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.