Monday, May 12

Wednesday's News for Neurologists: Here's 198 New Studies from 10/1 to Wednesday 10/23:

Comparative effectiveness of GILENYA (fingolimod) versus interferons or glatiramer acetate for relapse rates in multiple sclerosis: a retrospective US claims database analysis.
Curr Med Res Opin. 2013 Oct 1. [Epub ahead of print]
Abstract Objective: Disease-modifying therapies, such as fingolimod, interferon (IFN) and glatiramer acetate (GA), have differing effects on relapse rates in patients with multiple sclerosis (MS), but little is known about the real-world differences in relapse rates with these treatments. This retrospective study assessed relapse rates in patients with active MS initiating fingolimod, IFN or GA therapy in a real-world setting. Methods: Using administrative claims data from the US PharMetrics Plus database, we identified previously treated and untreated patients with MS who initiated fingolimod, IFN or GA treatment between 1 October 2010 and 31 March 2011 and had experienced a relapse in the previous year. A claims-based algorithm was used to identify relapses over the persistence period in patients with 540 days of post-index continuous enrolment. A logistic regression model assessed the probability of having at least one relapse and a generalized linear model estimated differences in annualized relapse rates (ARRs). Results: The study enrolled 525 patients (fingolimod, n = 128; combined IFN/GA cohort, n = 397) of the 31,041 initially identified. Similar findings for fingolimod and IFN/GA were observed for the unadjusted proportion of patients experiencing relapses (31.3% vs. 34.0%, respectively; p = 0.5653) and ARRs (0.50 vs. 0.55, respectively) while persistent to treatment. After adjusting for baseline differences, fingolimod was associated with a 52% reduction in the probability of having a relapse (odds ratio, 0.48; 95% confidence interval [CI], 0.28-0.84; p = 0.0097) and a 50% reduction in ARR (rate ratio, 0.50; 95% CI, 0.34-0.75; p = 0.0006) compared with IFN/GA.

Reduced axonal motor protein expression in non-lesional grey matter in multiple sclerosis

HLA-E restricted CD8+ T cell subsets are phenotypically altered in multiple sclerosis patients 

Review of daclizumab and its therapeutic potential in the treatment of relapsing-remitting multiple sclerosis.

Misdiagnosis of multiple sclerosis: frequency, causes, effects, and prevention.

The Treatment of Tremor.

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis.

Central nervous system infectious diseases mimicking multiple sclerosis: recognizing distinguishable features using MRI.

Diffusion tensor magnetic resonance imaging may show abnormalities in the normal-appearing cervical spinal cord from patients with multiple sclerosis.

Multiple sclerosis in South America: month of birth in different latitudes does not seem to interfere with the prevalence or progression of the disease.

SATIVEX SPREADS TO ONE MORE COUNTRY: Sativex Cannabinoid oromucosal spray is for the treatment of spasticity due to Multiple Sclerosis. Sativex is approved as a treatment for MS spasticity in 22 countries

Prevalence of white matter lesions and stroke in children with migraine

Simultaneous PML-IRIS and myelitis in a patient with neuromyelitis optica spectrum disorder

Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season.

Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial.

Modulators of the Sphingosine 1-phosphate receptor 1.

The influence of disease duration, clinical course, and immunosuppressive therapy on the synthesis of intrathecal oligoclonal IgG bands in multiple sclerosis.

Development of a high-resolution fat and CSFsuppressed optic nerve DTI protocol at 3T: application in multiple sclerosis.

[Natalizumab as induction therapy in multiple sclerosis.]

Laquinimod: A Disproportional Effect on Disability in MS
Exercising away the blues: can it help multiple sclerosis-related depression?

Multiple sclerosis Five new things

BG-12: Sustained Efficacy, Safety Out to 4 Years in MS

Tumefactive multiple sclerosis and fingolimod

Tumefactive MS lesions under fingolimod

MicroRNA Profiling May Provide Biomarkers for Monitoring MS

MicroRNA Profiling May Provide Biomarkers for Monitoring MS

Factor VIII Levels After Stroke May Flag Recurrent Events

A bird's-eye view of T cells during natalizumab therapy

The interaction between smoking and Epstein-Barr virus as multiple sclerosis risk factors may depend on age

Confounding Underlies the Apparent Month of Birth Effect in Multiple Sclerosis

Can we prevent or treat multiple sclerosis by individualised vitamin D supply?

The impact of fatigue on patients with multiple sclerosis.

Relapses and Progression of Disability in Multiple Sclerosis

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description, Validation of Severity Scale, and Exploration of BMI Effects on Disease Course

Intramuscular Interferon Beta-1A Therapy Initiated during a First Demyelinating Event in Multiple Sclerosis

267 Occupation and Multiple Sclerosis: an Italian case-control study
Our preliminary findings indicate that solvent exposures could be related to the risk of MS, as both shoe/leather workers and mechanical manufacturing industry workers are exposed to organic solvents. Interestingly, a major risk of MS was also found among workers engaged in agriculture, suggesting a role of pesticides, whose neurotoxic effect is well known.  

Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis 

Dalfampridine improves walking speed, walking endurance, and community participation in veterans with multiple sclerosis: a longitudinal cohort study 
Dalfampridine-ER was associated with short-term improvements in walking speed and community participation, and sustained improvements in walking endurance and self-perceived impact of MS on walking for one year. Our study supports the utility of this medication in late MS.  

Disease modification in multiple sclerosis: an update
Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis 
The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.  

Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome
Characterising aggressive multiple sclerosis
AMS was identified in 4–14% of patients, depending on the definition used. Although there was a relative preponderance of men and primary progressive MS presenting with AMS, the majority of patients were still women and those with relapsing-onset MS.  

Evidence-based patient information programme in early multiple sclerosis: a randomised controlled trial
The intervention significantly increased informed choice and relevant risk knowledge without negative side effects.  

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.

Significant increases in sodium were seen in lesions and normal appearing brain tissues in MS. Increased concentration of sodium in lesions, cortical grey matter, NAWM and basal ganglia in SPMS versus RRMS indicates greater neuroaxonal metabolic dysfunction and/or loss in the former group. MRI measurement of sodium concentration in vivo is likely to reflect clinically relevant neuroaxonal pathophysiology and may be a useful outcome measure in trials of putative neuroprotective treatments.



The demographic characteristics of the White MS patients in our cohort are very similar to those recently described in another UK–based geographically–linked MS cohort of 620 patients in Wales which was 97% White (J Neurol, Neurosurg & Psychiatry 80 (4):386–391). They described a mean age of 51, a female:male ratio of 2.4:1, and a prevalence of 146 per 100,000. 


Predictors and dynamics of postpartum relapses in women with multiple sclerosis
Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.  

A nexus between lipids and multiple sclerosis?

This study demonstrates a significantly increased risk of progression from RRMS to SPMS in patients who become NAb positive. As no current disease modifying treatments are effective in this phase of the disease patients at risk should be detected early and routine NAb testing can help to inform this decision.

A bird's-eye view of T cells during TYSABRI (natalizumab) therapy

Epstein-Barr virus in oral shedding of children with multiple sclerosis
Children with MS demonstrate abnormally increased rates of EBV viral reactivation and a broader range of genetic variants, suggesting a selective impairment in their immunologic control of EBV.  

Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis
Profound TCR repertoire restrictions in CSF of patients treated with natalizumab reflect an altered immune surveillance of the CNS, which may contribute to an increased risk of developing PML. Natalizumab seems to prompt an impaired or delayed peripheral expansion of antigen-specific T cells, whereas increased reconstitution of peripheral T-cell expansion following plasma exchange may trigger PML-IRIS. Our data suggest that treatment with natalizumab results in broader changes in the T-cell immune repertoire beyond lymphocyte migration.  

Brainstem PML lesion mimicking MS plaque in a natalizumab-treated MS patient

Right Brain: How to treat the untreatable

Astragaloside IV Attenuates Experimental Autoimmune Encephalomyelitis of Mice by Counteracting Oxidative Stress at Multiple Levels.

Global and 3D Spatial Assessment of Neuroinflammation in Rodent Models of Multiple Sclerosis.

Speed of word retrieval in multiple sclerosis.
The speed of processing is impaired in MS patients. Consequently, more evaluation and planning treatment programs based of speed processing for memory in these patients are necessary for them because of the role of memory in daily activities of life.

Bridging, switching or drug holidays - how to treat a patient who stops natalizumab?

Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic 

Strategy for the Treatment of Multiple Sclerosis.

The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35-55-Induced Experimental Autoimmune Encephalomyelitis.

7th International Symposium on Enabling Technologies for Life Sciences (ETP).

Molecular Architecture of Myelinated Nerve Fibers: Leaky Paranodal Junctions and Paranodal Dysmyelination.

Gray matter damage predicts the accumulation of disability 13 years later in MS.

Multiple sclerosis: Five new things

Astragaloside IV Attenuates Experimental Autoimmune Encephalomyelitis of Mice by Counteracting Oxidative Stress at Multiple Levels.

Urinary complications and risk factors in symptomatic multiple sclerosis patients. Study of a cohort of 328 patients.
Urinary complications are common in symptomatic MS, these results imply screening and specialized care to limit the impact on the quality of life but also to prevent urinary complications. Neurourol. Urodynam.

Relationship between Cerebrospinal Fluid Biomarkers for Inflammation, Demyelination and Neurodegeneration in Acute Optic Neuritis.

8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications.

A review of the cultivation and processing of cannabis (Cannabis sativa L.) for production of prescription medicines in the UK.

Visualization of acute focal lesions in rats with experimental autoimmune encephalomyelitis by magnetic nanoparticles, comparing different MRI sequences including phase imaging.

Cerebral arterial and venous blood flow in adolescent multiple sclerosis patients and age-matched controls using phase contrast MRI.
No population difference in flow rate was detected in adolescent MS participants relative to age-matched controls. J. Magn. Reson. Imaging 2013.

Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.
An introduction with medical applications to functional data analysis.
The present retrospective study did not show a specific profile of long-term deleterious drug effects on children born from mothers who were exposed to drugs for MS treatment.

Toxicological aspects of injectable gold-hyaluronan combination as a treatment for neuroinflammation.

New Insights in the Pathogenesis of Multiple Sclerosis-Role of Acrolein in Neuronal and Myelin Damage.

Frontotemporal Cortical Thinning in Amyotrophic Lateral Sclerosis.
Superficial brain stimulation in multiple sclerosis.

Central motor conduction time.

Deep brain stimulation for pain.

Δ9-THC was not better than placebo at reducing the rates of new T1 or T2 lesions or brain atrophy in patients with progressive MS.

Deep brain stimulation for other tremors, myoclonus, and chorea.

Prognostic Indicators of Acute Transverse Myelitis in 39 Children.
A short time to maximal defects, long time of peak neurological impairment and initial time of treatment, increased protein levels of cerebrospinal fluid, and secondary infection played important roles in predicting poor prognosis.

Dimethylfumarate induces apoptosis in human mast cells.


Presentation of MS in older adults is often atypical, with sensorimotor and cerebellar symptoms constituting the predominant clinical syndrome, negative investigations including OCBs, fewer relapses and earlier progression of disability. This may make diagnosis of LOMS problematic. Once LOMS is established, disability progresses more rapidly than in younger onset patients. Although at present there are no effective treatments for progressive neurodegeneration in MS, it is important to identify this group of patients who are likely to require greater input from MS services, and who may benefit from early treatments for progression of disease in the future.

Autologous MSCs can be safely administered in secondary progressive MS with evidence to suggest structural, functional and physiological improvement following treatment consistent with neuroprotection. The transient treatment response seen implied a likely requirement for repeat infusions to sustain benefit in the long-term.

White cell pleocytosis was the most frequent abnormality (48%) followed by raised CSF protein (54%) and positive OCBs (41%) and were most commonly observed within 30 days of relapse. Cell counts of >50/ml and CSF protein of >1.0 g/dl, contrary to popular belief, were unusual. In addition CSF changes in NMO were frequently dynamic and likely to relate to recent disease activity. Whilst these changes may be useful in monitoring some aspects of disease activity OCBs should not be employed to discriminate between NMO and other neuroinflammatory disorders and in particular MS, and also challenge the concept that development of positive OCB status is irreversible.

Application of the Oxford 2012 diagnostic criteria in a clinical setting resulted in an 85% specificity for differentiating NMO from RRMS, the most common differential diagnosis compared to only 67% for Barkhof's criteria. This data should be considered in the MRI assessment of patients in whom the diagnosis of NMO is being considered. In particular patients fulfilling Barkhof's criteria should also be assessed with the Oxford 2012 criteria to improve the interpretation of brain MR imaging and its diagnostic accuracy.

There was a high frequency of both low BMD and Vitamin D deficiency in this cohort of relatively young and largely ambulatory patients with an acute relapse. Current tools, such as the WHO FRAX algorithm, are inadequate in assessing bone status and fracture risk in this patient group, predominantly as they are focused on older age groups. We present a simple clinical management algorithm.

Our data indicate significant variation in practice amongst Scottish neurologists regarding the diagnosis of MS. It seems that few are enthusiastic about applying the current diagnostic criteria after a single attack (CIS), even if the diagnostic criteria are met. Case mix, clinical expertise and experience may explain some of this variation, and given the lack of evidence for aggressive treatment of CIS, such diagnostic caution is perhaps justified. It would be of interest to repeat the audit UK wide, and internationally, and our prediction would be that some countries may embrace the criteria with more enthusiasm than others. This will inevitably affect future epidemiological and therapeutic studies.

Using PSIR at 3T, lesions involving CGM were visible in all lobes. A higher number of CGM lesions were noted in the frontal and temporal lobes both relapsing remitting and progressive MS subgroups. Occipital CGM lesions were uncommon.


In this interim analysis of UK TOP results, patients treated with natalizumab had significantly improved ARRs, regardless of baseline treatment or relapse history. EDSS scores remained stable over time. Safety data were consistent with natalizumab's known safety profile. Analyses of UK TOP data over longer periods of time will further characterise the effect of natalizumab on disability, as well as on other long-term efficacy and safety parameters in a real-world setting.

Predictors of successful acceptance of home telemanagement in veterans with Multiple Sclerosis.

Time and time-frequency analysis of near-infrared signals for the assessment of ozone autohemotherapy long-term effects in multiple sclerosis.

Younger age, female sex, and high number of awakenings and arousals are predictive of fatigue in sleep-disordered patients. Further investigations are needed to find the pathophysiological explanation for these relationships.

The dimeric Tβ4 exhibited enhanced activity on wound healing than native Tβ4, and the purification process was simple and cost-effective. This data could be of significant benefit for the high pain and morbidity associated with chronic wounds disease. A better strategy to develop Tβ4 as a treatment for other diseases caused by injuries such as heart attack, neurotrophic keratitis, and multiple sclerosis was also described.

Internet-based FS and EDSS show good agreement with physician-measured scores. Agreement was better in patients with higher scores, indicating that internet-based assessment may be useful for patients with greater disability. Interestingly, >90% patients self-scored higher in the bowel/bladder FS than the physician-rated scores, highlighting that a web-based assessment may be useful for patient who have difficulty describing personal symptoms. 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; not least for those patients who have difficulty travelling to see physicians regularly due to the severity of their disease.

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.

Our study begins to explore possible epistatic effects between genes in MS employing extremes of outcome, which increases power and may be able to detect effects that conventional models are underpowered for. Our findings suggest that interactions between antigen presenting cell activation and other components of the inflammatory cascade predispose patients to early-onset disease, and indicate a possible role for KIF21B in the onset of disease progression. We have set out a methodology for exploration of epistatic effects on MS phenotype which requires confirmation in replication studies.

The BRAIN test is a widely-available, objective test of upper limb motor function in neurological disease and can be use in the outpatient clinic, home and in clinical trials. Tapping speed is reduced in MS patients when compared to healthy controls and by a similar extent to that seen in PD. MS patients do not have prolonged dwell time when pressing keys, which is a feature of the PD patient group and perhaps extra-pyramidal slowing. This potential for the BRAIN test in differentiating pyramidal from extra-pyramidal motor dysfunction requires further study.

Assuming that reduced GM MTR implies demyelination and atrophy reflects neuronal loss, the results suggest that: (i) in progressive (SP and PP) MS there is overall more extensive GM demyelination than neuronal loss; (ii) in RRMS there is overall more extensive GM neuronal loss with less noticeable demyelination, (iii) cortical demyelination occurs in more regions in SPMS and PPMS than RRMS; (iv) demyelination and neuronal loss often occur in different locations in the cortex, and (v) co-existent demyelination and neuronal loss is most evident in the thalamus. The variation in regional abnormalities argue against a single common mechanism for demyelination and neuronal loss in MS GM.

This study demonstrates a significantly increased risk of progression from RRMS to SPMS in patients who become NAb positive. As no current disease modifying treatments are effective in this phase of the disease patients at risk should be detected early and routine NAb testing can help to inform this decision.

In addition to a prominent global influence on cognitive performance, patients with progressive MS commonly exhibit independent language and visuospatial deficits. Evaluation of these abilities should therefore be included in clinical assessment of cognition in progressive MS. The underrepresentation of frontal-executive dysfunction also seen in our study raises the possibility that language and visuospatial deficits may be characteristic of cognitive impairment in progressive MS.

The demographic characteristics of the White MS patients in our cohort are very similar to those recently described in another UK-based geographically-linked MS cohort of 620 patients in Wales which was 97% White (J Neurol, Neurosurg & Psychiatry 80 (4):386-391). They described a mean age of 51, a female:male ratio of 2.4:1, and a prevalence of 146 per 100,000. However, what is unique to our cohort is its ethnic diversity, allowing us to show prevalences for ethnic minorities. What is more, when data coding is complete, we will be able to conduct further epidemiological studies, including migration studies, treatment effectiveness studies, and case-control studies of risk factors.


Splenectomy may increase the risk for the development of natalizumab-associated PML via effects on the B cell compartment. It may be regarded as a risk factor in MS patients independent from the duration of disease.
Medscape Education for Neurologist: 2013 Insomnia Update: A Focus on Clinical Pathways and Why They Matter

Evidence-based patient information program in early multiple sclerosis: a randomised controlled trial

 Elan Announces Webcast of Third Quarter 2013 Financial Results - 4:16pm EDT

Characterizing aggressive multiple sclerosis



Characterising aggressive multiple sclerosis

Decreased NAA in Gray Matter is Correlated with Decreased Availability of Acetate in White Matter in Postmortem Multiple Sclerosis Cortex.

Depressive syndromes in neurological disorders.

Maintenance percutaneous posterior nerve stimulation for refractory lower urinary tract symptoms in patients with multiple sclerosis.
Prolonged PTNS treatment leads to a persistent improvement of LUTS in MS patients.

Cell-Based Reparative Therapies for Multiple Sclerosis.

Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-κB- and STAT1-dependent chemokine production in astrocytes.

Pivotal role of augmented αB-crystallin in tumor development induced by deficient TSC1/2 complex.

False positive radiographical evidence of pump catheter migration into the spinal cord.

Environmental factors acting during development to influence MS risk: insights from animal studies.

Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

TNF Receptor 2 protects oligodendrocyte progenitor cells against oxidative stress.

Targeting Interleukin-6 in Inflammatory Autoimmune Diseases and Cancers.

Review of the pharmacoeconomics of early treatment of multiple sclerosis using interferon beta.

The usefulness of brain MRI at onset in the differentiation of multiple sclerosis and seropositive neuromyelitis optica spectrum disorders.

 Dalfampridine improves walking speed, walking endurance, and community participation in veterans with multiple sclerosis: a longitudinal cohort study

Evidence-based patient information programme in early multiple sclerosis: randomised controlled trial

Evidence-based patient information programme in early multiple sclerosis: a randomised controlled trial

Characterising aggressive multiple sclerosis

Disease modification in multiple sclerosis: an update

Early White Matter Changes in Childhood Multiple Sclerosis: A Diffusion Tensor Imaging Study

Compliance to GILENYA (fingolimod) and other disease modifying treatments in multiple sclerosis patients, a retrospective cohort study.
Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later than patients who initiated self-injected DMT.

[Is MRI monitoring useful in clinical practice in patients with relapsing-remitting multiple sclerosis? Yes.]

Visualization of inflammation and demyelination in 2D2 transgenic mice with rodent MRI.

25-hydroxyvitamin D3 Concentration in Serum and Cerebrospinal Fluid of Patients with Remitting-relapse Multiple Sclerosis.

Adipocytokine Profile, Cytokine Levels and Foxp3 Expression in Multiple Sclerosis: a Possible Link to Susceptibility and Clinical Course of Disease.

Progression, Symptoms and Psychosocial Concerns among Those Severely Affected by Multiple Sclerosis: A Mixed-Methods Cross-Sectional Study of Black Caribbean and White British People.

Tumefactive multiple sclerosis and fingolimod: Immunotherapies and unintended consequences.

The neuropathology of obesity: insights from human disease.

Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2.

Cell therapy for multiple sclerosis: an evolving concept with implications for other neurodegenerative diseases.