Monday, 31 December 2012

Research: fingolimod after natalizumab keeps relapses at bay

#MSBlog: How soon after stopping natalizumab (Tysabri) do you start fingolimod (Gilenya)?

Epub: Havla et al. Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis. J Neurol. 2012.

Background: After discontinuation of natalizumab (Nz), MS disease activity often recurs. 


"The level of rebound activity can be very severe!"

Objective: This study assessed the recurrence of clinical disease activity during the first year after switching from Nz to fingolimod (Fingo) in RRMSers. 

Methods: The number of relapses and the annualized relapse rate (ARR) before, during and after Nz discontinuation were determined and compared between 26 MSers who switched to Fingo within 24 weeks, and 10 MSers who remained without disease modifying therapy (therapy free group = TFG). 

Results: Median follow-up post-Nz discontinuation was 55.1 weeks. In a subgroup (n = 20), the occurrence of contrast-enhancing-lesions (Gd+) on magnetic resonance imaging (MRI) was determined. Eleven MSers (42 %) in the Fingo group and seven MSers (70 %) in the TFG had one or more relapses after cessation of Nz during follow-up (p < 0.05). One of the 11 (9 %) MSers in the Fingo group and 6/9 (67 %) MSers in the TFG showed Gd+ lesions during follow-up (p < 0.05). MSers who switched to Fingo  ≤ 12 weeks after Nz discontinuation (n = 9) showed a trend for a lower post-Nz ARR compared to MSers who started Fingo therapy >12 weeks after Nz was stopped (n = 17). Most relapses in the Fingo group occurred just before or within 8 weeks after starting Fingo. 

Conclusion: These observation suggests that initiation of Fingo treatment after Nz discontinuation reduces the recurrence of disease activity compared to withdrawal without further immunomodulatory treatment. In the Fingo group the ARR tended to depend on the time interval between discontinuation of Nz and initiation of Fingo.

"These results support our recent change in practice to limit the washout period when switching from Nz to Fingo. The sooner you switch the greater the likelihood of preventing post-Nz rebound!"


Other related posts of interest:

01 Dec 2012
"The potential rebound in MS disease activity that is commonly seen after withdrawal of natalizumab, and now fingolimod, reminds me of the book 'Waiting for the Barbarians' by JM Coetzee, which I read as a teenager.

27 Jul 2012
Rebound in MS disease activity on fingolimod withdrawal. Epub: Hakiki et al. Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases. Mult Scler. 2012 Jul. The objective of this study is to ...

19 Feb 2012
Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol. 2012;69:262-4. BACKGROUND: The oral sphingosine-1-phosphate receptor modulator fingolimod (FTY720/Gilenya) was recently ...

03 Jul 2012
BACKGROUND AND PURPOSE: MSers discontinuing natalizumab are at risk of rebound of disease activity. METHODS: In the present multi-center, open-label, non-randomized, prospective, pilot study, the investigators' ...

31 Oct 2012
Natalizumab dramatically reduces relapses in MSers with active MS, but it may induce progressive multifocal leukoencephalopathy (PML).(1) A rebound of MS or an immune reconstitution inflammatory syndrome (IRIS) were ...

30 Oct 2012
Clinical and/or MRI signs suggestive of disease rebound were observed in three MSers. ... "These studies and case reports confirm mine and many other neurologists' observations of rebound on natalizumab withdrawal.

CoI: multiple

Research: Effect of Natalizumab on T cells

Epub: Börnsen et al. Effect of Natalizumab on Circulating CD4(+) T-Cells in Multiple Sclerosis. PLoS One. 2012;7(11):e47578. doi: 10.1371/journal.pone.0047578. Epub 2012 Nov 30.

In multiple sclerosis (MS), treatment with the monoclonal antibody natalizumab effectively reduces the formation of acute lesions in the central nervous system (CNS). Natalizumab binds the integrin very late antigen (VLA)-4, expressed on the surface of immune cells, and inhibits VLA-4 dependent transmigration of circulating immune-cells across the vascular endothelium into the CNS. Recent studies suggested that natalizumab treated MS patients have an increased T-cell pool in the blood compartment which may be selectively enriched in activated T-cells. Proposed causes are sequestration of activated T-cells due to reduced extravasation of activated and pro-inflammatory T-cells or due to induction of VLA-4 mediated co-stimulatory signals by natalizumab. In this study we examined how natalizumab treatment altered the distribution of effector and memory T-cell subsets in the blood compartment and if T-cells in general or myelin-reactive T-cells in particular showed signs of increased immune activation. Furthermore we examined the effects of natalizumab on CD4(+) T-cell responses to myelin in vitro. Natalizumab-treated MS patients had significantly increased numbers of effector-memory T-cells in the blood. In T-cells from natalizumab-treated MS patients, the expression of TNF-α mRNA was increased whereas the expression of fourteen other effector cytokines or transcription factors was unchanged. Natalizumab-treated MS patients had significantly decreased expression of the co-stimulatory molecule CD134 on CD4(+)CD26(HIGH) T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26(HIGH)CD4(+) T-cells in vitro. Otherwise CD4(+) T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. Research: Predicting MS from CIS.


This study essentially shows that Natalizumab blocked white blood cells from leaving the blood we know this already.

Exercise for MS

Tonight is New Years Eve, so some exercise for this evening.




Drink in Moderation and Don't Drink and Drive.

Research Day 31

So this Concludes the House of Mouse Month. It is back to the boring white lab coat.




Tomorrow brings another Year, 
with New Challenges and New Goals. 

It may have been a monstrous 2012 to some people and Not Others..Prof G is easily pleased, but lets hope we do better in 2013.

Have a festive New Years Eve where every you are and 

Don't drink too much Pop!

If you can't make it let us know of register interest fro returns
            


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This is your last Chance to Pose any Questions!!!!


CoI: We receive nothing from the House of Mouse, but the enjoyment that these little felt creatures bring.

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Sunday, 30 December 2012

Research: clearing up myelin debris

Epub: Fernandez-Castaneda et al. Identification of the LDL Receptor-Related Protein-1 Interactome in Central Nervous System myelin suggests a role in the clearance of necrotic cell debris. J Biol Chem. 2012 Dec 

In the central nervous system (CNS), fast neuronal signals are facilitated by the oligodendrocyte-produced myelin sheath. Oligodendrocyte turnover or injury generates myelin debris that is usually promptly cleared by phagocytic cells. Failure to remove dying oligodendrocytes leads to accumulation of degraded myelin, which, if recognized by the immune system, may contribute to the development of autoimmunity in diseases such as Multiple Sclerosis (MS). We recently identified low density lipoprotein receptor-related protein-1 (LRP1) as a novel phagocytic receptor for myelin debris. Here, we report characterization of the LRP1 interactome in CNS myelin. Fusion proteins were designed corresponding to the extracellular ligand-binding domains of LRP1. LRP1 partners were isolated by affinity purification and characterized by mass spectrometry. We report that LRP1 binds intracellular proteins via its extracellular domain, and functions as a receptor for necrotic (dead and dying) cells. Peptidyl arginine deiminase-2 (PAD2) and cyclic-nucleotide phosphodiesterase (CNP) are novel LRP1 ligands identified in our screen, which interact with full-length LRP1. Furthermore, the extracellular domain of LRP1 is a target of PAD2-mediated deimination in vitro. We propose that LRP1 functions as a receptor for endocytosis of intracellular components released during cellular damage and necrosis.

Epub: Skripuletz et al. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain. 2012 Dec.

Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of demyelination. This led to strong astrogliosis accompanied by microgliosis and demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic protein-thymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.




Following demyelinating attack, removal of myelin debris is vital for repair to occur. Whilst we know that microglia, (phagocytic/engulfing cells or the Hoovers or vacuum cleaners of the brain) are involved in clearing up the myelin and to do this they use the LRP1 which binds to bits in myelin such as CNPase. However it appears that it is the astrocytes that are also vital for helping in the clear up.

Research Gender differences in MS

Epub: Rojas et al. Sex-related differences in atrophy and lesion load in multiple sclerosis patients. Neurologia. 2012 Dec 13. doi:pii: S0213-4853(12)00277-0. 10.1016/j.nrl.2012.10.008.

INTRODUCTION: Previous studies showed gender-associated clinical and MRI differences in multiple sclerosis (MS) evolution. However, only few studies were done with non conventional MRI techniques and no one was done in a South American MS population. The aim of this study was to investigate gender differences according to nonconventional MRI measures in patients with MS from Buenos Aires, Argentina.
METHODS: Relapsing-remitting MS patients (RRMS) with at least 6 years of follow up and an MRI at onset and at 6 years were included. Patients were assessed using nonconventional MRI measures: total brain volume (TBV), neocortical grey brain volume (GBV), white brain volume (WBV), lesion load (LL), % of brain volume change between onset and year 6 (% BVC) and regional brain volume change. Gender-related MRI differences were investigated using general linear model analysis.

RESULTS: The 45 patients were included (25 female). Mean follow up time was 7.3±0.2 years. No differences in age, EDSS at onset, DMD treatment, TBV, GBV, WBV neither LL were found between gender at baseline. Six years later, males showed a decrease in TBV (P=.002) and GBV (P≤0.001) and an increase in LL (P=.02) and % BVC (P<.001) vs. females. Female patients showed a decrease in the volume of frontal subcortical region.

DISCUSSION: This is the first study showing differences in brain volume changes between gender in MS patients from South America. Future studies will confirm our initial findings.


Difficult to say too much here as the numbers of MSers included in this study is too low to be definitive. 

Research: Genetic pathways of MS

Epub: Song et al. Genome-wide pathway analysis of a genome-wide association study on multiple sclerosis. Mol Biol Rep. 2012 Dec 14.

Aims: The aims of this study were to identify candidate single nucleotide polymorphisms (SNPs) and mechanisms of multiple sclerosis (MS) and to generate SNP to gene to pathway hypotheses.


Methods: A MS genome-wide association study (GWAS) dataset that included 505,763 SNPs in 500 cases and 500 controls of European descent was used in this study. Identify candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset.

Results: ICSN Pathway analysis identified 9 candidate SNPs and 5 pathways, which provided 5 hypothetical biological mechanisms. The candidate SNPs, namely, rs1802127 (MSH5), rs9277471 (human leukocyte antigen [HLA]-DPB1), rs8084 (HLA-DRA), rs7192 (HLA-DRA), rs2072895 (HLA-F), rs2735059 (HLA-F), rs915669 (HLA-G), rs915668 (HLA-G), and rs1063320 (HLA-G) were all at HLA loci (-log(10)(P) = 3.301-4.000). The most strongly associated pathway was rs1802127 to MSH5 to meiotic recombination and meiotic cell cycle (nominal P < 0.001, false discovery rate [FDR] < 0.001). When HLA loci were excluded, ICSNPathway analysis identified seven candidate non-HLA SNPs (rs5896 [F2], rs8181979 [SHC1], rs9297605 [TAF2], rs669 [A2 M], rs2228043 [IL6ST], rs1061622 [TNFRSF1B], rs1801516 [ATM]) and ten candidate causal pathways, which provided seven hypothetical biological mechanisms (nominal P ≤ 0.001, FDR ≤ 0.047). The most strongly associated pathway was SNP rs5896 to F2 to the transcriptional activation DNA-binding protein B from mRNA (nominal P < 0.001, FDR = 0.006). 

Conclusions: The application of ICSN Pathway analysis to the MS GWAS dataset resulted in the identification of candidate SNPs, pathways, and biological mechanisms that might contribute to MS susceptibility.





Not sure what this is really telling us, there are genes associated with susceptibility to MS and that these may work in a co-ordinated fashion. In other words there are biological mechanisms, or pathways, that underpin the genes that are linked to MS. 

Research Day 30

The stars of the Preclinical Research Work of TeamG
Mr & Mrs BiozziMouse


Guido Biozzi was a Brazilian working in the Institute Curie in Paris, France. 

In order to study the genetic regulation of the Immune response he made a cross between white Swiss mice. 

At each generation took the mice that produced either high or low amounts of antibody and bred them together so that eventually he had two populations one that produced low amounts of antibody (ABL) and antoehr produced high amounts of antibody (ABH). 

It was found that the Biozzi ABH produced good relapsing progressive EAE by Prof B. 



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Unrelated Blogger Comments 30

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Saturday, 29 December 2012

Research vessels at the centre of the lesion

Epub: Gaitán et al. Initial investigation of the blood-brain barrier in MS lesions at 7 tesla. Mult Scler. 2012 Dec 17.

BACKGROUND: We previously described two dynamics of contrast enhancement in scans of active multiple sclerosis lesions: Medium-sized, early lesions enhance centrifugally, whereas larger, slightly older lesions enhance centripetally. Due to technical limitations, our previous study did not characterize lesions < 5 mm in diameter, cortical enhancement, and anatomical structures within lesions.

OBJECTIVE: The objective of this paper is to obtain initial observations of these important aspects of lesion development on a 7 tesla scanner at high spatial resolution. 

METHODS: We scanned eight patients, acquiring precontrast T2*-weighted scans, T1-weighted scans before and after contrast, and high-resolution dynamic contrast-enhanced scans during and up to 30 min after contrast. 

RESULTS: We detected 15 enhancing lesions, obtaining dynamic data in 10: Five lesions < 4 mm enhanced centrifugally (initial central enhancement expanded outward), and five lesions > 4 mm enhanced centripetally (initial peripheral enhancement gradually filled the lesion). A leukocortical lesion (lesion spanning the grey and white matter) initially showed enhancement in its white matter portion, which gradually spread into the cortex. Seventy-three percent of lesions were clearly perivenular.

CONCLUSION: Most active lesions are perivenular, and the smallest lesions enhance centrifugally. This supports the idea that lesions grow outward from a central vein.



Well more data indicating that the lesions expand from around vessels. This is consistent with the histology, but it does not necessaily say what the trigger is and may not centre on the vasculature but may be just outside this. The MRI does not have the resolution for this 4mm could be 40-400 cells thick  and we know that gadolium (the tracer) is entering the brain from the vasculature but as it expands from it does point to a central role in lesion formation.

Blood flow in grey matter lesions

Epub: Peruzzo et al. Heterogeneity of cortical lesions in multiple sclerosis: an MRI perfusion study. J Cereb Blood Flow Metab. 2012 Dec. doi: 10.1038jcbfm. 2012.192.

In this study, dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) was used to quantify the cerebral blood flow (CBF), the cerebral blood volume (CBV), and the mean transit time (MTT) and to analyze the changes in cerebral perfusion associated with the cortical (grey matter on the outer bit of the brain) lesions in 44 patients with relapsing-remitting multiple sclerosis. The cortical lesions showed a statistically significant reduction in CBF and CBV compared with the normal-appearing gray matter, whereas there were no significant changes in the MTT. The reduced perfusion suggests a reduction of metabolism because of the loss of cortical neurons. A small population of outliers showing an increased CBF and/or CBV was also detected. The presence of hyperperfused outliers may imply that perfusion could evolve during inflammation. These findings show that perfusion is altered in cortical lesions and that DSC-MRI can be a useful tool to investigate more deeply the evolution of cortical lesions in multiple sclerosis.




This study reports altered blood flow in grey matter lesions, this generally lower but can be higher but it is not clear what this means is it because there is less oxygen demand in the lesions?  Maybe the vascular biologists amongst you can put your spin on it?

CCSVI Monthly-December

Research: CCSVI a consequence not cause

EpubDenislic et al. Disability caused by multiple sclerosis is associated with the number of extra cranial venous stenoses: possible improvement by venous angioplasty. Results of a prospective study. Phlebology. 2012 Nov.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS). The hypothesis of the vascular aetiology provides a new approach in the investigation and treatment of MS.METHODS: Our open-label study included 94 MS patients who fulfilled ultrasound sonographic criteria required for CCSVI. The internal jugular and/or azygous veins by a catheter venography were dilated.

RESULTS: In 34.8% of the patients unilateral, in 65.2% bilateral venous abnormalities and in 2.1% no luminal obstructions were demonstrated. The patient group with the higher disability score had a significantly higher number of venous lesions (P < 0.005). Significant improvement of clinical disability in relapsing-remitting patients was (P < 0.001) achieved. In our study no stents were used. Re-stenosis occurred in 21.7% of the patients.

CONCLUSION: The number of venous narrowings is higher in more disabled patients. A significant improvement in clinical disability in the relapsing-remitting group was observed.

As the potential number of lesions increased with increase disability, which is a product of disease duration, then it is further evidence against CCSVI being causal in MS, if the condition truely exisits-based on some peoples findings. The good news that their was a significant treatmet effect so all it needs now is to be successful in a proper blinded control, so it can convince us that it is not some big placebo effect. Apparent re-stenosis occurred 22% of time, so many of you will need to go back for another few grands worth, it will be even more grands worth if people start doing by-pass vein grafts. This is a worrying escalation.

EpubHaacke et al. Tissue similarity maps (TSMs): A new means of mapping vascular behavior and calculating relative blood volume in perfusion weighted imaging. Magn Reson Imaging. 2012 Nov. 

This study introduces a new processing means that uses the original signal (rather than contrast agent concentration) from dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) to calculate a relative cerebral blood volume map and a tissue similarity map (TSM). Ten healthy volunteers and eight multiple sclerosis (MS) patients were studied using high resolution PWI. The TSM is found by choosing a reference region in one slice and comparing its signal in a mean squared error sense to the signal from every pixel in all images throughout the brain. The TSMs provide a means to determine which tissues have similar flow characteristics with high contrast and signal-to-noise ratios. The effective blood volume measured from this approach is nearly identical to that from conventional relative cerebral blood volume (rCBV) maps but with better signal-to-noise. Of interest is the fact that choosing one MS lesion as the reference tissue appears to be enough to find nearly all lesions throughout the brain. That is, these lesions all behave the same from a vascular point of view. The TSM results are robust within and across slices properly nulling the same type of tissue throughout the brain for a given reference region. TSM derived rCBV agrees well with the conventional derived rCBV using contrast agent concentration. TSM may provide a new means to study similarities between blood flow patterns in tissue in the brain and in better diagnosing vascular differences between tissues and lesions.

Epub: Van den Berg et al. Occurrence of CCSVI in patients with MS and its relationship with iron metabolism and varicose veins. Eur J Neurol. 2012 doi: 10.1111/ene.12010.

BACKGROUND: A new treatable venous disorder, chronic cerebrospinal venous insufficiency (CCSVI), has been proposed in patients with multiple sclerosis (MS). Its relationship with iron metabolism is suggested, but has not been examined prospectively.

METHODS: We performed extra- and transcranial echo colour Doppler (ECD) in 90 patients with MS and 41 healthy controls (HC). Indices of iron metabolism and the presence of peripheral signs of impaired venous flow were also examined.

RESULTS: The ECD examination showed CCSVI in 8 (9%) of the 90 patients with MS and 0 HC (P = 0.11). The 8 CCSVI-positive MS patients were older (P = 0.02), had less often RR-MS (P = 0.02) and had more neurological disability assessed by expanded disability status scale (EDSS, P = 0.001) and longer duration of disease (P = 0.02) in comparison with the 82 CCSVI-negative MS patients. Multivariate analysis revealed that EDSS remained an independent factor associated with CCSVI (odds ratio 1.89, 95%CI 1.17-3.05, P-value = 0.009). CCSVI MS patients more often had bilateral telangiectasia at the legs (P = 0.008), reticular veins (P = 0.006) and venous stasis dermatitis (P = 0.004). No relationship was found between CCSVI and impaired iron metabolism in patients with MS.

CONCLUSIONS: CCSVI is uncommon and is a secondary epiphenomenon in MS and related to more neurological disability and the presence of varicose veins at the legs

More evidence that the CCSVI effect is uncommon and is secondary consequence and not the cause of MS.

van Zuuren et al. Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients.Cochrane Database Syst Rev. 2012 Dec 12;12:CD009903. doi: 10.1002/14651858.CD009903.pub2.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of neurological disability in young adults. The most widely accepted hypothesis regarding its pathogenesis is that it is an immune-mediated disease. It has been hypothesised more recently that chronic venous congestion may be an important factor in the pathogenesis of MS. This concept has been named 'chronic cerebrospinal venous insufficiency' (CCSVI) and is characterised by stenoses of either the internal jugular or azygos veins, or both. It is suggested that these stenoses restrict the normal blood flow from the brain, causing the deposition of iron in the brain and the eventual triggering of an auto-immune response. The proposed treatment for CCSVI is percutaneous transluminal angioplasty, also known as the 'liberation procedure', which is claimed to improve the blood flow in the brain thereby alleviating some of the symptoms of MS.

OBJECTIVES: To assess the effects of percutaneous transluminal angioplasty for the treatment of CCSVI in people with MS.

SEARCH METHODS: We searched the following databases up to June 2012: The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register, CENTRAL in The Cochrane Library 2012, Issue 5, MEDLINE (from 1946), EMBASE (from 1974), and reference lists of articles. We also searched several online trials registries for ongoing trials.

SELECTION CRITERIA: Randomised controlled trials assessing the effects of percutaneous transluminal angioplasty in adults with multiple sclerosis, that have been diagnosed to have CCSVI.

DATA COLLECTION AND ANALYSIS: Our searches retrieved 159 references, six of which were to ongoing trials. Based on assessment of the title or abstract, or both, we excluded all of the studies, with the exception of one which was evaluated following examination of the full text report. However, this study also did not meet our inclusion criteria and was subsequently excluded.

MAIN RESULTS: No randomised controlled trials met our inclusion criteria.

AUTHORS' CONCLUSIONS: There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. Clinical practice should be guided by evidence supported by well-designed randomised controlled trials: closure of some of the gaps in the evidence may be feasible at the time of completion of the six ongoing clinical trials.

Just wasted a few minutes of my life reading this...em Duh..I think we all know there are no trials yet....get a move on and let's see the effect or not!

CCSVI continues it downward trend on Google:


Research Day 29

Come along and Talk to Alison our Resident Designer...


She Does not like to be called an Artist-That's Me.


She's only miffed because she was not on the Advent Calender.




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Unrelated Blogger Comments 29

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Friday, 28 December 2012

Research: veins sizes in the MS brain

Epub: Gaitán MI, de Alwis MP, Sati P, Nair G, Reich DS. Multiple sclerosis shrinks intralesional, and enlarges extralesional, brain parenchymal veins. Neurology. 2012 Dec 19.

OBJECTIVES: Many multiple sclerosis (MS) lesions develop around small veins that are surrounded by perivenular inflammatory cells, but whether veins in the brains of people with MS are smaller or larger than similar veins in healthy volunteers or people with other neurologic diseases remains unknown. This question can be addressed by high-resolution, high-field-strength MRI.

METHODS: In a cross-sectional study performed on a standard 3 T clinical scanner, we acquired whole-brain T2*-weighted images with 0.55 mm isotropic voxels and reconstructed the courses of deep and superficial veins within the white matter. We compared the apparent diameters of intralesional and perilesional veins to those of extralesional MS veins, veins in healthy volunteers, and veins in individuals with other neurologic diseases. 

RESULTS: We studied veins in 19 MS cases, 9 healthy volunteers, and 8 individuals with other neurologic diseases, analyzing a total of 349 veins. The mean diameter of intralesional veins (0.76 ± 0.14 mm) was smaller than that of perilesional (1.18 ± 0.13 mm; p < 0.001) and extralesional (1.13 ± 0.14 mm; p < 0.001) veins, regardless of lesion size and location. Perilesional and extralesional MS veins were larger than non-MS veins (0.94 ± 0.14 mm; p < 0.001), and intralesional MS veins were smaller (p < 0.001).

CONCLUSIONS: The small apparent size of intralesional MS veins may reflect compression by the perivascular inflammatory cuff within active lesions or hardening of the vascular wall in chronic lesions. The finding that extralesional veins are larger than similar veins in non-MS lesions may result from diffuse disease-related processes.


More effort triggered by the CCSVI debate.

Research: MS and employment

Epub: Schiavolin et al. Factors related to difficulties with employment in patients with multiple sclerosis: a review of 2002-2011 literature. Int J Rehabil Res. 2012 Dec.

We assess the knowledge available on the difficulties experienced by multiple sclerosis (MS) patients in work-related activities. A literature review was carried out using the keywords 'multiple sclerosis' and 'employment' or 'work' through PubMed and EMBASE. Papers reporting patient-derived data on difficulties at work as primary or secondary outcome measures and published in the period 2002-December 2011 were searched. A total of 26 papers were selected, for a total of 32 507 patients (mean age 46.2 years; 42.1% with relapsing-remitting MS). Most papers reported observational studies or cross-sectional surveys focused on health-related quality of life and MS costs. Symptoms more frequently addressed are fatigue, mobility and cognitive impairments. Limited research has been carried out on the working environment. We found a relatively small number of papers published in the last 10 years on the difficulties that patients with MS can experience at work, and this kind of information always appeared as a secondary outcome. In general, it is possible to affirm that MS has a strong impact on patients' employment status, as the mean unemployment rate was 59%. Research on factors promoting maintenance of remunerative employment is required.


Not good news that MS affects employment, but we know this already.

Research Day 28

Your chance to give a Neuro/Scientists a verbal beating at the Question Time, so we need your questions. 

Time is running out, the posts finish at the end of the month!

                                                              ClockworkOrange Mouse

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Thursday, 27 December 2012

Cardiovascular risk in MS

#MSBlog: Does your MS affect your risk of having a cardiovascular event. i.e. myocardial infarction or stroke?

Epub: Sternberg et al. The Prevalence of the Classical and non-Classical Cardiovascular Risk Factors in Multiple Sclerosis Patients. CNS Neurol Disord Drug Targets. 2012 Dec

Background: Inflammation is known to play a role in cererovascular (CV) risk. MS is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. The investigators' hypothesized that due to chronic inflammation, MSers would present with a higher levels of CV risk factors than non-MSers. 


Methods: They performed a retrospective chart review on 206 MSers and 142 non-MSers suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic BP, serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MSers. 

Results: MSers had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P <0.001, but lower plasma glucose, P <0.001, and systolic blood pressure, P = 0.001, than non-MSers. In addition, MSers had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MSers. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001. 

Conclusion: The MS pathophysiology may be among factors for the lower CV risk factors in MSers. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MSers.

Cardiovascular risk!

"This study may have had a simple hypothesis, but is has left many unanswered questions and posed some new ones. I suspect the study is too small to draw any serious conclusions. These sorts of studies needs 10,000+ subjects, and exploratory and validation cohorts, to make sure the finding are real."
"Superficially MSers appear to have a better cardiovascular risk profile than non-MSers. Surprising? Not really!"

"In this study MSers had higher vD levels; I suspect this is confounded by vD supplementation. A lot of MSers now take vD supplements."

"I am intrigued by the observation that there was a positive correlation between plasma glucose levels and EDSS and rate of clinical relapse. This may be confounded by exercise or lack of exercise. People who exercise have lower glucose levels than non-exercisers. The more disabled you are the less likely you are to exercise  Another factor may relate to energy fluxes; could this indicate a problem in consuming glucose? Could the mitochondria or energy factories in MSers have a problem using glucose? There is some evidence than MS affects the functioning of mitochondria. This will need more work."

"I am aware that most of you would criticise this study as being underpowered and of no relevance to MS. However, it is exactly these sorts of studies that make scientists to think in different ways. For example, I think we should start investigating MS from a metabolic perspective and think about it in terms of energetics. Who knows where this will take us?"

Research: Smoking increases Risk of MS

Epub: Salzer et al. Smoking as a risk factor for multiple sclerosis. Mult Scler. 2012 Dec 20.

BACKGROUND: Smoking has been associated with an increased risk for multiple sclerosis, but no studies have measured levels of the nicotine metabolite cotinine in prospectively collected samples to assess exposure.

OBJECTIVE: To investigate the effects of laboratory defined tobacco use on the risk for multiple sclerosis using prospectively collected biobank blood samples.

METHODS: Levels of cotinine were measured in n=192 cases, and n=384 matched controls, using an immunoassay. The risk for multiple sclerosis was estimated using matched logistic regression.

RESULTS: Elevated cotinine levels (≥10 ng/ml) were associated with a significantly increased risk for multiple sclerosis, (odds ratio, OR 1.5, 95% confidence interval, CI 1.0-2.1). This association was only present in young individuals (below median age at blood sampling, <26.4 years), (OR 2.2, 95% CI 1.3-3.8).

CONCLUSIONS: This study confirms that smoking is a risk factor for multiple sclerosis. It has the advantage of using analyses of cotinine levels in samples that were collected several years before disease onset, thus excluding any risk for recall bias and minimising the risk for reversed causation. Our results also suggest that the smoking related immunological events that contribute to the development of multiple sclerosis occur early in life.


Yet more evidence of the increased risk of developing MS if you  smoke. You also need to spread the message to your children and family, who are all at increased risk of developing MS if they smoke.

Tc17 a new player in cause of MS

IL-17-producing CD8+ T (Tc17) cells are detectable in MS lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a mouse model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when transferred together with CD8+ T cells, IL-17-producing CD4+ (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tc17 cells are required to promote CD4+ T cell-mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.



Many immunologists believed that CD4- T helper cells were the problem in MS, but the pathologists suggested that the dominant T in MS lesions were CD8 cells. So the EAE studies began to concentrate on CD8 T cells. When you see CD8 T cells you should first think virus! Now immunologists are reporting that a subset of CD8+ T cells called Tc17 cells.  They do not appear to have the destruction machinery of viral-killing CD8+ T cells, but it seems they can augment the damage caused by Th17 cells. Inhibition of these cells using blockade of Interleukin-17 or granulocyte macrophage colony stimulating factor is ongoing. Maybe another treatment for RRMS in the future.

Research: Monitoring Movement

Epub: Motl et al. Accelerometry as a measure of walking behavior in multiple sclerosis. Acta Neurol Scand. 2012. doi: 10.1111/ane.12036.

OBJECTIVE: Accelerometry has been identified as a possible ecologically valid and objective approach for measuring community ambulation inmultiple sclerosis (MS). This study provides a validation of accelerometer output based on associations with Expanded Disability Status Scale (EDSS), Patient Determined Disease Steps (PDDS) Scale, and Multiple Sclerosis Walking Scale-12 (MSWS-12) scores, timed 25-foot walk (T25FW) and 6-min walk (6MW) performance, oxygen cost (O(2) cost) of walking, and spatial and temporal parameters of gait.

MATERIALS AND METHODS: 256 persons with MS completed the PDDS and MSWS-12, underwent an examination for the generation of an EDSS score, undertook two T25FW tests and a 6MW while wearing a portable metabolic unit for measuring the O(2) cost of walking, completed two trials of comfortable walking on a GAITRite electronic walkway for measuring spatial and temporal parameters of gait, and then wore an Actigraph accelerometer during the waking hours of a 7-day period.

RESULTS: The accelerometer output was significantly correlated with EDSS (ρ = -0.522), PDDS (ρ = -0.551), and MSWS-12 (ρ = -0.617) scores, T25FW (ρ = -0.595) and 6MW (ρ = 0.630) performance, and O(2) cost of walking (ρ = -0.457). Regarding gait parameters, the accelerometer output was significantly correlated with velocity (ρ = 0.420), cadence (ρ = 0.349), step time (ρ = -0.353), step length (ρ = 0.395), double support (ρ = -0.424), and single support (ρ = 0.400).

CONCLUSION: We provide comprehensive evidence from a large sample of persons with MS that further supports accelerometry as a measure of walking behaviour.


Accelerometry measures motion and there are loads of devices that can pick this up as was shown previously by work from Team G. Yet more ways to get qualitative measures of mobility. At some stage neurology and assessment of MS will move into the 21st century. 

Research Day 27

Talk to a  Neuro and ........



Do not Forget the Research Day..The men in Grey ..and a few women too.




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Wednesday, 26 December 2012

Health status changes

#MSBlog: Would treating early and hard have made a difference? What do you think?

EpubGiordano et al; The POSMOS study. Self-assessed health status changes in a community cohort of people with multiple sclerosis: 11 years of follow-up. Eur J Neurol. 2012 Dec 6. doi: 10.1111/ene.12028.

BACKGROUND AND PURPOSE: Few data are available on the health status of MSers in the community. These investigators assessed changes in self-perceived health status and health related quality of life of a community-based cohort of MSers over a decade, and identified predictors of such changes.

METHODS: In 1999 they started the POSMOS study (Postal Survey of Self-Assessed Health of MS Adults and their Significant Others) on a random sample of 251 adults MSers from the Milan area (mean age 42 years, range 18-71 years), and prospectively assessed changes in self-perceived health status over 11 years. Participants completed the Multiple Sclerosis Quality-of-Life-54 (MSQOL-54) and a general/clinical questionnaire. We re-assessed the cohort in 2004 and 2010, sending the same questionnaires plus the Chicago Multiscale Depression Inventory.

RESULTS: There were 205 (86%) respondents in 2004, 171 (74%) in 2010; 28 (11%) died during the study. Severely impaired [self-determined Expanded Disability Status Scale (EDSS) > 6.5] increased from 19% to 32%. One-fifth remained fully ambulatory (EDSS < 4.0): 25% women (median age 44 years [interquartile range, IQR 39-53], median years from diagnosis 16 [IQR 12-19]); and 17% men (median age 40 years [IQR 38-45], median years from diagnosis 14 [IQR 12-17]). Changes in MSQOL-54 composite scores were negligible; but among individual scales, change in health, cognitive function and general health worsened, and social function and emotional wellbeing improved significantly. Depressive symptoms were high and stable.

CONCLUSIONS: Multiple sclerosis had a pervasive but inhomogeneous impact on the lives of these Italian MSers. Notwithstanding overall clinical deterioration and aging, hospital admissions and medical consultations decreased, suggesting reduced use of health care resources. By contrast, housing adaptations and home care increased, psychological burden was high and self-perceived cognitive functioning worsened.

"The results of this survey speak for themselves and demonstrate the impact MS has on a population, this is despite the era of DMTs. Hopefully, the new era of more aggressive therapy  with adoption of the treatment philosophy of treat early and hard things will change!"


Research: Smelling Problems with MS

Epub: Rolet et al. Olfactory Dysfunction in Multiple Sclerosis: Evidence of a Decrease in Different Aspects of Olfactory Function. Eur Neurol. 2012;69(3):166-170.

Background/Aims: Numerous authors have described olfactory dysfunction in multiple sclerosis (MS) in recent years. The aim of this study was to specify the aspects of olfactory perception that are most affected and to identify any correlations with clinical, anatomical and functional data.

Methods: 50 patients with remitting or secondary progressive MS were included. Personal data were collected (medical history, characteristics of their disease, depression and disability scores and number of lesions on cerebral imaging). An olfactory test (Sniffin Sticks®) was used to evaluate subjects' olfactory function.

Results: The odor detection threshold is the most sensitive marker, with 40% of patients presenting hyposmia. The ability to identify odors is affected later on, and is inversely correlated with the level of disability.

Conclusion: Our results confirm that several aspects of olfactory function are altered in MS, particularly those aspects requiring greater cognitive involvement, such as discrimination and identification of odors.


 


What's your experience?

Reseaearch:Falling not sure what causes them?



BACKGROUND: Falls are a significant issue in Multiple Sclerosis (MS), with research demonstrating falls rates of more than 50%.

PURPOSE: To evaluate the risk factors associated with falling in people with MS.

DATA SOURCES: Mixed search methods were used including computer based and manual searches. Additionally, hand searches of reference lists and conference abstracts were performed. All literature published from their earliest date to January 2012 was included; only English language sources (or those where a translation was available), where full text was available, were included.

STUDY SELECTION: Eligibility criteria specified articles evaluating any aspect of falls risk in adults with a confirmed MS diagnosis, where the incidence of falling as determined by prospective or retrospective participant report was included.

DATA EXTRACTION: Data were extracted independently by two reviewers using a written protocol and standardized extraction documentation. Detailed assessment of each article was independently undertaken by both reviewers, including assessment of study quality using an adaptation of the Newcastle Ottawa Scale plus extraction of key data (participant characteristics, falls incidence and outcomes).

DATA SYNTHESIS: The final review comprised eight papers with a total of 1,929 participants; 1,037 (53.75%) were classified as fallers. Eighteen different risk factors were assessed within the included studies. Meta-analysis demonstrated an increase in falls risk associated with impairments of balance and cognition, progressive MS and use of a mobility aid. Narrative review of the qualitative papers and those factors where meta-analysis was not possible was also undertaken.

LIMITATIONS: Variation in assessment, analysis, and reporting methods only allowed meta-analysis for four factors.

CONCLUSION: There is limited evidence of the factors associated with falls risk in MS. 


Falling was associated with impairments of balance and cognition, progressive MS and use of a mobility aid. This study tells us essentially nothing. There are loads of posts on falls in MSers on this blog, search on "Falls". Many of the risk factors, identified here have been highlighted before. However, ensure that you have good bone health, which will help you deal with the consequences of falls.

Research: EAEers questioning steroid use


Glucocorticoids (GCs) represent the standard treatment for acute disease bouts in multiple sclerosis (MS) patients, for which methylprednisolone (MP) pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application in MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner. Surprisingly, MP administration around the time of immunization was contraindicated as it even increased leucocyte infiltration into the CNS and worsened the disease symptoms. Our analyses suggest that in the latter case an incomplete depletion of peripheral T cells by MP triggers homeostatic proliferation, which presumably results in an enhanced priming of autoreactive T cells and causes an aggravated disease course. Thus, the timing and selection of a particular GC derivative require careful consideration in MS therapy.




This week I was moaning about EAEers because they do not use their animal models how the drugs are administered to MSers.  So here they say that steroids used therapeutically after onset inhibited the severity of disease, which is what occurs in human MS, but if they give it at the time of induction it makes EAE worse. This was attributed to causing T cell proliferation that was not similarly found with dexamethosome, another steroid. So what does this say. That if you take steroids when you are not in an attack it makes your MS worse. Well I think we can eliminate this because it is not supported by what occurs in MSers. However the question comes, why ask this question in the first place? You do not go on steroids before you get the disease.

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