Thursday, 25 August 2016

ClinicSpeak: physical rehabilitation using your imagination

Never underestimate the power of imagination. #MSResearch #MSBlog #ClinicSpeak

"My brother-in-law who is a petrol head was a major Ayrton Senna fan and had the opportunity of meeting him. He told me that one of the reasons why Senna was so good is that he used motor imagery to practice; in addition to practising out on the track he used to spend hours, and hours, imaging racing on a particular track. He would mentally go through the gear changes, imagine the accelerations, decelerations and driving on and off the racing line. He told my brother-in-law that for every physical lap he practice he would 10 or more imaginary laps and he would vary the laps in his thoughts. He would even practice different overtaking manoeuvres in his mind. He claimed the mental imagery was what gave him the edge. I am, therefore, not surprised that cued motor imagery in relation to walking helps improve walking speed, fatigue and quality of life in MSers. I am not saying this can replace physical exercise, but it can augment it and all you need is a pair of headphones, music and an imagination. Easier said than done?"

Seebacher et al.  The effect of rhythmic-cued motor imagery on walking, fatigue and quality of life in people withmultiple sclerosis: A randomised controlled trial.Mult Scler. 2016 Apr 7. pii: 1352458516644058. [Epub]

BACKGROUND: Motor imagery and rhythmic auditory stimulation are physiotherapy strategies for walking rehabilitation.

OBJECTIVES: To investigate the effect of motor imagery combined with rhythmic cueing on walking, fatigue and quality of life (QoL) in people with multiple sclerosis (MS).

METHODS: Individuals with MS and Expanded Disability Status Scale scores of 1.5-4.5 were randomised into one of three groups: 17 minutes of motor imagery, six times per week, for 4 weeks, with music (A) or metronome cues (B), both with verbal cueing, and (C) controls. Primary outcomes were walking speed (Timed 25-Foot Walk) and distance (6-Minute Walk Test). Secondary outcomes were walking perception (Multiple Sclerosis Walking Scale-12), fatigue (Modified Fatigue Impact Scale) and QoL (Short Form-36 Health Survey, Multiple Sclerosis Impact Scale-29, Euroquol-5D-3L Questionnaire).

RESULTS: Of the 112 participants randomised, 101 completed the study. Compared to controls, both interventions significantly improved walking speed, distance and perception. Significant improvements in cognitive but not psychosocial fatigue were seen in the intervention groups, and physical fatigue improved only in the music-based group. Both interventions improved QoL; however, music-cued motor imagery was superior at improving health-related QoL.

CONCLUSIONS: Rhythmic-cued motor imagery improves walking, fatigue and QoL in people with MS, with music-cued motor imagery being more effective.

Clonal Expansions in MS Society

de Paula Alves Sousa A, Johnson KR, Nicholas R, Darko S, Price DA, Douek DC, Jacobson S, Muraro PA.Intrathecal T-cell clonal expansions in patients with multiple sclerosis.Ann Clin Transl Neurol. 2016 Apr 20;3(6):422-33.

OBJECTIVE:Analysis of the T-cell receptor (TCR) repertoire in the cerebrospinal fluid (CSF) of patients withmultiple sclerosis (MS) can reveal antigen-specific immune responses potentially implicated in the disease process. We applied a new unbiased deep-sequencing method for TCR repertoire analysis to accurately measure and compare receptor diversity and clonal expansions within the peripheral and CSF-trafficking T-cell populations of patients with MS and control individuals with idiopathic intracranial hypertension (IIH).
METHODS:Paired blood and CSF TCR β-chain libraries from five MS patients and five IIH controls were sequenced, yielding a total of 80 million reads.
RESULTS:Although TCR repertoire diversity was greater in the blood and CSF compartments of MS patients when compared with IIH controls, it is notable that the frequency of clonal expansions was also significantly higher in both compartments of MS patients. Highly expanded T-cell clones were enriched in the CSF compartment of MS patients compared to peripheral blood, very few of them were detected in both compartments.
INTERPRETATION:Collectively, our data provide a proof of principle that private compartmentalized T-cell expansion exists in the intrathecal space of MS patients.
The target detecting molecules of a T cell is called the T cell receptor. If MS is autoimmune you would think that the disease causing cell would be expanded from the initial naive cell to the effector cell causing the disease.  By sequencing the T cell receptor you can work out if two cells are clonal i.e. are the same because they come from the same originating cell. In this study they looked at the T cell receptor sequences and found that in MS there were evidence of expansions and there were expansions in the CNS, but are these the autoimmune? 

This the next challenge is to work out what they are binding to 

Wednesday, 24 August 2016

ClinicSpeak: risk benefit, risk harm analyses

Do we need a new way to communicate benefits and risks? #ClinicSpeak #MSBlog #MSResearch
'Lies, damned lies, and statistics', Mark Twain

"The analysis below looks at the benefit and risk of DMTs from a different statistical perspective, i.e. how many patients do you need to treat with DMT to benefit, or harm, one patient? 

NNTB = number-needed-to-treat to benefit
NNTH = number-needed-to-treat to harm
LHH = likelihood to be helped-or-harmed
AAR = annualized relapse rate
PPR-F = proportion of relapse-free patients
PP-F-CDPS3M = proportion of disability progression free patients confirmed or sustained at 3 months

When analysed like this it is remarkable how well subcutaneous interferon-beta-1a (Rebif) does compared to the newer DMTs. Of the newer agents Natalizumab fares the best. Is this a compelling way to present data to people with MS? If I presented data in this way I suspect many of my patients may select interferon-beta as their agent of choice. The problem with this analysis is that it classifies harm very broadly and not all 'harmful events' are necessarily serious or life threatening. For example, raised liver enzyme that are asymptomatic and reversible is very different to PML or a life-threatening infusion reaction. In addition, this type of analysis does not take into account individual patient characteristics (prognostic profile and baseline disease activity) nor does it take into account lifestyle issues (family planning, cosmetic issues, etc.). I may be wrong but I am not sure it will be easy to present the relative risks and benefits of each of these DMTs to patients in this way without getting bogged down in the small print about rare adverse events. However, I may be wrong. What do you think?"

Mendes et al. Benefit-Risk of Therapies for Relapsing-Remitting Multiple Sclerosis: Testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A Systematic Review and Meta-Analysis. CNS Drugs. 2016 Aug 18. [Epub]

OBJECTIVE: This study aimed to test the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) when assessing benefits, risks, and benefit-risk ratios of disease-modifying treatments (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS).

METHODS: In May 2016, we conducted a systematic review using the PubMed and Cochrane Central Register of Controlled Trials databases to identify phase III, randomized controlled trials with a duration of ≥2 years that assessed first-line (dimethyl fumarate [DMF], glatiramer acetate [GA], β-interferons [IFN], and teriflunomide) or second-line (alemtuzumab, fingolimod, and natalizumab) DMTs in patients with RRMS. Meta-analyses were performed to estimate relative risks (RRs) on annualized relapse rate (ARR), proportion of relapse-free patients (PPR-F), disability progression (PP-F-CDPS3M), and safety outcomes. NNTB and NNTH values were calculated applying RRs to control event rates. LHH was calculated as NNTH/NNTB ratio.

RESULTS: The lowest NNTBs on ARR, PPR-F, and PP-F-CDPS3M were found with IFN-β-1a-SC (NNTB 3, 95 % CI 2-4; NNTB 7, 95 % CI 4-18; NNTB 4, 95 % CI 3-7, respectively) and natalizumab (NNTB 2, 95 % CI 2-3; NNTB 4, 95 % CI 3-6; NNTB 9, 95 % CI 6-19, respectively). The lowest NNTH on adverse events leading to treatment discontinuation was found with IFN-β-1b (NNTH 14, 95 % 2-426) versus placebo; a protective effect was noted with alemtuzumab versus IFN-β-1a-SC (NNTB 22, 95 % 17-41). LHHs >1 were more frequent with IFN-β-1a-SC and natalizumab.

CONCLUSIONS: These metrics may be valuable for benefit-risk assessments, as they reflect baseline risks and are easily interpreted. Before making treatment decisions, clinicians must acknowledge that a higher RR reduction with drug A as compared with drug B (versus a common comparator in trial A and trial B, respectively) does not necessarily mean that the number of patients needed to be treated for one patient to encounter one additional outcome of interest over a defined period of time is lower with drug A than with drug B. Overall, IFN-β-1a-SC and natalizumab seem to have the most favourable benefit-risk ratios among first- and second-line DMTs, respectively.

CoI: multiple

Tuesday, 23 August 2016

The 3Rs of Animal research

If you work with animals in the European Union you have to think about and apply the 3Rs (reduction refinement and replacement) principles to animal research. 

MS research in animals is considered to be one of the more "severe" procedures that nasty researchers do to animals. Therefore the regulators watch out for things that may make the EAE procedure less severe.

Many years ago, the way to induce disease in beasties was to inject animals in the feet with nerve proteins mixed with an immune stimulator. This used to make an immune response in the feet of the animals and so it became swollen, and sensitive to pressure and so the poor animals could not walk properly, because it was painful.  I hear you say Uck!. I say Uck too!

So not surprisingly this procedure was banned.

This occurred in the UK many, many years ago. The EU was a bit slower when it came to banning this and some countries don't really give a stuff about ethics of use of animals and still do this practice.

I never accept any paper that does this, as it is unethical, and have urged other people to do the same. I was lambasted by some person for saying this. However, my retort was that there are ways to achieve sensitization without causing the pain to the animals, so time to change rather that doing nothing.

Some groups have been looking in how to avoid the injection reactions and one approach is 

Saul L, Besusso D, Mellanby RJ.LPS-matured CD11c+ bone marrow-derived dendritic cells can initiate autoimmune pathology with minimal injection site inflammation.Lab Anim. 2016 Aug 3. pii: 0023677216663584. [Epub ahead of print]

The pathogenesis of human autoimmune disorders is incompletely understood. This has led to the development of numerous mouse models in which the pathogenesis of autoimmunity can be probed and the efficacy of novel therapies can be tested. One of the most widely-used mouse models of autoimmunity is experimental autoimmune encephalomyelitis (EAE). To induce autoimmune pathology, mice are often immunized with an autoantigen alongside an adjuvant, typically complete Freund's adjuvant (CFA). Unfortunately, CFA causes significant inflammation at the site of administration. Despite the well-recognized complication of injection site inflammation, CFA with autoantigen immunization is widely used to induce central nervous system autoimmunity. We performed a literature review which allowed us to estimate that over 10,000 mice were immunized with CFA in published EAE studies in 2013. In this study, we demonstrated that subcutaneously administered myelin basic protein (MBP)-pulsed CD11c+ bone marrow-derived dendritic cells (BMDC) were as effective at inducing EAE as subcutaneously administered MBP plus CFA. Importantly, we also discovered that the CD11c+ BMDC caused significantly less injection site inflammation than MBP plus CFA immunization. This study demonstrated that the use of CD11c+ BMDC can enable the development of autopathogenic T-cells to be studied in vivo without the unwanted side-effects of long-lasting injection site inflammation. This model represents a significant refinement to existing EAE models and may lead to the improvement of the welfare of experimental mice used to study the development of autoimmunity in vivo.

So in this study they look at C57BL/10.PLx C57BL/6 mice which are not that susceptible to EAE and show that if you transfer dendritic cells (an immune stimulator immune cell) that have been bound to myelin basic protein that you can induce disease that is as good as the EAE induced by injecting mice with a nasty immune stimulating adjuvant. 

The Home Office in the UK, waters its lips and sees a way to reduce the severity of animal research because the study is published in an animal care rag.  

However, the problem is that most animal strains do not respond to myelin basic protein and there are no transgenic animals for alll antigens and for all strains and species, to do all the background work

Importnantly, you can also induce disease using myelin specific T cells, rather than doing the procedures done in the current study.

Importantly, nobody in Europe injects into the legs and feet anymore or nobody should be injecting into feet, so the revelation is so much not a revelation but a misnoma. 

However this is never mentioned in the manuscript. The nasty adjuvant is injected under the skin in the flank and so does not cause the distress that this manuscript aims to suggest.

Most people now inject the immune stimulator under loose skin in the flank. It is certainly less painful there and one may ask if it is painful at all? Certainly the injections site do not appear painful to touch in mice, based on pain faces and the lack of appreciable responses to the injection sites being touched.

In this study they first inject normal animals with T cells that respond to the myelin antigen and then they inject the animals with antigen on dendritic cells.

They get good disease, but the injection site reaction is better compared to the nasty adjuvant, which is never now used in the way reported.

Now I am waiting for the Home office Inspector to come and say why not use this 3Rs approach, and we will spend weeks and thousands investigating this.

Stop beating around the bush in aggressive MS!

Neuropsychiatr Dis Treat. 2016 Aug 1;12:1907-12. doi: 10.2147/NDT.S111885. eCollection 2016.

A study of patients with aggressive multiple sclerosis at disease onset.

Kaunzner UW, Kumar G, Askin G, Gauthier SA, Nealon NN, Vartanian T, Perumal JS.



Identify aggressive onset multiple sclerosis (AOMS) and describe its clinical course.


AOMS patients were identified from a multiple sclerosis (MS) database based on a set of criteria. The subsequent clinical course of AOMS patients was then reviewed with the goal of potentially identifying the best approaches to manage these patients.


Fifty-eight of 783 (7.4%) patients in the MS database met the criteria for AOMS, and 43 patients who had complete data for the duration of their follow-up were included in the subsequent analysis. The mean duration of the follow-up was 54 months. Thirty-five patients (81%) were started on a conventional first-line agent (injectable therapies for MS). Only two of these 35 patients (5.7%) had no evidence of disease activity. Twenty-two of 35 patients suffering from refractory disease were switched to a more aggressive treatment (natalizumab, rituximab, alemtuzumab, cyclophosphamide). Eight patients were started on aggressive treatment as their initial therapy, and seven of these eight (87.5%) patients showed no evidence of disease activity.


With recognition of the crucial significance of early optimal treatment during the potential window of opportunity for best long-term outcomes, we describe AOMS within 1 year of disease onset and discuss possible treatment considerations for these patients.

In general terms it's difficult to predict the course of MS at onset, it's retrospectively made, but at the same time disastrous if you get it wrong.

Evidence points to roughly 9% of MS being of the aggressive variety and can progress to requiring a walking stick within 5 years of first symptom onset (Gholipour T et al. Demographic and clinical characteristics of malignant multiple sclerosis. Neurology. 2011;76(23):1996–2001). There is then only a small window of opportunity to modify the course of the disease.

Work by Kaunzer et al. just adds to what we already know from previous database studies. They demonstrate that only 6% of those with aggressive disease started on first line treatment (i.e. injectables such as the interferons or glatiramer acetate) have no evidence of disease activity (NEDA). This is compared to 88% who are put on second line treatment (i.e. natalizumab, rituximab, alemtuzumab, cyclophosphamide). Therefore, we are potentially losing valuable time by doing escalation therapy in those with aggressive MS!

So, how do we pick out those who would have a poor long-term outcome? Answer - neurofilament analysis; and how do you prevent poor outcome in aggressive disease? Answer - don't put them on first-line treatment, but move directly to second line treatment.