Monday, 11 December 2017

Temperature dependence of impulse conduction in optic nerve axons



Thanks for the comments
We were grateful when a number of readers responded to our enquiry regarding temperature dependent symptoms in MS, and we learned more about how people cope with the symptoms. Following this conversation, I thought it worthwhile to draw attention to a paper we recently published, that suggests that there are functional differences between normal peripheral and central axons, and these differences provide a new view on temperature sensitivity.   

Optic nerve amazingly sensitive to changes in temperature
A few years ago, my colleagues and I found unexpectedly that the function of rodent optic nerve axons, maintained in a nerve bath, is amazingly sensitive to temperature changes. The nerve bath that we use is a chamber in which a nerve can be maintained with nutrient and oxygen outside the body. The comparison we were subsequently able to make with normal sensory axons in the human hand in vivo, with a colleague at the University of Sydney, makes it look like the phenomenon is one that affects the optic nerve (and therefore potentially central axons more generally) but not the peripheral nerve. One of the advantages of doing experiments in a nerve bath is that one can control temperature really precisely, and also the application of drugs to the tissue. Since then we have tried to confirm that the temperature sensitivity really exists, and we have done it a number of ways now, so at least in terms of our experimental preparation there seems little doubt it exists, and secondly we have been trying to find out what the mechanism of such sensitivity might be. This is the paper: Diuretic-sensitive electroneutral Na+ movement and temperature effects on central axons by Meneka Kanagaratnam, Christopher Pendleton. Danilo Almeida Souza, Joseph Pettit, James Howells and Mark Baker. Journal of Physiology 595.11 (2017) 3471-3482.

Ideas about the mechanism of temperature sensitivity
The way I became aware of temperature dependent symptoms was initially through the work of Hugh Bostock, where he used a peripheral nerve model of demyelination, and demonstrated conduction failure in single axons when raising temperature acutely. There is a classical explanation for this, based on work done by the Nobel Prize winners, Alan Hodgkin and Bernard Katz. The classical explanation says that the nerve impulse gets briefer when the axon warms up, and this brevity means that the impulse is more likely to fail at sites along the axon that have been damaged by demyelination. Of course, there is every expectation that this principle is still likely applicable, but what we have found suggests that normally in central axons, as one warms up, the axons get less excitable in a way unrelated to the brevity of the impulse but for another reason. It is because the warming alters the resting properties of the axon, making an impulse harder to generate and also harder to propagate (ie to jump along). In normal axons, this effect of warming we would suggest is within the tolerance of the nervous system, and symptoms don’t appear. (That said, it is common knowledge that relatively minor rises or falls in core body temperature in fit and healthy people can dramatically alter properties of the nervous system, including causing loss of conscious for example with hypothermia). So we could now offer an additional insight and say that where impulse conduction is touch-and-go at sites in damaged axons, one possibility is that this newly described property could contribute to make the impulse fail, and so exacerbate symptoms. We are still working on the biophysical mechanism, and once we have more confidence in that mechanism it is our hope that a route to pharmacologically manipulating the property will become apparent, and so in the future more help may be offered to people experiencing temperature dependent symptoms. 

Do you have temperature dependent symptoms that affect your vision? Those were the first temperature dependent symptoms described. Perhaps you have double vision, perhaps altered acuity? How does getting too warm affect your vision? We would value your comments
Thank you!

Mark Baker

Education: What do antibodies do

You have full text access to this OnlineOpen article
Prospects from systems serology research
Kelly B. Arnold and Amy W. Chung
Version of Record online: 1 DEC 2017 | DOI: 10.1111/imm.12861

An internal cell signalling molecule found to support remyelination

The protein tyrosine phosphatase Shp2 regulates oligodendrocyte differentiation and early myelination and contributes to timely remyelination. Ahrendsen JT, Harlow DE, Finseth LT, Bourne JN, Hickey SP, Gould EA, Culp CM, Macklin WB. J Neurosci. 2017 pii: 2864-16.

Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mTOR and ERK signaling pathways in multiple cellular contexts, including oligodendrocytes. Its role during later postnatal CNS development or in response to demyelination injury has not been examined. Based on the current studies, we hypothesize that Shp2 is a negative regulator of CNS myelination. Using transgenic mouse technology, we show that Shp2 is involved in oligodendrocyte differentiation and early myelination, but is not necessary for myelin maintenance. We also show that Shp2 regulates the timely differentiation of oligodendrocytes following lysolecithin-induced demyelination, although apparently normal remyelination occurs at a delayed time point. These data suggest that Shp2 is a relevant therapeutic target in demyelinating diseases such as multiple sclerosis.

SIGNIFICANCE STATEMENT In the present study, we show that the protein phosphatase Shp2 is an important mediator of oligodendrocyte differentiation and myelination, both during developmental myelination as well as in myelin regeneration. We provide important insight into the signaling mechanisms regulating myelination and propose that Shp2 acts as a transient brake to the developmental myelination process. Furthermore, we show that Shp2 regulates oligodendrocyte differentiation following demyelination and therefore has important therapeutic implications in diseases such as multiple sclerosis
                                     Expression from Brain seq
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), SHP-2, or protein-tyrosine phosphatase 2C (PTP-2C) is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. 

This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. 

Mutations in this gene are a cause of Noonan syndrome and Leopard syndrome as well as acute myeloid leukemia.

Is this going to be a good target for remyelination without side-effects, one would think this will be unlikely as the molecule is expressed at high levels all over the place. 

This feature seems to be common for many of the remyelination .pathways. However do we need to treat long term or give a pulse treatment?

We dont know...becuase we are not testing for this. The models used naturally repair without any treatment so all we are seeing in an enhanced repair. People never look at what happens in a model where there is chronic demyelination yet we jump from these simple models straight into human trials.

Is it surprising that we often struggle to see benefit.

Sunday, 10 December 2017

Measuring Hand Function

Online monitoring of hand function. Are you up for doing the BRAIN test or will the cardboard 9HPT do the job? 



Saturday, 9 December 2017

Relapse without cell depletion in the blood

As you may be aware I have been banging on about the importance of B memory cells for most of the year, but it has been an uphill struggle to get this view accepted. 

However, response to therapy creates a powerful piece of insight that frankly can't be ignored. But I meet Ostriches ever day.




Friday, 8 December 2017

Fingolimod: does it help with upper limb function?

ProfG G has been been saying that we should #Thinkhand and target hand function for outcomes in clinical trials. This idea may be supported by studies with ocrelizumab and natalizumab but there are a couple of exceptions.

Thursday, 7 December 2017

Reflections on the ECF 2017

I have just returned from the European Charcot Foundation meeting in Baveno, Italy. The meeting is small (< 500 attendees) with no parallel sessions and ample time to mix with attendees and chew the cud. I did a plenary presentation on "dealing with increasing economic constraints".  The feedback I received after my talk, and subsequently via email, has been extraordinary. An eminent neurologist said he was glad that someone was thinking about these issues and taking it on. I have also been contacted by a health economist and have been urged to write up the talk.




Wednesday, 6 December 2017

Yet more data supports the B memory Cell idea

I can hear you saying, "Oh no not another B-cell paper!". However, this is where the action is. It is the B-cell and not the T-cell. Do you agree or disagree? Have your say. 


Tuesday, 5 December 2017

Blood cancers after fingolimod treatment

How immunosuppressive is fingolimod? Does fingolimod's longterm immunosuppression result in an increased cancer risk? 

Monday, 4 December 2017

Guest Post: an update from Saúl Reyes

It has been a while since I last wrote a post for this blog and figured it was time to update you all! I have recently completed my training with Professor Giovannoni and it really confirmed my desire to pursue a career in MS. I am back home in Colombia just getting ready to finish my residency in Neurology. I am incredibly grateful for the time I spent with the Barts and The London Neuroimmunology Group. Every member of the team was very passionate about MS and brought that excitement to teach me. I am delighted to be able to keep in touch with you all through this blog. Please enjoy my new post and don't forget to leave your comments below!

Sunday, 3 December 2017

Danger! Danger! How does the brain sense damage?

The mechanisms which drive inflammation and neuron death in MS are very complicated. These processes involve interactions between multiple cell types in and outside the brain. The crosstalk between nerve cells (neurons), immune cells from the blood, and brain-resident supporting cells (glia) is important to study because it could open up new avenues for disease-modifying therapy. 


Saturday, 2 December 2017

Plasma cells live for a long time in the CNS

Pollok K, Mothes R, Ulbricht C, Liebheit A, Gerken JD, Uhlmann S, Paul F, Niesner R, Radbruch H, Hauser AE. The chronically inflamed central nervous system provides niches for long-lived plasma cells. Acta Neuropathol Commun. 2017 Nov 25;5(1):88

Although oligoclonal bands in the cerebrospinal fluid have been a hallmark of multiple sclerosis diagnosis for over three decades, the role of antibody-secreting cells in multiple sclerosis remains unclear. T and B cells are critical for multiple sclerosis pathogenesis, but increasing evidence suggests that plasma cells also contribute, through secretion of autoantibodies. Long-lived plasma cells are known to drive various chronic inflammatory conditions as e.g. systemic lupus erythematosus, however, to what extent they are present in autoimmune central nervous system inflammation has not yet been investigated. (Who are they kidding...oh yes the referees) In brain biopsies from multiple sclerosis patients and other neurological diseases, we could detect non-proliferating plasma cells (CD138+Ki67-) in the parenchyma. Based on this finding, we hypothesized that long-lived plasma cells can persist in the central nervous system (CNS). In order to test this hypothesis, we adapted the multiple sclerosis mouse model experimental autoimmune encephalomyelitis to generate a B cell memory response. Plasma cells were found in the meninges and the parenchyma of the inflamed spinal cord, surrounded by tissue areas resembling survival niches for these cells, characterized by an up-regulation of chemokines (CXCL12), adhesion molecules (VCAM-1) and survival factors (APRIL and BAFF). In order to determine the lifetime of plasma cells in the chronically inflamed CNS, we labeled the DNA of proliferating cells with 5-ethynyl-2'-deoxyuridine (EdU). Up to five weeks later, we could detect EdU+ long-lived plasma cells in the murine (mouse) CNS. To our knowledge, this is the first study describing non-proliferating plasma cells directly in the target tissue of a chronic inflammation in humans, as well as the first evidence demonstrating the ability of plasma cells to persist in the CNS, and the ability of the chronically inflamed CNS tissue to promote this persistence. Hence, our results suggest that the CNS provides survival niches for long-lived plasma cells, similar to the niches found in other organs. Targeting these cells in the CNS offers new perspectives for treatment of chronic autoimmune neuroinflammatory diseases, especially in patients who do not respond to conventional therapies.


Plasma cells which produce antibody are often found in bone marrow and can live for years but you put them in cell culture and they are dead in a few days. This is because the cells survive in niches where they recieve survival factors from surrounding cells. In this study they track the presence of plasma cells over weeks in animals and suggest that plasma ells survive for some time. I guess we have thought this happens for some time and it is evident that many of the plasma cells in the CNS are not directed to myelin antigens.

The question is what are we going to do?

Have a read if you are interested

The problem here ,is the pictures show the random isolated plasma cell and not B cell follcles


Friday, 1 December 2017

Clinical trial destroys another good idea

McKee JB, Cottriall CL, Elston J, Epps S, Evangelou N, Gerry S, Kennard C, Kong Y, Koelewyn A, Kueker W, Leite MI, Palace J, Craner M.
Mult Scler. 2017 Nov 1:1352458517742979.

BACKGROUND:

Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC).

OBJECTIVE:

To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON).

METHODS:

A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18-55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( clinicaltrials.gov , NCT 01802489).

RESULTS:

Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer.

CONCLUSION:

Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.
                                     Data from Brain Seq

Amiloride is blocker of ASICS1 channel. This is a neuronal voltage-insensitive sodium channel activated by extracellular protons permeable to Na+, however ASIC1 also shows low Ca2+permeability. It was shown to be neuroprotective in animal models so of we go and do a trial and as we can see as occurred here...the trial fails and animals studies take a beating, like so many other studies.

However I have been arguing that animal studies are not always the problem. I am sorry to say clinicians conspire to mess things up. Sorry but it bursts my bubbles too.

In this study people who had optic neuritis had a month to get on drug. But this is too late as the damage has been done. The damage is done within a few days as we showed in animals, which led to a positive trial when people were recruited and put on treatment within 1-2 weeks as shown in

Raftopoulos, R, Hickman, SJ, Toosy, A. Phenytoin for neuroprotection in patients with acute optic neuritis: A randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 259–269

However, this has chucked away our animal data as this trial was not followed up to change practice such that people with optic neuritis get treated with phenytoin. However I think the amiloride has another problem as it made the nerve transmission slower suggesting that it block remyelination.

It is interesting that oligodendrocyte presusor cells have loads of ion channels on them and this includes ASIC1 (ACCN2) and this drops once cells produce myelin. See the picture. So is this chnnel involved in myelination

Comments, Questions and Answers-December

If you have a question unrelated to the Posts this is the place for you. 

In the past we have done an advent calendar in December, to advertise the Research Day.

However, we do not know about the planning of this, 

So the mice are off on tour.

Thursday, 30 November 2017

Copaxone: yet another mechanism

Previously on this blog I've written about Copaxone and its "mechanism of the week". For example, here and here. I haven't done it for a while, but can't resist bringing this one to your attention.

Now it's anti-bacterial. What next? It inhibits EBV :-)

But I guess it must be working by blocking the microbiome:-).



Wednesday, 29 November 2017

Can coffee really be good for you?

As you see we are trying to post less often on the blog so that you have more time to read and discuss the posts. The following blog post is a bit of a cheat as I have reviewed three papers. However, they are all related to coffee and are relevant to pwMS and their families.

Are you addicted to coffee? If you are, don't worry, the latest research suggests it may be good for you. However, if you have urinary symptoms, anxiety, tremor or sleep problems there may be a downside. 



Tuesday, 28 November 2017

Monday, 27 November 2017

Training the next generation of UK's MSologists

Tony Blair is famously quoted as saying 'Education, education, education, ...' and putting education at the centre of New Labour's manifesto in 1997. However, is it the type or the quality of education that makes the difference and changes the world?




We are trying to change the world of MS treatment.

Sunday, 26 November 2017

Study shows a B cell depleting treatment is effective

A new study tests a B cell depleting treatment in MS. The results are interesting.


Saturday, 25 November 2017

Are we Overdosing Ocrelizumab

The eagles (ocrelizumab for RRMS and PPMS)  may have landed in Europe, but how often should the birds be used to kill cells in MS?

A view-point argues it's too often and that it can be personalised and smart.  I agree but for different reasons.....

Friday, 24 November 2017

Searching for the Miracle Cure. MS in the Media

Last night we had a programme in the UK on  someones journey to Israel to examine the effect of mesenchymal stem cells.



It was dubbed a "Search for a Miracle Cure" and was on Channel 4, but there was no evidence presented to suggest it was a cure.

Thursday, 23 November 2017

Guest post: Young carers in Newcastle try Digesting Science

We have recently reached out to a number of young carer organisations across the country, encouraging them to hold a Digesting Science event (the Barts-MS set of activities explaining MS to 6-12 year olds). Recently, we got some great feedback from the South Tyneside Young Carers, and thought we'd share their fantastic work with you. Post by Levi Cosker, South Tyneside Young Carers Activity Officer.


Wednesday, 22 November 2017

Results of Rumble in the Jungle 2

As you are aware Prof. Baker (Proud Yorkshireman / Englishman) took on Prof. Heinz Weindl (Proud German) in a dramatic debate. Who won?

Who Needs T cells..Not EBV infected Memory B cells

To finish off the debate...a prominent T cell immunologist in the red corner said B cells need T cells.....However, do some reading and listening and as said with EBV in the equation...maybe not.
Did people listen to the Evidence with an open mind and no preconceptions?

Imaging B cells

B cells are becoming increasingly seen as an important subset of cells and they have been implicated as drivers of progressive MS. 

There will be an increasing number of B cell therapies arriving and so being able to assess whether they get rid of B cells in the brain is an important step. 

This study reports on the production of an imaging tool.  They use rituximab to image B cells in EAE. They show an increased disease. I was excited

Monday, 20 November 2017

Rumble in the Jungle Part II

The "Rumble in le Jungle" at ECTRIMS2017 turned into a "Bumble in the Immunological jungle" as the Heavyweight clash turned into a love-fest. 

UPDATE: Slides added

Sunday, 19 November 2017

Have you been involved in shared-decision making?

A recent study published in the British Medical Journal (BMJ) proposes a simple three talk model for shared-decision making in the clinic. 

Have you been involved in a shared-decision making process, or have you simply been told what is best for you? 

Please have your say.


Saturday, 18 November 2017

The good, the bands, and the ugly: do oligoclonal bands mean more brain shrinkage?


Oligoclonal bands (OCBs) are now back in the diagnostic criteria for MS - they can be used to support a diagnosis. If someone has a clinically-isolated syndrome - an episode of symptoms or signs due to demyelination without any evidence of previous events - the presence of OCBs makes it much more likely that they will go on to develop clinically-definite MS

Friday, 17 November 2017

Guest Post: Self-catheterisation

Note: This is a no-nonsense and detailed post on self-catheterisation.

As MS progresses we often have to self-catheterise. This presents few problems for some. Others, like me, aren’t so lucky.



Thursday, 16 November 2017

Latest natalizumab PML risk update

The latest PML risk figures from Biogen. If you are on natalizumab and are JCV seropositive this post is for you.

Why does smoking increase your risk of MS?

We don’t understand yet why people get MS. The accepted view is that there is an interaction between risk genes and environmental factors like EBV, smoking, and vitamin D status. Epidemiological studies have helped to identify these risk factors for developing MS, but it is unclear how these factors actually contribute to disease evolution and progression.




Wednesday, 15 November 2017

LDN does not affect MS

"Low dose naltrexone (LDN) has become a popular off-label therapy for multiple sclerosis (MS). A few small, randomized studies indicate that LDN may have beneficial effects in MS and other autoimmune diseases. If proven efficacious, it would be a cheap and safe alternative to the expensive treatments currently recommended for MS. We investigated whether a sudden increase in LDN use in Norway in 2013 was followed by changes in dispensing of other medications used to treat MS."

Tuesday, 14 November 2017

HSCT in MS - what have we learnt?

More and more HSCT procedures (aka bone marrow transplants) are being performed for MS around the world than ever before. Currently, we lack convincing data on the conditioning regimen that best balances efficacy and safety. Patient selection is key and HSCT should be considered as an early option in aggressive cases of inflammatory MS, rather than as salvage therapy in later disease. 


Monday, 13 November 2017

Translocator protein: useful to see, useful to target?

Translocator protein (TSPO) is found on the outer mitochondrial membrane (in other words, on the outside of the powerhouse of the cell). It is thought to be involved in regulation of several cellular processes but its actual function is still up for debate. 


Sunday, 12 November 2017

Seizures, epilepsy, and MS

Any type of injury to the brain - whether focal or diffuse - can increase your risk of developing epileptic seizures. pwMS who have lots of lesions or significant atrophy are probably more at risk of developing epilepsy. The exact risk of epilepsy in MS has been a bit variable in reported studies. Because the absolute numbers of pwMS who also develop epilepsy is quite low, you need a really big cohort to see if there is any increased risk compared to people without MS. 

Saturday, 11 November 2017

Guest Post: Dr Rune. Høglund A potential pathological mechanism for memory B cells

A potential pathological mechanism for memory B cells

Bio: RAH is a Norwegian MD, currently a PhD candidate in the MS section of the Clinical Neuroscience group at Akershus University Hospital. Previous work includes examining the many effects of glatiramer acetate on the immune system. Our current work is focusing on B cells in particular, and their potential pathological collaboration with T cells in pwMS.



Friday, 10 November 2017

Ocrelizumab news: finally two eagles have landed

Landmark decision by the CHMP; ocrelizumab gets licensed for both relapsing and primary progressive MS.




The season of MS: Glandular fever may not be linked to time of year

Vitamin D (as measured by time of year) and glandular fever are not linked. Should we be surprised?

I guess it boils down to how you think it is all working. 

Thursday, 9 November 2017

#MS News. NICE being Nice for a change. Oral Cladribine now available on NHS in England

Imaging Microglia

Although this won't make me popular with the "imagers", here you have it from the horse's mouth "magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression".

Wednesday, 8 November 2017

Will Biogen walk-the-talk and do another natalizumab SPMS trial?

At #MSParis207 I presented a new analysis of the data of the ASCEND trial (natalizumab in SPMS) that shows natalizumab is very effective in protecting upper limb function, and to a lesser extent lower limb function, in people with more advanced MS (majority needing walking aids). 

Tuesday, 7 November 2017

The turn of the fungi

Fungal infections have not been widely studied in MS, many lines of evidence are consistent with a fungal etiology.

Sunday, 5 November 2017

Guest post: will the COMBAT-MS study disrupt the MS market?

You may be aware that people living with MS in resource-poor environments are often not treated with disease-modifying therapies. To address this we have been promoting a Barts-MS Essential Off-label list of DMTsThe problem with this list is that it is often not backed by a so-called 'class 1 evidence'. 

To address this lack of evidence, trials such as COMBAT-MS are being performed to provide data from real-life practice to support off-label prescribing. We are therefore privileged to have a guest post from the team running the COMBAT-MS trial explaining what the trial is about.

Saturday, 4 November 2017

Can blood neurofilaments be used to monitor disease activity?

Are we ready for a simple blood test to monitor MS disease activity?

Unrelated Comments & Questions - November 2017

Sometimes you want to say something unrelated to the thread or ask a clinical question or some other MS-related question that has not been answered in past. This is the place for you.

Friday, 3 November 2017

A BAFFling tale: how does fingolimod affect B cells?

Fingolimod is an effective DMT which binds to the sphingosine-1-phosphate receptor on white blood cells. We don’t fully understand why it works in MS, but the most popular theory is that it traps lymphocytes inside the lymph nodes, preventing them from entering the blood and therefore from penetrating into the CNS. It may also have direct anti-inflammatory effects, protect the integrity of the blood-brain barrier, and (possibly) act directly in the CNS as a neuroprotective agent.

Thursday, 2 November 2017

Cognition: to measure routinely or not?

At ECTRIMS I gave a short TED-type talk on why I think we need to measure cognition in people with MS in routine clinical practice. Do you agree?


Podcast




Wednesday, 1 November 2017

News: daclizumab handcuffed by the EMA

After a second person with early RRMS died from fulminant liver failure whilst being treated with daclizumab the EMA are restricting daclizumab's use. 

Tuesday, 31 October 2017

Monday, 30 October 2017

Are you what you eat?

Circumstantial evidence has suggested an association between diet and MS, but hard evidence proving a causal link has been lacking. 

A new multicentre, prospective, longitudinal cohort study from the USA tried to crack this problem. They recruited children with MS from 11 centres.