Sunday, 27 May 2018

Silent Symposium: combination therapies for treating MS

The following two presentations are from last week's ABN meeting in Birmingham on the topic of the need for combination therapies. It is clear that based on the current efficacy profile of DMTs if we are going to make a difference to people with MS we are going to need to build a sandwich of treatments targeting different pathogenic, including premature ageing.



Friday, 25 May 2018

Stem cell trial is Safe

Stem cells are the "buzz word" and trials abound.

This one reports that they appear safe.

However, the question needs to be posed do they work?
Are our expectations too high?

Thursday, 24 May 2018

Scar Wars: Battle of the Labs

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Survey Results: Treating PPMS

In response to my marmite post on 'Not managing expectations in someone with PPMS' I did a survey on treating PPMS. 


You either love it or hate it; a reminder that you can't please everyone!

The following are the survey results, which I find rather interesting. Thoughts?

Wednesday, 23 May 2018

Microglial Control of Astrocytes

There is cross talk between glial cells in the CNS, which will contribute to inflammation and damage.

Today we have a science post from animals (If not interested don't read on) looking at mechanisms of this

Tuesday, 22 May 2018

The neurologists tool kit - Stornoway talk

Photograph: (left to right) myself, Klaus Schmierer, Gareth Pryce, Gavin Giovannoni, David Baker, Stewart Webb, Sarah-Jane Martin, (below) Isle of Lewis.

I've been asked to put in writing the second of my Stornoway (on the Isle of Lewis) talks. The title is 'the neurologists tool kit' and provides an overview of your visit to your neurologist in plain speak. In many ways what is written below are my thoughts on the topic, and is by no means the sum of all practical wisdom!!!

Look back at your first clinical encounter, I would say a vast majority of you would have left without a clear understanding of what just happened - am I right? That's because often the objectives from the two sides are not always the same. 

In the UK, on average a person with MS waits 3-4 months to see an MS neurologist. Through necessity the main source of information becomes Dr Google; I'm not saying this is wrong, but simply a fact. Everything beyond this is simply a succession of moments in time, layered in legitimate facts and misinformation. Conversely, your MSologist at your first visit is viewing you in the following terms: is the diagnosis correct, do I need to do more investigations, what is the prognosis, are they eligible for treatment or suitable for clinical trials, how do I manage expectations - and the list goes on. 

If this sounds unfamiliar, familiarizing yourself with the two sides will go a long way to improving your experience. 

My goal with those that I see is to educate, educate, educate...and ultimately empower each person to be able to direct their own care. It is often an exacerbating experience to start off with, but one that is more fulfilling in the future.

So what is in an MS neurologists tool kit?

1) Clinical skills

This by far is the most important thing we have in our tool kit as clinicians. Our training is often protracted, and full of additional courses and degrees to allow us to accurately diagnose and manage neurological conditions. To the more senior of us the diagnostic process is almost pattern recognition and begins when you walk into the consulting room. 

A person's history is very important in the diagnostic process and informs us of the chronology of events, whether it's progressive, and the rate of progression. While the clinical examination informs us of the pathways involved, which allows us to determine where the problem is. Any investigations that follow are based on the information garnered from the two. 

This is why a computer may never replace what we do to good effect; the best diagnostician is our own brain.

Figure: Myotomes; muscle innervation by nerve roots. One aspect of what is involved in a neurological exam.

2) Investigations: MRI & lumbar puncture

An MRI head and spine study provides the descriptive information about the area of brain or spinal cord involved. The underlying causes of these lesions can be more than one, but the pattern of distribution may make one more likely rather than another, i.e. inflammatory lesions vs. stroke/small vessel disease. Sequential MRIs may also allow us to prognosticate; wherein the accrual of new lesions is indicative of active disease or treatment failure. Neurologists may also comment on brain volume loss at the outset, and will almost certainly direct you to the more highly active therapies. 

A lumbar puncture, on the other hand, provides the biological reason behind the disease. The presence of oligoclonal bands/antibody production in your spinal fluid is almost diagnostic of MS. Not surprisingly, the presence of bands in your spinal fluid also increases your risk of continued disease activity and clinical progression. Recently, we introduced the testing of neurofilament proteins that reflect the degree of breakdown of neurons in your brain and spinal cord. If you have high levels of neurofilaments in your spinal fluid, then you have more of a chance of disease progression and accruing disability faster than a person with normal levels. If you'd like this tested by your doctor, here is the link: http://multiple-sclerosis-research.blogspot.com/2018/02/barts-health-csf-neurofilament-light.html

Photograph: We received this years Innovation Award 2018 for the introduction of neurofilament testing at Barts Health (left to right: Francesca Ammoscato, myself and David Holden; not in the picture Lucia Bianchi)

3) Clinical trials: EDSS, 9-HPT

Always inquire about clinical trials. Clinical trials allow you to access newer treatments 6 to 10y before they are available for clinical use. Moreover, participation in the trials may mean that after trial completion you have access to the treatment in question on a compassionate basis, whilst the drug is in the process acquiring license for prescribing. 

The visits can be sometimes long-winded and often involve assessments of disability (EDSS, timed 24 foot walk and 9-hole peg test for the upper limb function), imaging and in some cases a lumbar puncture. 

Trials are also an important educational resource about MS and provide an insight into current MS research.

Figure: The EDSS score

4) Future: self-monitoring

Online applications and wearables empower us to track our own health. It is almost impossible to clearly remember your last relapse or how your overall health fared this year compared to the last. The hope is that as we use the data from these devices, the consultations become more tangible and more targeted (i.e. personalized), so that the hospital visit is more informative. 

If you haven't already done so, check out the Apps available for the iphone/android devices: Microsoft health vault, Sym Trac, MSAA (My MS Manager), and disability calculator (provided by Rebif manufacturers).

Hope you have found this post useful, and good luck!

Monday, 21 May 2018

What is HSCT?

I seem to be spending a lot more clinic time explaining to my patients about HSCT. What is happening and why?




Sunday, 20 May 2018

Saturday, 19 May 2018

Have your say on the big NHS England MS debate?

You may be aware that NHS England has just closed the public consultation period for the new NHS England Treatment MS DMT Algorithm. The aim of the algorithm is part of a troika, along with Blueteq and MDTs (multidisciplinary team meetings) to reduce the variation in prescribing of DMTs across England. The question is will this algorithm achieve its aim?

The following is the debate we had on this topic last week at the ABN in Birmingham. Please have your say; watch the debate and vote.


2018 List of Best MS Blogs

We have made the Healthline 2018 list of "Best MS Blogs". We have changed the blog in the last 6 months; fewer posts, more guests and less science. Do you think this has improved the blog? We would welcome suggestions going forward. For example, we are thinking of migrating the blog from Blogger onto a better and more responsive platform. 

Friday, 18 May 2018

Your brain stiffens

Rheology is the study of the flow of matter

An interesting brain fact if you are interested

Thursday, 17 May 2018

Depression to reduce MS

Sacramento PM, Monteiro C, Dias ASO, Kasahara TM, Ferreira TB, Hygino J, Wing AC, Andrade RM, Rueda F, Sales MC, Vasconcelos CC, Bento CAM. Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T cell subsets in multiple sclerosis patients. Eur J Immunol. 2018 May 2. doi: 10.1002/eji.201847525. [Epub ahead of print

Excessive levels of pro-inflammatory cytokines in the central nervous system (CNS) are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behaviour of patients with multiple sclerosis (MS), a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8+ T-cells. By contrast, 5-HT increased IL-10 production by CD4+ T-cells from MS patients. A more accurate analysis of these IL-10-secreting CD4+ T-cells revealed that 5-HT favours the expansion of FoxP3+ CD39+ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in up-regulating CD39+ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.


In this study they found that serotonin (5-HT), which is the "happy" neurotransmitter that stimulates brain areas, may help animals with EAE. If this is true they we should have the answer quite soon as MS SMART has been using fluoxitine, which is also known as a prozac and is an SSRI (selective serotonin reuptake inhibitor) meaning that it induces more serotonin in the system....leading to less depression, but does it mean less Th1/Th17 and less MS.

"The objective of the Fluoxetine for Progressive MS study in Belgium and the Netherlands was to see if fluoxetine could slow the progression of MS. The trial (ECTRIM2016) covered both people with primary progressive MS and secondary progressive MS. Participants were divided into two groups. The 69 people in the first group received a 40 mg-per-day dose of fluoxetine (Prozac) for 108 weeks. The 68 people in the second group received a placebo.
Researchers found no significant difference in disease progression between the two groups".

So is the idea a bad one or was it that the trial design meant that a sensible answer could not be found.

Wednesday, 16 May 2018

The Cost of MS is more than just your Health

Last week, we said that Neuros could supplement their income from pharma-related activities.

Next there was a flurry of emails, asking for disclosure of how much, if anything, I get from MS pharma and elsewhere.

Having skirted round the issue, as I am not discussing my personal life, the question is what happens to your income?

Whilst on an individual level, I think it is none of my business, but as I am sure you know, MS does not just cost you your health...but also your wealth.

Even more reason to make sure you deal with MS as best you can as early as you can.

Tuesday, 15 May 2018

The importance of weight in MS

Acta Neurol Scand. 2018 May 11. doi: 10.1111/ane.12959. [Epub ahead of print]


Body mass index and cardiorespiratory fitness in persons with multiple sclerosis.

Monday, 14 May 2018

Guest Post- Animal Studies Enough Already

In response to Yesterday's Post


My photo
Enough with the mouse studies, already! In the 15 years since my diagnosis, I've read countless research reports involving EAE and other mouse models of multiple sclerosis. Only an infinitesimal amount of these reports have ever proven to have any real relevance to the human MS population.

The simple fact is this: mice don't get ms. You can inject them with myelin or other toxins and achieve something that kind of sort of looks like MS, but it's not ms. Then, it seems as if staring intently at the mice long enough or breathing on them shows some kind of benefit. Honestly, it's almost come to that level of ridiculousness.

We must come up with better models of the disease to work on. The amount of time and money wasted on mouse studies is – given the the enormity of the impact of MS on those humans it attacks – obscene.

Really, it's time to rethink our entire approach to MS research. Thus far the best we've come up with are treatments that profoundly suppress parts of the intricate human immune system, the long-term effects of which are a complete unknown. And these treatments do absolutely nothing towards effecting a cure.

Given modern laboratory techniques, the rapid advances in computational power, the emergence of AI, and the vast body of knowledge accumulated by ms researchers and clinicians, one would think a coordinated, concerted effort to finally identify the cause or causes of the disease might finally bear fruit. Time spent fixated on mice with induced conditions that sort of resemble MS is, at this point, time wasted. And those of us forced to watch ourselves disappear by inches don't have that time to waste.

Patients should be rising up against the status quo, but unfortunately most are too busy just trying to get through the day with some modicum of functionality and dignity left intact. MS has gone from medical backwater to one of the most profitable areas of medical practice in the last two decades. It's high time to cure the damn thing and send it back from whence it came. We now have the technology and basic understandings of the mechanisms to get this done, given the will. Coming up with an effective anti-EBV treatment would be a great first step…"
This was a comment made yesterday and is an opinion I am sure many people hold. Likewise, many neuros think the same.  However, basic science is the basis of where treatments come from. 
I was at a recent meeting about finding treatments, which may involve a bit of screening in animals and a very eminent scientist said (Paraphrased) I'm not going to do that as I'm not interested. All I am interested in doing is looking at mechanisms of biology. 

However they are very happy to take money from disease-related charities.


What you do think?


The science publishing system has created a "mechanism is all mentaility" and disease can simply be a vehicle to get research support. 

However times are changing and it is increasingly difficult to get funding for animal studies. However, without knowledge, we will continue to shoot in the dark.

Sunday, 13 May 2018

Care Home vs. Independence

A commentator brought this BBC interview to our attention as an example of what is happening to people with MS living in England. I would be interested to know if there are any other examples of this happening across the country. We need to do something about it. Can anyone help? 


ProfG    

Imaging the Rim




A chronic Active Lesion has a demyelinated centre and rim of myelin damage/removal by macrophages. These can be seen on a 7T magnetic resonance imaging scanner, but this study shows they can also be seen on a lower power 3T machine. If you can see it then you can monitor it.

Absinta M, Sati P, Fechner A, Schindler MK, Nair G, Reich DS. 
Identification of Chronic Active Multiple Sclerosis Lesions on 3T MRI. AJNR Am J Neuroradiol. 2018. doi: 10.3174/ajnr.A5660. [Epub ahead of print]

BACKGROUND AND PURPOSE: MR imaging-pathologic studies have reported that paramagnetic rims on 7T susceptibility-based MR imaging identify, in vivo, the subset of MS lesions with compartmentalized inflammation at the lesion edge and associated remyelination failure. Here, we assessed the reliability of detecting these rims on high-resolution 3T phase images.
MATERIALS AND METHODS: High-resolution T2* and phase MR imaging was collected in 20 patients with MS at 3T (3D segmented EPI, 0.65 mm3) and 7T (2D gradient-echo, 0.2 × 0.2 × 1 mm) MR imaging. In each case, 5 discrete chronic (non-enhancing) MS lesions were selected on T2 FLAIR images for rim evaluation. Five raters experienced in MS imaging contributed to the rim assessment, of whom 3 worked independently on 3T data, and 2, on 7T data. Consensus agreement was reached for both 3T and 7T rim evaluations. Discrepancies between 3T and 7T were discussed, and consensus was reached.
RESULTS: Phase rims were seen in 34 lesions at 7T and in 36 lesions at 3T by consensus. Inter- and intrarater reliability were "substantial/good" both at 3T and 7T analysis (Cohen κ, >0.71). Based on consensus agreement, the reliability of rim visualization at 3T versus 7T was 0.78 (κ) with a pair-wise agreement of 90%. More lesions were judged to be false-positive or false-negative at 3T than at 7T.
CONCLUSIONS: Nearly all 7T paramagnetic rims can also be seen at 3T. Imaging at 3T opens the possibility of implementing paramagnetic rims as an outcome measure in multicenter, MR imaging-based clinical trials aimed at treating perilesional persistent inflammation and its potential effects on remyelination.


http://www.ajnr.org/content/ajnr/early/2018/05/03/ajnr.A5660/F2.large.jpg?width=800&height=600&carousel=1

Saturday, 12 May 2018

Mirror Mirror on the wall, what is the greatest cause of all?

This is a chant that we have been saying to ourselves for years as we try to understand what is the cause of MS.

In this study we are told that it is myelin, altered myelin.  

New concept?

But is it really..as we know dysmyelinated mutants get neurological problems.

News: children with MS get their first licensed DMT

It may be old news, but it is very good news; the FDA has just licensed fingolimod as the first DMT for paediatric MS

I am sure parents of children with MS living in the US are relieved that they finally have a licensed therapy for their children. I sincerely hope the EMA now steps up to the mark and does the same in Europe.




Friday, 11 May 2018

Thursday, 10 May 2018

Neurologists supplement their income

The NHS Doctor can supplement their income by private practice, but also from the Pharma Industry.

In the USA they are transparent about this, So what do they get?

Guest post: FES and the #ThinkHand campaign

Back in the day I had RRMS, now I have advanced MS. A common problem of this disease is dropped foot, the inability to lift the foot when walking, it get progressively worse and worse. It is usually the front of the foot or the toe of the shoe that catches on the ground. I stopped walking the dog in 2004 when walking several miles in woodland was too tiring but in about 2005 dropped foot became a serious issue. Just walking on the pavements I would fall over and suddenly I’m flat on my face and it hurt me. Not something I would recommend.

Wednesday, 9 May 2018

Guest Post: Is spinal cord volume an independent parameter in MS?

In our recent study, we found significant correlations between the volumes of several brain structures and the spinal cord (SC) in patients with mild disability. However, in patients with moderate to severe disability this correlation was significantly reduced. 

Tuesday, 8 May 2018

Therapeutic doubts - regression of skin cancer after stopping fingolimod

Mult Scler. 2018 May 1:1352458518774444. doi: 10.1177/1352458518774444. [Epub ahead of print]

Spontaneous regression of tumor-stage cutaneous T-cell lymphoma in a multiple sclerosis patient after discontinuing fingolimod.

Monday, 7 May 2018

Ask Barts-MS - May 2018

If you have any questions unrelated to the posts this is the place for you.



Sunday, 6 May 2018

MS on the increase

MS is on the increase, notably in women,
What's the cause?

Is it their shoes?

The case for physician assisted dying - one MSer’s view

If reading about death and MS is too difficult for those of you with the disease, please skip this piece. I do not want to offend or hurt anyone. This is just my view.

Saturday, 5 May 2018

A trial of a possible remyelinating drug in multiple sclerosis

Do you live in the UK? You may want to consider volunteering to participate in a very exciting remyelination trial.



Friday, 4 May 2018

Are you attending the ABN?

Are you attending the ABN next week? If, yes you may be interested in hearing a debate. 



#MSis1not2or3diseases: do you agree?

This post makes the case, yet again, for MS being one disease and that PPMS is no different to other types of MS. Do you agree?



Thursday, 3 May 2018

Memory B cells and MS

Last year we started to point the finger at memory B cells

In this study they looked at B cell subsets in people with the first demyelinating event, people who went on to be diagnosed with MS and MS had perturbations in their memory B cell pool and they conclude that there were suppressed memory cells. 

The title seems interesting if you are following this story read on

Tuesday, 1 May 2018

My drug is better than your drug? Science or marketing?

Differences are being suggested between the interferons. 

Is this biology or marketing?

Worrying sheep

Mult Scler. 2018 Apr 1:1352458518767327. doi: 10.1177/1352458518767327. [Epub ahead of print]

Evidence of Clostridium perfringens epsilon toxin associated with multiple sclerosis.

Wagley S, Bokori-Brown M, Morcrette H, Malaspina A, D'Arcy C, Gnanapavan S, Lewis N, Popoff MR, Raciborska D, Nicholas R, Turner B, Titball RW.


Abstract

BACKGROUND:

It was recently reported that, using Western blotting, some multiple sclerosis (MS) patients in the United States had antibodies against epsilon toxin (Etx) from Clostridium perfringens, suggesting that the toxin may play a role in the disease.

OBJECTIVE:

We investigated for serum antibodies against Etx in UK patients with clinically definite multiple sclerosis (CDMS) or presenting with clinically isolated syndrome (CIS) or optic neuritis (ON) and in age- and gender-matched controls.

METHODS:

We tested sera from CDMS, CIS or ON patients or controls by Western blotting. We also tested CDMS sera for reactivity with linear overlapping peptides spanning the amino acid sequence (Pepscan) of Etx.

RESULTS:

Using Western blotting, 24% of sera in the combined CDMS, CIS and ON groups ( n = 125) reacted with Etx. In the control group ( n = 125), 10% of the samples reacted. Using Pepscan, 33% of sera tested reacted with at least one peptide, whereas in the control group only 16% of sera reacted. Out of 61 samples, 21 (43%) were positive to one or other testing methodology. Three samples were positive by Western blotting and Pepscan.

CONCLUSION:

Our results broadly support the previous findings and the role of Etx in the aetiology of MS warrants further investigation.

Believe it or not it is illegal in England & Wales to worry sheep - although this generally applies to dogs, and in certain cases to rambling tourists...But are sheep worrying for us humans? According to Wagley and colleagues, getting too close to our fury friends may not be a good idea as it first seems. 

Clostridium perfringens epsilon toxin is a spore-forming toxin that triggers fatal enterotoxaemia in sheep and goats. It is normally present in the soil and healthy gut of these animals, but under certain conditions may rapidly multiply resulting in large quantities of the toxin. The toxin builds up in the kidneys and the brain where it can damage neuronal structures, including oligodendrocytes (myelin forming cells).

Antibodies to epsilon toxin have been previously found in MS cases and may be a potential aetiological source, such as EBV, HERVS and HSV.  Wagley and colleagues studied the occurrence of antibodies to epsilon toxin in the blood of MS, clinically isolated syndrome (CIS; first presentation of MS) and optic neuritis (ON) cases. They found that 24% of MS/CIS/ON groups compared to 10% of controls had antibodies to the epsilon toxin. The presence of antibodies in controls suggests that their occurrence cannot wholly be explained by the over expression of autoantibodies in MS. 

It is not certain what the significant finding here is; the antibody to the toxin in MS or the initial exposure to the toxin. The Telegraph coverage (above) points out that sheep farming is more common in the northern altitudes, as is MS. This may be a leap too far, but the signal warrants more in-depth investigation.

CoI: Prof G, Dr Turner, Dr Raciborska and myself were involved in this work.