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.