Saturday, 27 March 2010

Sativex in MS-related spasticity

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Treating spasticity in MS is a big problem; it is very common and the current drugs we use are too sedating and tend to have a negative impact on cognition, which limits their use early on in the course of the disease.

This study compares Sativex (the active ingredient in cannabis) with placebo in a 15-week study. The design of this study is interesting for two reasons: (1) it used an enrichment phase to select responders before randomising them to blinded active comparator stage of the trial; and (2) it used a numeric rating scale (NRS) as the primary outcome rather than the Ashworth scale (the traditional outcome measure in spasticity trials). In summary the change in NRS score and responder-status (defined as a greater than or equal to 30% improvement from baseline) were both significantly superior for Sativex, compared with placebo. Importantly, Sativex appears to be well tolerated in this group of patients with quite advanced MS.

It will be interesting to see if Sativex gets a license based on the results of this trial. The availability of Sativex will allow us to "spread the hope" and offer something to patients in whom our current medications are not enough to control their spasticity.

Tuesday, 23 March 2010

Vitamin D status is associated with relapse rate in pediatric-onset MS

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Among 110 North American paediatric CIS/MS subjects, every 10 ng/mL increase in the adjusted 25 hydroxyvitamin D3 level was associated with a 34% decrease in the rate of subsequent relapses.
This study adds compelling evidence in support of a role for vitamin D in reducing MS relapse rates as initially seen in smaller studies in adult MS cohorts (Wingerchuk et al, JNNP 2005; Soilu-Hänninen et al, JNNP, 2008). As vitamin D deficiency/insufficiency is endemic worldwide (Holick, NEJM, 2007), further studies of vitamin D as a treatment measure in MS are warranted.

Sreeram Ramagopalan

43 confirmed post-marketing Natalizumab-related cases of PML

The news of 43 confirmed cases of post-marketing Natalizumab-related PML coincides with the timely publication of the description of the first 28 such cases and a review on the topic:

Clifford DB, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010 Apr;9(4):438-446.

Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010 Apr;9(4):425-437.

These developments underpin the urgent efforts to implement an appropriate risk-stratification strategy to lower the risks of developing PML for people with MS receiving Natalizumab.

Please watch this space for an update.

Human leukocyte antigen-DR15, low infant sibling exposure and multiple sclerosis: Gene-environment interaction

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The cause of multiple sclerosis (MS) is not yet conclusively known but both genes and the environment are important. A region on chromosome 6, the HLA class II, exerts the single strongest genetic effect but the involvement of the environment is also inescapable and is no better illustrated than by the geographical distribution of the disease. The identity of the environmental factors involved in MS is not known unequivocally but there are a few leading candidates, namely, Epstein-Barr virus, vitamin D and smoking. It has been suggested that low sibling infant exposure (classed as having no older siblings and any younger siblings having an age difference of at least 5 years) increases MS risk (Ponsonby et al, JAMA, 2005). Genetic and environmental factors are not independent. In an intriguing study, van der Mei and colleagues observed that HLA-DRB1*15 (a form of the gene involved in MS on chromosome 6) interacted with low sibling infant exposure to increase MS risk. This result could thus be of importance in disease aetiology but requires replication. Other groups have been unable to support an effect of low infant sibling exposure on the risk of MS (Sadovnick et al, Lancet Neurol, 2005; Bager et al, Am J Epidemiol, 2006) so the gene-environment interaction uncovered by van der Mei and others may be specific to Australia; this will require confirmation.

Dr Sreeram Ramagopalan

Tuesday, 16 March 2010

2010 Annual Evidence Update on Multiple Sclerosis

You may find the following NHS resource useful:

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Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Another blank. Sargsyan and colleagues failed to find evidence of persistent infection in the cells that produce antibodies (plasma and B cells) within the brains of people with MS. Only in active MS plaques was EBV-encoded RNA (EBER)-1 rarely detected.

Click here

Conclusion: My take on this is that we need to focus on active and preactive MS lesions; I suspect that is where the action will be. Although the score at the moment is strongly against overt CNS EBV infection being a direct factor in MS pathogenesis we need to keep an open mind to the contrary. Post-mortem tissue studies are not necessarily the best means of investigating the link between active EBV infection within the central nervous system and MS.

Thursday, 4 March 2010

EBV specific killer cells in early MS

A new study looking into the immune response to EBV in people with MS has shown that a group of white blood cells responsible for killing EBV, the so called CD8+ cytotoxic lymphocytes or CTLs, are increased in theblood of people with early MS as compared to controls and other patients. Importantly these cells were shown to be increased in the spinal fluid of subjects with MS compared to subjects with other diseases. This data further strengthens the association between EBV and MS, in particular early disease.

Jaquiéry E, et al. Intrathecal immune responses to EBV in early MS. Eur J Immunol. 2009 Dec 16;40(3):878-887. [Click here]