Multiple Sclerosis Research

Prof G Got Man-Flu

2012-02-14T08:17:00.005Z

You wrote: "MouseDoc Have you considered expanding the collection...........well not really....until today that is, as the mice are more interesting but as Prof G is ill, a Get Well Present for his Man Flu,

Flu Virus

Hope he doesn't give it to Mrs G...Not much of a Valentines Present

February 2:Unrelated blogger comments

2012-02-14T00:56:00.001Z

Sometimes You want to post a comment that is Unrelated to the thread.

Therefore I have Created this Spot for You
It jumps around so that it is visible

Research:Remyelination and Olesoxime

2012-02-14T00:46:00.001Z

Magalon K et al. Olesoxime accelerates myelination and promotes repair in models of demyelination. Anals of Neurology. Feb 2012 DoI: 10.1002/ana.22593 [Epub ahead of print)

Objective: Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study we have tested the ability of olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo.

Methods: The effect of olesoxime on OPC differentiation and myelin synthesis was tested directly in organotypic slice cultures and OPC-neuron co-cultures. Using naïve animals and different mouse models of demyelination, we morphologically and functionally assessed the effect of the compound on myelination in vivo.

Results: Olesoxine accelerated oligodendrocyte maturation and enhanced myelination in vitro and in vivo in naïve animals during development and also in the adult brain without affecting oligodendrocyte survival or proliferation. In mouse models of demyelination and remyelination, olesoxime favoured the repair process favouring myelin formation with consequent functional improvement.

Interpretation: Our observations support the strategy to promote oligodendrocyte maturation and myelin synthesis to enhance myelin repair and functional recovery. We also provide the proof of concept that olesoxime could be useful for the treatment of demyelinating diseases.

Olesoxime (TRO19622)is a compound in development for motor neuron disease it remains to be seen whether it will be developed for MS. Maybe it could be part of a cockail to help oligodendrocyte maturation, with other agents that promote proliferation. This drug is in trials in humans aimed at motor neuron disease. This drug affects mitochondrial function and so it has the potential to affect nerve damage that could be useful for slowing progression.

CoI: None

Research: Another remyelinating molecule-LIF

2012-02-14T00:45:00.002Z

Deverman BE, Patterson PH. Exogenous leukemia inhibitory factor stimulates oligodendrocyte progenitor cell proliferation and enhances hippocampal remyelination. J Neurosci. 2012 ;32:2100-9.

New CNS neurons and glia are generated throughout adulthood from endogenous neural stem and progenitor cells. These progenitors can respond to injury, but their ability to proliferate, migrate, differentiate, and survive is usually insufficient to replace lost cells and restore normal function. Potentiating the progenitor response with exogenous factors is an attractive strategy for the treatment of nervous system injuries and neurodegenerative and demyelinating disorders. Previously, we reported that delivery of Leukemia inhibitory factor (LIF) to the CNS stimulates the self-renewal of neural stem cells and the proliferation of parenchymal glial progenitors. Here we identify these parenchymal glia as oligodendrocyte (OL) progenitor cells (OPCs) and show that LIF delivery stimulates their proliferation through the activation of gp130 receptor signaling within these cells. Importantly, this effect of LIF on OPC proliferation can be harnessed to enhance the generation of OLs that express myelin proteins and reform nodes of Ranvier in the context of chronic demyelination in the adult mouse hippocampus. Our findings, considered together with the known beneficial effects of LIF on OL and neuron survival, suggest that LIF has both reparative and protective activities that make it a promising potential therapy for CNS demyelinating disorders and injuries.

Axons (green) in mouse hippocampus lose all myelin (purple) after 12 weeks of cuprizone (a toxin that kills oligodendrocytes) treatment (left). Although some spontaneous remyelination occurs (center), remyelination is greatly increased by LIF (right)

Although I do not tend to discuss animal studies too much as it is abit sceince fiction and a long way from the clinic, but I know you are particulalrly interested in repair, so I serve up some new research that reports on another avenue to promote remyelination.

In multiple sclerosis (MS), chronic demyelination leads to axonal damage. Although oligodendrocyte precursors (cells that mature to become cells that make myelin) proliferate, differentiate, mature, and remyelinate axons in adult brains, this happens too slowly to compensate for the loss in MS. Stimulating endogenous processes might be an effective means to treat the disease, however. Leukemia inhibitory factor (LIF) stimulates oligodendrocyte precursor cell (OPC) proliferation, oligodendrocyte maturation, and myelination in cultures, and as shown here it produces similar effects in living animals. Injection into the brain of adenovirus expressing LIF (Ad-LIF) increased OPC proliferation in mice. Furthermore, after cuprizone (a chemical poison of oligodendrocytes)-induced demyelination, Ad-LIF greatly increased the number of mature oligodendrocytes and the extent of myelination in the hippocampus. Interestingly, some remyelination does not depend on LIF: enhanced proliferation and maturation were not detected in white matter tracts that underwent extensive spontaneous remyelination after cuprizone treatment, and inactivating the LIF receptor blocked the effects of Ad-LIF without affecting spontaneous recovery.

However, let us not get too carried away ye, as we will have to determine whether adenoviral vectors are a real way to deliver the LIF. Historically adenoviral vectors have been great at producing lots of proteins encoded by the viral vectors, but they have been immunogenic and so the immune system has got rid of them and presumably the cells expressing the virus after a short while. Whilst the new generation adenoviral vectors are less likely to stimulate the immune response this can still be a problem. So maybe we need to find other ways to stimulate the LIF receptor to promote remyelination.

Dr. Alasdair Coles: Guest Spot. Long-term follow up of CAMPATHers

2012-02-14T00:10:00.002Z

You asked "Regarding a Cure; The earliest MSers to be treated with alemtuzumab were in the 90's. Even if there were only a handful, have any of them progressed yet?"

Prof G said "At some stage we will have to ask Alastair Coles to post on this issue".

So why not now, so we have passed on the question of one of the A's from Cambridge and wrote "I was wondering if you are able to make any comment for the blog on your experiences on the long-term follow-up of CAMPATHers".

Revd Dr Alasdair Coles, yes a neuro ordained in 2009, wrote

"An excellent question. We are in the business of trying to get just such an analysis together for a paper…...Should have news in a couple of months"

Without the persistance of Alasdair Coles and Alastair Compston, I doubt that CAMPATH-1H, (the worlds first humanised monoclonal antibody)/Alemtuzumab/Lemtrada would be on the MS agenda. This drug has told us a great deal about the disease already and has more to offer.

However as you know, if Dr. C has the answer in a few months it will take about 6 months to a year to hit the newstands. However as Neuros often present at meetings before the paper we may get to hear more. We will keep you posted.

Happy Valentines Day.

2012-02-14T00:01:00.001Z

MouseDoc says Happy Valentines Day....show a little Love and make it 200,000 hits today

The "Big 5" questions in MS research in 2012

2012-02-13T13:47:00.000Z

In response to a recent question; the following are my choices of the "big 5" questions that are currently being asked in MS research.

1. CURE: Can we cure MS by rebooting the immune system early in the course of the disease?

This question is currently being asked by treating MS'ers early in the course of their disease with drugs such as alemtuzumab and cladribine or with autologous bone marrow transplantation. We know these therapies often render MS'ers disease-activity free (no relapses, no MRI activity and no disability progression), however, will these treatments prevent these MS'ers developing secondary progressive MS? To answer this question we will need to wait about 15-20 years for an answer. If these treatments don't prevent the secondary progressive MS then it is likely that MS is a primary neurodegenerative disease.

2. NEUROPROTECTION: Can we protect nerves and axons during acute focal inflammatory events, for example optic neuritis, or in progressive MS so that they can be saved to preserve function?

Several treatment strategies are currently being tested in clinical trials to answer these questions. If these trials are positive this will almost certainly lead to large combination therapy studies, with one therapy targeting inflammation and another therapy aimed at protecting nerves to maintain function.

3. PREVENTION: Can we prevent MS with physiological vitamin D supplementation?

The hurdles and logistics of doing the correct studies to test this hypothesis are enormous. However, I am confident that we will eventually get public health officials to see the light (sunlight) and to start a population-based food fortification study. The costs of not doing something are simply too high not to do something. Can we let a whole new generation of MS'ers be born?

4. CAUSATION: How do all the risk factors for developing MS interact with each other?

Over the last 20 to 30 years several genetic and environmental risk factors for developing MS have been identified. If we can work out how these factors interact with each other, and the timing of these interactions, we may have a better idea of how to prevent MS in people at high-risk of developing MS (siblings and children of MS'ers). Several research groups, including ours, are working on this problem. This research question gets to the heart of the cause of MS.

5. SYMPTOM MANAGEMENT: Symptomatic therapies for MS'ers are in general sub-optimal. In particular our ability to treat fatigue, cognitive impairment, spasticity and pain. Developing and optimising symptomatic therapies will have a major impact on the quality of life of MS'ers.

We are and others are working on symptomatic therapies. The solution to these problems, however, lie with big pharma. Pharma have the resources to best tackle these problems.

You will be disappointed, particularly if you have progressive MS, that I have not added restoration of neurological function to this list. The reasons for this are complex; firstly, I don't want to raise unrealistic expectations (neurorestoration in the MS arena is a long way off) and secondly, the evidence that we can do this is poor at present. The improvement we see in people with highly-active MS going onto an effective DMT is probably due to recovery from natural mechanisms as a result of the particular DMT suppressing further damage, rather than the DMT triggering repair mechanisms directly. However, I remain open to the idea that some DMTs may have a dual action; on the one hand suppressing inflammation and on the other hand stimulating recovery. In my experience recovery of function tends to occur in MS'ers early in their disease course rather than later in the disease, presumably because compensatory mechanisms fail or burn out with time and possibly with age. The latter seems to a common theme across the spectrum of neurological diseases.

The holy grail of MS is neurorestoration!

I would be interested to know what you think of my "big 5"? Do you agree? If you disagree please tell me why?

Research: Other conditions in MSers

2012-02-13T09:06:00.001Z

Marrie RA et al. Rising prevalence of vascular comorbidities in multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and hyperlipidemia Mult Scler J Feb 2012

Background: Despite the importance of comorbidity in multiple sclerosis (MS), methods for comorbidity assessment in MS are poorly developed.

Objective: We validated and applied administrative case definitions for diabetes, hypertension (high blood pressure) and hyperlipidemia (high cholesterol) in MS.

Methods: Using provincial administrative data we identified persons with MS and a matched general population cohort. Case definitions for diabetes, hypertension, and hyperlipidemia were derived using hospital, physician, and prescription claims, and validated in 430 persons with MS. We examined temporal trends in the age-adjusted prevalence of these conditions from 1984–2006.

Results: The 2005 age-adjusted prevalence of diabetes was similar in the MS (7.62%) and general populations (8.31%; prevalence ratio [PR] 0.91; 0.81–1.03). The age-adjusted prevalence did not differ for hypertension (MS: 20.8% versus general: 22.5% [PR 0.91; 0.78–1.06]), or hyperlipidemia (MS: 13.8% versus general: 15.2% [PR 0.90; 0.67–1.22]). The prevalence of all conditions rose in both populations over the study period.

Conclusion: Administrative data are a valid means of tracking diabetes, hypertension, and hyperlipidemia in MS. The prevalence of these comorbidities is similar in the MS and general populations.

Fat in Blood

So in a different current study the development of diabetes, high blood pressure and high cholesterol did not associate with having MS. This is yet another example where inconsistent results are found. This study is based on 430 people in Canada verses thousands more in the study of US military. Are the different occurrances of these problems, due to differneces in study design or perhaps the different populations of people being studied?

Research: Other Conditions in Male MSer Warriors

2012-02-13T09:05:00.002Z

Lavela SL, Prohaska TR, Furner S, Weaver FM. Chronic diseases in male veterans with multiple sclerosis.Prev Chronic Dis. 2012 Feb;9:E55. Epub 2012 Feb 9.

INTRODUCTION:Chronic disease risk may be high in people with multiple sclerosis (MS). Our objective was to identify chronic health conditions that may disproportionately affect male veterans with MS.

METHODS: We collected primary survey data for male (USA) veterans with MS (n = 1,142) in 2003 and 2004 and compared the data with 2003 Behavioral Risk Factor Surveillance System secondary data for comparison groups without MS (veteran population, n = 31,500; general population = 68,357). We compared disease prevalence by group and identified variables associated with chronic diseases in male veterans with MS.

RESULTS: Overall, veterans with MS had a high prevalence of hypercholesterolemia (high cholesterol 49%), hypertension (high blood pressure 47%), diabetes (16%), coronary heart disease (11%), and stroke (7%). Overall and for the subset of people aged 50 years or older, diabetes, hypertension, hypercholesterolemia, coronary heart disease, and stroke were significantly more prevalent among male veterans with MS than among the general population. Diabetes, hypertension, hypercholesterolemia, and stroke were more prevalent overall among male veterans with MS than among the general veteran population; however, except for stroke, differences were not significant for the group aged 50 or older. Explanatory variables (eg, age, education, race) and dynamic associations between conditions (higher odds for each when ≥1 of the other conditions were present) for chronic disease in men with MS were similar to findings in the general population literature for select conditions.

CONCLUSION: These findings raise awareness of chronic disease in a veteran cohort and help bridge a gap in the literature on chronic disease epidemiology in men with MS. We identified chronic disease priorities that may benefit from focused interventions to reduce disparities.

The American military is a wonderful source of information about the health of its soldiers during and after service.

Meet Team G

2012-02-13T09:00:00.004Z

If you want another opertunity to see & meet members of Team G. The folks at Shift MS offered up Dr M&M with top tips for excersice.
Now you can see Dr M&M give her Show and Tell (click now) so you can see the person behind the science.
If you don't want to see, don't press the links

Tysabri:- Activity over 3 years

2012-02-12T12:30:00.001Z

Epub: Kallweit et al. Sustained Efficacy of Natalizumab in the Treatment of Relapsing-Remitting Multiple Sclerosis Independent of Disease Activity and Disability at Baseline: Real-Life Data From a Swiss Cohort. Clin Neuropharm 012 Feb

OBJECTIVES: Therapy for relapsing-remitting multiple sclerosis with natalizumab (Tysabri) has been shown to be effective in the reduction of the clinical relapse rate and disability progression. However, real-life longitudinal data, including years before baseline, are rare.

METHODS: An observational single-center study was carried out. We analyzed data from 64 consecutive patients with multiple sclerosis.

RESULTS: After 1 year of treatment (n = 64), score on the Expanded Disability Status Scale (EDSS) decreased by 0.47 points (P = 0.047) and the annualized relapse rate (ARR) decreased by 82% (P less than 0.001). After 2 years (n = 41), EDSS score was still reduced by 0.28 (not significant) and ARR was reduced by 69% (P less than 0.001). After 3 years (n = 23), EDSS score was reduced by 0.26 (not significant), and ARR was reduced by 77% (P less than 0.001). Reduction of EDSS score and ARR did not depend on baseline ARR (1-2 vs & greater than 2) or EDSS score and was not biased by exceptional high disease activity or relapses around baseline.

CONCLUSIONS: These real-life data reinforce that natalizumab is effective over years, reduces ARR, and stabilizes EDSS score independent of baseline ARR, baseline EDSS score, or baseline.

This study shows that tysabri works at slowing the rate of relapsws, but as our monthly updates show this can be associated with significant risk from the development of PML if you are JC virus positive and have taken prior immunosuppressive agents and have had more than 24 infusions.

Research: Cell Migration

2012-02-12T08:00:00.002Z

Epub: Meares et al. Regulation of CCL20 expression in astrocytes by IL-6 and IL-17.Glia. 2012 Feb

Astrocytes have an important role in the regulation of inflammation within the central nervous system (CNS). In neuroinflammatory conditions such as multiple sclerosis, numerous cytokines and chemokine are elevated including interleukin 6 (IL-6), interleukin 17 (IL-17), and Macrophage Inflammatory Protein-3 (CCL20). IL-17 enhances IL-6 signaling and subsequent IL-6 expression in astrocytes. CCL20 is a chemokine that functions as a chemoattractant to facilitate the recruitment of CCR6 (CCL20 receptor-expressing cells, including Th17 cells (a type of T cell that is thought to cause autoimmunity). In this study, we examined the role of IL-6 and IL-17 on CCL20 production in primary mouse astrocytes. IL-6 in combination with the soluble interleukin 6 receptors (the receptor is cleaved from its anchorage in the cell) stimulated CCL20 expression in part through STAT3 activation, whereas IL-17 alone had no effect. However, the combination of IL-6, sIL-6R, and IL-17 led to a robust increase in CCL20 production. IL-17 increased the activation-associated phosphorylation of NF-κB, and inhibition of the NF-κB pathway significantly inhibited the enhancement of CCL20 expression by IL-17. In addition, chromatin immunoprecipitation revealed that stimulation of primary astrocytes with IL-6 plus the sIL-6R induced STAT3 binding to the CCL20 promoter. Combined stimulation with IL-6, sIL-6R, and IL-17 increased the recruitment of phosphorylated NF-κB to the CCL20 promoter (the bit that promotes the gene to be activated to make the CCL20 protein) and other things consistent with a transcriptionally active gene. The astrocyte-produced CCL20 increased T cell migration as determined by transwell migration assay. Collectively, these results suggest that astrocytes, in response to IL-6, sIL-6R, and IL-17, may shift chemokine production to that favoring T cell recruitment to the CNS.Early this week we reported evidence of the same cascade occurred to promote Th17 white blood cell migration into the CNS. This is what this study is reporting. That is not surprising as you are often not the only one to have a bright idea. So two scientists can do things at the same time, unaware of the other. However whilst they agree on the process, they do not agree on the cell type involved, one implies it comes from cells in the blood vessel the other an astrocyte. Could they both be right..maybe, could one be wrong...maybe. Astrocytes are inimately associated with blood vessels of the brain. Is this the answer..who knows. This is a good example how things can differ in the literature, we need someone else to come in with their view. Eventually weight of evidence occcurs to indicate the most likely answer. This type of debate is occurring in other aspects of MS all the time....Disagreement is part of the research process.

Research: Trial Cognitive Rehabilitation Intervention

2012-02-11T06:00:00.000Z

Epub ahead of print: Stuifbergen et al. A randomized controlled trial of a cognitive rehabilitation intervention for persons with multiple sclerosis. Clin Rehabil. 2012 Feb

Objective: To explore the feasibility and effects of a computer-assisted cognitive rehabilitation intervention - Memory, Attention, and Problem Solving Skills (MAPSS-MS) - for MS'ers on cognitive performance, memory strategy use, self-efficacy for control of symptoms and neuropsychological competence in activities of daily living (ADL).

Intervention: The eight-week MAPSS-MS intervention program included two components: (a) eight weekly group sessions focused on building efficacy for use of cognitive compensatory strategies and (b) a computer-assisted cognitive rehabilitation program with home-based training.

Outcome measures: A neuropsychological battery of performance tests comprising the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) and self-report instruments (use of memory strategies, self-efficacy for control of MS and neuropsychological competence in ADL) were completed at baseline, two months (after classes), and at five months.

Results: Both groups improved significantly (P less than 0.05) over time on most measures in the MACFIMS battery as well as the measures of strategy use and neuropsychological competence in ADL. There was a significant group-by-time interaction for scores on the measures of verbal memory and the use of compensatory strategies.

Conclusions: The MAPSS-MS intervention was feasible and well-accepted by participants. Given the large relative increase in use of compensatory strategies by the intervention group, it holds promise for enhancing cognitive function in persons with MS.

"Are you up for it?"

The Truly Staggering Cost Of Inventing New Drugs

2012-02-11T04:00:00.000Z

Please read this article from Forbes?

Forbes

"And we wonder why new MS drugs cost so much?"

Human skin pigmentation, migration and disease susceptibility

2012-02-10T07:07:00.002Z

Jablonski NG, Chaplin G. Human skin pigmentation, migration and disease susceptibility. Philos Trans R Soc Lond B Biol Sci. 2012 Mar 19;367(1590):785-92.

Human skin pigmentation evolved as a compromise between the conflicting physiological demands of protection against the deleterious effects of ultraviolet radiation (UVR) and photosynthesis of UVB-dependent vitamin D(3). Living under high UVR near the equator, ancestral Homo sapiens had skin rich in protective eumelanin. Dispersals outside of the tropics were associated with positive selection for depigmentation to maximize cutaneous biosynthesis of pre-vitamin D(3) under low and highly seasonal UVB conditions. In recent centuries, migrations and high-speed transportation have brought many people into UVR regimes different from those experienced by their ancestors and, accordingly, exposed them to new disease risks. These have been increased by urbanization and changes in diet and lifestyle. Three examples-nutritional rickets, multiple sclerosis (MS) and cutaneous malignant melanoma (CMM)-are chosen to illustrate the serious health effects of mismatches between skin pigmentation and UVR. The aetiology of MS in particular provides insight into complex and contingent interactions of genetic and environmental factors necessary to trigger lethal disease states. Low UVB levels and vitamin D deficiencies produced by changes in location and lifestyle pose some of the most serious disease risks of the twenty-first century.

"The evolution of skin colour is a very interesting story and the effects migration and social changes are having on our health as a result of our skin colour is becoming increasingly important."

"Rickets almost certainly drove selection of pale skin when our ancestors migrated out of Africa; woman with rickety or deformed pelvises died in child birth therefore selecting against dark skin colour. Once our ancestors arrived in Europe and more northerly latitudes they got their vD from fish. Now that I diets have changed (less fish or farmed fish), we are doing less outdoor activity (face booking and gaming), wearing make-up with sun block or sun-block period, covering-up for cultural (being pale is beautiful) or religious regions (Muslim woman) our vD levels have plummeted. In addition, increasing air pollution is filtering out more UVB than ever before. What can we do about it? Take vD supplements!"

"Please note that farmed fish has less vD than wild fish. Why? Wild fish get their vD from eating a certain type of plankton; farmed fish who are force feed feed in the form of pellets don't enough vD in their feed."

"This article is a very good read for those interested in the subject."

Reduced head size in children with MS

2012-02-09T15:30:00.001Z

Kerbrat et al. Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS. Neurology. 2012 Jan 17;78(3):194-201. Epub 2012 Jan 4.

OBJECTIVE: MRI was used to quantify the volume or size of different brain structures pediatric MS'ers.

METHODS: Subjects included 38 MS'ers (mean age 15.2 ± 2.4 years) and 33 age- and sex-matched healthy control (HC) participants.

RESULTS: The intracranial volume was significantly lower in the pediatric MS'ers (-0.45 ± 1.16; mean ± SD) compared with the HC participants (+0.25 ± 0.98; p = 0.01). MS'ers also demonstrated significant decreases in normalized brain volume z scores (-1.09 ± 1.49 vs -0.05 ± 1.22; p = 0.002). After correction for global brain volume, thalamic (deep gray matter) volumes in the MS'ers remained lower than those of HCs (-0.68 ± 1.72 vs 0.15 ± 1.35; p = 0.02), indicating an even greater loss of thalamic tissue relative to more global brain measures.

CONCLUSIONS: When compared with age- and sex-matched control subjects, the onset of MS during childhood is associated with a smaller overall head size, brain volume, and an even smaller thalamic volume.

"Wow, this is very very interesting and implies that there is something going on in the brains of children with MS, possibly before they even develop MS, or at least very early on in the disease course."

"The study's findings support our study on the MS endophenotype; i.e. can we identify changes in people at risk of MS before they develop the disease? If yes, we may be able to target preventative strategies at high-risk subjects."

Feedback 3rd Barts and The London MS Research Day

2012-02-09T12:42:00.001Z

I would like to take this opportunity to thank those who attended our third research day for your valuable feedback. To try and collect more reliable data for each speaker we would appreciate it if you could complete the following survey (2 minutes):

3rd Research Day Feedback Survey

Research: Teriflunomide 8 years on

2012-02-09T10:00:00.000Z

C Confavreux et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years [Mult scler J. Feb Epub ahead of print]

Background: Teriflunomide, an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis (RMS), was well tolerated and effective in reducing magnetic resonance imaging (MRI) lesions in 179 RMS patients in a phase 2 36-week, placebo-controlled study.

Methods: A total of 147 patients who completed the core study entered an open-label extension. Teriflunomide patients continued their assigned dose, and placebo patients were re-allocated to teriflunomide, 7 mg/day or 14 mg/day. An interim analysis was performed at a cut-off on January 8 2010.

Results: The mean and median duration of study treatment, including both the core and extension phase, from baseline to the interim cut-off, was 5.6 years (standard deviation: 2.7 years) and 7.1 years (range: 0.05–8.5 years), respectively. Of 147 patients, 62 (42.2%) discontinued (19% due to treatment-emergent adverse events (TEAEs)). The most common TEAEs were mild infections, fatigue, sensory disturbances and diarrhoea. No serious opportunistic infections occurred, with no discontinuations due to infection. Asymptomatic alanine aminotransferase increases (≤3× upper limit of normal (ULN)) were common (7 mg, 64.2%; 14 mg, 62.1%); increases greater thanv ;3×ULN were similar across groups (7 mg, 12.3%; 14 mg, 12.1%). Mild decreases in neutrophil counts occurred; none led to discontinuation. The incidence of malignancies was comparable to that of the general population, and cases were not reminiscent of those observed in immunocompromised patients.

Annualised relapse rates remained low, minimal disability progression was observed, with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters.

Conclusion: Teriflunomide had a favourable safety profile for up to 8.5 years.

Although Teriflunomide may appear to be relatively safe, the issue of level of efficacy may determine how well this orally-active compound is recieved. So whilst teriflunomide is effective it is not that effective. In the initial phase II trial , from which the followi-up is derived there was no significant inhibition of the relapse rate but did affect some other outcomes. However this drug has been studied in a phase III trial involving over 1000 people and oral Teriflunomide (Trade name Aubagio-Who comes up with these names?) inhibits the relapse rate only by about 30% and is no better than beta interferon when compared in a head to head fashion in recent studies involving over 300 hundered MSers. Whilst it has the advantage of being an oral drug verses interferons, it will be interesting to see how it will do compared to Gilenya and BG-12 that are much more active. However, this will depend on safety profiles and we have yet to see if the recent deaths of people taking Gilenya are going to impact on the use of the drug.

World-leading MS research to be showcased at MS Life in Manchester

2012-02-09T07:00:00.001Z

The MS Society has announced that Manchester is to host its flagship national event, MS Life - Europe’s largest event of its kind – for the third time when it returns to the city from 14th-15th April.

The free two-day lifestyle event will take place at Manchester Central and is aimed at everyone affected by multiple sclerosis (MS), whether personally or professionally.

Providing an impressive programme of speakers, MS Life 2012 will allow attendees to learn about the latest in MS research from experts including renowned Professors Robin Franklin and Charles ffrench-Constant who are leading the MS Society’s groundbreaking Centre for Myelin Repair and the Edinburgh Centre for Translational Research.

There will also be a plethora of individual workshops covering a range of topics for visitors to attend, while the exhibition space will be split into separate zones. Within this space, visitors will be able to gain one-to-one advice and information from the Support, Employment, Mobility and Lifestyle Zones as well as meet the event speakers at the Meet the Experts Zone. On a further interactive level, visitors will also be invited to take part in activities such as yoga and pilates at the Get Active Zone, while the Spa Zone will offer the chance to relax with a massage or complementary therapy.

MS is a complex neurological condition with many symptoms which might include fatigue, vision problems and difficulties with walking. In the UK, over 100,000 people have MS.

Simon Gillespie, Chief Executive of the MS Society, revealed the popular event, which has seen around 7,400 visitors and over 200 exhibitors over the course of previous years, will be bigger than ever before. While the event is free, people are being urged to sign-up to confirm their place as soon as possible.

Simon says: “MS Life 2012 will have the theme ‘Get Active’, tying in with the Olympic year, so a range of activities will be on offer to celebrate this. In addition to research talks from world-renowned scientists, there will also be complementary health, relaxation and beauty sessions and exhibition stands offering support, information and advice on MS, so we are advising those hoping to come along to book their place early.”

A number of interactive workshops will take place during the course of the event, from advice on how to manage symptoms, such as fatigue and tremor, to how to keep active with MS through cycling and exercise. Also included in the comprehensive programme are workshops on childhood MS and how positive psychology can be of benefit.

A colourful Wheel & Walk fundraising event, following the streets of Manchester will allow participants to take in famous landmarks like Albert Square and Manchester Cathedral while raising money for the MS Society. The 6km route is suitable for wheelchair users and buggies and it is hoped families and friends will join in the fun. The past two Wheel & Walk events held at MS Life have raised over £20,000 for the charity and it is hoped that a significant amount of funds will again be raised this year.

Simon adds: “Anyone with a connection to MS will benefit from the range of information available during the weekend. This is the best time for people to find out what scientists are doing to beat MS as well as take part in the more fun aspects of the event.

“MS Life has made its mark in Manchester, cementing a strong presence in the North West region and we have received enormous support from Marketing Manchester which we are very grateful for. The event in 2008 gained support from Manchester United’s Danny Wallace, Ryan Giggs, Gary Neville and Paul Scholes so we are delighted to be back hosting MS Life in such a fantastic and responsive city.”

For further information about MS Life 2012 and to book a free place, please visit www.mssociety.org.uk/mslife or call 020 8438 0941.

"If you attend the meeting you can meet us. The Barts and The London team will be there at the Meet the Scientists stand."

Become an activist; demand peer-reviewed evidence

2012-02-09T03:00:00.000Z

"Become an activist and demand high-quality data! No more poor quality MS studies that are not definitive. There is no place for Bad Science in the modern era."

New trial of Natalizumab in SPMS: the ASCEND study

2012-02-08T14:37:00.002Z

A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMS (ASCEND in SPMS)

Eligibility

Ages Eligible for Study:	18 Years to 58 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Major Inclusion Criteria:

Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
Be between the ages of 18 and 58, inclusive, at the time of informed consent.
SPMS defined as relapsing-remitting disease followed by progression of disability independent of or not explained by MS relapses for at least 2 years.
EDSS score of 3.0 to 6.5, inclusive.
MS Severity Score (MSSS) of 4 or higher.
Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.

Major Exclusion Criteria:

RRMS or primary progressive MS as defined by the revised McDonald Committee criteria.
Clinical relapse (within 3 months) prior to randomization.
T25FW test of >30 seconds during the screening.
Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.
Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.
Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed).
History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.
History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
Known history of or positive test result for Human Immunodeficiency Virus (HIV).
Positive test result for hepatitis C virus (test for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (test for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).
History of transplantation or any anti-rejection therapy.
Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.
History of PML or other opportunistic infections.

Treatment History

Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.
Any prior treatment with natalizumab.
Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization.
Treatment with IV or oral corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis for treatment of MS within the 3 months prior to randomization.
Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.
Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.

This study is being sponsored by Biogen-Idec

Sudden death in MS or SUDMUS (1)

2012-02-08T06:07:00.001Z

Hengstman & Kusters. Sudden cardiac death in multiple sclerosis caused by active demyelination of the medulla oblongata. Mult Scler. 2011 Sep;17(9):1146-8.

Cardiovascular autonomic dysfunction is not uncommon in multiple sclerosis (MS) and is related to the involvement of the autonomic areas of the brain that supply the heart; these are located in the area of the brain stem called the medulla oblongata. It has been suggested that involvement of these areas may contribute to the occurrence of sudden death in MS.

In this case report, the authors present a MS'er with active relapsing-remitting MS who died unexpectedly due to the sudden onset of cardiac arrythmias. Post-mortem examination showed the presence of active demyelinating lesions in the medulla oblongata. As far as they know, this is the first case report clearly linking sudden cardiac death to active MS on the histopathological level.

"Sudden death is very topical in view of the recent death of a patient on Fingolimod and the European Medicine Agency's decision to review the safety of the drug. I would be very interested to know if the unfortunate MS'er who died had involvement of the medulla oblongata that could have contributed to his or her death."

"Sudden death in MS or SUDMUS may be commoner than we think. In epilepsy, for example, it took decades for neurologists to recognise sudden death in epilepsy or SUDEP as being a major problem."

"I feel a research project coming on; we clearly need to get to the bottom of this issue before drawing premature conclusions about the fingolimod case."

CoI: multiple

Research Autoinjectors

2012-02-08T05:36:00.001Z

D'Arcy et al. Patient assessment of an electronic device for subcutaneous self-injection of interferon β-1a for multiple sclerosis: an observational study in the UK and Ireland.Patient Prefer Adherence. 2012;6:55-61.

BACKGROUND: Injectable disease-modifying drugs (DMDs) reduce the number of relapses and delay disability progression in RRMS'ers. Regular self-injection can be stressful and impeded by MS symptoms. Auto-injection devices can simplify self-injection, overcome injection-related issues, and increase treatment satisfaction. This study investigated patient responses to an electronic auto-injection device.

METHODS: RRMS'ers (n = 63), aged 18-65 years, naïve to subcutaneous (sc) interferon (IFN) β-1a therapy, were recruited to a Phase IV, observational, open-label, multicenter study (NCT01195870). MS'ers self-injected sc IFN β-1a using the RebiSmart™ (Merck Serono S.A. - Geneva, Switzerland) electronic auto-injector for 12 weeks, including an initial titration period if recommended by the prescribing physician. In week 12, MS'ers completed a questionnaire comprising of a visual analog scale (VAS) to rate how much they liked using the device, a four-point response question on ease of use ('very difficult', 'difficult', 'easy', or 'very easy'), and a list of ten device functions to rank, based upon their experiences.

RESULTS: Six MS'ers (9.5%) discontinued the study: one switched to manual injection; two discontinued all treatment; three changed therapy. In total, 59 out of 63 MS'ers (93.7%) completed the VAS; 54 out of 59 (91.5%; 95% confidence interval: 81.3%-97.2%) 'liked' using the electronic auto-injector (score ≥6), whereas 57 out of 59 (96.6%) rated the device overall as 'easy' or 'very easy' to use. Device features rated as most useful were the hidden needle (mean [standard deviation] score: 3.3 [3.01]; n = 56), confirmation sound (3.9 [2.45]), and multidose cartridge (4.6 [2.32]). The least useful functions were the dose history list (8.0 [2.57]) and dose history calendar (7.5 [2.30]).

CONCLUSIONS: These findings suggest that the electronic auto-injector may be suitable for MS'ers who are new to injectable DMD therapy. Devices that simplify the injection process may help to ensure that MS'ers receive the full benefits of treatment.

"The results suggest that MSers like the autoinjectors; or more useful comparison would be to see how MS'ers established on a treatment rate the device if switched. Our MS clinical nurse specialists have concerns about the device; complicated to use and they are worried about it malfunctioning. I would be interested to hear their thoughts on the paper."

"If you are switcher to RebiSmart let us known how you rate the device?"

CoI: multiple

Research: Entry of Cells into the CNS

2012-02-08T00:30:00.007Z

Arima et al. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell. 2012;148:447-57

Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier, which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that disease causing white blood cells T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 (Macrophage Inflammatory Protein-3) in associated blood vessels at the top of the spinal cord, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.

The study reports on how the white blood cells can enter the central nervous system and involves the expression of a chemical that attracts cells via activation of an immune hormone called interleukin 17 via another immune hormone called interleukin 6 that acts on interleukin 6 receptors in blood vessel cells that triggers more interleukin 6 to be released in an amplifying loop that results in the expression of a chemoattractant chemical called CCL20 that attracts T cells to attach and migrate through the blood vessel.

Therefore blockade of IL-17 (IL-17 receptor), IL-6 (IL-6 receptor) or CCL-20 (CCR6 = CCL-20 receptor) may have some benefit to halt this process.

This has been sort of shown for some of these targets in MS models and some of these aspects are currrently being examined in MS. Blockade or the white cell recruitment pathway is the mechanism of action of Tysabri

This study links this initial recruitment to the spinal cord, whereas others had tried to link this initial lesion into the brain. In the animal model used the lesions in the brain occur after the spinal cord lesions had developed suggesting that spinal cord lesions were earlier. These studies imply that these locations are the gateways through which white blood cells flow.

However if you look at affected tissues once lesions start the gates appear all over the CNS, but lesion location can be very different in MS. The interesting thing that this study suggests that nerve activity can trigger this cascade to be initiated in certain locations.

In this study they implicate a muscle group that deals with posture. If true then it would have implications concerning activating muscle groups and the development of lesions in MS. Surely if this were the case that similar muscles in the front legs would activate the same pathway as the backlegs, surely they feel the effects of gravity, and the results remains to replicated This would be easy. The way this Japanese group did the experiments was to remove gravitational effects off the hindlegs and and while the results appear compelling they used an experimental design that is somewhat disturbing and involved suspending mice by their tails so they could only weight-bear on their front legs and not their back legs. They did this for weeks.........Yuck. How would you feel going to the toilet and sleeping upside down? Just because you can does not mean you should!

So what are the implications for MS, well probably little, except pointing further to targets for treatment of MS. But if neural activity really does dictate lesion locations then it really would be important. However, as we all have sterotyped motor behaviours, one would think that lesion locations would be very, very similar between all MSers and you would all have the same symptoms...... they are not and you do not.

Cell is one of the best journals in the world. If the referees of this paper had paid attention to or actually read our guidelines for reporting EAE studies then at the very least the correct statistics may have been used, without out proper statistics are the right conclusions drawn?..... Another example of bad refereeing, perhaps too much attention was paid to reading the fancy science, whilst forgetting about the basics.

Education: Clinical trials

2012-02-07T06:05:00.000Z

Dr Pixie from Channel 4 explains the clinical trials process

So it takes about as long to get an anti-cancer drugs to market as it does for an MS drug.

Read more about the drug development process on the blog

Research: Lumbar punctures- BlogG to the Publishers

2012-02-07T06:00:00.001Z

Gafson AR, Giovannoni G. Towards the incorporation of lumbar puncture into clinical trials for multiple sclerosis. Mult Scler. 2012 Feb. [Epub ahead of print]

This study reports the preliminary findings about your views on the potential of having repeated lumbar punctures as part of a novel trial design. Prof G made a video for watching before taking the survey. This indicated that 78% of people would be willing to have multiple lumbar punctures as part of a trial, 15% of people were undecided and 7% were not prepared to have so many lumbar punctures. Peoples experience with having a lumbar puncture was often not great, but the potential use of the sprotte needle and ultrasound to limit problems with the procedure was a positive factor in 60% of responses.

Your responses where important to this study and shows that the surveys do have value and can lead to publishable results. The result was instrumental in taking this approach forward, fingers crossed that the study gets the green light.

CoI: This is a publication from Team G

Shorter trials?

2012-02-07T05:33:00.001Z

Epub: Wang et al. Short-Term Relapse Quantitation as a Fully Surrogate Endpoint for Long-Term Sustained Progression of Disability in RRMS Patients Treated with Natalizumab.Neurol Res Int. 2011:195831

Time to sustained worsening in the expanded disability status scale (EDSS) as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect.

Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test.

This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year.

CoI: This study was undertaken by Biogen.

"What this study shows is that events in the first 12 months of a clinical trial predict what is going to happen at the end of the study and possibly beyond. I am aware of data sets beyond this data that show the same thing. I think this is valid and may be it is time for the regulators (FDA and EMA) to accept short-term surrogates to help speed-up drug development. The problem with this approach it won't allow sufficient data to be collected to make a judgement on safety."

Feb:Unrelated Comments

2012-02-07T00:01:00.000Z

Sometimes You want to post a comment that is Unrelated to the thread.

Therefore I have Created this Spot for You
It jumps around so that it is visible
ADVERTS will be DELETED!

Research: Steroids and Bloodclots

2012-02-06T09:05:00.001Z

Kalanie et al. Venous thrombosis in multiple sclerosis patients after high-dose intravenous methylprednisolone: the preventive effect of enoxaparin.Thrombosis ;2011:785459 [Epub].

Aim. This study was designed to examine the possible role of high-dose intravenous methylprednisolone (IVMP) in the development of venous thrombosis (VT). The cerebral one anecdotally had been reported in patients with relapsing remitting multiple sclerosis (RRMS) in acute attacks and the possible preventive role of enoxaparin.

Material and Methods. From a pool of 520 patients, 388 patients with definite RRMS who fulfilled entry characteristics were selected and randomly received either a 5-day course of daily 1 gr IVMP or the aforementioned plus 5 days of daily subcutaneous 40 units of enoxaparin according to a predefined protocol.

Results. Mean age, gender ratio, mean relapse rate, and EDSS were similar in both groups of patients (P less than 0.05). Finally, 366 patients remained in the study. Of 188 patients treated with IVMP with 855 relapses, 5 developed VT (0.37% per patient per year and 0.58% per each course of IVMP) within 3 to 15 days of starting therapy. None of the 178 patients who experienced 809 relapses who received IVMP plus enoxaparin developed such complications.

Conclusion. The study implies that high-dose IVMP in MS exacerbation may increase the risk of VT and prophylactic anticoagulant treatment in this setting is warranted.
Although you should be aware of risk of thrombosis following high dose steroid treatment, early detection and prompt treatment are more realistic than prophylactic enoxiparin for everyone. For people with MS and with a history of thrombosis or at high risk (see previous post on DVT) it should be considered.

CoI: None

Research: Risk of DVT and MS

2012-02-06T09:00:00.002Z

Venous thromboembolism (blood clots in the veins) is a serious condition that affects people with MS more than the general population. Deep vein thrombosis can cause pulmonary embolism (blood clots block the lungs) if not detected and treated. It is known to be more frequent with obesity, infection, immobility, hormonal contraception, cigarettes, advancing age and thrombophilia (genetic predisposition to develop abnormal clots). This study does not tell us which other factors occurred in the MS and non-MS population, but this is one more reason to keep a healthy weight, treat infections promptly, stay mobile even during a relapse and avoid smoking.

Christensen et al.Multiple Sclerosis and Risk of Venous Thromboembolism: A Population-Based Cohort Study. Neuroepidemiology. 2012;38:76-83. [Epub ahead of print]

Background: Multiple sclerosis (MS) patients may be at increased risk of venous thromboembolism (VTE), but evidence is limited.

Objectives: To examine long-term risk of VTE among MS patients.

Patients and Methods: We conducted a population-based cohort study among 17,418 Danish MS patients and 87,090 comparison cohort members from the general population. Data on MS, VTE and comorbidities were obtained from the Danish National Registry of Patients including all admissions to Danish hospitals since 1977. We computed cumulative risks for VTE and adjusted incidence rate ratios (IRRs).

Results: A total of 34 (0.2% = 1 in 500) MS patients and 36 (0.04% 1 in 2-3 thousand) comparison cohort members had a deep venous thrombosis (DVT) within 1 year following the date of initial MS diagnosis/index date [adjusted IRR = 3.02 (95% CI: 2.14-4.27)]. During this period, 16 (0.09%) MS patients and 26 (0.03%) comparison cohort members had a documented pulmonary embolism (PE) [adjusted IRR = 2.85 (95% CI: 1.72-4.70)]. During the subsequent up to 29 years, 315 (1.9% of MS patients alive at year 1) MS patients had a record of a DVT [adjusted IRR = 2.28 (95% CI: 2.01-2.59)] and 129 (0.8%) had PE [IRR = 1.58 (95% CI: 1.31-1.92].

Conclusion: MS is a risk factor for VTE, but the absolute risk is low.
The conclusions sort of say it all. There is a small increased risk of DVT in MSers, but as MSers may get steroids as part of their management this may influence the observation. See next DVT post.

Survey results: nutriceutical use amongst MS'ers

2012-02-06T08:36:00.000Z

"Almost all MS'ers use supplements, despite a very poor evidence-base. I wonder if all the money spent on putative nutriceuticals went on funding MS research if we would be closer to an MS cure and an effective MS prevention strategy?"

"I wonder how many of you, in the current financial climate, are finding it increasingly difficult to afford supplements?"

Research Complementary Medicines

2012-02-06T08:34:00.000Z

Stoll, et al. Use of therapies other than disease-modifying agents, including complementary and alternative medicine, by patients with multiple sclerosis: a survey study. J Am Osteopath Assoc. 2012;112:22-8.

CONTEXT: Many MS'ers use complementary and alternative medicine (CAM) to supplement their traditional treatment.

OBJECTIVE: To identify both the prevalence and frequency of use of therapies other than disease-modifying Drugs (DMD), including CAM, among patients with multiple sclerosis

DESIGN: The authors administered a 13-question survey regarding patients' current use of non-DMD therapies-including dietary supplements, exercise, and "true" CAM (eg, acupuncture, chiropractic, massage)-and mainstream treatments, including physical therapy and osteopathic manipulative treatment. Patients rated their level of disability on a scale of 1 to 10 (with 10 being most severe).

RESULTS: A total of 111 MS'ers completed the survey properly. All respondents used non-DMD therapies. Twenty-three patients (20.7%) used these therapies without concomitantly taking a DMD. A plurality (34.8%) of those patients reported a disability score of 7 or 8. Sixty-two of the 88 participants (70.5 %) who used DMD reported disability scores of 5 or less. Sixty-five patients (58.6.%) reported exercising on a weekly basis. Among those patients, 47 (72.3%) reported a disability score of 5 or less. Sixty-four patients (57.7%) used such CAM therapies as acupuncture and massage, or such other non-DMD treatments as osteopathic manipulative treatment and psychotherapy. Among those patients, 37 (64.9%) reported a disability score of 5 or less.

CONCLUSION: Many patients with multiple sclerosis are seeking more than traditional medical treatment. Physicians and other health care professionals must be aware of the extensive use of alternative modalities among these patients, and these professionals must provide guidance and monitoring in use of these therapies to improve outcomes.

"In contrast to our survey were 86% of respondents used non-DMD therapies, in this study 100% of people were using non-DMD therapies. The problem is that there is no evidence base for the use of the majority of non-DMD therapies in MS. How do we obtain evidence? It will be difficult as there is little money or motivation by the medical community, nor by the companies that produce and market these therapies, to do proper clinical trials."

"Ben Goldacre, discusses the supplement industry in detail in his book bad science. It is worth a read."

Cognitive impairment in asymptomatic MS (or RIS)

2012-02-06T08:25:00.003Z

Epub ahead of print: Amato et al. Association of MRI metrics and cognitive impairment in radiologically isolated syndromes. Neurology. 2012 Jan.

OBJECTIVE: To evaluate cognitive changes in a cohort of radiologically isolated syndromes (RIS) suggestive of MS and to assess their relationship with quantitative MRI measures such as white matter (WM), lesion loads, and cerebral atrophy.

METHODS: We assessed the cognitive performance in a group of 29 subjects with RIS recruited from 5 Italian MS centers and in a group of 26 patients with RRMS. A subgroup of 19 subjects with RIS, 26 patients with RRMS, and 21 healthy control (HC) subjects also underwent quantitative MR assessments, which included WM T1 and T2 lesion volumes and global and cortical brain volumes.

RESULTS: Cognitive impairment of the same profile as that of RRMS was found in 27.6% of our subjects with RIS. On MR scans, we found comparable levels of lesion loads and brain atrophy in subjects with RIS and well-established RRMS. In subjects with RIS, high T1 lesion volume (ρ = 0.526, p = 0.025) and low cortical volume (ρ = -0.481, p = 0.043) were associated with worse cognitive performance.

CONCLUSIONS: These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.

"The results of this study are not unexpected. In the earliest stages of MS prior to the first clinical attack there is evidence of cortical or gray matter involvement that is associated with cognitive impairment."

"As a corollary to this; I have seen a few MS'ers presenting with cognitive impairment as their only complaint that on work-up proves to be due to MS. Although this is rare is does occur and indicates that gray matter disease is a problem."

"The implications of this study will be troubling for MS'ers. How much hidden cortical function is lost before my first attack and will I get this function back if my MS is treated with a DMT?"

"You have to remember that the aim of DMTs is prevent further damage; full recovery of lost function is unlikely. Despite this the brain is very plastic and adapts well to damage so most MS'ers won't notice a problem. To detect this damage you have to have detailed neuropsychological assessments."

"This data further argues for aggressive suppression of MS disease activity, i.e. ASAP after diagnosis. Hopefully this will prevent or at least slow down further damage to the gray matter and cognition. The question is who would be willing to have DMTs if they have never had an attack to be able to allow neurologist to make the diagnosis of MS? May be our diagnostic criteria for MS need revision?"

Research: Sunlight and Vitamin D

2012-02-06T07:15:00.006Z

Epub ahead of print: Bäärnhielm et al. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15. Eur J Neurol. 2012 Jan. doi: 10.1111/j.1468-1331.2011.03650.x.

HLA molecule loaded with peptide (short protein). The immune system uses the HLA to activate immune cells so as to fight off foreign organisms. In autoimmune diseases, such as MS, self-proteins activate the immune system to attack self.

Background: Both insufficient exposure to sunlight and vitamin D deficiency have been associated with an increased risk of MS. An interaction between human leukocyte antigen HLA-DRB1*15 (a gene that is responsible for immune activation) and vitamin D in MS was recently proposed. We investigated the association between previous exposure to ultraviolet radiation (UVR), vitamin D status at inclusion in the study, and MS risk including the interaction of these factors with HLA-DRB1*15.

Methods: A population-based case-control study involving 1013 incident cases of MS and 1194 controls was performed in Sweden during 2005-2010. Subjects were classified according to their UVR exposure habits, vitamin D status, and HLA genotypes. The associations between different sun exposure habits/vitamin D levels and MS were calculated as odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. Potential interaction was evaluated by calculating the attributable proportion due to interaction.

Results: Subjects with low UVR exposure had a significantly increased risk of MS compared with those who reported the highest exposure (OR 2.2, 95% CI 1.5-3.3). Similarly, subjects who had 25-hydroxy-vitamin D levels less than 50 nM/l had an increased risk for MS (OR 1.4, 95% CI 1.2-1.7). The association between UVR exposure and MS risk persisted after adjustment for vitamin D status. There was no interaction with HLA-DRB1*15 carriage.

Conclusions: UVR and vitamin D seem to affect MS risk in adults independently of HLA-DRB1*15 status. UVR exposure may also exert a protective effect against developing MS via other pathways than those involving vitamin D.

"These results confirm the association between MS risk and sunlight exposure and vD levels; this is not surprising. No interaction was found between vD/sunlight and HLA genes; this is despite the observation that vD controls how active that gene is within the body. I suspect the study is too small; i.e. lacks sufficient power to see an interaction."

"We can't get away from the data that strongly supports vD as a preventative fator in MS; PLEASE DON'T FORGET TO TAKE YOUR SUPPLEMENTS. 5,000U / DAY!!!"

"The evidence that UVR exposure may also exert a protective effect against developing MS via other pathways than those involving vitamin D is interesting, but speculative. UV may affect the function of immune cells as they pass through the skin. Despite this theoretical advantage of UVB (sunlight) over vD supplements, the case is not strong enough to stop supplementation. From a practical point of view it is difficult to find sunlight in winter, unless you purchase a UVB lamp."

"Please note that most sunbeds provide UVA light and not UVB light; so you can't get the necessary light from popping into your local tanning store."

Additional reading: Human Leukocyte Antigens

Research:Hope Prof G remembered to look at Colour Vision in his new Trial

2012-02-05T10:00:00.002Z

Villoslada P, Cuneo A, Gelfand J, Hauser SL, Green A.Color vision is strongly associated with retinal thinning in multiple sclerosis.Mult Scler. 2012 Jan [Epub ahead of print]

Objectives: Multiple Sclerosis (MS) frequently causes injury to the anterior visual pathway (AVP), impairing quality of life due to visual dysfunction. Development of biomarkers in MS is a high priority and both low-contrast visual acuity (LCVA. Grey Coloured reading chart) and time-domain optical coherence tomography (TD-OCT. Optical coherence tomography (OCT) is like ultrasound of the eye that uses infra red light rather than sound to get the image) have been proposed as candidates for this purpose. We sought to assess whether psychophysical assessments of color vision are similarly correlated with structural measures of AVP injury, and therefore augment measures of visual disability in MS.

Methods: We studied the association between high-contrast visual acuity (HCVA. Black colour charts), LCVA, color vision (Hardy-Rand-Rittler plates (HRR Colourblind charts) and Lanthony D15 tests colour arrangement test) and OCT, using both high-resolution spectral-domain OCT (SD-OCT. New generation machine) and TD-OCT (Older type machine) in a group of 213 MS patients (52 with previous optic neuritis) and 47 matched controls in a cross-sectional study.
Lanthony Test

Results: We found that MS patients have impairments in HCVA and LCVA (p less than 0.001) but that they suffer from even more profound abnormalities in color discrimination (p less than 0.0001). We found strong correlation between color vision and SD-OCT measures of retinal nerve fiber layer (RNFL) thickness (average RNFL, r = 0.594 (p less than; 0.001) and papillomacular bundle thickness (r = -0.565, p less than 0.001). The correlation between OCT scores and functional visual impairments of all types was much stronger for SD-OCT than for TD-OCT.

Conclusion: Our results indicate that color vision is highly correlated with these OCT scores when compared with traditional measures of visual acuity. Also we found that SD-OCT is superior to TD-OCT for detecting anterior visual pathway damage in MS. This makes both colour-visual measures and SD-OCT strong candidate biomarkers of disease progression.
(Hardy-Rand-Rittler plates)

This study further indicates that nerve damage that occurs during Ms can be seen in the function of the eye. They say that there is a STRONG correlation between the degree of colour vision and the thickness of the retinal nerve fibre layer (RNFL as a measure of nerve content) which contains the nerve heads of the optic nerve, which are damaged during MS. They put an r value of r = 0.594 (this is not strong, r=1.0 (positive correlation as one outcome gets bigger the other outcome gets bigger or r= -1 is strong as one outcome gets bigger the other outcome gets smaller). Likewise as the macula (place where light is focussed in the eye and is the place where most accurate vision occurs) gets thicker, possibly due to swelling, colour vision gets reduced.

Based on some studies from Team G, Prof G has produced a novel trial design for the treatment of nerve damage, with the hope of finding drugs for progressive MSers. This is based around studying eye function. This study is a further example that this is not such a bad idea. Hope Prof G is testing colour descrimination. This trial has recently begun.

Natalizumab January 2012 PML Update

2012-02-04T13:37:00.003Z

Another way of looking at the risk is to inverse the figures; for example 10.6/1000 = 1 person in 94, who is JCV seropositive, has received previous immunosuppression, and has had 25 to 48 infusions of natalizumab, will develop PML.

Source: Biogen-Idec

CoI: Multiple

Pharma behaving badly

2012-02-04T10:14:00.003Z

Recent big penalty payouts by Pharma for promoting drugs off-label in the US.

"The figures speak for themselves!"

Biogen-Idec promotional activities

2012-02-04T09:48:00.005Z

Biogen Idec the pharma company that markets Avonex (interferon-beta-1a) and Tysabri (natalizumab) put out a statement on Friday that state and federal authorities in the United States are investigating its sales and promotional practices.The company disclosed the investigation in an annual report filed Friday with the U.S. Securities and Exchange Commission.

Source: Nasdaq

"Let's hope this is not another case of Pharma behaving badly; every time it occurs the fall-out is massive. MS'ers and MS healthcare professionals don't need another scandal! Confidence in Industry, and with Neurologists linked with industry, is already at an all-time low."

The first case of MS. The Madness of King George

2012-02-04T09:00:00.006Z

Garrard P, Peters TJ. Multiple sclerosis or neuromyelitis optica? Re-evaluating an 18th-century illness using 21st-century software. JRSM Short Rep. 2012 Jan;3(1):1. Epub 2012 Jan 12.

In this paper we report the application of an extensive database of symptoms, signs, laboratory findings and illnesses, to the diagnosis of an historical figure. The medical diagnosis of Augustus d'Este (1794-1848) - widely held to be the first documented case of multiple sclerosis - is reviewed, using the detailed symptom diary, which he kept over many years, as clinical data. Some of the reported features prompted the competing claim that d'Este suffered from acute porphyria, which in turn was used in support of the hypothesis that his grandfather, King George III, also suffered from the disease. We find that multiple sclerosis is statistically the most likely diagnosis, with neuromyelitis optica a strong alternative possibility. The database did not support a diagnosis of any of the acute porphyrias.

King George

We have discussed Augustus d'Este before on the blog. He was the illegimate grandson of King George the III, who in his madness gave away the USA to the Americans. The King was mental and some thought he had porphyria, a disease associated with a defecit in production of a blood molecule. Using up to date tools......like reading the cases notes, a diagnosis of MS was made, rather than porphyria.

I am sure that many clinicians will love this as they like a bit of medical History, but to others it is like asking what happened one second before the beginning of time..it doesn't matter and not provable. Hopefully more interesting stuff tomorrow.

Charcot Tapestry

2012-02-04T01:07:00.003Z

You may have heard this week about the Charcot Project, but now its time to go back to the Charcot Tapestry. We are going to start putting it together in March, so if you have knitted any cells , myelin etc. Please send it to us with name and address and we will refund postage.

Send to

Dr Love's Charcot Tapestry.
c/o Professor G Giovannoni
Centre for Neuroscience and Trauma,
Blizard Institute
Barts and The London School of Medicine and Dentistry,
4 Newark Street,
London E1 2AT,
United Kingdom

Thanking you in advance and we hope to unveil it by April.

Research: Certain EBV types are not associated with MS

2012-02-03T16:48:00.003Z

Epub ahead of print: Lay et al. Epstein-Barr Virus Genotypes and Strains in Central Nervous System Demyelinating Disease and Epstein-Barr Virus-Related Illnesses in Australia.Intervirology. 2012 Jan 24.

Objectives: To identify Epstein-Barr virus (EBV) genotypes and strains in samples from individuals with and without a first diagnosis of central nervous system (CNS) demyelinating disease (a possible precursor to multiple sclerosis) or CIS and patients with EBV-associated diseases in Australia.

Methods: Samples from 55 EBV DNA and serology positive subjects including individuals with (n = 17) and without (n = 21) a first clinical diagnosis of CNS demyelination and patients with EBV-related diseases (n = 17) were examined. EBV genotype and strain were identified by sequence mutations within the Epstein-Barr nuclear antigen-2 region (EBNA-2) using DNA sequence analysis.

Results: Both EBV genotypes, A and B, were detected (genotype A, 54/55, 98.2%; genotype B, 1/55, 1.8%). Within genotype A, GD1 was the most commonly detected strain (42/54, 77.7%), followed by B95-8 (9/54, 16.7%) and M-ABA (3/54, 5.6%). Genotype B, strain AG876, was found in one individual with CNS demyelinating disease.

Conclusions: EBV genotype A and the GD1 strain were the common EBV genotypes isolated from individuals with and without CNS demyelinating disease, and in subjects with various EBV-related diseases. Although disease-specific genotypes or strains were not identified, this study provides useful insights into the molecular epidemiology of EBV infection in Australia.

"Please note that EBV is a family of viruses; i.e. EBV has evolved into two main genotypes (sub-species) and many strains. The question remains is there a specific strain of EBV that is associated with MS? This study tries to address that question. Unfortunately, the strains circulating in Australia seem to be relatively homogeneous. This data does not support the presence of a MS-specific strain. This would mean that of if EBV caused MS it would be the host response to the virus that is important rather specific viral factors that causes MS."

Research: Rationing and deprivation of DMT

2012-02-03T10:00:00.000Z

Owens T, Evangelou N, Whynes DK. Rationing and deprivation: disease-modifying therapies for multiple sclerosis in the United Kingdom.Eur J Health Econ. 2012 Jan [Epub ahead of print]

Unlike other industrialised countries, the UK deferred the routine introduction of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in favour of an experiment. Between 2002 and 2005, MS sufferers were identified, were offered DMTs only if deemed suitable by their physicians, and were monitored thereafter to assess long-term outcomes.

It has been demonstrated for other therapies that judgements about suitability to receive treatment are conditioned by the patients deprivation status. We hypothesised that this would have been the case for DMT also.

Using individual patient data for samples in Nottingham and in Glasgow, we matched patients' postcodes of residence (zipcodes) with deprivation scores and confirmed that patients from more deprived areas were less likely to have been prescribed DMT. A more detailed analysis of the Nottingham data revealed two channels through which this outcome was effected.

First, people from less-deprived areas were more likely to possess clinical characteristics, such as less severe disease severity and shorter duration of the disease, that enhanced their suitability for treatment.

Second, the analysis of the clinical notes detailing patients' correspondence with the medical teams suggested that less-deprived people were more able to exercise a voice capable of influencing physicians' prescribing decisions.

Therefore it pays to be vocal and ask for things!

Research: A change in Drug can Help when the first one starts to Fail

2012-02-02T09:00:00.006Z

Río J, Tintoré M, Sastre-Garriga J, Nos C, Castilló J, Tur C, Comabella M, Montalban X Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response.Eur J Neurol. 2012 Jan 31. doi: 10.1111/j.1468-1331.2011.03648.x. [Epub ahead of print]

Background: Therapy for multiple sclerosis (MS) has a partial efficacy, and a significant proportion of treated patients will develop a suboptimal response with first-line disease-modifying drugs (DMD). Therapy switch in patients with MS can be a strategy after a treatment failure. We studied the change in clinical activity after switching of first-line DMD because of a treatment failure.

Methods: Relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-beta (IFNB) or glatiramer acetate (GA) were divided into (i) patients without change in DMD, (ii) patients with a change in DMD because of a poor response, and (iii) those with a change in DMD without relation with response. Annualized relapse rate (ARR) and relapse-free proportions were analyzed.

Results: We identified 923 patients with RRMS. Of the 180 who experienced a change because of suboptimal response, 90 switched to another first-line DMT, 38 to mitoxantrone, and 52 to natalizumab. Median ARR in the pre-DMD period on first DMD and second DMD was the following: 1, 1, and 0 for switchers from IFNB to another IFNB (P = 0.0001); 0.67, 1, and 0 for switchers from GA to IFNB (P = 0.01); 1, 1, and 0 for switchers from an IFNB to GA (P = 0.02); 1.1, 1.5, 0.2 for switchers from IFNB or GA to mitoxantrone (P = 0.0001); 0.9, 1, 0 for switchers from IFNB or GA to natalizumab (P = 0.0001).

Conclusions: In patients with RRMS who have a poor response, switch to another DMD may reduce the clinical activity of the disease.

So if you look at the relapse rate in RR Msers, where the drug fails the relapse rate (number of relapses per year) is no better but if you switch then there is a good chance that the new drug starts to have some benefit. If you take the middle reading of the number of relapses per year, this is the median and went from one relapse a year to no relapses per year (This just the average effect). So if you feel your drug is not working it is always worth speaking to your neuro

The Charcot Project-Towards a Cure for MS

2012-02-01T10:00:00.022Z

THE CHARCOT PROJECT- TOWARDS A CURE FOR MS.

Last weekend at the Research Day Prof Gold (Prof G Down Under) from Team G aired his new vision for the treatment of MS, but you will have to wait for the video evidence to appear. As many do not view the blog but get their news by non computer means. I do this post. Is this IG11?, a pipe dream that needs development before it gets off the ground or an alternative view that is worth a shot?

BACKGROUND:

There is increasing evidence to support the hypothesis that multiple sclerosis (MS) is either caused, or triggered, by an infectious agent, probably a virus.

The most compelling evidence points to Epstein-Barr Virus (EBV) as there is now overwhelming evidence that infection with EBV is essential to development of MS. Therefore, it appears that it is not possible to have adult MS without having previously been infected with EBV. However, the corollary is not true so having EBV infection does not always lead to MS.

Other factors have also been linked to acquiring MS such as vitamin D deficiency (related to living in the far northern and southern hemispheres), smoking and genetic susceptibility. Each of these factors, taken separately contributes to the risk of acquiring MS, but individually they do not explain the disease and its effect on the immune and neurological systems. Recently, there is interesting evidence that may link some or all of these factors to a recently discovered virus and their influence on it and this may provide a biologically plausible cause for MS.

If true, there is the possibility, of treating MS with targeted anti-viral therapies.

The link between the various risk factors is the discovery of a Human Endogenous Retrovirus (HERV) that is significantly present in patients with MS and not in patients with other neurological conditions or in healthy controls.

HERVs are extremely interesting viruses. Following mapping of the human genome during the past decade, scientists discovered that 8% of our genome is composed of viral DNA. This viral DNA was integrated into our genome at various times over the past 6 to 8 million of years and has been passed down from generation-to-generation as our genes are inheritance by our children.

Most of these viruses are no longer active, but some recent laboratory work in Switzerland, Denmark, the U.K. and the U.S.A. indicates a selected number of these viruses can, in fact, be reactivated and can cause the same myelin and axonal loss that we see in patients with MS.

It has further been observed that EBV can up-regulate (activate) these HERVs, which would help to explain the key role that EBV plays in the pathogenesis of MS. This field of research is very early and is both challenging and exciting.

The field of MS treatment is currently dominated by drug companies who have focused their attention on developing lifelong therapies that target the immune system, without necessarily addressing the possible causes of MS. These therapies are problematic to administer, have considerable side-effects and risks and are expensive and lifelong.

There are drug companies out there that specialise in developments of treatments for infectious diseases but have so far not taken an interest in MS.......so Wakey, Wakey, Wakey

Before progressing with launching The Charcot Project (Jean-Martin Charcot first described Multiple Sclerosis in 1868), we have consulted with some of the world authorities on retroviruses and we believe HERVs should be investigated as a possible cause for MS and could possibly be controlled using treatments currently available for other retroviruses. The most well-known retrovirus is Human Immuno deficicency virus or HIV (which causes AIDS) and while it has little in common with the HERV virus that may cause MS, it is possible that treatments developed and effective for HIV, may benefit patients with MS. These treatments are aimed at controlling retroviruses, by interrupting various stages of the virus life-cycle. and they have proven to be very efficient. We have some anecdotal evidence that HIV anti-retroviral drugs may have benefit in MS.

Is this a fluke? or are they on to something?

AIMS:The Charcot Project will aim to elucidate the direct role of viruses as the trigger and cause of MS and to test available drugs to interrupt the life-cycle of these viruses in order to control MS. In this context ‘control’ is defined as possibly taking a tablet each day that would completely suppress viral activity, with minimal or no potential for disease progression.

JEAN-MARTIN CHAROT

If this is seen as a bit of fresh (or hot) air, it has to be seen that it is only the starting point. Some people will embrace this idea and a lot of people will be sceptical. However, we know that many of the sceptics will feel it is worth a shot, because the gains can be so big. For the project to really gain momentum still needs a will for the necessary studies to be resourced and happen. Maybe the Prof Gs are cruising for a brusing as many things have to happen before this is truely off the ground. But you heard about it here first!

There is no evidence that HERVs influence vascular alterations, yet trials are beginning to examine this latter idea, so why not take a punt on this new idea, it would be cheaper to do these studies!.

Many years ago it was thought that stomach ulcers were caused by lifestyle and there was this bonkers bloke who said it was a problem of bacteria. The establishment thought he was a nutter, so he infected himself with the bacteria, got an ucler and then treated himself with anti-biotics...Simples. Today we do not think twice about using anti-biotics for ulcers.

Now here is an interesting tit bit.

How many people with MS also have HIV?, the answer seems to be not very many as far as we can tell.

Historically, it was interesting because HIV used to trigger the development of AIDS that resulted in immunosuppression caused by the virus killing off white blood cells. We know that such type of immunosuppression, that can be sort of replicated with drugs such as Alemtuzumab has been shown to halt some aspects of MS.

These days the virus is kept in check by the development of anti-viral agents, so people do not get Immunosuppressed because of the virus, but there are still are not many reports of MSers with HIV. Is the MS diagnosis missed? Do the drugs that stop HIV, stop the triggers of MS? This is one of the aims of the Charcot Project.

If you have HIV and MS or MS then HIV, Prof Gold ( j.gold@unsw.edu.au) would love to hear from you, in confidence, as you are his Golddust.

Bacteria and EBV as triggers of MS

2012-02-01T08:27:00.001Z

Epub ahead of print: Cossu D , Masala S , Cocco E , Paccagnini D , Frau J , Marrosu MG , Sechi LA . Are Mycobacterium avium subsp. paratuberculosis and Epstein-Barr virus triggers of multiple sclerosis in Sardinia? Mult Scler J. 2012 Jan

Sardinia acts as an ideal setting for MS studies because its prevalence of MS is one of the highest worldwide. Several pathogens have been investigated amongst 119 Sardinian MS patients and 117 healthy controls to determine whether they might have a role in triggering MS in genetically predisposed individuals. Mycobacterium avium subsp. paratuberculosis (MAP; a bacteria or microbe that is related to TB) and Epstein Barr virus DNA were detected in 27.5% and 17.3%, respectively, of the MS patients, compared to 6.3% and 4.5% in normal controls.

EBV

Moreover an extremely high antibody response against MAP recombinant protein MAP FprB (similar to the human myelin protein P0) was observed, whereas no significant results were found against the FprA from TB and HP986 protein from the bacteria that causes stomach ulcers (Helicobacter pylori).

Mycobacterium avium

"What does this mean? Without additional studies very little. These findings do not necessarily imply causation. Numerous other studies will need to be done to understand the significance of these results. This is why I always stress Bardford-Hill's criteria for causation; they provide a well-established framework for thinking about possible causative factors in MS."

Please see:

Multiple Sclerosis Research: EBV & Bradford-Hill

21 Aug 2011

EBV & Bradford-Hill. Re: Curious Orange's post on "An EBV controversy": "Hello, in a previous thread you mentioned that in adult MS, EBV is found in 99.9% of cases. This struck me as an amazing statistic, then I googled a bit ...

Drinking alcohol and MS

2012-01-31T00:47:00.001Z

Epub: Foster et al. Associations of moderate alcohol consumption with clinical and MRI measures in multiple sclerosis. J Neuroimmunol. 2012 Jan.

OBJECTIVE: To examine the associations of alcohol consumption patterns with disability and brain injury in MS'ers.

DESIGN: This study included 423 subjects (272 MS'ers, 151 healthy controls) participating in a study of clinical, environmental and genetic risk factors in MS. Disability was assessed with the EDSS and the MS Severity Scale (MSSS). Brain injury was assessed using MRI. Information related to alcohol-consumption patterns was obtained with standardized questionnaires.

RESULTS: The frequency of MS'ers who did not consume alcohol after the diagnosis of MS (19.4%) was higher than the frequency before MS (p<0.001). The EDSS and MRI parameters exhibited a non-linear dependence on duration of alcohol consumption after MS onset.

CONCLUSION: The duration of alcohol consumption is associated with disability and MRI measures in MS.

"This study is saying that alcohol consumption is bad for MS and is associated with a worse outcome clinically and on MRI."

"Until these results are confirmed I wouldn't take these result as fact. Alcohol consumption is associated with reversible shrinkage of the brain in normal people. May be the same effect is happening in MS'ers?"

Are you on natalizumab (Tysabri)? Do you know your JCV status?

2012-01-30T11:36:00.000Z

Epub ahead of print: Fox & Rudick. Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology. 2012 Jan 25.

Natalizumab has demonstrated efficacy in multiple sclerosis (MS), but is associated with increased risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection caused by the JC virus. At the time of natalizumab's reapproval in 2006, the estimated risk of PML was 1:1,000 (95% confidence interval 0.2-2.80) over 17.9 months of treatment. Since then, 3 risk factors for natalizumab-related PML have emerged:

Cumulative exposure to natalizumab, with risk increasing up to 3 years, after which risk appears to plateau.
Previous treatment with cytotoxic or immunosuppressive (IS) drugs
Prior history of JCV infection, as indicated by the presence of JCV antibodies.

Using a new assay for anti-JCV antibodies ~55% of MS'ers are anti-JCV antibody positive; with false-negative rate of ~2.5% (unfortunately no laboratory assay is perfect).

To date, 28 natalizumab-related PML cases had blood specimens available 1 year or more prior to the development of PML. Using this assay, all 28 patients were JCV seropositive, which is highly statistically significant (p = 3.21 × 10(-8)).

MRI of someone with PML

This assay is now clinically available in the United States and Europe.

See Stratify JCV website.

"The negative predictive value of this assay is important. In other words if you are JCV seronegative (negative test) your risk of getting PML is very low. If you are either on natalizumab, or deciding to go onto natalizumab, you may find this information very helpful."

Please see the latest post on this blog about risk stratification:

Multiple Sclerosis Research: Natalizumab - Safety Update ...

14 Jan 2012

Please note that if you have been on Natalizumab longer than 24 months, have previously been treated with immunosuppressive drugs, for example mitoxantrone, and you are JC virus positive (blood tests shows you have ...

CoI: Multiple

Research: Viral Trigger of Relapse

2012-01-30T09:35:00.004Z

Laska MJ, Brudek T, Nissen KK, Christensen T, Anné ML, Petersen T, Nexø BA. Expression of HERV-Fc1, a human endogenous retrovirus, is increased in patients with active Multiple Sclerosis. J Virol. 2012 Jan.[Epub ahead of print]

Multiple Sclerosis (MS) is considered to be an autoimmune disease with unknown cause and with immune system dysregulation. Among environmental factors, viruses are most often connected with the aetiology of MS. Human Endogenous Retroviruses (HERVs) constitute 5-8% of human genomic DNA and have been detected as transcripts and proteins in the central nervous system (CNS) and peripheral blood, frequently in the context of neuroinflammation.

The HERV-Fc1, which belongs to the HERV-H/F family, has received our attention largely because of the genetic association with MS. The expression of a capsid (Gag) coat protein of HERV-H/F origin by flow cytometry in blood cells from healthy controls and from MS patients with non-active or active disease.

There was a significant increase in HERV-H/F Gag expression in CD4+ (P less than 0.001) and CD8+ T lymphocytes (P less than 0.001) and in monocytes (P=0.0356*) in the blood from MS patients with active disease. Furthermore, we have undertaken the first rigorous qualitative PCR (were you amplify the genes so that they can be detected and quantitated) to quantify extracellular HERV-Fc1 RNA viral loads in the plasma (blood fluid) from MS patients and healthy controls.

A 4 fold increase in extracellular HERV-Fc1 RNA titres in patients with active MS was found compared with healthy controls (P less than 0.001). These findings strengthen the link between HERV-Fc1 and the pathology of MS. The cause and biological consequences of these differential expressions will be the subject of further investigation. HERV-Fc1 biology could be a compelling area for understanding the pathology of MS and possibly other autoimmune disorders.

If you managed to attend the Research Day, you will have heard about the Charcot Project, which aims to try and tackle the possibility of a viral cause of MS.

As you will be aware Prof G has been investigating the link of MS with Epstein-Barr Virus, but Prof G Down Under has ideas about other viruses and these may be HERVs. There has been studies suggesting that HERVs may be more common in MSers. This current study suggests these endogenous retrovirus may become active during active disease in MS, so is this the trigger? Is there a link with EBV? There is one way to find out. That is deal with these viruses to stop them becomiing activated and see what happens in MS.

Please see previous posts

HERVS you heard it here
Is MS caused by a retro virus
Do human endogenous retroviruses play a role in MS

Research: Virus Causing autoimmunity

2012-01-30T09:30:00.005Z

Libbey JE, Cusick MF, Tsunoda I, Fujinami RS. Antiviral CD8(+) T cells cause an experimental autoimmune encephalomyelitis-like disease in naive mice. J Neurovirol. 2012 Jan 27. [Epub ahead of print]

Major histocompatibility complex class I-restricted CD8(+) cytotoxic T lymphocytes are involved in the pathogenesis of multiple sclerosis (MS) and both autoimmune, experimental autoimmune encephalomyelitis, and viral, Theiler's murine encephalomyelitis virus (TMEV) infection, animal models of MS.

Following TMEV infection, certain T cell hybridomas, generated from cloned (single identical cells) TMEV-induced CD8(+) T cells, were able to produce clinical signs of disease (flaccid hind limb paralysis) upon adoptive transfer into naive mice. Dual T cell receptors (TCR) are present on the surface of these cells as both Vβ3 and Vβ6 were detected by polymerase chain reaction (PCR) screening and flow cytometry and multiple Vα mRNAs were detected by PCR screening.

This is the first demonstration of antiviral CD8(+) T cells having more than one TCR initiating an autoimmune disease in the natural host of the virus. We hypothesize that this is a potential mechanism for virus-induced autoimmune disease initiated by CD8(+) T cells.

Theiler's murine encephalomyelitis virus is a natural pathogen of mice, which sometimes gets into the brain and causes a demyelinating disease, that may generate the development of autoimmunity by a number of different mechanisms such as molecular mimicry (sequence similarities between foreign(virus) and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen derive peptides. So viral directed immune responses are mis-directed to attack the nervous tissue) or deteriminant spread (where damage generated in response to the immune attack of virus, triggers the development of a immune responses to the damaged protiens and thus trigger autoimmune attack. This study suggests another mechanism.

The T cell receptor is the stucture that allows the T cell to see its target. This is anchored in the cell membrane and consists of two halves, which form a pair of protein chains. The halves are called the alpha (α) and beta (β) fragments (in γ/δ T cells, the halves are gamma (γ) and delta (δ) fragments). Each fragment is divided in turn into a constant (C) and variable (V) region. These are constructed by the action of joining the gene products of a variable number of constant, joining, diversity and variable T cell receptor gene. There are about 50 variable genes for the beta chain and over 70 for the alpha.

So in this cell there were two variants (3 and 6) of the beta chain variable reion and many different alpha genes. Normally only one alpha and beta are present and can recognise one target if there is an extra beta then it could recognise a different target. T cells that reacted with the virus were cloned (so all the cells are identifical) and so the T cell receptor would react with the virus. So that they have a source of immortal cells to do reach with they fused the T cell clone with a tumor that lacks T cell receptor. They found that the T cell clone must have contained many different T cell receptor and when they put one of these tumours in mice it caused neurological problems suggesting that some of the T cell receptors were reacting with a nerve component. So by having more than one set of T cell receptors viral specific cells could also react with nerve proteins and trigger autoimmunity.

This concept whereby cells have dual (two) T cell receptors has been demonstrated many years ago, particularly with cells containing extra alpha chains in the context of of other viral infection or autoimmune conditions. This is yet another way that autoimmunity could develop following viral infection.

Barts and London Research Day

2012-01-29T10:00:00.003Z

A Big Thank You
to
All the People that Attended the Research Day Yesterday

Hope you All Had a Good Day and a Safe Journey Home

January. Unrelated Blogger Comments 4

2012-01-29T09:00:00.005Z

Sometimes You want to post a comment that is Unrelated to the thread.

Therefore I have Created this Spot for You
It jumps around so that it is visible
ADVERTS will be DELETED!

Research: Monitoring Progression

2012-01-29T09:00:00.004Z

Gnanapavan S, Grant D, Pryce G, Jackson S, Baker D, Giovannoni G. Neurofilament a biomarker of neurodegeneration in autoimmune encephalomyelitis.Autoimmunity. 2012 Jan 26. [Epub ahead of print]

Monitoring neuroaxonal loss in multiple sclerosis is an important objective to study the pathogenesis and response to treatment of the disease. The release of neurofilaments is a potential surrogate biomarker of neurodegeneration. One route to explore this aspect further is through the use of animal models that have well-defined, and predictable, disease courses.

The release of neurofilaments into plasma (blood) across the course of relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis in mice was assessed.

It was found that there was an immediate release in neurofilaments into the blood following the initial paralytic attack. Neurofilament release was continuous in relapse and remission but returned towards baseline in chronic disease, as animals entered the slowly developing post-relapsing progressive phase of the disease.

In contrast neurofilament levels increased dramatically as neurodegeneration and clinical disease occurred in the G93A SOD1 transgenic model of amyotrophic lateral sclerosis.

These data further support neurofilament levels as a good surrogate measure of neurodegeneration and their potential use as a surrogate endpoint in neuroprotective studies.

Green colour shows the neurofilament as an internal protein of the nerve. Red = glial cells

Progression of clinical disease occurs too slowly to undertake lots of clinicalt trials based on clinical features. Therefore we have we have been seeking indicators of disease worsening that can change quicker than clinical disability and so we could use those outcomes as surrogates to show disease activity. One thing we have found is neurofilament.

This is an internal part of the nerve and as nerves get damaged the nerves content is released first in to the cerebrospinal fluid and then into the blood. This study looked at two models of nerve damage, one that is known to occur by attacks of the immune system and another that is caused by neurodegenerative effects independent of autoimmunity. This study shows that with immune attack neurofilament can even be detected in the blood and tells us that stopping relapsing disease is a good thing. We know that each attack is indeed associated with nerve damage and that we can pick break down products of nerve attack in the blood supports this.

Next it says that in progressive MS models that slow progression that is independent of autoimmunity, such as secondary and primary progressive disease was not picked up in the blood in one model of neurodegeneration but was found in the blood in another model of neurodegeneration in a model that resembles motor neuron disease.

This tells us two things that measuring neurofilament release into biological fluids such as cerebrospinal fluid and the blood can give us an indication of the damage that is occuring in the central nervous system and that we may have to look in the cerebrospinal fluid rather than the blood.

Therefore if you have not watched the video and answered the survey on having three lumbar punctures as a method of detecting nerve damage and its control in a new trial disease design that will speed getting drugs to progressive MSers. Please watch the video and do the survey on the left. If you will not do it is just as important to know as if you will do it. These is no point in developing an idea that can not get off the ground

Are you up for having lumbar puncture

CoI: This is the work of Team G as part of Promse 2010

Bad Science:Interferons after Mitoxantrone

2012-01-28T10:00:00.021Z

Today is our research day and I have to deliver Bad Science. When you read papers you have to digest whether they actually tell us anything. You do not always believe things you read. Importantly is it worth reading them in the first place?

Todays story is an an example. NO LINK PROVIDED, READING VALUE IS LOW

Objective: The objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy.

Methods: This was an open-label, randomized, multicentre, rater-blinded, 96-week observational study. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1-6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96.

Results: A total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group (p = 0.26 THIS ACTUALLY MEANS THERE WAS NO DIFFERENCE DESPITE THE INFERENCE). IFN β-1a delayed the time to first relapse versus no treatment (p = 0.14. THIS ACTUALLY MEANS THERE WAS NO DIFFERENCE IN TIME TO RELAPSE DESPITE THE INFERENCE); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups (p = 0.79 THIS ACTUALLY MEANS THERE WAS NO DIFFERENCE). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups (THEY ACTUALLY TELLL US THAT THERE WAS NO DIFFERENCE). There were no new or unexpected adverse events related to IFN β-1a treatment.

Conclusions: Several endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. THEY TELL US NOTHING WAS SHOWN Therefore, these data only permit, at best, tentative conclusions (THEY DO NOT PERMIT CONCLUSIONS AS THE DATA COULD EASILY BE DUE TO CHANCE AND MEAN NOTHING) about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.

While we want to know if after you stop mitoxantrone (you can only have so many doses because of risks to the heart) can beta interferon be of benefit in halting relapses. But we have to digest the information and ask, is there anything of real importance occuring here?

If one looked at more people would there be benefit to be seen? However, as the results stand you have to conclude that they show nothing concrete. This is a reason why it is important that studies are properly powered (that is contain a lare enough number of samples to provide meaningful information) so that you get a result that informs otherwise you have to do it all again. The authours should have waitied until they had enough data to say something.

Bad Refereeing: New model for Progression

2012-01-28T10:00:00.020Z

Normally I do not report on animal models of MS but as Mouse Doc is doing "Bad Science Day" at our research Day and the media have found that "Diabetic mice have provided a surprising breakthrough for MS research 1:5:2012" todays new breakthrough extends this further.

We have been talking about the publication process. Part of this is the independent review process. The peer review process of publication aims to see if work is original and whether the claims made are supported by the data shown and whehter the data presented is put into context of the exisitng knowledge. Sometimes this works sometimes it is not so good.

Anderson AC, Chandwaskar R, Lee DH, Sullivan JM, Solomon A, Rodriguez-Manzanet R, Greve B, Sobel RA, Kuchroo VK. A Transgenic Model of Central Nervous System Autoimmunity Mediated by CD4+ and CD8+ T and B Cells. J Immunol. 2012 Jan [Epub ahead of print]

Experimental autoimmune encephalomyelitis (EAE) is a widely used model of multiple sclerosis. Non obsese diabetic (NOD) mice that can develop type I diabetes, develop EAE as a relapsing-remitting disease that transitions to a chronic progressive disease, making the NOD model the only mouse model that recapitulates the full clinical disease course observed in most multiple sclerosis patients. [Sack the peer-reviewers.........as they do not know how to do a literature review to see if this is not the ONLY model. Maybe they could have found others maybe one a few or many years ago...likewise do a literature review and wonder if it is really a progressive model or maybe a relapsing neurodegenerative model see figure 1]. If you just look at diagrams with out knowing the course in individual animals it is easy to say that studies show that disease is progressive, when it is degenerative, relapsing-remitting disease that is not occurring in a asychronous fashion (See below).

A T cell receptor (TCR) transgenic mouse that expresses the α and β-chains of a myelin oligodendrocyte glycoprotein (MOG) 35-55-reactive TCR (1C6) on the NOD mouse (shown earlier to be rather resistant to the development of EAE) genetic background was made and called 1C6 TCR transgenic mice. These spontaneously generate both CD4(+) and CD8(+) T cells that recognize MOG and produce proinflammatory cytokines, allowing for the first time to our knowledge the simultaneous examination of myelin-reactive CD4(+) and CD8(+) T cells in the same host. [Check out studies of which there are loads, in normal mice with CD4 and CB8 -specific antibodies]

1C6 CD8(+) T cells alone can induce optic neuritis and mild EAE with delayed onset; however, 1C6 CD4(+) T cells alone induce severe EAE and predominate in driving disease when both cell types are present. [As shown previously about 15-20 years earlier with monoclonal antibodies] When 1C6 mice were crossed with mice bearing an Immunoglobulin heavy chain (antibody) specific for MOG, the mice develop spontaneous EAE with high incidence, but surprisingly the disease pattern does not resemble the neuromyelitis optica-like disease observed in mice bearing CD4(+) T cells and B cells reactive to MOG on the C57BL/6 background. [Most EAE models show optic nerve and spinal cord disease without significant brain involvement.....so crappy reviewers to papers in the past. This is not neuromyelitis optica and the brain lesions found in mice in this study in the cerebellum of mice without typical neurological disease have been reported previously and again ignored in the paper. The authors have spun their story and the reviewers have let them get away with it. The peer-reviewers should retire from the review process due to incompetence] Collectively, the data show that although myelin-reactive CD8(+) T cells contribute to disease, disease is primarily driven by myelin-reactive CD4(+) T cells and that the coexistence of myelin-reactive T and B cells does not necessarily result in a distinct pathological phenotype. [As shown previously in many other mouse studies]

The graph from Team G shows the results of the development of disease in a group of animals with EAE. Disability is on the scale on the left so 3 is more disabled than 1 and time is days after the disease was induced. After the first attack is this progressive disability? Well it looks like it. However this is the result of relapsing disease with neurodegeneration that occurs as a consequence of the relapse. Disease worsening is occuring in a step wise fashion with each attack in each individual animal but apart for the first attack the relapses are not synchronised. Therefore sometimes you need more information to know what is going on than simply looking at line graphs

Is this study interesting "yes it is", is it good quality work.."yes it is", are these mice going to be useful "yes they probably are" Can I decipher the good stuff in the paper? Yes I can, but does it over-egg the importance "yes it does". Just an example of you don't have to believe everything you read or you have to decipher what is being said. This is what we are trying to do on the blog. Obviously we have our own bias when we review the studies. Any critism being made is supposed to be constructive... as this is an interesting study.

Research Beta Interferon does not stop secondary Progressive MS

2012-01-27T10:00:00.002Z

La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, Rovaris M, Fredrikson S, Filippini G. Interferon beta for secondary progressive multiple sclerosis.Cochrane Database Syst Rev. 2012 Jan;1:CD005181.

BACKGROUND: Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease.

OBJECTIVES:The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression.

SEARCH METHODS: Cochrane Multiple Sclerosis Group's Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings were searched. Regulatory agencies were used as additional sources of information. All randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients were included.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals (CI) for the binary outcomes and Standard Mean Difference with 95% CI for the continuous outcomes.

MAIN RESULTS: Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (Relative risk, 95% CI: 0.98, [0.82-1.16]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% CI: 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [0.84-0.97]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN-treated patients.

AUTHORS' CONCLUSIONS: Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse-related disability. Overall, these results show that IFNs' anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS.
The Cochrane Collaboration is an international not-for-profit and independent organization, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide. It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. The Cochrane Collaboration was founded in 1993 and named after the British epidemiologist, Archie Cochrane.

Recombinant IFN beta does not prevent the development of permanent physical disability in Secondary Progressive MS. This is old news

Research: IL-1 inhibits Nerve Damage

2012-01-27T09:00:00.002Z

Rossi S, Furlan R, De Chiara V, Motta C, Studer V, Mori F, Musella A, Bergami A, Muzio L, Bernardi G, Battistini L, Martino G, Centonze D. Interleukin-1β causes synaptic hyperexcitability in multiple sclerosis. Ann Neurol. 2012; 71:76-83. doi: 10.1002/ana.22512.

OBJECTIVE: The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons.

METHODS:We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-α, of interleukin-1β (IL-1β), and of IL-1 receptor antagonist (IL-1ra, an IL-1 blocker), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS).

RESULTS: CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in cell culture through a mechanism dependent on enhanced IL-1β signaling and increased glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor stimulation. Furthermore, IL-1β/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, a measure of glutamate transmission. Finally, we identified transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1β on central glutamatergic synapses.

INTERPRETATION: Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS.

Glutamate is the major neurotransmitter (chemical that triggers nerve impulses) that stimulates nerves. However if a nerve gets too much stimulation it can trigger the cells to commit suicide which is known as excitotoxicity. Using mouse brain tissue the electrical activity of nerves was measured before and after cerebrospinal fluid was used to bathe the brain tissue. This was taken when MS was active and when it was non-active. It was found that when disease was active there were chemicals released that could cause nerve damage. Using this approach one of the damaging molecules was identified and away that it can stimulation of glutamate through AMPA glutamate receptors. Glutamate receptor anagonists could be a potential treatment that could be suggested from this work, but have the potential to cause side-effects or Vannilod receptor antagonists could be an alternative new avenue for treatment.

CoI: G. Martino from Milan is Part of Team G

Research: MicroRNA in Multiple Sclerosis

2012-01-27T01:00:00.004Z

Paraboschi EM , Soldà G , Gemmati D , Orioli E , Zeri G , Benedetti MD , Salviati A , Barizzone N , Leone M , Duga S , Asselta R . Genetic association and altered gene expression of mir-155 in multiple sclerosis patients.Int J Mol Sci. 2011;12:8695-712.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance.

In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology.

Three miRNAs resulted greater than 2 folds up-regulated in MS vs controls, whereas none resulted down-regulated. Interestingly, the most up-regulated miRNA (mir-155; fold change = 3.30; P = 0.013) was previously reported to be up-regulated also in MS brain lesions. Mir-155 up-regulation was confirmed by qPCR experiments. The role of mir-155 in MS susceptibility was also investigated by genotyping four single nucleotide polymorphisms (SNPs) mapping in the mir-155 genomic region. A haplotype of three SNPs, corresponding to a 12-kb region encompassing the last exon of BIC (the B-cell Integration Cluster non-coding RNA, from which mir-155 is processed), resulted associated with the disease status (P = 0.035; OR = 1.36, 95% CI = 1.05-1.77), suggesting that this locus strongly deserves further study.

Recently we introduced you to the concept of microRNA and that they may influence the effects of proteins, Mir 155 has been implicated in controlling the immune response, which is aletered during MS. Animal studies have suggested that Mir55 can promote autoimmune inflammation by enhancing inflammatory T cell development Mice that lack Mir55 develop less MS-like disease than mice that produce Mir155. That Msers have elevated levels of Mir55 may not be a good thing, but it suggests that by inhibiting the development of Mir55 there may be benefit to be had.

Interleukin 7 and T cell function

2012-01-26T10:00:00.002Z

Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ. The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis. J Immunol. 2012 Jan [Epub ahead of print]

The interleukin 7 receptor alpha chain (IL-7Rα) single nucleotide polymorphism rs6897932 is associated with an increased genetic risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell function, proliferation, and anti-apoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood.

We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls. A significantly higher frequency of IL-7Rα(+) CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055).

No correlation was found between the expression level or frequency of IL-7Rα(+)CD8(+) and rs6897932 risk allele carriership.

Upon IL-7 stimulation, MS patients had stronger STAT5 (a transcription factor) activation in CD8EM compared with Healthy controls. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B (a protein that punches holes in its target. Imagine a pin prick to a balloon this is what granzymes can do to virally infected cells) between MS and HC. Stainings of different lesions in post-mortem MS brain material showed expression of IL-7 and CD8(+)IL-7Rα(+) in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα(+) lymphocytes in lesion development.

The intralesional production of IL-7 in combination with the lower threshold for IL-7-induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

Variants in Interleukin seven receptor are associated with an increase risk of developing MS. We know that interleukin 7 is associated with the function of the immune system but how does the variant affect MS?. This study does not answer this question as the expression of IL-7R on T cells did not correlate with the variant of IL-7R genes, but it does suggest that cells expressing IL-7R are part of the disease process. There was more IL-7R on T cells from people with MS compared with healthy people and cells expressing this molecule accumlate in early MS lesions.

Brain Training: The results

2012-01-26T01:00:00.006Z

Can you remember the figures on the brain training picture from last week?

Could not be bothered.....

or did you remember:

A guy with shaded eyes; a fish; a guy with Big Teeth; Two one cent coins; a middle Eastern Man; a light bulb with a dollar sign and a newspaper.

Did your association or a story help?

Prof C thinks mine was too crytic to comment on....he says get some sleep.

Research: Human Stem cells

2012-01-25T08:23:00.003Z

Song B, Sun G, Herszfeld D, Sylvain A, Campanale NV, Hirst CE, Caine S, Parkington HC, Tonta MA, Coleman HA, Short M, Ricardo SD, Reubinoff B, Bernard CC. Neural differentiation of patient specific iPS cells as a novel approach to study the pathophysiology of multiple sclerosis.Stem Cell Res. 2012;8:259-73.

The recent introduction of technologies capable of reprogramming human somatic cells into induced pluripotent stem (iPS) cells offers a unique opportunity to study many aspects of neurodegenerative diseases in vitro that could ultimately lead to novel drug development and testing.

Here, we report for the first time that human dermal fibroblasts from a patient with relapsing-remitting Multiple Sclerosis (MS) were reprogrammed to pluripotency by retroviral transduction using defined factors (OCT4, SOX2, KLF4, and c-MYC).

The MSiPS cell lines resembled human embryonic stem (hES) cell-like colonies in morphology and gene expression and exhibited silencing of the retroviral transgenes after four passages. MSiPS cells formed embryoid bodies that expressed markers of all three germ layers by immunostaining and Reverse Transcriptase (RT)-PCR.

The injection of undifferentiated iPS cell colonies into immunodeficient mice (so that they do not reject the human cells) formed teratomas (an encapsulated tumour), thereby demonstrating pluripotency. The MSiPS cells were successfully differentiated into mature astrocytes, oligodendrocytes and neurons with normal karyotypes. Although MSiPS-derived neurons displayed some differences in their electrophysiological characteristics as compared to the control cell line, they exhibit properties of functional neurons, with robust resting membrane potentials, large fast tetrodotoxin-sensitive action potentials and voltage-gated sodium currents. This study provides for the first time proof of concept that disease cell lines derived from skin cells obtained from an MS patient can be generated and successfully differentiated into mature neural lineages. This represents an important step in a novel approach for the study of MS pathophysiology and potential drug discovery.

The abstract says it all and is encouraging for stem cell technology but there will be be more twists and turns as these technologies are developed towards the clinic, but a step in the right direction. Furthermore, this types of technologies can provide access to cells to study human biology that may lead to other benefits.

Research:Biomarkers for MS

2012-01-25T08:20:00.001Z

Avsar T, Korkmaz D, Tütüncü M, Demirci NO, Saip S, Kamasak M, Siva A, Turanli ET. Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis. Mult Scler. 2012 Jan [Epub]

Background: The complex pathogenesis of multiple sclerosis, combined with an unpredictable prognosis, requires identification of disease-specific diagnostic and prognostic biomarkers.Objective: To determine whether inflammatory proteins, such as neurofilament light chain (marker of nerves), myelin oligodendrocyte glycoprotein and myelin basic protein (markers of myelin), and neurodegenerative proteins, such as tau (distressed nerves) and glial fibrillary acidic protein (active astrocytes), can serve as biomarkers for predicting the clinical subtype and prognosis of MS.

Methods: Cerebrospinal fluid and serum samples were collected from patients with a diagnosis of clinically isolated syndrome (n = 46), relapsing-remitting MS (n = 67) or primary-progressive MS (n = 22) along with controls having other non-inflammatory neurological disease (n = 22). Western blot analyses were performed for the listed proteins. Protein levels were compared among different clinical subtypes using one-way analysis of variance analysis.

Results: The results showed that each of tau, GFAP, MOG and NFL protein concentrations differed significantly (p less than 0.001) in multiple sclerosis clinical subtypes compared with the controls. Levels of the proteins also differed between the multiple sclerosis clinical subtypes, which may be associated with the underlying disease process. Classification studies revealed that these proteins might be useful for identifying multiple sclerosis clinical subtypes.

Biomarkers We showed that select biomarkers may have potential in identifying multiple sclerosis clinical subtypes. We also showed that the predictive value of the prognosis increased when using a combination of the proteins versus using them individually.

Radar diagram of the value of differnt proteins in predicting relapisng remitting primary progressive non converting clinically isolated sydromes and CIS converting to MS and other neurological controls.

Although many of the markers were higher in the MS groups compared to control samples when they the results from analysis of 4 different proteins were compared they had a 95% chance of detecting MS from other neurological condidtions and analysis of three of them together had a 95% chance of predicting whether you are PP MS or RRMS. It this can be repeated then it may be of value in selecting MSers for treatments that may work verses those that do not work on PPMS for example.

Research: BG12 targeting Nrf2 to help save nerves

2012-01-25T07:52:00.007Z

Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ. Fumarates Promote Cytoprotection of Central Nervous System Cells Against Oxidative Stress via the Nrf2 Pathway.J Pharmacol Exp Ther. 2012 Jan 20. [Epub ahead of print]

Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis (MS), and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels (levels within the cell nucleus) of active Nrf2, with subsequent upregulation of antioxidant target genes. DMF-dependent upregulation of antioxidant genes in vivo was lost in mice lacking Nrf2 (Nrf2-/-). DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2.

These data suggest that DMF and MMF are cytoprotective (protrcts the cell) for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via upregulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase 3 trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.

Yesterday we were exploring ways that mtiochondrial energy depletion in astrocytes....and based on past posts nerves......may lead to nerve damage.

You wondered if there were an know causes and whether anything has been done about this. Well this study shows a way that something is being done about it.

There is a new oral drug called BG12 that has been found to be effective at inhibiting relapses (reduction of around 50%) in MSers in the phase III studies, but the question is whether it does other things that may be beneficial in progressive MS also?

This study suggests that there may be some potential. This drug may be working via a molecule called Nrf2 which acts to control oxidative stress that represents an imbalance between the production and manifestation of reactive oxygen species (damaging in high concentrations) and a biological systems ability to readily detoxify the reactive intermediates or to repair the resulting damage. But simplified means that it has anti-oxidant properties that will block some of the molecules that are known to block mitochondrial function that depletes the cells energy that can lead to nerve damage, as reported yesterday. Mice that lack Nrf2 do not do well when they are given an MS-like disease so a drug that can stimulate Nrf2 has the potential to be beneficial in MS. BG12 is based on a drug used to treat psorias for many years and so hopefully will have a good safety profile. Time will tell is there is any bnefit to be had in progressive MS, but there is some logical biology behind this hope.

CoI: This work was undertaken by Biogen Idec, the producers of BG12

Another Idea about the Causes of Progression

2012-01-24T10:00:00.001Z

White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis. Cambron M, D'Haeseleer M, Laureys G, Clinckers R, Debruyne J, De Keyser J. J Cereb Blood Flow Metab. 2012 Jan [Epub ahead of print]

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear.

This study describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration.

White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake.

Astrocytes in MS white matter appear to be deficient in β(2) adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase. Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration.

In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

We have described the energy deficit pathway before in nerves, this hypothesis claims the this occurs in astrocytes

Research: Loss of Citrullization of energy making protein is associated with disease RNA transporter

2012-01-24T10:00:00.000Z

Ding D, Enriquez-Algeciras M, Dave KR, Perez-Pinzon M, Bhattacharya SK. The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis.EMBO Rep. 2012 Jan doi: 10.1038/embor.2011.264. [Epub ahead of print]

Deimination refers to conversion of protein-bound arginine into citrulline as a post-translational modification after DNA, is transcribed to form RNA and translated into the production of proteins. An mRNA carrier, RNA binding export factor (REF), present on mitochondria undergoes loss of deimination with impaired ATP5b mRNA transport in ND4
mice (model of multiple sclerosis) compared with the controls. We present evidence of (1) reduced ATP5b mRNA binding strength of non-deiminated REF compared with deiminated REF, (2) impaired ATP5b mRNA transport in ND4 mice and (3) reduced mitochondrial ATP synthase activity on inhibition of deimination in PC12 cells. Impaired deimination of REF and defect in mitochondrial mRNA transport are critical factors in mitochondrial dysfunction in ND4 mice.

The conversion of arginine into citrulline can have important consequences for the structure and function of proteins, since arginine is positively charged at a neutral pH, whereas citrulline is uncharged. This increases the hydrophobicity (fat solubility) of the protein, leading to changes in protein folding (gives 3D structure). Myelin basic protein is citrulated as are other proteins.

ND4 mice contain 70 copies (normally it would be two copies of genes, one from your mum and one from your dad) of the transgene encoding DM20, a myelin proteolipid protein. They appear clinically normal up to 3 months of age. By 8-10 months, they show tremors, unsteady gait, and die shortly thereafter. This is associated with the development of demyelination.

This study shows that mRNA carrier, RNA binding export factor (REF), present on mitochondria undergoes loss of deimination in ND4 mice. This leads to loss of energy supply to the mitochondria (the powerhouses of cells) in nerve cells. As we have reported previously loss of energy supply in nerves that have been demyelinated can lead to progressive nerve loss. Therefore, it will be of interest to determine whether this process occurs in mutliple sclerosis as there is increasing evidence for a failure of mitochondrial function in the pathogenesis of MS.

When you know the cause you are nearer to a cure of the problem

Edible Science

2012-01-23T13:12:00.002Z

Two of the "5 minute meal" films, that Alison Thomson made last year with members of the team will be shown in Dublin's Science Gallery from next month.

"How the eye is affected in Multiple Sclerosis." By Katie Lidster

5 minute meal - Katie Lidster, PhD student from somehow related on Vimeo.

"How nerve impulses are controlled by cannabis (synaptic neurotransmission)." By Professor David Baker .

5 minute meal - Prof. David Baker from somehow related on Vimeo.

Edible: A taste of things to come. A free exhibition exploring the future of food. http://www.sciencegallery.com/

Exhibition:
10th Feb - 6th April 2012
Tue - Fri 12:00 - 20:00
Sat & Sun 12:00 - 18:00

Science Gallery
Pearse Street
Trinity College
Dublin 2

"Well done Alison, we are proud of you!"

Fingolimod deaths and the EMA

2012-01-23T08:54:00.002Z

Anxious? If you are on fingolimod (Gilenya) and have any queries please read the European Medicines Agency's press release, their Q&A paper or leave a comment on the blog which we will respond to.

Spinal fluid oligoclonal bands: are they the secret to uncovering the cause of MS?

2012-01-23T08:48:00.001Z

Epub ahead of print: Korn & Tumani. Patterns of intrathecal autoreactive antibodies in MS using antigen microarrays. Neurology. 2012 Jan 18.

The role of autoreactive antibodies in MS has received intense attention since the discovery of oligoclonal immunoglobulin (Ig) bands in the spinal fluid of the majority (>95%) of MS'ers. However, many questions remain. We still do not know whether the production of Ig in the brain of MS'ers is an epiphenomenon of CNS autoimmunity, resulting from growth factor-driven expansion of long-lived B cells (the cells that make antibodies) in the meningeal* compartment or whether Ig production from antigen-driven proliferation of B-cell clones contributes to CNS pathology. CSF Ig from oligoclonal bands is produced by CSF B lineage cells and primarily recognizes epitopes of multiple neurotropic viruses and Epstein-Barr virus antigens. However, antimyelin antibodies also occur in the serum and CSF of patients with MS.

*meningeal or meninges = the layer of membranes to covers the brain and spinal cord

"In my opinion the secret to the cause of MS lies in uncovering the antigen or proteins against which the antibodies are directed. In disease with known causes (e.g. viral encephalitis) that have oligoclonal IgG bands, the bands react to proteins from the causative agent."

"Cosimo Maggiore in our group is completing a PhD to try and delineate the antigens against which OCBs in MS'ers react. The project has a long way to run. Let's hope he gets there."

Research MSers react against myelin proteins

2012-01-23T08:47:00.005Z

Epub ahead of print Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. Antigen microarrays identify CNS-produced autoantibodies in RRMS.Neurology. 2012 Jan

OBJECTIVE:Multiple sclerosis (MS) is characterized by the local production of antibodies in the CNS and the presence of oligoclonal bands in the CSF. Antigen arrays allow the study of antibody reactivity against a large number of antigens using small volumes of fluid with greater sensitivity than ELISA. We investigated whether there were unique autoantibodies in the CSF of patients with MS as measured by antigen arrays and whether these antibodies differed from those in serum.

METHODS: We used antigen arrays to analyze the reactivity of antibodies in matched serum and CSF samples of 20 patients with untreated relapsing-remitting MS (RRMS), 26 methylprednisolone-treated patients with RRMS, and 20 control patients with other noninflammatory neurologic conditions (ONDs) against 334 different antigens including heat shock proteins, lipids, and myelin antigens.

RESULTS: We found different antibody signatures in matched Cerebospinal fluid (CSF) and serum samples The targets of these antibodies included epitopes of the myelin antigens cyclic nucleotide phophodiesterase, myelin basic protein, myelin-associated oligodendrocyte basic protein, proteolipid protein (59%), Heat shock protein 60 KDa and heat shock protein 70 Kda (38%), and the 68-kDa neurofilament (3%).

The antibody response in patients with MS was heterogeneous; CSF antibodies in individual patients reacted with different autoantigens. These autoantibodies were locally synthesized in the CNS and were of the immunoglobulin G class. Finally, we found that treatment with steroids decreased autoantibody reactivity, epitope spreading (when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. With time the number of targets expand) and intrathecal (within the space surrounding the brain and spinal cord) autoantibody synthesis.

CONCLUSIONS: These studies provide a new avenue to investigate the local antibody response in the CNS, which may serve as a biomarker to monitor both disease progression and response to therapy in MS.

Heterogeneous autoantibody reactivity in CSF antibodies from Relapsing remitting MS. Heatmap in which each column represents an RRMS patient, and each row shows the antibody reactivity to an antigen according to the colorimetric scale shown on the left.

The role of autoreactive antibodies in multiple sclerosis (MS) has received intense attention since the discovery of oligoclonal immunoglobulin (Ig) bands in the majority of patients with MS. However, many questions remain. It is still possible that the intrathecal production of antibody is an epiphenomenon of CNS autoimmunity, resulting from growth factor-driven expansion of long-lived B cells in the meningeal compartment. Alternatively antibody production from antigen-driven proliferation of B-cell clones could be a component of CNS immunopathology. Antibodies from oligoclonal bands is produced by B lineage cells within the CNS. These have been shown to recognizes epitopes of multiple neurotropic viruses and Epstein-Barr virus antigens. However, as this study shows anti-myelin antibodies also occur in the serum and CSF of patients with MS.

The array contained a large number of myelin protein epitopes that could be probed to see what antibodies were present in the blood and cerebrospinal fluid of MSers but these were largely linear peptide sequences of about 20 amino acids (proteins are often around 300-400 amino acids) and thus would fail to detect antibodies that detect conformational epitopes, which detect three-dimentional structures that have been found to be more important with regard to pathogenic-disease causing antibodies. There were some whole proteins and tissue extracts on this arrray.

As found previously in animal autoimmunity, there can be a wide diverisity of autoantibody (antibodies that react to the body) response and that this can broaden with time. There was alot of diversity seen between individuals and there was not one protein that everybody reacted to but it was evident that everyone with MS was reacting to at least one of the proteins. This occurred with relative high frequency for some of the epitopes such as over 60% of MSers vereses 0% in health individuals. However myelin is being damaged in MS and one wonders if this triggers an antibody response so it is secondary to the problem rather than being a primary problem.

If you get immunosuppression with your drug of interest, it may be hoped that the antibody responses would be reduced. This may be a new tool to detect this.

3rd Barts and The London MS Research Day

2012-01-23T08:20:00.005Z

A reminder that the 3rd Barts and The London MS Research Day takes place this Saturday, 28th Jan 2012, at the Church House Conference Centre in Westminster.

Registration is from 9h30 - 10h00 and the day will end at ~15h30.

Download Final programme

Directions to get to Church House Conference Centre

If you have queries please do not hesitate to contact Maria (m.espasandin@qmul.ac.uk) or Beki (beki@shift.ms)

Education: The Publication Process

2012-01-22T10:00:00.003Z

You wondered. How can you see a post on the web, but the actual report only appears in the news stands (scientific literature) about a year later?

If you read the comments don't bother reading this as I posted on this a few days ago, but if not read on.

The quickest way to get an idea into the open is to stick it directly online or to speak to a journalist who sticks it online in a blog or some other electronic medium. Alternatively you can speak at a scientific meeting and journalists are in the audience looking for a story/scoop, quickly filter out things and report anything with a bit of juice that can be squeezed to sound interesting. Sometimes your data is so hot off the press it may be burning your fingers as you have only got the information a few days before the scientific meeting.

ECTRIMS is a good example of information that is circulated quickly. At scientific , compared to clinical, meetings there are fewer journalists lurking in the wings. Scientists may be less likely to present their hot data if it is broadly spread round the world the minute it is said because there is more competition from other scientists and so you can get scooped when it comes to publishing the work. Therefore some people tend not to present work until it has been published or accepted for publication.

Clinical studies such as drug studies take years to do and inariably need to involve alot of people in order to recruit enough people for the trial. Also the drug supply is controlled by the drug company and so there is little chance of being scooped and indeed the marketing people from pharma will co-ordinated the presentations and press releases to create a big splash.

So how long does it take to get the work published in the scientific literature. Well it usually takes a minimum of 6 months from submission to publication.

First you select your target audience and pick an appropriate journal. You aim high and work your way down the pecking order.

Many years ago it was done by snail mail and you had to draw the figures and then photograph them. Now its all electronic. After circulating around all authors for comments and agreement of content, you submit your paper and the Journal Editor will send it out to 2-3 independent referees for Peer review.

This can be a positive experience as the reviwer may see an angle of the work that you have not even thought about or a hole that you have not thoughtabout. The idea is tat it is a constructive process. However it can be and often is a negative experience where your work or you directly (which is not OK) can be assassinated.

Generally reviewers are given 2 weeks to a month to do ther review. One reviwer does not review it on time (Many people are very busy you do not get paid to do it). Therefore getting the review back can take 1-4months (Maybe a reviewer may just sit on it whilst they do similar work or worse they quickly repeat the study as they now know what to do as the paper they are reviewing tells you what to do...Trust me it happens)

The reviewers then want changes made and a month or 3 could laspe whilst you do the things that the reviewers want.

It then goes back to the Editor who sends it back to the original reviewers (or new ones that come up with new questions). They may take another month or more to deal with it. They are happy and it goes back to the editor the manuscript is accepted.

The manuscript then must be typeset at the publishers. A few weeks go by, you then have to review this and correct any mistakes and then it may be put online then take quite a few more months for it to be published. So most of the year gone before it gets to the BLOG.

Now let us have the common scenario you send it to one journal (you aim high and work your way down the pecking order) it goes through the reviewing process and then gets rejected after being reviewed once, twice maybe three times. Therefore months have gone by and you are back to square one. You then go through the process again and sometimes again.

So it is not hard to take a year to get something published.

Interventions for fatigue

2012-01-22T01:00:00.002Z

Payne C, Wiffen PJ, Martin S. Interventions for fatigue and weight loss in adults with advanced progressive illness.Cochrane Database Syst Rev. 2012 Jan 18;1:CD008427.

BACKGROUND: Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress.

OBJECTIVES:To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness.

METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness. We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review.

MAIN RESULTS: We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies.

Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.

AUTHORS' CONCLUSIONS:There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies. Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.

There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients.

This study analysed the treatment of fatigue in a number of conditions and concluded that we need to do better.......so no news there

Research: The Biology Behind Cannabinoid Control of Spasticity

2012-01-21T00:02:00.002Z

Baker D et al. The Biology that underpins the therapeutic potential of cannabis based medicines for the control of spasticity in multiple sclerosis. MultipleSclerosisandRelatedDisorders (2012), doi:10.1016/j.msard.2011.11.001

Cannabis-based medicines have recently been approved for the treatment of pain and spasticity in multiple sclerosis (MS). This supports the original perceptions of people with MS, who were using illegal street cannabis for symptom control and pre-clinical testing in animal models of MS. This activity is supported both by the biology of the disease and the biology of the cannabis plant and the endocannabinoid system. MS results from disease that impairs neurotransmission and this is controlled by cannabinoid receptors and endogenous cannabinoid ligands. This can limit spasticity and may also influence the processes that drive the accumulation of progressive disability.

Glutamate is the major excitatory nerve transmitter chemical. GABA is the major inhibitory nerve transmitter chemical that down regulates glutamate activity

This study describes the role of the cannabinoid system through which cannabis acts to control excessive nerve-impulse transmission during spasticity. It starts with MSers reporting their experiences and then our experimental evidence that provided the first objective evidence to support those experiences. That was part of the equation that lead to unraveling of what the cannabinoid system does and importantly to the eventual delivery of a drug that has some benefit for the control of spasticity.

Sativex has been licenced for treatment of MS in Canada and some European Countries (UK, Spain Germany, Denmark and Sweden), but has yet to recieve NICE approval in the UK and is therefore sometimes difficult to get access to the drug.

This study also reports on future avenues that could provide the next generation of cannabis-like drugs that avoids the side-effects associated with cannabis use. It also explains how this system can be manipulated to have a potential benefitical effect in Progressive MS. A trial to test this idea is already fully recruited (600MSers) and is ongoing with the UK.

CoI: This work was undertaken by Team G. It provides a rational for and demonstrates (supported by GW pharmaceuticals) the activity of Sativex in the control of spasticity. GW pharmaceuticals had no influence on the content of the article.

Gilenya: May increase blood pressure in cases of hypertension (in rats)

2012-01-21T00:01:00.004Z

Spijkers LJ, Alewijnse AE, Peters SL. FTY720 (Fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase. Br J Pharmacol. 2012 Jan 17. doi: 10.1111/j.1476-5381.2012.01865.x. [Epub]

Background and purpose. FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases blood pressure. We have previously shown that inhibition of sphingosine kinase increases vascular tone and blood pressure in hypertensive (high blood pressure), but not normotensive (normal) rats. Since FTY720 is reported to have sphingosine kinase inhibitory effects, we investigated whether FTY720 increases vascular tone and blood pressure only in hypertensive rats via this mechanism.

Experimental approach. The contractile and blood pressure modulating effects of FTY720 were studied in vivo and ex vivo (tissues taken from the animal) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Key results. Oral administration of FTY720 induced an increase in mean arterial pressure in hypertensive rats, whereas a decrease in blood pressure was observed in normal rats, as measured 24 hours after administration. In analogy to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced major contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 (FTY720-P, which is the active immunosuppressive drug that rapidly forms following injection of FTY720) did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions (like DMS-induced contractions) proved to be endothelium-dependent and to be mediated by thromboxane A(2) , since these contractions could be inhibited by endothelium denudation (removal of the blood vessel lining cells), cyclooxygenase and thromboxane synthase inhibitors and by thromboxane receptor antagonism.

Conclusions and Implications. These data demonstrate that FTY720 increases vascular tone and blood pressure only in hypertensive rats, most likely due to its sphingosine kinase inhibitory effect.

Following the sad news of a number of deaths apparently following taken gilenya, this paper may gain increased importance. Whilst details about the deaths are sparse, according to Bloomberg Business Week there may have been problems with the heart and heart attacks.

It is known that Gilenya can cause your heart rate to slow down, particularly right after the first dose, with the drop being most significant at about six hours after the dose is taken. This is why doctors should monitor you during the first dose. Heart rate should to return to normal within one month of starting the medication, but feelings of dizziness and tiredness, or a slowed or uneven heartbeat should be reported to your doctor as should any pre-existing problems with blood pressure.

This research in rats indicates that whilst there may be a drop in blood pressure in normal rats, in rats that are genetically prone to high blood pressure can develop even higher blood pressure following gilenya. High blood pressure was caused by constriction of the artery and this causes the heart to work harder to circulate the blood. Hypertension can be associated with an increase risk of stroke and heart attack. In the rats asperin-like drugs could counteract the arterial constricting effects of fingolimod

At present more than 30,000 people have taken Gilenya and these deaths may be unrelated to the drug. Novartis are no doubt doing overtime to try and get to the bottom of this.

Following marketing of a drug, Pharmaceutical companies continue to perform "Pharmaco-vigilence" to spot any adverse effects that may be related to the drug. Death always ring alarm bells and need to be investigated. On a trial that Prof G did there was a death due to drowning. This was hardly likely to be drug-related but such things had to be reported just in case others cases occurred

We will keep you informed as this story develops.

Fingolimod to be reviewed by EU and US after 11 deaths

2012-01-20T17:47:00.001Z

Breaking news:

European and U.S. regulators are reviewing Novartis AG’s Gilenya pill for multiple sclerosis after reports of 11 deaths among patients who took the drug. The shares fell the most in more than five months......

For full report see Bloomberg

January 3. Unrelated blogger comments

2012-01-20T12:01:00.000Z

Sometimes You want to post a comment that is Unrelated to the thread.

Therefore I have Created this Spot for You
It jumps around so that it is visible

ADVERTS will be DELETED!

Poor quality sleep impacts on quality of life in MS'ers

2012-01-20T08:20:00.001Z

"As a follow-up to some comments about fatigue yesterday, this article makes the point that poor sleep hygiene is an important problem in MS."

Epub ahead of print: Trojan et al. Polysomnographic measures of disturbed sleep are associated with reduced quality of life in multiple sclerosis. J Neurol Sci. 2012 Jan 16.

BACKGROUND: The relationship of objective sleep parameters with health-related quality of life (HRQoL) in MS'ers has not been adequately studied.

OBJECTIVE: To evaluate the relationship between polysomnographic (PSG) parameters and HRQoL in MS.

METHODS: Ambulatory MS'ers without a known sleep disorder completed the Short Form (36) Health Survey (SF-36), pain visual analog scale, and two consecutive overnight PSGs. HRQoL was assessed using SF-36 Physical and Mental Component Summary (PCS, MCS) scores. Standard objective PSG measures of sleep quality were determined.

RESULTS: 62 MS'ers were included. PSG measures of sleep disruption including stage changes, awakenings, time in phase 1 of sleep, and apnea-hypopnea and total arousal indices were negatively associated (p<0.05) with MCS scores (lower scores indicating poorer HRQoL). PSG parameters reflective of better sleep quality including total sleep time, sleep efficiency, and time in rapid eye movement or REM sleep were positively associated with MCS scores. PSG parameters were not significantly associated with PCS scores.

CONCLUSIONS: PSG-documented sleep disruption negatively impacts, while better objective sleep quality positively impacts on the mental domain of HRQoL in MS.

"The results of this study show that poor quality sleep impacts on quality of life; it is therefore important to remember this if you feel tired all the time. A simple overnight sleep study can get to the bottom of your problems. If you have a query regarding this I suggest you ask your neurologist for advice."

Other posts of interest on this blog in relation to sleep:

Multiple Sclerosis Research: research: sleep

31 Dec 2011

Objective: We evaluated the relationship of obstructive sleep apnea to fatigue and sleepiness in MS patients.Methods: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic ...

Multiple Sclerosis Research: Research: Sleep Distruption:

10 Dec 2011

BACKGROUND: Sleep disruption and fatigue are common in Multiple Sclerosis (MS). Melatonin is one of the major regulators of sleep-wake cycle. The role of melatonin in MS-related sleep disturbances and fatigue as well as ...

Multiple Sclerosis Research: How do you know if you have a sleep ...

06 Aug 2011

"Please review the information in An Overview of Sleep Disorders on the Harvard Medical School Healthy Sleep site, which explains the commonest sleep disorders in plain English. In addition, I would strongly encouraged ...

Multiple Sclerosis Research: How is your sleep?

06 Aug 2011

The main sleep disorders associated with MS include: insomnia, circadian rhythm disorders, drug-induced sleep disturbances, restless legs syndrome and periodic leg movements, breathing disorders during sleep (for ...

Multiple Sclerosis Research: Sleep disorders and fatigue in MS ...

20 Jan 2011

This paper reviews sleep disturbances in MS and it association with fatigue. In people with significant fatigue sleep hygiene should be on top of the management plan; without a good night's sleep how can you expect to feel ...

Making alemtuzumab or campath infusions safer

2012-01-20T08:08:00.001Z

Epub ahead of print: Perumal et al. Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis. Mult Scler. 2012 Jan 17.

As you know alemtuzumab or campath-1h has remarkable efficacy in relapsing MS. In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia and some oncology guidelines recommend alemtuzumab is given subcutaneously (SC). There is no report of alemtuzumab SC in MS.

These investigators report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events.

SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events.

Other posts of interest on this blog in relation to alemtuzumab:

Second successful phase III Results for Alemtuzumab in MS

14 Nov 2011

In the CARE MS II randomized trial involving 840 patients, a 49% reduction in relapse rate was observed in patients treated with alemtuzumab 12 mg compared to interferon beta-1a over two years of study (p<0.0001).

Research: White blood cell depletion and Alemtuzumab

12 Nov 2011

Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has marked efficacy for relapsing-remitting multiple sclerosis (MS). One unresolved issue is the duration and significance of the lymphopenia ...

Multiple Sclerosis Research: News: Alemtuzumab $60000 per annum

11 Sep 2011

"Based on its superior efficacy Alemtuzumab should command a premium price. However, the cost will affect its cost-effectiveness and its license in the UK under NICE. Ideally we would like to use Alemtuzumab in early MS; ...

Multiple Sclerosis Research: Immune complications of alemtuzumab

03 Oct 2011

In a phase 2 clinical trial of annual alemtuzumab for the treatment of relapsing-remitting MS, 6/216 (2.8%) patients developed immune thrombocytopenia (ITP). "Thrombocytes or platelets are the cells in the blood responsible ...

Multiple Sclerosis Research: Alemtuzumab - risks of developing ...

30 Jul 2011

"What is alemtuzumab? You may know the drug as Campath-1h. This is a powerful immuno-modulator that is given as a course of intravenous infusions. It depletes the immune system and allows it to recover. I refer to it as an ...

Multiple Sclerosis Research: Alemtuzumab results - further analysis

18 Jul 2011

"This was not a negative study; Alemtuzumab is still a very promising disease-modifying therapy! The patients in this trial were less active than previously therefore the trial lacked power to detect a difference in relation to ...

Multiple Sclerosis Research: More on the Alemtuzumab trial

12 Jul 2011

More on the Alemtuzumab trial. The previous post is simply the headline results; we need to wait for the full results that will be presented at the ECTRIMS/ACTRIMS meeting from the 19 – 22 October 2011, in Amsterdam, The ...

Multiple Sclerosis Research: Research: Alemtuzumab treatment of ...

09 Sep 2011

This is more of the same (good) news, with regard to Alemtuzumab. This un-controlled and unblinded study indicates that Alemtuzumab (an antibody that kills white blood cells) quells disease activity in MSers who have ...

Multiple Sclerosis Research: Alemtuzumab (Lemtrada) misses a ...

11 Jul 2011

A press release on the headline results of the Alemtuzumab vs. Interferon-beta-1a trial: "Sanofi said Lemtrada worked better than an older drug, Rebif, in preventing relapses, as patients treated with Lemtrada were 55 percent ...

Genzyme details market potential of Alemtuzumab for MS

17 Jan 2011

Genzyme details market potential of Alemtuzumab for MS. Wow! Let's hope it is not too expensive for the NHS. Click here to read the press release! Posted by Gavin Giovannoni at 22:55 · Email ThisBlogThis!Share to ...

Multiple Sclerosis Research: Genzyme is bought by Sanofi: what will ...

16 Feb 2011

Genzyme is the company that is developing Alemtuzumab (formerly known as Campath-1h) for MS. Alemtuzumab is clearly the most effective of the emerging drugs in clinical development. Sanofi on the other hand are ...

Multiple Sclerosis Research: Research: MS Fatigue

17 Jan 2012

Alemtuzumab removes white cells from the blood in RRMS and works, Alemtuzumab removes the white cells from the blood in SPMS and does not work. So is it all about blood flow?. Are there any current drugs that work in ...

Multiple Sclerosis Research: Do the markets know more than we do?

12 Jul 2011

Sanofi-Aventis's share price dropped by nearly 2% yesterday after the headline results of the Alemtuzumab trial were made public. "Do the markets know more than we do about the results of clinical trials? Depressing if they ...

Multiple Sclerosis Research: Some MS-related News from the AAN ...

18 Apr 2010

Five other cases were subsequently diagnosed with ITP with onset between 1.5 and 16 months after alemtuzumab. In one case ITP resolved without treatment. In 2 cases, remission was achieved with corticosteroid treatment ...

Multiple Sclerosis Research: Top of the Pops: Dr Giles Elrington

19 Jun 2011

Re Alemtuzumab & "... my guess is in a few years time we will offer this to everyone with new MS": Could this also be a natural next step for those completing 2 years of Tysabri? With current knowledge what would be better ...

Multiple Sclerosis Research: Education: Treating Progressive MS ...

23 Sep 2011

These (Alemtuzumab, Rituzimab, Cladribine, Bone marrow transplantation, beta interferon) do not appear to stop the non-relapsing aspects of progressive MS. Therefore we need a new approach to treat progressive MS, ...

High calcium levels on vitamin D supplements

2012-01-20T06:00:00.001Z

Marcus et al. Severe hypercalcemia following vitamin d supplementation in a patient with multiple sclerosis: a note of caution. Arch Neurol. 2012 Jan;69(1):129-32.

OBJECTIVE: To describe a patient with multiple sclerosis (MS) who developed severe hypercalcemia, attributed to the additive effect of 5500 IU of cholecalciferol and 2020 mg of calcium daily.

RESULTS: The patient's corrected serum calcium level was 15.2 mg/dL (reference range, 8.7-10.1 mg/dL; to convert to millimoles per liter, multiply by 0.25), and her 25-hydroxyvitamin D level was 103 ng/mL (to convert to nanomoles per liter, multiply by 2.496). The results of extensive laboratory tests to rule out hyperparathyroidism, malignant neoplasms, and other causes of hypercalcemia were unrevealing.

CONCLUSIONS: It is common practice to prescribe high-dose vD to MS'ers for its possible role in immunomodulation and relapse-rate reduction. Nevertheless, vD may increase serum calcium, and there seems to be an additive effect when patients simultaneously use calcium supplements. This case underscores the need for physicians to be attentive to the possibility of hypercalcemia in MS'ers treated with both high-dose vD and calcium.

"The take home message is that if you are taking vD supplements you should not be taking Calcium supplements as well."

"Please note this complication of vD supplementation is very rare."

"Please note vD and calcium are given in combination to treat osteoporosis or diseases with bone thinning."

You need to be aware of the symptoms of high calcium levels:

Stones (renal or biliary)
Bones (bone pain)
Groans (abdominal pain, nausea and vomiting)
Thrones (sit on throne - polyuria or increased urination)
Psychiatric overtones (Depression 30-40%, anxiety, cognitive dysfunction, coma)
Other symptoms can include fatigue, anorexia, nausea, vomiting and pancreatitis (inflammation of the pancreas).
Abnormal heart rhythms can result and are associated with abnormal ECG findings

"If in doubt get your calcium levels checked; prevention is better than cure."