Wednesday, 31 May 2017

World MS Day

Since 2009 the last Wednesday in May marks World MS Day, raising awareness and facilitating support among MS organisations around the Globe. The Day is coordinated by the Multiple Sclerosis International Federation (MSIF). This year's theme is #Life with MS.

A number of events across the Globe mark the day.  I will be in Belém near Lisbon at an event organised by the British Medical Journal to discuss MS brain health matters, with a focus on treatment at more advanced disease stages. Please note the MSIF has recently adopted *access to disease modifying treatments* among their five key strategic aims

With your support BartsMS will hopefully be able to make a difference in terms of access too, so please remember to give to our new charity if you can.

I will post my slides after the event, however if you're keen you can register for live streaming (unless you happen to be in Lisbon today in which case you're welcome to join the action in person!).

World MS Day: The event in Belém is supported by an unrestricted educational grant from F. Hoffmann-La Roche and Roche Farmacêutica e Química.  
DrK: multiple (see under "about")

World MS Day

Today is World MS day
A message from BartsMS

P.S. It's really only 4 minutes long....Have a look
You can view ProfG and DrK through his Rose-tinted Glasses.

To get any new initiative off the ground you often need pilot data and this takes resource. We have launched BartsMS Charity as vehicle that may allow that to happen in a more timely manner. 
It may allow us to tackle your research questions, as a 2-way process, if they are appropriate.
Please note BartsMS Charity is not a stand alone charity, but a dedicated fund held by Queen Mary University of London, which has charitable status
We chose this solution - rather than starting a charity from scratch - to keep any associated administrative cost at a minimum. Indeed, they are currently zero, i.e. all donations to BartsMS will go 100% towards the objectives we have outlined.

If people like what we do, then this is a place they can go, to help us to help people with MS.
Just go to the drop down menu on this page and chose destination "01. Barts MS". Any amount will help!

T regs

Barsheshet Y, Wildbaum G, Levy E, Vitenshtein A, Akinseye C, Griggs J, Lira SA, Karin N. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A. 2017. pii: 201621280.

The current study identifies CCR8+ regulatory T cells (Treg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of Treg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating Treg cells. 

The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by Treg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8+ regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in Treg cells was further dissected through adoptive transfer studies using CCR8-/- mice. Collectively, we demonstrate the pivotal role of CCR8+ Treg cells in restraining immunity and highlight the potential clinical implications of this discovery.

Some bedtime reading for those interested

Tuesday, 30 May 2017

World MS Day tomorrow. Introducing #BartsMS-Charity TODAY

I trust most of you are aware tomorrow is:
including this event:

On this occasion we decided to announce a project we've been pondering over for some time. 

It is:

Don't worry the logo will look much nicer once our design department are ready:-)
What is the objective of BartsMS Charity?

To enable Barts-MS to undertake hard-to-fund, or to prime important, MS research projects.

Our first key objective is to enable every person with MS access to effective disease modifying therapies (DMT), regardless of their disability and their economic background.
Evidence suggests that DMT:
(i)          Should be started as early as possible, irrespective of the economic setting within which people live
(ii)         Is effective in many pwMS even at a more advanced stage of their disease
Many pwMS now have access to effective DMT. However, two important groups are excluded:
(i)          pwMS with a high level of disability, for example, wheelchair users
(ii)         pwMS at any stage of their disease who are typically living in lower and middle income countries (LMIC) or have poor access to DMT because they are not covered by healthcare insurance. 

Do we need yet another MS charity?
Both in resource-restricted health care settings, and from a certain level of disability onwards, where cost-effectiveness guidelines lead to limited access, the cost of DMT represents a significant hurdle for access.
The use of ‘off-label’ drugs has the potential to enable significant change to the problem of access, however doctors are often either not aware of these drugs or they may be concerned about their use in strongly guideline-driven healthcare environments.
Some doctors are also concerned about the evidence base and their personal risk of litigation in case of adverse events.
Funds to support proof-of-concept studies as well as larger clinical trials are limited as off-label DMT candidates are generic drugs, i.e. off-patent, with only minor - if any - incentives for drug companies to engage.
Several MS charities provide a different proposition, however do not specifically address the need to focus on the clinical advancement and availability of DMT for all pwMS.
What will BartsMS Charity do?
The Charity intends to raise awareness of the utility of currently available DMT at any disease stage and support the development of new DMT and to help generate the required evidence to support the use of these DMT.
The Charity will therefore raise funds to:
(i)           Perform enabling work and support pilot studies into promising new DMT and
(ii)         Get the word out to patients and practitioners alike that we urgently need both investment in new treatments and a decisive strategy to make DMT more widely available.
BartsMS Charity will tie together and support several themes many of you are familiar with, including our initiatives #ThinkHand, #OffLabel prescribing, #ClinicSpeak, the #CharcotProject and #CHARIOT-MS.
Please note BartsMS Charity is not a stand alone charity, but a dedicated fund held by Queen Mary University of London, which has charitable statusWe chose this solution - rather than starting a charity from scratch - to keep any associated administrative cost at a minimum. Indeed, they are currently zero, i.e. all donations to BartsMS will go 100% towards the objectives outlined above. Just go to the drop down menu on this page and chose destination "01. Barts MS". Any amount will help!
You can also follow us on Twitter.
Thanks for your support!

Life's a beach

Eur J Neurol. 2017 Jun;24(6):851-857. doi: 10.1111/ene.13301.

No relevant impact of ambient temperature on disability measurements in a large cohort of patients with multiple sclerosis.

Stellmann JP, Young KL, Vettorazzi E, Pöttgen J, Heesen C.



Many patients with multiple sclerosis (MS) report a worsening of symptoms due to high ambient temperatures, but objective data about this association are rare and contradictory. The aim of this study was to investigate the influence of ambient temperature on standard clinical tests.


We extracted the Symbol Digit Modality Test, Nine Hole Peg Test, Timed 25 Foot Walk (T25FW), Timed Tandem Walk, Expanded Disability Status Scale (EDSS) and quality-of-life items on cognition, fatigue and depression from our clinical database and matched them to historical temperatures. We used linear mixed-effect models to investigate the association between temperature and outcomes.


A total of 1254 patients with MS (mean age, 42.7 years; 69.9% females; 52.1% relapsing-remitting MS, mean EDSS, 3.8) had 5751 assessments between 1996 and 2012. We observed a worsening in the T25FW with higher ambient temperatures in moderately disabled patients (EDSS ≥ 4) but not in less disabled patients. However, an increase of 10°C prolonged the T25FW by just 0.4 s. Other outcomes were not associated with ambient temperatures.


Higher ambient temperature might compromise walking capabilities in patients with MS with a manifest walking impairment. However, effects are small and not detectable in mildly disabled patients. Hand function, cognition, mood and fatigue do not appear to be correlated with ambient temperature.

The UK is infamous for its non-existent summers, hence the saying 'enjoy your one week of summer'. Like most UK holiday-goers I chase the sun, but it goes without saying that I am also glad of the few weeks when its finally hot enough to complain about how hot it is back home! Granted, not a view shared by many PwMS. In one survey of 2500 PwMS, 70% reported worsening of MS symptoms after heat exposure (Simmons RD et al. Mult Scler 2004 p202).

The eponymous name for this phenomenon is 'Uhthoff's phenomenon', described by Wilhelm Uhthoff in 1890 and is thought to be due to reduced conduction of nerve impulses in demyelinated nerves during high temperatures.

In this study, Stellmann et al. looked at various historical assessments in PwMS (1254 in total) in their clinical database and matched the date of each persons visit to the daily temperature on that day (at 1400h from the German weather service Deutscher Wetteerdienst).

They found that the EDSS score was not altered by temperature changes. However, for mobility tests the Timed 25 foot walk was influenced by temperature in those who were more disabled (i.e. EDSS>3.5), where each 10℃ rise in temperature prolonged the walking times by 0.35s (see figure below) or approx 4%. Interestingly, however, neither Nine hole peg test (which tests upper limb function) or cognition as measured by the Symbol digit modality test were influenced by temperature. This is good to know, although there is such a phenomenon called 'heat stress' which office workers are know to suffer from during the peak of summer.

The question is whether the lack of strong associations in this study is secondary to under powering (i.e. not enough people). The study group did analyze in around 800 patients recurrent visits where the temperature varied quite significantly (on average 14.5℃), but again found no association between the measures and temperature. Which begs the question, what makes walking or more pertinent the nerves supplying the legs more susceptible to temperature than the rest of the nervous system? Is it simply a length dependent phenomenon?

Figure: Estimated effects on T25FW performance from the linear mixed-effect model. (a) Disease duration; (b) gender; (c) age; (d) temperature and Expanded Disability Status Scale (EDSS).

CD44 is it all about the Gut?

There is a real move to suggest that the influence of the immune system is because of bacteria in the gut. Every science meeting has a session on it.

The following is one example, but as I get airbrushed out of history I am not so sure it is all so simple

Chitrala KN, Guan H, Singh NP, Busbee B, Gandy A, Mehrpouya-Bahrami P, Ganewatta MS, Tang C, Chatterjee S, Nagarkatti P, Nagarkatti M.CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice. Eur J Immunol. 2017 May 23. doi: 10.1002/eji.201646792. [Epub ahead of print
Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of experimental autoimmune encephalomyelitis (EAE), a murine (They mean mouse) model of multiple sclerosis (I bet the people doing marmoset studies would like to think they do EAE studies). In the current study, we determined whether these effects resulted from an alteration in gut microbiota in CD44KO mice (CD44 is a molecule on white blood cells that gets upregulated in memory T cells. This binds to hylauronic acid which gets deposited in lesions).

Feacal transfer from naïve CD44KO but not CD44WT mice, into EAE-induced CD44WT mice, led to significant amelioration of EAE. 

High-throughput bacterial 16S rRNA gene sequencing and biochemical analysis, revealed that EAE-induced CD44KO mice showed significant diversity, richness, and evenness when compared to EAE-induced CD44WT mice at the phylum level, with dominant Bacteroidetes (68.5%) and low Firmicutes (26.8%). 

In conclusion, our results demonstrate that the attenuation of EAE seen following CD44 gene deletion in mice may result from alterations in the gut microbiota. Furthermore, our studies also demonstrate that the phenotype of gene knock-out animals may be shaped by gut microbiota

Monday, 29 May 2017

MS isn't caused by antibodies to myelin

Prineas JW, Parratt JDE. Multiple sclerosis: Serum anti-CNS autoantibodies. Mult Scler. 2017:1352458517706037.

BACKGROUND: It is uncertain whether there are autoantibodies detectable by indirect immunofluorescence in the serum of patients with multiple sclerosis (MS).
OBJECTIVE: To determine whether there are anti-central nervous system (CNS) autoantibodies detectable by indirect immunofluorescence in the serum of MS patients.
METHODS:Sera and in some cases cerebrospinal fluid from 106 patients with multiple sclerosis, 156 patients with other neurological diseases, and 70 healthy control subjects were examined by indirect immunofluorescence using cryostat sections of rat cerebrum fixed by perfusion with paraformaldehyde.
RESULTS:Autoantibodies were detected that recognized more than 30 neuronal, glial, and mesodermal structures in 28 of 106 MS cases. Most were also detected in patients with other related and unrelated neurological diseases and several were also found in healthy controls. Novel anti-CNS autoantibodies recognizing particular sets of interneurons were detected in both normal controls and in subjects with CNS diseases.
INTERPRETATION: Serum anti-CNS autoantibodies of diverse specificities are common in MS patients. The same anti-CNS autoantibodies are not uncommon in patients with other neurological diseases. The findings provide no support for the proposition that myelin breakdown in MS is caused by exposure of intact myelin sheaths or oligodendrocytes to a pathogenic serum anti-myelin or anti-oligodendrocyte autoantibody.

The works of Dr Prineus have cast doubt on whether MS is a problem of immune cells entering the CNS to cause damage or whether damage in the CNS cause immune cells to enter. Now they say there is no evidence that exposure of myelin to pathogenic antibodies, so the mechanism must be something else. Maybe implying the damage starts inside the CNS.

It was wondered whether there are antibodies to myelin protein and tissue structures in the blood of pwMS. The answer is simple do some reading the answer is clearly yes...they can be there, and it depends on which study you read to say how people respond.
However, there is disagreement. The suggestion that 50% pwMS have antibodies to the Kir4.1 potassium channel has been disproved,  over and over and over and over again. He's a new one

Marino M, Frisullo G, Di Sante G, Samengo DM, Provenzano C, Mirabella M, Pani G, Ria F, Bartoccioni E. Low reliability of anti-KIR4.1 83-120 peptide auto-antibodies in multiple sclerosis patients. Mult Scler. 2017 1:1352458517711275
 However, if you read, it is evident that the antibodies detected are often not against myelin. They are often against targets inside the cell. In this study there were thirty structures targeted

The question was are they detectable by immunoflourescence. So you bind antibodies in the serum to a protein in this case in a rat brain and them detect the human antibody by a fluorescent ant-human immunoglobulin = antibody and detect it with an ultraviolet or laser light.  Do they find any...yes they do. 

This is hardly surprising given the many, many claims in the literature. The fact that they are detected by many other methods is irrelevant. 

Most recently people have taken the genes of B cells from MS, including the CNS and have cloned the antibody molecules and they have looked what they are binding to and the answer again is not myelin. 

In this study they find about 30% of pwMS with antibodies that bind to the CNS of a rat. But they found similar things in people who did not have MS. There will likely be more that would bind to the CNS of someone with MS.

First if the antibody targets human proteins they may not react with the rat protein, second the protein may not be exposed on a surface so that it can be bound by the antibody in the tissues seections. Then the fixation method may destroy the target. There are other issues.

Many years ago (1995) a study to see what MS T cells reacted in the MS brain was not myelin, but a protein called alpha B crystallin a cell-stress related (small heat-shock) protein. This would not be present in the rat brain used for screening. This is because there would be no stress in the health rodent brain just as there is no alpha B crystallin in the healthy human brain. 

We did a study many years ago where we sensitized animals to alpha B crystallin and then saw no disease except in one animal and this animals was expressing alpha B crystallin in oligodendrocytes.

However looking in the blood of a mouse a few months after you have induced disease with a known protien, will lead to the detection of antibodies to lots of targets. This is because as damage occurs cell contents are liberated and antibody responses to these are detected. Do this in humans a few years or decades after it all started and it may be unintelligible, just as occurs here and in the many papers on this subject area.

I don't buy the logic that MS is an autoimmune disease to myelin basic protein,. This current concept is so weak and has more holes in it than a piece of Swiss Cheese. It was made up by short-sighted immunologists who could only make and test water-soluble major myelin proteins. Many people may disagree with me on this one.

My answer is do some reading without blinkers.

Sunday, 28 May 2017

Damaging Cholesterol

I recently asked how can statins work in secondary progressive MS.

In the absense of any real insight, I came up with a few ideas one of which was involving the cholesterol pathway to control/induce nerve damage

Bezine M, Debbabi M, Nury T, Ben-Khalifa R, Samadi M, Cherkaoui-Malki M, Vejux A, Raas Q, de Sèze J, Moreau T, El-Ayeb M, Lizard G. Evidence of K+ homeostasis disruption in cellular dysfunction triggered by 7-ketocholesterol, 24S-hydroxycholesterol, and tetracosanoic acid (C24:0) in 158N murine oligodendrocytes. Chem Phys Lipids. 2017 pii: S0009-3084(17)30011-7

Imbalance in the homeostasis of K+ ions has been reported to contribute to the pathogenesis of neurodegenerative diseases. 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC), and tetracosanoic acid (C24:0), often found at increased levels in patients with Alzheimer's disease and Multiple Sclerosis, are able to trigger numerous nerve cell dysfunctions.  We therefore studied the impact of 7KC, 24S-OHC, and C24:0 on 158N mouse oligodendrocytes, and determined their impact on K+ homeostasis. The effects of 7KC, 24S-OHC and C24:0 on lipid membrane organization and membrane potential were examined. 7KC, 24S-OHC and C24:0 induced changes in lipid content and the cytoplasmic membrane. These events were associated with increased [K+]i. The positive correlation between [K+]i and cell death supports the potential involvement of K+ in 7KC-, 24S-OHC-, and C24:0-induced cytotoxicity.
Cholesterol can be oxidised to become agents called oxysterols (see the diagram above). These can bind to cells including oligodendrocytes and they can block the action of a number of ion channels including some potasium channels and also potassium and sodium exhangers. These cause a rise in the concentration of potassium within the cell, which eventually trigger the entry of calcium and the suicide of the cell. This is a mechanism of inducing cell death in oligodendrocytes as shown here, but probablyother cell types as well

Statins will get rid of the cholesterol and in doing so will remove oxysterols and so this damaging mechanism will not occur. Perhaps getting rid of some of the potassium from inside the cell may be a route to countering this problem. I could suggest how this appraoch may be achieved but that's another post.

Saturday, 27 May 2017

GABA and Remyelination-Its Confusing I know but no cause for concern

Yesterday I caused a bit of concern by a post on myelination as a GABA (inhibitory nerve transmitter) blocker stimulated developmental myelination, so people were worried about their GABA receptor stimulating drugs. Would they block repair? Answer is I do not definitively know but suspect not.

In contrast there could be implications that stimulation of GABA could save nerves. Again we don't have the data.

I will try explain a bit, but it is very, very complicated.

First things first, the report of GABAergic control of myelination is based on developmental myelination (myelinating nerves from the first time), and as the docs from Cambridge/Edinburgh have shown remyelination may not be the same process as developmental myelination.

Next it is far more complex than just GABA. What else has to be stimulated?

We have already been told that the oligodendrocyte precursor cells get stimulated by glutamate (excitatory nerve transmitter). This transmits their function via activity on glutamate receptors. Here there are lots of types, over twenty receptor genes.  There are three main ionotrophic (opens channels for electrically charged (ion) sodium calcium or potassium) subtypes AMPA, Kainate and NMDA binding subtypes

Myelination first acts via the AMPA sensitive variants, then their influence stops whilst the NMDA-sensitive subtypes come into play. This process will be influenced by the GABA receptors. This stimulates developmental maturation of the oligodendrocyte precursor cell and myelination of un-myelinated nerves. During this process the glutamate receptors and ion channels get down regulated. It is not the odd one, but loads of them.
Here are the potassium channels) or should I say some as I got bored and stopped at about M  ie. KCNM) but could have gone on eg N KCNN etc

Next there are more than one type of GABA receptor. There are two main types. One is GABA A and the other is GABAB. GABA A is an ionotrophic (via chloride) channel that can be stimulated by different types of drug as it has multiple sites and there are multiple genes making a multi-component receptor.

GABA B is a metabotrophic receptor which G protein coupled receptor that is linked signalling to control calcium channel activity and can signal via potassium channels.

Baclofen is the main GABA B receptor stimulator, used for spasticity. GABApentin, Pregabalin look like GABA but do not bind to the GABA receptors, although they may influence GABA production they act via ion channels to be anti-convulsants and pain controllers. The story about GABA and oligodendrocytes involved GABA A receptors, so the story is not about these drugs

Indeed in the experimental study they blocked the GABA response with a drug called Gabazine (SR-95531). It is used in scientific research and has no role in medicine, as it would be expected to produce convulsions. 

Any drug used in humans would never block the GABA A receptor to the extent used in the experiments so a block would never happen in humans. Experimental studies often use crazy doses of drugs to show a theorhectic possibility or define a mechanism. But they have no translational value. 

If the authors had read the ARRIVE guidelines about reporting experimental studies, they could have talked about the translatable aspects and if they had used clinical concentrations of GABA A blocking drugs, I bet they would have shown nothing...Nothing does not make for a good publication. But until this expriment is done, no cause for concern.

The importance of this post was to show that oligodendrocytes have ionotrophic function and they have loads of ion channels including loads of potassium channels.

#PatientSpeak: I have primary progressive MS ..........

I am preparing myself to let my patients with PPMS down. Are you? #PatientSpeak, #MSBlog #Ocrelizumab

I saw one of my patients the other day who has PPMS. His disability is worsening and clearly wants something done about it. He was very excited about the news that the FDA had licensed ocrelizumab for PPMS and wanted to know when ocrelizumab would be available under the NHS. I explained to him that ocrelizumab had yet to be licensed by the EMA and as the EMA tends to be more conservative than the FDA it wasn't certain by any means that it would be licensed in Europe for PPMS.  Even if ocrelizumab is licensed for PPMS, I suspect the EMA won't give it as broad a label as the FDA has done and may limit it to a particular population of pwPPMS. If this happens I informed this patient he may fall outside of the licensed indication, for example his PPMS may not be active enough. 

In addition, if and when the EMA licenses ocrelizumab for PPMS then NICE has to green-light it for use in the NHS. The latter may be a problem, particularly if ocrelizumab is priced to be cost-effective for RRMS. At the RRMS price NICE will need to compare it to best supportive care (no DMT) for PPMS and it is unlikely to be cost-effective using this comparator. I have been arguing for sometime now that this may be the time for Pharma to explore differential pricing and charge the NHS less when ocrelizumab is prescribed for PPMS. 

When I told this patient about the various hurdles that will need to be overcome for me to prescribe ocrelizumab for him he was very disappointed, so I asked him to put something down in words to start a conversation with other pwPPMS who live in Europe. 

Please note that Mark has given me permission to publish his name. In fact Mark sits on the Barts-MS Advisory Group and wrote a blog post on this in December 2015

A patient-with-PPMS's Perspective on Ocrelizumab

"Some 4 months after I was diagnosed with PPMS in May 2008, I remember speaking to a man who had had MS for a number of years and he said that I would be one of the lucky ones – there would be treatment for PPMS in the next ten years or so. I have always remembered this but of course with less and less conviction as the years have gone by. Now I think I will be just another of the countless unlucky ones, there will be no treatment for me.

So when Ocrelizumab was announced as a possible treatment for PPMS I was overjoyed and thought, you know, maybe he was indeed correct. However, as ever with this disease any joy is always mixed with disappointment and so it was when I discovered that I was too old to be considered for the trial – I was 57. This was a bitter disappointment as I do not consider myself to be old, let alone too old. Indeed I have taken part in 3 trials since being diagnosed, I am generally fit, look after myself, lost weight, go to the physio twice weekly and maintain a good positive outlook. I do “my bit” but, there you are, I am too old.

Following the Ocrelizumab trials I like others with PPMS are very keen for the drug to licensed as currently it is our only hope. I understand that whilst it is not particularly effective where MS has taken a hold - eg on the lower limbs, it is effective on the upper limbs. For this reason alone it should be prescribed as our upper limbs must be saved they act as our legs by allowing us to use a stick and maintain some independence by using mobility scooters and other aids. Once our arms are as stiff as our legs we are effectively quadriplegic - if that can be avoided or at least delayed then surely we should have the drug. After all if there was a cancer treatment that whist not effective on the primary tumour but reduced or delayed the spread of secondary tumours, I am sure that would be licensed."

Mark Harrington, May 2017, London

Friday, 26 May 2017

#BrainHealth: a brain health guide for nurses

CMSC launch of our #BrainHealth guide for MS nurse specialists. #CMSC2017 

The main focus of the CMSC meeting is CME (continuing medical education) for allied medical professionals in particular MS clinical nurse specialists. For this reason we have used this meeting to launch our Brain Health guide for MS specialist nurses, or nurse practitioners as they are frequently referred to in the US. Please download the guide, read it and use it in your clinical practice. 

Jodi Haartsen
MS Brain Health Champion & MS Nurse Practitioner extraordinaire, 

on our Brain Health stand at the CMSC in New Orleans.

CoI: multiple

First case of PML on Ocrelizumab reported

We have been saying one of the important considerations when starting treatment is how do you switch off your drug, we reported rebound after fingolimod and this is a well known problem with Natalizumab. PML is the other major problem with natalizumab.

The first case of PML on ocrelizumab has been reported. Again one suspects that subclinical PML due to natalizumab was the problem. According to Media the case occurred in a JC virus-positive pwMS who had stopped taking natalizumab in February after being on the drug for three years, and switched to ocrelizumab with a first dose given in April. Ocrelizumab is not licenced within Europe but it was apparently used in Germany where the case occurred.

ProfG will no doubt get the details, but perhaps not the news you want when going to the regulators to get approval for use in Europe.

GABA controls oligodendrocytes

Hamilton NB, Clarke LE, Arancibia-Carcamo IL, Kougioumtzidou E, Matthey M, Káradóttir R, Whiteley L, Bergersen LH, Richardson WD, Attwell D. Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length. Glia. 2017;65(2):309-321

Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10-positive oligodendrocytes, that endogenously released GABA, acting on GABAA receptors, greatly reduces the number of oligodendrocyte lineage cells. The decrease in oligodendrocyte number correlates with a reduction in the amount of myelination but also an increase in internode length, a parameter previously thought to be set by the axon diameter or to be a property intrinsic to oligodendrocytes. Importantly, while TTX block of neuronal activity had no effect on oligodendrocyte lineage cell number when applied alone, it was able to completely abolish the effect of blocking GABAA receptors, suggesting that control of myelination by endogenous GABA may require a permissive factor to be released from axons. In contrast, block of AMPA/KA receptors had no effect on oligodendrocyte lineage cell number or myelination. These results imply that, during development, GABA can act as a local environmental cue to control myelination and thus influence the conduction velocity of action potentials within the CNS.

GABA is the major inhibitory neurotransmitter and blocks signals from excitatory nerves such as glutamate. A few years ago, it was found that oligodendrocyte precursors have glutamate receptors and when these get stimulated it probably acts as a signal to the oligodendrocyte precursor cells to change into an oligodendrocyte and to start myelination. The glutamate is essentially a calcium channel making the inside of the  cell more electrically positive. however blocking this made no infuence on cell numbers. However, if you stimulate with GABA A which is a chloride channel meaning the inside becomes more electrically negative you get less oligos and less myelination. Is there any evidence that benzodiazepines block or stimulate myelination ?  Don't think so, but have people looked ?. 

Thursday, 25 May 2017

#NewsSpeak: Jet-lag and the CMSC 2017 meeting in New Orleans

Jet-lagged, tired and MSed-out in New Orleans; time to take a break? #CMSC2017 #MSBlog #NewsSpeak

I arrived late last night in New Orleans and will be talking at a teaching session this morning. The main objectives of my talk are:
  1. MS is 1 and not 2, 3 or 4 diseases
  2. MS is a length-dependent axonopathy 
  3. Progressive MS is a tractable problem
  4. Neuro-repair is feasible and provides hope for the future
  5. Holistic management of MS#
I am very jet-lagged and tired. I have less than 3 hours sleep on top of several weeks of sleep deprivation. I was meant to be flying back this evening to travel to Scotland for a week's walking holiday doing the Cape Wrath trail. But had to pull out of the walk because of my hip problem; I simply can't do 100+ miles carrying a 20+ kg backpack. I was really looking forward to some time out, but instead my supposed week-off has already filled up rapidly with MS-related activities. I reopened my NHS clinic,  have scheduled several meetings including attending an important biomarker meeting.

The one positive thing about a long trans-Atlantic flight is that I managed to finish 9 writing tasks with plenty more to do. Hopefully, I will be able to maximise some of my free time in New Orleans and next week to complete some more tasks. The life of an academic is no different to any other; we are on a treadmill that seems to be going faster and faster.  

The following is my talk that I will be giving this morning, the programme for the CMSC meeting and a satellite I have been asked to chair are below. Regarding the latter  the previous chair was unable to attend the meeting. The satellite is being hosted by 'MS in the 21st Century' an initiative that focuses on patient engagement. It should be good so if you are in New Orleans please come along. In addition, I am presenting several abstracts and have done already done a Medscape panel discussion.  

CoI: multiple


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May 2017

Letter from the President

Welcome to the second ECTRIMS newsletter of 2017. Being already in the month of May, I begin by highlighting that this year's World MS Day is May 31st. World MS Day is an excellent initiative of the MS International Federation and its members to raise awareness of MS throughout the world. For further information see (

Plans continue to proceed well for this year's Congress (MSParis2017). As happens every three years, the meeting this year is being held jointly with ACTRIMS. It will be the 7th such joint meeting and will take place in Paris on October 25th - 28th. Comprehensive Scientific and Teaching Course Programmes have been established and further details of these are available on the website, along with other  information relevant to the meeting ( The deadline for abstract submission is May 31st. This year, ECTRIMS will be providing a limited number of rooms at a very reduced rate for non-profit, non-governmental specialty groups or organisations in the MS field that may want to hold a meeting at the time of the Congress. For further information, see (

ECTRIMS keeps busy with a number of regular activities other than the annual Congress. This year's Focused Workshop on the topic of "Advancing Trial design in MS" was held in Rome in March in association with the Progressive MS Alliance. It was a very successful, informative and interactive two-day meeting. This month (May 2017), the third ECTRIMS Regional Teaching Course was successfully held in Vilnius, in conjunction with the Baltic MS council. In June, the 5th ECTRIMS Annual Summer School, which is on "Rehabilitation and Symptomatic Treatment in MS", will take place in Santiago de Compostela. The summer school programme and faculty will provide an excellent educational experience for the attendees. Plans are already underway to hold further Regional Teaching Courses in 2018, along with a Focused Workshop and Summer School. Warmest thanks to all my Executive Committee colleagues for their leadership for taking forward these activities.

The 2017 round of ECTRIMS fellowship awards was recently decided. There were many very good applications this year and a total of 10 fellowships have been awarded as follows: Post-doctoral Research Exchange Fellowship (4), Clinical Training Fellowship (3), ECTRIMS-MAGNIMS Fellowship (2) and MS Nurse Training Fellowship (1). Elsewhere in the newsletter you will find reports from several previously awarded fellows.

I hope you find this newsletter enjoyable and informative.
David Miller


World MS Day 2017

What is World MS Day?
World MS Day, which will occur on May 31st this year, brings the global MS community together to share stories, raise awareness and campaign with and for everyone affected by multiple sclerosis. World MS Day is the only global awareness raising campaign for MS. Every year, the MS movement comes together to provide public with information about MS and to raise awareness on how it affects the lives of more than 2.3 million people around the world.
In 2017, the theme for World MS Day is "Life with MS". As life with MS can be difficult and each day brings its new challenges, valuable tips for living well with MS will be made available.
Since its inception in 2009, the World MS Day has grown from strength to strength, reaching hundreds of thousands of people in more than 78 countries worldwide and continuing to grow every year.
How can you get involved?
Read more about World MS Day at and learn about how you can take part in the World MS Day.

ECTRIMS Focused Workshop 2017/ 9-10 March 2017 in Rome, Italy

The ECTRIMS 2017 Focused Workshop took place on March 9th and 10th in Rome. The topic was "Advancing Trial Design in Progressive MS" and it was held in association with the International Progressive MS Alliance. There were about 50 participants encompassing a broad range of expertise, including clinical neurology, neuropathology, trial design, statistical, pharmaceutical, regulatory and lay viewpoints. Themes included treatment targets; trials to date; clinical outcome measures; interim outcome measures focused on neuroprotection that included MRI, OCT, CSF, neurophysiology and PET;   trial designs and statistical analysis; insights from big datasets and ongoing phase 2 trials; and pharmaceutical and regulatory considerations. There were didactic presentations and ample time was allocated for round table and open discussions. The workshop covered a lot of ground and there were many lively discussions. It is proposed that the proceedings will be published as a series of short papers in a themed issue of the Multiple Sclerosis Journal with authors coming from amongst the workshop attendees. We thank Jeremy Chataway and Bob Fox for being the guest editors on this publication.

ECTRIMS Regional Teaching Course 2017/ 11-12 May 2017 in Vilnius, Lithuania

ECTRIMS regional teaching courses have been established in 2016. After two successful teaching courses in St.Petersburg/Russia and Dubai last year this educational activity continued this year with the third teaching course in Vilnius/Lithuania. The course was organized by the ECTRIMS Teaching Course Committee in close collaboration with the Baltic Neurological community. The programme covered basic aspects of MS like the involvement of genes and environmental factors in the pathogenesis of MS and the immunopathophysiology of MS. The main focus of the teaching course was practice relevant topics including differential diagnosis, treatment monitoring and discussions about the rationale for switching or escalating therapies. The teaching course was well attended with 90 participants. The active interaction and high quality of the presentations made this teaching course again a great success, which is also exemplified by a very positive feedback from the participants.
For further information on upcoming teaching courses and detailed programme please visit the ECTRIMS Website here.

ECTRIMS Summer School 2017 / 13 - 15 June 2017 in Santiago de Compostela, Spain

The 2017 ECTRIMS Summer School on "Rehabilitation and symptomatic treatment in multiple sclerosis", organized in collaboration with RIMS, will take place in Santiago de Compostela, Spain, on June 13th – 15th.
The target audience is represented  by high-potential young researchers and clinical experts from different backgrounds (neurologists, rehabilitation physicians and multi-disciplinary therapy team) who want to generate and implement best evidence-based treatment and rehabilitation care.
Through formal presentations delivered by international experts,  interactive, multidisciplinary group discussions and multi-disciplinary group work on research projects,  this course will provide an update on the framework of rehabilitation and available evidence for the effectiveness of motor and cognitive, as well as emotional symptomatic treatment and rehabilitation interventions in MS. Moreover, it will cover epidemiology, physiopathology, diagnosis and evidence base behind the various pharmacologic and non-pharmacologic approaches to the management of MS symptoms, which in most cases requires multidisciplinary input. The course will pursue as main learning objectives understanding the indications and concepts of symptomatic treatment and rehabilitation, and its effects on the patient everyday functioning, integrating evidence from multiple disciplines into clinical case management and identifying key research questions and challenges for clinical implementation of holistic symptomatic treatment and rehabilitation.

ECTRIMS Fellowship 2017

ECTRIMS offers a comprehensive range of fellowship programmes for different target groups.
In 2017 10 new fellowships were awarded:
Dr. Gloria Castellazzi (Italy): 2-year fellowship at UCL Institute of Neurology, Queen Square MS Centre, Department of Neuroinflammation, London, United Kingdom, under mentorship of Prof. Claudia Gandini Wheeler-Kingshott. Project: Developing a clinical decision system based on characterising shared and specific functional features of MS subtypes.
Dr. Joanna Marczynska (Poland): 2-year fellowship at University of Southern Denmark, Neurobiology, Odense C, Denmark, under the mentorship of Prof. Trevor Owens. Project: Mechanisms suppressing autoimmune responses in the central nervous system.
Dr. Kyla McKay (Canada): 2-year fellowship at the Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden, under the mentorship of Prof. Jan Hillert. Project: The causes and consequences of paediatric multiple sclerosis: A population-based study.
Dr. Emanuela Oldoni (Italy): 2-year fellowship at KU Leuven, Department of Neurosciences, Leuven, Belgium, under the mentorship of Prof. An Goris and Prof. Bénédicte Dubois. Project: Multiple sclerosis heterogeneity: patient-to-patient variation in cerebrospinal fluid biomarkers
Dr. Nuria Cerdà Fuertes (Spain): 1-year clinical training fellowship at the University Hospital Basel, Neurologisch-Neurochirurgische Poliklinik, Basel, Switzerland, under the mentorship of Prof. Tobias Derfuss. Project: Evaluation of clinical bedside tests (primitive reflexes e.g. palmomental reflex) of MS patients in correlation with neuropsychological tests.
Dr. Giordani dos Passos (Brazil): 1-year clinical training fellowship at the University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom, under the mentorship of Prof. Jacqueline Palace. Project: Are there differences in MS severity, as assessed by MRI and clinical parameters, between different racial and ethnic groups?
Dr. Pietro Maggi (Belgium): 1-year clinical training fellowship at the Lausanne University Hospital, Department of Neurology, Lausanne, Switzerland, under the mentorship of Prof. Renaud Du Pasquier. Project: High field gradient echo MRI enhances the differentiation between multiple sclerosis and other inflamatory disorders: a further step beyond the concept of "no better explanation".
Macarena Rus Hidalgo (Spain): 6-months fellowship at the IRCCS Foundation Carlo Besta Neurological Institute, Neurology 4 Unit-neuroimmunology and neuromuscular disorders, Milan, Italy, under the mentorship of Prof. Prof. Silvia Rossi. Project: A multicentric randomized PRAGmatic trial to compare the effectiveness of fingolimod versus
dimethyl‐ fumarate on patient overall disease experience in relapsing remitting Multiple
Sclerosis: novel data to inform decision‐makers – (PRAG‐MS).
Dr. Soheil Damangir (Sweden): 1-year fellowship at the VU University Medical Center, Amsterdam, Netherlands, with collaboration at the Vall d'Hebron University Hospital, Barcelona, Spain under the mentorship of Dr. Vrenken and Prof. Barkhof. Project: Optimizing crowd-sourced solutions toward generating large reference datasets for WM lesion segmentation in MS.
Dr. Marcello Moccia (Italy): 1-year fellowship at the UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, United Kingdom under the mentorship of Prof. Ciccarelli and Prof. Barkhof. Project: Improving longitudinal spinal cord atrophy measurements for clinical trials in multiple sclerosis by using the Generalised Boundary Shift Integral (GBSI).

MSIF-ECTRIMS McDonald Fellowship

Starting in 2016, MSIF (Multiple Sclerosis International Federation) and ECTRIMS jointly support a 2-year McDonald fellowship every year. This fellowship is offered to young researchers from emerging countries and enables the recipient to travel to an established research institution anywhere in the world to work with leading researchers in the field of MS. It is intended that these fellows return to their home countries after finishing the fellowship program to establish their own research using the newly learned techniques.
For more information regarding the fellowship program and for application please visit the MSIF webpage:
Application deadline: 30 June 2017

Reports of ECTRIMS Fellows


Ana Luisa Falcão PhD – 2015 Awardee
Research Topic
Epigenetic states underlying oligodendrocyte precursor differentiation in Multiple Sclerosis
Fellowship Institution
Karolinska Institute, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden
Dr. Gonçalo Caselo-Branco
Fellowship Duration
2 years
Summary as ECTRIMS Postdoctoral Research Exchange Fellow 2015 - 2017
The research objective of this fellowship project was to understand the epigenetic mechanisms underlying oligodendrocyte precursor cell (OPC) differentiation during development and in Multiple Sclerosis (MS). In the first part of the project we investigated the role of citrullination in oligodendrocyte (OL) differentiation and myelin maintenance. Citrullination is the conversion of an arginine to the neutral citrulline, a process mediated by Peptdidylarginine Deiminases (Padi) and found induced in MS. We have uncovered the PADI2-mediated citrullination targets in OLs and found that both cytoplasmic and nuclear proteins are citrullinated, such as myelin proteins and histones. Our study shows that PADI2 citrullination impacts on proper OL development acting as an epigenetic regulator through histone citrullination, but also displays other functions in the cytoplasm and myelin as observed by its interaction with several myelin proteins. In a second part of the project we have performed single cell sequencing profiling in OL lineage cells isolated from the brain and spinal cord of the MS mouse model EAE, and from healthy controls. We observed a remarkable segregation between cell populations from controls and diseased animals that discloses many targets of the disease.
We are currently preparing the 2 manuscripts describing the findings from these projects and we have recently published part of the results from the single cell RNA-seq profiling in OLs (Marques et al, Science).


María Isabel Zuluaga MD – 2015 Awardee
Research Topic
The effect of hormonal changes on women MS risk and prognosis
Fellowship Institution
Centro de Esclerosis Mútiple de Catalunya – CEMCat, Barcelona, Spain
Dr. Mar Tintoré 
Fellowship Duration
6 months
Summary as ECTRIMS Clinical Training Fellowship Programme Fellow 2015
I developed my ECTRIMS Clinical training fellowship at the CEMCat. During these months, I participated in activities of patient care and clinical research. My project was to investigate the possible association of reproductive background, hormonal changes and environmental factors in the risk and prognosis of MS. We found that age at menarche was not associated with an early CIS, neither with the risk of second attack or accrual disability. We also found that pregnancy before or after CIS did not modify the risk of CDMS or accrual disability. Regarding environmental factors, we found that vitamin D deficiency and smoking are risk factors for disability progression in the BARCELONA CIS cohort.
I´m very thankful with ECTRIMS, my mentors and co-workers at CEMCat; this experience had enriched my professional and personal life, and also will positively impact the care of MS patients back in my country.


Arman Eshaghi MD, PhD – 2015 Awardee
Research Topic
"To explore imaging phenotypes of patients with multiple sclerosis using 4-dimensional voxel-based morphometry"
Fellowship Institution
UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, United Kingdom
Prof. Olga Ciccarelli
Fellowship Duration
1 year
Summary as ECTRIMS MAGNIMS Fellowship in Magnetic Resonance Imaging in MS Fellow 2015 - 2016
During my ECTRIMS-MAGNIMS fellowship, I collected a big dataset of more than a thousand patients with multiple sclerosis, who have been followed longitudinally. I looked at the temporal and spatial evolution of brain atrophy. I looked at the differences of atrophy across neuroanatomical regions in multiple sclerosis phenotypes, and baseline imaging markers to predict disability accumulation in advance of time. This fellowship allowed me to work in a truly multidisciplinary environment, where I worked in between the UCL Institute of Neurology and UCL Department of Computer Science to learn computational methods and apply them in neurology. I presented my work as a platform presentation during ECTRIMS 2016 in London and was awarded "the Best Oral Presentation Given by a Young Investigator". I have prepared the results of my fellowship as a manuscript, which is now submitted and is under peer review.

Meeting Dates

ECTRIMS Summer School 2017
Santiago de Compostela / Spain: 13 – 15 June 2017
MSParis2017 - 7th Joint ECTRIMS - ACTRIMS Meeting
Paris / France: 25 – 28 October 2017
Berlin / Germany: 10 - 12 October 2018
We are looking forward to seeing you in Paris!

Please be aware of fraudulent organisations!

There are an increasing number of fraudulent websites that impersonate MSParis2017. We would like to alert all participants to be aware of possible scams and to strongly advise you to only use the official MSParis2017 registration and ECTRIMS accommodation agency Congrex Travel.
ECTRIMS Executive Committee
D. Miller, London/UK, President
B. Hemmer, Munich/DE, Vice President
M. P. Amato, Florence/IT, Secretary
T. Derfuss, Basel/CH, Treasurer & Newsletter Editor
M. Tintoré, Barcelona/ES
S. Vikusic, Lyon/FR
L. Brundin, Stockholm/SE