Monday, 31 July 2017

#PoliticalSpeak & #ThinkSpeak: access inequality has not caught up with knowledge access

How can we democratise access to good quality healthcare? #PoliticalSpeak #ClinicSpeak

I am often asked why I dedicate so much time to blogging. One of the reasons is to help disseminate knowledge and to help curate knowledge, i.e. to highlight what is important to pwMS. By doing this I am participating in a 'healthcare revolution' that is leading rapidly to an era when people with a chronic disease will be able to self-manage their disease. Another important reason for blogging is to counteract 'fake knowledge', 'pseudoscience' and 'fake news'. Unfortunately, the latter often brings out the worst in some of our followers (aka trolls). 

A big issue with the democratisation of knowledge is that healthcare systems, such as the NHS, are stuck in the past and have yet to embrace the new era. As a result the NHS is the main stumbling block, or hurdle, for the self-management revolution to take-off. I therefore find the study below very upsetting. In short it shows widening health inequalities in England that seem to to coincide with a change of government, the financial crash or the resulting austerity. 

In an era where there is no barriers to access of information there are clearly barriers to accessing quality healthcare, i.e. the NHS. Why should the management of your MS be so dependent on our postcode? This research is another example of why health and politics are so intricately linked and that it is impossible to separate them. I sincerely hope that politicians and healthcare managers read this paper and ask themselves how can we reverse this trend given the current financial constraints we find ourselves in? A potential solution is democratise healthcare and the ask the crowd for ideas and solutions. 

Trends in life expectancy in the most deprived local authorities and the rest of England,
and the relative and absolute differences 1983-2015. (Source BMJ)

In response to some of these insights we are are changing the format of our group clinics to allow them to be run, and lead, by pwMS. We want pwMS to self-manage their condition and to only call on us when they need help, or access, to a specialist technology. The medical profession needs to wake-up to the 'power of the crowd' and join the crowd. The crowd will reshape the doctor-patient relationship and will change the way we work. I am sure this will be for the better, job satisfaction will improve and our patients will be happier with the service we provide. 

Is the medical community ready for a revolution or are they blinded by 'status quo bias'?

Barr et al. Investigating the impact of the English health inequalities strategy: time trend analysis. BMJ 2017;358:j3310.

Objective: To investigate whether the English health inequalities strategy was associated with a decline in geographical health inequalities, compared with trends before and after the strategy.

Design: Time trend analysis.

Setting: Two groups of lower tier local authorities in England. The most deprived, bottom fifth and the rest of England.

Intervention: The English health inequalities strategy—a cross government strategy implemented between 1997 and 2010 to reduce health inequalities in England. Trends in geographical health inequalities were assessed before (1983-2003), during (2004-12), and after (2013-15) the strategy using segmented linear regression.

Main outcome measure: Geographical health inequalities measured as the relative and absolute differences in male and female life expectancy at birth between the most deprived local authorities in England and the rest of the country.

Results: Before the strategy the gap in male and female life expectancy between the most deprived local authorities in England and the rest of the country increased at a rate of 0.57 months each year (95% confidence interval 0.40 to 0.74 months) and 0.30 months each year (0.12 to 0.48 months). During the strategy period this trend reversed and the gap in life expectancy for men reduced by 0.91 months each year (0.54 to 1.27 months) and for women by 0.50 months each year (0.15 to 0.86 months). Since the end of the strategy period the inequality gap has increased again at a rate of 0.68 months each year (−0.20 to 1.56 months) for men and 0.31 months each year (−0.26 to 0.88) for women. By 2012 the gap in male life expectancy was 1.2 years smaller (95% confidence interval 0.8 to 1.5 years smaller) and the gap in female life expectancy was 0.6 years smaller (0.3 to 1.0 years smaller) than it would have been if the trends in inequalities before the strategy had continued.

Conclusion: The English health inequalities strategy was associated with a decline in geographical inequalities in life expectancy, reversing a previously increasing trend. Since the strategy ended, inequalities have started to increase again. The strategy may have reduced geographical health inequalities in life expectancy, and future approaches should learn from this experience. The concerns are that current policies are reversing the achievements of the strategy.

Repeating Botox for bladder problems

Ni J, Wang X, Cao N, Si J, Gu B.Is repeat Botulinum Toxin A injection valuable for neurogenic detrusor overactivity-A systematic review and meta-analysis. Neurourol Urodyn. 2017 Jul 26. doi: 10.1002/nau.23354. [Epub ahead of print]

AIM:To investigate the value of repeat botulinum toxin A (BTX-A) injections in patients with neurogenic detrusor overactivity (NDO).
METHODS:We searched the PubMed, EMBASE, and EBSCO databases for articles published until June 2016. Studies that reported the efficacy and safety of repeat BTX-A injections for adult patients with NDO were eligible. The effect size for each outcome was calculated as the standardized mean difference ± standard error and 95% confidence interval, and was graded as small, >0.2; moderate, >0.5; or large, >0.8. The outcomes included maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), reflex volume (RV), bladder compliance (BC), quality of life (QOL), and injection interval. Descriptive reviews were performed for urinary incontinence (UI) and adverse events (AEs).
RESULTS: Eighteen studies involving 1533 patients were included in this study. We noted non-significant changes in MCC, MDP, RV, and BC between the first and last injections. Patients who had received ≤4 injections were found to have stable QOL improvements after the first and last injections, whereas patients who had received ≥5 injections were found to have a significant decrease in QOL after the last injection. No significant differences in injection intervals were noted after repeat BTX-A injections, and the repeat injection failure rate was low.
CONCLUSION: Our study demonstrated that repeat BTX-A injections allow sustained improvements in patients with NDO. The rate of AEs was stable and low. However, additional high-quality, large-scale, and long-term trials are necessary to establish the efficacy and safety of ≥5 repeat BTX-A injections.


I guess you can read this but what are your thoughts about having more than five injections

Sunday, 30 July 2017

Tadpoles for MS drugs

Mannioui A, Vauzanges Q, Fini JB, Henriet E, Sekizar S, Azoyan L, Thomas JL, Pasquier DD, Giovannangeli C, Demeneix B, Lubetzki C, Zalc B. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.Mult Scler. 2017 Jul 1:1352458517721355. doi: 10.1177/1352458517721355. [Epub ahead of print]

BACKGROUND:

In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.

OBJECTIVE:

A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.

METHODS:

In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin (cell killing drug) . Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve.

RESULTS:

Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 (gene excising) gene editing showed that the pro-myelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5.

CONCLUSION:

This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known pro-myelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

Whilst we have been hearing about monkey work and you know about the meecie stuff, but there is a movement to replace such animals with animals that are lower down the  chain of sentience. We recently heard about an EAE model in Zebra fish. They have transparent bodies and you can make their nerves or oligodendrocytes "glow in the dark" so you can watch things happening in real time.

So this study moves down the evolutionary ladder and moves us to amphibians. Xenopus is the African clawed toad, that many of you may have seen at school.   This study makes tadpoles with oligodendrocytes that glow in the dark and have been engineered so that they kill them in response to a drug. The default then is repair and remyelination.  So its abit like the chemical-induced demyelination in mice. 
In this study they test to see if drugs will make the myelin appear quicker.

In this study they report that that siponimod is one of the best agents to promote myelin. Is this good and bad news? 

The good news therefore is that here you have an agent that can block the immune response by modulating Sphingosine-1 phosphate one IS1P1) receptor and block relapsing EAE but as shown here it can promote remyelination, via an action on Sphingosine-1-phosphate five (S1P5) receptor. Siponimod has been shown to inhibit secondary progressive MS in phase II, so it could be round the corner from use. 
But the bad news is it does not appear to make miraculous recoveries, and so if this is remyelinating it warns that we have to be realistic of what remyelination therapies may offer. Furthermore remyelinating a nerve that will remyelinate any way may not be the same as trying to remyelinate chronic gliotic lesions.
Next question what is the difference between siponimod and fingolimod? Fingolimod targets S1P1 and S1P5 and also S1P3, and S1P4. there are many inferences that fingolimod was also remyelinatory, but there was contradictory evidence, but remember this agent failed in progressive MS. Was this because they didn't measure hand function?

You asked which compounds were screened
As you can see there is Biotin, Clemastine, Benztropine, fingolimod. At the top of the pile was Clemastine, albeit at a much higher doses than UC-42-WP04, then siponimod and then fingolimod, RXR and Bentropine. At the bottom of the pile was Lithium and MDL29951

Saturday, 29 July 2017

#NewsSpeak & #ClinicSpeak: PML and fingolimod

How common is PML in fingolimoders? #NewsSpeak #ClinicSpeak

I would like to congratulate Novartis for providing periodic updates on the PML risk associated with fingolimod. There have now been 13 cases of PML on fingolimod unrelated to prior natalizumab exposure, which provides a risk of getting PML on fingolimod of less than 1 in 10,000.

Please note that the PML risk, and other opportunistic infection risk, is unrelated to your lymphocyte count, which is why you can't derisk the problem on fingolimod. You simply need to vigilant and  take any new neurological, and other, symptoms seriously and report them to your MS HCP (healthcare professional). 


"I could not bring myself to believe that if knowledge presented danger, the solution was ignorance. To me, it always seemed that the solution had to be wisdom. You did not refuse to look at danger, rather you learned how to handle it safely." 
Issac Asimov


Novartis Quarterly PML Update

The overall rate of confirmed PML under fingolimod therapy not attributed to previous natalizumab treatment is very rare and estimated to be less than 1:10,000 patients

13 confirmed PML cases in >213,000 fingolimod treated patients (>453,000 patient-years) as of May 2017.

(Estimated risk (95% CI) is 0.061 (0.032, 0.1)/1,000 patients and incidence rate (95% CI) is 2.87 (1.53, 4.9)/100,000 patient-years exposure.)
  • Two cases had confounding medical conditions (1 previous cancer and 1 ulcerative colitis/immunosuppressive therapy).
  • One patient had previous natalizumab exposure for 10 months (3 years 9 months before PML diagnosis)
  • In one patient, PML occurred during 3-month natalizumab exposure, after 4.5 years fingolimod treatment; this patient also had a history of recent exposure to steroids
  • Twelve of the 13 patients were within the age range of 43 to 63 years, while one patient was 34 years old
  • Twelve of the 13 patients had fingolimod exposure ranging between 29 and 75 months, while one received fingolimod for 18 months
  • There was no pattern of sustained grade 4 lymphopenia; JCV DNA PCR test was positive in all cases.
CoI: multiple

Reconstitution with fingolimod is not always quick

Ghadiri M, Fitz-Gerald L, Rezk A, Li R, Nyirenda M, Haegert D, Giacomini PS, Bar-Or A, Antel J.Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod Mult Scler. 2017;23(9):1225-1232. doi: 10.1177/1352458517713147.

BACKGROUND:Following fingolimod cessation, immune reconstitution or lack thereof may have consequences for disease rebound or safety of commencing alternative therapies.
OBJECTIVE:To examine the degree and profile of peripheral blood lymphocyte reconstitution following fingolimod withdrawal.
METHODS: Total lymphocyte counts (TLC) and CD4+/CD8+ T-cell counts were measured in 18 multiple sclerosis (MS) patients pre-treatment, on fingolimod, and up to 8-9 months post-cessation. T-cell subsets were analyzed using flow cytometry.
RESULTS: At 2-week post-fingolimod cessation, TLC reconstitution was variable and not correlated with age, treatment duration, pre-, or on-treatment TLC. Despite normalization of TLC and CD4+:CD8+ ratios over months, naive subsets remained lower and effector memory subsets higher in frequency compared with pre-treatment. Drug-induced increases in ratios of regulatory to pathogenic Th17-containing central memory populations appeared to rapidly return to baseline.
CONCLUSION: Early peripheral lymphocyte reconstitution after fingolimod withdrawal remains partial and heterogeneous. Relative frequencies of circulating naive and memory T-cell subsets may not recover for many months, even when clinical laboratory tests have normalized. Analyzing specific components of the peripheral immune repertoire helps define the overall immune status of patients. To be determined is whether assessment of such immune measures will have implications for the timing and safety of commencing alternative therapies.


Fingolimod is a an immune-migration inhibition agent. This means that rebound can occur when cells come out of their niche where they are supposedly held by loss of sphingosine one phosphate receptor. However when you examine the blood you can not only see that some subset of white cell disappear from the blood, you can also see that in some individuals there is a loss of white blood cells. This study  reiterates this issue and says that despite withdrawal of drug there are some people that do not reconstitute their immune system. This would perhaps suggest that fingolimod may be depleting immune stem cells/progenitors and so that people do not reconstitute properly. This is saying that there are actions other than simple blockade of migration and I may suggest that it can kill cells. We know this can happen as there is evidence in the literature,

The question is how common is this issue because if you do not reconstitute your immune system then you will be open to infections. That effector memory cells are more common is consistent with the mechanism as they do not express CCR7 which with Sphingosine-0ne-phosphate one receptor is used to allow naive and central memory T cells to exit lymphoid glands. Furthermore, when T cells reconstitute it is always the memory T cells that repopulate quicker than the naive T cells. However of concern there are a few individuals that do not reconstitute and this means that you may be at risk from infection.

So this leaves the problem how to transition from fingolimod. If you wait too long before starting the next treatment, rebound disease activity could occur. However, you may have heard the suggestion that  a fingolimod-switch to alemtuzumab can mean that disease activity returns (in about 25%) of cases, because the fingolimod traps the cells in the lymph glands, I think it is bone-marrow, and alemtuzumab can't get to them an delete them. But because the antibody is quickly gone, the fingolimod keeps the cells away from the antibody.  However,what if there is lack of lymphocytes if the depletion is long-term it will be problematical. We have seen people where the cell numbers, recover after use another immune depleter.

COI:None

Friday, 28 July 2017

Legalising Cannabis. What's your view?

Should we be legalising cannabis for use in multiple sclerosis? 

There is an article in the Guardian about it.

https://www.theguardian.com/society/2017/jul/27/legalise-cannabis-as-treatment-of-last-resort-for-multiple-sclerosis-says-charity


Currently there is a licensed version of Cannabis called Sativex, the problem is it costs too much and so it is not approved for use in Scotland, Northern Ireland and England yet it is available in NHS in Wales. Surely this is wrong! 

Another example of the post code lottery.

In the paper it says

“We (the MS Society) think cannabis should be legalised for medicinal use for people with MS to relieve their pain and muscle spasms when other treatments haven’t worked,” said Genevieve Edwards, the MS Society’s director of external affairs".

"The charity is also urging NHS bosses to make Sativex, a cannabis-based drug used by some people with MS, available on prescription across the UK so that patients who can afford it no longer have to acquire it privately, at a cost of about £2,000 a year. Wales is the only home nation to provide the mouth spray through the NHS".

Pharma make the existing (Cheapish) drugs  but if street cannabis becomes legalised, will pharma bother developing new drugs, if they can't make a return. I suspect the answer is No.  

It is simply not worth it.

A longer-acting version of baclofen has been approved in US but where is it?

As someone who has been developing a new treatment, this question is very pertinent. Will someone invest in its further development?

I am detached from the financial issues and have no power to influence costings/pricing, but I am acutely aware that cheap price may mean no interest

Sativex is not approved in the USA, yet now there are loads of States that have Medical Marijuana at a fraction of the cost, 
I suspect it may never get approved.

Therefore, the profits from the American sales cannot be used to offset cheaper drug prices for the NHS. 

Should the MS Society really get behind Off-label prescription, as there are alternatives to many of the current MS medications and their high cost is no doubt is causing rationing. 

Should Marijuana be legalised for MS, I have my views but I'll keep them to myself.

CoI. I am developing an alternative to Cannabis and so I will keep my mouth-shut aout the merits of Lagalisation

EAE becomes a B cell Disease

't Hart BA, Dunham J, Faber BW, Laman JD, van Horssen J, Bauer J, Kap YS.A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model.
Front Immunol. 2017 Jul 11;8:804. doi: 10.3389/fimmu.2017.00804.


The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34-56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund's adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund's adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34-56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey's immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.

This study they make it a disease of virally infected B cell, but it doesn't stop there EAE is made into a B cell disease.

Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.Bail K, Notz Q, Rovituso DM, Schampel A, Wunsch M, Koeniger T, Schropp V, Bharti R, Scholz CJ, Foerstner KU, Kleinschnitz C, Kuerten S.J Neuroinflammation. 2017 Jul 24;14(1):148. doi: 10.1186/s12974-017-0924-4.

BACKGROUND: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS).
METHODS:MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P1 receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro.
RESULTS: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220+ B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into lymphoid organs.
CONCLUSIONS:The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.

Fingolimod is said to be an treatment that traps white blood cells in lymph glands in this study but the B cells in the blood weren't affected but B cell numbers go up in spleen and so is it blocking their exit into the blood.  Does fingolimod make your lymph glands get bigger? It should if the theory about how it works is correct.  It may has a some anti-B cells effect but this model is so toned-down such that a B cell effect may be seen, but the simple message I think is that EAE is a T cell-mediated issue and so it probably lacks predictive value to detect agents that affect relapsing MS

Thursday, 27 July 2017

What do you prefer


BACKGROUND:Treatment adherence in patients with multiple sclerosis (MS) is essential to reduce the rate of acute neurological attacks, severity of relapses, and hospitalizations and to slow its progression. Adherence rates in MS patients have been shown to be affected by multiple factors, including physical or cognitive difficulties, perceived lack of treatment efficacy, treatment-related adverse events, injection anxiety, and frequency of administration.
OBJECTIVE:To elicit the preferences of MS patients for noneconomic and economic attributes of current disease-modifying therapies (DMTs).
METHODS:We used conjoint analysis to estimate preferences from a convenience sample through a web-based online survey. 


Patients were invited to participate in the study using web portals and newsletters for MS patients. The conjoint survey included the following 6 attributes: 
(1) overall efficacy based on autoimmune disease progression stabilization; 
(2) acute increase in disease activity (flare-up); 
(3) rate of respiratory tract infections; 
(4) rate of serious respiratory tract infections (leading to hospitalization); 
(5) medication use; 
and (6) patient monthly out-of-pocket medication costs.

 Using a fractional factorial design, 24 product profiles were created. Each respondent reviewed a random selection of 8 profiles. With each profile, subjects were asked to indicate their likelihood to try the hypothetical products on a scale from 0 to 100. Random effects linear regression was used to elicit preferences.
RESULTS:After exclusion of respondents with incomplete information, data from 129 subjects were included in the analysis. The overall relative importance of each attribute for the ranges presented were 
(1) 38.4% for monthly out-of-pocket cost; 
(2) 21.5% for route and frequency of administration; 
(3) 15.9% for risk of hospitalization by infection; 
(4) 11.9% for risk of respiratory tract infection; 
(5) 7.4% for risk of flare-ups; and 
(6) 5.0% for disease progression stabilization. 

Preference weights indicated that subjects favored: 
subcutaneous (beta coefficient [β] = -2.26, 95% CI = -4.22 to -0.22) and oral administration (β = 7.93, 95% CI = 5.95 to 10.2) over intramuscular (β = -5.67, 95% CI = -8.67 to -3.56), but no significant differences were found between subcutaneous over intramuscular administration. 

Monthly out-of-pocket cost was the most influential attribute, with an overall relative importance of 38%. The most preferred level was $75 (β = 12.85, 95% CI = 10.64 to 15.06) followed by $150 (β = 3.41, 95% CI = 0.98 to 5.84) when compared between $75, $150, $300, and $450 a month.

CONCLUSIONS:Conjoint analysis proved to be a convenient tool to quantify respondents' relative preferences for DMT characteristics. Respondents gave higher weight to DMT monthly out-of-pocket costs and mode of administration than to adverse effects or efficacy. These findings may assist in the development of DMT cost-sharing strategies and shared decision making at the point of care


What do you prefer? My guess would have been lack of side effects as top of your tree. Otherwise how do you explain that glatiramer acetate is number one best seller. Maybe Lazy-assed Neuros influence things as this does not require much monitoring. 
This survey confirms that efficacy is not high on the requirements, but cost is. Now if we had a low cost alternative maybe that would fly with pwMS, not so sure neuros are so happy....oh I forgot we do have this.

Wednesday, 26 July 2017

#GuestPost: More on the safety of MRI contrast agents

A recent post on the safety of Gadolinium based contrast agents used in MRI caused some concern, so I thought we should follow up with yet more expertise and analysis. I therefore asked Dr Tom Campion to summarise his thoughts on a recent guidance statement by the International Society for Magnetic Resonance in Medicine (ISMRM) on this important topic.

Tom Campion is a senior radiology registrar at Barts Health NHS Trust, where he is currently undergoing neuroradiology training. He has an MSc in Neuroimaging for Research, and a research interest in imaging in multiple sclerosis. He is the trainee representative for the British Society of Neuroradiologists and runs a blog at www.bsnrtrainees.com. Tom has recently published a well received paper on a new method to improve the diagnosis of MS (free for download here). He has no conflicts of interest.


"Gadolinium-based contrast agents (GBCAs) are safe medications widely used in medical imaging, but have come under scrutiny due to the finding over the last few years that residual gadolinium is left in specific areas of the brain following their usage. The ISMRM published a recent guidance statement summarizing the evidence available so far, so here’s what we know [1]:

- In multiple studies, gadolinium has been found deposited in the brain, by imaging and by autopsy, long after GBCA administration
- This deposition appears more pronounced when people have had repeated doses of GBCA.
- Of the two types of GBCA, ‘linear’ and ‘macrocyclic’ (for a detailed explanation of the difference, see [2]), deposition is significantly more pronounced with linear compared to macrocyclic agents but has been demonstrated in both.
- The mechanism for the deposition is not yet understood.
- This has not been shown to cause any harm in human or animal models.

So what do we, as doctors and patients, do with this information? It is important to realize that we don’t give GBCAs for every MRI scan – each case is evaluated on an individual basis taking into account the potential benefits and risks. The benefits of GBCAs, simply put, are that they give us better images of abnormalities in the brain; the reason for this is that they penetrate the barrier between the blood vessels and the brain if there is a problem with the barrier, which is what we see in many people with neurological disease. Our ability to detect these problems is reduced by not using GBCAs. In the setting of multiple sclerosis, this is particularly important to evaluate the activity of the disease at a given time, as well as to exclude other potential causes for symptoms. 

Clearly, the benefit/risk consideration is now slightly different due to the introduction of a theoretical risk from gadolinium deposition, and should continue to be assessed on an individual case basis. But the multiple studies performed thus far, including large-scale population studies [3], have not shown any functional deficit related to the areas affected by the gadolinium deposition (the dentate nucleus and globus pallidus, which are primarily involved in the initiation and control of movement), or indeed any evidence of harm that can be directly linked to the deposition. 

My interpretation of the current evidence as a radiologist, particularly the ISMRM guidance [1] and the FDA safety statement [4], is this:
1. In the vast majority of contexts in which we give GBCAs, the benefits will outweigh these theoretical risks. Important treatment decisions are made based on these MRI scans, and these decisions are significantly better informed by our use of GBCAs, and thus more likely to lead to better outcomes for people with neurological disease.
2. This doesn’t mean we should dismiss these potential risks. On the contrary, we should seek further evidence on long term outcomes, find out the mechanism of gadolinium deposition, and design and use newer agents to prevent it if proved to be harmful.
3. We should also always be looking for other ways to image safely – researchers are already investigating other imaging techniques which could be used in future to avoid contrast administration [5].

Of course these findings are anxiety-provoking for people undergoing MRI scans, and it is important not to offer false reassurance; however, we should also not allow people to come to more harm as a result of avoiding a test that may be of significant benefit.

For those interested in further information, I recommend reading the recent ISMRM guidance statement [1] and the US Food & Drug Administration Drug Safety Communication [5], both of which are available for free online."


References
1. Gulani et al. (2017) Gadolinium Deposition in the Brain: Summary of Evidence and Recommendations. Lancet Neurol 16:564-70. Available at: http://www.ismrm.org/ismrm-position-paper-on-gd-deposition/
2. Kanal et al. (2014) Gadolinium contrast agents for CNS imaging: current concepts and clinical evidence. AJNR 35:2215-26.
3. Welk et al. (2016) Association Between Gadolinium Contrast Exposure and the Risk of Parkinsonism. JAMA 316:96-9.
4. FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm559007.htm
5. Gupta et al. (2017) The Use of Noncontrast Quantitative MRI to Detect Gadolinium-Enhancing Multiple Sclerosis Brain Lesions: A Systematic Review and Meta-Analysis. AJNR 38:1317-22.

Tuesday, 25 July 2017

Seizures in MS - what we don't know

Brain Behav. 2017 May 24;7(7):e00726. doi: 10.1002/brb3.726. eCollection 2017 Jul.

Unprovoked seizures in multiple sclerosis: Why are they rare?

Kavčič A, Hofmann WE.


Abstract

INTRODUCTION:

The frequency of seizures in patients with multiple sclerosis (MS) ranges from 1.5% to 7.8% and is considerably more common than chance events. The etiopathogenesis of seizures in MS is still poorly understood.

METHOD:

A review of the literature on seizures and MS using PubMed.

RESULTS:

Cortical gray matter involvement appears to be an all-too-common pathological finding in MS to play a primary role in the pathogenesis of seizures in MS patients. There is no clear relationship between seizures and the severity of MS. In approximately 10% of cases, a seizure is actually an initial neurological symptom of MS.

CONCLUSION:

Searching for coherence in the occurrence of unprovoked seizures in MS directs attention to the dichotomy in MS pathology characterized by a complex intertwining of neuroinflammatory and neurodegenerative processes. The appearance (or nonappearance) of seizures in MS in relation to disease activity and disease progression indicates a distinct clinical phenotype of MS that opens up new perspectives in MS research.


Despite our vast knowledge and understanding of MS, there are vexingly the unknown knowns about the simplest things in MS. We can only know that we know nothing about something; and sadly this is the only thing we know anything about! The occurrence and cause of seizures in MS is one such example.

From a logical perspective, seizures in MS should either be a reflection of more severe disease (like in other neurological disorders, such as brain tumours and Alzheimer's disease) or an indication of an above threshold occurrence of cortical involvement (the potion of the brain that houses the nerve center and a focal point of seizure onset). This is neither the case. 

Here Kavčič and Kofmann, after reviewing a series of publications on seizures in MS report exactly this. They note that despite the rarity of incidence of MS, the frequency of seizure presentations varies between 1.5-7.8%, a number which is more than what would be expected by chance alone (the background rate of seizure occurrence in the general population is 3%). However, in overall terms the frequency is still rarer than the degree of involvement of the cortex of the brain by MS. Moreover, in the most severe cases of MS, you're not guaranteed to have seizures, and conversely, seizures are not a sign of severe MS. Whilst in around 10% of early MS cases, seizures are sometimes the presenting feature!

So, the aetiology of seizures in MS is something of a mystery. Is it because in MS there is significant reserve in the brain which is playing a contributory role? Or, is it that the neurodegenerative process paradoxically diminishes the neural network hyper-excitability in MS and hence, seizure occurrence?

Monday, 24 July 2017

#GuestPost: taking the MS Society to task

Has the MS Society been caught navel gazing? #GuestPost 

I have in the past criticised the MS Society over various issues. It was therefore surprising when one of our patients complained to me about them as well. I think the issue he has raised is important enough to be discussed in public and I therefore asked him to prepare a guest post.  


MS Society. Together we walk

On 24th September 2017 the MS Society is organising a sponsored walk. On their website they state ‘This September hundreds of MS Superstars, our friends and families, will join forces in London to take in the sights and raise funds to stop MS. Will you join us?’

There will be walks of 3 different lengths, 6km, 10 km and 20 km. The two shorter walks are fully accessible

In October 2016 the MS Society published the following:

Exercise is known to have a positive impact in MS. As well as promoting general health, research has found that exercise can help manage fatigue and improve quality of life for people with MS. It can also improve particular MS symptoms, including cognitive changes, balance and walking.

So we are all agreed that exercise can help people with MS. The MS Society is organising a walk and they would like people to be sponsored and raise money for the MS Society.

I have one significant issue with ‘Together we walk’; I really enjoy taking exercise but I will be unable to participate. I suffer from secondary progressive multiple sclerosis and one of the problems of my MS is that I have serious foot drop. I cannot walk unaided. It takes me about 45 minutes to walk 1km which is my limit and I must use a rollator.

There are plenty of people with progressive MS who suffer from mobility issues and would love to take part in the walk. As well as participating they would like to achieve a goal. The sense of satisfaction in achieving a goal cannot be underestimated.

Surely it cannot be too difficult to organise walks of say 1km and 500m. This would allow people like me who suffer from progressive MS and have serious mobility issues to participate. We can raise money for the MS Society and achieve a goal. This is a win-win for everyone.

Yes I could go on my mobility scooter and complete a distance of between 6 and 20 km but that is not a challenge. Where is the sense of achievement?

Why has the MS Society taken it upon itself to discriminate against people who would like to raise money for the MS Society but are physically unable to walk more than a short distance? Why can’t I join in with the walk, be sponsored for walking an agreed distance?



I am Patrick Burke, I was diagnosed with RRMS in 1995 but I believe the symptoms started in 1972.The disease turned into SPMS in about 1999/2000. I took medical retirement in 2012 and setup the website Aid4Disabled in the same year. The website is the story of my MS since retirement and it also identifies a wide range of objects that are readily available and can improve quality of life. I am also a member of the Barts MS Advisory Group.


CoI: None

Sunday, 23 July 2017

EBV and Vitamin D..reducing antibodies

Rolf L, Muris AH, Mathias A, Du Pasquier R, Koneczny I, Disanto G, Kuhle J, Ramagopalan S, Damoiseaux J, Smolders J, Hupperts R. Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis. Mult Scler. 2017:1352458517722646. 

BACKGROUND:Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis(MS).
OBJECTIVES:To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels.
METHODS:This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored.
RESULTS:The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures.
CONCLUSION:High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.
As ProfG sits on a beach pondering the "meaning of MS", does this study hit the jackpot,?

It has vitamin D and EBV as two things close to his heart as the centre of MS susceptibility. 

What does this study  say? 

It is a trial of vitamin D supplementation and they look at EBV antibody levels and find that if you supplement with vitamin D the levels of of antibodies against parts of the EBV virus go down. 

However, this has no impact on viral load. They then conclude this result does not implicate a promoted immune response against EBV.

Whilst ProfG contemplates whats this means, I ask what is the relevant biology here?

The implication is that vitamin D has an impact in utero (in the womb) and perhaps shapes the immune response in early life. This is what is implicated from studies in type 1 diabetes. EBV is a trigger factor when it infects someone years later. 

Now I can go with the flow that studying the effect of vitamin D supplementation,decades after birth, has impact. This idea has caused a myriad of clinical studies in all sorts of conditions, many outside MS. The charities are shelling out loads of cash investigating this, in response to the interest whipped up by the Docs doing the trials. However,  this study highlights one of the problems I have with the vitamin D brigade and the clinical fraternity.

This is a trial involving 53 people. 

What is this really going to tell us about vitamin D?

It is hopelessly underpowered to tell us much and certainly can't tell us whether vitamin D impacts on MS. A P value = 0.023 so about a 1 in fifty chance that this occurs by chance. It will need repeating...another unpowered trial:-(

It is just like the omega oils...lots of useless small trials giving no answers.

They give a whiff of something but are never big enough to give a useful answer about the benefit or lack of it, and we will be supplementing forever so H& B (vitamin Shop) are happy. 

How many individual trials are being funded on vitamin D?.

I suspect that in MSm vitamin D will not be a very good immune modulator, if it was great you would have all sorts of side effects....you don't... so don't expect the earth. Can it be of benefit, sure it can and you need to ensure good bone health.


Saturday, 22 July 2017

#ResearchSpeak: are you a drinker?

What is the evidence that alcohol is good for you? #ResearchSpeak #MSBlog

The following study implies that moderate alcohol consumption is associated with lower disability and suggest red wine is good for you. However, moderate red wine consumption (1-3 glasses per week) was associated with a faster increased in MRI T2 lesion volume, i.e. focal MRI activity. How do we square this circle? We don't the results are not that convincing and suggest an association. In other words alcohol drinking may be associated with other factors that are actually responsible for the lower levels of disability. The association with red wine drinking looks like a false positive and the positive spin in this article could be due a framing effect based on the marketing of red wine as an anti-ageing agent. A framing effect is the interpretation of results in a particular way based on a bias (frame) that has been established by past experiences or prior knowledge. 


There has been work done on resveratrol, an anti-oxidant, in red wine as an anti-ageing, and neuroprotective, compound. The problem is that the amount of resveratrol you get from drinking red wine is too low to have much biological impact. Despite this the French wine industry has managed to get the message across that red wine is good for you.

This paper must be balanced against the literature showing how bad excessive alcohol intake is for your health overall. More recently excessive, and even moderate, alcohol consumption has also been shown to reduce cognition. 

I must point out that the levels of consumption of alcohol studied in this paper are quite low. This study in not going to alter my practice and I will continue to recommend that if you choose to drink please do so in moderation and if you choose to be teetotal that is also fine. The evidence that alcohol is neuroprotective is very weak. We need well designed and larger studies to control for con-founders before making any unrealistic claims about the benefits of alcohol to pwMS. 

Diaz-Cruza et al. The effect of alcohol and red wine consumption on clinical and MRI outcomes in multiple sclerosis. Multiple Sclerosis and Related Disorders. Volume 17, October 2017, Pages 47-53.

Background: Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS).

Objective: To assess the association between alcohol and red wine consumption and MS course.

Methods: MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol.

Results: 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, − 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, − 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1–3 glasses of red wine per week compared to nondrinkers.

Conclusions: Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms.


CoI: I am wine lover.

Mouse Flu is it really informative about Man Flu

Blackmore S, Hernandez J, Juda M, Ryder E, Freund GG, Johnson RW, Steelman AJ. Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2017. pii: 201620415

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.


So here we have a mouse stuffed full of T cells waiting to attack the spinal cord and optic nerve and you do nothing and 5% get disease, you stimulate their T cells with the toxin from whooping cough and 100% get disease and here you give a live virus and about 30% get disease. They give a normal mice the flu and they find changes in the genes in the brain suggestive some cellular activation and say a cytokine is involved.. However if they had done anything to stimulate the T cells they would get disease and so the inference in that the paper that flu is a trigger of MS fails down. 

Friday, 21 July 2017

Sorry I messed up

I have to apologise but I was immersed in the World Para Athletics 2017 and the Last Leg and was supposed to launch your comments but deleted them by pressing the wrong button by mistake, so if you have the comments please submit again.

Autoimmunity in MS: Neurofilament light

Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament Light as an Immune Target for Pathogenic Antibodies. Immunology. 2017. doi: 10.1111/imm.12797. [Epub ahead of print]

Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunisation with neuronal antigens such as neurofilament light NF-L, a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, while antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.

When nerves are damaged they breakdown and release their contents and these products are measured as a marker of disease activity. However, it is clear that neurofilament directed antibodies are generated to clear up these breakdown products. 

We have shown that if you cause the antibodies to be produced in mice that they can cause neurological problems. 

This study shows that these antibodies, however can be potentially damaging and so clearly shows there is autoimmunity occurring in MS. In this study neurofilament specific antibodies were injected into animals and it made EAE worst, once T cells had opened the blood brain barrier to allow the antibody to enter the brain. This was not surprising as this has been shown with a number of antibodies. More surprisingly when injected directly into the brain these antibodies caused signs of disease. It was surprising because neurofilament is inside a nerve and so would not be easily assessable.  The signs occurring were very different to the signs occurring when antibodies targeting basal ganglia from a person with a tic disease was injected into the brain. 

These neurofilment directed antibodies can kill nerves and so could contribute to damage in MS.

CoI. This is work bt TeamG

#GuestPost & #NewsSpeak: feedback from the MS-Chariot meeting

An MSer's perspective the MS-Chariot meeting. #GuestPost #ThinkHand #MSChariot

Last week, I attended the first MS Chariot meeting at St Barts. Around the table were about twenty of us - mostly neurologists from the UK and abroad, health researchers, an MS Society  representative and a few of us MSers - all there to discuss the possibilities, funding, treatments and yes - frustrations - of those with advanced MS who have traditionally been overlooked in the quest for disease modifying drugs.

This was made all the more apparent at the start of the day when Craig Milverton sat down at a piano and began playing a handful of songs by George Gershwin, Cole Porter and other jazz greats.

Playing is the key word here.

You see in 2010, the very year Milverton was named Jazz Pianist of the Year, he was diagnosed with PPMS. With each passing month, his symptoms got worse. His walking deteriorated, his fingers became more and more numb and he began missing notes on the piano. His career as a pianist was over, he thought.


Then in 2012 he was able to get on ocrelizumab - an experimental drug currently being assessed for drug licensing by the EMA for RRMS and PPMS. Almost immediately after his first infusion he started to feel better. Since then, his symptoms have stabilised and he has been able to continue playing across the country.

Craig is one of the lucky ones. Until very recently, it was thought that a person with advanced  MS - with an EDSS score above 5.5 and requiring a walking aid - would not benefit from a disease modifying treatment (DMT). It was not quite “Diagnosis and Adios,” but pretty close.

Why? Selective interpretation of trial data, too much focus on EDSS scores as a key outcome, a belief immunotherapy did not work “beyond the wheelchair,” regulatory process, cost and numbers. Advanced MS is uncommon. Only 10-15% of MSers are initially diagnosed with it.

Such a belief also meant that for those with advanced MS preserving upper limb function was not seen as a priority. But if you think about it, what keeps pwMS independent is their arms and hands. When you lose the ability to walk - that is bad enough. But at least with your hands, you are able to get into your wheelchair, dress yourself, clean your teeth, feed yourself, make a telephone call, use a keyboard, self-catheterize, work a remote control… Lose that and your quality of life plummets.

Thankfully this mindset is starting to change. “At the moment, there are no established options for advanced MS, but emerging therapies are offering hope,” said Cris Constantinescu, a neurologist from Nottingham University, to the group.

For Dr. Klaus Schmierer, a neurologist at St Barts who organised the forum, real promise lies in cladribine, a drug traditionally used for the past 25 years to treat hairy cell leukemia, but which has also proved to be highly effective in treating RRMS. As an MS drug, it has many advantages. It is safe, easy to use, convenient - it is an injectable but also comes in tablet form -  and cheap as it is a generic drug.

Intriguingly, there is also evidence, dating from the early 1990’s, that cladribine may also slow advanced MS. At the moment, about one hundred patients at the Royal London Hospital with advanced MS - who have failed other therapies - are using it and finding it effective. “It meets the needs of some patients for whom we have little to offer,” says Schmierer. But definitive trials are lacking, a source of frustration for Schmierer, who is currently looking for funding.

Another MS drug which offers hope is rituximab, an injectable, which works in a similar fashion to ocrelizumab.  Though the NHS has declined to fund rituximab for the treatment of MS in the UK - citing insufficient trial results - Swedish neurologists have been using the drug for RRMS and advanced MS for more than a decade. “It fulfilled an unmet need and there were fewer options available for advanced MS,” said Frederik Piehl, a neurologist from the Karolinska Institute. In Sweden, he said rituximab has been found to have been highly effective and well tolerated. However in the UK, neurologists are not allowed to prescribe it for their patients.

By the end of the day, it had become apparent that there were no one-off easy answers regarding treatment options for those with advanced MS. The challenging nature of treating MS, plus wrangles over drug licensing, potential funding and drug company priorities ensures this However there was a feeling that, at least, attention is finally being focused on those with advanced MS who might have been previously ignored. Studies have shown - and as Craig Milverton apply demonstrated - advanced MS is modifiable. Now it is key to get the rest of the community on board.

As Aisling McMahon, head of clinical research at the MS Society, said: “We are very aware that progressive MS is the greatest area of unmet need.”

RMH