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.

Monday, 30 April 2018

Alemtuzumab, is one course enough?

...... data suggest that induction of disease remission for some patients might occur following just one dose of alemtuzumab. 


Sunday, 29 April 2018

Another CD20 depleting agent shows efficacy

First there was rituximab (part mouse, part human), then there was ocrelizumab (largely human and a tiny bit mouse) and now there is ofatumumab (which is all human) as yet another B cell depleting antibody.


AAN2018: Laquinimod joins the PPMS graveyard

I am just back from LaLa Land and the AAN2018 meeting. I am feeling exhausted, MSed-out, conferenced-out and very concerned about the future of neurology (more on this on my Medium post). 


The AAN2018 was far too long, too spread-out (the venue was cavernous with rooms that were in general too large) and too expensive (conference fees, LA hotels, restaurants, regional wines and flights). The AAN is definitely not the premier MS meeting it used to be. ECTRIMS and ACTRIMS have usurped the AAN to such a degree that there was very little new MS data presented at this meeting. My presentation on the Arpeggio results was at least novel. As promised I have uploaded it onto SlideShare for you to browse. 

Saturday, 28 April 2018

Changing Gut microbes with a probiotic

Its AAN this week and ProfG and many of the other Neuros are in LaLa Land to get their annual fill of all things neurology. 

What interests you this year?

As soon as the microbiome (Gut Microbe) appeared it was obvious that the scammers would be there to make money off vulnerable people.

People will asked to pay money to have their bowels cleared and the they have to eat a feacal extract to change their microbiome. Ker-ching. 

Academics would then follow do a trial and show that it doesn't really work...OK that's me just guessing. However they will do a study to see if it works and the MS Socieites spend aload of money.
Sound familiar?..CCSVI?

It is happening a trial of feacal transplant ..... Yep you get your bowels cleared and then you eat it.

Fecal Microbial Transplantation in Multiple Sclerosis: trial design. 
Ana Cristina Wing, Marcelo Kremenchutzky: 
To describe a trial design to evaluate FMT effects on MS patients. A single site, randomized, open label, controlled, crossover study. Forty patients will be randomized 1:1 into two groups. One group will receive FMT by rectal enema, while the other group will receive treatment as per standard of care (control group) for the first 6 months. Thereafter, the early intervention group will no longer receive FMT and the initially control group will receive FMT for the remaining 6 months. A 3rd group of healthy volunteers will be a reference control. Primary outcome will be peripheral blood cytokines measured by Luminex assay. As secondary outcomes blood DNA bacteria and urinalysis to evaluate gut permeability, head MRI as a safety marker and trial feasibility metrics. Results: Eight patients have already been enrolled to this study, 4 (50%) females and 4 (50%) males. Mean age of disease onset is 32 years old (22 – 40). Mean current EDSS is 4.0 (1.5 – 6.5). Patients manifested their MS symptom in average 20 years ago (7-44). All except two are currently using disease modifying therapy. Conclusions: This proof of concept, first in humans, independent pilot study will shed light on the relationships between gut bacteria and MS. We present here study design and preliminary baseline demographics, and discuss its possible impact on disease inflammation to guide future large-scale studies.

Many people have been conned to part with their hard-earned cash They no doubt give you some R & R  and fed someone elses number two's.  Canada forked out a few million to rebuff the CSSVI idea and this study is looking at changes in the microbiome

In this study from Canada you get an enema, but at the AAN, you wont get result for a few years? So do we want to know that a trial is occuring.

But in this study from Harvard, They are taking a Probiotic.


Tankou SK, Regev K, Healy BC, Tjon E, Laghi L, Cox LM, Kivisäkk P, Pierre IV, Lokhande H, Gandhi R, Cook S, Glanz B, Stankiewicz J, Weiner HL. Ann Neurol. 2018 Apr 20. doi: 10.1002/ana.25244. [Epub ahead of print]

OBJECTIVE:

Effect of a probiotic on the gut microbiome and peripheral immune function in healthy controls and relapsing-remitting multiple sclerosis (RRMS) patients.

METHODS:

MS patients (N=9) and controls (N=13) were orally administered a probiotic containing Lactobacillus, Bifidobacterium and Streptococcus twice daily for two months. Blood and stool specimens were collected at baseline, after completion of the 2-month treatment, and 3 months after discontinuation of therapy. Frozen peripheral blood mononuclear cells (PBMCs) were used for immune cell profiling. Stool samples were used for 16S rRNA profiling and metabolomics.

RESULTS:

Probiotic administration increased the abundance of several taxa known to be depleted in MS such as Lactobacillus. We found that probiotic use decreased the abundance of taxa previously associated with dysbiosis in MS including Akkermansia and Blautia. Predictive metagenomic analysis revealed a decrease in the abundance of several KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathways associated with altered gut microbiota function in MS patients such as methane metabolism following probiotic supplementation. At the immune level, probiotic administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of inflammatory monocytes, decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes as well as decreased HLA-DR MFI on dendritic cells. Probiotic administration was also associated with decreased expression of MS risk allele HLA-DQA1 in controls. Probiotic induced increased in the abundance of Lactobacillus and Bifidobacterium were associated with decreased expression of MS risk allele HLA.DPB1 in controls.

INTERPRETATION:

Our results suggest that probiotic could have a synergistic effect with current MS therapies. 

Synergism is a word that is often overused in science. Synergiism means more than the additive effect of two things. What is the evidence for this?. Maybe the probiotic influences immunity but we need to see the effect on clinical parameters 

Friday, 27 April 2018

Improving the taste of cannabis spray

AIM:

Complaints about Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®; GW Pharma Ltd, Sailsbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies. This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects.

MATERIALS & METHODS:

Patients with multiple sclerosis spasticity (n = 52) at six sites in Italy who were receiving THC:CBD oromucosal spray and had associated oral mucosal effects were randomized into Group A (chewing gum; n = 15); Group B (cold bottle; n = 20); and Group C (cold bottle + chewing gum; n = 17).

RESULTS:

Taste perception in patients receiving chewing gum ± cold bottle intervention (Groups A and C combined) was significantly (p = 0.0001) improved from baseline to week 4 while maintaining spasticity control.

CONCLUSION:

Patient comfort, satisfaction and treatment adherence may benefit from these interventions
This article may be useful to anyone who gets sativex. Sativex is an alcoholic extract of cannabis (i.e a tincture), I thik with a peppermint flavour, so it is like a Creme-de-Menthe spray under the toungue. However, as it is reletively pure alcohol,means that it is going to be a fixative to the inside of the cheek and it is going to taste unpleasant. We know this because in the placebo controlled tirals where people could have 0-20+ puffs of the sativex inhaler and those on placebo where there is no drug to work, should have been puffing away, but they didn't ,and on average had lesss than a half of available. This says the taste isn't good. However, above may be some use if you can get access to treatment

Thursday, 26 April 2018

MSTV has launched!

It's MS Awareness Week from the 23rd-29th April and the MS Trust have launched a new YouTube channel and project for young people aged 11 to 17 who are affected by MS.


MSTV-landing-tile_0.png

Wednesday, 25 April 2018

MS@thelimits 2018

Do you want to attend the MS@thelimits 2018 meeting?  This year the focus is on cellular therapies, comorbidities and trials in more advanced MS. 

Have a look at the programme. 

For those not there. Here is At the Limits 2017

If you don't live near London, fear not, because the meeting will no doubt be filmed, 

Indeed last year it was "live streamed" and the events went online.
You can watch it, if you follow the links here

Pharma comes out

Last year we spent quite some time hastling  Eli Lilly about the fact that they had not published the data about tabalumab (anti-BAFF) in MS.

Atacicicept (anti-BAFF & APRIL) made MS worse. SO what happened with Tabalumab. I guess we now find out

Tuesday, 24 April 2018

PML risk in fingolimod

Progressive multifocal leukoencephalopathy after fingolimod treatment

Joseph R. Berger, Bruce A. Cree, Benjamin Greenberg, Bernhard Hemmer, Brian J. Ward, Victor M. Dong and Martin Merschhemke
First published April 18, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005529 loads

Abstract


Objective We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder.

Methods The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod.

Results As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL).

Conclusions The risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039–0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75–5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.

Gaussian or "normal" distribution

When Nassim Taleb in his book 'The Black Swan' talks about the impact of the highly improbable, he references 9/11, the Walls St crash, and the so-called experts and "empty suits" who provide a minute by minute narration of the events, but in real terms do not know more on the subject than the general population. According to Taleb the occurrence of a black swan is a rare event, but a single sighting can invalidate a statement based on sightings of swans being white going back a millennia. Interestingly, it took me some time to recognise that the occurrence of PML following immunosuppressant use is an example of a black swan.

Taleb also talks about the pitfall of human/academic arrogance, he calls this GIF (Great Intellectual Fraud), whereby we look at data in terms of normality (the bell shaped curve or Gaussian distribution) and talk of commonalities from the outset at the cost of outliers. This gives rise to a false state of reassurance that we have tamed the rare occurrences, which is far from the truth. This concept also applies to our interpretation of PML risk.

Here, Novartis (who make fingolimod, also known as Gilenya) present the risk and incidence of PML in those on fingolimod. They have 15 cases (12 definite, 3 probable) following fingolimod use up to Aug 2017. This excludes cases that may be attributed to carry over risk from previous natalizumab use over the last 6 months.


The estimate the risk of occurrence of PML is 0.07 per 1000 patients treated (i.e. <1:10,000). The mean age affected was 53, of the 15 cases, 11 were women, and the duration of MS was 4-35 years, 1 had previous cancer, while another had bowel colitis with prior immunosuppressant use. Interestingly, like with the natalizumab risk stratification 14/15 cases had been on fingolimod for >2y. Only 4 of the cases exhibited grade for lymphopenia (i.e. </= 200 cells/ul).
 
The author’s conclude that “the number of PML cases reported so far with fingolimod is too low to trigger any specific interventions at this point in time”. I wonder if they realise that the incidence of PML is a black swan? Their occurrence so rare as to render risk-mitigation strategies effectively useless. And yet as doctors we need guidelines to cushion our intellectual sensibilities.
 
Along these lines below is the existing MHRA (Medicines and Healthcare products Regulatory Agency) for risk of PML on fingolimod.
 
Before starting fingolimod treatment:
  • Perform a full blood count including lymphocyte subsets
  • Perform a baseline cranial MRI scan as a reference, usually within 3 months of starting fingolimod treatment
  • Counsel patients and carers on the risk of PML; advise them on the symptoms to watch out for and to get medical help urgently if they occur
  • If testing for JCV is undertaken, consider that the influence of lymphopenia on the accuracy of the anti-JCV antibody test has not been studied in fingolimod-treated patients

During fingolimod treatment
  • If PML is suspected, stop fingolimod treatment immediately and investigate appropriately, eg MRI scan; ultrasensitive polymerase chain reaction (PCR) assay for JCV DNA
  • Monitor full blood count 3 months after starting fingolimod treatment and at least yearly thereafter
  • We remind you to interrupt fingolimod treatment if lymphocyte count falls below 0.2x109/L, do not restart treatment until lymphocyte levels have recovered
  • When analysing routine MRI scans, pay attention to PML-suggestive lesions
  • Consider further MRI scans as part of increased vigilance in patients considered at high risk of PML, in accordance with national and local recommendations
  • Monitor patients for signs and symptoms or appearance of new neurological dysfunction (eg motor, cognitive, or psychiatric symptoms), bearing in mind that PML can present with features similar to multiple sclerosis
  • Note that patients might still develop a JCV infection, even if they have a normal lymphocyte count and previously tested negative for anti-JCV antibodies

Saturday, 21 April 2018

Prof G the feminist

Three things happened to me this week that made realise that I am a feminist.


Friday, 20 April 2018

Is the B cell idea broken?....Sort of Th17 and Th1 are the problem.

The B cell hypothesis gains momentum with the Pharma Industry, but do our academic colleagues know better and it really is the TH17 cell at the top of the pyramid.

Thursday, 19 April 2018

Vaccines and Vaccinations: The Big Differentiator

I predict vaccines and the timing of vaccinations will in time become a major differentiator between the maintenance therapies and the immune reconstitution therapies (IRTs). 



What do you think? 

Wednesday, 18 April 2018

Guest post: Your attention please: MS hurts!



Visual impairment, sensory disturbances, weakness and fatigue are among the most commons symptoms in MS, but there are others such as pain, which is highly distressing and can easily affect day-to-day life. This symptom is often difficult to describe by patients and is sometimes difficult to diagnose and treat by clinicians.

Tuesday, 17 April 2018

EBV and the not so magnificant 7. A cause of autoimmunity

New genetic research has linked EBV infection to seven autoimmune diseases and include multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, celiac disease and SLE

What do they have in common?


A glass half full? Benign MS in Australia

Are you a glass-half-full or a glass-half-empty person? 


Monday, 16 April 2018

Reflections on all things MS from Stornoway

We have just finished our 2018 Barts-MS Research Day on Stornoway with the Glasgow-MS team. The experience has been very humbling and quite and an eye-opener in terms of living with a chronic disease, such as MS, on a remote Island.

Barts-MS and Glasgow-MS hugging the Callanish Stones, Western Isles.


Saturday, 14 April 2018

Friday, 13 April 2018

TeamG News

Sorry No posts today but we have been busy in Sunny , Stornoway for a Research Day with the Neuros from Glasgow. 

We were on BBCAlba (Gaelic TV) at 19.00 if interested. As you can see we have been filming the day, so the event will be on Youtube once edited.




See the News video below

Thursday, 12 April 2018

The B cell bandwagon gains momentum

Every one is getting in on the B cell bandwagon. 

There is review after review. Many give a lot of facts, but limited real insight. However, they contain some pretty pictures that may help you understand B cell development.

What is so special about Stornoway?

A post to celebrate some of the MS Champions who help make the MS-World go around.

Stornoway, Lewis, Western Isles of Scotland

Wednesday, 11 April 2018

Sunday, 8 April 2018

Guest post: Stopping therapy - is it worth the risk?



Some MSers ask if they can stop taking DMTs after being stable for a long time, especially older pwMS and people with advanced MS. This is a two-sided discussion: There are those who are for it and those who are against it. Let’s take a closer look at the arguments of those on each side of this fence:

Friday, 6 April 2018

Are you about to be treated with Alemtuzumab?

If you are about to be treated with alemtuzumab you may want to know about acute acalculous cholecystitis?  

Acalculous cholecystitis with pericholecystic fluid collection as demonstrated by abdominal computed tomography scans (G). (Figure from ResearchGate)
This is a relatively new complication that occurs early after starting alemtuzumab infusions. I can hear you all saying 'Oh no, not something else to consider when making a decision to go high-efficacy high-risk'.

Wednesday, 4 April 2018

Brain damage and the Black Dog

MSers are often depressed. Depression leads to poor quality of life, the breakdown in relationships, a sense of hopelessness, social isolation, unemployment and suicide. It is important that MSers are regularly screened for depression and treated.



Are you interested in knowing more about depression in MS?


Tuesday, 3 April 2018

Invitation to Future-proofing Healthcare: NeuroSense

I have been invited to speak this Thursday evening at a meeting in London. There are still free places if you want to attend. As usual, I will post my slides online.


Measuring brain permeability - a new marker of disease activity?

How permeable, or leaky, is your blood-brain-barrier? Does it make a difference? 


Monday, 2 April 2018

MS Suceptibility Genes may link to EBV viral Loads

Genetic variants found in people with MS appear to be associated with viral infection with EBV.
Is this genetic locus making understanding of MS susceptibility clearer

Sunday, 1 April 2018

Ask Barts-MS - April 2018

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



Remember when you read the Barts-MS Newsflash on the 1st April 1st that it was an April Fools' Day Joke.  We don't think DrK is leaving us. 

Guest post: Smoking and worsening disability in MS

As medical students we read in our textbooks about smoking increasing the risk of MS, but timing and the extent of exposure to tobacco smoke in MS pathogenesis remained unclear. Pioneering studies showed this increased risk, which was further analyzed in meta-analyses. 



Newflash TeamG News

Distressing Barts-MS Team News.

Saturday, 31 March 2018

The MS Establishment

The recent commentary by Alasdair Coles and riposte by Jack Antel has sparked a prickly debate about the role of a relatively small number of academic neurologists, who are also known as KOLs (key opinion leaders), in relation to MS clinical trials and their subsequent publications. 


Friday, 30 March 2018

Thursday, 29 March 2018

Guest post: Alasdair Coles on An Instinct for Kindness

Prof G asked me to listen to An Instinct for Kindness and offer some comments. As I was mulling over what I might say, I read the posts about the play on this blog: some appreciative, some angry, some disturbed. 


Wednesday, 28 March 2018

NEDA after ocrelizumab

No-evidence of disease activity (NEDA) means 
  • No Clinical Relapse
  • No New Lesion activity
  • No progression of EDSS
ProfG works some magic with Oreclizumab to make it better than any other chemical DMT.

What's he done?

Monday, 26 March 2018

Trying to emulate the Cleveland Clinic at Barts-MS

I have just spent two days attending the 2018 or third Cleveland Clinic Neurological Institute MS Summit on 'MS Treatment Strategies'. I had to give a talk on composite outcomes in trials and clinical practice. I am not sure why I was asked to cover this topic as I would not rate myself as being an expert on MS-related outcome measures.



As promised I have made my slides available.


News Update: positive GNbAC1 phase 2 results

Has the black swan arrived? Could MS be due to a viral infection? Is the #CharcotProject alive and kicking?

Sunday, 25 March 2018

B regulatory cells promote remyelination

First we had T regulatory cells promoting remyelination. 

In this report it is the turn of the B regulatory cells to do the same thing

Saturday, 24 March 2018

Estimating the future Prognosis

If you live in the UK, If you haven't done this yet, why not sign up to the UK MS register.


Friday, 23 March 2018

Is MOG the important autantigen in MS, like it is in EAE

MS is an autoimmune disease...isn't it.

Where is the proof?  

There is plenty of circumstantial evidence and there is clearly autoimmunity in MS, but is it the chief problem

"Of course it is" I hear many of my colleagues say.

Look at EAE, that is autoimmunity and that's MS isn't it.

Thursday, 22 March 2018

The Phoenix has risen: the era of disease modification in progressive MS has truly arrived

The EXPAND study is the first positive study in people with secondary progressive MS and marks a new landmark in the treatment of MS.


Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings. 

Fingolimod inducing low white blood cell levels but saving brain

What are the consequences of having a low lymphocyte count when starting fingolimod?