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 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."

1. Gulani et al. (2017) Gadolinium Deposition in the Brain: Summary of Evidence and Recommendations. Lancet Neurol 16:564-70. Available at:
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:
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.



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.


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


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.


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 don't... so don't expect the earth. Can it be of benefit, sure it can and you need to ensure good bone health.