Friday, 31 July 2015

The MPs response to the Off Patent Drugs Bill

This the response by my MP

"Thank you for contacting me recently regarding the Off-Patent Drugs Bill [and the related 'unlock drugs' campaign by Breast Cancer Now].

I appreciate the frustration and concern that many people feel about the delays that can occur in accessing new and potentially effective drugs and treatments. I also appreciate that through their 'Unlock Drugs' and previously 'Unlock Lifesaving Drugs' campaigns, Breast Cancer Now continue to raise the issue of how many low cost and potentially effective drugs are being prevented from being made routinely available due to a lack of licensing.

As you know the Private Members' Bill - the Off-Patent Drugs Bill - introduced by my colleague Nick Thomas-Symonds MP, would require the UK Government to seek licences for such off-patent drugs and therefore improve access to low-cost treatments for a range of conditions, including breast cancer, multiple sclerosis and Parkinson's.

I am aware that there was a previous Private Members' Bill in 2014 which unfortunately the coalition Government did not support when it was debated on 7th November 2014 and, as a result, it did not progress further.

Improving timely access to medicines that can benefit patients is something that we all want to see. The Off-Patent Drugs Bill has yet to be published and I will look at the detail of the legislation. However, I support the principles of the Off-Patent Drugs Bill.

With specific regard to cancer treatment, I also believe we need to ensure that people have access to a wide range of treatments including drugs, radiotherapy and surgery, and that patients get tested quickly if cancer is suspected. At the 2015 General Election I stood on a manifesto which included commitments to improve early cancer diagnosis, speed up waiting times for cancer test results and create a new Cancer Treatments Fund so that patients have access to the latest drugs, surgery and radiotherapy.

The Off-Patent Drugs Bill is due to have its Second Reading in the House of Commons on 6th November 2015. Please be assured I will monitor its progress with interest.

Thank you once again for writing to me and for sharing your views".

So this seems the usual blah, blah, blah, stock response, blah blah, blah, cut and paste, blah, blah, blah, I'll tell you what you already know, blah, blah, blah I am not really reading your letter as my answers aren't quite right and I am not really answering your letter, blah, blah, blah, I won't get off my bum, blah, blah, blah, nothing.

Maybe you can post and I can up load what are countries leaders can do.

Maybe we can give the Scottish National Party MPs something to do? There are over forty of them so they can get to the second reading and it would benefit Scotland...as it is MS Central.
Maybe in the words of Fraser maybe "Were Doomed" as we all can watch a ship sink.
Private Members Bills often don't succeed 

A hammer to crack a nut, is it nuts to think that immunosupressives do not cause PML

Van Schependom J, Gielen J, Laton J, Nagels G. Assessing PML risk under immunotherapy: if all you have is a hammer, everything looks like a nail. Mult Scler. 2015 pii: 1352458515596458. [Epub ahead of print]
Recently, three progressive multifocal leukoencephalopathy (PML) cases have been reported in multiple sclerosis (MS) patients, two treated with fingolimod (Gilenya, Novartis), the third with dimethyl fumarate (Tecfidera, Biogen). Because our immunotherapeutic arsenal in MS and other diseases is increasing, and because PML is a very serious health risk, it is of interest to the clinical community to show how we can assess this risk in a statistically sound way. The null-hypothesis for this analysis was that there is no elevated risk for PML in patients treated with one of these recent drugs, compared to the incidence in the general population. We conclude that the null hypothesis cannot be refuted.

So this stuff says they think that some oral DMT that are generalised immunosuppressives do not cause PML. Wake up an smell the roses people. Long term leucopeania caused by such drugs is going to leave you at risk of infection. It may not be a high risk but it is a risk.

ClinicSpeak: derisking natalizumab

De-risking natalizumab has not proved as simple as I had expected. #ClinicSpeak #MSBlog #MSResearch

How do you switch from natalizumab to alemtuzumab? #ClinicSpeak #MSBlog #MSResearch


"At Barts-MS we are trying to de-risk natalizumab-treated MSers as much as possible. Now that we have other options for MSers why would anyone want to stay on natalizumab who is JCV seropositive? In addition, there are more treatments coming, for example, ocrelizumab and daclizumab. In Sweden the drug of choice is rituximab that is being used off-label."


"I am reposting on this as one of my patients has now finished 12 months of bridging with fingolimod (option 3 below) and has decided that as she is doing so well on fingolimod she doesn't want alemtuzumab; c'est la vie!"

"The switch is relatively straight forward if you are JC virus seronegative and are switching because of lack of  efficacy, or for a life-style choice, for example if you are tired of monthly infusions, or you want to an induction therapy that offers you the freedom to fall pregnant without worrying about rebound activity, or you simply prefer the long-term potential that an induction therapy offers. In this situation switching without a wash-out period to prevent rebound makes sense and should be relatively safe (option 1 below)."


"The situation if you are JC virus seropositive is much more problematic because of the risk of carry-over PML. With a maintenance agent such as fingolimod we simply exclude asymptomatic PML by doing a lumbar puncture to look for JCV DNA in the spinal fluid and an MRI; if these tests are clear we start fingolimod as soon as possible after the last natalizumab infusion with the knowledge that if PML should develop we can always stop fingolimod and it will be cleared from the body within in 6-8 weeks. This early switching strategy also prevents rebound activity when natalizumab wears after approximately 3-4 months." 

"With an induction agent, such as alemtuzumab, things are more complicated because we can't reverse its action hence we have to be confident that there is no carry-over PML. Why am I so concerned? Simple, if you develop carry-over PML post-alemtuzumab before reconstitution of your immune system your are likely to succumb to the PML. I am aware of one person already who has died under these circumstances. The reason for this is that we have to rely on a functioning immune system to clear the virus, in particular a population of cells called CD8+ cytotoxic T-lymphocytes (CTLs). As you can see from the graph below CD8+ lymphocytes take many months to reconstitute and even at 12 months, the time you would be due your second course of alemtuzumab, they are not back to normal."



From Coles et al. Multiple Sclerosis 1998; 4:232-238.

"The pivotal questions are: (1) how long is the period of asymptomatic PML and (2) can we be confident in excluding asymptomatic PML by simply doing a lumbar puncture for spinal fluid JCV DNA detection and an MRI for suspicious lesions? I suspect not. The process that underlies the development of PML is long and complicated. The JC virus has to acquire several mutations to be able to cause PML; acquiring mutations takes time typically more than 12-24 months. Once the virus has acquired the mutations it must then infect the glial cells within the brain and start dividing and spreading. This initial infection must start microscopically below the threshold of detection by MRI and spinal fluid analysis. So simply switching to alemtuzumab without a break from natalizumab is risky; how risky is difficult to say at present."


"I envisage 3 scenarios: 


(1) The most risky one is the immediate switch from natalizumab to alemtuzumab without a wash-out; the risk being a small chance of carrying over asymptomatic PML.


(2) A switch after a 3-6 month wash-out of natalizumab; this will allow time for asymptomatic PML to declare itself and it will also allow immune surveillance to of the nervous system to find any mutant JC virus. This strategy was initially proposed with fingolimod and had to be stopped because of the risk of rebound MS activity. Because of rebound, I don't think this is a strategy that most MSers will be prepared to take. 


(3) A bridging strategy in which you switch to a maintenance oral agent, such as teriflunomide, dimethyl fumarate or fingolimod. The bridging agent will hopefully prevent rebound MS activity and give you a sufficient period of time to observe for the development of PML. I suggest this period of observation would need to be for a 6-12 months. Once this period of observation is over and PML has not emerged you could probably transition to alemtuzumab without too many concerns. The one proviso is we don't have data in using alemtuzumab after these new oral agents and hence can't be confident that the kinetics of immune system reconstitution will be the same as when using alemtuzumab as a 1st-line therapy or following interferon-beta or glatiramer acetate. Please note that at present only fingolimod has robust enough data to be confident that it prevents rebound. There have been several poster presentations at meetings showing that DMF is not up to the task. I also have personal experience with one of my patients who transferred to me from the USA that had a devastating spinal cord relapse 4 months after stopping natalizumab despite being started on DMF without a washout."



Click on picture to see large image.

"Please note that this advice is not evidence-based and is my opinion backed-up by clinical experience and a theoretical knowledge. Hopefully, Genzyme will do a formal clinical study to test these different options. I think it is very important to know what happens when using alemtuzumab after the oral bridging agents; in particular we need data on safety. Another factor that I have not discussed is availability and local guidelines; firstly you may not have access to the agents outlined above and you may be restricted by local guidelines on how you to use these agents. Finally, a lot of you may disagree with the above proposal; If you are considering switching from natalizumab to alemtuzumab I suggest you have a discussion about these issues with your neurologist. At present I favour option 3; but as with all treatment decisions in MS this should be personalised to the individual concerned and hopefully it will become evidence-based in the future."


CoI: multiple

Thursday, 30 July 2015

Why Barts MS not Queen Mary

What should we be called? This is an ongoing cause of contention between Queen Mary University of London and its medical school Barts and the London School of Medicine and Dentistry.
                                 Why Barts MS



Queen Mary University of London (officially abbreviated to QMUL, informally known as QM) is a public research university located in East London, United Kingdom. With roots dating back to the founding of the London Hospital Medical College in 1785, Queen Mary College was admitted to the University of London in 1915, named after Mary of Teck, Queen of the United Kingdom.




Barts and The London School of Medicine and Dentistry is now the medical and dental school of Queen Mary.The school was formed in 1995 by the merger of the London Hospital Medical College(the first school to be granted an official charter for medical teaching in 1785) and the Medical College of St Bartholomew's Hospital (the oldest remaining hospital in the United Kingdom, having been founded in 1123 by Rahere (died 1144, and entombed in the nearby Priory Church of St Bartholomew the Great). 

The Dissolution of the Monasteries did not affect the running of Barts as a hospital, but left it in a precarious position by removing its income. It was refounded by King Henry VIII in December 1546, on the signing of an agreement granting the hospital to the Corporation of London, which was reaffirmed by Letters Patent of January 1547 endowing it with properties and income entitlements. The hospital became legally styled as the "House of the Poore in West Smithfield in the suburbs of the City of London of Henry VIII's Foundation", although the title was never used by the general public. 
 
So Barts is not named after Bart Simpson but Barts - the oldest Medical Establishment in Europe and you don't get better info for branding than that.

P.S. It also fools Google + as a name (Bart MSblog) so we can have blog email that works on Google+ BartsMSBlog@gmail.com....Mousedoctor is blocked bo-Ho:-)
                       Entrance to the Hospital through King Henry VIII gate built in 1752.

Novartis maybe now believes Biogen. Fingolimod does not promote remyelination

Alme MN, Nystad AE, Bø L, Myhr KM, Vedeler CA, Wergeland S, Torkildsen Ø. Fingolimod does not enhance cerebellar remyelination in the cuprizone model. J Neuroimmunol. 2015  15;285:180-6.Fingolimod (FTY720) is approved for treatment of relapsing-remitting multiple sclerosis. In vitro studies have found that fingolimod stimulates remyelination in cerebellar slices, but in vivo animal studies have not detected any positive effect on cerebral remyelination. The discrepant findings could be a result of different mechanisms underlying cerebral and cerebellar remyelination. The cuprizone model for de- and remyelination was used to evaluate whether fingolimod had an impact on cerebellar remyelination in vivo. We found that fingolimod did not have any effect on cerebellar remyelination, number of mature oligodendrocytes, microglia or astrocytes when fed after cuprizone exposure.


Fingolimod is a sphingosine -1 -phosphate receptor modulator. It stops white blood cells by modulating the S1P1 receptor. But S1P5 is expresse by glial cells and Novaritis would have it that fingolimod was going to induce remyelination. However as a spoiler Biogen sponsored a study to show no remyelination potential. Novartis have sponsored a study and now found the same thing, so maybe time to put this to bed. This may be part of the reason why fingolimod did not stop progressive MS

Wednesday, 29 July 2015

ClinicSpeak: poor recovery from relapses predict progression

Are you a good, or bad, recoverer from relapses? #ClinicSpeak #MSBlog #MSResearch

"The study below shows that if you have a poor recovery from relapses you are much more likely to enter the clinically-apparent progressive phase of the disease sooner; in fact in this study it was ~22 years sooner (8.3 years vs. 30.2 years). These results are important for several reasons:

  1. Firstly, it is clear that recovery from relapse is determined by the amount of functional reserve. If you have spare capacity in the affected, and compensatory, neuronal pathways you are more likely to make a good, or complete, recovery from relapses. Functional reserve is dictated by how long you have had MS and the lesion load in the affected pathway. The more damage you have, the less reserve you have, the more likely you will have poor recovery. This is why we say 'treat early and effectively'; 'time is brain' (and spinal cord).
  2. Age is another factor; the younger you are the more likely you are to recover function. This is simple biology; ageing affects the regenerative capacity of all tissues. This helps explain why age is the best predictor of the onset of the clinically-apparent secondary progressive phase of MS. Please note I use this term clinically-apparent as there is evidence that the pathological substrate that underpins progressive MS is there from the beginning. This is why we are actively promoting the concept that early effective treatment is in fact a treatment strategy that is targeting progressive MS. It is better to prevent the onset of progressive MS than to try and treat it.
  3. DMTs reduce the severity of attacks and hence result in better recovery from relapses. It is now clear that DMTs, in particular highly-effective DMTs, not only reduce the attack frequency, but also reduce attack severity (need for steroids and/or hospital admission). This is why DMTs delay the onset of clinically-apparent SPMS; despite some commentators saying the opposite there is now data to support this position.
  4. Another factor that is lesions location. Brainstem, cerebellar, or spinal cord relapses were associated with a poor recovery from the initial relapse. I have discussed this topic before. I suspect that sensory relapses are more likely to be due to smaller, less damaging, lesions. Why? Sensory, or so called afferent, systems (vision, hearing, cutaneous sensation) are more likely to cause symptoms from small lesions as these symptoms are optimised to sense the environment. In comparison, motor or efferent systems (coordination, power) are more likely to cause symptoms when affected by larger more damaging lesions. This is why we take lesions in motor, or efferent, systems more seriously.
  5. Genetic factors may also play a role. In the animal model of MS, or EAE, some strains of mice recover more quickly than others and the best recoverers become progressive more slowly. Those strains who do badly and recovery less well are more likely to become progressive sooner. As yet we haven't convincingly defined genetic factors in people with MS that predict recovery, but I am sure there are several to be found.
How is the relevant to you, a person with MS? I think it is highly relevant. If you have non-recovery from early relapses this is a poor prognostic sign and hence you may want to choose one of the big guns (highly effective therapies) from the beginning. If you have active MS you almost certainly want to be on a DMT to prevent new lesions from forming and to become attack free. In essence you want to have NEDA (no evident disease activity) and preferably no ongoing end-organ damage (normalised brain atrophy rates). I am sure some of you may agree with me on this, whilst others will disagree. I think preventing end-organ damage is a no-brainer."

"Please note, one way of acquiring disability is non-recovery from relapses, and not only the gradual progression we see in the clinically apparent progressive phase of  the disease (SPMS & PPMS). Non-recovery from relapses is more common than we realise. I simply don't understand why someone with MS would take the chance of having relapses, when they can reduce  their chances with effective DMTs (licensed or unlicensed). I stress unlicensed DMTs, because in resource poor settings people with MS still have affordable options." 


Epub: Novotna et al. Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis. Neurology. 2015 J. pii: 10.1212/WNL.0000000000001856.

OBJECTIVE: To evaluate the relationship between early relapse recovery and onset of progressive multiple sclerosis (MS).


METHODS: We studied a population-based cohort (105 patients with relapsing-remitting MS, 86 with bout-onset progressive MS) and a clinic-based cohort (415 patients with bout-onset progressive MS), excluding patients with primary progressive MS. Bout-onset progressive MS includes patients with single-attack progressive and secondary progressive MS. "Good recovery" (as opposed to "poor recovery") was assigned if the peak deficit of the relapse improved completely or almost completely (patient-reported and examination-confirmed outcome measured ≥6 months post relapse). Impact of initial relapse recovery and first 5-year average relapse recovery on cumulative incidence of progressive MS was studied accounting for patients yet to develop progressive MS in the population-based cohort . Impact of initial relapse recovery on time to progressive MS onset was also studied in the clinic-based cohort with already-established progressive MS (t test).

RESULTS: In the population-based cohort, 153 patients (80.1%) had on average good recovery from first 5-year relapses, whereas 30 patients (15.7%) had on average poor recovery. Half of the good recoverers developed progressive MS by 30.2 years after MS onset, whereas half of the poor recoverers developed progressive MS by 8.3 years after MS onset (p = 0.001). In the clinic-based cohort, good recovery from the first relapse alone was also associated with a delay in progressive disease onset (p < 0.001). A brainstem, cerebellar, or spinal cord syndrome (p = 0.001) or a fulminant relapse (p < 0.0001) was associated with a poor recovery from the initial relapse.

CONCLUSIONS: Patients with MS with poor recovery from early relapses will develop progressive disease course earlier than those with good recovery.

CoI: multiple

A classification system for science news

A classification system for science news.

I have lifted this piece from the Guardian and covers something that I was considering when I first started blogging.

Science news and articles are becoming increasingly popular, but with so much being written about so many things, it can be confusing for the beginner science enthusiast to grasp what they’re reading and how to interpret it. 


However, science and science news/reporting/writing is the work of humans, and humans are rarely 100% logical. So, to step into the world of science is to step into years/decades/centuries of disputes, controversies, unfamiliar habits, power-plays, strange politics and countless other things that manifest in science articles and could befuddle the unwary reader. 

What can we do about this?

One option is to adopt an approach from the world of film. Every film released to the public comes with a classification, to warn potential viewers of the type of content to expect without spoiling the actual thing itself, so the viewer can go in prepared. 

SCIENCE CLASSIFICATION
So here’s a potential classification system for science writing. It’s a bit more complex admittedly, and unlike films, multiple classifications can be applied to a single piece. How like science, to be so uncertain.
Axe Grinding

Sometimes you may stumble upon an article about something that, as far as you’re aware, is reasonably well established. 

However, no matter how established the subject, it’s guaranteed there’ll be someone somewhere who disagrees with it. If it’s a particular bugbear of theirs, they’ll take any opportunity they can to rail against it, such as by writing articles about it.

Often, such an approach is entirely valid. Much that people accept as based on established principles really isn’t, no matter how important. But sometimes the writer can lose objectivity or effectiveness, and it ends up reading like someone yelling at pigeons (albeit in a surprisingly articulate manner)
.

Soapbox 


Soapboxing is similar to Axe Grinding. The writer is focusing on an issue important to them. Unlike Axe Grinding, it’s more an attempt to draw attention to an issue or idea that the writer considers important and does not get the publicity/acceptance they feel it merits, so is writing an article to try and change this.

There are many possible motivations for this; some noble, others less so. The writer may genuinely believe that an important issue is being overlooked to the detriment of many. Or it may be that it’s an idea or concept that they came up with or that benefits them in some way, and are promoting it more out of self-interest. Like Axe Grinding, you can expect many pieces on the same subject from Soapboxing authors.

Wild Extrapolation:
 


Most scientific experiments are actually quite specific, eg what one specific protein does in one specific type of bacterium. But in the modern media, it’s vitally important that a news story or piece get as much attention as possible, and this is often achieved by highlighting the consequences that could affect the potential reader. 

Indeed this is the case and this is how I started to blog to correct some nonsense from the BBC and the newspapers. There an an
 innocent press release about a grant on the use of adult neural stem cells in mice, becomes a stem cell trial using aborted human foetuses

These are more likely to be mainstream press articles, which ignore the “small thing definitely happened” story to focus on the “BIG THING MAY POSSIBLY HAPPEN MAYBE!” 


Provocative Title

The Provocative Title is a similar approach to Wild Extrapolation, but is more constrained. It’s still typically a mainstream article intended to grab attention, and does so by using an eye-catching title that isn’t necessarily backed up by the text itself. The title may be based on an offhand phrase or comment by someone involved in the study, usually included toward the end of the piece to “justify” the title. But overall, there’s a notable disparity between the headline and the body of the piece, so you might start reading something about a study that reports a newly observed minor mutation in a known virus when the title promised you “Killer disease discovered could wipe out humanity!”


Usually this is this drug cures MS in the 'EAE cure of the week'

Impenetrable

Communicating science to other scientists is a totally different skill to communicating it to non-scientists. Most scientists opt to focus on their research, rather than tell people about it. 


Sometimes we end up with a piece written by an experienced scientist who has no experience of communicating with people, and thus is crammed with jargon, unfamiliar terms, painstaking explanation, and so on. It’s not “wrong”, but does not make for easy reading.

The temptation to run it through Google translator can be strong.


Oh course this never happens on the blog does it:-)

Uninformed

The polar opposite of the Impenetrable article, an Uninformed piece hasn’t had anyone with any actual science knowledge look at it before publication. A more mainstream publication may want an item about a science-based thing that is currently or potentially quite popular, but doesn’t actually have any scientists on the staff (science is nowhere near popular enough for this to be a totally unlikely scenario).

So the piece ends up being written by someone who doesn’t really understand what they’re talking about. And usually, it shows.


This is called the science media that you get every day in the media

False Balance

False Balance Science Certification
A False Balance piece may be well-intentioned, but is potentially more harmful than a straightforward Uninformed piece. The writer may be aware that a scientific subject is important, but they are also aware that there are those who dispute the claims underpinning it. However, the author either lacks the understanding to evaluate the merit of both positions, or hasn’t the resources to deal with the inevitable criticism of ignoring the detractors.

The result is a piece that treats the claims of those opposed to the scientific subject as equally credible to those that support it, despite the former lacking any real evidence. It can be quite a distressing read, especially as the views of those opposed are usually presented without criticism at the end of the piece, creating a “fallen at the last hurdle” feeling.


Where does profG now stand on vitamin D?

Reheated PR 

Many organisations or institutes want media attention for their latest discovery or product, so send press releases to mainstream media organisations. The press release emphasises the importance of what they’re trying to promote, but is hardly an impartial, thorough report of the subject matter.

Sadly, many major platforms will essentially publish the PR as is making 
it look like it’s an actual piece of science news, rather than promotional material written by those who benefit from it. You can usually spot this as the wording is basically the same in all articles covering the “story”.

This may have some truth but in my experience this often feeds into the Uniformed

Shoehorn
WARNING: Shoehorn

If an author wants to write about a particular area of science but doesn’t really know how to get people interested in it, one common approach is to discuss it in the context of a subject that’s currently popular or topical.

This can be an entirely relevant and valid approach, as pretty much anything in the news has aspects that can be explained by science. But it can go too far, and you end up with writers awkwardly inserting science matters into popular subjects where they don’t really belong, making the whole thing look somewhat cynical and baffling, like those ads where women seem to achieve sexual climax when using shampoo.


Condescending 

Condescending science classification

Science stories are a bit difficult to get right. You want to be accurate and thorough, but you know you’re not writing for people in the field so they won’t have the vocabulary or experience needed for understanding detailed explanations, so it needs to be written in clear, decipherable language. Unfortunately, some scientists interpret that as “everyone who reads this is a small child of below-average intelligence”, and ends up producing a piece that assumed the reader knows literally nothing and is liable to get upset whenever they see a word they don’t understand.

Sorry we have been there, but it is not always easy to get the right balance and not every body is up to the same speed with the same level of knowledge.

Let's look forward to the next analogy at the next research day:-).
(serious they are useful to some people)

Go to any scientific talk at as say ECTRIMS and condescending abounds

It’s not that the piece is “wrong”, it’s just that it’s very grating to read, like listening to a pub bore explaining to you why you’re wrong about a film you like.

Cargo Cult
Cargo Cult science classification

Some articles are written to look and read just like science articles, but aren’t. Things like alternative medicine, anti-vaccination campaigns, climate-change denial and more, these want to be seen as credible scientific positions but lack the evidence for this. One alternative approach is to act like a legitimate science, and this can sometimes manifest in producing articles that look just like scientific ones.

Hey, you just have to add SVI to this. an we have CC

Niche Concern

 
Science being such a big subject involving thousands of different organisations, it’s inevitable that some issues will be more relevant to certain groups and organisations. People affected by an issue may care about it deeply, and take every opportunity to highlight or address it, especially if there is an opposing opinion on it held by others in the field. This can lead to many successive articles and pieces offering stances and solutions and discussions and analysis of the issue.

However, should a casual reader not familiar with the issue stumble upon the piece, it can baffle them.


Some may say MS is a niche concern in Neuroscience and as a result many neurosscientitsts do not understand the complexity of MS, so they do experiments with a symptom control drug and expect to see the results of a disease modifying drug.

New Book Release

.

The writer of the article has written a book. The article you’re reading is intended to make you interested in buying and reading this book.

 The author may be rehashing old arguments, stirring harmful controversies or adopting dubious positions and writing about them, purely to generate some attention for their book.


Sounds like a review article to me

Link Fest
 
A Link Fest isn’t an article per se, it’s more a gateway to other articles. The author has collected a bunch of pieces that they think are worthy of attention and wants to get their regular readers to check them out too.

Nothing wrong with doing this, but if you were hoping to spend 10 minutes reading these it can actually end up being more like 2 hours.


Yes I thought about going this and so.......

would have been fine and dandy, but then I thought we could end up with......

I get in enough trouble with my peers and so the thought of classifying posts is a step too much. 

In addition, so much is opinion. What I think is great others may think is pants, so there is no point giving it a star:-)

Have a more powerful tool and you see more

Dula AN, Pawate S, Dortch RD, Barry RL, George-Durrett KM, Lyttle BD, Dethrage LM, Gore JC, Smith SA. Magnetic resonance imaging of the cervical spinal cord in multiple sclerosis at 7T. Mult Scler. 2015. pii: 1352458515591070. [Epub ahead of print]

BACKGROUND: The clinical course of multiple sclerosis (MS) is mainly attributable to cervical and upper thoracic spinal cord dysfunction. High-resolution, 7T anatomical imaging of the cervical spinal cord is presented. Image contrast between gray/white matter and lesions surpasses conventional, clinical T1- and T2-weighted sequences at lower field strengths.
OBJECTIVE: To study the spinal cord of healthy controls and patients with MS using magnetic resonance imaging at 7T.
METHODS: Axial (C2-C5) T1- and T2*-weighted and sagittal T2* were acquired at 7T in 13 healthy volunteers (age 22-40 years), and 15 clinically diagnosed MS patients (age 19-53 years, Extended Disability Status Scale, (EDSS) 0-3) in addition to clinical 3T scans. Evaluation included signal and contrast to noise ratios and lesion counts for healthy and patient volunteers, respectively.
RESULTS/CONCLUSION: High-resolution images at 7T exceeded resolutions reported at lower field strengths. Gray and white matter were sharply demarcated and MS lesions were more readily visualized at 7T compared to clinical acquisitions, with lesions apparent at both fields. Nerve roots were clearly visualized. White matter lesion counts averaged 4.7 vs 3.1 (52% increase) per patient at 7T vs 3T, respectively


So all imagers will be saying "please, please, please, can we have a 7T scanner" so they can repeat the studies at 1.5T and 3T. If you have a more powerful tool is is obvious that you can see more. This study shows that  more lesions were seen...how does this compare to the gold standard, which is post-mortem histology, because the question is how much does MRI miss. 

If we are thinking of NEDA-4 and measuring atrophy it is much more precise with 7T than the blurred lines given by 3T. 

The Blog will now evolve

Thank you we will now allow the blog to continue to evolve? #MSBlog #MSResearch

"The response and results of yesterday's survey on the evolution of the blog was very clear. More importantly the discussion was very useful. Apologies about getting byline and strapline confused. In fact both the byline and strapline refer to individual articles. Based on the comments and results of the survey we will be changing the strapline/byline to the following"


A blog for people affected by multiple sclerosis
"Interpreting good, bad and other research news"

"The term affected captures all comers and we agree the main focus of the blog should remain news, research news."
 

affected
əˈfɛktɪd/
adjective
  1. 1.
    influenced or touched by an external factor.
    "affected areas"


Tuesday, 28 July 2015

What's in a Name

Dear All

Thank you for voting for the Survey...What's in a name. 

If you haven't done it sign up to MS Register in the UK,
and 
NARCOMS in North America.
                                                       
I will post the paper when it is accepted but


Your choice preference was remarkably similar in all Surveys 
However, this is not what Scientists/Clinicians use.

Evolution of the blog

Is it time to change the blog? To let it evolve? #MSBlog #MSResearch

"First the internet, and then the web, has transformed society and how we interact with each other. I would argue that the greatest benefit to mankind has been its effect on the democratisation of knowledge and the easy access to knowledge via efficient search engines. Gone are the paternalistic days when neurologists knew it all and the patient (yes, the patient rather than the MSer, or person with MS) knew very little."

"One thing I have learnt from this blog is that there are no real boundaries between people with MS, their families, healthcare professionals, researchers, politicians and other people with an interest in MS, when it comes to access to knowledge. I frequently learn things I don't know from comments made by you the reader. Therefore, we are proposing changing our byline to the following:


A blog for people interested in multiple sclerosis
"Interpreting good, bad and other MS news"

Why the proposed change? We run a MS Preceptorship, or teaching course, for trainee healthcare professionals (HCPs) with an interest in MS. As part of this course we want to extend the teaching online. We could do this via a separate website requiring online registration, but feel this would be wrong. You have already expressed a desire to be able to learn about MS in existing teaching portals that are restricted to HCPs only. We want to challenge the status quo. We also feel that you would benefit greatly from reading the case studies and learning about the thought processes and complexities behind clinical decision making and management. Hopefully, the case studies will generate lively debates, to illustrate that medicine remains an art and is not a science."
"In short this site is evolving into a multi-dimensional site for HCPs as well. In reality, this has happened already. I rarely attend a meeting without hearing from HCPs how useful they find some aspects of the blog and how they use it as a resource for information. In fact we are proud of this. We also don't want to force change that you don't want. Therefore we are asking you to vote on the proposed change."

MS Basics - SPASTICITY

I promised to post on spasticity in MS a while back. Hope you find this post useful...

Firstly, here is the wikepedia version [click].

And now mine - as clinicians when we say there's spasticity in an arm/leg we mean that there's increased resistance to movement of the arm/leg at the level of it's joint. For example, this is the knee joint for the lower leg, or the hip for the upper leg.

This happens due to increased muscle tone (termed a high tone/hypertonus) and varies with the speed of movement at the joint. This is opposed to rigidity which is present throughout the range of movement, and is seen in conditions such as Parkinson's disease.
Spasticity can be mild with simply a catch on bending and extending the leg at the knee joint or severe where the leg may remain in a flexed posture even at rest and lead to contractures (permanent shortening of the muscle) and painful spasms. Spinal cord lesions as opposed to brain lesions tend to have more spasticity than brain lesions.

Spasticity often does not occur in isolation and is commonly seen together with:
  • Abnormal reflex transmission with increased gain on reflexes
  • Clonus (muscle spasm with repeated, rhythmic contractions - on flexing a muscle or simply on movement) 
  • Painful muscle spasms (which are sudden involuntary [i.e. happen without any planned intention] movements involving multiple muscles in response to movement or touch)
  • Dystonia (tonic muscle overactivity without triggers due to an inability of the nerve innervating the muscle to stop firing after voluntary movement or reflex activity)
  • Co-contraction (inappropriate activation of the opposing muscles during voluntary movement leading to loss of dexterity and slowed movements)


Cross-section through the spinal cord (ascending and descending tracts to and from the brain).

In the spinal cord for sometime the wildly held belief was that spasiticity was caused by damage to the corticospinal tract (all of these pathways except the medial reticulospinal tract and vestibulospinal tract are held under INHIBITORY control by the brain), but it is now understood that other motor tracts may also play a role:
  • The lateral reticulospinal tract which is adjacent to the corticospinal tract (see diagram above) may be involved in MS where lesions have a predilection for the lateral surface of spinal cord. This pathway has an inhibitory effect on stretch reflexes. 
  • The medial reticulospinal tract and vestibulospinal tract (see diagram above) which have excitatory effects on extensor muscle tone.
The over activity of the spinal neurones leads to involuntary activation of muscles.

Whereas lesions affecting the brain leads to increased excitation of the spinal pathways and a lowering of the threshold (i.e. easily triggered) to respond to stimuli such as stretch.

There are certain things which worsen spasticity:
  • skin ulcers, ingrown toenails, skin infections
  • constipation, UTIs, kidney stones, and pain 
  • improper seating, ill fitting orthotics
  • rapid withdrawal of anti-spasticity medication
  • other- deep vein thrombosis/DVT, injuries, stress

Pharmacological medications commonly used include Baclofen (GABAergic drug which relieves spasms) often in combination with Tizandine (centrally acting alpha2-noradrengic drug) as their mechanism of action is complimetary. Gabapentin is also a useful anti-spasmodic but limited by its sedative side effects, the latter also occurs with Baclofen. Botox is useful when individual muscles are involved. When oral anti-spasticity medications are of limited use, intrathecal Baclofen which delivers Baclofen into the spinal space may be used. Rarely, drastic measures are taken for painful immobile spastic legs with reflex spasms using intrathecal phenol or alcohol which causes irreversible nerve damage. Other measures include relief of pain and discomfort, improvement in posture, stretch exercises, facilitation of sitting, standing and walking, and prevention of complications such as contractures and pressure sores. Contractures which are not severe can be corrected using sequential casting (see below).












Stretch exercises (left) and manual sequential casts (right)

Monday, 27 July 2015

PoliticalSpeak: is this the beginning of the end of the NHS as we know it?

What will happen to the care of MSers in the new NHS? #PoliticalSpeak #MSBlog

"I have always maintained that if you have MS you would want to live in the UK and be managed under the NHS, or one of  the other socialist healthcare systems in Europe. I still believe this. However, there are worrying political clouds on the horizon. The following news piece summarises the issues very well. It its present form the NHS appears to be too expensive for central funding and the government is looking for alternative funding models. What do you think?"


Ingrid Torjesen. Government plans inquiry that could mean end of NHS free at point of use. BMJ 2015;351:h3971

Excerpts:

.... The Department of Health for England is considering an inquiry to look at how the NHS should be funded to ensure its future sustainability, which some doctors fear could put in jeopardy a founding principle of the NHS: that it is free at the point of use....

.... The inquiry was suggested during a House of Lords debate on the “sustainability of the National Health Service as a public service free at the point of need,” which took place on 9 July.....

.... Commenting on the potential inquiry, Clive Peedell, co-founder and co-leader of the National Health Action Party, said that the proposal seemed to have “slipped by very quietly.” ....

.... In the House of Lords Patel pointed out that close to 9% of gross domestic product was spent on the NHS, that 89% of NHS trusts were forecasting deficits, that outcomes, including those relating to cancer and avoidable deaths, were poor, and that the NHS needed to achieve productivity gains far in excess of the 0.4% year on year that it had attained historically. “In this scenario the NHS will need an annual budget of nearly £200bn [€290bn; $310bn] by 2030 and one fifth of the nation’s entire wealth by 2060,” Patel said.....

.... The health secretary for England, Jeremy Hunt, last week refused to guarantee that the current system of funding would remain. After a speech at the King’s Fund in which he set out a 25 year vision for the NHS,1 Hunt was asked whether the budget would continue to be funded by taxpayers for the next 25 years. He replied, “I am confident, but I don’t have a crystal ball.”....

CoI: none

ClinicSpeak: vitamin D supplementation guidelines in the dog box

The long arm of industry and vitamin D supplements. #ClinicSpeak #MSBlog #MSResearch

"I have been making the claim that MSers should keep themselves vD replete and have recommended the Vitamin D Council's guidelines. The rationale for my advice is not because vD is a disease-modifying treatment - definitive evidence for the this is lacking - but to optimise bone health. The latter is not evidence-based, but comes from extrapolating results from studies that have been done in older women with osteopenia and osteoporosis. I am aware that there is a lack of evidence on this issue from the field of MS, which why Dr Ruth is currently preparing a post-doctoral fellowship application to address this issue."


"I am not a bone expert, which is why I defer to my esteemed colleagues in the field of vD biology and endocrinology for advice. This is why I was astounded when I read the following analysis over the weekend from last week's British Medical Journal that calls all the advice on vD and calcium supplementation in relation to bone health into question. Please note I have never recommended calcium supplements to MSers; there is no scientific rationale for this. Importantly, the authors' finger the influence of Industry in the setting of national and international guidelines in relation to vD and calcium supplements for the prevention of fractures. The esteemed Vitamin D Council is not exempt from the list (see table below)?"




"What should we do? I don't think I will change my advice just yet. I still think there is a strong argument from an evolutionary medicine perspective to be vD replete. However, to make the claim that this is for bone health reasons seems to be at odds with the evidence presented in this paper and recent meta-analyses. More importantly there is no evidence from studies done in MSers to support the bone health position. I will need to seek expert advice from my metabolic bone disease colleagues before coming back to you."




Excerpts


.... For many years, recommendations for prevention and treatment of osteoporosis have included increasing calcium intake (by diet or supplements) and use of vitamin D supplements. Since the average dietary calcium intake in most countries is much less than that recommended by guidelines, many older people (and MSers) are advised to take calcium supplements to prevent osteoporosis. The recommendations have been implemented successfully: over half of older Americans take calcium and vitamin D supplements, either prescribed or over the counter, and bone health is the most common specific motivation for use of nutritional supplements....

..... However, this behaviour does not reflect evidence that has emerged since 2002 that such supplements do not reduce the risk of fracture and may result in harm. Guideline bodies also continue to recommend calcium and vitamin D supplements. Here, we argue that change is made difficult by a complex web of interactions between industry, advocacy organisations, and academia.....

.... We conclude that increased calcium and vitamin D intake should not have been recommended for older adults living independently after 2007, a view consistent with the conclusion of the 2009 Cochrane review.18 However, many guidelines published since then recommend increasing calcium intake (to 1000-1200 mg/day) or use of vitamin D supplements (600-2000 IU/day) for managing osteoporosis. An exception is the United States Preventive Services Task Force, which recommended against calcium and vitamin D supplementation for primary fracture prevention in 2013....

.... Calcium and vitamin D supplements are very profitable. Global annual sales of calcium supplements in 2013 were about $6bn (£4bn; €5bn),w1 and those of vitamin D in the US in 2012 were $748m.w2 Companies that market foods rich in calcium or vitamin D also profit from the notion that these nutrients prevent osteoporosis. Notable examples include Fonterra, whose $NZ4bn (£2bn; €3bn; $3bn) annual sales in Asia include those of its calcium enriched milk products marketed for optimal bone health,w3 and Danone, whose annual sales of fresh dairy products are around €12bn (£9bn; $13bn), including products marketed as promoting bone health because they contain calcium and vitamin D....

..... Other industries benefit from enthusiasm for use of supplements for osteoporosis. Measurement of serum 25-hydroxyvitamin D has become widely used, benefiting both the manufacturers of assay kits and the laboratories that perform the tests. The commercial rewards are substantial— annual costs of vitamin D testing in Australia increased from $A1m (£500 000; €700 000; $800 000) in 2001 to $A96m in 2010.....

.... The US National Osteoporosis Foundation (NOF) and the Europe based International Osteoporosis Foundation (IOF) are highly influential advocacy organisations. Both state their aim as improving patient outcomes, but their objectivity may be compromised by the influence of a range of commercial sponsors, including companies that market supplements, dairy products, and nutrition related laboratory tests. In their drive to attract corporate sponsorship, the IOF and NOF emphasise their academic and scientific strengths and global influence, and offer the opportunity for corporate members to influence the strategic direction of the organisation at both formal and informal levels....

.... Other industry sponsored advocacy organisations have failed to acknowledge the unfavourable evidence. The news section of the website of the Vitamin D Council does not mention the recent meta-analyses of randomised trials that reported no health benefits of vitamin D supplements, while less rigorous research findings that encourage vitamin D testing and use are enthusiastically endorsed....

.... Setting aside finances, academic leaders may also have academic conflicts of interest. For example, their career development may be enhanced by the persistence of beliefs that nutritional supplements benefit the skeleton. Such conflicts of interest may have influenced the Endocrine Society’s endorsement of widespread moderate dose vitamin D supplementation in contrast with the Institute of Medicine (IOM), which recommended low level supplementation for older adults, and the Preventive Services Task Force, which advised against vitamin D supplementation......

...... The interactions among the nutrition industry, advocacy organisations, and academia are complex. Each party benefits. Industry gains scientific credibility, which protects or enhances sales of its products, and indirect marketing through advocacy groups. Advocacy organisations and specialist societies gain funds to support their existence. Academics gain by maintenance of their status and by obtaining access to research funds and career enhancing publications and presentations. The party that may lose, and be harmed, is the public. Failure to reverse inappropriate practice leads to overtreatment, systematic waste of healthcare resources, unnecessary costs for patients, and missed opportunities for application of interventions with proved efficacy. Ultimately, the cost is erosion of trust in the medical system......

CoI: none

EBV-specific CD8 cells in CSF

van Nierop GP, Mautner J, Mitterreiter JG, Hintzen RQ, Verjans GM. Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins.Mult Scler. 2015 Jun 3. pii: 1352458515588581. [Epub ahead of print]

BACKGROUND:The association between Epstein-Barr virus (EBV) and multiple sclerosis (MS) may involve intrathecal EBV-specific T-cell responses targeting the virus or indirectly, autoantigens.
OBJECTIVE:Compare the prevalence and fine-specificity of EBV-specific T-cells in the cerebrospinal fluid (CSF) of patients with MS (n = 12), clinically-isolated syndrome (CIS) (n = 17) and other neurological diseases (OND) (n = 13).
METHODS:Intrathecal EBV-specific T-cell reactivity was assayed using CSF-derived T-cell lines (CSF-TCL) and autologous EBV-transformed B-cells (autoBLCL) as antigen-presenting cells (APC). EBV proteins recognized by autoBLCL-specific CD8 T-cells were identified using human leukocyte antigen class I (HLA-I)-negative monkey cells as artificial APC, co-transfected with 59 different EBV genes and the corresponding patient's HLA-I alleles that were involved in autoBLCL T-cell reactivity. Reactivity towards the MS-associated autoantigen αB-crystallin (CRYAB) was determined analogously.
RESULTS:CSF-TCL from CIS and MS patients had significantly higher frequencies of autoBLCL-reactive CD4 T-cells, compared to the OND patients. CIS patients also had significantly higher autoBLCL-reactive CD8 T cells, which correlated with reactive CD4 T-cell frequencies. AutoBLCL-specific CD8 T-cell responses of four CSF-TCL analyzed in detail were oligoclonal and directed to lytic EBV proteins, but not CRYAB endogenously expressed by autoBLCL.
CONCLUSIONS:Enhanced intrathecal autoBLCL-specific T-cell reactivity, selectively directed towards lytic EBV proteins in two CSF-TCL, suggested a localized T-cell response to EBV in patients with MS. Our data warrant further characterization of the magnitude and breadth of intrathecal EBV-specific T-cell responses in larger patient cohorts.
EBV immortalises B cells and so you can infect B cells to make a cell line to present antigen so you can make a T cell line by stimulating it with its target antigen. They then used these T cells to work out which protein was being recognised by stimulating them with mock antigen presenting cells expressing different antigens. They found more EBV reactive CD4 T cells in the CSF of MSers an more CD8 cells into CISers. There responded to EBV proteins. Is this the main target.

Rebound occurs after withdrawal of natalizumab and the cells arriving in the brain at this time are going to contain the cells that cause relapse in MS. What are these cells reactive to?  EBV, CRYAB or myelin proteins

CD52 depletion inhibits EAE

Turner MJ, Pang PT, Chretien N, Havari E, LaMorte MJ, Oliver J, Pande N, Masterjohn E, Carter K, Reczek D, Brondyk W, Roberts BL, Kaplan JM, Siders WM. Reduction of inflammation and preservation of neurological function by anti-CD52 therapy in murine experimental autoimmune encephalomyelitis. J Neuroimmunol. 2015;285:4-12.

Alemtuzumab, a monoclonal antibody directed against human CD52, is used in the treatment of MS. To characterize the impact of anti-CD52 administration, a monoclonal antibody to mouse CD52 (anti-muCD52) was generated and evaluated in EAE mouse models of MS. A single course of anti-muCD52 provided a therapeutic benefit accompanied by a reduction in the frequency of autoreactive T lymphocytes and production of pro-inflammatory cytokines. Examination of the CNS revealed a decrease in infiltrating lymphocytes, demyelination and axonal loss. Electrophysiological assessment showed preservation of axonal conductance in the spinal cord. These findings suggest that anti-CD52 therapy may help preserve CNS integrity.


So depletion of  CD52 expressing cells inhibits EAE....This in not surprising as depletion of CD4 T cells inhibits EAE.

Sunday, 26 July 2015

Is there really an association between EBV antibodies and antibody Synthesis

Pfuhl C, Oechtering J, Rasche L, Gieß RM, Behrens JR, Wakonig K, Freitag E, Pache FC, Otto C, Hofmann J, Eberspächer B, Bellmann-Strobl J, Paul F, Ruprecht K. Association of serum Epstein-Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis. 
J Neuroimmunol. 2015;285:156-60

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection. A characteristic feature of MS is an intrathecal synthesis of immunoglobulin (Ig)G. In 90 patients with clinically isolated syndromes/early relapsing-remitting MS, serum antibodies to Epstein-Barr nuclear antigen-1, but not to EBV viral capsid antigen, rubella, or varicella zoster virus, were higher (p=0.03) in those with than those without a calculated intrathecal IgG synthesis >0% and correlated with the percentage (r=0.27, p=0.009) and concentration (r=0.27, p=0.012) of intrathecally produced IgG. These findings suggest a link between EBV infection and the events leading to intrathecal IgG synthesis in patients with MS.

Just looking through the blog and clearing out abstracts that did not make it on the blog and I came across this one. There is a very significant effect but you have to ask is it biologically important association or do you think that bits of the equation is missing. This is what you have to do when you read papers.

ImmunologySpeak: IL-17 and vitamin D

I am totally confused about the role IL-17 plays in MS. #ImmunologySpeak #MSBlog #MSResearch

"The following study on the effect of high-dose vitamin D supplementation on immune function is difficult to interpret. They have focused on one molecule, or cytokine (immune messenger), called IL-17 that is involved in T-cell autoimmunity. Firstly, I am not sure what form of IL-17 was being measured? I assume IL-17A. In addition to IL-17A, the IL-17 family includes IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. They show that there is no change in levels between baseline and 12 weeks in both the group of MSers given high-dose vD and the group who did not receive vD. Despite not signficant change in serum levels across the groups they then provide an analysis then the consumption of vD was positively associated with serum IL-17 levels with R2=0.91; in other words 91% of the variance of IL-17 levels can be explained by the consumption of vD. I would be interested to see the scatter plot of the data; with a R, or correlation coefficient of 0.95 (95%), it should be straight line. Unfortunately, there is no graph in the paper to look at."
"In terms of the biological meaning of this data I haven't a clue. In other studies vD has been shown to reduce the production of IL-17 from immune cells and have little effect on serum IL-17 levels. These results are counterintuitive and will need to reproduced and linked to other markers of immune activation and disease activity."

"This study is typical of most MS immunology studies; it asks more questions than it answers, it doesn't support the current dogma and contradicts other published data in the literature. This is why I haven't a clue about the role of IL-17 in MS; let's hope the new trial of a monoclonal antibody that inhibits IL-17 will answer the question for us."



BACKGROUND: Vitamin D has immunomodulatory effects in multiple sclerosis (MS). Vitamin D acts through various mechanisms such as secretion of cytokines. Interleukin-17 (IL-17) is a critical interleukin in inflammatory response in MS.

OBJECTIVE: This study assessed the effect of oral high dose vitamin D intake on IL-17 levels in MS patients in a double blind randomized clinical trial.

METHODS: 94 patients with a diagnosis of relapsing remitting multiple sclerosis (RRMS) were randomized to two groups. One group received 50,000 IU vitamin D3 every five days for 12 weeks. The other group was given placebo. Both groups received interferon-β (IFN-β) treatment. Serum levels of IL-17 were measured at the beginning of the study and after 12 weeks.

RESULTS: IL-17 serum levels were 56.75±28.72pg/ml and 30.31±75.85pg/ml in the intervention and placebo group at the beginning of the study, respectively (Median±IQR, p=0.338). After 12 weeks, IL-17 levels were 58.93±67.93pg/ml and 46.13±94.70pg/ml in the intervention and placebo group, respectively (Median±IQR, p=0.960). The multiple linear regression analysis indicated that the consumption of vitamin D3 was positively and significantly associated with the logarithm of IL-17 measures (β=1.719; p=0.002 and R2=0.91), adjusted by EDSS scores.

CONCLUSION: IL-17 levels showed significant change in RRMS patients after receiving high dose vitamin D3 for 12 weeks.