Tuesday, 24 January 2017

Your nose is the scenter of your face

PLoS One. 2017 Jan 20;12(1):e0170492. doi: 10.1371/journal.pone.0170492. eCollection 2017.

Longitudinal Testing of Olfactory and Gustatory Function in Patients with Multiple Sclerosis. Uecker FC, Olze H, Kunte H, Gerz C, Göktas Ö, Harms L, Schmidt FA

The aim of the study was to investigate changes of the olfactory and gustatory capacity in patients with multiple sclerosis (MS).

20 MS patients were tested longitudinally for 3 years after initial testing. The Threshold Discrimination Identification test (TDI) was used for subjective olfactometry. Objective olfactometry was performed by registering olfactory evoked potentials (OEP) by EEG. The Taste Strip Test (TST) was used for gustatory testing.

45% of the patients showed olfactory dysfunction in the follow-up TDI test and 50% showed delayed OEP´s. 20% of the patients showed gustatory dysfunction on follow-up visit. The patients showed mild disease activity with 0,3 ± 0,5 relapses over the testing period and no significant change of their olfactory and gustatory capacity. The olfactory capacity for the discrimination of odors correlated inversely with the number of relapses (r = -0.5, p ≤ 0.05). The patients were aware of their olfactory deficit.

Olfactory and gustatory dysfunction is a symptom in MS patients and may be a useful parameter to estimate disease progression in MS patients. As the discrimination of odors is processed in higher central regions of the central nervous system (CNS), the results suggest that olfactory dysfunction could be due to CNS damage.

I'd be lying if I said I didn't wear perfume; admittedly it's one of my vanities, having spent most of my formative years searching for that signature perfume. What if you couldn't smell? Your sense of smell also allows you to taste. Dysfunction in smell is commonly featured in Parkinson's disease and Alzheimer's disease, preceding the development of clinical symptoms by a number of years. And not surprisingly, it would appear MS has also joined the list. Studies have reported rates of 11-41% in MS.

Here, Uecker et al. research whether there is a link with disease evolution over 3y. Undoubtedly, their sample size leaves a lot to be desired with a high drop out, but they report smell dysfunction in 10/20 subjects at the start of the study! This figure didn't change much over the 3y if you compensate for the drop outs and their disability did not alter either over the study period (70% of subjects being on treatment may have had something to do with this!). They also noted that 3/4 expressing difficulty with taste also had smell problems.

The more interesting question is why does it occur in MS in the first place? The authors point out that olfactory bulb/tract (smell organ) and adjacent inferior frontal cortex (front of the brain) is demyelinated in ~70% of MS cases confirmed at autopsy.

Testing this may not be that informative as far as disease activity is concerned, but it still has wider implications for management. Food for thought!

Monday, 23 January 2017

#ClinicSpeak & #BrainHealth: are you a weekend warrior?

Time to pack away the feelings of self-loathing and guilt; just do it! #ClinicSpeak #BrainHealth #WeekendWarrior

Self-loathing and guilt are some of the emotions that people experience when their New Year's resolutions turn out to be wishful thinking or you don't seem to find the time in the week to exercise. The good news is that if you are a 'Weekend Warrior' it may be good enough. Weekend Warriors are people who cram their exercise into 1 or 2 sessions on the weekend. 

The study below shows that physical activity patterns characterised by 1 or 2 sessions per week may be sufficient to reduce all-cause, cardiovascular disease (CVD) and cancer mortality risks regardless of adherence to prevailing physical activity guidelines. This is likely to apply to cognitive impairment as well due to the strong association between dementia and CVD. I would be interested to know how many of you are 'Weekend Warriors' or 'Couch Potatoes'?

O’Donovan et al. Association of “Weekend Warrior” and Other Leisure Time Physical Activity Patterns With Risks for All-Cause, Cardiovascular Disease, and Cancer Mortality.  JAMA Intern Med. Published online January 9, 2017. doi:10.1001/jamainternmed.2016.8014

Importance:  More research is required to clarify the association between physical activity and health in “weekend warriors” who perform all their exercise in 1 or 2 sessions per week.

Objective:  To investigate associations between the weekend warrior and other physical activity patterns and the risks for all-cause, cardiovascular disease (CVD), and cancer mortality.

Design, Setting, and Participants:  This pooled analysis of household-based surveillance studies included 11 cohorts of respondents to the Health Survey for England and Scottish Health Survey with prospective linkage to mortality records. Respondents 40 years or older were included in the analysis. Data were collected from 1994 to 2012 and analyzed in 2016.

Exposures:  Self-reported leisure time physical activity, with activity patterns defined as inactive (reporting no moderate- or vigorous-intensity activities), insufficiently active (reporting <150 min/wk in moderate-intensity and <75 min/wk in vigorous-intensity activities), weekend warrior (reporting ≥150 min/wk in moderate-intensity or ≥75 min/wk in vigorous-intensity activities from 1 or 2 sessions), and regularly active (reporting ≥150 min/wk in moderate-intensity or ≥75 min/wk in vigorous-intensity activities from ≥3 sessions). The insufficiently active participants were also characterized by physical activity frequency.

Main Outcomes and Measures:  All-cause, CVD, and cancer mortality ascertained from death certificates.

Results:  Among the 63 591 adult respondents (45.9% male; 44.1% female; mean [SD] age, 58.6 [11.9] years), 8802 deaths from all causes, 2780 deaths from CVD, and 2526 from cancer occurred during 561 159 person-years of follow-up. Compared with the inactive participants, the hazard ratio (HR) for all-cause mortality was 0.66 (95% CI, 0.62-0.72) in insufficiently active participants who reported 1 to 2 sessions per week, 0.70 (95% CI, 0.60-0.82) in weekend warrior participants, and 0.65 (95% CI, 0.58-0.73) in regularly active participants. Compared with the inactive participants, the HR for CVD mortality was 0.60 (95% CI, 0.52-0.69) in insufficiently active participants who reported 1 or 2 sessions per week, 0.60 (95% CI, 0.45-0.82) in weekend warrior participants, and 0.59 (95% CI, 0.48-0.73) in regularly active participants. Compared with the inactive participants, the HR for cancer mortality was 0.83 (95% CI, 0.73-0.94) in insufficiently active participants who reported 1 or 2 sessions per week, 0.82 (95% CI, 0.63-1.06) in weekend warrior participants, and 0.79 (95% CI, 0.66-0.94) in regularly active participants.

Conclusions and Relevance:  Weekend warrior and other leisure time physical activity patterns characterized by 1 or 2 sessions per week may be sufficient to reduce all-cause, CVD, and cancer mortality risks regardless of adherence to prevailing physical activity guidelines.

Understarters Orders...whats the plan to ensure the race ends in a good outcome

This weekend's post about alemtuzumab not working in some people after fingolimod begs the question "How we should transition people from fingolimod onto something else?"

We have had this debate about natalizumab already. Look for the posts on this aspect.

  • Fingolimod and Natalizumab are "racehorse" drugs
  • They keep cells trapped to stop them entering the brain
  • As they are not killing drugs, disease forming cells can accumulate over time

  •  They are "under starters orders" to race to the brain.
  • Stop drugs and disease "rebounds" in some people
  •  There are many *****LIMOD trials ongoing to take on fingolimod and Siponimod.
  •  What measures are in place for me when the drug supply stops at the end of the trial. How is rebound going to be prevented, even if it is a progressive (or what every you want to call it) MS trial?

These drugs are not killing drugs... they are trapping drugs and for fingolimod they trap disease-causing cells in lymphoid tissue and for natalizumab they trap-disease causing cells in the blood. 

They do not stop the disease process and so the disease causing cells can accumulate and are trapped, whilst drug treatment is in place.

However, see these cells as racehorses waiting to run into your brain, and they are "under starters orders" waiting to go. The gates open and "they're off"

Remove drugs and the cells escape, get into the brain and disease activity occurs.

Whilst some people view progressive MS, as a different disease, this I think is a dumb view and importantly a dangerous view. It is very clear than there are many people with active lesions that come and go as the progressive course carries on. If you look in the pathology of people with progressive MS there are active lesions.

It is clear that some people with progressive MS benefit from immune-inhibition.

However, I think it is also the case that the "racehorse drugs" allow the accumulation of damaging cells in people with progressive MS to such an extent that the drugs convert their subclinical relapsing pathology into relapsing-active MS, with a time-bomb ticking once drugs are stopped.

This is because the horses are all lined up and waiting to go.

Stop drugs and relapse occurs...this is sometimes called Rebound. 
Call it "resumed (synchronized) relapse" in case you don't like the word rebound...but they are damaging by what ever name you call them and it need to be avoided.

Does this happen? Sure it does! DrK a case report please

DrK says "Here you are MD: Davion JB, et al. Two cases of relapses in primary progressive multiple sclerosis after fingolimod withdrawal. J Neurol 2016;263: 1361–3.

However, how do you treat somebody with PPMS and rebound with no licensed options available?  We will hopefully see soon..."

Thanks DrK!

We are in the race for the "Mod me toos" and "Mods in progressive MS" and there are loads and loads of trials in relapsing MS and we will see them in progressive MS too if siponimod gets a green light. 

If deemed a success companies may contiune to supply drug as this gives them important safety data, but if the study is deems to have failed drug supply may be stopped, or if it is a small company a failure means they are gone and drug supply will be stopped

If it clear to me, that you need to ask "Once the trial ( I am volunteering for) finishes, what are the plans after the trial if it is a success or a failure? What happens when the drug stops and what is in place to limit rebound?

Rebounds won't have happen in everybody but if they do, people can not afford to loose more brain, because we haven't thought of a solution and got a plan in place. This goes out to pharma and the neuros.

Sunday, 22 January 2017

#ClinicSpeak & #ThinkHand: self-compassion

Patient-empowerment and self-management have many benefits; self-compassion being just one of them. #ClinicSpeak #ThinkHand #MSBlog

The study below shows that when pwMS, or other chronic diseases, can self-manage your disease, your physical health depends strongly on the expectancy of a positive outcome (realistic thinking). The corollary is that when options for self-management in controlling your disease are limited (no DMTs, no prevention of infections, no lifestyle modifications, etc.) then your physical health depends more strongly on unrealistic thinking, or dare I say beliefs and/or pseudoscience.

When some pwMS are told that they have passed from the so called 'relapsing phase' to the more 'advanced phase' (formerly called SPMS) they shift from an having an expectancy of a positive outcome to either a 'sense of hopelessness' or in some cases to a phase of 'unrealistic thinking'. For example, several of my patients with more advanced MS have gone onto to explore risky therapies abroad, contrary to my advice, in the hope of curing their MS and reversing their disability. Unfortunately, this phenomenon is fuelled by dogma that states MS is a two-staged disease, the first stage driven by inflammation and the second stage being due to neurodegeneration, and that there is a 'window of opportunity' to treat MS. Many experts in the field simply don't accept the possibility that MS can be modified through-out its course, which perpetuates the problem. 

At Barts-MS we actively promote patient-empowerment and self-management of MS. It is clear that by doing this pwMS learn 'self-compassion'. We also make it clear that we subscribe to the hypothesis that MS is potentially modifiable throughout its course, which is why we have launched our #ThinkHand campaign and explains why we want to do a trial in pwMS with more advanced MS. We want to test whether, or not, a highly-effective anti-inflammatory drug, with CNS penetration, is able to delay worsening of disability in the upper limbs and beyond. We are not deliberately promoting unrealistic expectations; our strategy won't reverse existing disability it is simply being designed on the expectation that we may be able to keep pwMS with more advanced disease independent a little longer. 

Patient-empowerment and self-management have many benefits; they improve anxiety and mood and make pwMS feel the have something to offer. They also teach pwMS to have self-compassion; i.e. extending compassion to one's self in instances of perceived inadequacy, failure, or general suffering (Wikipedia). 

Fournier et al. Optimism and adaptation to chronic disease: The role of optimism in relation to self-care options of type 1 diabetes mellitus, rheumatoid arthritis and multiple sclerosis. Br J Health Psychol. 2002 Nov;7(Part 4):409-432.

OBJECTIVES: To determine the role of optimistic beliefs in adaptation processes of three chronic diseases different in controllability by self-care. It was expected that optimism towards the future would relate to adaptation independently of the controllability of disease. Optimism regarding one's coping ability should be beneficial in controllable diseases. Unrealistic optimism was expected to be beneficial in uncontrollable disease.

DESIGN: The cross-sectional design involved 104 patients with type 1 diabetes, 95 patients with rheumatoid arthritis and 98 patients with multiple sclerosis, recruited via their physician at the out-patient department of five hospitals.

METHOD: Confirmatory Factor Analysis (LISREL) was employed to confirm a three-dimensional approach of optimism: outcome expectancies, efficacy expectancies and unrealistic thinking. Multi-sample analysis by path modelling was used to examine whether the relationship of the three optimistic beliefs with coping (CISS-21), depression and anxiety (HADS), and physical functioning (SF-36) differs with the controllability based on the self-care options of chronic disease.

RESULTS: These show that when chronic disease must be controlled by self-care, physical health depends more strongly on positive efficacy expectancies. In contrast, when self-care options for controlling chronic disease are limited, physical health depends more strongly on positive unrealistic thinking and relates negatively to positive efficacy expectancies. The impact of the three optimistic beliefs on mental health is independent of the controllability by self-care.

CONCLUSION: Optimistic beliefs are differently beneficial for physical health dependent on the controllability of chronic disease. Unrealistic beliefs are helpful when patients are confronted with moderately to largely uncontrollable disease where self-care options are limited, in contrast to positive efficacy expectancies that are helpful when patients deal with largely controllable disease where self-care is required.

Bullet Points to explain something important for people on fingolimod

Willis M, Pearson O, Illes Z, Sejbaek T, Nielsen C, Duddy M, Petheram K, van Munster C, Killestein J, Malmeström C, Tallantyre E, Robertson N. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017 Jan 10;4(2):e320.

Yesterday the "Headmaster" complained my post was too complicated.


So maybe we should just do highlights for the people that like their info in sound bites

  • Fingolimod traps T and B cells in Lymph Glands

  • Alemtuzumab kills T and B cells in the Blood

  • However alemtuzumab is not that effective at killing cells in lymph glands and bone marrow

  • Fingolimod can stop Alemtuzumab working
  • Be careful what you do when you switch treatment from fingolimod !

  • More evidence that B cells are the main targets for treatment..hang on shouldn't this be T cells!
  • Maybe more evidence for alemtuzmab neutralizing antibodies
            However, where is the analysis, explanation?  What do you think?

This rebound will not occur in every body. In this study
there were 36 six people, who had used fingolimod before alemtuzumab and the disease activity was seen in 9 people i.e. 25%. Remember, alemtuzumab is not infallible and relapse (4% in the cardiff cohort) in the first year occurs.

Of these people 8/9 were disease free after the second set of infusions