- MS Research Days
- Trials and studies
Friday, 20 January 2017
It has been suggested that some people with Multiple Sclerosis have subtle evidence of disease activity long before they develop clinically-definite disease. The argument goes that if you performed detailed examinations and investigations, you would detect these subtle abnormalities in certain people before they meet diagnostic criteria for MS. In fact, according to one estimate, about 1/3 of people who have evidence of MS on neuroimaging go on to develop MS within 5 years.
We also now have good evidence that early, aggressive treatment improves long-term outcomes for people with Clinically Isolated Syndrome (‘pre-MS’). It is theoretically plausible that treating people even earlier – e.g. when they have abnormalities on brain imaging but no clinical signs or symptoms of MS – could reduce their risk of developing MS proper.
If preventing MS is going to be an achievable goal for the future, it is crucial that we are able to determine who is at risk of developing the disease so that we can target our therapy appropriately. The Genes and Environment in Multiple Sclerosis (GEMS) project has set out to do just this – it recruited 2632 1st degree relatives of people with MS to get a better understanding of how to predict the development and the progression of this protean disease.
In a new paper, the GEMS investigators asked whether their MS risk score could predict who would have subtle clinical or radiological abnormalities suggestive of MS. To do this, they took a subset of 100 people from their study cohort, calculated each person’s risk using their previously published risk score, and then took the people in the top and bottom 10% of risk scores to investigate in more detail. They hypothesised that there would be a difference in clinical and radiological parameters relevant to MS between the ‘high’ and ‘low’ risk groups.
To avoid a gender bias, they focussed their analysis on women only. They compared 40 ‘high risk’ women to 25 ‘low risk’ women. Despite using a battery of clinical and imaging measures, they found no statistically significant differences between the groups in terms of age, height, cigarette smoking, vitamin D level, history of infectious mononucleosis, history of migraine, number of MRI lesions suggestive of MS, the prevalence of radiologically-isolated syndrome, EDSS, NHPT, or PASAT scores. There was, however, a significant difference in vibration sensitivity between the high and low risk groups, with the high risk group demonstrating a diminished sensitivity to vibration.
This study demonstrates nicely how difficult it is to detect subtle abnormalities in a small cohort. Even when comparing the highest and lowest risk groups as stratified by the GEMS risk score, only one parameter – vibration sensitivity – was significantly different between the groups. This is unsurprising. If early, ‘pre-MS’ is defined by subtle clinical or imaging abnormalities, then a big cohort is required to demonstrate this. When trying to study small effects, we need big numbers to reduce the chances of false negative results. The cohort of 60 or so people used in this study is simply not big enough to meaningfully prove or disprove the hypothesis at hand. I would take their lack of positive findings with a pinch of salt.
The motivation behind the GEMS project is really laudable, and I imagine that lots of interesting data will come out as they follow their cohort over the next few years. Armed with a better understanding of who is at risk of MS, the paradigm may begin to shift from early treatment to prevention. Part of the problem is that it is notoriously difficult to demonstrate benefit in prevention trials as the number of people who will develop the disease without any treatment is small. Once we work out who is at high risk of developing MS we will be much better placed to design clinical trials that could show meaningful benefit for preventative therapies.
Importance Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS).
Objective To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.
Design, Setting, and Participants The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant’s risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual’s genetic burden and environmental exposures. The study dates were August 2012 to July 2015.
Main Outcomes and Measures Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.
Results This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.
Conclusions and Relevance Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.
Trial Registration clinicaltrials.gov Identifier: NCT01353547
Healthcare professionals working in MS may find the MS Trust's new web resource helpful #NeuroSpeak
Health Professionals Web Resources
Here at the MS Trust we are always working to ensure that people with MS and the specialist health professionals who support them have access to up-to-date, relevant, accurate and useful information. Recently, we've been working with health professionals to look into the information resources currently used, and where there may be gaps. Many thanks to everyone who has been involved in this project and those who completed our survey.
A few topics emerged that professionals wanted more information on, so we decided to send a reminder about the resources we already provide in those areas. We believe the following resources will prove useful to MS health professionals, and support them in their professional development and in providing quality care to people with MS.
Writing an effective business case
We have recently updated a page on our website about capacity planning and writing a good business case, featuring highlights from our guide to writing an effective business case and our capacity planning tool, which are available in full on request.
Understanding commissioning and funding flows in MS services in England
This is a vastly complex subject, but can be hugely beneficial to understand when making a case for service improvement/development. We've created a straightforward, practical guide to funding flows in MS services in England.
Sharing examples of innovative practice
We have recently put together a resource for health professionals highlighting opportunities to implement change in MS services. Featured on this webpage are a number of examples of innovative practice from MS teams across the UK (and the opportunity to add to this list yourself) and suggestions for small steps you can implement to help take forward the action statements from MS Forward View.
Developing an effective, responsive and efficient relapse service
In the summer of 2016, we sent every MS nurse a copy of our guide Eight steps to improving your relapse service: a guide to best practice for MS specialist nurses, which explained relapses, discussed the clinical management of relapses, and set out our 'eight steps' needed to deliver an effective relapse service. We also hoped that this resource may be useful for other MS health professionals and GPs.
Auditing your service with a user survey
The MS Trust offers all UK MS nurse and therapist teams the chance to use this survey through a free service whereby we take away most of the work involved. By taking part, you will receive a valuable presentation giving evidence of the benefits of your service to patients along with service users' experiences and suggestions for improvement.
Improving the efficiency of disease modifying drug provision
As part of MS Forward View, we looked at the DMD pathway in MS and investigated how capacity may be created in this area of MS care. This report provides a detailed explanation of the current workload associated with DMDs and how this impacts MS teams, models how this workload may develop in future and where capacity may be freed up in this pathway.
Improving services for people with advanced MS
Another area of MS services we looked at as part of MS Forward View was care for people with advanced MS. Recently, concerns have arisen that this was an aspect of care that was often difficult for teams to fully implement as demands on MS services in general continue to rise. This report outlines the findings of our work on this area, and our recommendations for how services can better meet the needs of people with advanced MS.
Other resources you may find useful
We hope you find these resources useful, let us know if you have feedback on any of them – we're keen to hear what you think.
All the best,
Health Professionals Programme Team
Crowley D, Collins C, Delargy I, Laird E, Van Hout MC. Irish general practitioner attitudes toward decriminalisation and medical use of cannabis: results from a national survey. Harm Reduct J. 2017; 14(1):4. doi: 10.1186/s12954-016-0129-7.
Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. Zombie" Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017 Jan 19;376(3):235-242. doi: 10.1056/NEJMoa1610300.
Background New psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a "zombie" outbreak because of the appearance of the intoxicated persons. Methods We obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal "incense" product "AK-47 24 Karat Gold," which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography-quadrupole time-of-flight mass spectrometry. Results The synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB) was identified in AK-47 24 Karat Gold at a mean (±SD) concentration of 16.0±3.9 mg per gram. The de-esterified acid metabolite was found in the serum or whole blood of all eight patients, with concentrations ranging from 77 to 636 ng per milliliter. Conclusions The potency of the synthetic cannabinoid identified in these analyses is consistent with strong depressant effects that account for the "zombielike" behavior reported in this mass intoxication. AMB-FUBINACA is an example of the emerging class of "ultrapotent" synthetic cannabinoids and poses a public health concern. Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action.
This reports about the effects of synthetic cannabinoids and how it makes Zombies out of the stoners who try it.
Pfizer not only invented Pfizer-riser but also one of the first to come up with uber-dope. This is synthetic and are miles more potent than cannabis, in this report it the drug is 85 times more potent...These are drugs for light weights, we have used stuff a thousand times more potent, long since destroyed,
The urban legend of the early cannabinoid researcher who tried these on themselves....they were paralysed on the kitchen floor lying in there own Pooh for three days.
My advice to anyone thinking of this...stay well clear.
Posted by MouseDoctor at 07:00
Ahn YH, Jeon SB, Chang CY, Goh EA, Kim SS, Kim HJ, Song J, Park EJ.Glatiramer acetate attenuates the activation of CD4+ T cells by modulating STAT1 and -3 signaling in glia.
Sci Rep. 2017 Jan 17;7:40484
Interactions between immune effector cells of the central nervous system appear to directly or indirectly influence the progress/regression of multiple sclerosis (MS). Here, we report that glial STAT1 and -3 are distinctively phosphorylated following the interaction of activated lymphocytes and glia, and this effect is significantly inhibited by glatiramer acetate (GA), a disease-modifying drug for MS. GA also reduces the activations of STAT1 and -3 by MS-associated stimuli such as IFNγ or LPS in primary glia, but not neurons. Experiments in IFNγ- and IFNγ receptor-deficient mice revealed that GA-induced inhibitions of STAT signaling are independent of IFNγ and its receptor. Interestingly, GA induces the expression levels of suppressor of cytokine signaling-1 and -3, representative negative regulators of STAT signaling in glia. We further found that GA attenuates the LPS-triggered enhancement of IL-2, a highly produced cytokine in patients with active MS, in CD4+ T cells co-cultured with glia, but not in CD4+ T cells alone. Collectively, these results provide that activation of glial STATs is an essential event in the interaction between glia and T cells, which is a possible underlying mechanism of GA action in MS. These findings provide an insight for the development of targeted therapies against MS
STAT1 and STAT3 are transcription factor i.e. they affect the production levels of proteins from the DNA.
The study says that GA reduces the effect of the STATS in response to interferon gamma and LPS. LPS is lipopolysaccharide a sugar like molecule on bacteria...So this implies that MS is caused by bacteria!.
They examine the effect of glia....in this case it is usually a mix of microGLIA and astroGLIA but they do experiments in single cell types too.
So it shows how good the referees and editors are:-)
However, is this real? Why because the glatiramer acetate was from a chemical supply company and not the real McCoy. So is this generic any good.
COI : None
Posted by MouseDoctor at 07:00