Saturday, 22 July 2017

#ResearchSpeak: are you a drinker?

What is the evidence that alcohol is good for you? #ResearchSpeak #MSBlog

The following study implies that moderate alcohol consumption is associated with lower disability and suggest red wine is good for you. However, moderate red wine consumption (1-3 glasses per week) was associated with a faster increased in MRI T2 lesion volume, i.e. focal MRI activity. How do we square this circle? We don't the results are not that convincing and suggest an association. In other words alcohol drinking may be associated with other factors that are actually responsible for the lower levels of disability. The association with red wine drinking looks like a false positive and the positive spin in this article could be due a framing effect based on the marketing of red wine as an anti-ageing agent. A framing effect is the interpretation of results in a particular way based on a bias (frame) that has been established by past experiences or prior knowledge. 

There has been work done on resveratrol, an anti-oxidant, in red wine as an anti-ageing, and neuroprotective, compound. The problem is that the amount of resveratrol you get from drinking red wine is too low to have much biological impact. Despite this the French wine industry has managed to get the message across that red wine is good for you.

This paper must be balanced against the literature showing how bad excessive alcohol intake is for your health overall. More recently excessive, and even moderate, alcohol consumption has also been shown to reduce cognition. 

I must point out that the levels of consumption of alcohol studied in this paper are quite low. This study in not going to alter my practice and I will continue to recommend that if you choose to drink please do so in moderation and if you choose to be teetotal that is also fine. The evidence that alcohol is neuroprotective is very weak. We need well designed and larger studies to control for con-founders before making any unrealistic claims about the benefits of alcohol to pwMS. 

Diaz-Cruza et al. The effect of alcohol and red wine consumption on clinical and MRI outcomes in multiple sclerosis. Multiple Sclerosis and Related Disorders. Volume 17, October 2017, Pages 47-53.

Background: Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS).

Objective: To assess the association between alcohol and red wine consumption and MS course.

Methods: MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol.

Results: 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, − 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, − 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1–3 glasses of red wine per week compared to nondrinkers.

Conclusions: Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms.

CoI: I am wine lover.

Mouse Flu is it really informative about Man Flu

Blackmore S, Hernandez J, Juda M, Ryder E, Freund GG, Johnson RW, Steelman AJ. Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2017. pii: 201620415

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.

So here we have a mouse stuffed full of T cells waiting to attack the spinal cord and optic nerve and you do nothing and 5% get disease, you stimulate their T cells with the toxin from whooping cough and 100% get disease and here you give a live virus and about 30% get disease. They give a normal mice the flu and they find changes in the genes in the brain suggestive some cellular activation and say a cytokine is involved.. However if they had done anything to stimulate the T cells they would get disease and so the inference in that the paper that flu is a trigger of MS fails down. 

Friday, 21 July 2017

Sorry I messed up

I have to apologise but I was immersed in the World Para Athletics 2017 and the Last Leg and was supposed to launch your comments but deleted them by pressing the wrong button by mistake, so if you have the comments please submit again.

Autoimmunity in MS: Neurofilament light

Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament Light as an Immune Target for Pathogenic Antibodies. Immunology. 2017. doi: 10.1111/imm.12797. [Epub ahead of print]

Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunisation with neuronal antigens such as neurofilament light NF-L, a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, while antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.

When nerves are damaged they breakdown and release their contents and these products are measured as a marker of disease activity. However, it is clear that neurofilament directed antibodies are generated to clear up these breakdown products. 

We have shown that if you cause the antibodies to be produced in mice that they can cause neurological problems. 

This study shows that these antibodies, however can be potentially damaging and so clearly shows there is autoimmunity occurring in MS. In this study neurofilament specific antibodies were injected into animals and it made EAE worst, once T cells had opened the blood brain barrier to allow the antibody to enter the brain. This was not surprising as this has been shown with a number of antibodies. More surprisingly when injected directly into the brain these antibodies caused signs of disease. It was surprising because neurofilament is inside a nerve and so would not be easily assessable.  The signs occurring were very different to the signs occurring when antibodies targeting basal ganglia from a person with a tic disease was injected into the brain. 

These neurofilment directed antibodies can kill nerves and so could contribute to damage in MS.

CoI. This is work bt TeamG

#GuestPost & #NewsSpeak: feedback from the MS-Chariot meeting

An MSer's perspective the MS-Chariot meeting. #GuestPost #ThinkHand #MSChariot

Last week, I attended the first MS Chariot meeting at St Barts. Around the table were about twenty of us - mostly neurologists from the UK and abroad, health researchers, an MS Society  representative and a few of us MSers - all there to discuss the possibilities, funding, treatments and yes - frustrations - of those with advanced MS who have traditionally been overlooked in the quest for disease modifying drugs.

This was made all the more apparent at the start of the day when Craig Milverton sat down at a piano and began playing a handful of songs by George Gershwin, Cole Porter and other jazz greats.

Playing is the key word here.

You see in 2010, the very year Milverton was named Jazz Pianist of the Year, he was diagnosed with PPMS. With each passing month, his symptoms got worse. His walking deteriorated, his fingers became more and more numb and he began missing notes on the piano. His career as a pianist was over, he thought.

Then in 2012 he was able to get on ocrelizumab - an experimental drug currently being assessed for drug licensing by the EMA for RRMS and PPMS. Almost immediately after his first infusion he started to feel better. Since then, his symptoms have stabilised and he has been able to continue playing across the country.

Craig is one of the lucky ones. Until very recently, it was thought that a person with advanced  MS - with an EDSS score above 5.5 and requiring a walking aid - would not benefit from a disease modifying treatment (DMT). It was not quite “Diagnosis and Adios,” but pretty close.

Why? Selective interpretation of trial data, too much focus on EDSS scores as a key outcome, a belief immunotherapy did not work “beyond the wheelchair,” regulatory process, cost and numbers. Advanced MS is uncommon. Only 10-15% of MSers are initially diagnosed with it.

Such a belief also meant that for those with advanced MS preserving upper limb function was not seen as a priority. But if you think about it, what keeps pwMS independent is their arms and hands. When you lose the ability to walk - that is bad enough. But at least with your hands, you are able to get into your wheelchair, dress yourself, clean your teeth, feed yourself, make a telephone call, use a keyboard, self-catheterize, work a remote control… Lose that and your quality of life plummets.

Thankfully this mindset is starting to change. “At the moment, there are no established options for advanced MS, but emerging therapies are offering hope,” said Cris Constantinescu, a neurologist from Nottingham University, to the group.

For Dr. Klaus Schmierer, a neurologist at St Barts who organised the forum, real promise lies in cladribine, a drug traditionally used for the past 25 years to treat hairy cell leukemia, but which has also proved to be highly effective in treating RRMS. As an MS drug, it has many advantages. It is safe, easy to use, convenient - it is an injectable but also comes in tablet form -  and cheap as it is a generic drug.

Intriguingly, there is also evidence, dating from the early 1990’s, that cladribine may also slow advanced MS. At the moment, about one hundred patients at the Royal London Hospital with advanced MS - who have failed other therapies - are using it and finding it effective. “It meets the needs of some patients for whom we have little to offer,” says Schmierer. But definitive trials are lacking, a source of frustration for Schmierer, who is currently looking for funding.

Another MS drug which offers hope is rituximab, an injectable, which works in a similar fashion to ocrelizumab.  Though the NHS has declined to fund rituximab for the treatment of MS in the UK - citing insufficient trial results - Swedish neurologists have been using the drug for RRMS and advanced MS for more than a decade. “It fulfilled an unmet need and there were fewer options available for advanced MS,” said Frederik Piehl, a neurologist from the Karolinska Institute. In Sweden, he said rituximab has been found to have been highly effective and well tolerated. However in the UK, neurologists are not allowed to prescribe it for their patients.

By the end of the day, it had become apparent that there were no one-off easy answers regarding treatment options for those with advanced MS. The challenging nature of treating MS, plus wrangles over drug licensing, potential funding and drug company priorities ensures this However there was a feeling that, at least, attention is finally being focused on those with advanced MS who might have been previously ignored. Studies have shown - and as Craig Milverton apply demonstrated - advanced MS is modifiable. Now it is key to get the rest of the community on board.

As Aisling McMahon, head of clinical research at the MS Society, said: “We are very aware that progressive MS is the greatest area of unmet need.”