Posters Galore @ECTRIMS #MSParis2017

ECTRIMS/ACTRIMS 2017 in Paris

How would I describe this year's ECTRIMS/ACTRIMS?



With 10,000 participants and more than 2000 abstracts this year, it is undoubtedly one of the worlds largest neurology/science conferences. On Twitter, alone @ECTRIMS reached a total audience of 2.9 million, with 6.2 million impressions worldwide (stats from @ECTRIMS). Walking along the halls of Le Palais des Congres de Paris (venue), I felt a sense of awe and wonder. With the conference now over, the keynote messages will soon move from memory to history; immortalized in reports, seminars, blogs and tweets the world over.

Every year there are a vast number of posters to review, and this year was no different. They were of a very high quality this year, each adding more to our knowledge and our understanding of MS than ever before. Below, I have tried to pick out some of the quirky ones for you!!!

1) BENIGN MS

Does it truly exist?; defined as those with an expanded disability status scale (EDSS) of  <3 from symptom onset after 10, 15 or 20y.

S. Marinez-Yelamos's team [Hospital Universitari de Bellvtage-IDIBELL, L'Hospitalet de Llogregat, Spain]: "Benign multiple sclerosis: does the initial outcome predict a favorable long term evolution?"

Of 485 PwMS evaluated in 1996, 82 were felt to be benign. At 2006 (taking into account those lost to follow-up) 62 PwMS were evaluated of which 51 had benign MS. They found that for every 10y of MS evolution, a reduction of 20% of patients with benign MS was detected.

M. Amato's team [University of Florence, Italy]: "Cognitive impairment can help to predict long-term disease course in benign multiple sclerosis patients: a 12 year follow-up study"

in 63 PwMS with EDSS ≼3 and disease duration of ≽15y cognitive function was assessed. By the end of follow-up, 20 were noted to be no longer benign with regard to EDSS score. Cognitive impairment was detected in 20. Those who were no longer benign had higher mean T1 lesion volumes. When clinical and MRI parameters were looked at, T1 lesion volumes, number of cognitive tests failed, longer disease duration were related to no longer benign status at follow-up.

2) RISK FACTORS IN MS

T. Olsson's team [Karolinska Institute, Sweden]: "Concussion in adolescence and multiple sclerosis risk"

Trauma has been hypothesised to initiate MS -related autoimmune processes, through proliferation of myelin-antigen-specific T cells (evidence from experimental works).

They used concussion as a marker of traumatic brain injury, and looked to see whether concussion in childhood (birth-adolescence) or adolescence (11-20y) was associated with an elevated risk of MS after the age of 20. Their analysis revealed that it was concussion at adolescence that raised the risk of MS, with evidence that multiple episodes of concussion conferred a greater risk. Moreover, a longer duration of hospital admission, indicating more severe trauma, was associated with a greater risk of MS. Whereas, limb fractures were not associated with MS risk (see Figure).

C. Bernstein's team [University of Manitoba, Canada]: "Increased incidence of psychiatric disorders five years before diagnosis in multiple sclerosis"

Prevalence of psychiatric comorbidities (anxiety, depression, bipolar disorder) is higher than expected in MS, but little is known of their incidence before diagnosis.

Between years of 1989-2012 all PwMS in Manitoba matched to a cohort from the general population.  They found that the incidence of psychiatric disorders was higher in MS than controls pre-diagnosis (depression relative risk [RR] 1.18, anxiety RR 1.09, bipolar RR 1.16). The occurrence of this is found as early as 5y before MS diagnosis (see Figure). They suggest that there may be a prodromal period for MS in which inflammation has developed sufficiently to precipitate psychiatric disorders but not the clinical symptoms of MS.

M. Tintore's group [Cemcat, Spain]: "Impact of body size on MS risk and prognosis: results from the Barcelona CIS cohort"

Obesity in young women has been associated with an increased risk of MS, but little is known about the prognosis.

They studied the possible association between perceived body size at menarche (underweight, normal or overweight) with the age at CIS (first demyelinating event) and the following outcomes: time to second attack (i.e. MS diagnosis) and time to EDSS 3. 518 women completed the survey and 5.6% were overweight at menarche. This was associated with a younger age at CIS, and there was a trend towards higher risk of disability accrual, although this needs to be confirmed in future studies.

3) HORMONES

Correia's team [Hospital Egas Moniz - Centro Hospitalar Lisboa Ocidental, Portugal]: "The influence of menopause in multiple sclerosis course"

The impact of menopause on the MS disease course is unknown, although it has been noted previously in PwMS after menopause there was faster disability progression and worsening MS symptoms in studies.

They looked at 34 women aged 45-55, post-menopausal, with a diagnosis of MS at least 2y before menopause. Only annualized relapse rate seemed to be influenced by menopause, and the effect was favourable, with a decrease in the number of relapses. After menopause, the disability increase (i.e. the rate of EDSS change) was comparable to the pre-menopausal period. Of course, these findings need to be confirmed in larger prospective studies.

M. Mavi's team [Karadeniz Technical University & Jasem Laboratory System and Solution, Turkey]: "Methylprednisolone concentrations in breast milk and serum in patients with multiple sclerosis treated with IV pulse methylprednisolone"

Women with MS are at an increased risk of relapses in the postpartum period. There is little data available about the concentrations of IV MP in breast milk and exposure to infants as a result. The study looks at this in 21 breastfeeding MS women. They found that the concentration of MP transferred into the breast milk was small and the infant exposure would be very low for a breastfeeding mother an hour after infusion. Mothers can choose to wait 2 to 4h to limit further exposure (see figure).

4) PAEDIATRIC MS

K. Kotulska's team [Children's Memorial Health Institute, Poland]: "Anti-JC virus antibodies in paediatric multiple sclerosis patients".

Immunosuppressants are becoming very relevant to paediatric MS, and therefore it is important to understand JCV prevalence in this population.

Using the Stratify-JCV test they studied JCV seropositivity in 106 diagnosed with MS/CIS and other neurological conditions (controls) in the paediatric population. They found that the percentage of JCV-seropositive in MS as well as controls was comparable (~ 50.9%) to that seen in adults. Therefore, JCV status may influence the choice of DMTs in this group.

J. Gartner's team [University Medical Center Gottingen, Georg August University Gottingen, Germany]: "Treatment of highly active multiple sclerosis in paediatric patients"

Little is known about the management of highly active paediatric cases of MS.

They studied the response to natalizumab and fingolimod and found that the two treatments resulted in a significant reduction in annualized relapse rate (95% in natalizumab and 75% in fingolimod), new T2 lesions (97% in natalizumab and 81% in fingolimod) and enhancing lesions (97% in natalizumab and 93% in fingolimod) - see figure. This is similar if not better than what's seen in adult MS.

ProfG    

Today at ECTRIMS: Barts MS Google Hangout

This afternoon Mouse Doctor and Neuro Doc Gnanapavan broadcast live from the MS Paris ECTRIMS ACTRIMS conference for a one hour Google Hangout. This was your opportunity to listen to the summary of what they've seen but also respond to questions posted by readers of this blog.

You can watch a recorded video of the event here: https://www.youtube.com/watch?v=hBiFr3f0GlY

Image above of the broadcast team, supported by Dr M&M putting in some thorough preparations.

Conference programme here: https://www.ectrims-congress.eu/2017/scientific-programme/scientific-programme.html

Today: The Burning Debate

Join us today for the Burning Debate at ECTRIMS

The aim of the Burning Debate is to get two top researchers to discuss a burning topic from the field of MS Research. This year the topic is: Rumble in the Jungle: B cells vs. T cells. Our two speakers will argue over whether MS is a T-cell mediated disease and if B-cells are therefore less important. 

The debate will take place on Thursday 26th October from 3.45-4.45pm in Hall D. For folks in the UK, we will be tweeting from the debate athe 2:45pm 

We have Dr David Hafler arguing FOR the motion and Dr Stephen Hauser arguing AGAINST. The debate will be chaired by Dr David Wraith. Unfortunately the debate will not be live streamed, but we will be covering it on Twitter where you can follow the discussion by searching for the hashtag #burningdebate. A twitter feed will be projected in the debate room, so any comments or questions will be voiced. 

At the end of the debate, the BartsMSblog twitter account will post two tweets, one FOR the motion, one AGAINST. The tweet that is re-tweeted the most will win the debate. A secondary aim of the debate is to encourage clinicians to use Twitter in their professional capacity. 

Cell lysis and anti-trafficking treatments in MS

My first presentation from Paris. A talk on DMTs that target cell trafficking and cell lysis mechanisms. 

ProfG    

ECTRIMS2017 Is Here! What do you want us to report on?

The Programme (UK)/Program (US) is online (CLICK HERE) The abstracts are now live

Come and see us at the Google Hangout 15.45-16.45 Central European Summer Time = GMT + 2 h) with NDG and ProfB your hosts to answer your questions and to report on what's "Hot" and What's "Not"....OK, they won't waste their time, and your time, with the what's not :-).

If you miss the Hangout some of us can be found on the ClinicSpeak and DigestingScience stands. 

Prof G and Barts MS win healthcare awards

The Barts MS team will go to ECTRIMS this week with a spring in our step. On Saturday night, we attended the Zenith Global Healthcare awards and won a Team Recognition award. Not only this, but Professor Giovannoni was awarded with a Lifetime achievement award. 

We were nominated by Trishna Bharadia, a (superstar) patient ambassador that we’ve known and worked with for a number of years - thank you so much Trishna for your nomination. 

At the award ceremony we were amongst some inspiring healthcare professionals who dedicate their lives to furthering treatment and care for their patients.

Although not all of the team could be there to pick up the award, it is for everyone! The research team in the lab, the nursing team on 11D, the students and trainees who work with us throughout the year and also for you, our blog readers. Your continued support and encouragement keeps us on the right lines. 

We look forward to a productive week at the ECTRIMS conference where we look forward to sharing MS Research news with you. Check out what we’re going to be doing, and don't forget to tune into our Hangout on Friday afternoon.

JCV index in Natalizumabers - does anyone really understand this?

Are you on natalizumab? This paper will be of interest to you. 


J Neurol. 2017 Oct 16. doi: 10.1007/s00415-017-8643-4. [Epub ahead of print]

Natalizumab therapy is associated with changes in serum JC virus antibody indices over time.

Peters J, Williamson E.


To examine changes in anti-JC Virus (JCV) index measurements over time in multiple sclerosis (MS) patients to better understand this test, which is used in assessing risk of progressive multifocal leukoencephalopathy (PML) with natalizumab. We aim to describe and compare seroconversion rates, variability of JCV antibody index values, and changes in index values over time between patients on natalizumab therapy and patients naïve to natalizumab. Anti-JCV index values are used to help decide whether to start, continue, or stop treatment. Assessing how index values vary over time is interpreted to allow a patient's risk of PML to be better characterized. Retrospective analysis was conducted using records of patients with multiple JCV antibody index measurements exposed to therapy with natalizumab (N = 150) or not (N = 145). Rates of seroconversion, variability of indices, and changes in index values over time were calculated and compared. Patients on natalizumab who were initially JCV antibody negative seroconverted at a significantly higher rate than patients naïve to natalizumab (23.9 vs. 9.1%, p < 0.01). Variability of anti-JCV indices was also found to be significantly higher for patients on natalizumab (p < 0.05). Patients on natalizumab additionally trended towards a larger increase in index values over time. Therapy with natalizumab was associated with higher rates of seroconversion and greater anti-JCV index variability, suggesting that therapy with natalizumab may influence this test used to assess risk of treatment with it.

Biogen's (BIIB) market performance has been outstanding this year (12.4% share price rise vs. 12.4% growth of the Medical-Biomed/Genetics over the same time frame; source: Zacks Equity Research); and is expected to beat expectations further when it reports its Q3 earnings today (Oct 24th). In the MS field, Biogen's name is synonymous with Tysabri (Natalizumab), one of the best drugs available in its class. However, Tysabri has a murky past, and was withdrawn following the first few cases of PML (progressive multifocal leukoencephalothy, secondary to JCV infection). Following a review of safety information by regulatory authorities, the drug was returned to the US and EU market with contingencies. The updated risk estimates for PML on Tysabri are believed to be small, and lower than previously estimated for JCV antibody index values of 0.9 or less. The JCV antibody index test is therefore invaluable, the advantage for Biogen is the value of the JCV antibody test vis-à-vis other drugs, which lack an objective stratification test.

The test, however, is not without its grating flaws - the biggest being that you cannot reliably predict the long term risk of PML at an individual level. Longitudinal evaluation of individual longitudinal JCV antibody index values will undoubtedly provide more information, particularly about the presumed cut off's of 0.9 and 1.5 utilised in the test. And then there is the unknown, known; the seroconversion rate from negative to positive result of 13% (at 18 months follow up) and rarely vice versa - prompting the EMA to suggest frequent testing. Over the past two years, there have also been concerning data about a significant increase in JCV antibody index over time on treatment. The clinical relevance of this finding is as yet unknown.

Peters et al., above aimed to characterize changes in the JCV antibody index overtime from the University of Pennysylvania (USA; previous similar work have come from Europe) in natalizumabers versus those not on treatment. The bottom line is that the rate of seroconversion (those going from negative to positive) was higher in those receiving Tysabri than not (24% vs 9%), with annualized rates of conversion of 17% on Tysabri vs 7% not on Tysabri. Moreover, the percentage of higher order magnitude change (>0.5) between sequential tests was seen in those on Tysabri vs those not on it.

The key here is that as the authors point out, clinical decisions are often based on these results and it would be difficult to contemplate a scenario where a positive JCV result will not influence treatment decision making. But the big questions are whether the changes in JCV antibody index values over time also increase the risk of PML, and what are the mechanisms whereby Tysabri leads to this change in index values? I believe it is in the best interests of the MS community to get to grip with this problem as soon as possible. For a while, it seemed these findings were a peculiarity of certain countries but it is now clear that this may be a global phenomenon.

MS in the news today

You may have seen this BBC news article today about two pwMS. One of which had a well-planned trip to Switzerland to end his life. After meeting a local woman with MS he appears to have a new outlook and has postponed his trip to Switzerland indefinitely.

(Image is a screen shot of the article on the BBC website)
http://www.bbc.co.uk/news/disability-40042731

The really interesting thing here is that the main way in which the woman has changed his views is through helping him find access to the services he is entitled to. I think this serves as an important reminder that many pwMS do not access all the care, facilities and services that are available to them. If you have such concerns, there is plenty of information and advice online, including the MS society website: https://www.mssociety.org.uk/ms-support

Or maybe people have their own tips to share on accessing services?

Programmed Death 1 disappears and leaves EBV to trigger Activity

Now that we know what PD-1 is, it's time to look at this paper

Cencioni MT, Magliozzi R, Nicholas R, Ali R, Malik O, Reynolds R, Borsellino G, Battistini L, Muraro PA. Programmed death 1 (PD1) is highly expressed on CD8+ CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus. Immunology. 2017. doi: 10.1111/imm.12808. [Epub ahead of print]

We know that virtually everybody with MS is infected with Epstein Barr Virus. Most people are as it is very common in humans.

We get infected through saliva. It then infects B cells and makes them proliferate like crazy and turn into memory B cells. The virus then shuts down and hides in the B cell, where it is not going to do much damage. But every now and then the virus activates, and sheds live virus. The immune response recognises the virus and kills the infected B cells and things all quieten down.

In Australia they are making T cells that will kill EBV, based on a very small, unreproduced study stating that it may influence the activity of MS.

MS and the CD8 that attack anti-EBV viral T cells 

A subset of CD8 cells express CD57  - which is
an enzyme - (Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1-B3GAT1) that recognises sugar molecules and is involved in the destruction of chemicals, and I guess viruses.

In healthy individuals they killed EBV infected cells but in stable MS these cells also expressed PD-1, suggesting that they had become immunologically exhausted so they were not killers, but in active MS the CD8 cells had PD-1 and were killing. 

This suggested that when MS is stable they do not control the EBV infection, maybe because it is at a silent stage, but this may enable the re-activation of virus, which could trigger disease. 

Is the disease caused by the attack of virus?. 

The question is, is it a cause or really a consequence?

ABSTRACT

Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8+ CD57+ T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8+ CD57+ T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8+ CD57+ T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

What is programmed death 1?

This is about a protein expressed by the immune system. It is a protein involved in limiting the immune response.

This post is going to be hard to understand unless you click on the links in this post and do some reading.

PD-1 is known as an immune checkpoint, which is a molecule in the immune system that either turn a signal (co-stimulatory molecules) or turn down a signal.

However, you need to know this to read the next post.

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There are many other immune checkpoints:

Four stimulatory checkpoint molecules are members of the 

tumor necrosis factor (TNF) receptor superfamily - 

CD27. This molecule supports antigen-specific expansion of naïve T cells and is vital for the generation of T cell memory. CD27 is also a memory marker of B cells. 

CD40. This molecule, found on a variety of immune system cells including antigen presenting cells This is expressed on B cells

CD122. This molecule, which is the Interleukin-2 receptor beta sub-unit, is known to increase proliferation of CD8+ effector T cells. This is expressed on memory B cells

OX40. This molecule, also called CD134, has OX40L, or CD252, as its ligand. Like CD27, OX40 promotes the expansion of effector and memory T cells, however it is also noted for its ability to suppress the differentiation and activity of T-regulatory cells, and also for its regulation of cytokine production. It is only upregulated on the most recently antigen-activated T cells within inflammatory lesions.This is expressed by B cells

This may be relevant to the effect of anti-TNF that can make MS worse as it shows that TNF is very important in the life and Dead of B cells. Anti-TNF makes memory cell survive, is this why it is bad for MS. However, it could also kill other B cell populations.

There are another two stimulatory checkpoint molecules that are members of the CD28 family:

ICOS. This molecule, short for Inducible T-cell costimulator, and also called CD278, is expressed on activated T cells. Its ligand is ICOSL, expressed mainly on B cells and dendritic cells.)This is expressed by B cells.

CD28. This molecule is constitutively expressed on almost all human CD4+ T cells and on around half of all CD8 T cells. Binding with its two ligands are CD80 and CD86, expressed on dendritic cells, prompts T cell expansion.  This is expressed on memory B cells.

There are inhibitory check points:

A2AR. The Adenosine A2A receptor 

B7-H3, also called CD276,

B7-H4, also called VTCN1, 

BTLA. This molecule, short for B and T Lymphocyte Attenuator and also called CD272. 

CTLA-4, short for Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152

IDO, short for Indoleamine 2,3-dioxygenase, is a tryptophan catabolic enzyme with immune-inhibitory properties. 

KIR, short for Killer-cell Immunoglobulin-like Receptor, is a receptor for MHC Class I molecules on Natural Killer cells. Bristol-Myers Squibb is working on Lirilumab, a monoclonal antibody to KIR.

LAG3, short for Lymphocyte Activation Gene-3, works to suppress an immune response by action to Tregs^[ as well as direct effects on CD8+ T cells.^[36] Bristol-Myers Squibb is in Phase I with an anti-LAG3 monoclonal antibody called BMS-986016.

PD-1, short for Programmed Death 1 (PD-1) receptor, has two ligands, PD-L1 and PD-L2. 

TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, expresses on activated human CD4+ T cells and regulates Th1 and Th17 cytokines.^[

VISTA (protein), Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on bone marrow-derived cells

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Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a cell surface receptor that plays an important role in down-regulating the immune system and promoting self tolerance, so you block autoimmunity by suppressing T cell inflammatory activity. PD-1 is an immune checkpoint and guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).

So PD-1 inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

Over-expression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion 

T-cell exhaustion is the progressive loss of T-cell function. It can occur after infections.

Temperature

Twists and turns in the MS research trails

Hi, I am Mark Baker, a university lecturer, and I teach neuroscience to medical and science students at QMUL. I am also a member of Barts MS and have maintained an interest in MS over many years. I have been involved in research investigating the mechanisms of excitability in normal and diseased nerve, involved in pain signalling and the effects of demyelination. What do I mean by the mechanisms of excitability? I mean that amazing characteristic that allows some specialized cells to generate impulses that are used for signalling, so in nerve this characteristic allows us to feel things and work our muscles.

Fundamental shifts

MS is a disease targeting nerve fibres in the brain. When I first became interested in what was going on in MS, as a student, the condition was thought of as mainly a demyelinating disease, but no longer. Well within my lifetime, the understanding has evolved, and MS is now thought of a demyelinating disease, but also a neurodegenerative disease. The emphasis now has changed. 

When this kind of thing happens it is important for science and medicine, and ultimately patients, because light can be shed into what were darkened corners and questions asked that had not been asked before. This whole process of discovery is about real people in a lab or clinic somewhere asking questions and noticing something perhaps for the first time, and then reporting it, but the question asked arises out of the knowledge base, at that time, and I guess it is important to appreciate that. I can think of another example in MS research when ideas have fundamentally changed, and of course, there may be others.

Temperature-dependent symptoms

An idea that was of some importance in the 1980s developed directly from the known temperature-dependent symptoms in MS. Many people reading this post will have temperature dependent symptoms that are serious enough for them to have to try to keep out of hot places, for example. 

One result that is not disputed and had stemmed from the basic science of physiology was that the nerve impulse got briefer when the temperature increased, and what was shown in elegant experiments was that when the myelin was damaged in nerve, having a briefer impulse made the impulse more likely to fail. 

This failure of impulse conduction along nerves in the brain and spinal cord with raised temperature, following demyelination, is the classical explanation for the appearance of new symptoms and exacerbation of existing ones with a rising core body temperature. 

One way of trying to do something about this was to try to make the nerve impulse longer by using drugs that block proteins in nerves called potassium channels. There have been several clinical trials and potassium channel blockers are still under investigation to determine any useful effects. 

The irony is that the widening of nerve impulses that provided the way into this area of research cannot be the basis of the useful therapeutic effect under investigation now, because the concentration of the drug that is necessary and safe for beneficial effects on walking is far lower than that required to make the nerve impulse longer.

Comments please:

Do you have temperature-dependent symptoms? 

If so, what do you do about them? Have you found any strategy or treatment effective?

Let me know in the comments 

What else you would like to know about the basic science behind MS? 

Thank you!