Saturday, 17 November 2018

How does HSCT work?

I have been asking myself about the non-myeablative HSCT and wondering how does it work?

It is often a combination of cyclophophamide and anti-thymocyte globulin.

Friday, 16 November 2018

Alternatives to Cladribine tablets appears

DrK has been beavering away and has now started to disclose his experience

Thursday, 15 November 2018

HSCT after natalizumab

Mariottini A, Innocenti C, Forci B, Magnani E, Mechi C, Barilaro A, Nistri R, Fani A, Saccardi R, Massacesi L, Repice AM. Safety and efficacy of autologous hematopoietic stem cell transplantation following natalizumab discontinuation in aggressive Multiple Sclerosis. Eur J Neurol. 2018 Nov 10. doi: 10.1111/ene.13866. [Epub ahead of print]

BACKGROUND: Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, safety and efficacy of autologous hematopoietic stem cell transplantation (aHSCT) performed following NTZ discontinuation was retrospectively compared with conventional DMTs.
METHODS: Patients with RRMS treated with NTZ and who discontinued the drug after at least six administrations and with at least six months of follow-up were included. Patients underwent aHSCT after a minimum period of six months following NTZ withdrawal, receiving in the meanwhile cyclophosphamide or corticosteroids, or received other DMTs approved for MS (control group) after an adequate wash-out period. Both haematological and neurological follow-up were assessed according to standard policies.
RESULTS: Fifty-two patients were included, 11 who received aHSCT and 41 DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including Progressive Multifocal Leukoencephalopathy, were observed. At three years following NTZ discontinuation no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared to 11.5% of those in the DMT group (p=0.0212); disease reactivation in the aHSCT patients was observed only during wash-out/bridging therapy and after aHSCT 100% of the cases were free from disease activity.
CONCLUSION: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. AHSCT after six months from NTZ withdrawal seems safe.

If you are not having a sub clinical infection of JC virus, conversion to a depleting antibody is safe. However there have been cases of fatality after alemtuzumab, where there was carry over infection. So the risks for HSCT are similar so ensure you don't have sub clinical PML before starting

Guest post: digital services for MSers

As we all are aware, there is an increasing number of organisations developing and providing digital services to help make life easier for people with MS.

Wednesday, 14 November 2018

Reminder about the free, one-day event for ‘plus ones’ of people recently diagnosed with MS

One week on Saturday we are involved in an information event for partners, family and friends of people newly diagnosed with MS - come along if you're in London!

Tuesday, 13 November 2018

Small gains, upper limb robotics

Front Neurol. 2018 Oct 24;9:905. doi: 10.3389/fneur.2018.00905. eCollection 2018.

Effects of High-intensity Robot-assisted Hand Training on Upper Limb Recovery and Muscle Activity in Individuals With Multiple Sclerosis: A Randomized, Controlled, Single-Blinded Trial.

Sunday, 11 November 2018

Alemtuzumab it isn't just problems with B cell Autoimmunities.

Alemtzumab induces CD8 mediated autoimmunity. 

Is it Shock, Horror, Probe! or time for more reading on how T cells
repopulate after depletion

Saturday, 10 November 2018

What should you expect to Save your Brain

The great and the good have got together to try and come to come to a consensus of what you should expect with regard to

Time for referral and diagnosis. 
Time to treatment decisions 
How you should be monitored 
How quick should you report issues 
How quick should the response be.

The finger is pointing to the B cell with disease reactivation

This is a case report.

Is it a fluke or does it tell us something

Friday, 9 November 2018

I don't usually do Cure of the Week but

I don't usually do "Cure of the Week", where someone treats a mouse and it somehow becomes the next great hope for MS. 

DrK sparked my interest by a twitter post

Thursday, 8 November 2018

Prediagnostic PML

PML is a major worry concerning treatment of MS

Can the PML lesion be picked up before the development 

Wednesday, 7 November 2018

ECTRIMS-Questioning the EBV

Epstein Barr Virus is it, isn't it. 
You do the experiment and try and disprove the hypothesis.

Tuesday, 6 November 2018

When Mist Becomes Most

Prof Burt from Chicago has presented "At the Limits 2018"
and shown the headline results of the MIST trial (A randomised, assessor blinded clinical trial), which finished recruitment in 2016. 

Very Interesting, but you'll have to wait until the results are announced/published before we will . Sorry but it is only fair to the USA, British,Swedish and Brazilian Teams to keep quiet.

However, before he started talking about the results, in his own words “Don’t do Progressive disease”

People with active disease respond best to this treatment which is cyclophosphamide and anti-thymocyte globulin followed by stem cells to block the infection risk of loss of neutrophils.

Next up is the Trial. Maximizing Outcome of Stem Cell Transplantation (MOST), We look forward to seeing what is planned.

PET imaging in MS: a marker of acute demyelination

Eur J Nucl Med Mol Imaging. 2018 Oct 21. doi: 10.1007/s00259-018-4182-1. [Epub ahead of print]

Amyloid PET as a marker of normal-appearing white matter early damage in multiple sclerosis: correlation with CSF β-amyloid levels and brain volumes.

Pietroboni AM, Carandini T, Colombi A, Mercurio M, Ghezzi L, Giulietti G, Scarioni M, Arighi A, Fenoglio C, De Riz MA, Fumagalli GG, Basilico P, Serpente M, Bozzali M, Scarpini E, Galimberti D, Marotta G.



The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with β-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) β-amyloid1-42 (Aβ) levels, amyloid tracer uptake, and brain volumes.


Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18F-florbetapir PET. Aβ levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted.


We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aβ concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01).


The correlation between CSF Aβ levels and NAWM-SUV suggests that the predictive role of β-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.

Figure: a T1-weighted MRI; b co-registered 18F-florbetapir PET and c T1-weighted MRI/PET fusion images (using the hot iron map); d T2-weighted FLAIR MRI; e lesion elaboration from the Lesion Segmentation Tool (yellow); f normal-appearing white matter (blue) and damaged white matter (red) segmentation on T2-weighted FLAIR MRI

Traditionally, majority of us when we hear the terms Aβ or PET imaging (positron emission tomography; developed to image amyloid deposition), we immediately think of the dementia disorders, such as, Alzheimer's disease. However, PET imaging has recently also been repurposed as an imaging marker in MS to study myelin loss and repair, utilizing its non-specific binding to the white matter - where demyelination (loss of myelin) leads to a reduction in uptake. Not surprisingly, it may be a more sensitive marker of acute white matter lesions than conventional MRI.

Here the investigators progress our understanding of amyloid markers further by asking whether a) amyloid uptake in white matter lesions and normal appearing white matter (i.e. the normal looking white matter on MRI scans) can be split according to disease activity and b) if there is a relationship between amyloid uptake and spinal fluid levels of Aβ, white matter brain volumes and disease progression?

As expected, they found that amyloid uptake in the largest white matter MS lesion for each participant was reduced compared to their normal appearing white matter; confirming its usefulness as a marker of myelin loss (this finding has been confirmed by other investigators also and is not a new finding). However, the tracer uptake was reduced in those with active disease than in non-active participants, suggesting that white matter myelin is damaged during the early course of disease activation. Moreover, this reduced uptake was not only visible in the diseased white matter but also in the normal appearing white matter - it is not unusual in pathology studies to see immune activity even in macroscopically normal looking brain! 

The normal appearing white matter amyloid uptake showed a positive correlation with white matter volume (i.e both increased in tandem), but although there was a trend toward a negative correlation with diseased white matter volume (when one was high, the other was low), it was not found to be statistically significant. There was also a positive correlation between spinal fluid Aβ levels and tracer uptake in the normal appearing white matter (the lower the CSF Aβ level, the lower the tracer uptake in the normal appearing white matter). CSF Aβ levels showed a positive correlation with PASAT2 (an assessment of cognition), but not with other measures of disability. The latter findings are not surprising as the study is small.

Overall, a nice piece of work. But one of the major limitations of PET, in my opinion, is the cost of PET relative to MRI alone. Moreover, CSF Aβ, aside from performing a lumbar puncture, is again a fraction of this cost and one can measure several other biomarkers in tandem if necessary.

Monday, 5 November 2018

Guest post: MSexism 3 - gender bias in the MS community

Women experts launch a call to action to end gender bias in the MS community.

More than one hundred female academic neurologists and neuroscientists worldwide have called on pharmaceutical companies, MS conference organisers and journal editorial boards to make changes to achieve greater gender equality. 

Sunday, 4 November 2018

More Salty stuff..

It has been suggested by "New England MS" that salt is a key problem in MS, Here they say this effect is mediated by β-catenin pathway.

Saturday, 3 November 2018

To Get the Why, You Need to Know where to Look

Someone had a go at me  (perhaps) saying "The ego-maniacs arguing about whether MS is T cell or B cell impacted is a wonderful example of the Pharma hold on the Medical Industry"

I disagree this is an academia led issue, MS pharma don't care, they know where they dropped their wallet:-)

"All the arguments and their associated time wasting hides the essence of the problem. The reason, the 'why' factor is the issue with the immune system involvement in any and all chronic diseases"

Your point is well taken, but I have been taking an extreme view on B cells to demonstrate to the T cell dogma, that it needs to think outside of the sterotyped box.  T and B cells do not exist in isolation but for many see "outside of a T cell sphere" only as an after-thought, when T cells a helper cells for others to do the business.

However this is important as highlighted by the "Streetlight effect" as you need to know where to look to find the why, and I thing we have been clear about one route to a "wht".

Depleting B cells inhibits MS

So this says if you keep CD19 B cell low it reduces your relapse rate...So much for T cells?

Friday, 2 November 2018

B cells in MS

Today I post on the pathology of the active MS lesion, which we missed in the summer

At the limits 2018

Next Week:  The Mice are Being Let out for a Conference after all it is in London.Maybe time to sign up if you are a health care professional.

Sheriff Rosco P Coltrane is coming to town. 

Thursday, 1 November 2018

Th9 is this the next big CD4 T cell?

I was teaching (giving some views) to some South American Neurologists last week and I gave a view about the immunopathogenesis of MS.  I had a slide with Th1 and Th17 CD4 cells at the core of MS, which i flipantly said was "Harvard MS". My audience gave me a good grilling about my outspoken ideas and I thank them for that.

However the ideas remain intact.

Harvard MS was a centre that created the view that MS was a Th17 problem. It has been very influential in people's thinking and now most people buy into the idea that MS is a Th17 problem. 

Th17 cells produce interleukin 17 thats how they got their name. 

However blockade of interleukin 17 in MS is relavively pants and blockade of Th1 and Th17 promoting IL-12 and 23 cytokines is pants in MS. Inhibition of IL-17 inhibited MRI lesion formation less than beta interferon, hardly an amazing effect when other agents can wipe them out. 

This could say Th17 in MS is unimportant. 

If I am in my anti-T cell mode, I press this point that Th17 are unlikely to be of major importance, 

However if I am in my biological mode where B cells do not exisit without T cell help and support, I say the animal data is also pants and I have no idea why the neurologists would waste their time doing a trial on an agent that doesn't affect EAE.  This is because the IL-17 knockout date is very weak as is the IL-17 neutralising antibody data .

Yep the effect in EAE is pants too. 

Time and time again we see this type of effect in EAE and it is reported to be important. Nature, Science and Cell is full of this over-interpreted rubbish. It is not stamped out, because it is the opinion-leaders that are peddling this nonsense.

Yet blinkered neurological T cell immunologists convinced (or should I say deluded) themselves and pharma to plough-on regardless.

End result..failed trial and hope dashed

We have another cytokine that T cells and this is called Interleukin 9 (IL9). So T cells that produce IL-9 are called Th9 (yawn). They are a new cell type important in MS.

November Q & A

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