalence rate of migraine in MS patients. By meta-analysing all available data we aimed to establish an overall estimate of any association in order to more accurately inform clinicians and care-givers about a potential association between MS and migraine. Methods Pubmed and EMBASE were searched to identify suitable studies. Studies were included if they were a case-control study or cohort study in which controls were not reported to have another neurological condition, were available in English, and specified migraine as a headache sub-type. The odds ratio (OR) of migraine in MS patients vs. controls was calculated using the inverse variance with random effects model in Review Manager 5.1. Results Eight studies were selected for inclusion, yielding a total of 1864 MS patients and 261563 control subjects. We found a significant association between migraine and MS (OR = 2.60, 95% CI 1.12-6.04), although there was significant heterogeneity. Sensitivity analysis showed that migraine without aura was associated with MS OR = 2.29 (95% CI 1.14-4.58), with no significant heterogeneity. Conclusions MS patients are more than twice as likely to report migraine as controls. Care providers should be alerted to ask MS patients about migraine in order to treat it and potentially improve quality of life. Future work should further investigate the temporal relationship of this association and relationship to the clinical characteristics of MS.

More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis.

There remains a need for sensitive and reliable biomarkers that can be used longitudinally in multiple sclerosis. Whilst both CSF and MRI have been extensively studied, they remain invasive and expensive methods of investigation. On the contrary, urine provides a valuable fluid which is readily available for serial sampling. Some work has been done on urinary biomarkers in multiple sclerosis; however, urinary biomarkers have not been extensively studied and validated for use in routine clinical practice, and urine remains understudied and underutilised. In this review the use of neopterin, urinary free light chains, nitric oxide metabolites and urinary myelin basic protein-like protein as potential biomarkers that have been identified in urine are discussed, and avenues for future study are raised.

Background/Objective: A clinically isolated syndrome compatible with demyelination (CIS) is the initial presentation for the majority of people that go on to develop multiple sclerosis (MS). There has previously been little work examining the effect of gender on the development and progression of CIS. Methods: Data from observational studies of CIS were used. In total, 33 suitable studies with 4732 subjects were identified. Results: The overall relative risk (RR) of CIS in females compared with males was 2.12 (95% CI 1.94–2.32). The RR of females developing MS following CIS was 1.20 (95% CI 0.98–1.46) compared with males. Conclusions: These data imply that the gender bias seen in MS is caused by factors acting early in the disease process.

Background: Multiple sclerosis (MS) is a leading cause of disability in young adults. Susceptibility to MS is determined by environmental exposure on the background of genetic risk factors. A previous meta-analysis suggested that smoking was an important risk factor for MS but many other studies have been published since then.Methods/principal findings: We performed a Medline search to identify articles published that investigated MS risk following cigarette smoking. A total of 14 articles were included in this study. This represented data on 3,052 cases and 457,619 controls. We analysed these studies in both a conservative (limiting our analysis to only those where smoking behaviour was described prior to disease onset) and non-conservative manner. Our results show that smokng is associated with MS susceptibility (conservative: risk ratio (RR) 1.48, 95% confidence interval (CI) 1.35-1.63, p15; no-conservative: RR 1.52, 95% CI 1.39-1.66, p19). We also aanalysed 4 studies reporting risk of secondary progression in MS and found that this fell just short of statistical significance with considerable heterogeneity (RR 1.88, 95% CI 0.98-3.61, p = 0.06).Discussion: Our results demonstrate that cigarette smoking is important in determining MS susceptibility but the effect on the progression of disease is less certain. Further work is needed to understand the mechanism behind this association and how smoking integrates with other established risk factors.

Background: Plasma and B cells are implicated in multiple sclerosis (MS) and produce free light chains (FLC) that are excreted in urine. Objective: To confirm that demyelinating diseases (DD) cause increased urinary FLCs.Method: Urinary FLC in 50 patients with DD were compared to 20 patients with posterior uveitis (PU), 19 with AIDS, 34 with rheumatoid arthritis (RA) and 19 normal controls (NC). Result: Subjects with DD, PU, RA and AIDS have higher urinary FLCs than NC (p

A previously fit and well 56 year old retired mechanic was admitted to hospital via the emergency department with a one week history of headache. He described the headache as being “moderately” severe and affecting his entire head. There were no exacerbating or relieving factors, and he had not had a similar headache previously. The day before admission he developed double vision, neck stiffness, and vomiting. On the day of admission he developed drooping of the right side of his face, weakness of the right leg, and difficulty walking, with some impairment of balance. He had no history of fevers, rigors, or other systemic symptoms before admission. He had not recently travelled and had no unwell contacts. His medical history was unremarkable. On examination he had a score of 15/15 on the Glasgow coma scale. His temperature was 38.5°C, his blood pressure was 135/68 mm Hg, and his pulse rate was 90 beats/min. He had moderate neck stiffness and a right sided facial droop indicative of a lower motor neurone seventh cranial nerve palsy. He also had subtle pass pointing and ataxia in the right upper limb, with mild heel-shin ataxia in the right lower limb consistent with right sided cerebellar signs. The remainder of the neurological examination was unremarkable. Blood tests on admission showed a peripheral white blood cell count of 17.7×109/l (neutrophils 15.55×109/l), C reactive protein 120 mg/l, and normal urea and creatinine. His serum sodium was slightly decreased at 131 mmol/l. Computed tomography and lumbar puncture were performed on admission. Magnetic resonance imaging was performed the next day (fig 1⇓). Analysis of his cerebrospinal fluid showed protein 0.96 g/l, glucose 1.2 mmol/l, and white cell count 535/mm3 (85% polymorphs, 10% lymphocytes, 5% atypical white cells). No organisms were seen on Gram …

A 21-year-old presented with a one-month history of confusion and headache, with collateral history suggestive of focal seizures. Examination revealed an encephalopathic patient with a bilateral internuclear ophthalmoplegia and a spastic ataxic quadraparesis. MRI demonstrated multiple non-enhancing hyperintense T2 lesions in the cerebellum, corpus callosum, grey and white matter, some with restricted diffusion. There was marked posterior fossa leptomeningeal enhancement. CSF protein was 2.32g, with 5 lymphocytes and negative oligoclonal bands. Brain biopsy showed non-specific inflammatory changes. Extensive infective, inflammatory and malignancy screening was negative. Despite an initial clinical response to a steroid pulse, new lesions developed, accompanied by clinical deterioration. Two months into the illness, whilst on high-dose oral steroids, he developed characteristic branch retinal artery occlusions. A diagnosis of Susac9s syndrome was made, despite normal audiometry. Treatment with aggressive immunosuppression was successful. Susac9s (‘small infarctions of cochlear, retinal and encephalic tissue’ (SICRET)) syndrome, is a rare, presumed autoimmune, endotheliopathy. Microvascular occlusions lead to the pathognomonic triad of encephalopathy, sensorineural deafness and branch retinal artery occlusions, rarely all present at presentation. Seizures are an unusual feature. Temporal dispersion of symptoms may delay diagnosis for months in some patients. A literature review of clinical features and treatment will be presented.

A 42-year-old man with longstanding type 1 diabetes presented with subjective memory difficulties. He was awaiting combined pancreas-kidney transplant for diabetic nephropathy. Assessment demonstrated no objective cognitive impairment and no focal neurological deficit. Initial MRI brain scanning revealed a focus of subtle abnormal high signal within the right fronto-parietal region, which on serial imaging became more prominent with extension into contralateral parietal and bilateral subcortical regions at one year. DWI and MRA were normal. Microhaemorrhages were seen on T2*. Nine months post-presentation he developed focal motor seizures. Given the concern regarding immunosuppression secondary to diabetes and chronic renal failure, together with the potential for further immunosuppression post-transplant, extensive screening for opportunistic infection and malignancy was undertaken but without diagnostic clarification. Brain biopsy was undertaken, with histological examination revealing striking deposition of amyloid-s consistent with cerebral amyloid angiopathy (CAA-As). CAA-As has a spectrum of clinical phenotypes and the usual mode of presentation is with spontaneous intracerebral haemorrhage. Typical MRI findings include cerebral microbleeds and haemorrhages, siderosis and leucoencephalopathy. Presentation as a focal, evolving, non-haemorrhagic lesion is rare. A review of similar cases will be presented and the implications of a diagnosis of CAA-As for potential transplant recipients discussed.

Background Depression is a potentially treatable condition which can co-exist with multiple sclerosis (MS). To date, the existing literature has not been collated in a systematic fashion. We set out to collate all available evidence and on the prevalence of depression in MS through a systematic review with meta-analysis. We also aimed to provide an up-to-date review of the use of antidepressants in MS. Methods An extensive electronic search of the literature yielded 36 relevant studies. Seven studies examined the pharmacological treatment of depression in MS. Results There is an increased prevalence of depression in MS patients compared to healthy controls, OR 2.77 (95% CI 1.57–4.91). The prevalence of depression in these patients was not increased when compared to controls with other chronic diseases, OR 1.56 (95% CI 0.97–2.52). There was a good response to antidepressant treatment in MS (OR of responding to treatment vs non-response of 1.88 (95% CI 1.10–3.21). Conclusions This review highlights the increased prevalence of depression in a patient group who appear to benefit from treatment. Further research is required in this area in order to fully understand the aetiology of depression in MS patients.

A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p = 4.08×10(-10)). The predictive performance of the model including all currently known MS associations (area under the curve = 79.7%, 95%CI = 72.4%-87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction.

A 67-year-old lady presented with disturbed vision. Three months earlier, she had noticed lights in her vision, resembling ripples in water with light shining on it. They were constant and visible in both dark and light. Colour and night vision remained normal. She had a past medical history of a skin tumour lateral to her left eyebrow removed 12 years previously. She had no other past medical history and was not on any medication. Examination revealed normal fundi with no relative afferent pupillary defect. Acuity and colour vision were normal. Visual fields were intact to confrontation, but perimetry showed large incongruous field defects in both eyes. The remainder of the examination was normal. A diagnosis of melanoma associated retinopathy (MAR) was suspected and an electroretinogram (ERG) was obtained, which confirmed the diagnosis. A CT scan revealed two nodules in the left lung, a mass in the mediastinum and a destructive lesion in the D6 vertebral body. Histology of a pulmonary nodule revealed metastatic malignant melanoma. MAR is a rare complication of malignant melanoma, typically presenting months to years after the initial diagnosis, heralding the discovery of metastatic disease. The clinical presentation is characteristic, and ERG is the investigation of choice. To date, no specific antibody has been conclusively associated with MAR, although antibodies against various retinal components are described. The role of immunosuppressive treatment remains controversial.

We asked our editorial consultants to highlight the significant advances made in their therapeutic areas over the past 20 years. Here we look at developments in neurology and dermatology. Copyright © 2010 Wiley Interface Ltd

Sir, I read the recently published results from Cappuccio et al . with great interest, given that compulsory European Working Time Directive (EWTD) rota compliance is mandatory from August 2009. However, there are a number of issues raised by the study that require further discussion. In 2006, the Royal College of Physicians Multidisciplinary Working Group stated that ‘junior doctors should not be rostered to work more than four nights in succession’.1 Murray et al . state that ‘… it is clear that a long stretch of night shifts results in an accumulation of daily sleep deficits and does not encourage adjustment of circadian rhythms. A week of night shifts is the pattern most associated with poor performance and accidents.’2 …

Objective An endophenotype is a concept that allows us to describe complex diseases with genetic and environmental contributions. This enables the identification of an “at risk” population. We aim to describe an endophenotypic gradient between healthy controls (HC), siblings of people with MS (PwMS) and PwMS. Background Siblings of PwMS have an increased risk of developing MS. This increased risk is thought to be a result of genetic and environmental contributions. Epidemiological studies have identified factors contributing to MS including smoking, vitamin–D, infection with and IgG titres against Epstein–Barr virus and HLA–DRB1*1501. A genome wide association study (GWAS) in 2011 gave information regarding the contribution of HLA–type and non–HLA SNPs to MS risk. We set out to integrate these into an endophenotypic risk score for MS. Methods PwMS (n=78), their unaffected siblings (n=121) and healthy controls (HC; n=103) were recruited. Serum anti–EBNA–1 IgG, vitamin D and cotinine were measured. Subjects were genotyped for HLA–DRB1*1501 and all HLA and non–HLA SNPs associated with MS using the Illumina immunochip. Previous infectious mononucleosis, smoking and month of birth were recorded. The relative risks associated with these factors were established from meta–analyses and integrated into an overall risk score for each individual. Full genetic data was available for 73 people with MS, 107 siblings and 99 HC. Risk scores with genetic contribution from HLA–DRB1*1501 only, and from all MS–associated genetic variants were calculated. Results When the genetic contribution from HLA–DRB1*1501 alone was used, the mean risk score was significantly higher for PwMS (2.82; SD 1.18) than for siblings (1.98; SD 1.38) or HC (1.53; SD 1.34) (p 1.25 SD higher than the mean HC score. When full genetic data was included, the mean risk score was highest for people with MS (9.71; SD 1.38) intermediate for siblings (8.83; SD 1.47) and lowest for HC (8.00; SD 1.49) (p Conclusions This study demonstrates the validity of the risk score generated, which integrates genetic and environmental risk factors. Siblings have a risk score intermediate to PwMS and HC, confirming their “at risk” position in the endophenotype construct. Much of the MS risk in siblings can be attributed to genetics, with environmental factors potentially providing the trigger for clinically apparent disease.

Background Impairment of walking and the resultant reduction in physical function together with pathological fatigue are major concerns for patients with Multiple Sclerosis (MS). Patients are in need of interventions to improve walking. Slow–release 4–aminopyridine (Fampridine; Fampyra) improves walking speed in approximately 35% of MS patients. The Timed 25–Foot Walk (T25FW) is used to measure response to treatment. There are concerns that the T25FW is a poor estimate of walking speed, and only able to provide a snapshot of walking impairment under controlled circumstances. Funding bodies have raised uncertainties regarding the possibility of increased falls with Fampridine. Objectives T25FW is not the most pragmatic measure of either walking impairment and or Fampridine efficacy. Alternative objective outcome measures including accelerometry or longer walking distance tests may be more informative of patients9 walking ability in real–life situations. We therefore set out to evaluate objective and subjective outcome measures of walking impairment, falls risk and fatigability for use in MS patients. Methods Thirty–two MS patients underwent a battery of objective and subjective assessments, including 48–hour accelerometry. Appropriate statistical tests were selected for data analysis. Pearson correlation coefficient and Spearman9s rho were used for parametric and non–parametric data, respectively. Group mean comparisons were made using the un–paired t–test and one–way analysis of variance (ANOVA) on parametric data, and Mann–Whitney U test and Kruskal–Wallis test on non–parametric data. Results The study group consisted of 13 women and 19 male (5 primary progressive, 19 secondary progressive, and 8 relapsing–remitting; EDSS range 2.5–7). Median age was 48.5, (range 30–68). All patients had fallen in the past 6 months, and 19 used an assistive device at all times. The mean duration since MS diagnosis was 8.3 years (SD=6.6). T25FW, 2–minute walk (2MWT) and average daily activity measured by accelerometry showed significant correlations with all other objective measures of walking impairment. The MS walking scale–12 (MSWS–12) correlated significantly with T25FW and 2MWT. The Activities–specific Balance Confidence (ABC) scale scores increased significantly with higher falls frequency (p=0.03). Assistive device use was significantly associated with worse scores on all subjective and objective tools, and with falls frequency. Accelerometry was a discriminator of physical fatigability in MS patients, when comparing the average activity in the morning with the average activity in the afternoon. Patients in this study suffering from fatigue were less active in the afternoon compared to the early morning (p=0.01). Conclusions The 2MWT and accelerometry are good objective measures of walking disability in addition to the T25FW. Accelerometry provides additional real–life data regarding activity during the day, and offers information regarding the impact of fatigue on a patient. The MSWS–12 subjectively measures impact of walking disability and the ABC score predicts falls. The use of an assistive device identifies walking disability and predicts risk of falls. Given the uncertainty regarding falls risk in patients using fampridine, physicians should consider using these tools to monitor patients under consideration for the drug.